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

• ClinicalTrials.gov Identifier: NCT04809376
• Recruitment Status: Active, not recruiting
• First Posted: March 22, 2021
• Last Update Posted: April 8, 2024
• Sponsor: Paradigm Biopharmaceuticals USA (INC)
• Information provided by (Responsible Party): Paradigm Biopharmaceuticals Ltd. ( Paradigm Biopharmaceuticals USA (INC) )

Study Description

Brief Summary:

The purpose of this study is to measure the change in pain and function with subcutaneous injections of pentosan polysulfate sodium (PPS) compared with subcutaneous injections of placebo in participants with knee osteoarthritis pain.

Study details include:

• The study duration will be up to 31 weeks per participant
• The treatment duration will be 6 weeks.
• The visit frequency will be twice weekly during treatment.
• The visit frequency will be every 4 weeks during the follow-up period.

Condition or disease	Intervention/treatment	Phase
Osteoarthritis, Knee	Drug: Pentosan Polysulfate Sodium twice weekly; Drug: Placebo (Sodium Chloride Injection, 0.9%); Drug: Pentosan Polysulfate Sodium Fixed Dose; Drug: Pentosan Polysulfate Sodium once weekly	Phase 2; Phase 3

Detailed Description:

This is a 2-stage, adaptive, randomized, double-blind, placebo-controlled, multicenter study that will evaluate the dose and treatment effect of PPS in participants with knee OA pain.

In Stage 1 (dose selection), approximately 468 participants will be randomised 1:1:1:1 to receive 1 of 3 PPS dose regimens or placebo for 6 weeks. A minimum of 96 participants (24 within each dose group) will be assigned to the Pharmacokinetic (PK) subset.

Participants in Stage 1 will be randomly allocated to receive:

• 1.5 mg/kg calculated for ideal body weight (IBW) PPS twice weekly
• 2 mg/kg IBW PPS once weekly + placebo once weekly
• 100/150/180 mg PPS if ≤ 65 kg/ ≥ 65 kg and ≤ 90kg/ > 90kg IBW+ placebo once weekly
• placebo twice weekly

In Stage 2, approximately 470 participants will be randomized 1:1 to receive the selected PPS dose regimen or placebo for 6 weeks. Approximately 150 participants (75 per group) will be assigned to the PK subset.

Participants in Stage 2 will be randomly allocated to receive:

• One of the 3 Stage 1 PPS dose regimens selected by the DMC
• placebo twice weekly

The maximum duration for each participant is approximately 31 weeks, which includes:

• 7-week Screening Period from Day -45 to Day -1
• 6-week Treatment Period from Day 1 to Day 39
• 18-week Follow-up Period from Day 40 to Day 168

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 602 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 2-stage, Adaptive, Randomised, Double-blind, Placebo-controlled, Multicentre Study to Evaluate Dose and Treatment Effect of Pentosan Polysulfate Sodium Compared With Placebo in Participants With Knee Osteoarthritis Pain
• Actual Study Start Date: October 19, 2021
• Estimated Primary Completion Date: October 15, 2024
• Estimated Study Completion Date: January 6, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: PPS Twice Weekly; Pentosan Polysulfate Sodium (PPS) twice weekly for 6 weeks	Drug: Pentosan Polysulfate Sodium twice weekly; Subcutaneous Injection, 1.5mg/kg Ideal body Weight (IBW); Other Name: PPS twice weekly
Experimental: PPS Once Weekly; Pentosan Polysulfate Sodium (PPS) + placebo once weekly for 6 weeks	Drug: Placebo (Sodium Chloride Injection, 0.9%); Placebo to match PPS; Other Name: Placebo; Drug: Pentosan Polysulfate Sodium once weekly; Subcutaneous Injection, 2.0mg/kg Ideal body Weight (IBW); Other Name: PPS once weekly
Experimental: PPS Fixed Dose Once Weekly; Pentosan Polysulfate Sodium (PPS) Fixed dose (100mg,150mg, or 180mg) once weekly + placebo once weekly for 6 weeks	Drug: Placebo (Sodium Chloride Injection, 0.9%); Placebo to match PPS; Other Name: Placebo; Drug: Pentosan Polysulfate Sodium Fixed Dose; Subcutaneous Injection, 100/150/180 mg if <65kg/ ≥ 65 kg and ≤ 90kg/ >90 kg IBW; Other Name: Fixed Dose
Placebo Comparator: Placebo; Placebo twice weekly for 6 weeks	Drug: Placebo (Sodium Chloride Injection, 0.9%); Placebo to match PPS; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change from baseline at Day 56 in knee pain as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index. [ Time Frame: Baseline, Day 56 ]
   WOMAC: The WOMAC® NRS 3.1 Index is a validated, self-administered, health status questionnaire that assesses pain, stiffness, and function in patients with hip or knee OA . The WOMAC pain sub-scale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee) during the past 48 hours. It is calculated as the mean of scores from 5 individual questions scored on a numerical rating scale (NRS). Scores for each question and WOMAC Pain sub-scale score on NRS ranged from 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain.

