Trial protocol: a multicentre randomised trial of first-line treatment pathways for newly diagnosed immune thrombocytopenia: standard steroid treatment versus combined steroid and mycophenolate. The FLIGHT trial

Introduction Immune thrombocytopenia (ITP) is an autoimmune condition that may cause thrombocytopenia-related bleeding. Current first-line ITP treatment is with high-dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems with only 20% remaining in sustained remission with this approach. Mycophenolate mofetil (MMF) is often used as the next treatment with efficacy in 50%–80% of patients and good tolerability but can take up to 2 months to work. Objective To test the hypothesis that MMF combined with corticosteroid is a more effective first-line treatment for immune thrombocytopenia (ITP) than current standard of corticosteroid alone. Methods and analysis Design Multicentre, UK-based, open-label, randomised controlled trial. Setting Haematology departments in secondary care. Participants We plan to recruit 120 patients >16 years old with a diagnosis of ITP and a platelet count <30x109/L who require first-line treatment. Patients will be followed up for a minimum of 12 months following randomisation. Primary outcome Time from randomisation to treatment failure defined as platelets <30x109/L and a need for second-line treatment. Secondary outcomes Side effects, bleeding events, remission rates, time to relapse, time to next therapy, cumulative corticosteroid dose, rescue therapy, splenectomy, socioeconomic costs, patient-reported outcomes (quality of life, fatigue, impact of bleeding, care costs). Analysis The sample size of 120 achieves a 91.5% power to detect a doubling of the median time to treatment failure from 5 to 10 months. This will be expressed as an HR with 95% CI, median time to event if more than 50% have had an event and illustrated with Kaplan-Meier curves. Cost-effectiveness will be based on the first 12 months from diagnosis. Ethics and dissemination Ethical approval from NRES Committee South West (IRAS number 225959). EudraCT Number: 2017-001171-23. Results will be submitted for publication in peer-reviewed journals. Trial registration number NCT03156452


INTRODUCTION
Immune thrombocytopenia (ITP) has an incidence of 2.9/100,000 person-years. 1 It is an autoimmune condition that presents with bleeding and bruising due to a low platelet count. In ITP, there is increased consumption and reduced production of platelets due to both antibody and cell mediated autoimmune attack of platelets and megakaryocytes involving dysregulated autoreactive T and B cell lymphocytes. [2][3][4][5] Current first line ITP treatment is with high dose corticosteroids but this has several downsides. First, the majority of patients suffer significant side effects including mood swings, difficulty sleeping, weight gain, high blood pressure, diabetes, gastric irritation, skin thinning and osteoporosis. A published survey of ITP patients reported 98% had at least one side effect and 38% stopped or reduced dosage due to intolerable side effects. 6 In the UK ITP registry, the most frequently reported co-morbidities were related to corticosteroids and correlated with duration of treatment (hypertension in 30%, diabetes in 19%) (Newland A et al, poster BSH 2015). The second problem is not responding at all and the majority of others (70%-90%) relapsing when the corticosteroids are reduced or stopped. [7][8][9] Patients who are refractory or relapse (the majority), remain at risk of bleeding/bruising, which occasionally can be severe including intracranial haemorrhage. 10 They often receive more corticosteroid with associated side effects. Some require hospital admission and expensive rescue therapies (e.g. IVIG for a 70kg patient=£3,906). They continue to require frequent blood tests and doctor visits and are usually unable to continue their normal activities until their illness is controlled. Fatigue is also associated with disease activity and can be severe. 11 Physical factors combine with psychological stress through fear of bleeding, need for time off work and lifestyle restrictions due to bleeding risk to adversely impact quality of life. 12 13 First line treatment for ITP is unsatisfactory but it has been unchallenged for decades. The lack of new approaches has arisen from a chronic lack of research funding and clinical trials. The few trials done have been funded by pharmaceutical companies, risking publication bias towards high cost non-generic drugs. The relative rarity (2.9/100,000 person-years), non-cancerous nature and rare impact on survival of ITP have prevented ITP being a priority for research funding in the past.
However, this underestimates the profound adverse impact a diagnosis of ITP and its treatment can have for individual patients, many of whom are young. There is also a costly financial impact for the NHS from the healthcare resources patients require when their illness is uncontrolled. In addition, the problems faced by patients with ITP mirror those with other autoimmune conditions which as a group are common, affecting 3% of the population. There is an urgent clinical need to address this inequality, improving first line treatment for ITP through high quality, independently funded research to allow patients with this condition access to improvements in care seen in other illnesses such as cancer or heart disease. Current popular options for second line or subsequent treatment include Mycophenolate, Rituximab, Thrombopoeitin receptor agonists (TPO RA) and splenectomy. Splenectomy is an effective treatment (60% long term remission rates) but irreversible and international guidelines recommend deferring splenectomy for the first 12 months following diagnosis due to the chance of spontaneous remission (risk of unnecessarily removing a healthy organ). 7,9 Surgical operations are not popular with patients and there is increasing awareness of the short and long term complications of splenectomy including infection, bleeding, arterial and venous thrombosis, cancer and relapse. 14 The splenectomy numbers performed in the UK has dramatically reduced over recent years (UK ITP registry data). Rituximab is a monoclonal antibody treatment which targets antibody production by B cells. It is relatively expensive, with disappointing long term remission rates similar to placebo. 14 TPO RA stimulate platelet production, are well tolerated and effective in the majority 15 but at significant financial cost, prohibiting widespread use in the UK for early treatment (NICE guidance). A small (n=12) non-randomised study using TPO RA with corticosteroid first line showed efficacy but perhaps less than expected. 16 By contrast, Mycophenolate (MMF) is a widely used second line agent in the UK due to good efficacy (response rates of 50-80%), safety and tolerability profile. [17][18][19][20][21][22][23][24] Mycophenolate has activity against both autoreactive T and B cells and has also shown efficacy in refractory ITP including steroid resistance suggesting a complimentary mechanism of action. 22 It is less expensive to the NHS than some other second line options costing approximately £182/year (generic cost) compared to costs for average doses of romiplostim (TPO RA) at £25 000/year, Eltrombopag (TPO RA) £20 000/year or rituximab at £8000 for a course of 4 infusions.
However, similar to other second line therapies, MMF has a relatively slow (up to 2 months) onset of action. In the meantime, patients often receive further steroid (to maintain a "safe platelet count") and continue to suffer problems associated with their illness (see above). Direct feedback from patients regarding the difficulties they face in the first months following ITP diagnosis has been the primary driving force for this clinical trial. Local (Bristol) and national patient groups (ITP support association) have been fundamental to the formulation of patient relevant priorities for treatment.

Rationale
The Flight trial is the first UK, NHS coordinated, Pharma independent multicentre randomised controlled trial, testing a "common sense/practical" new approach using MMF first line instead of second line with the aim of preventing the almost inevitable first relapse when corticosteroids stop.
Patients will be randomly allocated to one of 2 treatment arms, either standard of care (corticosteroid alone) or MMF combined with corticosteroid with the primary outcome of time to treatment failure. By giving patients a stable platelet count sooner, we expect to improve other outcomes such as quality of life and fatigue. By reducing the risk of relapse, patients may also be less likely to receive a second course of corticosteroid with associated side effects. Potential indirect benefits to the NHS include reduced need for rescue treatments, blood tests, hospital attendances and admissions and reduced need for high cost treatments such as TPO mimetics. However, there will be some patients who will be treated with MMF who may have been successfully treated with corticosteroids alone (10-30%). [7][8][9] Similar to other immunosuppressives, MMF may slightly increase infection and cancer risk with long term use (SmPC) In addition, MMF is teratogenic and therefore stringent pregnancy prevention is essential for men and women taking the drug. This puts the trial in The choice of this open label design was made in order to allow true patient treatment costs to be calculated for the cost effectiveness analysis, and to deal with the complexities of placebo controlling a drug that needed titrating at the start and tapering at the end. In addition, over encapsulation was only possible for the lower MMF dose (250 mg) and the resulting capsule was the largest size which would mean most patients taking 8 large capsules per day in both arms; something that patients in Bristol thought would put them off taking part in the study. Patients were clear that from their perspective that a straight forward open label design would be preferable and was easier for a new patient to understand and consent. In addition, the quotes from 2 separate companies also showed the financial costs of encapsulation to generate a placebo were prohibitively expensive.
This trial proposal has received support and input from clinicians and patients nationally (UK ITP forum and ITP support association). To ensure objective and meaningful outcomes, it will be a multicentre RCT, aiming to recruit 120 patients (expecting 100 full datasets). Patients will be given up to one week of corticosteroid prior to randomisation to enable sufficient time to read information, discuss and ask questions with informed consent in an appropriate setting. Patients will receive the usual follow up according to clinical need and local policy. Laboratory and clinical data will be collected from routine appointments. In addition, patient oriented outcomes will be recorded at diagnosis, 2, 4, 6, and 12 months using validated patient questionnaires. Patients are also offered consent to additional blood samples for translational research studies (time 0 and 2 months).

Primary objective
To compare two first line treatment pathways for ITP, standard corticosteroid only versus corticosteroid combined with MMF and demonstrate which pathway helps patients achieve a stable platelet count sooner, measured as survival free from treatment failure (time from randomisation to treatment failure). • data on time to treatment failure as measured objectively by a fall in platelet count to <30x10 9 /L and need for new treatment.
• clinical data on additional treatments (including "rescue treatments" such as IVIG).
• clinical data on cumulative steroid dose.
• clinical data on additional investigations, hospital appointments and admissions.
• patient reported outcomes through standardised questionnaires.
• resource use data relating to an NHS/PSS and societal perspective.
• data on treatment side effects and adverse events (including bleeding, infections and steroid side effects)

Trial design
A multicentre, open label randomised clinical trial of MMF with corticosteroid as first line treatment for patients with ITP versus the standard care pathway of corticosteroids alone as first line treatment.

Eligibility criteria
Inclusion criteria: Patients (males and females) >16 years old with a diagnosis of ITP, a platelet count <30x10 9 /L AND a clinical need for first line treatment. Patients have provided written informed consent.
Exclusion criteria: Pregnancy and breastfeeding (Women of child bearing potential require a pregnancy test result within 7 days prior to randomisation to rule out unintended pregnancy).
Patients with HIV, Hepatitis B or C, or Common Variable immunodeficiency. Contraindications to MMF or corticosteroid (see SmPC) including patients with active significant infections, hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients or active significant infection. Patients not capable of giving informed consent (e.g. due to incapacity). The trial processes will be run by the Centre for Trials Research (CTR), Cardiff University and sponsored by University Hospitals Bristol NHS Foundation Trust.

Randomisation
Patients who agree to participate will be randomised to MMF with corticosteroid or corticosteroid alone in a 1:1 ratio using a web based randomisation system based at Cardiff CTR. Randomisation will be stratified by primary or secondary ITP diagnosis. Due to the large number of centres and the small number of patients it will not be sensible to stratify randomisation by study centre. However, to ensure an even spread of patients across time, randomisation will be blocked using random block sizes of 6 and 8 to retain concealment.

Treatment arms (Figures 1 and 2):
1. Corticosteroid +MMF pathway: 1mg/kg od prednisolone 4 days (maximum of 100mg), 40mg od 2 weeks, 20mg od 2 weeks, 10mg od 2 weeks, 5mg od 2 weeks then 5mg alternate days 2 weeks then stop*. For the duration of steroid, patients will get a PPI or H2 antagonist to protect against gastric bleeding and appropriate bone protection. *Dexamethasone 20mg or 40mg daily for 4 days is an alternative option to prednisolone if deemed clinically more appropriate for individual circumstances. Any steroid commenced prior to randomisation will be deducted from the regime above.
From randomisation (alongside steroid), MMF 500mg bd starting dose then increased to 750mg bd after 2 weeks if tolerated and 1g bd after another 2 weeks if tolerated (4 weeks after starting).
Earlier dose escalation to MMF 1g bd can be considered if clinically indicated.
After 6 months of MMF therapy, all patients who have remained in complete remission (pl count> 100 x10 9 /L) will reduce the dose by 250mg (one capsule) each month. The aim is to continue on the lowest dose that achieves a haemostatic (safe) platelet count (pl >30 x10 9 /L) and to ensure that patients who have gone into a spontaneous remission do not continue to take the drug indefinitely. 2. Corticosteroid only pathway: 1mg/kg od prednisolone 4 days (maximum of 100mg), 40mg od 2 weeks, 20mg od 2 weeks, 10mg od 2 weeks, 5mg od 2 weeks then 5mg alternate days 2 weeks then stop*. For the duration of steroid, patients will get a PPI or H2 antagonist to protect against gastric bleeding and appropriate bone protection. *Dexamethasone 20mg or 40mg orally daily for 4 days is an alternative option to prednisolone if deemed clinically more appropriate for individual circumstances. Any steroid commenced prior to randomisation will be deducted from the regime above.
In both groups: Any steroid commenced prior to randomisation will be deducted from the regimes.
Importantly, emergency and rescue treatments will be permitted throughout the study. These include platelet transfusions, tranexamic acid and intravenous immunoglobulin. These are known not to impact on the natural history of ITP and it is recognised that they may be important for patient safety. The use of "rescue treatments" will be recorded on the CRF.
In addition, some degree of flexibility of corticosteroid dose and duration may be needed for individual patients according to comorbidity, tolerability and other factors.
If treatment failure occurs, choice of second line treatment will be individualised according to patient's clinical circumstances. Further steroid will be given according to clinical need. Primary outcome is time from randomisation to treatment failure defined as a pl count <30x10 9 /L AND a need to commence second line treatment. This will include patients who are refractory (pl <30x10 9 /L in spite of 2 weeks treatment in the steroid arm or pl <30x10 9 /L in spite of 2 months treatment in the steroid +MMF arm) or who initially respond but then relapse (defined clinically as pl <30x10 9 /L and need for further therapy).

Data collection (table 1)
Hospital monitoring of platelet levels (FBC) is part of routine care for ITP patients and these data will be collected and recorded on the CRF without requiring patients to come in for additional samples to be taken. These locally collected samples may be collected monthly (or less often) for patients believed to be in stable remission and weekly at lower or declining platelet levels. We expect this to allow us to calculate the time in remission and time to relapse with reasonable accuracy over the 12 to 24 month follow up period. Other clinical and laboratory data needed for the trial endpoints will be collected from the medical and electronic records and recorded on the CRF. In addition, we will also ask the patients to complete questionnaires on fatigue, quality of life and bleeding scores at baseline, 2, 4, 6, and 12 months.
Patient reported outcomes will be captured by the following questionnaires: Additional optional research blood samples (requiring separate consent) will be sent at baseline and 2 month follow up to the Bristol Biobank.

