A 2-stage, Adaptive, Randomised, Double-blind, Placebo-controlled, Multicentre Study to Evaluate Dose and Treatment Effect of Pentosan Polysulfate Sodium Compared with Placebo in Participants with Knee Osteoarthritis Pain
- Trial ID
- 2022-500228-31-00
- Protocol
- PARA_OA_002
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the treatment effect of **Pentosan Polysulfate Sodium (PPS)** on knee pain and function in participants with knee osteoarthritis pain. This is clinically relevant as knee osteoarthritis is a prevalent condition that significantly impacts mobility and quality of life, and effective treatments are essential for managing symptoms and improving patient outcomes.
Secondary objectives include evaluating the treatment effect of PPS on knee pain and function, with function being included as a co-primary endpoint for regulatory purposes by the European Medicines Agency (EMA) and the Medicines and Health Product Regulatory Agency (MHRA), but still tested in hierarchical order. This assessment is crucial for understanding the comprehensive impact of PPS on both pain relief and functional improvement in affected individuals.
Participants
The clinical trial involves a total of **858 participants** who are experiencing **knee osteoarthritis pain**. The study population includes both male and female participants aged 18 years or older. Participants were selected based on a clinical diagnosis of osteoarthritis in the index knee, confirmed by radiographic evidence and classified as K-L Grade 2, 3, or 4. The trial specifically targets individuals whose osteoarthritis pain in the index knee has been unresponsive to conservative therapy for at least six months prior to screening. Participants are required to have an average pain subscale score of 4 to 10 in the index knee at screening, with a minimum pain score of 4 on specific activities such as walking on a flat surface or climbing stairs. Additionally, an average function subscale score of 4 to 10 is required. The study includes individuals with a body mass index ranging from 18.0 to 35.0 kg/m². Participants must be willing to discontinue the use of oral and topical NSAIDs, as well as other systemic pain medications, except for acetaminophen/paracetamol as per the rescue protocol, from two weeks before the start of the study until its conclusion. The trial does not exclude vulnerable populations, and the selection criteria ensure a diverse representation of individuals affected by knee osteoarthritis pain.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the dose and treatment effect of **pentosan polysulfate sodium** in participants with knee osteoarthritis pain. The trial is structured in two stages and conducted across multiple centers. The primary objective is to assess the treatment effect on knee pain and function, with the primary endpoints being changes from baseline in knee pain and function as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) Numeric Rating Scale at Day 56. Secondary endpoints include further assessments at Day 84.
Participants will be involved in the study for a maximum treatment period of 6 weeks, with the overall trial expected to conclude by October 2024. The study begins with a screening visit to confirm eligibility based on criteria such as age, clinical and radiographic diagnosis of knee osteoarthritis, and pain levels. Participants must be willing to discontinue certain medications prior to and during the study. Following the screening, eligible participants will be randomized to receive either the investigational product or placebo. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the protocol.
The trial includes an end-of-study visit to evaluate the final outcomes and ensure participant safety. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the integrity and reliability of the data collected.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **Pentosan polysulfate sodium**, a semi-synthetic sulfated polyxylose, administered as a **solution for injection**. The pharmaceutical form is a solution intended for **subcutaneous** administration. The dosing regimen involves a maximum daily dose of 2.0 mg/kg, with a total maximum dose of 18 mg/kg over a treatment period of up to 6 weeks. This medication is provided by Paradigm Biopharmaceuticals Inc. and is identified by the sponsor product code PPS.
Another experimental treatment is **Synacthen**, containing the active substance **tetracosactide**. This medication is a **solution for injection** and is administered via the **injection** route. The maximum daily dose is 0.25 mg, with a total maximum dose of 8 mg over a treatment period of up to 8 weeks. Synacthen is manufactured by Alfasigma S.p.A.
In addition to the experimental treatments, the study includes several non-experimental treatments, primarily involving **paracetamol** in various formulations. These include Paracetamol Aurovitas, PARALEN, Paracetamol Biofarm, Paracetamol Accord, Paracetamol Teva, and Panadol Novum, all of which are administered in **tablet** form via the **oral** route. Each formulation contains 500 mg of paracetamol, with a maximum daily dose of 3 grams and a total maximum dose of 96 grams over a treatment period of up to 8 weeks. These medications are provided by different manufacturers, including Aurovitas Pharma Polska Sp. z o.o, Opella Healthcare Czech S.R.O, Biofarm Sp. z o.o., Accord Healthcare Polska Sp. z o.o., Teva Pharma Belgium N.V./S.A, and GlaxoSmithKline Consumer Healthcare Czech Republic S.R.O.
The study also utilizes **Sodium Chloride 0.9% w/v for injection** as an auxiliary treatment. This solution is used for injection purposes, although specific details regarding its administration route and dosage are not provided. This product serves as a standard auxiliary treatment in clinical settings.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial is designed to evaluate the efficacy and safety of the experimental treatments compared to placebo in participants with knee osteoarthritis pain.
Efficacy
The efficacy of the clinical trial will be assessed using specific endpoints to evaluate the treatment effect of **Pentosan Polysulfate Sodium** on knee pain and function in participants with knee osteoarthritis pain. The primary endpoints include the change from baseline at Day 56 in knee pain, as assessed by the average pain subscale score of the Western Ontario and McMaster Universities (WOMAC®) Numeric Rating Scale (NRS) 3.1 Index, and the change in function as assessed by the average functional subscale score of the WOMAC® NRS 3.1 Index. These assessments will be conducted using validated scales to ensure accuracy and reliability.
