Pentosan Polysulfate Sodium for Knee Osteoarthritis Pain

Inclusion Criteria: 1. Participant must be ≥18 years of age inclusive, at the time of signing the informed consent. 2. Clinical diagnosis of OA in the index knee by American College of Rheumatology 1986 criteria. 3. 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. 4. 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. 5. Average daily pain (ADP) numerical rating scale (NRS) score of 4-9 in the index knee at Screening. 6. Baseline average weekly ADP NRS score of 4-9 in the index knee in the 7 days prior to randomization. 7. No more than one 24-hr average pain score (0-10 NRS) reported as "10" during the 7 days prior to Day 1. 8. Body mass index of ≥18.0 to ≤39.0 kg/m2. 9. Female subjects of childbearing potential and Male subjects must agree to comply with protocol specified contraceptive requirements 10. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 11. Completion of at least 11 out of 14 ADP NRS scores for at least 14 days prior to randomisation. 12. Current non-pharmacologic treatment regimen for knee OA (excluding knee brace) must be stable for at least 2 weeks before Day 1 and remain stable throughout the study. Participant must be willing to abstain from starting a new or changing their non-pharmacologic treatment regimen for the duration of the study. 13. Willing to stop treatment with oral and topical NSAIDs, and all other systemic pain medications (except allowed rescue medication) from 2 weeks before Day 1 to end of study. 14. Agrees to use acetaminophen/paracetamol or topical analgesics (topical NSAIDs are prohibited) as rescue therapy if required. Exclusion Criteria: 1. History of idiopathic or immune-mediated thrombocytopenia including history of HIT with or without thrombosis. 2. History of major bleeding disorders including haemophilia. 3. Currently active or recent history (within preceding 12 months) of a gastric or duodenal ulcer, or suspicion of gastrointestinal tract bleeding. 4. Recent cerebral bleeding or operation on brain, spine, or eyes within 12 months of Day 1. 5. Spinal anaesthesia within 14 days of Day 1. 6. Fibromyalgia, regional pain caused by lumbar or cervical compression with radiculopathy, or other moderate to severe pain disorder 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. 7. History of other disease that may involve the index knee, including inflammatory joint disease such as rheumatoid arthritis (RA), seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease-related arthropathy), crystalline disease (e.g., gout), endocrinopathies, metabolic joint diseases, lupus erythematosus, joint infections, Paget's disease, or tumours. 8. History of hypersensitivity to PPS, heparin or heparin-like drugs, or drugs of a similar chemical or pharmacological class. 9. 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. 10. Allergy or contraindication to tetracosactide (Synacthen®), cosyntropin (Cortrosyn®). 11. Allergy or contraindication to gadolinium. 12. 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), Gilbert syndrome, uncontrolled diabetes, and uncontrolled hypothyroidism or hyperthyroidism, or mental or emotional disorders that preclude reliable study participation. 13. History of pituitary irradiation or recent (within 1 year) history of transsphenoidal surgery. 14. Any cancer within the previous 5 years, except for basal cell carcinomas. 15. History or current autoimmune polyglandular syndromes. 16. Presence of any underlying physical or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the participant will comply with the protocol or complete the study per the protocol. 17. Current treatment with anticoagulants or antiplatelet drugs within 2 weeks before Day 1, excluding aspirin ≤150 mg/day. 18. Previous treatment with PPS in any form. 19. Current or recent (within 90 days before Day 1) immunosuppressive or immunomodulatory (with immunosuppressive effects) systemic therapy including but not limited to oral, inhaled, intranasal, intra-articular (IA) and topical corticosteroids (occasional use of topical, inhaled or intranasal corticosteroids is acceptable). 20. Use of NSAIDs with 2 weeks before Day 1. 21. Use of opioids within 6 weeks before Day 1. 22. Use of glucosamine or chondroitin within 6 weeks before Day 1. 23. Use of bisphosphonates and denosumab within 12 weeks before Day 1. 24. Use of iloprost within 12 weeks before Day 1. 25. Use of a knee brace on the index knee within 2 weeks before Day 1. 26. Systemic steroids administered intravenously, intramuscularly, or orally for OA or other indications within 8 weeks before Day 1. 27. Intra-articular (IA) injections to the index knee: steroids within 12 weeks before Day 1; hyaluronic acid (HA) or any other IA injections within 24 weeks before Day 1. 28. Stem cells or platelet-rich plasma within 12 months of Day 1. 