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 OA pain.
Study details include:
* The study duration will be up to 64 weeks. * The treatment duration will be 6 weeks. * The visit frequency will be twice weekly during treatment. * The visit/contact frequency will be every 4-6 weeks during the 52-week Follow-up period. * Approximately 466 participants will be enrolled into this study.
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 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.
Participant is unresponsive for at least 6 months preceding Screening to any two combinations of OA therapies (one from each A and B) within the last 12 months that include: A.) conservative non-pharmacologic therapy (exercise, weight loss, physical therapy) or simple analgesics (e.g., acetaminophen) and B.) pharmacological treatment (topical or oral NSAIDs [or cyclooxygenase (COX) inhibitor], or intra-articular [IA] injections), or participant is unable to take NSAIDs because of contraindication or inability to tolerate.
History of idiopathic or immune-mediated thrombocytopenia including history of HIT with or without thrombosis.
History of major bleeding disorders including haemophilia.
Currently active or recent history (within preceding 12 months) of a gastric or duodenal ulcer, or suspicion of gastrointestinal tract bleeding.
Recent cerebral bleeding or operation on brain, spine, or eyes within 12 months of Day 1.
Parallel
Pentosan Polysulfate Sodium twice weekly
DrugSubcutaneous injection, 2 mg/kg twice weekly for 6 weeks
Placebo
DrugPlacebo, subcutaneous injection, twice weekly for 6 weeks
Change from baseline at Day 112 in knee pain as assessed by the weekly average of daily pain (ADP) score on the numerical rating scale (NRS) 11-point (0-10) scale.
The NRS is an 11-point unidimensional scale for self-report of pain. The participant selects a whole number (0-10) that best reflects the intensity of their pain. The anchors are 0=no pain and 10=extreme pain/worst possible pain. It is often categorised into no pain=0, mild pain=1-3, moderate pain=4-6, severe pain=7-10. Participants will be asked to consider their average pain over the last 24 hours.
Change from baseline in function as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index
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 (Bellamy et al., 1988). The WOMAC NRS 3.1 Index consists of 24 questions and produces 3 subscale scores for pain (5 questions), stiffness (2 questions), and function (17 questions) and a total score that summarises overall disability. Each question is scored from 0 to 10 using a standardised 11-point NRS. Each subscale score and the total score will be averaged to provide subscale and total scores between 0 and 10. Participants are to consider their last 4 hours when answering the questions.
Change from baseline in knee pain as assessed by the average pain subscale score of the WOMAC NRS 3.1 Index
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 (Bellamy et al., 1988). The WOMAC NRS 3.1 Index consists of 24 questions and produces 3 subscale scores for pain (5 questions), stiffness (2 questions), and function (17 questions) and a total score that summarises overall disability. Each question is scored from 0 to 10 using a standardised 11-point NRS. Each subscale score and the total score will be averaged to provide subscale and total scores between 0 and 10. Participants are to consider their last 4 hours when answering the questions.
Change from baseline in knee pain as assessed by the weekly average of daily pain (ADP) score on the numerical rating scale (NRS) 11-point (0-10) scale.
The NRS is an 11-point unidimensional scale for self-report of pain. The participant selects a whole number (0-10) that best reflects the intensity of their pain. The anchors are 0=no pain and 10=extreme pain/worst possible pain. It is often categorised into no pain=0, mild pain=1-3, moderate pain=4-6, severe pain=7-10. Participants will be asked to consider their average pain over the last 24 hours.
Change from baseline in Patient Global Impression of Change (PGIC)
The PGIC is a self-administered question that rates participants' overall improvement in chronic pain since beginning treatment from 1 "no change (or condition has worsened)" to 7 "a great deal better" in response to the question "Since beginning treatment, how would you describe the change (if any) in activity, limitation, symptoms, emotions, and overall QoL related to your arthritis".
Exploratory: Characterize the AUC profile of single and multiple doses based on sparse blood sampling. (pharmacokinetic subset only)
Blood samples for assay of plasma PPS concentration will be obtained from a subset of patients before dosing and 2, 4, and 6 hours after dosing on study Days 1, 15 and 39. On other days, a pre-dose sample will be collected. Samples will be assayed using a sensitive, validated bioanalytical method. Plasma concentrations of PPS will be tabulated by time and participant and inspected for relationship to dose during titration and stable treatment phases.
Exporatory: Number of participants with an Anti-Drug-Antibody (ADA) response after treatment and correlation with clinical events.
Human serum ADA samples will be analyzed for the presence or absence of anti-drug-antibodies by using a semi-quantitative enzyme linked immunosorbent assay (ELISA).
Exploratory: Change from baseline in serum biomarkers, including but not limited to, COMP, aggrecan ARGS, CRTAC-1, PRO-C2 PIIBNP, NTx-Ⅰ, and HA.
ARGS-(aggrecan) alanine-arginine-glycine-serine; COMP-cartilage oligomeric matrix protein; CRTAC-1-cartilage acidic protein-1; HA-hyaluronic acid; NTx-1-N-terminal telopeptide of type I collagen; PIIBNP-N-terminal propeptide of type II collagen; PRO-C2-type II collagen C-terminal propeptide.
Exploratory: Change from baseline of cartilage volume and thickness and whether these correlate with clinical pain outcomes.
The correlation co-efficient of changes in cartilage volume and thickness as measured on MRI and pain clinical outcomes.
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