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 informedconsent.
• Clinical diagnosis of OA in the index knee by American College of Rheumatologycriteria 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 stillexperiences pain) to conservative therapy for ≥ 6 months preceding Screening, definedas history indicating that:

1. Acetaminophen/paracetamol therapy has not provided sufficient pain relief orparticipant is unable to take acetaminophen/paracetamol chronically/long termbecause of contraindication or inability to tolerate; AND
2. At least 1 oral non-steroidal anti-inflammatory drug (NSAID, includingcyclooxygenase-2 inhibitors) and/or topical NSAID therapy that has not providedsufficient pain relief or participant is unable to take NSAIDs because ofcontraindication or inability to tolerate.

• Average WOMAC NRS 3.1 Index pain sub-scale score of 4 to 10 in the index knee atScreening AND a minimum pain score of 4 on either of the individual WOMAC NRS 3.1Index questions of pain on walking on a flat surface or pain on climbing stairs atScreening.
• Average WOMAC NRS 3.1 Index function sub-scale score of 4 to 10 in the index knee atScreening.
• Body mass index of >=18 to <=39.0 kg/m2
• Female subjects of childbearing potential and Male subjects must agree to comply withprotocol specified contraceptive requirements
• Capable of giving signed informed consent, which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol.
• Current non-pharmacologic treatment regimen for knee OA (excluding knee brace) must bestable 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.
• Willing to stop treatment with oral and topical NSAIDs, and all other systemic painmedications (except acetaminophen/paracetamol per rescue protocol) from 2 weeks beforeDay 1 to end of study.
• Agrees to use acetaminophen/paracetamol or topical analgesics (topical NSAIDs areprohibited) as rescue therapy if required.

Exclusion Criteria:

• Documented or reported history of increased bleeding in the absence of anticoagulantor antiplatelet drugs or prior history of major bleeding episode in the presence ofanticoagulant or antiplatelet therapy.

• History of idiopathic or immune-mediated thrombocytopenia including history of orlaboratory 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 orduodenal 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 ofDay 1.

• Spinal anaesthesia within 14 days of Day 1,

• Fibromyalgia, regional pain caused by lumbar or cervical compression withradiculopathy, or other moderate to severe pain that may confound assessments orself-evaluation of the pain associated with osteoarthritis. Participants with apresent (current) history of sciatica are not eligible for participation. Participantswith a history of sciatica who have been asymptomatic for ≥ 3 months and who have noevidence of radiculopathy or sciatic neuropathy on thorough neurologic examination areeligible for participation.

• History of other disease that may involve the index joint, including inflammatoryjoint disease such as rheumatoid arthritis, seronegative spondyloarthropathy (eg,ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease-relatedarthropathy), crystalline disease (eg, gout), endocrinopathies, metabolic jointdiseases, lupus erythematosus, joint infections, Paget's disease, or tumours.

• History of osteonecrosis or osteoporotic fracture (ie, a participant with a history ofosteoporosis and a minimally traumatic or atraumatic fracture).

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

• Predisposition to hypersensitivity due to multiple (2 or more) atopic diseases (suchas atopic eczema, asthma, and chronic allergic rhinitis and/or rhinoconjunctivitis) ormultiple (2 or more) severe allergies

• Allergy or contraindication to Tetracosactide

• 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, poorly controlled chronic obstructivepulmonary disease and asthma, coagulopathies, uncontrolled neurological conditions,active tuberculosis, active infections, symptomatic cardiac arrhythmias, adrenalinsufficiency (primary or central), nephrotic syndrome, Cirrhosis (Child-Pugh stage Bor C), uncontrolled diabetes and uncontrolled hypothyroidism or hyperthyroidism, ormental or emotional disorders that preclude reliable study participation.

• History of pituitary irradiation or recent (within 1 year) history of transsphenoidalsurgery

• 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 theopinion of the Investigator, would make it unlikely that the participant will complywith the protocol or complete the study per protocol.

• Current treatment with anticoagulants or antiplatelet drugs, excluding aspirin ≤100mg/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 oftopical, 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 orother indications within 8 weeks before Day 1.

• Intra-articular injections to the index knee: steroids within 24 weeks; hyaluronicacid 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 weeksbefore Day 1, including ajoene, birch bark, cayenne, Chinese black tree fungus, cumin,evening primrose oil, feverfew, garlic, ginger, ginkgo biloba, ginseng, grapeseedextract, 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 druguse or history of the following medical conditions or interventions: cardiac bypasssurgery or thromboembolic disease

• Treatment with dehydroepiandrosterone sulfates within 6 weeks before Day 1.similar chemical or pharmacological class.&#xD; &#xD;

• Predisposition to hypersensitivity due to multiple (2 or more) atopic diseases (such&#xD;as atopic eczema, asthma, and chronic allergic rhinitis and/or rhinoconjunctivitis) or&#xD;multiple (2 or more) severe allergies&#xD; &#xD;

