Article Text

Protocol
Efficacy and safety of pentosan polysulfate sodium in people with symptomatic knee osteoarthritis and dyslipidaemia: protocol of the MaRVeL trial
  1. Md Abu Bakar Siddiq1,2,
  2. Xiaoqian Liu1,2,
  3. Tatyana Fedorova3,
  4. Karen Bracken2,4,
  5. Sonika Virk1,2,
  6. Venkatesha Venkatesha5,
  7. Abdolhay Farivar1,2,
  8. Win Min Oo6,7,
  9. James Linklater8,
  10. David Cullis Hill9,
  11. David J Hunter1,2
  1. 1Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, Australia
  2. 2Sydney Musculoskeletal Health, The University of Sydney, Sydney, New South Wales, Australia, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia
  3. 3The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, Australia
  4. 4Musculoskeletal Health, Arabanoo Precinct, Kolling Institute, The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, Australia
  5. 5Rheumatology Department, Royal North Shore Hospital, St Leonards, New South Wales, Australia
  6. 6Rheumatology, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia
  7. 7University of Medicine, Mandalay, Mandalay, Myanmar
  8. 8Castlereagh Imaging, St Leonard, NSW, St Leonard, New South Wales, Australia
  9. 9Arthropharm Pty Ltd, St Leonard, New South Wales, Australia
  1. Correspondence to Dr Md Abu Bakar Siddiq; msid8426{at}uni.sydney.edu.au

Abstract

Introduction Knee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain relief; growing evidence suggests pentosan polysulfate sodium (PPS) is chondroprotective and could have anti-inflammatory effects in knee OA. This study aims to explore the efficacy and safety of oral PPS in symptomatic knee OA with dyslipidaemia.

Methods and analysis MaRVeL is a phase II, single-centre, parallel, superiority trial which will be conducted at Royal North Shore Hospital, Sydney, Australia. 92 participants (46 per arm) aged 40 and over with painful knee OA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) will be recruited from the community and randomly allocated to receive two cycles of either oral PPS or placebo for 5 weeks starting at baseline and week 11. Primary outcome will be the 16-week change in overall average knee pain severity measured using an 11-point Numeric Rating Scale. Main secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life and other structural changes. A biostatistician blinded to allocation groups will perform the statistical analysis according to the intention-to-treat principle.

Ethics and dissemination The protocol has been approved by the NSLHD Human Research Ethics Committee (HREC) (2021/ETH00315). All participants will provide written informed consent online. Study results will be disseminated through conferences, social media and academic publications.

Trial registration numbers Australian New Zealand Clinical Trial Registry (ACTRN12621000654853); U1111-1265-3750.

  • Clinical Trial
  • Knee
  • Osteoarthritis
  • PAIN MANAGEMENT
  • Phase II as Topic
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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • The MaRVel trial is an investigator-initiated, single-centre, placebo controlled randomised clinical trial with robust methodology assessing clinical and imaging endpoints which will provide high-quality evidence in examining the efficacy of oral pentosan polysulfate sodium in people with symptomatic early to moderate knee osteoarthritis (OA) with dyslipidaemia.

  • The trial includes both online screenings and study site visits of study participants maximising the recruitment efficiency.

  • The trial will only include patients with knee OA grades 2 and 3 limiting the generalisability of the research outcome to all grades of knee OA.

  • This will be a single-site study in Australia with a limited number of patients restricting the generalisability of the gained information to patients from all territories.

Introduction

Background and rationale

Osteoarthritis (OA) is a highly disabling disease resulting in an unsurpassed risk for mobility disability, especially in those above 65 years of age.1 2 Medical treatments for OA have mainly targeted the symptoms of the disease, rather than the underlying pathologies responsible. Pain management with analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) were, and still remain, the mainstay of treatment,3 4 with joint replacement a frequently used option for end-stage OA.5 There is no evidence that commonly used analgesics provide any beneficial effects on the underlying pathological abnormalities which exist in OA joints.

