NCT04809376进行中（未招募）2 期
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
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 602
- 试验地点
- 33
- 主要终点
- 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.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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
- •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.
排除标准
- •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
- •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
- •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
- •Use of bisphosphonates within 12 weeks before Day
- •Use of denosumab and iloprost within 12 weeks before Day
- •Use of a knee brace on the index knee within 2 weeks before Day
- •Systemic steroids administered intravenously, intramuscularly, and orally for OA or other indications within 8 weeks before Day
- •Intra-articular injections to the index knee: steroids within 24 weeks; hyaluronic acid or any other intra-articular injections within 24 weeks before Day
- •Cannabinoids within 30 days before Day
- •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
- •Chronic use of oral glucocorticoid receptor antagonists or cortisol synthesis inhibitors within12 weeks before Day
- •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
- •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:
- •subchondral insufficiency fractures
- •spontaneous osteonecrosis of the knee
- •osteonecrosis
- •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.
- 另有 8 项未显示
研究组 & 干预措施
PPS Twice Weekly
Experimental
Pentosan Polysulfate Sodium (PPS) twice weekly for 6 weeks
干预措施: Pentosan Polysulfate Sodium twice weekly (Drug)
PPS Once Weekly
Experimental
Pentosan Polysulfate Sodium (PPS) + placebo once weekly for 6 weeks
干预措施: Placebo (Sodium Chloride Injection, 0.9%) (Drug)
PPS Once Weekly
Experimental
Pentosan Polysulfate Sodium (PPS) + placebo once weekly for 6 weeks
干预措施: Pentosan Polysulfate Sodium once weekly (Drug)
PPS Fixed Dose Once Weekly
Experimental
Pentosan Polysulfate Sodium (PPS) Fixed dose (100mg,150mg, or 180mg) once weekly + placebo once weekly for 6 weeks
干预措施: Placebo (Sodium Chloride Injection, 0.9%) (Drug)
PPS Fixed Dose Once Weekly
Experimental
Pentosan Polysulfate Sodium (PPS) Fixed dose (100mg,150mg, or 180mg) once weekly + placebo once weekly for 6 weeks
干预措施: Pentosan Polysulfate Sodium Fixed Dose (Drug)
Placebo
Placebo Comparator
Placebo twice weekly for 6 weeks
干预措施: Placebo (Sodium Chloride Injection, 0.9%) (Drug)
结局指标
主要结局
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.
时间窗: 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.
次要结局
- 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(Baseline to Day 84)
- 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(Baseline to Day 56 and Day 84)
- 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(Baseline to Day 56 and Day 84)
- 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(Baseline to Day 56)
- 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(Baseline to Day 56 and Day 84)
- 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(Baseline to Day 84)
- 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(Baseline to Day 56 and Day 84)
- 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(Baseline to Day 56 and Day 84)
- 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(Baseline, Days 39, 56, 84, 112, 140 and 168)
- 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.(Baseline, Days 11, 25, 39, 112, 140 and 168)
- 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.(Baseline, Days 11, 25, 39, 112, 140 and 168)
- 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(Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168)
- 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(Baseline, Days 11, 25, 39, 112, 140 and 168)
- 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(Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168)
- Stage 1 and 2: PGIC scores at Days 39, 112, 140, and 168(Baseline, Days 39, 112, 140, and 168)
- Stage 1 and 2: Number of days of rescue medication used from Day 1 to Day 168(Baseline up to Day 168)
- 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(Baseline, Days 11, 25, 39, 112, 140, and 168)
- Stage 1 and 2: Clinically significant changes in electrocardiograms (ECG) compared with baseline (pharmacokinetic [PK] subset only)(Baseline, Day 1, Day 15, Day 36 and Day 39)
- 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)(Baseline, Days 11, 25, 39, 56, 84, 112, 140, and 168)
- Stage 1 and 2: Change from baseline at Days 56, 84, 112, 140, and 168 in Work Productivity and Activity Impairment (WPAI) questionnaire score(Baseline, Day 56, 84, 112, 140 and 168)
- Stage 1 and 2: Incidence of treatment-emergent Adverse Event (TEAEs), including serious AEs (SAEs)(Baseline up to Day 168)
- Stage 1 and 2: Treatment-emergent clinical laboratory abnormalities(Baseline up to Day 168)
研究者
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