Secondary Outcome Measures :

1. Key secondary: Change from baseline at Day 56 in function as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index [ Time Frame: Baseline to Day 56 ]
   WOMAC: Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function sub-scale is a 17-item questionnaire used to assess the degree of difficulty experienced due to OA in index joint (knee) during the past 48 hours.
2. Key secondary: Change from baseline at Day 84 in knee pain as assessed by the average pain subscale score of the WOMAC NRS 3.1 Index [ Time Frame: Baseline to Day 84 ]
   WOMAC: The WOMAC pain sub-scale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee) during the past 48 hours.
3. Key secondary: Change from baseline at Day 84 in function as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index [ Time Frame: Baseline to Day 84 ]
   WOMAC: Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function sub-scale is a 17-item questionnaire used to assess the degree of difficulty experienced due to OA in index joint (knee) during the past 48 hours.
4. Stage 1 only: Change from baseline at Day 56 and 84 in knee pain as assessed by the average pain subscale score of the WOMAC NRS 3.1 Index for PPS 1.5 mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly [ Time Frame: Baseline to Day 56 and Day 84 ]
   WOMAC: The WOMAC pain sub-scale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee) during the past 48 hours.
5. Stage 1 only: Reduction in knee pain of ≥ 30% and ≥ 50% as assessed by the average pain subscale score of the WOMAC NRS 3.1 Index at Days 56 and 84 for PPS 1.5mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly [ Time Frame: Baseline to Day 56 and Day 84 ]
   WOMAC: The WOMAC pain sub-scale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee) during the past 48 hours.
6. Stage 1 only: Stage 1 only: Change from baseline at Day 56 and 84 in function as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index for PPS 1.5 mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly [ Time Frame: Baseline to Day 56 and Day 84 ]
   WOMAC: Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function sub-scale is a 17-item questionnaire used to assess the degree of difficulty experienced due to OA in index joint (knee) during the past 48 hours.
7. Stage 1 only: Improvement in function of ≥ 30% and ≥ 50% as assessed by the average functional subscale score of the WOMAC NRS 3.1 Index at Days 56 and 84 for PPS 1.5mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly [ Time Frame: Baseline to Day 56 and Day 84 ]
   WOMAC: Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function sub-scale is a 17-item questionnaire used to assess the degree of difficulty experienced due to OA in index joint (knee) during the past 48 hours.
8. Stage 1 only: PGIC scores at Days 56 and 84 for PPS 1.5mg/kg twice weekly, PPS 2.0mg/kg once weekly, and PPS fixed dose once weekly [ Time Frame: Baseline to Day 56 and Day 84 ]
   The PGIC is a self-administered question that rates participants overall improvement in chronic pain since beginning treatment from 1 "no change (or condition has worsened)" to 7 "a great deal better" in response to the question "Since beginning treatment, how would you describe the change (if any) in activity, limitation, symptoms, emotions, and overall QoL related to your arthritis".
9. Stage 1 and 2: Outcomes Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) Responder Index response rate at Days 39, 56, 84, 112, 140, and 168 [ Time Frame: Baseline, Days 39, 56, 84, 112, 140 and 168 ]
   Participants are considered as an OMERACT-OARSI responder: if the change (improvement) from baseline to day of interest was greater than or equal to >= 50 percent and >= 2 units in either WOMAC pain sub-scale or physical function sub-scale score; if change (improvement) from baseline to week of interest was >=20 percent and >=1 unit in at least 2 of the following: 1) WOMAC pain sub-scale score, 2) WOMAC physical function sub-scale score, 3) Patient Global Impression of Change (PGIC).
10. Stage 1 and 2: Change from baseline at Days 11, 25, 39, 112, 140 and 168 in knee pain as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index. [ Time Frame: Baseline, Days 11, 25, 39, 112, 140 and 168 ]
    WOMAC: The WOMAC pain sub-scale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee) during the past 48 hours.
