Trial design

CONSTRUCT is a two-arm, pragmatic randomised trial (figure 1). Participating patients and their doctors knew which of the two drugs they were receiving. As the two modes of administration are different, any other approach would have been difficult. Fortunately this pragmatic approach enables us to compare the clinical and cost-effectiveness of the drugs in normal clinical practice, whereas the more explanatory double-blind placebo controlled trial would have compared the efficacy of the drugs under stricter, less realistic, conditions.22

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Figure 1

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: a Trial (CONSTRUCT) flowchart.

To this design we added a comprehensive cohort to help recruit patients into a complex trial. Following explanation we invited inpatients with known or suspected colitis to join the cohort as soon as possible after admission. We told them that if they had UC and did not respond to intravenous steroids, they might need other drug treatment; and, if they were suitable, we would invite them to have further treatment as part of a clinical trial. To increase the chance of recruiting them, and ensure the quality of their data, we collected their baseline data as soon as possible after they had given consent. Although our primary aim in recruiting this cohort was to enhance recruitment to the trial, it has potential to enhance future study of UC, notably through anonymised linkage to routine data.23

From May 2010 to the end of February 2013 we recruited from the cohort to the trial those participants diagnosed with UC (assessed by Truelove and Witts criteria,24 a Mayo score of at least 2 on endoscopy, or clinical judgement) who failed to respond to a course of up to about 5 days of intravenous steroids but did not need immediate surgery. After the clinical team had confirmed steroid resistance, and full oral and written explanation, we invited participants who fulfilled the trial inclusion criteria to consent to randomisation to either infliximab or ciclosporin. A placebo control group would have been unethical, as these patients are severely ill and need treatment, as the NICE Evidence Review Group recognised.21

Sample size and power

The current design of CONSTRUCT requires a combination of survival analysis and statistical imputation to get full value from the resulting dataset. As these techniques are difficult to incorporate into power calculations, we present a simpler calculation based on t tests of mean Crohn's and Colitis Questionnaire (CCQ) scores at 12 months. For CONSTRUCT to detect an effect size of 0.35 in these scores (ie, a difference between infliximab and ciclosporin groups of at least 0.35 of the population SE) with 80% power when using a 5% significance level requires that we analyse at least 250 of the 270 participants recruited to the trial. Although more than 10% of CONSTRUCT participants are likely to drop out over the follow-up period of at least 12 months, all analyses will exploit the techniques of statistical imputation used successfully by the Cancer of the Oesophagous or Gastricus: New Assessment of the Technology of Endosonography (COGNATE)25 and Folate Augmentation of Treatment—Evaluation of Depression (FolATED)26 trials to maintain the effective sample size at 250. Our initial, more conservative power calculation had proposed: to recruit 480 participants; not to impute missing data statistically; therefore to allow for 25% loss to follow-up; and thus to yield 80% power to detect a slightly smaller effect size of 0.30 in CCQ scores. We amended our target to 270 participants once the difficulty of identifying patients with acute steroid-resistant UC became clear early in recruitment.

Routine data

Designed research data collection will continue until April 2014. We shall supplement the designed data collected from cohort participants by operational data from their electronic records, routine data on National Health Service (NHS) resource use from Hospital Episode Statistics (HES) and mortality data from the Office for National Statistics (ONS).

We plan to continue follow-up for up to 10 years through record linkage of routine mortality, inpatient and primary care data using the existing facilities of the Medical Research Council (MRC)-funded Centre for Improving Population Health through E-health Research (CIPHER) in the College of Medicine of Swansea University. We hope to monitor all participants’ long-term outcomes, including mortality, emergency colectomy, elective colectomy and major morbidity including hospitalisation and surgery, and thus most of their NHS costs. Thus we aim to achieve both long-term follow-up for trial participants and to create a larger electronic comprehensive cohort of patients with inflammatory bowel disease (IBD).

Trial management

The management structure includes: Trial Steering Committee (TSC) which provides oversight of the trial and meets at six monthly intervals, Data Monitoring and Ethics Committee (DMEC) which monitors trial data in accordance with an agreed charter and reports to the TSC, and Trial Management Group (TMG) comprising academics, health professionals, researchers and representatives of service users and the Swansea Clinical Trials Unit—the West Wales Organisation for Rigorous Trials in Health (WWORTH). The TMG undertakes general management of the trial, meets every month and reports to the TSC. In accordance with the relevant WWORTH standard operating procedure,27 we include service users as active contributors at all stages of this study. They attend the TSC, DMEC and TMG where they contribute to the research process and provide valuable insights into UC.

