Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000654853
Ethics application status
Approved
Date submitted
25/02/2021
Date registered
31/05/2021
Date last updated
9/05/2024
Date data sharing statement initially provided
31/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Double-Blind, RandoMised, Placebo-Controlled Study to Assess the
Efficacy and Safety of oRal deliVery of sodium Pentosan Polysulfate (PPS)
compared to placebo in participants with symptomatic kneE osteoarthritis
(OA) and dysLipidemia (MaRVeL Study)
Scientific title
A Double-Blind, RandoMised, Placebo-Controlled Study to Assess the
Efficacy and Safety of oRal deliVery of sodium Pentosan Polysulfate (PPS)
compared to placebo in participants with symptomatic kneE osteoarthritis
(OA) and dysLipidemia (MaRVeL Study)
Secondary ID [1] 303542 0
Nil
Universal Trial Number (UTN)
U1111-1265-3750
Trial acronym
MaRVeL Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Musculoskeletal Knee Osteoarthritis 320889 0
Condition category
Condition code
Musculoskeletal 318705 318705 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
- Participants in both the active and placebo group will be provided with oral intervention capsules of Sodium Pentosan Polysulfate (PPS) or Placebo. Every single capsule is 300mg. Participants take the recommended dosage pre-calculated as per 10mg/kg of their actual body weight.
Cycle 1 of the intervention will commence at baseline for 5 weeks, followed by approximately 5 weeks without the medication.
Cycle 2 of the intervention will resume at week 11 and completes at week 16.
- There is no treatment crossover. This is the standard dosing regime used for the administration of Pentosan. The five-week cessation period is the same design used in the earlier Ethics approved successful PPS trial (Elmiron) 2019 / ETH11450. The participants take the same capsules as per their group allocation for both cycles.
- To measure adherence, each participant will be provided with an e-diary application installed on their mobile devices (smartphone or iPad) Alternatively, they will be able to use a paper diary. Diary will help participants to stay on track with the medication uptake schedule. Participants will be reminded to take study medication at a scheduled time point by push-up notifications set up within the e-diary application. Participants will be instructed to return all unused medication at the next study visit. The remaining capsules will be counted and recorded for the compliance check. Participants will be reminded to commence on the second 5 weeks course at week 11 by an email or a phone call from the study coordinator. Paper diaries or e-diary will be collected at each time point to ensure compliance is achieved.
Intervention code [1] 319836 0
Treatment: Drugs
Comparator / control treatment
The comparator is the microcrystalline cellulose hard gelatin capsules, 300 mg, which looks identical to the active PPS capsules in appearance but without the active ingredient.

Control group
Placebo

Outcomes
Primary outcome [1] 326652 0
Changes in 24-hour pain intensity numeric rating scale (NRS) at week 16
Timepoint [1] 326652 0
Week 16 post-intervention commencement
Secondary outcome [1] 392282 0
Change in 24-h Pain Intensity NR scale at week 6 and 26.
Timepoint [1] 392282 0
Week 6, and 26 post-intervention commencement
Secondary outcome [2] 392283 0
Change in KOOS pain subscale at week 6, 16, and 26.
Timepoint [2] 392283 0
Week 6, 16, and 26 post-intervention commencement
Secondary outcome [3] 392284 0
Changes in consumption of analgesic medications at week 6, 16, and 26.
Timepoint [3] 392284 0
Week 6,16 and 26 post-intervention commencement
Secondary outcome [4] 392285 0
Change in the patient global assessment (PGA) of disease activity from baseline to
week 6, 16, and 26.
Timepoint [4] 392285 0
Week 6, 16, and 26 post-intervention commencement
.
Secondary outcome [5] 392286 0
Change in health-related quality of life assessed using the Assessment of Quality
of Life eight dimension (AqoL-8D) from baseline to week 6, 16 and 26
Timepoint [5] 392286 0
Week 6, 16, and 26 post-intervention commencement
Secondary outcome [6] 392287 0
Change in MRI MOAKS Semi-quantitative measures from baseline to week 26.
Timepoint [6] 392287 0
Baseline and Week 26 post-intervention commencement
Secondary outcome [7] 392288 0
Change in fasting HDL/ LDL cholesterol, total cholesterol, and triglyceride levels
from baseline to week 26..
Note: It is a composite secondary outcome
Timepoint [7] 392288 0
Baseline and week 26 post-intervention commencement
Secondary outcome [8] 392289 0
AEs - assessed by inspection of weekly surveys. Mild effects of swelling, headache, dizziness, nausea, indigestion, or diarrhea may be observed in people taking active pentosan.
Timepoint [8] 392289 0
Weekly from baseline to Week 26 post-intervention commencement
Note: All participants are advised to report any adverse effects experienced by them in the online weekly surveys. Thorough monitoring is also done during the study visits.
Secondary outcome [9] 392290 0
Safety assessments – physical examination, clinical laboratory; assessments of
blood and urine;
Timepoint [9] 392290 0
Baseline to Week 26 post-intervention commencement. Weekly from baseline to week 26 post-intervention commencement, all weekly surveys assessed at week 26 post-intervention commencement,
Secondary outcome [10] 434883 0
Change in the KOOS function subscale at week 6,16 and 26
Timepoint [10] 434883 0
Secondary outcome [11] 434884 0
Change in the KOOS function subscale at week 6,16 and 26
Timepoint [11] 434884 0
Week 6, 16, and 26 post-intervention commencement.
Secondary outcome [12] 434885 0
Change in ultrasound scores from baseline to week 26.
Timepoint [12] 434885 0
Week 6, 16, and 26 post-intervention commencement.
Secondary outcome [13] 434886 0
Change in ultrasound scores from baseline to week 26.
Timepoint [13] 434886 0
Baseline visit and week 26 post-intervention commencement.