11. Stage 1 and 2: Change from baseline in knee pain of >=30% and >=50% as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index at Days 11, 25, 39, 112, 140, and 168 [ Time Frame: Baseline, Days 11, 25, 39, 112, 140 and 168 ]
    Percentage of participants with reduction in WOMAC pain intensity of at least >=30% or >=50% compared to baseline as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index at Days 11, 25, 39, 56, 84, 112, 140, and 168.
12. Stage 1 and 2: Change from baseline at Days 11, 25, 39, 112, 140 and 168 in function as assessed by the average functional sub-scale score of the WOMAC® Index. [ Time Frame: Baseline, Days 11, 25, 39, 112, 140 and 168 ]
    WOMAC: Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function sub-scale is a 17-item questionnaire used to assess the degree of difficulty experienced due to OA in index joint (knee) during the past 48 hours.
13. Stage 1 and 2: Improvement in function of >=30% and >=50% as assessed by the average functional sub-scale score of the WOMAC® NRS 3.1 Index from baseline at Days 11, 25, 39, 112, 140, and 168 [ Time Frame: Baseline, Days 11, 25, 39, 112, 140, and 168 ]
    Percentage of participants with improvement in WOMAC function of at least >=30% or >=50% compared to baseline as assessed by the average function sub-scale score of the WOMAC® NRS 3.1 Index at Days 11, 25, 39, 56, 84, 112, 140, and 168.
14. Stage 1 and 2: Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, and 168 in knee stiffness as assessed by the average stiffness sub-scale score of the WOMAC® NRS 3.1 Index [ Time Frame: Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168 ]
    WOMAC: The WOMAC stiffness sub-scale is a 2-item questionnaire used to assess the amount of stiffness experienced due to OA in the index joint (knee) during the past 48 hours.
15. Stage 1 and 2: Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, and 168 overall as assessed by the overall score of WOMAC® NRS 3.1 Index [ Time Frame: Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168 ]
    WOMAC: The WOMAC® NRS 3.1 Index consists of 24 questions and produces 3 sub-scales scores for pain (5 questions), stiffness (2 questions), and function (17 questions) and a total score that summarizes overall disability.
16. Stage 1 and 2: Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, and 168 in Quality of Life (QoL) as assessed by Short Form-36 General Health Survey (SF-36) [ Time Frame: Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168 ]
    The SF-36 v2 is a 36-item, patient-reported survey of patient health, consisting of 8 scaled scores, which are the weighted sums of the questions in their section. The 1-week recall form asks the respondent to answer the questions as they pertain to the way he or she felt or acted during the past week.
17. Stage 1 and 2: PGIC scores at Days 39, 112, 140, and 168 [ Time Frame: Baseline, Days 39, 112, 140, and 168 ]
    The PGIC is a self-administered question that rates participants overall improvement in chronic pain since beginning treatment from 1 "no change (or condition has worsened)" to 7 "a great deal better" in response to the question "Since beginning treatment, how would you describe the change (if any) in activity, limitation, symptoms, emotions, and overall QoL related to your arthritis".
18. Stage 1 and 2: Change from baseline at Days 56, 84, 112, 140, and 168 in Work Productivity and Activity Impairment (WPAI) questionnaire score [ Time Frame: Baseline, Day 56, 84, 112, 140 and 168 ]
    This WPAI questionnaire (WPAI:OA-knee) is a validated self-administered questionnaire that assesses work impairment due to OA . The questionnaire gathers information on employment status, hours worked, hours missed due to OA, and hours missed for any other reasons.
19. Stage 1 and 2: Number of days of rescue medication used from Day 1 to Day 168 [ Time Frame: Baseline up to Day 168 ]
    In case of inadequate pain relief, either acetaminophen/paracetamol up to 3000 mg per day or topical analgesics, up to 4 days in a week could be taken as rescue medication between day 1 and Day 168. Number of participants with any use of rescue medication during the particular study week will be summarized
20. Stage 1 and 2: Incidence of treatment-emergent Adverse Event (TEAEs), including serious AEs (SAEs) [ Time Frame: Baseline up to Day 168 ]

    An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment.

