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
Overview
- Phase
- Phase 2
- Intervention
- Pentosan Polysulfate Sodium twice weekly
- Conditions
- Osteoarthritis, Knee
- Sponsor
- Paradigm Biopharmaceuticals USA (INC)
- Enrollment
- 602
- Locations
- 33
- Primary Endpoint
- Change from baseline at Day 56 in knee pain as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index.
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this study is to measure the change in pain and function with subcutaneous injections of pentosan polysulfate sodium (PPS) compared with subcutaneous injections of placebo in participants with knee osteoarthritis pain.
Study details include:
- The study duration will be up to 31 weeks per participant
- The treatment duration will be 6 weeks.
- The visit frequency will be twice weekly during treatment.
- The visit frequency will be every 4 weeks during the follow-up period.
Detailed Description
This is a 2-stage, adaptive, randomized, double-blind, placebo-controlled, multicenter study that will evaluate the dose and treatment effect of PPS in participants with knee OA pain. In Stage 1 (dose selection), approximately 468 participants will be randomised 1:1:1:1 to receive 1 of 3 PPS dose regimens or placebo for 6 weeks. A minimum of 96 participants (24 within each dose group) will be assigned to the Pharmacokinetic (PK) subset. Participants in Stage 1 will be randomly allocated to receive: * 1.5 mg/kg calculated for ideal body weight (IBW) PPS twice weekly * 2 mg/kg IBW PPS once weekly + placebo once weekly * 100/150/180 mg PPS if ≤ 65 kg/ ≥ 65 kg and ≤ 90kg/ \> 90kg IBW+ placebo once weekly * placebo twice weekly In Stage 2, approximately 470 participants will be randomized 1:1 to receive the selected PPS dose regimen or placebo for 6 weeks. Approximately 150 participants (75 per group) will be assigned to the PK subset. Participants in Stage 2 will be randomly allocated to receive: * One of the 3 Stage 1 PPS dose regimens selected by the DMC * placebo twice weekly The maximum duration for each participant is approximately 31 weeks, which includes: * 7-week Screening Period from Day -45 to Day -1 * 6-week Treatment Period from Day 1 to Day 39 * 18-week Follow-up Period from Day 40 to Day 168
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participant must be \>= 18 years of age inclusive, at the time of signing the informed consent.
- •Clinical diagnosis of OA in the index knee by American College of Rheumatology criteria 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 (ie, the participant still experiences pain) to conservative therapy for ≥ 6 months preceding Screening, defined as history indicating that:
- •Acetaminophen/paracetamol therapy has not provided sufficient pain relief or participant is unable to take acetaminophen/paracetamol chronically/long term because of contraindication or inability to tolerate; AND
- •At least 1 oral non-steroidal anti-inflammatory drug (NSAID, including cyclooxygenase-2 inhibitors) and/or topical NSAID therapy that has not provided sufficient pain relief or participant is unable to take NSAIDs because of contraindication or inability to tolerate.
- •Average WOMAC NRS 3.1 Index pain sub-scale score of 4 to 10 in the index knee at Screening AND a minimum pain score of 4 on either of the individual WOMAC NRS 3.1 Index questions of pain on walking on a flat surface or pain on climbing stairs at Screening.
- •Average WOMAC NRS 3.1 Index function sub-scale score of 4 to 10 in the index knee at Screening.
- •Body mass index of \>=18 to \<=39.0 kg/m2
- •Female subjects of childbearing potential and Male subjects must agree to comply with protocol specified contraceptive requirements
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 \[ie, PF4\] and positive Serotonin Release Assay (SRA)\].
- •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
- •Spinal anaesthesia within 14 days of Day 1,
- •Fibromyalgia, regional pain caused by lumbar or cervical compression with radiculopathy, 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 osteonecrosis or osteoporotic fracture (ie, a participant with a history of osteoporosis and a minimally traumatic or atraumatic fracture).
- •History of hypersensitivity to PPS, heparin or heparin-like drugs, or drugs of a similar chemical or pharmacological class.
Arms & Interventions
PPS Twice Weekly
Pentosan Polysulfate Sodium (PPS) twice weekly for 6 weeks
Intervention: Pentosan Polysulfate Sodium twice weekly
PPS Once Weekly
Pentosan Polysulfate Sodium (PPS) + placebo once weekly for 6 weeks
Intervention: Placebo (Sodium Chloride Injection, 0.9%)
PPS Once Weekly
Pentosan Polysulfate Sodium (PPS) + placebo once weekly for 6 weeks
Intervention: Pentosan Polysulfate Sodium once weekly
PPS Fixed Dose Once Weekly
Pentosan Polysulfate Sodium (PPS) Fixed dose (100mg,150mg, or 180mg) once weekly + placebo once weekly for 6 weeks
Intervention: Placebo (Sodium Chloride Injection, 0.9%)
PPS Fixed Dose Once Weekly
Pentosan Polysulfate Sodium (PPS) Fixed dose (100mg,150mg, or 180mg) once weekly + placebo once weekly for 6 weeks
Intervention: Pentosan Polysulfate Sodium Fixed Dose
Placebo
Placebo twice weekly for 6 weeks
Intervention: Placebo (Sodium Chloride Injection, 0.9%)
Outcomes
Primary Outcomes
Change from baseline at Day 56 in knee pain as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index.