Data Management
Source documents produced for this trial will be kept in the patient's hospital records and source data will be transcribed into trial-specific Case Report Forms (CRFs) at the end of each patient visit.
Data recording for this trial will be via a web based system. This is a secure encrypted system accessed by an institutional password which complies with Data Protection Act standards. The database will be stored and regularly backed up on a Cardiff University Server. The CRFs will be coded with the study number and will not include patients' names and addresses

Sample size calculation
There is no published clinical data available for MMF use first line in ITP as this is a novel approach.
We have analysed local data on MMF used second line in ITP in 12 patients which shows an estimated median survival free from treatment failure of more than 10 months. We have data on 68 who experienced corticosteroids as a first line treatment showing that 70% of them had experienced a treatment failure by 12 months and that the median survival free from treatment failure was 5.0 months (95% CI [3.2, 6.8]). Data for the 12 patients treated with MMF second line therapy have shorter follow-up times, with only 5 patients having follow up beyond 12 months. The cox proportional hazards ratio model demonstrates the 90% confidence interval for the hazard ratio to be between 0.13 and 0.59, showing that our decision to power this on an estimate of a hazard of lower than 0.5 is potentially achievable.
Clinically a doubling in the time to remission was thought to be something that the patients would have welcomed. Less than that was not thought to be sufficient grounds for switching this treatment from second line to first line due to the potential for additional toxicity and immune suppression in those who may have remained in remission with corticosteroids alone.
The sample size of 120 (60 per group) with less than 5% loss to follow-up achieves 91.5% power to detect a doubling of the median time to treatment failure from 5 months to 10 months if the patients are recruited at a steady rate or 10 per month for 12 months and all followed up until the last patients reaches 12 months follow up.

Statistical analysis
The full statistical analysis will be written into a statistical analysis plan available separately. The analysis will produce a CONSORT diagram for the reporting of clinical trials.
The baseline characteristics of the two groups will be tabulated but not tested for statistically significant differences between the groups. The primary analysis is by intention to treat. However an investigation of compliance with the treatment pathway and compliance with the criteria for changing to a second line therapy will be carried out prior to the primary analysis to check the date of the primary event. The primary event is the date at which there was a requirement for second line therapy. Where the platelet count falls below the level required for this treatment decision, the first date at which either symptoms or a blood test revealing this event will be used. If a clinician decides to use a second line therapy without a platelet count below the criteria, the date of the treatment decision/new prescription will be taken to represent that event. The results will be expressed as a hazard ratio with 95% confidence interval, median time to event if more than 50% have had an event and plotted as Kaplan Meier curves.
The primary analysis will contain all patients who are randomised for as long as they have been followed up or until their first event in a survival analysis using intention to treat methodology. All patients will be followed up to 12 months. In addition, patients who have not had an event in the first 12 months post randomisation will be followed until their first event or until the last patient has reached the 12 month point -whichever is the sooner and included in the analysis until that time accordingly.
Analysis of other outcomes will use as full a data set as possible and focus on the 12 month data point or area under the curve as appropriate and detailed in the analysis plan.
No interim analyses of the main endpoint will be supplied to the independent Data Monitoring Committee (DMC) due to the short time frame (12 months recruitment) in which all patients will be recruited by the time the first patient has completed follow-up. Serious adverse event rates will be reported on a monthly basis to the trial management group (TMG) and the DMC. The DMC could advise the chairman of the Trial Steering Committee and Chief Investigator if these provide proof beyond reasonable doubt that it would be unethical to continue with the trial.

Patient and Public Involvement and Engagement
During the trial development, a group of 8 ITP patients discussed the study design, burden of outcome measure completion to patients and the size of a potential placebo capsule which they reported could put them off getting involved in a trial. They reported that avoidance of relapse, early achievement of a stable platelet count, reduced overall corticosteroid dose and reduced hospital attendances are the most important goals for ITP management from their perspective.

BACKGROUND AND RATIONALE
Immune thrombocytopenia (ITP) has an incidence of 2.9/100,000 person-years . It is an autoimmune condition that presents with bleeding and bruising due to a low platelet count. In ITP, there is increased consumption and reduced production of platelets due to both antibody and cell mediated autoimmune attack of platelets and megakaryocytes involving dysregulated autoreactive T and B cell lymphocytes (McKenzie et al  Current first line treatment following ITP diagnosis is with high dose steroids but this has several downsides. First, the majority of patients suffer significant side effects including mood swings, difficulty sleeping, weight gain, high blood pressure, diabetes, gastric irritation, skin thinning and osteoporosis. A published survey of ITP patients reported 98% had at least one side effect and 38% stopped or reduced dosage due to intolerable side effects . In the UK ITP registry, the most frequently reported co-morbidities were related to steroids and correlated with duration of treatment (hypertension in 30%, diabetes in 19%) ( 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   Page 17 of 67  FLIGHT, V3.0, 24-Oct-2017 is also associated with disease activity and can be severe . Physical factors combine with psychological stress through fear of bleeding, need for time off work and lifestyle restrictions due to bleeding risk to adversely impact quality of life . First line treatment for ITP is unsatisfactory but it has been unchallenged for decades. The lack of new approaches has arisen from a chronic lack of research funding and clinical trials. The few trials done have been funded by pharmaceutical companies, risking publication bias towards high cost non-generic drugs. The relative rarity (2.9/100,000 person-years), non-cancerous nature and rare impact on survival of ITP have prevented it being a priority for research funding in the past. However, this underestimates the profound adverse impact a diagnosis of ITP and its treatment can have for individual patients, many of whom are young. There is also a costly financial impact for the NHS from the healthcare resources patients require when their illness is uncontrolled. In addition, the problems faced by patients with ITP mirror those with other autoimmune conditions which as a group are common, affecting 3% of the population. There is an urgent clinical need to address this inequality, improving first line treatment for ITP through high quality, independently funded research to allow patients with this condition access to improvements in care seen in other illnesses such as cancer or heart disease.
Current popular options for second line or subsequent treatment include Mycophenolate, Rituximab, Thrombopoeitin mimetics and splenectomy. Splenectomy is an effective treatment (60% long term remission rates) but international guidelines recommend deferring splenectomy for the first 12 months following diagnosis due to the chance of spontaneous remission (risk of unnecessarily removing a healthy organ) ( In the meantime, patients often receive further steroid (to maintain a "safe platelet count") and continue to suffer problems associated with their illness (see above).
Direct feedback from patients regarding the difficulties they face in the first months following ITP diagnosis has been the primary driving force for this research proposal. Local (Bristol) and national patient groups (ITP support This trial proposal has received support from clinicians and patients nationally (UK ITP forum and ITP support association). To ensure objective and meaningful outcomes, it will be a multicentre RCT comparing MMF with steroid vs steroid alone for first line ITP treatment, expecting to recruit 120 patients (expecting 100 full datasets). Patients can be given up to one week of steroid prior to randomisation to enable sufficient time to read information, discuss and ask questions with informed consent in an appropriate setting. Patients will receive the usual follow up according to clinical need and local policy. Laboratory and clinical data will be collected from routine appointments. In addition, patient oriented outcomes will be recorded at diagnosis, 2, 4, 6, and 12 months using validated patient questionnaires. Consent to additional blood samples for translational research studies will be optional (time 0 and 2 months).
The choice of this open label design was made both in order to allow true patient treatment costs to be calculated for the cost effectiveness analysis, and to deal with the complexities of placebo controlling a drug that needed titrating at the start and tapering at the end. In addition, over encapsulation was only possible for the lower MMF dose (250 mg) and the resulting capsule was the largest size which would mean most patients taking 8 large capsules per day in both arms. Following discussion with patients in Bristol, this was something that would put them off taking part in the study. Patients were clear that from their perspective the straight forward open label design would be preferable and was easier for a new patient to understand, increasing likelihood of consent (it was recognised that these patients sometimes feel overwhelmed already with the impact of a new diagnosis and simplicity was a priority). The quotes from 2 separate companies also showed the financial costs of encapsulation to generate a placebo were prohibitively expensive (>£100,000 excluding VAT for 80 patients).
Patients in Bristol supported the proposed trial design, end points and data collection and encouraged inclusion of patient oriented outcomes (quality of life, time off work). They suggested that any extra blood tests needed for the trial and data collection should be done during usual care appointments. These suggestions have been incorporated into the design. This will be the first UK multicentre ITP RCT and if successful represents a platform for future trials in ITP and other non-cancerous rare disorders. The trial is expected to include 120 patients with a diagnosis of ITP receiving first line treatment. We will select approximately 30 of the highest throughput centres to set up the trial. The trial processes will be run by the Centre for Trials Research, Cardiff University and sponsored by University Hospital Bristol NHS Foundation Trust.

AIMS, OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS
The overarching aim of this study is to test the hypothesis that for patients with Immune thrombocytopenia (ITP) requiring first line treatment, Mycophenolate (MMF) commenced with steroids is a more effective treatment pathway than the current standard care of steroids alone.
We would expect survival free from treatment failure to be longer when MMF is used with corticosteroid first line than with steroid alone. We also aim to test whether this is a safe and well tolerated approach and whether other outcomes are improved: x Remission rates x Patient oriented outcomes (quality of life, fatigue, time off work) x Cumulative steroid dose x Hospital attendances and admissions x Bleeding episodes x Need for rescue and second line treatment

Primary objective
To demonstrate which first line treatment pathway helps patients with ITP achieve a stable platelet count sooner, measured as survival free from treatment failure (time from randomisation to treatment failure).
To assess this question definitively in a fully powered multicentre randomised controlled trial of the two different treatment pathways in patients followed up for a minimum of 12 months from randomisation.

Secondary objectives
The secondary objectives include: x Collecting data on time to treatment failure as measured objectively by a fall in platelet count to <30x10 9 /L and need for new treatment.
x Collecting clinical data on additional treatments (including "rescue treatments" such as IVIG).  x Collecting clinical data on cumulative steroid dose.
x Collecting clinical data on additional investigations, hospital appointments and admissions.
x Collecting patient reported outcomes through standardised questionnaires.
x Collecting resource use data relating to an NHS/PSS and societal perspective.
x Collecting data on treatment side effects and adverse events (including bleeding, infections and steroid side effects)

Primary endpoint/outcome
The primary outcome is time from randomisation to treatment failure . This will include patients who are refractory (pl <30x10 9 /L in spite of 2 weeks treatment in the steroid arm or pl <30x10 9 /L in spite of 2 months treatment in the steroid +MMF arm) or who initially respond but then relapse (defined clinically as pl <30x10 9 /L and need for further therapy).
Hospital monitoring of platelet levels is part of routine care for ITP patients and we will collect these details from the medical notes without requiring patients to come in for additional samples to be taken. These locally collected samples may be collected monthly (or less often) for patients believed to be in stable remission and weekly at lower or declining platelet levels. We expect this to allow us to calculate the time in remission and time in relapse with reasonable accuracy over the 12 to 24 month follow up period. In addition to clinical data taken from medical records, we will also ask the patients to complete questionnaires on fatigue, quality of life and bleeding scores at baseline, 2, 6, and 12 months.
6.4 Secondary endpoints/outcomes 1. Remission rates (pl >30 x10 9 /L and at least 2 fold increase from baseline). Complete >100x10 9 /L, partial 30-100x10 9 /L 2. Time to relapse and time to next therapy 3. Cumulative steroid dose 4. Bleeding events 5. Need for rescue therapies 6. Need for splenectomy 7. Time off work 8. Number of hospital admissions, day unit and clinic attendances 9. Fatigue and Quality of life 10. Medication side effects, toxicity or other adverse events (including infection episodes) 11. NHS costs and Personal and social costs Patient reported outcomes will be captured by the following questionnaires:   x The exclusion criteria include pregnancy and breastfeeding x Patients with HIV, Hepatitis B or C, or Common Variable immunodeficiency.
x Women of child bearing potential require a pregnancy test result within 7 days prior to randomisation (as per 7.1 below) to rule out unintended pregnancy x Contraindications to MMF or corticosteroid (see SPC, Appendix 2) including patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients or active significant infection x Patients not capable of giving informed consent (e.g. due to incapacity) x Patients unwilling to follow contraceptive advice if allocated to MMF treatment arm (this information must be confirmed prior to randomization): i. WOMEN: Because of the genotoxic and teratogenic potential of MMF, women of childbearing potential must use two reliable forms of contraception simultaneously before starting MMF, during therapy and six weeks after stopping MMF (hormonal or barrier method of birth control; abstinence). Contraceptive methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: ii.
x combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:   x vasectomised partner* x sexual abstinence defined as refraining from heterosexual intercourse during the entire period of risk associated with the trial treatments.
*These contraception methods are considered to be low user dependency.
NB: Women are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
iii. MEN: Sexually active men with female partners that are potentially child bearing are recommended to use condoms during treatment and for at least 90 days after cessation of treatment. Condom use applies for both reproductively competent and vasectomised men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients treated with MMF are recommended to use highly effective contraception during treatment and for a total of 90 days after the last dose of MMF.

Risk Assessment
A Trial Risk Assessment has been completed to identify the potential hazards associated with the trial and to assess the likelihood of those hazards occurring and resulting in harm. This risk assessment has been completed ]v }OE v Á]šZ šZ DZ l ,lD,Z :}]vš ‰OE}i š Pµ] v } µu vš ZZ]•l-adapted approaches to the x The known and potential risks and benefits to human subjects x How high the risk is compared to normal standard practice x How the risk will be minimised/managed This trial has been categorised as a Type A where the level of risk is no higher than the risk of standard medical care. A copy of the trial risk assessment may be requested from the Trial Manager. The trial risk assessment is used to determine the intensity and focus of monitoring activity.

Site Selection
The study has been widely publicised through UK ITP Forum, CRNs and the CI has advertised the study at the British Society for Haematology. Potential savings to sites for treatment costs may be an incentive to take part. Sites have also indicated that this would be a relatively straightforward study to set up and run. This trial will be carried out at approximately 30 participating sites within the UK. All sites who are interested in participating in the trial will be required to complete a registration form to confirm that they have adequate resources and experience to conduct the trial.
x A signed Trial Agreement, including MTA for the translational component x Current Curriculum Vitae and GCP training certificate of the Principal Investigator (PI) x Completed Site Delegation Log and Roles and Responsibilities document x Full contact details for all host care organisation personnel involved, indicating preferred contact x A copy of the most recent approved version of the Participant Information Sheet(s) and Consent Form(s) on host care organisation headed paper x A copy of the most recent approved GP letter on host care organisation headed paper x A set of laboratory normal ranges and laboratory certification/accreditation from the host care organisation laboratory being used for analyses x Returned copy of the Self-Evident Correction Log signed by the PI.
Upon receipt of all the above documents, the Trial Manager will send written confirmation to the Principal Investigator/lead Research Nurse detailing that the centre is now ready to recruit participants into the trial. Occasionally during the trial, amendments may be made to the trial documentation listed above. CTR will issue the site with the latest version of the documents as soon as they become available. It is the responsibility of the CTR to ensure that they obtain local R&D approval for the new documents. Site initiation will be by teleconferencing.