Eligibility
Key inclusion criteria
(1) Male or female patients with a minimum of 40 years of age;
(2) Are able to give written informed consent (e-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 hypercholesterolemia 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 visit and confirmation of OA based on the clinical and radiological criteria of American College of Rheumatology Criteria for OA (Altman et al, 1986) 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 six months of the screening visit;
(6) Have Index knee pain on most days over the last month.
(7) Knee Pain Severity Scale between 4 and 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 visit;
(9) Agree to maintain their usual activity level and diet throughout the study;
(10) Female of child-bearing 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;
(11) Must have internet access for online surveys;
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
E 1 Documented history of Fibromyalgia, Reiter’s syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease;
E 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 the last 6 months before screening.
E 3 Previous PPS therapy in last 6 months;
E 4 Known hypersensitivity to Pentosan Polysulfate or related compounds (e.g., heparins);
E 5 Any unstable concurrent clinically significant acute, chronic medical conditions or abnormal laboratory findings that, in the judgment 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;
E6 History of lymphoproliferative disease or any known malignancy of any organ system, interfere with the objectives of the protocol or affect the patient's compliance with the study requirements, as determined by the investigator;
E 7 Contraindications for MRI including but not limited to pacemaker, metal sutures, presence of shrapnel, or claustrophobia;
E 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;
E 9 Haemophilia;
E 10 Planned/anticipated invasive procedure (or surgery) within 6 months;
E 11 Any recent surgery (last 3 months)
E 12 Bilateral total knee replacement
E 13 Concurrent heparin or oral anticoagulant therapy;
E 14 Concurrent therapy with lipid-modifying drugs for hypercholesterolemia;
E 15 Female patients who are pregnant, nursing, or intend to get pregnant;
E 16 Use of prohibited medications such as:
NSAIDS (anti-inflammatory drugs like ibuprofen, Mobic);
Aspirin(>325 mg per day)
Centrally-acting pain medications (e.g pregabalin, gabapentin, duloxetine)
Opioids (e.g tramadol)
Topical therapies (e.g NSAIDs) applied to the index knee
Muscle relaxants (e.g diazepam)
lipid-modifying drugs: Statins like Lipitor, atorvastatin, pravastatin and simvastatin) or ezetimibe (Ezeterol);
Fenofibrates (e.g Antara, Fenoglide, Lipofen, Lofibra, TriCor, Triglide)
Anticoagulants like heparin, warfarin, apixaban (Eliquis), dabigatran (Pradaxa), and rivaroxaban (Xeralto);
Biological / disease-modifying anti-rheumatic drugs for arthritis;
muscle relaxants like diazepam;
Steroid drug for systemic use

