Study to Assess the Safety, Pharmacokinetics, and Efficacy of KPL-404 in Participants With Rheumatoid Arthritis With Inadequate Response or Intolerance to at Least One Biologic Disease-modifying Anti-rheumatic Drug or a Janus Kinase Inhibitor
- Registration Number
- NCT05198310
- Lead Sponsor
- Kiniksa Pharmaceuticals, Ltd.
- Brief Summary
Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis.
- Detailed Description
This is a 28-week (up to 4-week screening period, 12-week treatment period, and 12-week safety follow-up period), multicenter, randomized, double-blind, placebo-controlled, multiple dose, proof-of-concept study with PK lead-in designed to assess the safety, PK, efficacy and PD of KPL-404 in subjects with moderate to severe, active Rheumatoid Arthritis (RA) who have an inadequate response to or are intolerant to a Janus kinase inhibitor (JAKi) AND/OR at least one biologic disease-modifying anti-rheumatic drug (bDMARD). The objectives of the study are to evaluate safety, efficacy, and PD of KPL-404 compared with placebo across the estimated therapeutic range and to characterize PK across varying dose levels of KPL-404.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 145
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Body weight ≥ 40 to ≤ 140 kg for all cohorts.
-
Diagnosis of RA for ≥ 3 months fulfilling the 2010 American College of Rheumatology (ACR)/European Union League Against Rheumatism (EULAR) classification criteria for RA and that is categorized as ACR RA functional Class 1-3.
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Treated with a biological disease-modifying anti-rheumatic drug (bDMARDs) AND/OR Janus kinase inhibitor (JAKi) therapy for RA for ≥ 3 months and had inadequate response or had to discontinue bDMARD AND/OR JAKi therapy due to intolerance or toxicity, regardless of treatment duration.
-
Currently receiving conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) therapy ≥ 3 months and on a stable dose for ≥ 4 weeks before the first dose of investigational product.
- The following csDMARDs are allowed: oral or parenteral methotrexate ([MTX]; 7.5 to 25 mg/week), sulfasalazine (≤ 3000 mg/day), hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and leflunomide (≤ 20 mg/day).
- A combination of up to 2 background csDMARDs is allowed, except the combination of MTX and leflunomide.
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Meets all of the following disease activity criteria:
- Six or more swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at screening and baseline visits;
- Level of high-sensitivity C-reactive protein ≥ 3 mg/L (by central laboratory);
- Documented seropositivity for serum Rheumatoid Factor (RF) and/or Anti-citrullinated protein antibody (ACPA) (>ULN) at screening or by prior laboratory evaluation.
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Has completed a locally approved authorized COVID-19 vaccine regimen according to local guidance at least 3 weeks before the first dose of the Investigational Product.
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Must have discontinued all bDMARDs or JAKi prior to the first dose of investigational product. The washout period for bDMARDs or JAKi prior to the first dose of investigational product is specified below. For bDMARDs or JAKi not listed below washout should be at least 5 times the mean elimination half-life of a drug:
- ≥ 4 weeks for etanercept;
- ≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, tocilizumab, and sarilumab;
- ≥ 1 year for rituximab;
- ≥ 2 weeks for JAKi (either investigational or commercially available treatment).
-
Voluntarily sign and date an informed consent form approved by independent ethics committee/Institutional Review Board (IRB)
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Prior exposure to any other anti-CD40/CD40L agent.
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Inadequate response to 5 or more classes of advanced targeted therapies (bDMARD or tsDMARD; e.g., TNF inhibitors, IL-6 receptor inhibitors, T-cell costimulatory inhibitors, anti-CD-20 antibodies, JAK inhibitors). This does not include prior discontinuation due to drug intolerance.
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Injectable corticosteroids (including intra-articular) or treatment with > 10 mg/day dose oral prednisone or equivalent within 8 weeks prior to randomization.
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History of any arthritis with onset prior to age 16 years or current diagnosis of inflammatory joint disease other than RA (Current diagnosis of secondary Sjogren's syndrome is permitted).
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History of thromboembolic event or a significant risk of future thromboembolic events
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Clinically significant active infection including signs/symptoms suggestive of infection, any significant recurrent or chronic infection, or subjects at a high risk of infection
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History of cancer within the last 5 years from screening, except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured.
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History of any of the following cardiovascular conditions:
- Moderate to severe congestive heart failure (New York Heart Association class III or IV);
- Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting;
- Uncontrolled hypertension as defined by a confirmed systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
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Clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG with QT interval corrected for heart rate (QTc) > 500 msec.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1 Placebo Placebo Placebo for KPL-404 SC q2wk for 12 weeks Cohort 2 KPL-404 KPL-404 KPL-404 5mg/kg SC q2wk for 12 weeks Cohort 2 Placebo Placebo Placebo for KPL-404 SC q2wk for 12 weeks Cohort 3 KPL-404 KPL-404 KPL-404 5mg/kg SC qwk for 12 weeks Cohort 3 KPL-404 and Placebo Placebo KPL-404 5mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks Cohort 3 Placebo Placebo Placebo for KPL-404 SC qwk for 12 weeks Cohort 4 Placebo Placebo Placebo for KPL-404 SC q4wk for 12 weeks Cohort 1 KPL-404 KPL-404 KPL-404 2mg/kg Subcutaneous (SC) q2wk for 12 weeks Cohort 3 KPL-404 and Placebo KPL-404 KPL-404 5mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks Cohort 4 KPL-404 KPL-404 KPL-404 SC q4wk for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at weeks 4 and 8.
