Treatment Effects of Subcutaneous Injections of Pentosan Polysulfate Sodium vs Placebo in Participants With Knee OA Pain

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: 1. 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 2. 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 * 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. * 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. * 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. * Agrees to use acetaminophen/paracetamol or topical analgesics (topical NSAIDs are prohibited) as rescue therapy if required. 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 1. * 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. * 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 * Allergy or contraindication to Tetracosactide * 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), uncontrolled diabetes and uncontrolled hypothyroidism or hyperthyroidism, or mental or emotional disorders that preclude reliable study participation. * History of pituitary irradiation or recent (within 1 year) history of transsphenoidal surgery * Any cancer within the previous 5 years, except for basal cell carcinomas. * Current hyperkalemia and/or hyponatremia. * History or current autoimmune polyglandular syndromes * 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 protocol. * Current treatment with anticoagulants or antiplatelet drugs, excluding aspirin ≤100 mg/day. * Previous treatment with PPS in any form. * 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 and topical corticosteroids (occasional use of topical, inhaled or intranasal corticosteroids is acceptable). * Use of opioids within 6 weeks before Day 1. * Use of bisphosphonates within 12 weeks before Day 1. * Use of denosumab and iloprost within 12 weeks before Day 1. * Use of a knee brace on the index knee within 2 weeks before Day 1. * Systemic steroids administered intravenously, intramuscularly, and orally for OA or other indications within 8 weeks before Day 1. * Intra-articular injections to the index knee: steroids within 24 weeks; hyaluronic acid or any other intra-articular injections within 24 weeks before Day 1. * Cannabinoids within 30 days before Day 1. * Use of 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. * 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 * Treatment with dehydroepiandrosterone sulfates within 6 weeks before Day 1. * Chronic use of oral glucocorticoid receptor antagonists or cortisol synthesis inhibitors within12 weeks before Day 1. * Biotin within 72 hours of screening. * Megestrol Acetate within 6 weeks before Day 1 * Current treatment with any medication that may lead to Maculopathy (see Table 3) * Any medication that alters sodium and/or potassium levels (see Table Prohibited Therapy) * 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. * 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. * 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. * Radiographic evidence of any of the following conditions in any Screening radiograph: excessive malalignment of the knee, severe chondrocalcinosis; other arthropathies (eg, rheumatoid arthritis, psoriatic arthritis, gout), systemic metabolic bone disease (eg, Paget's disease, metastatic calcifications), primary or metastatic tumour lesions, stress, or traumatic fracture. * Radiographic evidence of any of the following conditions at Screening: 1. subchondral insufficiency fractures 2. spontaneous osteonecrosis of the knee 3. osteonecrosis 4. pathologic fracture * 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). * 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 anti-hypertensive 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. * Evidence of pigmentary maculopathy identified by a retinal specialist during Screening. * Morning Cortisol ≤ 3 µg/dL. * ACTH \<10 pg/ml; Morning Cortisol \>3 µg/dL and \<10 µg/dL and peak cortisol (by ACTH stimulation test) \<18 µg/dL. * Largely or wholly incapacitated (eg, bedridden or confined to a wheelchair, permitting little or no self-care). * Major surgery or anticipated surgery during the study. * Currently hospitalized or any planned hospitalizations during the study. * Plan for total knee reconstruction in affected knee(s) during the study. * Knee surgery or trauma to the index knee within 1 year before Day 1. * 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. * An employee of the Sponsor, clinical research organisations 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.