• Allergy or contraindication to Tetracosactide&#xD; &#xD;

• Chronic medical conditions including but not limited to those stated below requiring&#xD;medical regime changes within 60 days before Day 1. Concurrent unstable peripheral,&#xD;cardiac, and cerebral vascular disease, poorly controlled chronic obstructive&#xD;pulmonary disease and asthma, coagulopathies, uncontrolled neurological conditions,&#xD;active tuberculosis, active infections, symptomatic cardiac arrhythmias, adrenal&#xD;insufficiency (primary or central), nephrotic syndrome, Cirrhosis (Child-Pugh stage B&#xD;or C), uncontrolled diabetes and uncontrolled hypothyroidism or hyperthyroidism, or&#xD;mental or emotional disorders that preclude reliable study participation.&#xD; &#xD;

• History of pituitary irradiation or recent (within 1 year) history of transsphenoidal&#xD;surgery&#xD; &#xD;

• Any cancer within the previous 5 years, except for basal cell carcinomas.&#xD; &#xD;

• Current hyperkalemia and/or hyponatremia.&#xD; &#xD;

• History or current autoimmune polyglandular syndromes&#xD; &#xD;

• Presence of any underlying physical or psychological medical condition that, in the&#xD;opinion of the Investigator, would make it unlikely that the participant will comply&#xD;with the protocol or complete the study per protocol.&#xD; &#xD;

• Current treatment with anticoagulants or antiplatelet drugs, excluding aspirin ≤100&#xD;mg/day.&#xD; &#xD;

• Previous treatment with PPS in any form.&#xD; &#xD;

• Current or recent (within 90 days before Day 1) immunosuppressive or immunomodulatory&#xD; (with immunosuppressive effects) systemic therapy including but not limited to oral,&#xD;inhaled, intranasal, intra-articular and topical corticosteroids (occasional use of&#xD;topical, inhaled or intranasal corticosteroids is acceptable).&#xD; &#xD;

• Use of opioids within 6 weeks before Day 1.&#xD; &#xD;

• Use of bisphosphonates within 12 weeks before Day 1.&#xD; &#xD;

• Use of denosumab and iloprost within 12 weeks before Day 1.&#xD; &#xD;

• Use of a knee brace on the index knee within 2 weeks before Day 1.&#xD; &#xD;

• Systemic steroids administered intravenously, intramuscularly, and orally for OA or&#xD;other indications within 8 weeks before Day 1.&#xD; &#xD;

• Intra-articular injections to the index knee: steroids within 24 weeks; hyaluronic&#xD;acid or any other intra-articular injections within 24 weeks before Day 1.&#xD; &#xD;

• Cannabinoids within 30 days before Day 1.&#xD; &#xD;

• Use of vitamins and dietary supplements known to alter haemostasis within 2 weeks&#xD;before Day 1, including ajoene, birch bark, cayenne, Chinese black tree fungus, cumin,&#xD;evening primrose oil, feverfew, garlic, ginger, ginkgo biloba, ginseng, grapeseed&#xD;extract, milk thistle, omega 3 fatty acids, onion extract, St. John's wort, turmeric,&#xD;vitamins C and E, vitamin K.&#xD; &#xD;

• Known exposure to heparin within the last 100 days as determined by history of drug&#xD;use or history of the following medical conditions or interventions: cardiac bypass&#xD;surgery or thromboembolic disease&#xD; &#xD;

• Treatment with dehydroepiandrosterone sulfates within 6 weeks before Day 1.&#xD;

• Chronic use of oral glucocorticoid receptor antagonists or cortisol synthesisinhibitors 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 ProhibitedTherapy)

• 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.

• Activated partial thromboplastin time [aPTT]) > 36 seconds, platelets <150,000/µL, orliver 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 onchronic 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 asjudged by the Investigator (at Screening).
• Resting, supine blood pressure (BP) ≥160 mmHg in systolic pressure or ≥100 mmHg indiastolic pressure at Screening. If a participant is found to have uncontrolled and/oruntreated significant hypertension at Screening and anti-hypertensive treatment isinitiated, assessment for study eligibility should be deferred until BP andantihypertensive medication have been stable for at least 1 month. For participantswith previously diagnosed hypertension, antihypertensive medications must be stablefor at least 1 month before Screening.
• Evidence of pigmentary maculopathy identified by a retinal specialist duringScreening.
• Morning Cortisol ≤ 3 µg/dL.
• ACTH <10 pg/ml; Morning Cortisol >3 µg/dL and <10 µg/dL and peak cortisol (by ACTHstimulation test) <18 µg/dL.
• Largely or wholly incapacitated (eg, bedridden or confined to a wheelchair, permittinglittle 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 beforeScreening that, in the opinion of the investigator, may affect participant ability tocomply with study requirements.
• An employee of the Sponsor, clinical research organisations or research site personneldirectly affiliated with this study or their immediate family members defined as aspouse, parent, sibling, or child, whether biological or legally adopted.