Recruitment
At each hospital haematology centre, patients with a diagnosis of ITP will be assessed for eligibility for the trial. Patients will be given information on the trial and allowed ample time to read this, discuss it with healthcare professionals, family members and given the opportunity to ask questions. Up to one week of steroid may be used prior to randomisation to allow the patients enough time to consider trial participation without compromising either their health or the therapeutic effect of MMF as a first line treatment. Informed consent will be taken by the local clinical investigator or specialist nurse in the appropriate setting following good clinical practice guidelines.
A screening log of all ineligible and eligible but not consented/not approached will be kept at each site so that any biases from differential recruitment will be detected. The screening log will capture reasons for ineligibility. When at site, logs may contain identifiable information but this must be redacted prior to being sent to CTR. The screening log should be sent to the Trial Manager on request.  x Identification will involve reviewing and screening the identifiable personal information of patients, undertaken by members of the normal clinical team.
x Eligible patients will be identified by a Haematology Consultant or Specialist Registrar before or soon after the patient is commenced on first line steroid.
x Patients[ notes (history and examination) and results of investigations (hospital computer records) will be used to identify patients.

Screening
ITP is a diagnosis of exclusion and investigation should follow consensus guidelines (Provan et al 2010).
x Clinical information x laboratory tests should follow consensus guidance (including blood film, HIV, Hepatitis B and C serology, Immunoglobulins, liver and renal function, LDH) x Pregnancy test if woman with child bearing potential (must be performed within 7 days prior to randomisation)

Consent
The Principal Investigator (PI) retains overall responsibility for the informed consent of participants at their site and must ensure that any person delegated responsibility to participate in the informed consent process is duly authorised, trained and competent to participate according to the ethically approved protocol, principles of Good Clinical Practice (GCP) and Declaration of Helsinki.
Informed consent must be obtained prior to the participant undergoing procedures that are specifically for the purposes of the trial, using Patient Information Sheet 1.
The right of a participant to refuse participation without giving reasons must be respected.
Patients can consent to enter the trial but decline to have additional bloods taken for the lab study including bio banking for future research.
The participant must remain free to withdraw at any time from the trial without giving reasons and without prejudicing his/her further treatment and must be provided with a contact point where he/she may obtain further information about the trial. Where a participant is required to re-consent or new information is required to be provided to a participant it is the responsibility of the PI to ensure this is done in a timely manner.
A person is assumed to have the mental capacity to make a decision unless it is shown to be absent. Mental capacity is considered to be lacking if, in a specific circumstance, a person is unable to make a decision for him or herself because of impairment or a disturbance in the functioning of their mind or brain. Participants with mental incapacity are excluded from participating.
Where a participant is able to consent but later becomes incapacitated, the patient will be withdrawn from further trial procedures and standard medical care will be followed. However, the data collected up to the point  x Clinical data and biological specimens for ancillary studies will be acquired and stored during the trial.
x Participation in the ancillary research is not required for participation in trial and participants may opt out but still be included in the main study x Following consent, if a subject withdraws from the ancillary research further samples, data will not be collected and if they choose, data collected prior to withdrawal will be destroyed x Samples ready collected will not be used further in the trial and will be destroyed according to locally approved practices. Any results derived from the samples that have already been used prior to the withdrawal of consent will continue to be used in the trial.

8.5
The randomisation scheme Patients who agree to participate will be randomised to MMF with corticosteroid or corticosteroid alone in a 1:1 ratio using a web based randomisation system based at Cardiff CTR. Due to the large number of centres and the small number of patients it will not be sensible to stratify randomisation by study centre, however randomisation will be blocked using random block sizes of 6 and 8 to ensure an even spread of patients across time and to retain concealment.

Method of implementing the allocation sequence
The sequence of allocation will be generated in advance using random block sizes in a Cardiff University validated randomisation system. The sequence will be kept hidden from all recruiting staff and only released patient by patient as patients are randomised. Throughout the study the list of randomised patient IDs and their allocation will be available to the trial statistician, and only recruiting research staff following last patient follow-up. The trial is not blinded or placebo controlled, and so access to this list š} ] vš](Ç v ]v ]À] µ o ‰ š] vš[• oo} š]}v is not considered a breach of protocol.
The randomisation will be provided by remote computerised web-based allocation and will be supported by telephone service during working hours should network failure occur.
The recruiting nurse or clinician will need to have the following details available: Name, date of birth, date of ITP diagnosis, study site.
The treatment allocation will be confirmed to site staff and members of the trial team via e-mail. The patient will be given a copy of the relevant pathway and a copy of the pathway will be placed in the patient notes.
The randomisation system will comply with the Data Protection Act. Steroid +MMF pathway: 1mg/kg od prednisolone 4 days (maximum of 100mg), 40mg od 2 weeks, 20mg od 2 weeks, 10mg od 2 weeks, 5mg od 2 weeks then 5mg alternate days 2 weeks then stop*. For the duration of steroid, patients will get a PPI or H2 antagonist to protect against gastric bleeding and appropriate bone protection.
*Dexamethasone 20mg or 40mg daily for 4 days is an alternative option to prednisolone if deemed clinically more appropriate for individual circumstances.
Any steroid commenced prior to randomisation will be deducted from the regime above. Some degree of flexibility of steroid dose and duration may be needed for individual patients according to comorbidity, tolerability and other factors.
From randomisation (alongside steroid), MMF 500mg bd starting dose then increased to 750mg bd after 2 weeks if tolerated and 1g bd after another 2 weeks if tolerated (4 weeks after starting).
After 6 months of MMF therapy, all patients who have remained in complete remission (pl count> 100 x10 9 /L) will reduce the dose by 250mg (one capsule) each month. The aim is to continue on the lowest dose that achieves a haemostatic (safe) platelet count (pl >30 x10 9 /L) and to ensure that patients who have gone into a spontaneous remission do not continue to take the drug indefinitely.
Steroid only group: 1mg/kg od prednisolone 4 days (maximum of 100mg), 40mg od 2 weeks, 20mg od 2 weeks, 10mg od 2 weeks, 5mg od 2 weeks then 5mg alternate days 2 weeks then stop*. For the duration of steroid, patients will get a PPI or H2 antagonist to protect against gastric bleeding and appropriate bone protection.
*Dexamethasone 20mg or 40mg orally daily for 4 days is an alternative option to prednisolone if deemed clinically more appropriate for individual circumstances.
Any steroid commenced prior to randomisation will be deducted from the regime above. In both groups: Importantly, emergency and rescue treatments will be permitted throughout the study. These include platelet transfusions, tranexamic acid and intravenous immunoglobulin. These are known not to impact on the natural history of ITP and it is recognised that they may be important for patient safety. dZ µ• }( ^OE • µ šOE šu vš•_ will be recorded on the CRF. x Date of treatment failure (refractory or relapse AND need for second line therapy) x Weight x Blood pressure x x Medication side effects (including infections) x Dose and duration of corticosteroids x Need for rescue or other treatments (including second or third line) x Hospital attendances or admissions x Days off work x Patient questionnaires: Quality of life assessment x Immunoglobulins rechecked at 6 months and 12 months 8.10 End of trial assessment

12-24 m
In order to confirm the treatment failure endpoint has been reached, we will collect the platelet levels details from sites (as described in 6.3) after all their patients have completed their follow up visits at any given site to the end of the trial. Priority data to be collected would be platelet count data (remission, relapse) and treatment data (treatment taken or not taken).

Withdrawal criteria
Participants have the right to withdraw their consent from the study at any time for any reason. Should a patient decide to withdraw from the study, all efforts should be made to report the reason for withdrawal as thoroughly as possible. The investigator should ascertain from which aspects of the trial the patient wishes to withdraw and record the details in the appropriate part of the CRF. If a patient chooses to withdraw from treatment only, the patient should continue to be assessed in accordance with the protocol. If a patient wishes to withdraw from the trial (i.e. including trial-specific assessments) but is willing for further data to be supplied to CTR, then further routine follow-up data such as disease response status and further treatment, will continue to be supplied by the investigator to CTR according to the protocol.
The local investigator also has the right to withdraw patients from the study treatment for a number of justifiable reasons including unacceptable toxicity (an adverse event or events that, in the judgment of the investigator, may cause severe or permanent harm or which rule out continuation of the study drug), unforeseen events which in the opinion of the investigator make further treatment inadvisable, serious violation of the study protocol (including persistent patient non-attendance and non-compliance) or for clinical reasons not related to the study treatment. Patients withdrawn by the investigator should continue to undergo safety assessments as per the trial schedule and to receive standard care as per local policy.  If patients are lost to follow up then their local centre should attempt to find out the reason for this by local sites contacting the patient and GP according to standard policy.
It may be possible for limited data collection to continue for patients lost to follow up (for example through their GP blood results or an alternative hospital if they are relocated or by telephone if they are unable to attend).
If possible, follow up data should continue to be collected to the end of the trial.

Storage and analysis of samples
x Bloods required for routine ITP standard of care should be collected, processed and destroyed locally according to site specific standard policy (e.g. FBC, immunoglobulins, virology) x Patients who have consented for the laboratory sub-study (translational basic science research) will have additional bloods taken using the sample packs provided by the FLIGHT study team. These bloods will be taken at baseline and 2 months x Ideally blood samples should be taken from Monday to Thursday and posted promptly the same day by Royal mail to: Bristol Biobank, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, BS2 8AE, Telephone: 0117 342 3190/07813 344 577, Email: Bristol-biobank@bristol.ac.uk x Prior to sending, no sample processing by local laboratories is required and samples do not need refrigerating and can be kept at room temperature x The form within the sample packs should be completed and the blood tubes labelled before they are enclosed together in the pre-paid sample packs and sent the same day Royal Mail in the safe packs provided x These additional blood samples will be processed at the University of Bristol and stored in specialist freezers e.g. a -80°C +/-10°C in Bristol Biobank (ethically approved) according to standard procedure x Additional blood samples will be held in long-term storage for future unspecified use as outlined in patient information sheet.
x The additional blood samples will be destroyed following standard procedure.
It is the responsibility of the trial site to ensure that samples are appropriately labelled in accordance with the trial procedures to comply with the 1998 Data Protection Act. Biological samples collected from participants as part of this trial will be transported, stored, accessed and processed in accordance with national legislation relating to the use and storage of human tissue for research purposes and such activities shall at least meet the requirements as set out in the 2004 Human Tissue Act and the 2006 Human Tissue (Scotland) Act. The trial will end for a patient after they have completed their final study visit (12m from randomisation). The end of the trial is after all trial participants have completed their final study visit at 12m and follow up data (end of trial assessment data collected from sites (8.10) collected to the end of the trial, all data queries resolved, the database locked and the analysis completed. The IMP is a generic drug, therefore any brand of the IMP can be used.

9.2
Legal status of the drug Mycophenolate Mofetil is indicated in combination with Ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Although commonly used for ITP treatment it is not licensed for this indication (as it is a rare illness, many treatments are not licensed for this indication).

Drug storage and supply
As this is an open label trial of different treatment pathways rather than a placebo controlled trial, the dispensing will all be carried out by the local hospital pharmacy after randomisation. The medication should be stored as described in the Summary of Product Characteristics. Other drug interactions for consideration but unlikely to be clinically significant in this RCT due to the MMF doses used and the indication (not solid organ transplant): x Aciclovir, ciclosporin, ganciclovir, probenecid: Potential to slightly increase levels. At expected doses used in this RCT, this is not considered clinically significant. x Antacids and proton pump inhibitors (PPIs), cholestyramine, temilsartan, Rifampicin, Sevelamer, ciprofloxacin, Augmentin: Potential to slightly reduce MMF levels.

9.6
Trial restrictions MMF is teratogenic. Therefore, the most important restrictions apply to men and women to prevent conception and pregnancy whilst taking this medication (see exclusion criteria).
Standard of care is to clearly inform patients of risk of pregnancy, importance of pregnancy prevention and test for pregnancy prior to starting MMF; the latter only repeated if clinically indicated (e.g. gap in contraception). Sites will check patient contraception compliance at all visits for both males and females, this will be confirmed in the case report form. If any non-compliance with the contraception advice is discovered during the contraception check, then a pregnancy test will be performed on female participants. Male participants will be asked for their partners to have a pregnancy test performed and report the result to their local site.

Accountability Procedures
Local site pharmacies will be provided with a pharmacy manual which will include a trial specific accountability form. Pharmacies will also be asked to record batch numbers and expiry dates on the prescription when dispensing.

Assessment of compliance
x Compliance will be monitored and recorded at the routine hospital appointments.
x Patients who are non-compliant will remain in the study with the reason for non-compliance documented and recorded on the CRF.
x The reason for non-compliance should be addressed if possible. If due to medication side effects, this is an important secondary outcome. For other reasons, compliance should be encouraged with constructive advice on how this could be improved (e.g. phone alarm reminder).

Definitions Term Definition
Adverse Event (AE) Any untoward medical occurrence in a participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product.
Adverse Reaction (AR) An untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant.

Serious Adverse Event (SAE)
An adverse event that: x results in death x is life-threatening* x requires inpatient hospitalisation or prolongation of existing hospitalisation** x results in persistent or significant disability/incapacity x consists of a congenital anomaly or birth defect x other medically important condition***  ***Note: other events that may not result in death, are not life-threatening, or do not require hospitalisation, may be considered as an SAE when, based upon appropriate medical judgement, the event may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed above.

Serious Adverse Reaction (SAR)
An SAE occurring in a clinical trial participant for which there is a reasonable possibility that it is related to the IMP at any dose administered.

Suspected Unexpected Serious Adverse Reaction (SUSAR)
A SAR, the nature and severity of which is not consistent with the Reference Safety Information (RSI) for the IMP.

Trial Specific SAE reporting requirements
In addition to the reporting requirements above, for the purposes of this trial the following expected adverse events or reactions listed in the SPC ()

Causality
Causal relationship will be assessed for IMPs (Mycophenolate, MMF), other trial treatments (non IMPs Steroid) and procedures.
The Principal Investigator (or another delegated medically qualified doctor from the trial team) and Chief Investigator will assess each SAE to determine the casual relationship: There is evidence to suggest a causal relationship and the influence of other factors is unlikely.

Definite
There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out.

Yes
The causality assessment given by the Principal Investigator (or delegate) cannot be downgraded by the Chief Investigator (or delegate) and in the case of disagreement both opinions will be provided.

10.4: Expectedness
The Chief Investigator (or another delegated appropriate qualified individual) will assess each SAE to perform the assessment of expectedness.
The expectedness assessment should be made with reference to the current Reference Safety Information (RSI) for each IMP. Expectedness decisions must be based purely on the content of the RSI; other factors such as the participant population and participant history should not be taken into account. Expectedness is not related to what is an anticipated event within a particular disease.
SARs which add significant information on specificity or severity of a known, already documented adverse event constitute unexpected events. For example, an event more specific or more severe than that described in the RSI is considered unexpected.
Any SAR that has a fatal or truly serious life threatening outcome will be reported as unexpected and therefore a SUSAR due to the RSI not specifying death and life-threatening events as an expected outcome.
The RSI to be used for the expectedness assessments for this trial are listed in Table 1 below. The Reference Safety Information (RSI) on any CTR trial will be reviewed regularly according to CTR procedures.

