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)
The University of Sydney
92 participants
Jul 5, 2023
Interventional
Conditions
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.
Eligibility
Inclusion Criteria12
- (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 twelve 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;
Exclusion Criteria28
- 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
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Interventions
- 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, participant's will receive an SMS dosage reminder and will be asked to confirm adherence by completion of a survey in REDCap 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.
Locations(1)
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ACTRN12621000654853