Time Frame: Baseline, Day 56
WOMAC: The WOMAC® NRS 3.1 Index is a validated, self-administered, health status questionnaire that assesses pain, stiffness, and function in patients with hip or knee OA . The WOMAC pain sub-scale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee) during the past 48 hours. It is calculated as the mean of scores from 5 individual questions scored on a numerical rating scale (NRS). Scores for each question and WOMAC Pain sub-scale score on NRS ranged from 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain.
Secondary Outcomes
- Key secondary: Change from baseline at Day 84 in knee pain as assessed by the average pain subscale score of the WOMAC NRS 3.1 Index(Baseline to Day 84)
- Stage 1 only: Reduction in knee pain of ≥ 30% and ≥ 50% as assessed by the average pain subscale score of the WOMAC NRS 3.1 Index at Days 56 and 84 for PPS 1.5mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly(Baseline to Day 56 and Day 84)
- Stage 1 only: Stage 1 only: Change from baseline at Day 56 and 84 in function as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index for PPS 1.5 mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly(Baseline to Day 56 and Day 84)
- Key secondary: Change from baseline at Day 56 in function as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index(Baseline to Day 56)
- Stage 1 only: Change from baseline at Day 56 and 84 in knee pain as assessed by the average pain subscale score of the WOMAC NRS 3.1 Index for PPS 1.5 mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly(Baseline to Day 56 and Day 84)
- Key secondary: Change from baseline at Day 84 in function as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index(Baseline to Day 84)
- Stage 1 only: PGIC scores at Days 56 and 84 for PPS 1.5mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly(Baseline to Day 56 and Day 84)
- Stage 1 only: Improvement in function of ≥ 30% and ≥ 50% as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index at Days 56 and 84 for PPS 1.5mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly(Baseline to Day 56 and Day 84)
- Stage 1 and 2: Outcomes Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) Responder Index response rate at Days 39, 56, 84, 112, 140, and 168(Baseline, Days 39, 56, 84, 112, 140 and 168)
- Stage 1 and 2: Change from baseline at Days 11, 25, 39, 112, 140 and 168 in knee pain as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index.(Baseline, Days 11, 25, 39, 112, 140 and 168)
- Stage 1 and 2: Change from baseline at Days 11, 25, 39, 112, 140 and 168 in function as assessed by the average functional sub-scale score of the WOMAC® Index.(Baseline, Days 11, 25, 39, 112, 140 and 168)
- Stage 1 and 2: Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, and 168 in knee stiffness as assessed by the average stiffness sub-scale score of the WOMAC® NRS 3.1 Index(Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168)
- Stage 1 and 2: Change from baseline in knee pain of >=30% and >=50% as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index at Days 11, 25, 39, 112, 140, and 168(Baseline, Days 11, 25, 39, 112, 140 and 168)
- Stage 1 and 2: Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, and 168 overall as assessed by the overall score of WOMAC® NRS 3.1 Index(Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168)
- Stage 1 and 2: PGIC scores at Days 39, 112, 140, and 168(Baseline, Days 39, 112, 140, and 168)
- Stage 1 and 2: Number of days of rescue medication used from Day 1 to Day 168(Baseline up to Day 168)
- Stage 1 and 2: Improvement in function of >=30% and >=50% as assessed by the average functional sub-scale score of the WOMAC® NRS 3.1 Index from baseline at Days 11, 25, 39, 112, 140, and 168(Baseline, Days 11, 25, 39, 112, 140, and 168)
- Stage 1 and 2: Clinically significant changes in electrocardiograms (ECG) compared with baseline (pharmacokinetic [PK] subset only)(Baseline, Day 1, Day 15, Day 36 and Day 39)
- Stage 1 and 2: Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, and 168 in Quality of Life (QoL) as assessed by Short Form-36 General Health Survey (SF-36)(Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168)
- Stage 1 and 2: Change from baseline at Days 56, 84, 112, 140, and 168 in Work Productivity and Activity Impairment (WPAI) questionnaire score(Baseline, Day 56, 84, 112, 140 and 168)
- Stage 1 and 2: Incidence of treatment-emergent Adverse Event (TEAEs), including serious AEs (SAEs)(Baseline up to Day 168)
- Stage 1 and 2: Treatment-emergent clinical laboratory abnormalities(Baseline up to Day 168)