Summary of Product Characteristics (SPC) for Mycophenolate Mofetil 250 mg film-coated Tablets (Appendix 2).
Updates made to the SPC for MMF will be reviewed by the Chief Investigator and Sponsor and a joint decision made whether the updated SPC will be submitted to the MHRA for use as the RSI in the trial. It is also required that sites respond to and clarify any queries raised on any reported SAEs and report any additional information as and when it becomes available through to the resolution of the event. Additionally, CTR may request additional information relating to any SAE/SARs and the site should provide as much information as is available to them in order to resolve these queries.
The period of time over which AEs, ARs, SAEs, SARs and SUSARs must be recorded and reported must start from consent: Where a participant withdraws consent for further processing of data, this does not preclude the reporting of SARs and SUSARs which are required to continue being reported according to the protocol for regulatory purposes.
Adverse events (AE) should be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version (4.0) (Appendix 5). The toxicity grades should be recorded on the toxicity part of the CRF: x Full participant trial number x An Adverse Event / Adverse Reaction x A completed assessment of the seriousness and causality as performed by PI (or another appropriately medically qualified doctor registered on the delegation log). All other AEs should be reported on the CRF following the CRF procedure (section 11)

CTR Responsibilities
Following the initial report, all SAEs should be followed up to resolution wherever possible and further information may be requested by CTR. Follow up information must be provided on a new SAE form.
The CTR should continue reporting SAEs and SARs until 6 weeks after cessation of last dose of MMF. SARs should continue to be reported until the end of follow up.
Once an SAE is received at the CTR, it will be evaluated by staff at the CTR and sent to the Chief Investigator (or their delegate) for an assessment of expectedness. 10 SUSARs which are fatal or life-threatening must be reported to the MHRA and REC within 7 calendar days of receipt at the CTR. If report is incomplete then additional follow-up information should be reported within a further 8 calendar days of submitting the initial report.
SUSARs that are not fatal or life-threatening must be reported to the MHRA and REC within 15 days of receipt at the CTR. Any additional, relevant information must be reported within a further 15 days.
N.B. There is no requirement for the CTR to report SUSARs to nIMPs to the MHRA except in the following instances: { If the adverse reaction is suspected to be linked to an interaction between a nIMP and IMP, and is serious and unexpected, CTR should report as a SUSAR due to the interaction with the IMP.

{
If a SUSAR is suspected and might be linked to either a nIMP or an IMP and cannot be attributed to only one of these.

{
If the adverse reaction due to the nIMP is likely to affect the safety of trial subjects then CTR should report it to the MHRA and REC in accordance with the relevant Standard Operating Procedure for reporting Urgent Safety Measures. All deaths are to be reported as an SAE. Deaths that are related to the IMP are not expected and therefore will always be reported as SUSAR. Only deaths that are assessed to be caused by the IMP will be reported to the sponsor as an SAE. This report will be immediate. Other deaths during treatment or follow up will be captured on the CRF.

Overdose
Reports of overdoses with Mycophenolate Mofetil have previously been received from clinical trials and during post-marketing experience, in many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.
It is expected that an overdose of Mycophenolate Mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression.

10.9
Contraception and Pregnancy reporting whilst participating in the trial As detailed in the exclusion criteria MMF in this trial has a genotoxic and teratogenic potential. Women of childbearing potential must use two reliable forms of contraception simultaneously before starting MMF, during therapy and six weeks after stopping MMF (hormonal or barrier method of birth control; abstinence). Contraceptive methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods are included in the Exclusion Criteria (7.2) Pregnancy, or the pregnancy of a partner occurring whilst participating in the trial, is not considered an SAE, however, a congenital anomaly or birth defect is. Other cases (e.g. termination of pregnancy without information on congenital malformation, and reports of pregnancy exposure without outcome data) should not normally be reported as such. When pregnancy occurs in a trial, either in a female participant or the female partner of a male participant, this should be followed up until at least the end of pregnancy, whether that is a live birth, abortion etc. Without follow-up of the pregnancy, it would not be possible for the CTR to know if a congenital anomaly or birth defect occurred, and therefore if there was an SAE that must be included in the safety evaluation of the IMP. Information on a pregnancy in a trial participant will be captured on the CTR Pregnancy Report Form (this also includes confirmation of participant consent) supplied to sites by the CTR.
Sites should report pregnancy occurring within SAE reporting periods (see Section 9.5). Congenital anomalies or birth defects are considered an SAE and so these events must also be reported to the CTR on a trial-specific SAE form. Congenital anomalies or birth defects related to the IMP and unexpected with respect to the IMP Reference Safety Information (RSI) must be submitted by the CTR within expedited SUSAR time frames (7 or 15 days) to the MHRA, relevant REC. An urgent safety measure is an action that the Sponsor, Chief Investigator or Principal Investigator may carry out in order to protect the subjects of a trial against any immediate hazard to their health or safety. Any urgent safety measure relating to this trial must be notified to the MHRA and Research Ethics Committee immediately by telephone, and in any event within 3 days in writing, that such a measure has been taken. USMs reported to the CTR will be handled according to CTR processes.

Sample size
There is no published clinical data available for MMF use first line in ITP as this is a novel approach. We have analysed local data on MMF used second line in ITP in 12 patients which shows a median survival free from treatment failure of more than 10 months. We have data on 68 who experienced steroids as a first line treatment showing that 70% of them had experienced a treatment failure by 12 months and that the median survival free from treatment failure was 5.0 months (95% CI [3.2, 6.8]). Data for the 12 patients treated with MMF second line therapy have shorter follow-up times, with only 5 with 12 month data. The cox proportional hazards ratio model demonstrates the 90% confidence interval for the hazard ratio to be between 0.13 and 0.59, showing that our decision to power this on an estimate of a hazard of lower than 0.5 is potentially achievable.
Clinically a doubling in the time to remission was thought to be something that the patients would have welcomed. Less than that was not thought to be sufficient grounds for switching this treatment from second line to first line due to the potential for additional toxicity and immune suppression in those who may have remained in remission with steroids alone.
The sample size of 120 (60 per group) with less than 5% loss to follow-up achieves 91.5% power to detect a doubling of the median time to treatment failure from 5 months to 10 months if the patients are recruited at a steady rate or 10 per month for 12 months and all followed up until the last patients reaches 12 months followup.

Statistical analysis
The full statistical analysis will be written into a statistical analysis plan available separately.
The analysis will produce a CONSORT diagram for the reporting of clinical trials.
The baseline characteristics of the two groups will be tabulated but not tested for statistically significant differences between the groups.
The primary analysis is by intention to treat; however an investigation of compliance with the treatment pathway and compliance with the criteria for changing to a second line therapy will be carried out prior to the primary analysis to check the date of the primary event. The primary event is the date at which there was a requirement for second line therapy. Where the platelet count falls below the level required for this treatment decision, the first date at which either symptoms or a blood test revealing this event will be used. If a clinician decides to use a second line therapy without a platelet count below the criteria, the date of the treatment decision/new prescription will be taken to represent that event. The results will be expressed as a hazard ratio with 95% confidence interval, median time to event if more than 50% have had an event and plotted as Kaplen-Mier curves.
The primary analysis will contain all patients who are randomised for as long as they have been followed up or until their first event in a survival analysis using intention to treat methodology. All patients will be followed up to 12 months. In addition patients who have not had an event in the first 12 months post randomisation will be followed until their first event or until the last patient has reached the 12 month point t whichever is the sooner and included in the analysis until that time accordingly.
Analysis of other outcomes will use as full a data set as possible and focus on the 12 month data point or area under the curve as appropriate and detailed in the analysis plan.

Interim analysis
No interim analyses of the main endpoint will be supplied to the independent Data Monitoring Committee (DMC) due to the short time frame (12 months recruitment) in which all patients will be recruited by the time the first patient has completed follow-up. Adverse event rates will be reported on a monthly basis to the TMG, may be tabulated and provided to the DMC. The DMC could advise the chairman of the Trial Steering Committee and Chief Investigator if these provide proof beyond reasonable doubt that it would be unethical to continue with the trial.
A graph showing expected accrual and actual accrual will be presented to the trial management team, steering committee and DMC at timely intervals.

Procedure(s) to account for missing or spurious data
For the primary outcome of time to first event t all patients will be included for as long as they were followed up. Patients who deviate from the protocol will be analysed under intention to treat methodology. Patients who choose to completely withdraw from the study will be included from the date of randomisation to the date at which they withdrew. Patients who are lost to follow-up will be included from the date of randomisation to the date at which they were last seen.

Economic evaluation
An economic evaluation of the intervention will be conducted from an NHS and personal and social services perspective, with results expressed in terms of both cost per relapse averted and per QALY. Health related quality of life will be collected via EQ-5D-5L at baseline, 2, 6 and 12 months.
Detailed resource use will be collected from haematology services (i.e. clinic visits, blood tests, medication use and procedures for treating bleeding events and side effects) and use of all NHS & personal and social services will be monitored via CRF and questionnaires. To estimate costs, resource use will be valued using national sources Curtis 2014, DoH 2014) for a standard price year. Where national unit cost data is not available for items of resource use, local data will be identified pertaining to the participating centres. A secondary analysis will consider the societal perspective and therefore patient level indirect costs (i.e. lost productivity, out of pocket expenses) will be collected. Analysis will follow good practice guidelines (NICE 2013, Gold 1996, Glick 2007) and will include the construction of cost-effectiveness acceptability curves to evaluate sampling uncertainty as appropriate.
Both the aforementioned cost-effectiveness analysis and cost-utility analysis will be conducted as a within trial analysis. We note that the trial analysis will potentially be conservative about the benefits accruing to patients beyond the trial period due to the longer term osteoporotic implications associated with repeated steroid use. Therefore, if there is a difference in primary outcome at 1 year, we will use simple decision analytic techniques to provide a cost utility analysis over a longer time horizon.
Patients with ITP are seen in local haematology units at a rate of approximately 12 per year (depending on the size of the unit). Most are diagnosed in office hours and remain outpatients requiring frequent follow up appointments. Up to 30 of the largest will be used as centres, with additional patients referred from nearby interested centres. If a recruitment rate of 50% is achieved, the sample size of 120 patients will be reached within 12 months. Because there is normally only one consultant who sees these patients per site, the trial has excellent support from the patient group and there has been a lot of interest from clinicians in the study, the recruitment rates may be higher than 50%. It is intended that recruitment should aim for 120 patients, expecting to achieve 90 complete sets of data. š Á]oo transcribed into trial-specific Case Report Forms (CRFs) at the end of each patient visit. It is intended to develop data recording for this trial via a web based system. This is a secure encrypted system accessed by an institutional password which complies with Data Protection Act standards. The database will be stored and regularly backed up on a Cardiff University Server. The CRFs will be coded with the study number and will not Paper records will be kept in a locked cabinet in secure premises at all times when the record is not in use for a study visit. Access to the records will be restricted to researchers working on the study, Sponsor representatives and representatives of regulatory authorities required to audit the conduct of the research study.
from other data. All files will be password protected. Electronic data containing personalised information will be saved on Cardiff University computers only in password protected files and backed up regularly to hard copy on secure remote Cardiff University servers. Participant data will be anonymised by the use of study numbers. A copy of the study number code identifying subjects will be kept in a secure cabinet at local study sites accessible to the investigators at all times. Analysis will be conducted by the study team. Analysis will only be conducted on anonymised data. The Chief Investigator will act as custodian of the data, however for practical purposes this role will be delegated to CTR, Cardiff University. Personal data will be stored for a minimum of 15 years. Access will be controlled by the Chief Investigator who will continue to act as custodian for all data and will permit trial related monitoring, audits, REC review, and regulatory inspections (where appropriate) by providing direct access to source data av oo }šZ OE } µu vš The patient information sheet includes the above information, and the patient must consent to the above data access arrangements in order to enter the trial. Investigators should agree to allow trial related monitoring, including audits and regulatory inspections, by providing direct access to source data/documents as required. Participant consent for this will be obtained.
Findings generated from on-site and central monitoring will be shared with the Sponsor, CI, PI & local R&D.

Quality Control
Where applicable, a random sample of at least 10% of CRFs will be checked, by the trial Research Team or UHB Research & Innovation monitor, against entries within the database and with the source data for quality purposes. The percentage checked will be increased if a significant error rate is found. The data from the first patient recruited at a new site will be reviewed. This may include consent records, safety data and primary endpoint data.

ETHICAL AND REGULATORY CONSIDERATIONS
This study will be conducted in accordance with: x  This trial protocol will also be submitted through HRA (as it is an English led study) for global governance review. Approval will be obtained from the host care organisation t University Hospitals Bristol NHS Foundation Trustwho will consider local governance requirements and site feasibility. The Research Governance approval of the host care organisation will be obtained before recruitment of participants within that host care organisation.
The Sponsor and CTR will make the decision on non-substantial and substantial amendments for this trial. Valid substantial amendments will be submitted to REC and/or MHRA, dependent on whether the amendment applies to the original CTA and/or REC application, for review. Such amendments may also need to be reviewed and accepted by NHS R&D departments before they can be implemented in practice at sites. All amendment paperwork will be version and date controlled to ensure the amendment history is tracked.
The Chief Investigator (or delegate) will submit annual progress and safety reports and a final report at conclusion of the trial to the REC and the MHRA within the timelines defined in the Regulations.

Peer review
This trial has been subject to high quality independent and expert peer review. The NIHR funding application was also peer reviewed by the NIHR review committee board and 3 reviewers (independent and expert). It has also been peer reviewed and approved by members of the UK ITP forum (Haematologists specialising in ITP).

Public and Patient Involvement
Patients have been Involved in identifying the research topic/prioritising the research questions, and preparing the funding application. They have had invaluable input into the design of the research and will continue to contribute to management of the research (patient representation on the steering/advisory group), developing participant information resources, contributing to the reporting of the study report and dissemination of research findings.
Direct feedback from patients regarding the difficulties they face in the first months following ITP diagnosis has been the primary driving force for this research proposal. The current standard of care for first line treatment is high dose steroids, but this has several downsides for patients. Local (Bristol) and national patient groups (ITP support association) have been fundamental to the formulation of patient relevant priorities for treatment. Patients report that avoidance of relapse, early achievement of a stable platelet count, reduced overall steroid dose and reduced hospital attendances are the most important goals for ITP management from their perspective.
In the UK, Mycophenolate (MMF) is a popular second line treatment because it is well tolerated with good efficacy (50-80% response rates). Patients agreed that it was a good idea to try bringing forward the timing of MMF to first line so that it would have "taken over" by the time the first course of steroid had finished, preventing relapse. They supported the proposed trial end points and data collection and encouraged inclusion of patient oriented outcomes (quality of life, fatigue, time off work). They suggested that any extra blood tests needed for the trial and data collection should be done during usual care appointments. These suggestions have been incorporated into the design. This research proposal has been discussed and received the support from local and national patient groups.
This clinical trial is supported by the ITP support association which is a patient and public group formed in 1995 by Shirley Watson MBE who is an extremely valuable co-applicant for this clinical trial. As the only UK charity for this disorder, the ITP support Association has been in touch with over 4000 UK ITP sufferers to date, and has members in every continent. It organises annual patient conventions, monthly newsletters and through these and its website, is an important source of support and information for health care professionals, patients and their relatives. These communication links will be utilised to optimise communication to and feedback from the patients and public during and after this trial.