Secondary endpoints will further evaluate efficacy by measuring changes from baseline at Day 84 in both knee pain and function, again using the WOMAC® NRS 3.1 Index. The schedule for these assessments is structured to capture data at critical time points, specifically at Day 56 and Day 84, to provide a comprehensive evaluation of the treatment's impact over time. The analysis of these efficacy parameters will be conducted in a hierarchical order, with function being a key secondary endpoint in the United States. This structured approach ensures that the trial's objectives are met and that the data collected is robust and meaningful for evaluating the treatment's efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and Female Participants 18 years of age or older
- Clinical diagnosis of OA in the index knee by American College of Rheumatology 1986 criteria.
- Radiographic diagnosis (confirmed by radiologist) of knee OA classified K-L Grade 2, 3, or 4 on standing anterior-posterior X-ray of the index knee.
- Osteoarthritis pain in the index knee unresponsive to conservative therapy for ≥6 months preceding Screening
- Average pain subscale score of 4 to 10 in the index knee at Screening AND a minimum pain score of 4 on either of the individual questions of pain on walking on a flat surface or pain on climbing stairs at Screening.
- Average function subscale score of 4 to 10 in the index knee at Screening.
- Body mass index of ≥18.0 to ≤35.0 kg/m2
- Willing to stop treatment with oral and topical NSAIDs, and all other systemic pain medications (except acetaminophen/paracetamol per rescue protocol) from 2 weeks before Day 1 to end of study.
Exclusion Criteria
- Documented or reported history of increased bleeding in the absence of anticoagulant or antiplatelet drugs or prior history of major bleeding episode in the presence of anticoagulant or antiplatelet therapy.
- History of idiopathic or immune-mediated thrombocytopenia including history of or laboratory confirmed HIT (positive or equivocal antibodies against platelet factor 4 [ie, PF4]).
- Currently active or recent history (within preceding 12 months) of a gastric or duodenal ulcer, or suspicion of gastrointestinal tract bleeding.
- History of other bleeding disorders including haemophilia
- Recent cerebral bleeding or operation on brain, spine, or eyes within 6 months of Day 1
- Fibromyalgia or other moderate to severe pain that may confound assessments or self-evaluation of the pain associated with osteoarthritis. Participants with a present (current) history of sciatica are not eligible for participation. Participants with a history of sciatica who have been asymptomatic for ≥3 months and who have no evidence of radiculopathy or sciatic neuropathy on thorough neurologic examination are eligible for participation.
- History of other disease that may involve the index joint, including inflammatory joint disease such as rheumatoid arthritis, seronegative spondyloarthropathy (eg, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease-related arthropathy), crystalline disease (eg, gout), endocrinopathies, metabolic joint diseases, lupus erythematosus, joint infections, Paget’s disease, or tumours.
- History of hypersensitivity to PPS, heparin or heparin-like drugs, or drugs of a similar chemical or pharmacological class.
- Predisposition to hypersensitivity due to multiple (2 or more) atopic diseases (such as atopic eczema, asthma, and chronic allergic rhinitis and/or rhinoconjunctivitis) or multiple (2 or more) severe allergies.
- Chronic medical conditions including but not limited to those stated below requiring medical regime changes within 60 days before Day 1. Concurrent unstable peripheral, cardiac, and cerebral vascular disease, poorly controlled chronic obstructive pulmonary disease and asthma, coagulopathies, uncontrolled neurological conditions, active tuberculosis, active infections, symptomatic cardiac arrhythmias, adrenal insufficiency (primary or central), nephrotic syndrome, Cirrhosis (Child-Pugh stage B or C), Gilberts syndrome, uncontrolled diabetes and uncontrolled hypothyroidism or hyperthyroidism, or mental or emotional disorders that preclude reliable study participation.
- Current treatment with anticoagulants or antiplatelet drugs, excluding aspirin ≤100 mg/day.
- Previous treatment with PPS in any form.
- Known exposure to heparin within the last 100 days as determined by history of drug use or history of the following medical conditions or interventions: cardiac bypass surgery or thromboembolic disease
- Any clinically significant abnormalities on clinical chemistry, haematology, urinalysis, physical examination, medical history, 12-lead ECG, or vital signs as judged by the Investigator (at Screening).
- Major surgery or anticipated surgery during the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 15 Jul 2022 | 40 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Synacthen 0,25 mg/ml oplossing voor injectie | Other | OPLOSSING VOOR INJECTIE | SOLUTION FOR INJECTION | 0.25 | 8 | PRD5191129 |
Paracetamol Aurovitas, 500 mg, tabletki | Other | TABLETS | ORAL | 3 | 8 | PRD5963763 |
PARALEN 500 mg tablety | Other | TABLETY | ORAL | 3 | 8 | PRD2856011 |
Paracetamol Biofarm, 500 mg, tabletki | Other | TABLETKI | ORAL | 3 | 8 | PRD7394343 |
Paracetamol Accord, 500 mg, tabletki | Other | TABLETKI | ORAL | 3 | 8 | PRD4372207 |
Sodium Chloride 0.9% w/v for injection | Placebo | N/A | — | — | — | N/A |
Paracetamol Teva 500 mg Tabletten | Other | TABLETTEN | ORAL | 3 | 8 | PRD4167092 |
Pentosan polysulfate sodium | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 2.0 | 6 | PRD9539511 |
Panadol Novum 500 mg potahované tablety | Other | POTAHOVANÉ TABLETY | ORAL | 3 | 8 | PRD309060 |