A Study to Investigate the Treatment Effect of Subcutaneous Injections of Pentosan Polysulfate Sodium Compared With Placebo in Adult Participants With Knee Osteoarthritis Pain.

Inclusion Criteria:

1. Participant must be ≥18 years of age inclusive, at the time of signing the informedconsent.

2. Clinical diagnosis of OA in the index knee by American College of Rheumatology 1986criteria.

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 twocombinations of OA therapies (one from each A and B) within the last 12 months thatinclude: A.) conservative non-pharmacologic therapy (exercise, weight loss, physicaltherapy) or simple analgesics (e.g., acetaminophen) and B.) pharmacologicaltreatment (topical or oral NSAIDs [or cyclooxygenase (COX) inhibitor], orintra-articular [IA] injections), or participant is unable to take NSAIDs because ofcontraindication or inability to tolerate.

5. Average daily pain (ADP) numerical rating scale (NRS) score of 4-9 in the index kneeat Screening.

6. Baseline average weekly ADP NRS score of 4-9 in the index knee in the 7 days priorto randomization.

7. No more than one 24-hr average pain score (0-10 NRS) reported as "10" during the 7days 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 complywith protocol specified contraceptive requirements

10. Capable of giving signed informed consent, which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol.

11. Completion of at least 11 out of 14 ADP NRS scores for at least 14 days prior torandomisation.

12. Current non-pharmacologic treatment regimen for knee OA (excluding knee brace) mustbe 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 theirnon-pharmacologic treatment regimen for the duration of the study.

13. Willing to stop treatment with oral and topical NSAIDs, and all other systemic painmedications (except allowed rescue medication) from 2 weeks before Day 1 to end ofstudy.

14. Agrees to use acetaminophen/paracetamol or topical analgesics (topical NSAIDs areprohibited) as rescue therapy if required.

Exclusion Criteria:

1. History of idiopathic or immune-mediated thrombocytopenia including history of HITwith or without thrombosis.

2. History of major bleeding disorders including haemophilia.

3. Currently active or recent history (within preceding 12 months) of a gastric orduodenal ulcer, or suspicion of gastrointestinal tract bleeding.

4. Recent cerebral bleeding or operation on brain, spine, or eyes within 12 months ofDay 1.

5. Spinal anaesthesia within 14 days of Day 1.

6. Fibromyalgia, regional pain caused by lumbar or cervical compression withradiculopathy, or other moderate to severe pain disorder that may confoundassessments or self-evaluation of the pain associated with osteoarthritis.Participants with a present (current) history of sciatica are not eligible forparticipation. Participants with a history of sciatica who have been asymptomaticfor ≥3 months and who have no evidence of radiculopathy or sciatic neuropathy onthorough neurologic examination are eligible for participation.

7. History of other disease that may involve the index knee, including inflammatoryjoint disease such as rheumatoid arthritis (RA), seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, inflammatory boweldisease-related arthropathy), crystalline disease (e.g., gout), endocrinopathies,metabolic joint diseases, lupus erythematosus, joint infections, Paget's disease, ortumours.

8. History of hypersensitivity to PPS, heparin or heparin-like drugs, or drugs of asimilar chemical or pharmacological class.

9. Predisposition to hypersensitivity due to multiple (2 or more) atopic diseases (suchas 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 requiringmedical regime changes within 60 days before Day 1. Concurrent unstable peripheral, cardiac, and cerebral vascular disease, poorlycontrolled 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 mentalor emotional disorders that preclude reliable study participation.

13. History of pituitary irradiation or recent (within 1 year) history oftranssphenoidal 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 theopinion of the Investigator, would make it unlikely that the participant will complywith the protocol or complete the study per the protocol.

17. Current treatment with anticoagulants or antiplatelet drugs within 2 weeks beforeDay 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 orimmunomodulatory (with immunosuppressive effects) systemic therapy including but notlimited to oral, inhaled, intranasal, intra-articular (IA) and topicalcorticosteroids (occasional use of topical, inhaled or intranasal corticosteroids isacceptable).

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 orother indications within 8 weeks before Day 1.

27. Intra-articular (IA) injections to the index knee: steroids within 12 weeks beforeDay 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 treefungus, 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 druguse or history of the following medical conditions or interventions: cardiac bypasssurgery 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 synthesisinhibitors 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 experimentalproduct 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 HIVinfection (detectable virus or diagnosis of AIDS); participants with HIV infectionmust be on chronic suppressive antiviral medication.

40. Evidence of any of the following conditions in any screening imaging: excessivemalalignment (≥10 degrees varus or valgus) of the knee, subchondral insufficiencyfracture (SIF), osteonecrosis/bone infarct, osteochondritis dissecans, stress oracute 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, bonecontusion, bone marrow oedema syndrome, bone marrow infiltration, gout, severechondrocalcinosis, other arthropathies (e.g., RA, psoriatic arthritis), systemicmetabolic bone disease (e.g., Paget's disease, metastatic calcifications) or otherconditions identified by a radiologist or Medical Monitor which may interfere with aparticipant's assessment of pain.

41. Any clinically significant abnormalities on clinical chemistry, haematology,urinalysis, physical examination, medical history, or vital signs as judged by theInvestigator (at Screening).

42. Resting, supine blood pressure (BP) ≥160 mmHg in systolic pressure or ≥100 mmHg indiastolic pressure at Screening. If a participant is found to have uncontrolledand/or untreated significant hypertension at Screening and antihypertensivetreatment is initiated, assessment for study eligibility should be deferred until BPand antihypertensive medication have been stable for at least 1 month. Forparticipants with previously diagnosed hypertension, antihypertensive medicationsmust be stable for at least 1 month before Screening.

43. Any macular findings on clinical examination or imaging suggestive of: moderate oradvanced dry macular degeneration, geographic atrophy, moderate or advanced myopicdegeneration, wet macular degeneration, pattern dystrophy or other pigmentarymaculopathy, moderate or severe diabetic or hypertensive retinopathy, recent retinalvascular occlusion, macular hole or advanced epiretinal membrane with associatedmacular oedema, retinal dystrophy, toxic retinal maculopathy, chronic central serousretinopathy, presence of significant subretinal or intraretinal fluid (OCT finding),presence of vitelliform or vitelliform-like macular changes (OCT and clinicalfinding), 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 ACTHstimulation [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 beforeScreening that, in the opinion of the Investigator, may affect participant abilityto comply with study requirements.

55. An employee of the Sponsor, clinical research organisation(s), or research sitepersonnel directly affiliated with this study or their immediate family membersdefined as a spouse, parent, sibling, or child, whether biological or legallyadopted.