Protocol compliance
Protocol deviations, non-compliances, or breaches are departures from the approved protocol.
x prospective, planned deviations or waivers to the protocol are not allowed under the UK regulations on Clinical Trials and must not be used e.g. it is not acceptable to enrol a subject if they do not meet the eligibility criteria or restrictions specified in the trial protocol x accidental protocol deviations can happen at any time. They must be adequately documented on the relevant forms and reported to the Chief Investigator and Sponsor immediately.
x deviations from the protocol which are found to frequently recur are not acceptable, will require immediate action and could potentially be classified as a serious breach.
x Variations in steroid dose and duration are expected and may not exactly follow the treatment flow chart but are NOT considered protocol deviations. The initial daily dose of prednisolone should not exceed 1mg/kg with a maximum of 100mg.

Data protection and patient confidentiality
The CTR will act to preserve participant confidentiality and will not disclose or reproduce any information by which participants could be identified, except where specific consent is obtained. Data will be stored in a secure manner and will be registered in accordance with the Data Protection Act 1998. The data custodian and the translational sample custodian for this trial is the Chief Investigator.
This includes collection of NHS number (or equivalent t e.g. CHI number in Scotland), name and postcode to register and trace participants with the Health and Social Care Information Centre (HSCIC). Participants will be asked to consent separately for this 14.5 Financial and other competing interests for the chief investigator, PIs at each site and committee members for the overall trial management As MMF is a generic drug we do not expect any relevant competing interests that might influence trial design, conduct, or reporting. TMG members will be required to sign up to the remit and conditions as set out in the TMG Charter. The TMG will oversee the day to day trial management and will meet in person or by teleconference on a monthly basis for the duration of the study. The TMG will overview and provide guidance on all aspects of regulatory approval, set-up, recruitment, protocol deviations, adverse events, data management, data analysis and dissemination. The TMG will report 6 monthly to the TSC and to the study sponsor as required.

TSC (Trial Steering Committee)
TSC members will be required to sign up to the remit and conditions as set out in the TSC Charter. The TSC will meet in person or by teleconference at a minimum of 6 monthly intervals during the trial. The TSC principal responsibilities will be to: x Review the protocol and comment on any major concerns in the trial design that they feel would prevent it addressing the primary objectives. x Review progress reports on the trial and provide advice if problems arise.
x Comment on protocol amendments.
x Protect the interests of patients should safety issues arise.
x Ensure the integrity of the data as far as they are able.

DMC (Data Monitoring Committee)
DMC members will be required to sign up to the remit and conditions as set out in the DMC Charter and will review the accumulating safety and efficacy results of the trial on a continuous basis.

ANCILLARY TRANSLATIONAL RESEARCH SUB-STUDY
Patients will also be invited to participate in the following optional investigation for ancillary translation research study -(FLIGHT additional laboratory study) which has been funded by a combination of charitable sources: Patients will be asked to consent to provide additional blood samples at V1 and V2.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  The blood samples will be sent to the Bristol Biobank in the Bristol Royal Infirmary. The samples will be labelled with a unique identifier so that they can be linked to the blood results already collected by the FLIGHT study and compare laboratory results with patient outcomes. Laboratory staff will not be able to directly link the samples to patients. The samples will be processed by University of Bristol immediately after collection. Any remaining samples will be stored securely in the Bristol Biobank for an indefinite amount of time for future research within the UK. Patients will be asked to consent separately for this.
The objectives of this laboratory sub-study include the development of laboratory biomarkers to improve the prediction of clinical outcomes in ITP including illness severity, chronicity and response to treatment. The long term goal of the translational research is to individualise treatment strategy for patients with ITP, enabling earlier disease control and avoiding side effects of ineffective or unnecessary treatments.

DISSEMINATION POLICY
The trial will be registered on ISRCTN and Clinicaltrials.gov websites. On completion of the trial, the data will be analysed and tabulated and a Final Study Report prepared which can be accessed by EudraCT Clinical Trials Database. The responsibility for developing and disseminating the final trial report will reside with the trial team (CI, statistician, trial manager, Sponsor, etc.) The trial findings will be presented at national and international meetings and published in high quality peer review journals with acknowledgement of NIHR funding and participating centres. In addition, a lay summary for patients and public will be generated and published in šZ u P Ì]v ~^šZ ‰o š o š_• ‰µ o]•Z Ç šZ /dW Support Association.

ARCHIVING
The TMF and TSF containing essential documents will be archived at an approved external storage facility for a minimum of 15 years. The CTR will maintain the TMF and TSFs and prepare them for archiving on behalf of the Sponsor. The Principal Investigator is responsible for archival of the ISF at site as documented in the Site Agreement. Essential documents pertaining to the trial shall not be destroyed without permission from the Sponsor. x

Being independent
I am able to be completely independent 4 I am able to be independent in many things 3 I am able to be independent in a few things 2 I am unable to be at all independent 1       This set of questions is aimed at finding out the financial cost to you and your family and the health services over the last 2 months. Please think back over the past 2 months. If you are unsure about any answer please write in your best guess.

Please tick one box for the category that describes your current employment
In full time employment (30 hours or more a week) In part time employment (less than 30 hours a week) Employed but on sick leave Retired Not in paid employment If you are employed, approximately how much time have you taken off work in total during the last 3 months due to your health including to attend blood tests or appointments?

days hours
Have you provided support for someone else with health problems?

Yes No
Have you received help or support from family or friends due to your own health problems (including help to attend appointments)?

Yes No
If yes, approximately how much time have they set aside to help you in a typical week?

hours days
If yes, and if they work, approximately how much time have they taken off work in order to help you in a typical week?
hours days

Healthcare log
In the past 2 months, did you see any health or care professionals in the community? (this refers to all health care and social care that is not based in the hospital.
This includes for example your GP, practice or community nurse, social worker, home help or physiotherapist who is not based in the hospital.
Please indicate the person you saw, how many times you saw them. If the type of professional is not listed then please write this in. Please record all contact whether or not this was related to your condition.

Other Expenses
Please record any other expenses you have had to meet over the last 2 months because of your health or treatment. Please record all expenses, whether or not they were related to your thrombocytopenia. You are invited to take part in a research trial. Before you decide whether to take part or not, you need to understand why the research is being done and what it would involve for you. Taking part in research is voluntary. You have the right not to join the trial, or to join and later decide to withdraw from the trial without giving any reason for your decision. This will not affect your care.

Brief description Cost
Please take time to read the following information carefully. A member of our team will go through the information leaflet with you, explain the trial in more detail, and answer any questions you have. If anything is not clear or you would like more information, do not hesitate to ask a member of the research team. Talk to friends or relatives about the trial if you wish, and take time to decide. If you would like to take part, you will be asked to confirm by signing a separate consent form. You will also be given a copy for your own records.

What is the purpose of the trial?
The initial treatment for ITP is high dose steroids and has been the same for many years. For most patients these are effective at raising the platelet count and they work quite quickly (usually within 2 weeks). However, the illness usually comes back when the steroids are reduced or stopped leaving patients back at square one. The next treatment used is often Mycophenolate (MMF), which works well but takes time to work.
We plan to try using MMF with steroids from diagnosis to see how well this controls the ITP. To do this we will compare the current steroid only pathway with the new one (steroid with MMF). Patients from different hospitals will be asked to take part and half will be randomly chosen for the new pathway.

Why have I been invited?
We are looking for people like you, who have ITP and need a first course of treatment. We will ask about 120 people in the UK to take part in this trial. What will happen to me if I take part?
If you decide to take part you will be treated either with the normal first treatment for ITP= Steroid only group or the normal first treatment with MMF= Steroids and MMF group.
As part of your standard treatment for ITP, you will have regular blood tests and doctor or nurse reviews to check how you are getting on. This will be the same whether you chose to take part in this trial or not. There will be no extra doctor visits for the research trial and your usual visits will be used to collect information on how you are. It may mean that some of the visits take a bit longer as we will be gathering a bit more information than we normally would.

What advantages and disadvantages are there if I agree to do this trial?
For this trial, if you agree to take part, there will be no additional appointments for blood tests or doctor visits and your usual follow up visits will be used to record how you are. However, it is possible that some of these appointments will take a bit longer than they would do if you were not in the trial so that we can gather all the information needed to carefully record how you are. We will also ask you to fill in a questionnaire at the beginning, at 2 months, 4 months, 6 months and 12 months. This will help us assess how your illness and its treatment are affecting you.
If you are allocated to the steroid only group, you will be treated with the same medicines that you would do if you did not agree to take part. If you are allocated to the new steroids and MMF pathway, you will have the same medicines but will take an extra medicine called MMF. The advantage of receiving MMF first is that your ITP is more likely to be controlled sooner and less likely to come back. Overall, you are expected to need fewer steroids with the associated side effects. The disadvantage of receiving MMF first is that it is possible you may have been one of the few patients who only need steroids to get better (1 in 5) and therefore you will have taken MMF without needing it. In addition, you may be at slightly higher risk of infection and it will be very important that you or your partner do not become pregnant while taking MMF as MMF can cause harm to unborn babies. Importantly, the design of this trial includes an MMF dose reduction and stopping at 6 months if your ITP is well controlled to avoid unnecessary long term use.

Is there anything important I should know before agreeing to the trial?
z}µ uµ•š Á]oo]vP š} (}oo}Á šZ OE • OE Z vµOE• l } š}OE[• ]v•šOEµ š]}v•X z}µ uµ•š š l šZ trial medication as instructed. If you miss any doses, you should continue to the next scheduled dose. At each visit you must return any leftover trial medication that you do not take and the container, even if empty.
x It is very important you or your partner do not become pregnant whilst taking MMF or breast feed. Please see contraception advice on page 7 under Further information to know about taking Mycophenolate. x At the beginning of the trial, at 2 months, 4 months, 6 months and 12 months we will ask you some questions regarding your health. x A card with information about the trial v šZ OE • OE Z š u[• }ntact details will be given to you and you should carry it with you and show it to any other doctors or nurses that you might see.
x You cannot take part in any other research trial that involves taking medication while you are in this trial. What will happen to any samples I give?
Treatment for ITP includes regular blood tests to check how the illness is responding and these will be processed at your local hospital as they would if you were not in the trial. We will also ask your permission to take some additional blood samples for ITP research at the beginning and after 2 months of treatment. This is optional and you can still take part in the Flight trial but decline to have these blood samples taken, but please consider how valuable these are to our research before making such a decision. You will receive a separate information sheet and consent form for this. If you agree, these blood samples will be taken when you are having routine bloods done and will not need additional appointments or needles. These blood samples will be processed in Bristol Biobank Laboratories in the Bristol Royal Infirmary and used to help understand the causes of ITP and develop blood tests that can improve prediction of treatment responses and outcome in ITP. The aim of this additional research is to individualise treatments for ITP in the future.

What alternatives are there to taking part in the trial?
If you decide not to take part in the research trial, then you will continue standard treatment and follow up under your Haematologists supervision.

What happens when the research trial stops?
After 12 months of detailed follow up in the trial you will not need to answer any more questions and will continue on whatever treatment your haematologist recommends for you. However, we will continue collecting information from your blood tests and medical records until the trial closes.

tZ š Á]oo Z ‰‰ v ]( / }v[š Á vš š} OEOEÇ }v Á]šZ šZ trial?
You are free to stop filling in the questionnaires at any time without giving a reason. If you wish to stop any more of your clinical data from being used in the trial you can ask for us to stop collecting it, it will not affect your care in any way. If you wish to withdraw from either of the treatment arms of the study your clinician will have to discuss with you what the alternative treatments could be, but we would still be interested to know how you are doing and would ask if you mind continuing to fill in the questionnaires and allowing us to collect your clinical data. The information we have recorded about you and the samples you have provided whilst you were on the trial may still be used. You can ask for these to be destroyed.

What will happen to the results of the research trial?
The results of the research will not be known for about 2 years after the start of the trial. The results will be reported in medical journals or presented at scientific meetings but your identity will not be disclosed.

What if relevant new information becomes available?
The research team will tell you of any new important information that may influence your participation. Your doctor may also decide to stop your participation for medical reasons even without your consent. If the trial is stopped for any other reason, you will be told why and your continuing care will be arranged.

Will my taking part in the trial be kept confidential?
All information which is collected about you during the course of the research will be kept strictly confidential. This includes personal information such as your name, address and NHS number, to allow us to keep in touch with you during the trial, and information about your health, to allow us to compare the two treatment pathways. The information will be stored in a secure database at the University of Cardiff, will be anonymized and will only be accessed by authorised members of the research team who are managing the research and will be responsible for aspects of your follow-up such as arranging visits. Your medical notes will need to be seen by authorised members of the hospital research team so they can collect information needed for this research trial.
With your consent, your GP will also be informed that you are taking part in the research trial. Your GP may be asked to provide information from your records which is required for the research.
Occasionally, other members of NHS staff or research staff may need to check your medical records. This will be done by NHS staff or by researchers who are bound by the same rules of confidentiality as all NHS staff. The confidentiality of your medical records will be respected at all times. Under no circumstances will you be identified in any way in any report arising from the trial.
With your consent, after your leave the study we would still like to know how you are progressing using information routinely collected in the NHS and information held by the Health and Social Care Information Centre (HSCIC) and the National Health Service Central Register (NHSCR). Any information received in this way remains confidential. The information we collect about you may be useful for future medical research in this area, and if you give permission we may include the information in other ethically approved studies. However, you can still take part in this study if you would prefer that your data was not used for other research.
Computer and paper records relating to our study will be stored for 15 years according to the provisions of the Data Protection Act.

What if there is a problem?
If you are harmed by taking part in this research project, there are no special compensation arrangements. If you are harmed due to someone's negligence, then you may have grounds for a legal action but you may have to pay for it. If you wish to complain about any aspect of the way you have been approached or treated during the course of this trial, the normal National Health Service complaints mechanisms are available to you.

Who is organising and funding the research?
The research is funded by the National Institute for Health Research (research part of the NHS

Further information about taking steroids (Prednisolone or dexamethasone)
What are steroids? Some steroids occur naturally in the human body. Man-made steroids act like natural steroids to suppress the immune system and reduce inflammation. They are used in many different autoimmune illnesses (e.g. arthritis, asthma).

