Clinical trial: Treatment Effects of Subcutaneous Injections of Pentosan Polysulfate Sodium Versus Placebo in Participants With Knee Osteoarthritis Pain (NCT04809376)

Eligibility criteria:
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.

          -  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 Day 1 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 AND Day 1.

          -  Average WOMAC NRS 3.1 Index function sub-scale score of 4 to 10 in the index knee at
             Screening and Day 1.

          -  Body mass index of >=18 to <=39.0 kg/m2

          -  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 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, opioids, 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.

          -  Female subjects of childbearing potential and Male subjects must agree to comply with
             protocol specified contraceptive requirements

        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]).

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

          -  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.

          -  Current clinically significant medical conditions, medical history, physical findings,
             or laboratory abnormality that, in the Investigator's opinion, makes the participant
             unsuitable for the study. Chronic medical conditions will be allowed at the discretion
             of the Investigator but must be stable without necessitating medication changes within
             30 days before Day 1.

          -  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
             systemic therapy as follows:

               1. Chronic use of corticosteroids: >=15 mg/day of oral prednisolone or equivalent
                  daily,

               2. Intermittent corticosteroids: >=40 mg/day of oral prednisolone or equivalent for
                  1 or more short courses of >3 days.

          -  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 2 weeks before Day 1.

          -  Intra-articular injections to the index knee: steroids within 12 weeks; hyaluronic
             acid or any other intra-articular injections within 24 weeks 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.

          -  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]) > upper limit of normal (ULN), 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.

          -  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.

          -  Contraindication to MRI scans.

          -  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.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.


Patient description (medical language): A 47-year-old woman comes to the office complaining of pain in the calf and knee when she bends down. The pain limits her activity. Her medical history is significant for osteoarthritis, for which she uses nonsteroidal anti-inflammatory drugs (NSAIDs) for the past two years. She is living with her husband and has 3 children. She doesn't smoke but drinks alcohol occasionally. Her vital signs are normal. On physical examination, there is a small effusion in the right knee. The effusion grew a little larger and she developed a tender swelling in the popliteal fossa and calf. Both the pain and swelling worsened as she bent and straightened her knee.

Patient description (patient's own words): I'm a 47-year-old woman, married with 3 kids. I don't smoke and I drink occasionally. I went to the doctor because of pain in my calf and knee when I was bending down. This has been limiting my daily activities. I have been diagnosed with osteoarthritis for which I have taken anti-inflammatory drugs for the past 2 years. The doctor saw a small fluid buildup in my right knee. This buildup became a bit bigger and I have a swollen calf. The pain is worse when I bend and straighten my knee.

Does the patient match the trial criteria? Entailment