Setting and site selection

We invited consultant gastroenterologists to express interest in taking part in the study via the British Society of Gastroenterology by completing a feasibility questionnaire. We considered sites which had treated four or more patients with steroid-resistant UC in the previous 12 months to be eligible and invited them to seek local approval. As a result we are undertaking the study in 68 NHS Health Boards or Trusts, including large teaching and district general hospitals in England, Scotland and Wales.

Informed consent

Patients who were eligible for the cohort received Cohort Participant Information Leaflets and oral explanation about the cohort from consultant gastroenterologists or research professionals (usually research nurses); they gave written consent by signing and dating a Cohort Consent Form. Cohort participants who became eligible for the trial received Trial Participant Information Leaflets and oral explanation about the trial; they gave written consent by signing and dating a Trial Consent Form. For cohort and trial, those taking consent countersigned and dated the form to confirm that the participant had fully understood the nature of the study and had had opportunity to ask questions; they also put a copy of that consent in the medical record, and gave another copy to the participant.

Research professionals could take consent to the cohort if authorised to do so on the Site Delegation Log following appropriate training including Good Clinical Practice (GCP). Although they could also explain the trial to cohort participants, responsibility for countersigning lay with the site principal investigator (PI) or another doctor with delegated authority on the Site Delegation Log.

Withdrawal

The process of consenting participants stressed that they could withdraw from cohort or trial whenever they wished without giving a reason and without affecting their care in any way. We documented reasons given where available. We encouraged participants who withdrew from completing questionnaires to continue other types of follow-up. We encouraged site staff to trace participants lost to follow-up and document the reasons for their loss when possible.

Clinical judgements that participants had not responded to treatment with infliximab or ciclosporin usually led to surgical intervention; however, those participants remained in the trial, especially for analysis by treatment allocated, unless they chose to withdraw. Between randomisation and the end of the trial, there were many decisions made by clinicians to discontinue or change allocated treatments; again this did not constitute withdrawal from this pragmatic trial.

Trial inclusion criteria

Patients admitted as emergency admissions with severe colitis who fail to respond to up to about 5 days of intravenous hydrocortisone therapy, who also have either:

1. Histological diagnosis of UC in this episode;

2. Histological diagnosis of indeterminate colitis in this episode, where clinical judgement (based on macroscopic appearance, disease distribution or a history) suggests a diagnosis of UC rather than Crohn's disease;

3. Symptoms typical of UC while histology awaited;

4. History of UC (previously confirmed histologically).

We withdrew from treatment participants with B, C or D who were later found not to have UC but kept them in the trial and followed them up in the usual way.

Trial exclusion criteria

1. Age under 18 years on admission

2. Pre-randomisation histological diagnosis inconsistent with UC (cf inclusion criterion ‘B’)

3. Enteric infection confirmed before randomisation by stool microscopy, culture or histology (includes Campylobacter, Clostridium difficile, Cytomegalovirus, Salmonella and Shigella)

4. Vulnerable patient

5. Unable to consent

6. Positive pregnancy test or currently lactating

7. Woman of child-bearing potential but not prepared to use contraception during, and for 6 months after, treatment with infliximab in accordance with the Summary of Product Characteristics

8. Current malignancy, excluding basal cell carcinoma

9. Serious co-morbidity, including:

   1. Immunodeficiency

   2. Myocardial infarction (within last month)

   3. Moderate or severe heart failure (New York Heart Association (NYHA) class III or IV)

   4. Acute stroke (within last month)

   5. Respiratory failure

   6. Renal failure

   7. Hepatic failure

   8. Active or suspected active tuberculosis

   9. Other severe infections such as sepsis, abscesses and opportunistic infections

   10. History of hypersensitivity to infliximab, ciclosporin or polyethoxylated oils (Sandimmun Concentrate for intravenous infusion)

10. Concomitant use of tacrolimus or rosuvastatin

11. English not good in absence of local translation services

12. Clinical need to undergo emergency colectomy without further medical treatment

13. Currently taking part in another clinical trial

14. Treatment with either infliximab or ciclosporin in the 3 months before admission

15. Contraindication(s) to treatment with infliximab or ciclosporin

Randomisation

We allocated all patients who completed baseline observations, met the inclusion criteria but none of the exclusion criteria, and gave informed consent—at random between infliximab or ciclosporin. We used a web-based password-protected site with a dynamic algorithm to protect against subversion while ensuring that each arm of the RCT was balanced by centre.28

For validation, the website requested additional information.