- Primary Outcome Measures
Name Time Method Cohorts 1 and 2: Incidence of Treatment-Emergent Adverse Events (TEAEs) Up to 24 weeks Cohorts 1 and 2: Area Under the Curve from Time 0 to the Last Measurable Concentration (AUC0-t) Predose on Days 1-169 Cohorts 1 and 2: Maximum Serum Concentration (Cmax) Predose on Days 1-169 Cohort 3 and 4: Change from Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 Baseline, Week 12
- Secondary Outcome Measures
Name Time Method Cohort 3 and 4: Incidence of TEAEs Up to 24 weeks Cohort 3 and 4: Cmax Predose on Days 1-169 Cohort 3 and 4: AUC0-t Predose on Days 1-169 Cohorts 1 and 2: Change from Baseline in DAS28-CRP at Week 12 Baseline, Week 12
Trial Locations
- Locations (41)
Jacaranda Hospital
🇿🇦Pretoria, Gauteng, South Africa
Clinresco Centres (Pty) Ltd
🇿🇦Kempton Park, Gauteng, South Africa
Umhlanga Hospital Medical Center
🇿🇦Umhlanga, Kwazulu-Natal, South Africa
Carewell Arthritis Center
🇺🇸Apple Valley, California, United States
Medvin Clinical Research
🇺🇸Whittier, California, United States
Inland Rheumatology Clinical Trials
🇺🇸Upland, California, United States
International Medical Research
🇺🇸Daytona Beach, Florida, United States
Millennium Research
🇺🇸Ormond Beach, Florida, United States
Paramount Medical Research & Consulting, LLC
🇺🇸Middleburg Heights, Ohio, United States
Altoona Center for Clinical Research
🇺🇸Duncansville, Pennsylvania, United States
Saint Francis Hospital- Memphis
🇺🇸Memphis, Tennessee, United States
West Broward Rheumatology Associates, Inc.
🇺🇸Tamarac, Florida, United States
Trinity Universal Research Assoc
🇺🇸Carrollton, Texas, United States
Arthritis and Rheumatology Research Institute
🇺🇸Allen, Texas, United States
Southwest Rheumatology Research LLC
🇺🇸Mesquite, Texas, United States
Rheumatology and Pulmonary Clinic
🇺🇸Beckley, West Virginia, United States
Medical center "Artmed" LTD
🇧🇬Plovdiv, Bulgaria
Vesalion s.r.o.
🇨🇿Ostrava, Czechia
JSC Evex Hospitals
🇬🇪Tbilisi, Georgia
Revmatologicky Utsav
🇨🇿Praha 2, Czechia
Medical Plus S.R.O.
🇨🇿Uherské Hradiště, Czechia
Aleksandre Aladashvili Clinic LLC
🇬🇪Tbilisi, Georgia
LTD Israel-Georgian Medical Research Clinic Helsicore
🇬🇪Tbilisi, Georgia
LTD Georgian-Dutch Hospital
🇬🇪Tbilisi, Georgia
Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
🇭🇺Szeged, Csongrád, Hungary
Qualiclinic Ltd (Qualiclinic Inc)
🇭🇺Budapest, Hungary
Magyar Honvedseg Egeszsegugyi Kozpont
🇭🇺Budapest, Hungary
Porcika Klinika
🇭🇺Hódmezővásárhely, Hungary
Szabolcs-Szatmar-Bereg Megyei Korhazak es Egyetemi Oktatokorhaz
🇭🇺Nyíregyháza, Hungary
Vita Verum Medical Egeszsegugy
🇭🇺Székesfehérvár, Hungary
Centrum Kliniczno-Badawcze
🇵🇱Elblag, Poland
Silmedic sp. z o.o.
🇵🇱Katowice, Poland
RCMed Oddzial Sochaczew
🇵🇱Sochaczew, Poland
Prywatna Praktyka Lekarska Prof. UM dr hab.med. Pawel Hrycaj
🇵🇱Poznan, Poland
Centrum Medyczne Reuma Park
🇵🇱Warszawa, Poland
Sweet Hope Research Specialty, Inc.
🇺🇸Hialeah, Florida, United States
San Marcus Research Clinic, Inc.
🇺🇸Miami Lakes, Florida, United States
Arthritis & Osteoporosis Center of Coastal Bend
🇺🇸Corpus Christi, Texas, United States
DM Clinical Research
🇺🇸Tomball, Texas, United States
Rheumatology Clinic of Houston
🇺🇸Tomball, Texas, United States
Panorama Medical Centre
🇿🇦Cape Town, Western Cape, South Africa