    An SAE is any untoward medical occurrence that at any dose results in one or more of the following outcomes: death; life-threatening; requires in-patient hospitalization or prolongation of an existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; is an important medical event. Treatment-emergent are events between the first dose of study drug and up to Day 168 that were absent before treatment or that worsened relative to pre-treatment state.

21. Stage 1 and 2: Treatment-emergent clinical laboratory abnormalities [ Time Frame: Baseline up to Day 168 ]
    Treatment-emergent clinical laboratory abnormalities are abnormalities in labs between the first dose of study drug and up to Day 168 that were absent before treatment or that worsened relative to pre-treatment state
22. Stage 1 and 2: Clinically significant changes in electrocardiograms (ECG) compared with baseline (pharmacokinetic [PK] subset only) [ Time Frame: Baseline, Day 1, Day 15, Day 36 and Day 39 ]
    Clinically significant changes in ECGs between the first administration of study drug and up to Day 39 that were absent before treatment or that worsened relative to pre-treatment state.

Other Outcome Measures:

1. Exporatory: Number of participants with an Anti-Drug-Antibody (ADA) response after treatment [ Time Frame: Baseline, Days 11, 25, 39, 56 and 84 ]
   Human serum ADA samples will be analyzed for the presence or absence of anti-drug-antibodies by using a semi quantitative enzyme linked immunosorbent assay (ELISA).
2. Exploratory: Correlation of Anti-Drug-Antibody (ADA) response with clinical events [ Time Frame: Baseline, Days 11, 25, 39, 56, and 84 ]
   Human serum ADA samples will be analyzed for the presence or absence of anti-drug-antibodies by using a semi quantitative enzyme linked immunosorbent assay (ELISA).
3. Exploratory: PPS PK profile of single and multiple doses based on sparse blood sampling [ Time Frame: Stage 1: Day 1, 15 and 39 - pre-dose and 2, 4, and 6 hours. Pre-dose on Days 4, 8, 11, 18, 22, 25, 29, 32 and 36 ]
   Blood samples for assay of plasma PPS concentration will be obtained from a subset of patients before dosing and 2, 4, and 6 hours after dosing on study Days 1,15 and 39, and assayed using a sensitive, validated [binding, etc.] bioanalytical method. Plasma concentrations of PPS will be tabulated by time and participant and inspected for relationship to dose during titration and stable treatment phases.
4. Exploratory: Change in subchondral BML area and volume on MRI from baseline at Day 168 [ Time Frame: screening, Day 168 ]
   Bone Marrow lesions (BML) will be evaluated for changes based on MRI imaging
5. Exploratory: The effect of PPS on subchondral BML volume and area on MRI and whether these changes correlate with clinical outcomes [ Time Frame: screening, Day 168 ]
   Bone Marrow lesions (BML) will be evaluated for changes based on MRI imaging
6. Exploratory: Changes in joint synovitis/effusion volume on MRI from baseline on Day 168 [ Time Frame: screening, Day 168 ]
   Synovitis/effusion will be evaluated for changes based on MRI imaging
7. Exploratory: The effect of PPS on joint synovitis/effusion volume on MRI and whether these correlate with clinical outcomes [ Time Frame: screening, Day 168 ]
   Synovitis/effusion will be evaluated for changes based on MRI imaging
8. Exploratory: Change in cartilage volume on MRI from baseline at Day 168 [ Time Frame: screening, Day 168 ]
   Cartilage volume will be evaluated for changes based on MRI imaging
9. Exploratory: The effect of PPS on cartilage volume changes on MRI and whether these correlate with clinical outcomes [ Time Frame: screening, Day 168 ]
   Cartilage volume will be evaluated for changes based on MRI imaging
10. Exploratory: Change in bone shape on MRI from baseline at Day 168 [ Time Frame: screening, Day 168 ]
    Bone shape will be evaluated for changes based on MRI imaging
11. Exploratory: The effect of PPS on bone shape changes and whether these correlate with clinical outcomes [ Time Frame: screening, Day 168 ]
    Bone shape will be evaluated for changes based on MRI imaging
12. Exploratory: Change in joint space width on MRI from baseline at Day 168 [ Time Frame: screening, Day 168 ]
    Joint space will be evaluated for changes based on MRI imaging
13. Exploratory: The effect of PPS on joint space width changes and whether these correlate with clinical outcomes [ Time Frame: screening, Day 168 ]
    Joint space will be evaluated for changes based on MRI imaging