Dyslipidaemia is the presence of abnormal concentrations of lipoproteins in the blood; more specifically, high levels of low-density lipoproteins (LDLs) and, usually, low levels of high-density lipoproteins (HDLs).6 Hypercholesterolaemia is associated with both unilateral and bilateral knee OA7 and high serum cholesterol and/or triglycerides were associated with both knee and generalised OA.8–10 OA radiographic severity is independently associated with LDL-cholesterol11 and hypertriglyceridaemia is associated with a higher intensity of OA knee pain, independent of weight.12 13 A dysregulated lipid profile in the synovial fluid of OA patients has been observed and correlated with inflammatory parameters in the OA joint cavity.14

Dietary cholesterol can cause OA development in mice15 16 and increased synovial pro-inflammatory cytokines during experimental murine OA was associated with high LDL levels.17 18 Reducing cholesterol accumulation attenuated the severity of OA in mice in vivo and decreased the expression of proteases in human OA cartilage in vitro.19 Dyslipidaemia-induced deregulation of cellular lipid metabolism in joint tissues might, therefore, initiate OA development.20

The implication of dyslipidaemia and the lack of a disease-modifying agent for OA displays a potential gap where pentosan polysulfate sodium (PPS) may be of benefit. PPS has been used in Europe as an antithrombotic/lipolytic agent for more than 45 years and is currently approved in Australia as an oral treatment in humans for interstitial cystitis (Elmiron).

PPS mediates the release, from endothelial cells and the liver, of lipoprotein lipases, which split triglycerides into free fatty acids and glycerol, providing a lipolytic effect.21 When injected into horses, PPS at 1.3 mg/kg body weight significantly increased plasma total lipase activity.22 Administration of PPS to hyperoxaluric rats reduced tissue cholesterol and triglyceride levels significantly.23 Since the beneficial effect of pain relief and preservation of joint tissues is sustained after a 4-week course in animals and there are reports of PPS accumulating in a number of tissues/cells (eg, monocytes, macular of the retina), a break from dosing will give the recipient time to clear any accumulated drug, thus reducing side effects without affecting the efficacy.24–27 In any case, a break will allow the tissues to clear any accumulation of drug; the 5-week gap thus allows any potential accumulation of drug to dissipate, thus reducing any long-term side effects.

PPS has other useful properties for the amelioration of the pathophysiology and symptoms of OA. It inhibits the formation of activated factor Xa, resulting in limited anticoagulant activity (about 1/15 that of heparin).28 PPS further mobilises plasminogen activator, accounting for its fibrinolytic activity.29 In animal models of OA, PPS has been shown to have wide-ranging anti-inflammatory and chondroprotective actions.30–35

In human patients, a recent pilot open-label study (ACTRN12619000047190) conducted by the University of Sydney aimed to target dyslipidaemia in OA participants by oral administration of PPS.36 Pain and function information from participants were collected to determine if improvements in dyslipidaemia would also result in clinical improvements in symptoms associated with knee OA. The study outcomes revealed oral PPS significantly improved pain, stiffness and other functional measures in these patients. The study’s secondary outcomes also showed a statistically significant decrease in total and LDL cholesterol and a positive change in self-reported pain, stiffness and functional outcomes.36 This indicates good potential for further randomised double blinded placebo-controlled studies to demonstrate the beneficial effects of PPS in knee OA clinical outcomes.

This study aims to assess the effect of oral delivery of PPS compared with placebo on pain in participants with symptomatic knee OA and dyslipidaemia.

Methods and analysis

Study design

The MaRVeL study is a phase II, 26-week, double-blind, randomised, placebo-controlled, single-centre, parallel, superiority trial with equal allocation between the two treatment arms (PPS or placebo) (figure 1). The Standard Protocol Items: Recommendations for Interventional Trials guidelines are followed for the clinical trial protocol (https://www.spirit-statement.org/) and the trial reporting will be reported according to Consolidated Standards of Reporting Trials guidelines (http://www.consort-statement.org/) (online supplemental file 1 full study protocol version 6, 9 November 2023).

Figure 1

Study visits and procedures.

Study setting

The MaRVeL trial is sponsored by the University of Sydney and will be conducted at Royal North Shore Hospital (RNSH), North Sydney Local Health District (NSLHD) in collaboration with Kolling Institute of Medical Research, University of Sydney and Castlereagh Imaging (St Leonards and Cremorne), Sydney, Australia.