1. Participant's study number, and month and year of birth.

2. Name of the person who was requesting randomisation (limited to those trained and authorised).

3. Has consent been given?

4. Does the patient meet the inclusion criteria?

5. Does the patient have none of the exclusion criteria?

6. Has the baseline questionnaire been completed?

If the responses to the last four questions were ‘Yes’, the patient was randomised.

The research staff requesting randomisation received the name of the drug to be allocated to the participant and immediate confirmation of the study number and drug by email. The outcomes of randomisation are recorded on the randomisation database, in the trial master file at Swansea University, at the study site in participants’ records, and in the remotely hosted data repository.

The drugs were held in hospital pharmacies at trial sites. When a participant was randomised, the research staff faxed the relevant pharmacy a copy of the confirmation of participant study number and drug. The drug was labelled with the EudraCT number, sponsor, participant's study number, name and address of supplier, ‘For Clinical Trial Use Only’ and the dose directions.

Blinding

As this was an open trial, there was no need for procedures to enable study sites to reveal random allocations. Nevertheless we shall keep the CI, statistician and other staff responsible for analysis and reporting blind to treatment allocated and received until they complete primary analysis to the satisfaction of TSC and DMEC.

Interventions

Participants randomised to infliximab received it as remicade in 5 mg/kg intravenous infusions over 2 h—at baseline and 2 and 6 weeks after the first infusion, in accordance with local prescribing guidelines.

Participants randomised to ciclosporin received it as sandimmun by continuous infusion of 2 mg/kg/day. Sites were advised to change the infusion every 6 h using non-polyvinyl chloride bags and administration sets but, given the pragmatic nature of the trial, could follow local practice. Intravenous treatment continued for up to 7 days if successful. Sites switched participants responding to ciclosporin to twice-daily oral doses delivering 5.5 mg/kg/day, and adjusted doses to achieve trough ciclosporin concentration of 100–200 ng/mL. They measured whole-blood ciclosporin levels according to local practice, ideally 48 h after oral therapy and then every 2 weeks. After 12 weeks treatment was at the discretion of the participant's consultant. We asked centres to consult the online Summary of Product Characteristics for remicade or sandimmun and oral ciclosporin at the time of first prescription.

For both treatments we gave centres discretion to start azathioprine or 6-mercaptopurine at therapeutic doses in week 4. We asked them to eliminate steroids by week 12 in patients who remained well but to reinstate them in patients who became symptomatic. We also advised centres to give septrin as prophylaxis against Pneumocystis jiroveci (carinii) pneumonia in both groups.

Outcome measures

Until April 2014, that is between 1 and 3.5 years from randomisation, we shall continue to measure:

1. Primary outcome measure of quality-adjusted survival, weighted by scores on the disease-specific CCQ which we are validating concurrently. The CCQ expands the validated UK IBDQ29 to cover acute illness and the period after colectomy.

Quality of life:

• 2. Disease-specific quality of life, measured by the CCQ.

• 3. Generic quality of life, measured by SF-1230 and EQ-5D31 questionnaires.

Main clinical outcomes:

• 4. Mortality.

• 5. Colectomies, both emergency and planned.

• 6. Readmissions, including those for non-UC-specific causes.

• 7. Adverse events, subdivided into suspected unexpected serious adverse reactions (SUSARs), serious adverse reactions (SARs), serious AEs (SAEs), adverse reactions (ARs) and AE, including all relevant events in 4–6 above.

Incidence of rarer clinical outcomes:

• 8. Malignancies, subdivided between colorectal, other gastrointestinal and other.

• 9. Serious infections, including bacterial infections, pneumonia and abscesses.

• 10. Renal disorders.

• 11. Other new symptoms, especially attributable to treatment.

Disease activity:

• 12. Criteria proposed by Truelove and Witts24: full blood count, inflammatory markers and albumin at baseline and 3, 6, 12, 18, 24, 30 and 36 months.

Economic outcomes:

• 13. NHS costs, measured by a healthcare resource use questionnaire and hospital activity data.

• 14. Patient-borne costs, including number of days off work and travel costs to healthcare.