What are the risks and possible side effects of taking steroids?
The most common side-effects are: x weight gain and/or increase in appetite x Difficulty sleeping and mood changes-you may feel very high or very low. This change may be more common in people with a previous history of mood distur v X /( Ç}µ[OE worried please discuss this with your doctor x Increased blood sugar and blood pressure t If you have diabetes, high blood pressure or epilepsy, steroids can sometimes make these worse. Your doctor should check your blood pressure and blood sugar levels from time to time, and may adjust your medication if necessary. x Indigestion, stomach pains x A round face, stretch marks, thinning of the skin.
x Steroid tablets can also make glaucoma worse or cause cataracts with long term use. It may also cause muscle weakness or occasionally interfere with the menstrual cycle. x Taking steroid tablets can make you more likely to develop infections.
x If you feel feverish or unwell, or develop any new symptoms after starting taking steroid tablets it's important to tell your doctor or specialist nurse. You should also see your doctor if you develop chickenpox or shingles or come into contact with someone who has chickenpox or shingles. These can be severe in people on steroids, and you may need antiviral treatment. x You should avoid live vaccines (e.g. shingles) x Steroids can cause your bones to weaken, and make fractures more likely; this can lead to a condition known as osteoporosis. Regular exercise (especially weight-bearing) can help to reduce the risk of getting osteoporosis, as can making sure you get enough calcium in your diet (dairy products) and avoiding smoking and drinking too much alcohol.
x If you have any concerns about your treatment or its side-effects you should discuss these with your doctor, nurse or pharmacist.

Treatment in the Steroid only pathway:
Prednisolone (steroid) once daily. Initial dose of 1mg/kg (max 100mg) for 4 days Then 40mg daily for 2 weeks Then 20mg daily for 2 weeks Then 10mg daily for 2 weeks Then 5mg daily 2 weeks Then 5mg alternate days for 2 weeks, then stop*. *Dexamethasone (a different type of steroid) 20mg or 40mg daily for 4 days is an alternative option to prednisolone. Your doctor may think this is more suitable for you. For the duration of steroid, patients will get a medication to protect against stomach irritation.

Further information to know about taking Mycophenolate (MMF).
What is mycophenolate? Mycophenolate mofetil (MMF), similar to steroids is used to control autoimmune conditions including ITP by reducing the activity of the body's defence system (immune system).
What are the risks and side effects of MMF?
x If you are taking MMF and you are female you must not be pregnant or breast feeding as it can harm the baby. Therefore, you must use two reliable forms of contraception before starting MMF, during therapy and six weeks after stopping MMF (e.g. hormonal or barrier method of birth control; abstinence). Contraceptive methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: x combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal x progestogen-only hormonal contraception associated with inhibition of ovulation o oral o injectable o implantable* x intrauterine device (IUD)* x intrauterine hormone-releasing system ( IUS)* x bilateral tubal occlusion* x vasectomised partner* x sexual abstinence defined as refraining from heterosexual intercourse during the entire period of risk associated with the trial treatments.
*These contraception methods are considered to be low user dependency. NB: Women are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
x If you are male, with a partner of child bearing potential, you must agree to use condoms for the duration of MMF and 3 months after stopping. Condom use applies for both reproductively competent and vasectomised men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients treated with MMF are recommended to use highly effective contraception during treatment and for a total of 3 months after the last stop of MMF.
x The research team must be informed immediately if you or your partner become pregnant.
Women who become pregnant must stop the MMF straight away. The pregnancy will be monitored until its conclusion for safety reasons and the research team may require access to mother's and/or child's notes, and any possible follow up of the child including post-natal examinations. You will be asked to consent for this eventuality.
x If you are taking MMF, it is important not to drink more alcohol than the government recommended safe limits t no more than 14 units per week. It's strongly recommended to have alcohol free days, without 'saving up' units to drink in one go.
x If you're taking MMF it is recommended that you avoid live vaccines such as yellow fever or shingles. x Mycophenolate has been used in tens of thousands of people with ITP as second line treatment and is generally, an effective, well tolerated and acceptably safe medication. However, some patients have experienced side effects. The most common side-effects of MMF are nausea (feeling sick), diarrhoea, vomiting or stomach pain. x Mycophenolate can also affect your blood count (one of the effects is that fewer blood cells are made) and can make you more likely to develop infections. x If any of the symptoms listed above are severe, you should stop taking MMF and see your doctor immediately. Generally, however, it's best to talk to your doctor before stopping or reducing MMF. x You should also see your doctor if you develop chickenpox or shingles or come into contact with someone who has chickenpox or shingles. These infections can be severe if you're taking MMF. You may need antiviral treatment, and MMF may be stopped until you're better. x Although this is uncommon, there's a slightly increased risk of certain types of cancer in people using MMF for long term use. Please discuss this matter with your doctor if you're worried. Due to the small increase in risk of skin cancer, you should avoid exposure to strong sunlight and protect your skin with sunblock or sunscreen. x Because MMF can affect your blood count, and rarely cause liver or kidney problems, your doctor will arrange for you to have a blood test before you start treatment and regular blood checks while on MMF.
x For advice on avoiding infection from food, visit: http://www.nhs.uk/conditions/foodpoisoning/pages/prevention.aspx x There is a very small possibility of previously unknown side effects from MMF. We will take every precaution possible to monitor you for all side effects and will encourage you to report anything of concern to the research team on <Tel. Number>.

Treatment in the MMF + steroid pathway:
Prednisolone or dexamethasone (regime identical to standard care pathway as above) From randomisation (alongside steroid), MMF 500mg twice daily starting dose. Increased to 750mg twice a day after 2 weeks if no side effects and 1g twice daily after another 2 weeks if no side effects (4 weeks after starting).

In both groups
If you have already taken steroid for a few days before joining the trial, this amount will be deducted from the regime above.
If your doctor thinks you need emergency or rescue treatments then it is fine to have these in this trial. These may include platelet transfusions, tranexamic acid and intravenous immunoglobulin. You are being invited to provide additional blood samples for a research study and for future research because you have a diagnosis of Immune Thrombocytopenia (ITP). Before you decide, it is important for you to understand why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it with others if you wish. One of our team will go through the information sheet with you and answer any questions you have. We would suggest this should take about 10 minutes.
Ask us if there is anything that is not clear or if you would like more information and take time to decide whether or not you wish to take part. To do this research we need to collect blood samples from patients like you who have ITP and need to start some treatment.

Do I have to take part?
It is up to you to decide whether or not to take part. We will describe the study and go through this information sheet. If you agree to take part, we will then ask you to sign a consent form and we will take blood samples. If you decide to take part you are free to withdraw without giving a reason at any time up to the point where we have taken the blood sample. A decision to withdraw or not to take part, will not affect any aspect of your care.
You can still take part in the Flight study but decline to have these extra blood samples done.

What will happen to me if I take part and what will happen to the samples I give?
We will need a small quantity of your blood (Usually 10-30 ml up to a maximum of 50ml or a quarter of a teacup) at the start of treatment, then 2 months after starting. The blood sample will be taken when you have routine bloods done and will not involve any additional needles or appointments. The blood samples will be sent to the Bristol Biobank Laboratories in the Bristol Royal Infirmary. Your samples will be labelled with a unique identifier so that we can link them to the blood results already collected by the FLIGHT study and compare laboratory results with patient outcomes. Laboratory staff will not be able to directly link the samples to you. The samples will be processed immediately after receipt by the laboratory, including extraction of DNA and RNA to be used solely for research. Any remaining samples will be stored securely in a Biobank for an indefinite amount of time for future research.
All the laboratory and patient data will be securely stored and kept strictly confidential and you will not be told the laboratory results for your blood sample.

What will I have to do?
There is nothing that you should or should not do as a result of providing additional blood samples.

What are the possible benefits of taking part?
There are no clinical benefits for any person taking part in this project.

What are the possible disadvantages and risks of taking part?
Other than providing us with an extra small volume of blood, there are no anticipated disadvantages in taking part.

What will happen to the results of the research study?
Methods developed from this study may be published in medical and scientific journals. A summary wioo ‰µ o]•Z ]v šZ /dW ‰ š] vš µoo š]v ^šZ ‰o š o š_ v ‰OE • vš š šZ h< /dW •µ‰‰}OEš association patient convention. You will not be identified in any reports or publications from the study.

What happens when the research study stops?
New technologies that can help us look at biological components are emerging all the time. We would therefore wish to store any remaining samples and would ensure that they are anonymized at the end of the FLIGHT study.

tZ š Á]oo Z ‰‰ v ]( / }v[š Á vš š} OEOEÇ }v with the study?
If you decide you no longer want your additional blood samples used for research, they will be destroyed in accordance with standard practices.

What if there is a problem?
This research is not expected to cause harm to you. If you do wish to complain about any aspect of the way you have been approached or treated during the course of this study, the normal National Health Service complaints mechanisms are available to you.

Who is organising and funding the research?
University Hospitals Bristol NHS Foundation Trust has overall responsibility for conduct of the study. The research is led by Clinical and Haematology research teams at UHB and University of Bristol. Funding for the research is from a combination of sources including ITP charitable funding.

Who has reviewed the study?
All research involving samples from people is looked at by an independent group of individuals, called a Research Ethics Committee, to protect your interests. 5. I agree to DNA and RNA being extracted from my blood which will be used for research purposes only.
6. I give permission for my medical data to be stored at the trials unit at Cardiff University and that all information will be held securely and in strict confidence.
7. I understand that my samples may be processed in other laboratories in other parts of the UK, but that the laboratory staff will not be able to link the samples back to me.
8. I agree for my anonymized samples to be used in future research.
9. I agree to take part in the above study.

Instructions to authors
Complete this checklist by entering the page numbers from your manuscript where readers will find each of the items listed below.
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Introduction
Immune thrombocytopenia (ITP) is an autoimmune condition that may cause thrombocytopenia related bleeding. Current first line ITP treatment is with high dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems with only 20% remaining in sustained remission with this approach. Mycophenolate (MMF) is often used as the next treatment with efficacy in 50-80% of patients and good tolerability but can take up to 2 months to work.
Objective: To test the hypothesis that MMF combined with corticosteroid is a more effective first line treatment for immune thrombocytopenia (ITP) than current standard of corticosteroid alone.

Methods and analysis
Design: Multicentre, UK based, open label, randomised controlled trial

Setting: Haematology departments in secondary care
Participants: We plan to recruit 120 patients >16 years old with a diagnosis of ITP and a platelet count <30 x10 9 /L who require first line treatment. Patients will be followed up for a minimum of 12 months following randomisation.
Primary outcome: Time from randomisation to treatment failure defined as platelets <30x10 9 /L and a need for 2 nd line treatment.
Secondary outcomes: Side effects, bleeding events, remission rates, time to relapse, time to next therapy, cumulative corticosteroid dose, rescue therapy, splenectomy, socioeconomic costs, patient reported outcomes (quality of life, fatigue, impact of bleeding, care costs).

Analysis:
The sample size of 120 achieves a 91.5% power to detect a doubling of the median time to treatment failure from 5 to 10 months. This will be expressed as a hazard ratio with 95% confidence interval, median time to event if more than 50% have had an event and illustrated with Kaplan Meier curves. Cost effectiveness will be based on the first 12 months from diagnosis.

Ethics and dissemination
Ethical approval from NRES Committee South West (IRAS number 225959).

INTRODUCTION
Immune thrombocytopenia (ITP) has an incidence of 2.9/100,000 person-years. 1 It is an autoimmune condition that may present with bleeding and bruising due to a low platelet count. In ITP, there is increased consumption and reduced production of platelets due to both antibody and cell mediated autoimmune attack of platelets and megakaryocytes involving dysregulated autoreactive T and B cell lymphocytes. [2][3][4][5] ITP can be classified according to the duration of illness into newly diagnosed (<3 months), persistent (3-12 months) and chronic (>12 months) 6 . ITP may also be classified as either primary when it presents in isolation or secondary when ITP occurs in the context of an associated illness or medication 6 .  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   4 ITP is a diagnosis of exclusion and made when the platelet count <100x 109/L and other causes of thrombocytopenia are excluded by history, examination and laboratory evaluation 6 7 .
Current first line ITP treatment is with high dose corticosteroids but this has several downsides. First, the majority of patients suffer significant side effects including mood swings, difficulty sleeping, weight gain, high blood pressure, diabetes, gastric irritation, skin thinning and osteoporosis. A published survey of ITP patients reported 98% had at least one side effect and 38% stopped or reduced dosage due to intolerable side effects. 8 In the UK ITP registry, the most frequently reported co-morbidities were related to corticosteroids and correlated with duration of treatment (hypertension in 30%, diabetes in 19%) (Newland A et al, poster BSH 2015 25 ). The second problem is that patients are heterogeneous in their response to corticosteroid with some (approximately 20%) not responding at all and the majority of others (70%-90%) relapsing when the corticosteroids are reduced or stopped. 7 9 10 Patients who are refractory or relapse (the majority), remain at risk of bleeding/bruising, which occasionally can be severe including intracranial haemorrhage. 11 They often receive more corticosteroid with associated side effects. Some require hospital admission and expensive rescue therapies (e.g. IVIG for a 70kg patient=£3,906). They continue to require frequent blood tests and doctor visits and are usually unable to continue their normal activities until their illness is controlled. Fatigue is also associated with disease activity and can be severe. 12 Physical factors combine with psychological stress through fear of bleeding, need for time off work and lifestyle restrictions due to bleeding risk to adversely impact quality of life. 13 14 First line treatment for ITP is unsatisfactory but it remains unchanged for decades. Although a small number of studies have tested alternative approaches, a well-tolerated, effective and durable new approach has not been conclusively demonstrated. High dose corticosteroid remains the standard first line treatment recommended in most countries 9 .
Compared to cancers in haematology, ITP remains relatively under-researched. The few trials done in ITP have often been funded by pharmaceutical companies, risking publication bias towards high cost non-generic drugs. For example, many "cheap", generic drugs commonly prescribed for ITP such as azathioprine, mycophenolate and dapsone, have never been tested in randomised controlled trials in ITP. In contrast, the more expensive treatments, TPO-RAs and Rituximab have been tested in well-designed adequately powered RCTs. The relative rarity (2.9/100,000 personyears), non-cancerous nature and rare impact on survival of ITP have prevented ITP being a priority for research funding in the past. However, this underestimates the profound adverse impact a and relapse. 15 The splenectomy numbers performed in the UK has dramatically reduced over recent years (UK ITP registry data). Rituximab is a monoclonal antibody treatment which targets antibody production by B cells. It is relatively expensive, with disappointing long term remission rates similar to placebo. 15 TPO RA stimulate platelet production, are well tolerated and effective in the majority 16 but at significant financial cost, prohibiting widespread use in the UK for early treatment (NICE guidance). A small (n=12) non-randomised study using TPO RA with corticosteroid first line showed efficacy but perhaps less than expected. 17 By contrast, Mycophenolate (MMF) is a widely used second line agent in the UK due to good efficacy (response rates of 50-80%), safety and tolerability profile. [18][19][20][21][22][23][24][25] Mycophenolate has activity against both autoreactive T and B cells and has also shown efficacy in refractory ITP including steroid resistance suggesting a complimentary mechanism of action. 23 It is less expensive to the NHS than some other second line options costing approximately £182/year (generic cost) compared to costs for average doses of romiplostim (TPO RA) at £25 000/year, Eltrombopag (TPO RA) £20 000/year or rituximab at £8000 for a course of 4 infusions (375mg/m2 each dose) or £1000 (100mg each dose). However, similar to other second line therapies, MMF has a relatively slow (up to 2 months) onset of action. In the meantime, patients often receive further steroid (to maintain a "safe platelet count") and continue to suffer problems associated with their illness (see above). Direct feedback from patients regarding the difficulties they face in the first months following ITP diagnosis has been the primary driving force for this