Participants and eligibility criteria

92 participants (46 per arm) with symptomatic knee OA with dyslipidaemia (elevated cholesterol, >5.0 mmol/L) will be recruited from the community. The recruitment strategies will include: (a) inviting people from existing research database (REDCap, Research Electronic Database Capture), (b) NSLHD corporate communication channels: NSLHD Facebook, flyers or posters placed on the RNSH notice boards, advertising on NSLHD intranet, (c) local social clubs (such as RSL, Probus club, bowls clubs, university of the 3rd Age, the Men’s shed), (d) The University of Sydney digital social media communication channels: Kolling staff e-newsletters, Facebook, Twitter, (e) Radio, Podcasts or TV, (f) social media advertising including Facebook and Instagram. Eligible participants will be those aged 40 years or over, with a history of primary hypercholesterolaemia and total fasting cholesterol >5.0 mmol/L, symptoms of OA for ≥6 months, pain in index knee most days in the past month, knee pain severity 4–9 on 11-point (0–10) numerical severity scale, clinical and radiological confirmation of knee OA37 and meeting all other inclusion criteria and no exclusion criteria as detailed in box 1.

Box 1

Eligibility criteria of the study participants

Inclusion criteria

1. Male or female patients with a minimum of 40 years of age.

2. Are able to give written informed consent and to participate fully in the interventions and follow-up procedures including travel to the Royal North Shore Hospital.

3. Have a history of primary hypercholesterolaemia and total fasting cholesterol above 5.0 mmol/L at screening.

4. Have any symptoms associated with OA of the knee for at least 6 months prior to screening and confirmation of OA based on the clinical and radiological criteria of American College of Rheumatology Criteria for OA37 of the knee prior or at screening.

5. Kellgren-Lawrence (K-L) grade 2 or 3 in the index knee based on knee radiograph performed at screening or within 6 months of the screening visit.

6. Have index knee pain on most days over the last month.

7. Knee Pain Severity Scale of 4–9 (inclusive) using an 11-point (0–10) numerical severity scale where 0 is no pain at all and 10 is worst possible pain in the last 24 hours at baseline visit; if both knees are affected by OA, then the most symptomatic knee will be considered the index knee. If both knees are equally affected, the index knee will be determined by the investigator.

8. BMI<40 kg/m2 at screening.

9. Agree to maintain their usual activity level and diet throughout the study.

10. Female of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.

Must have internet access for online surveys.

Exclusion criteria

  1. Documented history of Fibromyalgia, Reiter’s syndrome, ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, palindromic rheumatism or other types of the inflammatory arthritis or arthritis associated with inflammatory bowel disease.

  2. IA injections of cortisone into any joint within 3 months, IA injection of hyaluronic acid, PRP, regenerative medicine or arthroscopy of the index knee within last 6 months before screening.

  3. Previous PPS therapy in the last 6 months.

  4. Known hypersensitivity to pentosan polysulfate or related compounds (eg, heparins).

  5. Any unstable concurrent clinically significant acute, chronic medical conditions or abnormal laboratory findings that, in the judgement of the investigator, would jeopardise the safety of the patient, interfere with the objectives of the protocol or affect the patient’s compliance with the study requirements, as determined by the investigator.

  6. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years of screening 1 (except for basal cell carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the past 3 months, or carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed).

  7. Contraindications for MRI, including but not limited to pacemaker, metal sutures, presence of shrapnel or claustrophobia.

  8. Current or a recent history (within last 12 months) of bleeding (a gastric or duodenal ulcer or suspicion of GI tract bleeding) or menorrhagia.

  9. Haemophilia.

  10. Planned/anticipated invasive procedure (or surgery) within 6 months.

  11. Any recent surgery (last 3 months).

  12. Bilateral total knee replacement.

  13. Concurrent heparin or oral anticoagulant therapy.

  14. Concurrent therapy with lipid-modifying drugs for hypercholesterolaemia.

  15. Female patients who are pregnant, nursing or intend to get pregnant.

  16. Use of prohibited medications.

  • BMI, body mass index; GI, gastrointestinal; IA, intra-articular; OA, osteoarthritis.