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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.

Contacts and Locations

Locations

United States, Arizona

Alliance for Multispecialty Research - Tempe

Tempe, Arizona, United States, 85281

Fiel Family and Sports Medicine

Tempe, Arizona, United States, 85283

Tucson Orthopaedic Institute

Tucson, Arizona, United States, 85712

United States, California

Core Healthcare Group

Cerritos, California, United States, 90703

Biosolutions Clinical Research Center

La Mesa, California, United States, 91942

Providence Clinical Research

North Hollywood, California, United States, 91606

Prospective Research Innovations Inc.

Rancho Cucamonga, California, United States, 91730

Encompass Clinical Research

Spring Valley, California, United States, 91978

United States, Florida

Clinical Research of West Florida- Clearwater

Clearwater, Florida, United States, 33765

University Clinical Research-Deland

DeLand, Florida, United States, 32720

LMG Research

Miami, Florida, United States, 33125

Well Pharma Medical Research, Corp.

Miami, Florida, United States, 33173

Progressive Medical Research

Port Orange, Florida, United States, 32127

Clinical Research of West Florida

Tampa, Florida, United States, 33606

Conquest Research

Winter Park, Florida, United States, 32789

United States, Illinois

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States, 60611

United States, Kansas

Alliance for Multispecialty Research - Newton

Newton, Kansas, United States, 67114

Alliance for Multispecialty Research - Wichita West

Wichita, Kansas, United States, 67205

Alliance for Multispecialty Research - Wichita East

Wichita, Kansas, United States, 67207

United States, Louisiana

Tandem Clinical Research

Marrero, Louisiana, United States, 77072

United States, Nevada

Alliance for Multispecialty Research - Las Vegas

Las Vegas, Nevada, United States, 89119

Kaplan Medical Research

Las Vegas, Nevada, United States, 89119

United States, South Carolina

Coastal Carolina Research Center

North Charleston, South Carolina, United States, 29405

United States, Tennessee

Alliance for Multispecialty Research - Knoxville

Knoxville, Tennessee, United States, 37909

United States, Texas

FutureSearch Trials - Austin

Austin, Texas, United States, 78731

Clinical Investigations of Texas

Plano, Texas, United States, 75075

Clinical Trials of Texas, Inc.

San Antonio, Texas, United States, 78229

Diagnostics Research Group - Northwest San Antonio

San Antonio, Texas, United States, 78229

Discovery Clinical Trials

San Antonio, Texas, United States, 78258

Australia, New South Wales

Australian Clinical Research Network

Maroubra, New South Wales, Australia, 2035

Australia, Queensland

Griffith University

Southport, Queensland, Australia, 4222

Australia, South Australia

Sportsmed

Stepney, South Australia, Australia, 5069

Australia, Western Australia

Linear Clinical Research Limited

Nedlands, Western Australia, Australia, 6009

Sponsors and Collaborators

Paradigm Biopharmaceuticals USA (INC)

Investigators

• Principal Investigator: Thomas Schnitzer; Northwestern University Feinberg School of Medicine

More Information

• Responsible Party: Paradigm Biopharmaceuticals USA (INC)
• ClinicalTrials.gov Identifier: NCT04809376
• Other Study ID Numbers: PARA_OA_002
• First Posted: March 22, 2021
• Last Update Posted: April 8, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Paradigm Biopharmaceuticals Ltd. ( Paradigm Biopharmaceuticals USA (INC) ):

Osteoarthritis; Knee

Additional relevant MeSH terms:

Osteoarthritis; Osteoarthritis, Knee; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Pentosan Sulfuric Polyester; Anticoagulants