Qualitative outcomes:

• 15. Patient views of both drugs and their implications.

• 16. Professional views about the drugs, their administration and ease of handling.

Safety monitoring and reporting

Responsibility for ensuring GCP adherence and reporting AEs in accordance with the clinical trial regulations is the delegated responsibility of the PI and the research team at each site, documented in a clinical trial agreement in place with each site.

All AEs are recorded and assessed by the PI or other designated person, using an AE Screening Form to judge the seriousness, causality and expectedness of the event. If uncertain the PI will summarise the event and refer the decision to the CI. Serious AEs, including SUSARS, are reported to the DMEC and an annual safety report, including serious adverse reactions, is submitted to the Medicines and Healthcare products Regulatory Agency (MHRA) and Research Ethics Committee (REC) for Wales.

To help identify AEs, trial participants are given a membership card showing their study ID. They are asked to show this whenever they are seen by a doctor who is not part of the team treating them for UC.

Data collection

We ask all trial participants to complete questionnaires (including CCQ, SF-12 and EQ-5D) at baseline and 3, 6 and 12 months; and to complete them at 18, 24, 30 and 36 months if they reach these timepoints before April 2014.

In addition, we also ask all trial participants who undergo a colectomy or subsequent corrective surgery to complete the postcolectomy version of CCQ on discharge following surgery, and at 4, 8 and 12 weeks after discharge; we have elaborated the original trial design in these ways to strengthen our estimation of quality-adjusted survival, the primary outcome measure for CONSTRUCT.

We collect baseline data for all patients at recruitment to cohort, including:

Sociodemographic data

1. Age, sex, ethnic group and truncated postcodes, which will be used to generate measures of social deprivation (Index of Multiple Deprivation for England, Welsh Index of Multiple Deprivation for Wales, Carstairs’ Deprivation Scores for Scotland, Northern Ireland Multiple Deprivation Measure scores, and Townsend scores for all four countries).

Administrative data

• B. Admission details

Clinical data

• C. Disease history including presenting symptom, duration of disease since first diagnosis, previous medical and surgical treatments received, and details of any previous biological, concomitant or steroid therapies.

• D. Comorbidities in particular cardiorespiratory, liver and renal disease, diabetes and hypertension.

• E. UC symptoms and signs including duration of symptoms in current episode, stool frequency, blood pressure, pulse and temperature.

• F. Treatment including type, dose and duration of steroid therapy.

• G. Pathology results including full blood count, erythrocyte sedimentation rate, C reactive protein, γ-glutamyltransferase, glomerular filtration rate, albumin, liver function tests, urea, creatinine, electrolytes, total cholesterol and total bilirubin.

• H. Extent of disease and colonic area affected (Montreal classification of IBD32).

• I. Histopathology results including stool culture results and histological diagnosis.

• J. Family history of IBD.

• K. General: height, weight and smoking status.

Quality of life

• L. Quality of life (QoL) measures. The three QoL measures are administered as one questionnaire as soon as feasible following consent to the cohort; completion of these questionnaires by trial participants must precede randomisation to infliximab or ciclosporin.

Economic evaluation

Cost-utility analysis will use the EQ-5D to estimate quality-adjusted life years (QALYs) and estimated costs from an NHS perspective. Patient-level data on resource use in hospital over the 3.5 years of the study is monitored using GeneCIS and routinely collected data, supplemented where necessary by scrutiny of hospital medical records. These include drugs, drug-related complications, surgery, inpatient stay (in intensive care unit (ICU), high dependency unit (HDU) or ward) and outpatient clinic attendances. NHS resource use outside hospital, including all contacts with health professionals in primary care and the community, is estimated by the CONSTRUCT resource use questionnaire, which is registered on the Database of Instruments for Resource Use Measurement (DIRUM).33 We shall use current UK national prices where available from published sources34 to value these costs; or, if not, from the finance departments of participating sites. Patient-borne costs are estimated by additional questions at baseline, 3, 6 and 12 months, and potentially at 18, 24, 30 and 36 months, but will be reported separately from the cost-utilty analysis.

Qualitative study

We interview participants by telephone to understand their experiences and perceptions of treatment with infliximab or ciclosporin and other therapies for acute severe UC. We invited all participants to show their willingness to be interviewed on the trial consent form. We used purposive quota sampling to identify 12 consenters from each arm of the trial. This yielded a wide representation of therapy, age and sex of patients from a range of centres. We interview them twice—at about 3 and 12 months after they receive treatment.