Treatment

Participants will receive either PPS (Arthropharm) (300 mg capsules) or matched placebo (300 mg). The dose of PPS will be calculated at 10 mg/kg on baseline body weight. The calculated dose will be taken two times per week over the two 5-week cycles—cycle 1 of the intervention will commence at baseline for 5 weeks, followed by approximately 5 weeks without the medication, and cycle 2 of the intervention will resume at week 11 and complete at week 16 after which no continuing access to the study treatment will be available.

Randomisation, allocation and blinding

Eligible and consenting individuals will be randomised in the REDCap system to either active or placebo group with a 1:1 allocation rate as per computer-generated randomisation schedule using random permuted block sizes and stratified by radiographic disease severity (Kellgren and Lawrence grade, KLG 2 or 3).

A single unblinded member of the study team who performs the randomisation, and the trial unblinded pharmacist will be aware of each participant’s group allocation but will not be involved in assessments. The study coordinators, participants, physician, imaging readers and study statistician will remain blinded to the treatment allocation until the main results are analysed. Emergency unblinding may be approved by the study physician if medical care cannot be provided without knowing the treatment assignment.

Concomitant and excluded medications and care

Participants will be asked to discontinue NSAIDs and other analgesics for knee pain from 7 days prior to baseline assessment until the 26 weeks follow-up assessment, except for paracetamol (maximum daily dose 3000 mg) as rescue pain relief. However, participants will be advised that no paracetamol is to be taken for 24 hours prior to knee pain assessments at baseline and follow-up visits.

The following medications and interventions will be prohibited during the study: (a) oral NSAIDs; (b) aspirin (>325 mg per day); (c) centrally acting pain medications (eg, pregabalin, gabapentin, duloxetine); (d) opioids (eg, tramadol); (e) topical therapies (eg, NSAIDs) applied to the index knee; (f) muscle relaxants (eg, diazepam); (g) lipid-modifying drugs: statins (eg, atorvastatin, pravastatin and simvastatin) or ezetimibe (Ezetrol); (h) fenofibrates (eg, Antara, Fenoglide, Lipofen, Lofibra, TriCor, Triglide); (i) anticoagulants including heparin, warfarin, apixaban, dabigatran (Pradaxa) and rivaroxaban; (j) biological/disease-modifying antirheumatic drugs for arthritis; and (k) systemic steroid.

Outcome measures

Primary

Change from baseline to 16 weeks in Numeric Rating Scale (NRS) scores for pain, a segmented numeric version of the Visual Analogue Scale (VAS) in which the participant selects a whole number (0–10 integers) that best reflects the intensity of their pain in a 24-hour period.36

Secondary

  1. Change from baseline in 24-hour pain intensity on NRS at week 6 and 26.36

  2. Knee Injury and Osteoarthritis Outcome Score (KOOS) at weeks 6, 16 and 26.38

    • Pain subscale (total nine items): scores are transformed to a 0–100 scale, with 0 representing extreme knee problems and 100 representing no knee problems as common in orthopaedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved.

    • KOOS function subscale (total 17 items): scores are transformed to a 0–100 scale, with 0 representing extreme knee problems and 100 representing no knee problems as common in orthopaedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved.

  3. Changes in consumption of analgesic medications in weekly online surveys.

  4. Change from in Patient Global Assessment (PGA) of disease activity at weeks 6, 16 and 26: PGA will be assessed using the question ‘Considering all the ways your knee osteoarthritis affects you, how have you been during the past week?’ along with a 0–100 VAS, where 0 is very well and 100 is very poor.

  5. Assessment of Quality of Life (AQoL) Eight Dimensions (AQoL-8D): the AQoL-8D is the latest revision of a multi-attribute utility tool used to measure well-being parameters with an emphasis on psychosocial components of health. AQoL-8D has 35 items composed of two super dimensions of physical and mental health or eight dimensions: independent living, pain, senses, mental health, happiness, coping, relationships and self-worth. Thirty-five questions on eight dimensions of physical and psychosocial QoL over the last week contribute to the score: score ranged between 0 and 100, higher the scores better the QoL.39