29. Cannabinoids within 30 days before Day 1. 30. Use of individual vitamins and dietary supplements known to alter haemostasis within 2 weeks before Day 1, including ajoene, birch bark, cayenne, Chinese black tree fungus, cumin, evening primrose oil, feverfew, garlic, ginger, ginkgo biloba, ginseng, grapeseed extract, milk thistle, omega 3 fatty acids, onion extract, St. John's wort, turmeric, vitamins C and E, vitamin K, (multivitamins allowed). 31. 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. 32. Treatment with dehydroepiandrosterone sulfates (DHEA-S) within 6 weeks before Day 1. 33. Chronic use of oral glucocorticoid receptor antagonists or cortisol synthesis inhibitors within 12 weeks before Day 1. 34. Biotin within 72 hours before Screening. 35. Megestrol acetate within 6 weeks before Day 1. 36. Participation in another clinical trial or administration of any IP or experimental product within 24 weeks or 5 half-lives (whichever is longer) before Day 1. 37. Activated partial thromboplastin time \[aPTT\]) \> 36 seconds, platelets \<150,000/μL, or liver enzyme tests (aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\]) ≥ 2 × ULN at Screening. 38. Total bilirubin ≥1.5 ULN. 39. Active or chronic hepatitis B virus, hepatitis C virus, or uncontrolled HIV infection (detectable virus or diagnosis of AIDS); participants with HIV infection must be on chronic suppressive antiviral medication. 40. Evidence of any of the following conditions in any screening imaging: excessive malalignment (≥10 degrees varus or valgus) of the knee, subchondral insufficiency fracture (SIF), osteonecrosis/bone infarct, osteochondritis dissecans, stress or acute fracture, atrophic OA, pathologic fracture, primary or metastatic tumour, infectious arthritis or osteomyelitis, chronic or acute, Charcot's knee joint, synovial chondromatosis, certain posterior root tears of the meniscus, bone contusion, bone marrow oedema syndrome, bone marrow infiltration, gout, severe chondrocalcinosis, other arthropathies (e.g., RA, psoriatic arthritis), systemic metabolic bone disease (e.g., Paget's disease, metastatic calcifications) or other conditions identified by a radiologist or Medical Monitor which may interfere with a participant's assessment of pain. 41. Any clinically significant abnormalities on clinical chemistry, haematology, urinalysis, physical examination, medical history, or vital signs as judged by the Investigator (at Screening). 42. Resting, supine blood pressure (BP) ≥160 mmHg in systolic pressure or ≥100 mmHg in diastolic pressure at Screening. If a participant is found to have uncontrolled and/or untreated significant hypertension at Screening and antihypertensive treatment is initiated, assessment for study eligibility should be deferred until BP and antihypertensive medication have been stable for at least 1 month. For participants with previously diagnosed hypertension, antihypertensive medications must be stable for at least 1 month before Screening. 43. Any macular findings on clinical examination or imaging suggestive of: moderate or advanced dry macular degeneration, geographic atrophy, moderate or advanced myopic degeneration, wet macular degeneration, pattern dystrophy or other pigmentary maculopathy, moderate or severe diabetic or hypertensive retinopathy, recent retinal vascular occlusion, macular hole or advanced epiretinal membrane with associated macular oedema, retinal dystrophy, toxic retinal maculopathy, chronic central serous retinopathy, presence of significant subretinal or intraretinal fluid (OCT finding), presence of vitelliform or vitelliform-like macular changes (OCT and clinical finding), severe maculopathy not otherwise specified. 44. Morning cortisol \<3 μg/dL. 45. Adrenocorticotropic hormone (ACTH) \<10 pg/mL. 46. US/Canada only: Morning cortisol ≥3 μg/dL and \<10 μg/dL and peak cortisol (by ACTH stimulation \[250 μg, IM\] test) \<18 μg/dL at both 30 min and 60 min post stimulation. 47. Current hyperkalaemia and/or hyponatremia. 48. Contraindication to MRI. 49. Largely or wholly incapacitated (e.g., bedridden or confined to a wheelchair, permitting little or no self-care). 50. Major surgery or anticipated surgery during the study. 51. Currently hospitalised or any planned hospitalizations during the study. 52. Plan for total knee reconstruction in affected knee(s) during the study. 53. Knee surgery or trauma to the index knee within 1 year before Day 1. 54. A history of drug or alcohol abuse and/or dependence within the 12 months before Screening that, in the opinion of the Investigator, may affect participant ability to comply with study requirements. 55. An employee of the Sponsor, clinical research organisation(s), or research site personnel directly affiliated with this study or their immediate family members defined as a spouse, parent, sibling, or child, whether biological or legally adopted.