Rationale
The Flight trial is the first UK, NHS coordinated, Pharma independent multicentre randomised controlled trial, testing a "common sense/practical" new approach using MMF first line instead of second line with the aim of preventing the almost inevitable first relapse when corticosteroids stop.
Patients will be randomly allocated to one of 2 treatment arms, either standard of care (corticosteroid alone) or MMF combined with corticosteroid with the primary outcome of time to treatment failure. By giving patients a stable platelet count sooner, we expect to improve other outcomes such as quality of life and fatigue. By reducing the risk of relapse, patients may also be less likely to receive a second course of corticosteroid with associated side effects. Potential indirect benefits to the NHS include reduced need for rescue treatments, blood tests, hospital attendances and admissions and reduced need for high cost treatments such as TPO mimetics. However, there will be some patients who will be treated with MMF who may have been successfully treated with corticosteroids alone (10-30%). [7][8][9] Similar to other immunosuppressives, MMF may slightly increase infection and cancer risk with long term use (SmPC) In addition, MMF is teratogenic and therefore stringent pregnancy prevention is essential for men and women taking the drug. This puts the trial in equipoise. The trial includes a strategy to reduce and stop MMF at 6 months for patients in complete remission to prevent unnecessary long-term use.
The choice of this open label design was made in order to allow true patient treatment costs to be calculated for the cost effectiveness analysis, and to deal with the complexities of placebo controlling a drug that needed titrating at the start and tapering at the end. In addition, over encapsulation was only possible for the lower MMF dose (250 mg) and the resulting capsule was the largest size which would mean most patients taking 8 large capsules per day in both arms; something that patients in Bristol thought would put them off taking part in the study. Patients were clear that from their perspective that a straight forward open label design would be preferable and was easier for a new patient to understand and consent. In addition, the quotes from 2 separate companies also showed the financial costs of encapsulation to generate a placebo were prohibitively expensive.
This trial proposal has received support and input from clinicians and patients nationally (UK ITP forum and ITP support association). To ensure objective and meaningful outcomes, it will be a multicentre RCT, aiming to recruit 120 patients (expecting 100 full datasets). Patients will be given up to one week of corticosteroid prior to randomisation to enable sufficient time to read information, discuss and ask questions with informed consent in an appropriate setting. Patients will receive the usual follow up according to clinical need and local policy. Laboratory and clinical data will be collected from routine appointments. In addition, patient-oriented outcomes will be recorded at diagnosis, 2, 4, 6, and 12 months using validated patient questionnaires. Patients are also offered consent to additional blood samples for translational research studies (time 0 and 2 months).

Primary objective
To compare two first line treatment pathways for ITP, standard corticosteroid only versus corticosteroid combined with MMF and demonstrate which pathway helps patients achieve a stable platelet count sooner, measured as survival free from treatment failure (time from randomisation to treatment failure).

Trial design
A multicentre, open label randomised clinical trial of MMF with corticosteroid as first line treatment for patients with ITP versus the standard care pathway of corticosteroids alone as first line treatment.

Eligibility criteria
Inclusion criteria: Patients >16 years old with a diagnosis of ITP (primary or secondary), a platelet count <30x10 9 /L AND a clinical need for first line treatment. Patients have provided written informed consent.
Patients can be recruited at any time after ITP diagnosis if they are suitable for first line treatment (i.e. Not previously or recently treated). Patients can receive up to 1 week of corticosteroid prior to recruitment to allow time to be informed about the trial, with the opportunity to ask questions and for consent to be taken during a routine specialist clinic appointment if preferred. The trial processes will be run by the Centre for Trials Research (CTR), Cardiff University and sponsored by University Hospitals Bristol NHS Foundation Trust.
The flight trial opened for recruitment on 26 th October 2017.

Randomisation
Patients who agree to participate will be randomised to MMF with corticosteroid or corticosteroid alone in a 1:1 ratio using a secure web based randomisation system based at Cardiff CTR.
Randomisation will be stratified by primary or secondary ITP diagnosis. Due to the large number of centres and the small number of patients it will not be sensible to stratify randomisation by study centre. However, to ensure an even spread of patients across time, randomisation will be blocked using random block sizes of 6 and 8 to retain concealment.
*Dexamethasone 20mg or 40mg orally daily for 4 days is an alternative option to prednisolone if deemed clinically more appropriate for individual circumstances.
2. Corticosteroid +MMF pathway (Figure 2): 1mg/kg od prednisolone 4 days (maximum of 100mg), 40mg od 2 weeks, 20mg od 2 weeks, 10mg od 2 weeks, 5mg od 2 weeks then 5mg alternate days 2 weeks then stop*. For the duration of steroid, patients will get a PPI or H2 antagonist to protect against gastric bleeding and appropriate bone protection. From randomisation (alongside steroid), MMF 500mg bd starting dose then increased to 750mg bd after 2 weeks if tolerated (no side effects or laboratory concerns such as neutropenia) and 1g bd after another 2 weeks if tolerated (4 weeks after starting). Earlier dose escalation to MMF 1g bd can be considered if clinically indicated.
After 6 months of MMF therapy, all patients who have remained in complete remission (pl count> 100 x10 9 /L) will reduce the dose by 250mg (one capsule) each month. The aim is to continue on the lowest dose that achieves a haemostatic (safe) platelet count (pl >30 x10 9 /L) and to ensure that patients who have gone into a remission do not continue to take the drug indefinitely.
In both groups: Any steroid commenced prior to randomisation will be deducted from the regimes.
Importantly, emergency and rescue treatments will be permitted throughout the study. These include platelet transfusions, tranexamic acid and intravenous immunoglobulin. These are known not to impact on the natural history of ITP and it is recognised that they may be important for patient safety. The use of "rescue treatments" will be recorded on the CRF.
In addition, some degree of flexibility of corticosteroid dose and duration may be needed for individual patients according to comorbidity, tolerability and other factors.
If treatment failure occurs, choice of second line treatment will be individualised according to patient's clinical circumstances. Further steroid will be given according to clinical need.
Primary outcome is time from randomisation to treatment failure defined as a pl count <30x10 9 /L AND a need to commence second line treatment. This will include patients who are refractory (pl <30x10 9 /L in spite of 2 weeks treatment in the steroid arm or pl <30x10 9 /L in spite of 2 months treatment in the steroid +MMF arm) or who initially respond but then relapse (defined clinically as pl <30x10 9 /L and need for further therapy).

Secondary outcomes
1. Medication side effects, toxicity or other adverse events (including infection episodes)

Patients follow up
Patients will be followed up until the end of the trial and for a minimum of 12 months. They will receive the usual follow up according to clinical need and local policy. Laboratory and clinical data will be collected from routine appointments. In addition, patient oriented outcomes and additional data will be recorded at diagnosis, 2, 4, 6, and 12 months using validated patient questionnaires.
Patients are also offered consent to additional blood samples for translational research studies (time 0 and 2 months).

Data collection (Table 1)
Hospital monitoring of platelet levels (FBC) is part of routine care for ITP patients and these data will be collected and recorded on the CRF without requiring patients to come in for additional samples to be taken. These locally collected samples may be collected monthly (or less often) for patients believed to be in stable remission and weekly at lower or declining platelet levels. We expect this to allow us to calculate the time in remission and time to relapse with reasonable accuracy over the 12 to 24 month follow up period. Other clinical and laboratory data needed for the trial endpoints will be collected from the medical and electronic records and recorded on the CRF. In addition, we will also ask the patients to complete questionnaires on fatigue, quality of life and bleeding scores at baseline, 2, 4, 6, and 12 months.
Patient reported outcomes will be captured by the following questionnaires: Additional optional research blood samples (requiring separate consent) will be sent at baseline and 2 month follow up to the Bristol Biobank.

Data Management
Source documents produced for this trial will be kept in the patient's hospital records and source data will be transcribed into trial-specific Case Report Forms (CRFs) at the end of each patient visit.
Data recording for this trial will be via a web based system. This is a secure encrypted system accessed by an institutional password which complies with Data Protection Act standards. The database will be stored and regularly backed up on a Cardiff University Server. The CRFs will be coded with the study number and will not include patients' names and addresses

Patient and Public Involvement and Engagement
During the trial development, a group of 8 ITP patients discussed the study design, burden of outcome measure completion to patients and the size of a potential placebo capsule which they reported could put them off getting involved in a trial. They reported that avoidance of relapse, early achievement of a stable platelet count, reduced overall corticosteroid dose and reduced hospital attendances are the most important goals for ITP management from their perspective.
We formed a Patient Advisory Group (PAG) with some of these patients and representatives from the ITP association that will advise the trial management group throughout the study. They have commented on all patient-facing documentation and will be instrumental in disseminating the study findings to patient groups and the public.

Sample size calculation
There is no published clinical data available for MMF use first line in ITP as this is a novel approach.
We have analysed local data on MMF used second line in ITP in 12 patients which shows an estimated median survival free from treatment failure of more than 10 months. Clinically a doubling in the time to remission was thought to be something that the patients would have welcomed. Less than that was not thought to be sufficient grounds for switching this treatment from second line to first line due to the potential for additional toxicity and immune suppression in those who may have remained in remission with corticosteroids alone.
The sample size of 120 (60 per group) with less than 5% loss to follow-up achieves 91.5% power to detect a doubling of the median time to treatment failure from 5 months to 10 months if the patients are recruited at a steady rate or 10 per month for 12 months and all followed up until the last patients reaches 12 months follow up.

Statistical analysis
The full statistical analysis will be written into a statistical analysis plan available separately. The analysis will produce a CONSORT diagram for the reporting of clinical trials.
The baseline characteristics of the two groups will be tabulated but not tested for statistically significant differences between the groups.
The primary analysis is by intention to treat. However an investigation of compliance with the treatment pathway and compliance with the criteria for changing to a second line therapy will be carried out prior to the primary analysis to check the date of the primary event. The primary event is the date at which there was a requirement for second line therapy. Where the platelet count falls below the level required for this treatment decision, the first date at which either symptoms or a blood test revealing this event will be used. If a clinician decides to use a second line therapy without a platelet count below the criteria, the date of the treatment decision/new prescription will be taken to represent that event. The results will be expressed as a hazard ratio with 95% confidence interval, median time to event if more than 50% have had an event and plotted as Kaplan Meier curves. The primary analysis will contain all patients who are randomised for as long as they have been followed up or until their first event in a survival analysis using intention to treat methodology. All patients will be followed up to 12 months. In addition, patients who have not had an event in the first 12 months post randomisation will be followed until their first event or until the last patient has reached the 12 month point -whichever is the sooner and included in the analysis until that time accordingly.
Analysis of other outcomes will use as full a data set as possible and focus on the 12 month data point or area under the curve as appropriate and detailed in the analysis plan.
No interim analyses of the main endpoint will be supplied to the independent Data Monitoring Committee (DMC) due to the short time frame (12 months recruitment) in which all patients will be recruited by the time the first patient has completed follow-up. Serious adverse event rates will be reported on a monthly basis to the trial management group (TMG) and the DMC. The DMC could advise the chairman of the Trial Steering Committee and Chief Investigator if these provide proof beyond reasonable doubt that it would be unethical to continue with the trial.

Pharmacovigilance
The collection and reporting of all adverse events is in accordance with the Medicines for Human MMF in this trial has a genotoxic and teratogenic potential and therefore pregnancy is contraindicated. Participants that are female of child bearing potential, or male with female partners of equal potential, are required to use contraception as indicated in the protocol.

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Introduction
Immune thrombocytopenia (ITP) is an autoimmune condition that may cause thrombocytopenia related bleeding. Current first line ITP treatment is with high dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems with only 20% remaining in sustained remission with this approach. Mycophenolate (MMF) is often used as the next treatment with efficacy in 50-80% of patients and good tolerability but can take up to 2 months to work.
Objective: To test the hypothesis that MMF combined with corticosteroid is a more effective first line treatment for immune thrombocytopenia (ITP) than current standard of corticosteroid alone.

Methods and analysis
Design: Multicentre, UK based, open label, randomised controlled trial

Setting: Haematology departments in secondary care
Participants: We plan to recruit 120 patients >16 years old with a diagnosis of ITP and a platelet count <30 x10 9 /L who require first line treatment. Patients will be followed up for a minimum of 12 months following randomisation.
Primary outcome: Time from randomisation to treatment failure defined as platelets <30x10 9 /L and a need for 2 nd line treatment.
Secondary outcomes: Side effects, bleeding events, remission rates, time to relapse, time to next therapy, cumulative corticosteroid dose, rescue therapy, splenectomy, socioeconomic costs, patient reported outcomes (quality of life, fatigue, impact of bleeding, care costs).

Analysis:
The sample size of 120 achieves a 91.5% power to detect a doubling of the median time to treatment failure from 5 to 10 months. This will be expressed as a hazard ratio with 95% confidence interval, median time to event if more than 50% have had an event and illustrated with Kaplan Meier curves. Cost effectiveness will be based on the first 12 months from diagnosis.