  6. MRI Osteoarthritis Knee Score (MOAKS) semi-quantitative score36 38 40: the MOAKS is developed and tested on images obtained on a 3.0T MRI system with a dedicated peripheral knee coil. The subscores of knee structural changes are detailed as below: (a) change in the number of areas with worsening in cartilage thickness categorised as 0, 1, 2 or ≥3; (b) worsening in osteophytes scored in each of the 12 locations according to size and graded as: grade 0 (no osteophyte), grade 1 (small osteophyte), grade 2 (medium osteophyte), grade 3 (large osteophyte); (c) change in bone marrow lesions on medial tibial and medial femoral condyle regions will be documented on the qualitative scoring (0–3 per region); (d) worsening in meniscal morphology features scored on medial and lateral meniscus for the anterior, body and posterior horn and graded as: grade 0 (meniscal extrusion <2 mm), grade 1 (meniscal extrusion, 2–2.9 mm), grade 2 (meniscal extrusion, 3–4.9 mm) and grade 3 (meniscal extrusion >5 mm); (e) change in whole knee effusion (effusion—synovitis) categorised as grade 0 (physiological volume), grade 1 (small—fluid continuous in the retro-patellar space), grade 2 (medium—slight convexity of the suprapatellar bursa) and grade 3 (large—evidence of capsular distension); (f) change in infrapatellar fat pad synovitis (Hoffa’s synovitis) categorised as: grade 0 (normal), grade 1 (mild), grade 2 (moderate) and grade 3 (severe). The details of MRI machines, dedicated knee coils and acquisition sequences are specified in online supplemental file 2.

  7. Change from baseline in fasting HDL/LDL cholesterol, total cholesterol and triglyceride levels at week 26.

  8. Adverse events will be assessed by inspection of weekly online surveys.

  9. Safety blood and urinary profile: full blood count, liver function tests, fasting lipids, glucose, electrolytes, urea and creatinine and C reactive protein, prothrombin time, activated partial thromboplastin time, international ratio, D-dimer, faecal occult blood test, lipoprotein(a), Gamma Glutamyl Transferase, will be done at RNSH pathology.

Exploratory outcomes

  1. Bone turnover markers such as alkaline phosphatase, bone-specific alkaline phosphatase, bone Gla protein (Osteocalcin) and serum collagen breakdown products, for example, C-telopeptide of type 1 collagen, N-telopeptide of type 1 collagen (NTX1), N-terminal propeptide of type 1 procollagen (P1NP), interleukin 6 (IL-6), plasminogen activator inhibitor 1, alpha-2A adrenergic receptor and urine (NTX1) turnover markers36 change will be measured at an accredited research laboratory at Arthropharm PTY at baseline and week 26.

  2. Concurrent and predictive validity of ultrasound (osteophyte, synovial effusion, synovial thickness, medial meniscal extrusion, synovitis score and power Doppler activity) against NRS pain, physical function and QoL measures will be done. Treatment effects on ultrasound measures will also be demonstrated. To define ultrasound features, Outcome Measures in Rheumatology guidelines will be followed41: semiquantitative scores for synovitis (0–3, combined synovial hypertrophy and effusion), osteophytes (0–3, medial and lateral joint aspects in a longitudinal plane), meniscal extrusion (0–2, medial joint aspects, in a longitudinal plane) and cartilage abnormalities (0–3, on transverse plane in maximally flexed knee); binary scores (0–1) for synovial hypertrophy (≥4 mm), effusion (≥4 mm) and power Doppler (PD) signals separate from suprapatellar recess in a longitudinal plane, medial and lateral para-patellar recesses in a transverse plane. Fixed ultrasound machine settings will be greyscale gain, probe frequency, Doppler frequency, Doppler gain, pulse repetition frequency and wall filter; however, physicians can adjust depth and focus. The maximum score approach, for example, the highest score of synovitis and osteophyte from a wide scanning area will be documented as the final score of the whole knee.

Other outcomes

  1. Investigational product (IP) accountability and compliance at weeks 6 and 16.

  2. Likelihood of a neuropathic pain component being present in individual patients with chronic knee pain OA will be assessed at baseline by painDETECT Questionnaire.42 43

  3. Individual patient personality and psychological characteristics associated with the placebo response assessed by the Multidimensional Psychological Questionnaires at screening (prebaseline), baseline and week 11. The questionnaires are self-reported by participant and each item is rated on a 5-point scale ranging from 1 (strongly disagree) to 5 (strongly agree).44 45

  4. Patient satisfaction with allocated treatment which will be assessed by the Medication Satisfaction Questionnaire at the end of the study.

Trial endpoints

Primary endpoint will be change in NRS from baseline to week 16. Secondary outcome measures will be measured at weeks 6, 16 and 26 and are outlined in table 1.

Table 1

Trial end points

Patient and public involvement

A patient focus group has not been formed. An open-level, non-randomised pilot study has been previously performed and published and informed the design of this study.

Study procedures

An outline of the study events and procedures is summarised in table 2.

Table 2

Assessments and study visits

Screening

The study overview will be placed on the Osteoarthritis Clinical Research Group website and promoted through social media platforms and other avenues. Electronic consent will be sought before collecting any personal details such as demographic, general medical history, history of knee OA and medication through the online screening survey.

Potential candidates will have access to the participant information sheet (PIS) and can ask questions by email before providing their informed consent. All responders will be provided with a copy of the PIS, the digitally signed informed consent and will be informed of whether or not they are eligible to participate in the study.

The study coordinator will contact potentially eligible candidates to check their study-related details and provide them with a link to the NRS knee pain survey to self-report their 24 hours knee pain after completion of 7 days NSAIDs washout period, if applicable. Potential participants will then be referred for fasting blood and urine tests, and knee X-ray for final eligibility check.

Radiological evaluation will be conducted on weight-bearing bilateral knee X-ray within the previous 12 months. The study physician will evaluate the radiographic images for OA severity using KLG and American College of Rheumatology criteria.37 If both knees meet the eligibility criteria, the most symptomatic knee will be marked as the study knee. Participants, in whom study knee KLG 2–3, cholesterol >5 mmol/L is confirmed, and who meet all the inclusion criteria and none of the exclusion criteria will be invited to attend the baseline study visit.

Baseline visit

After completing a medication wash-out, the participant will complete a series of prebaseline questionnaires online before attending the baseline visit at the site. Eligibility will be confirmed during the baseline visit, height and weight will be measured, and a series of further pain questionnaires will be completed. Following confirmation of eligibility, participants will be randomised, blood samples will be collected for biomarker testing and the participant will undergo an MRI and ultrasound. The participant will be dispensed the IP as per the group allocation to be orally taken for the next 5 weeks. The IP is recommended to be taken either 1 hour before the meals or 2 hours post meals for effective absorption.

On-study surveys

Participants will complete weekly online surveys on knee pain, use of pain medication and AEs throughout the study period.

Follow-up visits

Participant will attend for follow-up visits at 6, 16 and 26 weeks after baseline visit. At week 6, IP compliance and accountability checks will be conducted. Participants will be dispensed IP for cycle 2 to start at week 11. Blood and urine samples will be collected, and participants will complete the pain questionnaires.

No IP is taken from weeks 6 to 11. The second cycle of the intervention will start at week 11 and continue to week 16. A MPsQ questionnaire will be completed online before the first dose of the second cycle of intervention. Participants will return to the site for week 16 visit for collection of blood and urine samples and the pain questionnaires will be administered.

Participants will return to the site for the end of study visit at week 26. Blood and urine samples will be collected at this visit and subjects will complete the questionnaires. MRI and ultrasound scans of the study knee will also be performed.

Safety monitoring

Participants will be monitored for AEs through weekly online surveys and at each study visit. All AEs from the time of informed consent until the participant completes or withdraws from the study will be recorded, included the start and end date, details of the event, any actions taken and the outcome. The study physician will assess the severity of each AE and expedited reporting will be in accordance with regulatory and Human Research Ethics Committee (HREC) requirements and National Health and Medical Research Council guidelines. On-study pathology results will be reviewed by study physician and any abnormal test results will be further assessed as clinically significant or non-clinically significant. A Data and Safety Monitoring Board will review unblinded safety information bi-annually and will provide recommendations regarding continuation of the trial to the coordinating principal investigator.

Participants retention and withdrawal

Survey reminders, emails, phone calls and gift vouchers will be implemented to maximise participants’ participation. Participants who do not complete the surveys and are unable to be reached will be considered as dropouts. Participants can choose to leave the study at any time and will be asked to provide their reason for withdrawal. Regular data updates online are designed to maximise participant retention. If a participant chooses to stop their involvement completely, no further data will be collected from this participant, but previously collected data will be included in the analysis. Participants who withdraw from the study will not be replaced.

Statistical methods

Sample size estimation

The primary outcome will be the 16-week change in overall average knee pain severity over the last week measured using an 11-point NRS. The minimum clinically important difference to be detected in OA trials is a change in pain of 1.8 units (out of 10).46 A between-participant SD of change in pain of 2.4 and baseline to follow-up correlation in scores of 0.296 has been assumed. To estimate an effect size of 0.2 with a power of 80%, 29 study participants are required per study arm. Accounting for 20% non-compliance, the sample size has been calculated at 92 participants (46 per study arm).

Statistical analysis plan

A biostatistician blinded to the group allocation will perform the statistical analysis according to the intention-to-treat principle. Descriptive statistics of demographic characteristics and baseline scores will be provided. Continuous variables will be summarised in either mean and SD (normal data distribution) or median (range) (skewed data); categorical variables will be presented as frequency (percentage).

To investigate the relationship between the change in lipid levels and change in clinical outcomes across assessments, generalised estimating equation models will be used including time, clinical outcome and adjusting for baseline lipid level. Covariables of interest will include lipids change, NRS pain scores and body mass index. Comparison of pretreatment and post-treatment NRS and KOOS pain scores will be done between treatment arms preintervention and postinterventions. Change in mean NRS and KOOS pain subscores from baseline to weeks 6, 16 and 26 will be measured, and p<0.05 will be considered the level of statistical significance (at 95% CI).

As ultrasound is subject to interobserver variability, Cohen’s kappa (k) coefficient will be used to measure the intrarater and inter-rater reliability: 0.01–0.20 (none to slight agreement), 0.21–0.40 (fair agreement), 0.41–0.60 (moderate agreement), 0.61–0.80 (substantial agreement) and 0.81–1.00 (perfect agreement).47 Correlation coefficient (r) will be done to assess correlation between continuous variables. The predictive value of ultrasound and MRI about symptom improvement will be done using regression analysis. Where normality assumptions are not met, appropriate transformations of the data may be applied or other strategies (use of categories and/or non-parametric tests) will be employed.

Data management

All questionnaires and other study data will be collected using REDCap, a secure web-based application hosted by the University of Sydney. Regular self-monitoring of data entry will maximise data quality. After study close-out, a copy of the complete dataset will be stored at the University of Sydney Research Data Store. A de-identified dataset containing individual participant data of those who provided extended and non-specific consent will be published in an open-access data repository by the principal investigator 3 years after study close-out for sharing purposes. Frozen bio-specimen samples will be de-identified and stored in a – 80°C freezer for later testing at study completion. Only study staff will have access to these samples. The University of Sydney will be the custodian of the study data and biospecimens.

Ethics and dissemination

The protocol has been approved by the Northern Sydney Local Health District HREC (2021/ETH00315). Any modification of the protocol will be submitted to the HREC for approval. Dissemination of study results based on non-identifiable data will be in the form of plain-English summary, infographics, conferences and scientific publications.

Timelines

Enrolment commenced in June 2023 and is expected to be completed in mid to late 2024 with the final participant visit expected in early 2025.

Ethics statements

Patient consent for publication

Acknowledgments

We are thankful to the patient representatives and participants in the preceding open label trial for their valuable feedback on the study procedures and relevant documents. Arthropharm PTY is a Sydney-based pharmaceutical company that has agreed to supply investigational products (Pentosan Polysulfate for active cases; placebo for controls) to be used in the trial at no cost. However, the pharmaceutical company will not have any contribution to the data analysis, interpretation, preparation and submission of the manuscript to the journals for publication.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • X @ProfDavidHunter

  • Contributors DJH is the grant holder and conceived of the study. MAB drafted the paper. DJH, XL, TF, SV, KB, VV, AF, WMO, JL, DCH contributed to the study design. All investigators including MAB, DJH, XL, SV, KB, VV, AF, WMO, JL, DCH revised this protocol critically for important intellectual content. TF, KB and SV will be responsible for the implementation.

  • Competing interests DJH is supported by an NHMRC Practitioner Fellowship and provides consulting advice for Haleon, Novartis, TLC Bio, Tissuegene, Lilly and Pfizer.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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