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Concealment Mechanism and Blinding Arrangements:
After completing all baseline measures, the study coordinator at each site will notify the unblinded pharmacist who will then reveal the participant’s group allocation using the REDCap randomization module. An effort will be made to ensure the blind is not broken to the blinded study team.
The randomization survey in REDCap will be made available only to the unblinded pharmacist via user rights.
The study coordinators, study physicians, imaging readers, and study statistician will remain blinded to the treatment allocation until the main results are analyzed. Participants will not be told until the end of the study (6 months after baseline) which group they were allocated to. The unblinded pharmacist will dispense the capsules at Level 1 in the Royal North Shore clinical trials pharmacy. The study participants and coordinators will be blinded to group allocation. All clinical and MRI assessments will be conducted by an assessor blinded to treatment allocation.
The same dispensing process will be in place for the week 6 visit, which will be in consonance with the blinding of participants to their group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation:
Individuals who qualify and consent to take part in the study will be assigned to either an active or placebo group with a 1:1 allocation rate as per computer-generated randomization scheduled using random permuted block sizes and stratified by study site and radiographic disease severity (KLG 2 vs 3).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
This is a double-blind, randomized, placebo-controlled design study conducted at Royal North Shore Hospital in Sydney. The study will be conducted on male and female participants 45 years of age with symptomatic knee osteoarthritis and dyslipidemia. All participants will be asked to take either Sodium Pentosan Polysulfate capsules or placebo (as per the group allocation), starting at baseline for two 5-week cycles of intervention with 5 weeks “no medication” period in between the cycles.
Efficacy and safety of PPS will be evaluated in comparison with Placebo at 4-time points: week 6, week 11, week 16, and EOS/week 26.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A qualified biostatistician who will be blinded to the group allocation will perform the statistical analysis. The primary analysis will be according to the intention-to-treat principle (ITT).
Descriptive statistics of demographic characteristics and baseline scores will be provided; continuous variables will be summarised in terms of means and standard deviation (SD) where appropriate or median (range), categorical variables will be presented as frequency (percentage).
The baseline and week 26 NR scores will be summarised as mean and standard deviation. The change in scores from baseline and week26 assessment will be summarised as mean with corresponding 95% confidence intervals and assessed using a paired t-test.
Secondary outcomes will be summarised in terms of means and standard deviation at each time point and the change in outcome between baseline and follow-up assessments will be summarised in terms of mean (95% CI) and assessed using a paired t-test. To investigate the relationship between the change in lipid levels and change in clinical outcomes across assessments, general estimating equation (GEE) models will be used including time, clinical outcome, and adjusting for baseline lipid level. Co-variables of interest will include lipids change, NR pain scores, and BMI. Progression of symptoms, BMLs, synovitis, effusion score will also be examined.
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) may be employed.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/06/2022
Actual
5/07/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
92
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 18818 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 33269 0
2065 - Royal North Shore Hospital
Recruitment postcode(s) [2] 33268 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 307966 0
Commercial sector/Industry
Name [1] 307966 0
Arthropharm Pty Ltd
Country [1] 307966 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney, Research Portfolio, Level 3, Administration Building (F23), City Rd, Camperdown, NSW 2006.
Country
Australia
Secondary sponsor category [1] 308682 0
None
Name [1] 308682 0
Address [1] 308682 0
Country [1] 308682 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307960 0
Northern Sydney Local Health District
Ethics committee address [1] 307960 0
NSLHD Research Office, Level 13 Kolling Building, Royal North Shore Hospital, Reserve Road, St Leonards, NSW, 2065
Ethics committee country [1] 307960 0
Australia
Date submitted for ethics approval [1] 307960 0
25/02/2021
Approval date [1] 307960 0
22/04/2021
Ethics approval number [1] 307960 0
2021/ETH00315

Summary
Brief summary
Estimated to affect one in eight adults, osteoarthritis (OA) is a highly disabling disease resulting in the unsurpassed risk for mobility disability, especially in those above 65 years of age. Medical treatments for OA have mainly targeted the symptoms of the disease, rather than the underlying pathologies responsible. Pain management with analgesics and steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) were, and still remain, the mainstay of treatment with joint replacement the only option for end-stage OA. There is no evidence that steroidal or NSAIDs provide any beneficial effects on the underlying pathologic 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). Hypercholesterolemia was associated with both unilateral and bilateral knee OA and high serum cholesterol and/or triglycerides were associated with both knee and generalized OA. 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. 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 a limited anti-coagulant activity.
In human patients, a recent pilot open-label study (ACTRN12619000047190) conducted by the University of Sydney aimed to target dyslipidemia in OA participants by oral administration of PPS. Pain and function information from participants were collected to determine if improvements in dyslipidemia would also result in clinical improvements of symptoms associated with knee osteoarthritis. 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 outcomes and severity knee pain score, measured using KOOS and NRS scale together. The self-reported pain, stiffness, and functional outcomes show a significant positive improvement. This indicates good potential for the further randomized double-blinded placebo-controlled study to demonstrate the beneficial effects of PPS in knee osteoarthritis clinical outcomes.
Trial website

Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 109050 0
Prof David Hunter
Address 109050 0
Florance and Cope Chair of Rheumatology, Professor of Medicine, Rheumatologist
Level 10, Institute of Bone and Joint Research, Kolling Institute,
10 Westbourne St,
Royal North Shore Hospital
St. Leonards, NSW 2065
Country 109050 0
Australia
Phone 109050 0
+61 2 94631887
Fax 109050 0
+61 2 94631077
Email 109050 0
david.hunter@sydney.edu.au
Contact person for public queries
Name 109051 0
Mrs Sonika Virk
Address 109051 0
Rheumatology Department
Acute Services Building
Clinical Administration 7C
Royal North Shore Hospital,
Reserve Road, St. Leonards
NSW 2065
Country 109051 0
Australia
Phone 109051 0
+61 2 9926 7821
Fax 109051 0
+61 2 9463 1077
Email 109051 0
sonika.virk@sydney.edu.au
Contact person for scientific queries
Name 109052 0
Prof David Hunter
Address 109052 0
Florance and Cope Chair of Rheumatology, Professor of Medicine, Rheumatologist
Level 10, Institute of Bone and Joint Research, Kolling Institute,
Royal North Shore Hospital
10 Westbourne St,
St. Leonards, NSW 2065
Country 109052 0
Australia
Phone 109052 0
+61 2 94631887
Fax 109052 0
+61 2 94631077
Email 109052 0
david.hunter@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.