INTRODUCTION
Immune thrombocytopenia (ITP) has an incidence of 2.9/100,000 person-years. 1 It is an autoimmune condition that may present with bleeding and bruising due to a low platelet count. In ITP, there is increased consumption and reduced production of platelets due to both antibody and cell mediated autoimmune attack of platelets and megakaryocytes involving dysregulated autoreactive T and B cell lymphocytes. [2][3][4][5] ITP can be classified according to the duration of illness into newly diagnosed (<3 months), persistent (3-12 months) and chronic (>12 months). 6 ITP may also be classified as either primary when it presents in isolation or secondary when ITP occurs in the context of an associated illness or medication. 6  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   4 ITP is a diagnosis of exclusion and made when the platelet count <100x 109/L and other causes of thrombocytopenia are excluded by history, examination and laboratory evaluation. 6,7 Current first line ITP treatment is with high dose corticosteroids but this has several downsides. First, the majority of patients suffer significant side effects including mood swings, difficulty sleeping, weight gain, high blood pressure, diabetes, gastric irritation, skin thinning and osteoporosis. A published survey of ITP patients reported 98% had at least one side effect and 38% stopped or reduced dosage due to intolerable side effects. 8 In the UK ITP registry, the most frequently reported co-morbidities were related to corticosteroids and correlated with duration of treatment (hypertension in 30%, diabetes in 19%). 9 The second problem is that patients are heterogeneous in their response to corticosteroid with some (approximately 20%) not responding at all and the majority of others (70%-90%) relapsing when the corticosteroids are reduced or stopped. 7,10,11 Patients who are refractory or relapse (the majority), remain at risk of bleeding/bruising, which occasionally can be severe including intracranial haemorrhage. 12 They often receive more corticosteroid with associated side effects. Some require hospital admission and expensive rescue therapies (e.g. IVIG for a 70kg patient=£3,906). They continue to require frequent blood tests and doctor visits and are usually unable to continue their normal activities until their illness is controlled.
Fatigue is also associated with disease activity and can be severe. 13 Physical factors combine with psychological stress through fear of bleeding, need for time off work and lifestyle restrictions due to bleeding risk to adversely impact quality of life. 14,15 First line treatment for ITP is unsatisfactory but it remains unchanged for decades. Although a small number of studies have tested alternative approaches, a well-tolerated, effective and durable new approach has not been conclusively demonstrated. High dose corticosteroid remains the standard first line treatment recommended in most countries. 10 Compared to cancers in haematology, ITP remains relatively under-researched. The few trials done in ITP have often been funded by pharmaceutical companies, risking publication bias towards high cost non-generic drugs. For example, many "cheap", generic drugs commonly prescribed for ITP such as azathioprine, mycophenolate and dapsone, have never been tested in randomised controlled trials in ITP. In contrast, the more expensive treatments, TPO-RAs and Rituximab have been tested in well-designed adequately powered RCTs. The relative rarity (2.9/100,000 personyears), non-cancerous nature and rare impact on survival of ITP have prevented ITP being a priority for research funding in the past. However, this underestimates the profound adverse impact a  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   5 diagnosis of ITP and its treatment can have for individual patients, many of whom are young. There is also a costly financial impact for the NHS from the healthcare resources patients require when their illness is uncontrolled. In addition, the problems faced by patients with ITP mirror those with other autoimmune conditions which as a group are common, affecting 3% of the population. There is an urgent clinical need to address this inequality, improving first line treatment for ITP through high quality, independently funded research to allow patients with this condition access to improvements in care seen in other illnesses such as cancer or heart disease. Current popular options for second line or subsequent treatment include Mycophenolate, Rituximab, Thrombopoeitin receptor agonists (TPO RA) and splenectomy. Splenectomy is an effective treatment (60% long term remission rates) but irreversible and international guidelines recommend deferring splenectomy for the first 12 months following diagnosis due to the chance of spontaneous remission (risk of unnecessarily removing a healthy organ). 7,11 Surgical operations are not popular with patients and there is increasing awareness of the short and long term complications of splenectomy including infection, bleeding, arterial and venous thrombosis, cancer and relapse. 16 The splenectomy numbers performed in the UK has dramatically reduced over recent years (UK ITP registry data). Rituximab is a monoclonal antibody treatment which targets antibody production by B cells. It is relatively expensive, with disappointing long term remission rates similar to placebo. 16 TPO RA stimulate platelet production, are well tolerated and effective in the majority 17 but at significant financial cost, prohibiting widespread use in the UK for early treatment (NICE guidance). A small (n=12) non-randomised study using TPO RA with corticosteroid first line showed efficacy but perhaps less than expected. 18 By contrast, Mycophenolate (MMF) is a widely used second line agent in the UK due to good efficacy (response rates of 50-80%), safety and tolerability profile. [19][20][21][22][23][24][25][26] Mycophenolate has activity against both autoreactive T and B cells and has also shown efficacy in refractory ITP including steroid resistance suggesting a complimentary mechanism of action. 24 It is less expensive to the NHS than some other second line options costing approximately £182/year (generic cost) compared to costs for average doses of romiplostim (TPO RA) at £25 000/year, Eltrombopag (TPO RA) £20 000/year or rituximab at £8000 for a course of 4 infusions (375mg/m2 each dose) or £1000 (100mg each dose). However, similar to other second line therapies, MMF has a relatively slow (up to 2 months) onset of action. In the meantime, patients often receive further steroid (to maintain a "safe platelet count") and continue to suffer problems associated with their illness (see above). Direct feedback from patients regarding the difficulties they face in the first months following ITP diagnosis has been the primary driving force for this  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   6 clinical trial. Local (Bristol) and national patient groups (ITP support association) have been fundamental to the formulation of patient relevant priorities for treatment.

Rationale
The Flight trial is the first UK, NHS coordinated, Pharma independent multicentre randomised controlled trial, testing a "common sense/practical" new approach using MMF first line instead of second line with the aim of preventing the almost inevitable first relapse when corticosteroids stop.
Patients will be randomly allocated to one of 2 treatment arms, either standard of care (corticosteroid alone) or MMF combined with corticosteroid with the primary outcome of time to treatment failure. By giving patients a stable platelet count sooner, we expect to improve other outcomes such as quality of life and fatigue. By reducing the risk of relapse, patients may also be less likely to receive a second course of corticosteroid with associated side effects. Potential indirect benefits to the NHS include reduced need for rescue treatments, blood tests, hospital attendances and admissions and reduced need for high cost treatments such as TPO mimetics. However, there will be some patients who will be treated with MMF who may have been successfully treated with corticosteroids alone (10-30%). 7,9,10 Similar to other immunosuppressives, MMF may slightly increase infection and cancer risk with long term use (SmPC) In addition, MMF is teratogenic and therefore stringent pregnancy prevention is essential for men and women taking the drug. This puts the trial in equipoise. The trial includes a strategy to reduce and stop MMF at 6 months for patients in complete remission to prevent unnecessary long-term use.
The choice of this open label design was made in order to allow true patient treatment costs to be calculated for the cost effectiveness analysis, and to deal with the complexities of placebo controlling a drug that needed titrating at the start and tapering at the end. In addition, over encapsulation was only possible for the lower MMF dose (250 mg) and the resulting capsule was the largest size which would mean most patients taking 8 large capsules per day in both arms; something that patients in Bristol thought would put them off taking part in the study. Patients were clear that from their perspective that a straight forward open label design would be preferable and was easier for a new patient to understand and consent. In addition, the quotes from 2 separate companies also showed the financial costs of encapsulation to generate a placebo were prohibitively expensive.
This trial proposal has received support and input from clinicians and patients nationally (UK ITP forum and ITP support association). To ensure objective and meaningful outcomes, it will be a  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   7 multicentre RCT, aiming to recruit 120 patients (expecting 100 full datasets). Patients will be given up to one week of corticosteroid prior to randomisation to enable sufficient time to read information, discuss and ask questions with informed consent in an appropriate setting. Patients will receive the usual follow up according to clinical need and local policy. Laboratory and clinical data will be collected from routine appointments. In addition, patient-oriented outcomes will be recorded at diagnosis, 2, 4, 6, and 12 months using validated patient questionnaires. Patients are also offered consent to additional blood samples for translational research studies (time 0 and 2 months).

Primary objective
To compare two first line treatment pathways for ITP, standard corticosteroid only versus corticosteroid combined with MMF and demonstrate which pathway helps patients achieve a stable platelet count sooner, measured as survival free from treatment failure (time from randomisation to treatment failure).

Trial design
A multicentre, open label randomised clinical trial of MMF with corticosteroid as first line treatment for patients with ITP versus the standard care pathway of corticosteroids alone as first line treatment.

Eligibility criteria
Inclusion criteria: Patients >16 years old with a diagnosis of ITP (primary or secondary), a platelet count <30x10 9 /L AND a clinical need for first line treatment. Patients have provided written informed consent.

Randomisation
Patients who agree to participate will be randomised to MMF with corticosteroid or corticosteroid alone in a 1:1 ratio using a secure web based randomisation system based at Cardiff CTR. Randomisation will be stratified by primary or secondary ITP diagnosis. Due to the large number of centres and the small number of patients it will not be sensible to stratify randomisation by study centre. However, to ensure an even spread of patients across time, randomisation will be blocked using random block sizes of 6 and 8 to retain concealment.

Treatment arms (Figures 1 and 2):
1. Corticosteroid only pathway (Figure 1): 1mg/kg od prednisolone 4 days (maximum of 100mg), 40mg od 2 weeks, 20mg od 2 weeks, 10mg od 2 weeks, 5mg od 2 weeks then 5mg alternate days 2 weeks then stop*. For the duration of steroid, patients will get a PPI or H2 antagonist to protect against gastric bleeding and appropriate bone protection. *Dexamethasone 20mg or 40mg orally daily for 4 days is an alternative option to prednisolone if deemed clinically more appropriate for individual circumstances.
After 6 months of MMF therapy, all patients who have remained in complete remission (pl count> 100 x10 9 /L) will reduce the dose by 250mg (one capsule) each month. The aim is to continue on the lowest dose that achieves a haemostatic (safe) platelet count (pl >30 x10 9 /L) and to ensure that patients who have gone into a remission do not continue to take the drug indefinitely.
In both groups: Any steroid commenced prior to randomisation will be deducted from the regimes.
Importantly, emergency and rescue treatments will be permitted throughout the study. These include platelet transfusions, tranexamic acid and intravenous immunoglobulin. These are known not to impact on the natural history of ITP and it is recognised that they may be important for patient safety. The use of "rescue treatments" will be recorded on the CRF.
In addition, some degree of flexibility of corticosteroid dose and duration may be needed for individual patients according to comorbidity, tolerability and other factors.
If treatment failure occurs, choice of second line treatment will be individualised according to patient's clinical circumstances. Further steroid will be given according to clinical need. Primary outcome is time from randomisation to treatment failure defined as a pl count <30x10 9 /L AND a need to commence second line treatment. This will include patients who are refractory (pl <30x10 9 /L in spite of 2 weeks treatment in the steroid arm or pl <30x10 9 /L in spite of 2 months treatment in the steroid +MMF arm) or who initially respond but then relapse (defined clinically as pl <30x10 9 /L and need for further therapy). Patients with a clinical need to start 2 nd line treatment early (within 2 weeks for the steroid only arm and within 2 months for the MMF and steroid arm), for example due to significant bleeding, will also be classed as treatment failures.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59

Patients follow up
Patients will be followed up until the end of the trial and for a minimum of 12 months. They will receive the usual follow up according to clinical need and local policy. Laboratory and clinical data will be collected from routine appointments. In addition, patient oriented outcomes and additional data will be recorded at diagnosis, 2, 4, 6, and 12 months using validated patient questionnaires.
Patients are also offered consent to additional blood samples for translational research studies (time 0 and 2 months). Table 1) Hospital monitoring of platelet levels (FBC) is part of routine care for ITP patients and these data will be collected and recorded on the CRF without requiring patients to come in for additional samples to be taken. These locally collected samples may be collected monthly (or less often) for patients believed to be in stable remission and weekly at lower or declining platelet levels. We expect this to allow us to calculate the time in remission and time to relapse with reasonable accuracy over the 12 to 24 month follow up period. Other clinical and laboratory data needed for the trial endpoints will be collected from the medical and electronic records and recorded on the CRF. In addition, we will also ask the patients to complete questionnaires on fatigue, quality of life and bleeding scores at baseline, 2, 4, 6, and 12 months (Table 1).

Data Management
Source documents produced for this trial will be kept in the patient's hospital records and source data will be transcribed into trial-specific Case Report Forms (CRFs) at the end of each patient visit.
Data recording for this trial will be via a web based system. This is a secure encrypted system accessed by an institutional password which complies with Data Protection Act standards. The database will be stored and regularly backed up on a Cardiff University Server. The CRFs will be coded with the study number and will not include patients' names and addresses

Patient and Public Involvement and Engagement
During the trial development, a group of 8 ITP patients discussed the study design, burden of outcome measure completion to patients and the size of a potential placebo capsule which they reported could put them off getting involved in a trial. They reported that avoidance of relapse, early achievement of a stable platelet count, reduced overall corticosteroid dose and reduced hospital attendances are the most important goals for ITP management from their perspective.
We formed a Patient Advisory Group (PAG) with some of these patients and representatives from the ITP association that will advise the trial management group throughout the study. They have commented on all patient-facing documentation and will be instrumental in disseminating the study findings to patient groups and the public.

Sample size calculation
There is no published clinical data available for MMF use first line in ITP as this is a novel approach.
We have analysed local data on MMF used second line in ITP in 12 patients which shows an estimated median survival free from treatment failure of more than 10 months. We have data on 68 who experienced corticosteroids as a first line treatment showing that 70% of them had experienced  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  proportional hazards ratio model demonstrates the 90% confidence interval for the hazard ratio to be between 0.13 and 0.59, showing that our decision to power this on an estimate of a hazard of lower than 0.5 is potentially achievable.
Clinically a doubling in the time to remission was thought to be something that the patients would have welcomed. Less than that was not thought to be sufficient grounds for switching this treatment from second line to first line due to the potential for additional toxicity and immune suppression in those who may have remained in remission with corticosteroids alone.
The sample size of 120 (60 per group) with less than 5% loss to follow-up achieves 91.5% power to detect a doubling of the median time to treatment failure from 5 months to 10 months if the patients are recruited at a steady rate or 10 per month for 12 months and all followed up until the last patients reaches 12 months follow up.

Statistical analysis
The full statistical analysis will be written into a statistical analysis plan available separately. The analysis will produce a CONSORT diagram for the reporting of clinical trials.
The baseline characteristics of the two groups will be tabulated but not tested for statistically significant differences between the groups. The primary analysis is by intention to treat. However an investigation of compliance with the treatment pathway and compliance with the criteria for changing to a second line therapy will be carried out prior to the primary analysis to check the date of the primary event. The primary event is the date at which there was a requirement for second line therapy. Where the platelet count falls below the level required for this treatment decision, the first date at which either symptoms or a blood test revealing this event will be used. If a clinician decides to use a second line therapy without a platelet count below the criteria, the date of the treatment decision/new prescription will be taken to represent that event. The results will be expressed as a hazard ratio with 95% confidence interval, median time to event if more than 50% have had an event and plotted as Kaplan Meier curves.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   13 The primary analysis will contain all patients who are randomised for as long as they have been followed up or until their first event in a survival analysis using intention to treat methodology. All patients will be followed up to 12 months. In addition, patients who have not had an event in the first 12 months post randomisation will be followed until their first event or until the last patient has reached the 12 month point -whichever is the sooner and included in the analysis until that time accordingly. Sensitivity analyses will include landmark analysis or shifting the time line to classify all treatment failures before 2 months as at 2 months in order to prevent potential biases caused by different definitions of treatment failure time frames between the two groups.
Analysis of other outcomes will use as full a data set as possible and focus on the 12 month data point or area under the curve as appropriate and detailed in the analysis plan.
No interim analyses of the main endpoint will be supplied to the independent Data Monitoring Committee (DMC) due to the short time frame (12 months recruitment) in which all patients will be recruited by the time the first patient has completed follow-up. Serious adverse event rates will be reported on a monthly basis to the trial management group (TMG) and the DMC. The DMC could advise the chairman of the Trial Steering Committee and Chief Investigator if these provide proof beyond reasonable doubt that it would be unethical to continue with the trial.

Pharmacovigilance
The collection and reporting of all adverse events is in accordance with the Medicines for Human  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 14 MMF in this trial has a genotoxic and teratogenic potential and therefore pregnancy is contraindicated. Participants that are female of child bearing potential, or male with female partners of equal potential, are required to use contraception as indicated in the protocol.

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