First interviews follow a structured format to ensure consistency of data collection. The interviews investigate patients’ priorities for their health and well-being, ease of taking the drugs, side effects and response to treatment. Follow-up interviews use a similar schedule but include additional questions to explore what has happened to participants following treatment, including changes over time in their opinions of the treatment, their interactions with healthcare professionals, and their health.

We also interview healthcare professionals, by telephone or face-to-face, to understand their views about the two drugs, their administration and ease of handling. We have recruited 15 doctors and 9 nurses, stratified by number of patients recruited by their sites. These interviews address the ease of handling a range of drugs for UC, aspects of drug provision that might influence professional preference for one drug over another, and impressions of other professional contributions to treatment and care. This is particularly relevant if interviewing consultant and nurse at the same site. This will enable us to explore different professions’ ways of working, in particular in treating and administering drugs for UC, and thus professional interaction and psychological development.

Data management and record keeping

All data acquisition, storage and transmission comply with the Data Protection Act. The study uses the portfolio of standard operating procedures developed and maintained by the Swansea Clinical Trials Unit, WWORTH, and trains staff accordingly, especially in ensuring confidentiality.

We use our own securely hosted, generic clinical information system (GeneCIS) to support data handling and record keeping. Data are held in a remote, professionally managed repository and accessed over a virtual private network via the secure NHS N3 network. The system also supports data validation and facilitates quality assurance, and is backed up comprehensively every working day. We ask all patients to consent to data capture using this system, and to linkage of their electronically held routine data. Other data sources include participants’ medical records, pathology systems and routine data from HES, mortality data from ONS, and primary care systems. Participating sites have access only to identifiable data for those participants under their care, and cannot view any other records.

Aggregated data for analysis by the staff engaged in quantitative reporting are extracted in pseudonymised form. They do not have access to identifiable data and remain blind to treatment allocated and received until primary analysis is complete. In contrast qualitative researchers have access to identifiable data—non-clinical but not clinical. They audiotape and transcribe their qualitative data, and store them securely, identifying them only by the participant's trial number. The Trial Data Manager (TDM) is responsible for maintaining data quality, reporting on that to both TMG and DMEC, and supplying the DMEC with unblinded data in response to formal requests. Hence the TDM has access to all data, and will not contribute to analysis.

Analysis

Qualitative analysis

This addresses the last two objectives. We shall investigate patients’ priorities for their health and well-being, their experiences since treatment and their changing opinions of treatment. In parallel we shall explore healthcare professional views of the administration of infliximab and ciclosporin and the choice between them.

Telephone interviews with participants, both patients and professionals, will be recorded and transcribed. Transcripts will undergo rigorous analysis by standard thematic analysis based on the interview schedule and by schematic analysis of whole-page summations of transcripts.41 Thematic analysis is in keeping with a structured approach to data collection, whereby coding is used as the “method for conceptualising research data and classifying it into meaningful and relevant categories for participants in the study.”42

Three researchers will individually code transcripts from first-round interviews with patients as they are completed. When they have coded four interviews each, the researchers will work together to agree a coding structure and develop an analysis framework. The same analysis framework will be followed with all transcripts and data will be prepared for coding, including reading of all transcripts and familiarisation with data. The same process will be followed for the second-round interviews.

Three transcripts (one from a participant given infliximab, one given ciclosporin and one given ciclosporin followed by surgery) will also be taken forward to group analysis sessions for two reasons: to enhance the analysis framework by verifying if aspects are cogent and agreed by a wider group of analysts, and to give those analysing other study datasets an insight into the lives of people suffering from UC. Members of the study team will read the three transcripts and write three one-page overviews of the main features to tell the story of each participant's health and illness. There will then be a group discussion session to see if there is consensus and if the analysis framework is working. This iterative procedure ensures the validity of the analysis framework and its use.

Once agreement is reached and code saturation is achieved across transcripts, the remaining transcripts will be coded by two of the three original qualitative researchers using the adopted analysis framework. The analysis of the professional interviews will broadly follow the same structure.

Further analyses

No interim or subgroup analyses of trial outcomes are planned. We do plan to triangulate findings from different components of the study using the MATRICS approach.43

We hope to follow participants annually for up to 10 years by questionnaire and record linkage of routine data; the data thus obtained will identify future patterns of costs and effects following the treatment received by participants in the trial.