Clinical trial NCT04809376: Treatment Effects of Subcutaneous Injections of Pentosan Polysulfate Sodium vs Placebo in Participants With Knee OA Pain
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Osteoarthritis, Knee
Keywords: Osteoarthritis
Knee
Lead sponsor: Paradigm Biopharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2021-03-22
Enrollment: 602
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

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 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.

Primary outcomes:
measure: 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.
timeFrame: Baseline, Day 56
Secondary outcomes:
measure: 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
timeFrame: Baseline to Day 56
measure: 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
timeFrame: Baseline to Day 84
measure: 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
timeFrame: Baseline to Day 84
measure: 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
timeFrame: Baseline to Day 56 and Day 84
measure: 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
timeFrame: Baseline to Day 56 and Day 84
measure: 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
timeFrame: Baseline to Day 56 and Day 84
measure: 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
timeFrame: Baseline to Day 56 and Day 84
measure: 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
timeFrame: Baseline to Day 56 and Day 84
measure: 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
timeFrame: Baseline, Days 39, 56, 84, 112, 140 and 168
measure: 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.
timeFrame: Baseline, Days 11, 25, 39, 112, 140 and 168
measure: 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
timeFrame: Baseline, Days 11, 25, 39, 112, 140 and 168
measure: 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.
timeFrame: Baseline, Days 11, 25, 39, 112, 140 and 168
measure: 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
timeFrame: Baseline, Days 11, 25, 39, 112, 140, and 168
measure: 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
timeFrame: Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168
measure: 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
timeFrame: Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168
measure: 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)
timeFrame: Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168
measure: Stage 1 and 2: PGIC scores at Days 39, 112, 140, and 168
timeFrame: Baseline, Days 39, 112, 140, and 168
measure: Stage 1 and 2: Change from baseline at Days 56, 84, 112, 140, and 168 in Work Productivity and Activity Impairment (WPAI) questionnaire score
timeFrame: Baseline, Day 56, 84, 112, 140 and 168
measure: Stage 1 and 2: Number of days of rescue medication used from Day 1 to Day 168
timeFrame: Baseline up to Day 168
measure: Stage 1 and 2: Incidence of treatment-emergent Adverse Event (TEAEs), including serious AEs (SAEs)
timeFrame: Baseline up to Day 168
measure: Stage 1 and 2: Treatment-emergent clinical laboratory abnormalities
timeFrame: Baseline up to Day 168
measure: Stage 1 and 2: Clinically significant changes in electrocardiograms (ECG) compared with baseline (pharmacokinetic [PK] subset only)
timeFrame: Baseline, Day 1, Day 15, Day 36 and Day 39
Other outcomes:
measure: Exporatory: Number of participants with an Anti-Drug-Antibody (ADA) response after treatment
timeFrame: Baseline, Days 11, 25, 39, 56 and 84
measure: Exploratory: Correlation of Anti-Drug-Antibody (ADA) response with clinical events
timeFrame: Baseline, Days 11, 25, 39, 56, and 84
measure: Exploratory: PPS PK profile of single and multiple doses based on sparse blood sampling
timeFrame: 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
measure: Exploratory: Change in subchondral BML area and volume on MRI from baseline at Day 168
timeFrame: screening, Day 168
measure: Exploratory: The effect of PPS on subchondral BML volume and area on MRI and whether these changes correlate with clinical outcomes
timeFrame: screening, Day 168
measure: Exploratory: Changes in joint synovitis/effusion volume on MRI from baseline on Day 168
timeFrame: screening, Day 168
measure: Exploratory: The effect of PPS on joint synovitis/effusion volume on MRI and whether these correlate with clinical outcomes
timeFrame: screening, Day 168
measure: Exploratory: Change in cartilage volume on MRI from baseline at Day 168
timeFrame: screening, Day 168
measure: Exploratory: The effect of PPS on cartilage volume changes on MRI and whether these correlate with clinical outcomes
timeFrame: screening, Day 168
measure: Exploratory: Change in bone shape on MRI from baseline at Day 168
timeFrame: screening, Day 168
measure: Exploratory: The effect of PPS on bone shape changes and whether these correlate with clinical outcomes
timeFrame: screening, Day 168
measure: Exploratory: Change in joint space width on MRI from baseline at Day 168
timeFrame: screening, Day 168
measure: Exploratory: The effect of PPS on joint space width changes and whether these correlate with clinical outcomes
timeFrame: screening, Day 168
Locations:
city: Tempe
country: United States
facility: Alliance for Multispecialty Research - Tempe
state: Arizona
city: Tempe
country: United States
facility: Fiel Family and Sports Medicine
state: Arizona
city: Tucson
country: United States
facility: Tucson Orthopaedic Institute
state: Arizona
city: Cerritos
country: United States
facility: Core Healthcare Group
state: California
city: La Mesa
country: United States
facility: Biosolutions Clinical Research Center
state: California
city: North Hollywood
country: United States
facility: Providence Clinical Research
state: California
city: Rancho Cucamonga
country: United States
facility: Prospective Research Innovations Inc.
state: California
city: Spring Valley
country: United States
facility: Encompass Clinical Research
state: California
city: Clearwater
country: United States
facility: Clinical Research of West Florida- Clearwater
state: Florida
city: DeLand
country: United States
facility: University Clinical Research-Deland
state: Florida
city: Miami
country: United States
facility: LMG Research
state: Florida
city: Miami
country: United States
facility: Well Pharma Medical Research, Corp.
state: Florida
city: Port Orange
country: United States
facility: Progressive Medical Research
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida
state: Florida
city: Winter Park
country: United States
facility: Conquest Research
state: Florida
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Newton
country: United States
facility: Alliance for Multispecialty Research - Newton
state: Kansas
city: Wichita
country: United States
facility: Alliance for Multispecialty Research - Wichita West
state: Kansas
city: Wichita
country: United States
facility: Alliance for Multispecialty Research - Wichita East
state: Kansas
city: Marrero
country: United States
facility: Tandem Clinical Research
state: Louisiana
city: Las Vegas
country: United States
facility: Alliance for Multispecialty Research - Las Vegas
state: Nevada
city: Las Vegas
country: United States
facility: Kaplan Medical Research
state: Nevada
city: North Charleston
country: United States
facility: Coastal Carolina Research Center
state: South Carolina
city: Knoxville
country: United States
facility: Alliance for Multispecialty Research - Knoxville
state: Tennessee
city: Austin
country: United States
facility: FutureSearch Trials - Austin
state: Texas
city: Plano
country: United States
facility: Clinical Investigations of Texas
state: Texas
city: San Antonio
country: United States
facility: Clinical Trials of Texas, Inc.
state: Texas
city: San Antonio
country: United States
facility: Diagnostics Research Group - Northwest San Antonio
state: Texas
city: San Antonio
country: United States
facility: Discovery Clinical Trials
state: Texas
city: Maroubra
country: Australia
facility: Australian Clinical Research Network
state: New South Wales
city: Southport
country: Australia
facility: Griffith University
state: Queensland
city: Stepney
country: Australia
facility: Sportsmed
state: South Australia
city: Nedlands
country: Australia
facility: Linear Clinical Research Limited
state: Western Australia
Study officials:
affiliation: Northwestern University Feinberg School of Medicine
name: Thomas Schnitzer
role: PRINCIPAL_INVESTIGATOR
References: