Clinical trial NCT05198310: 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
Official title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo Controlled Study to Assess the Safety, Pharmacokinetics, and Efficacy of KPL-404 in Subjects With Moderate to Severe Active Rheumatoid Arthritis With Inadequate Response or Intolerance to at Least One Biologic Disease-modifying Anti-rheumatic Drug or a Janus Kinase Inhibitor
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Arthritis, Rheumatoid
Keywords: inadequate responders
moderate to severe
Rheumatoid Arthritis
Lead sponsor: Kiniksa Pharmaceuticals International, plc
Sponsor class: INDUSTRY
First posted: 2022-01-20
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* 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.
* 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.

  1. 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).
  2. A combination of up to 2 background csDMARDs is allowed, except the combination of MTX and leflunomide.
* Meets all of the following disease activity criteria:

  1. Six or more swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at screening and baseline visits;
  2. Level of high-sensitivity C-reactive protein ≥ 3 mg/L (by central laboratory);
  3. Documented seropositivity for serum Rheumatoid Factor (RF) and/or Anti-citrullinated protein antibody (ACPA) (\>ULN) at screening or by prior laboratory evaluation.
* 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.
* 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:

  1. ≥ 4 weeks for etanercept;
  2. ≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, tocilizumab, and sarilumab;
  3. ≥ 1 year for rituximab;
  4. ≥ 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)

Exclusion Criteria:

* Prior exposure to any other anti-CD40/CD40L agent.
* 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.
* Injectable corticosteroids (including intra-articular) or treatment with \> 10 mg/day dose oral prednisone or equivalent within 8 weeks prior to randomization.
* 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).
* History of thromboembolic event or a significant risk of future thromboembolic events
* Clinically significant active infection including signs/symptoms suggestive of infection, any significant recurrent or chronic infection, or subjects at a high risk of infection
* 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.
* History of any of the following cardiovascular conditions:

  1. Moderate to severe congestive heart failure (New York Heart Association class III or IV);
  2. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting;
  3. Uncontrolled hypertension as defined by a confirmed systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg.
* Clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG with QT interval corrected for heart rate (QTc) \> 500 msec.

Primary outcomes:
measure: Cohorts 1 and 2: Incidence of Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to 24 weeks
measure: Cohorts 1 and 2: Maximum Serum Concentration (Cmax)
timeFrame: Predose on Days 1-169
measure: Cohorts 1 and 2: Area Under the Curve from Time 0 to the Last Measurable Concentration (AUC0-t)
timeFrame: Predose on Days 1-169
measure: Cohort 3 and 4: Change from Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12
timeFrame: Baseline, Week 12
Secondary outcomes:
measure: Cohorts 1 and 2: Change from Baseline in DAS28-CRP at Week 12
timeFrame: Baseline, Week 12
measure: Cohort 3 and 4: Incidence of TEAEs
timeFrame: Up to 24 weeks
measure: Cohort 3 and 4: Cmax
timeFrame: Predose on Days 1-169
measure: Cohort 3 and 4: AUC0-t
timeFrame: Predose on Days 1-169
Other outcomes:
Locations:
city: Apple Valley
country: United States
facility: Carewell Arthritis Center
state: California
city: Covina
country: United States
facility: Medvin Clinical Research
state: California
city: Upland
country: United States
facility: Inland Rheumatology Clinical Trials
state: California
city: Whittier
country: United States
facility: Medvin Clinical Research
state: California
city: Daytona Beach
country: United States
facility: International Medical Research
state: Florida
city: Hialeah
country: United States
facility: Sweet Hope Research Specialty, Inc.
state: Florida
city: Miami Lakes
country: United States
facility: San Marcus Research Clinic, Inc.
state: Florida
city: Ormond Beach
country: United States
facility: Millennium Research
state: Florida
city: Tamarac
country: United States
facility: West Broward Rheumatology Associates, Inc.
state: Florida
city: Middleburg Heights
country: United States
facility: Paramount Medical Research & Consulting, LLC
state: Ohio
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Memphis
country: United States
facility: Saint Francis Hospital- Memphis
state: Tennessee
city: Allen
country: United States
facility: Arthritis and Rheumatology Research Institute
state: Texas
city: Carrollton
country: United States
facility: Trinity Universal Research Assoc
state: Texas
city: Corpus Christi
country: United States
facility: Arthritis & Osteoporosis Center of Coastal Bend
state: Texas
city: Mesquite
country: United States
facility: Southwest Rheumatology Research LLC
state: Texas
city: Tomball
country: United States
facility: DM Clinical Research
state: Texas
city: Tomball
country: United States
facility: Rheumatology Clinic of Houston
state: Texas
city: Beckley
country: United States
facility: Rheumatology and Pulmonary Clinic
state: West Virginia
city: Plovdiv
country: Bulgaria
facility: Medical center "Artmed" LTD
city: Ostrava
country: Czechia
facility: Vesalion s.r.o.
city: Praha 2
country: Czechia
facility: Revmatologicky Utsav
city: Uherské Hradiště
country: Czechia
facility: Medical Plus S.R.O.
city: Tbilisi
country: Georgia
facility: Aleksandre Aladashvili Clinic LLC
city: Tbilisi
country: Georgia
facility: LTD Israel-Georgian Medical Research Clinic Helsicore
city: Tbilisi
country: Georgia
facility: JSC Evex Hospitals
city: Tbilisi
country: Georgia
facility: LTD Georgian-Dutch Hospital
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
state: Csongrád
city: Budapest
country: Hungary
facility: Qualiclinic Ltd (Qualiclinic Inc)
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyi Kozpont
city: Hódmezővásárhely
country: Hungary
facility: Porcika Klinika
city: Nyíregyháza
country: Hungary
facility: Szabolcs-Szatmar-Bereg Megyei Korhazak es Egyetemi Oktatokorhaz
city: Székesfehérvár
country: Hungary
facility: Vita Verum Medical Egeszsegugy
city: Elblag
country: Poland
facility: Centrum Kliniczno-Badawcze
city: Katowice
country: Poland
facility: Silmedic sp. z o.o.
city: Poznan
country: Poland
facility: Prywatna Praktyka Lekarska Prof. UM dr hab.med. Pawel Hrycaj
city: Sochaczew
country: Poland
facility: RCMed Oddzial Sochaczew
city: Warszawa
country: Poland
facility: Centrum Medyczne Reuma Park
city: Kempton Park
country: South Africa
facility: Clinresco Centres (Pty) Ltd
state: Gauteng
city: Pretoria
country: South Africa
facility: Jacaranda Hospital
state: Gauteng
city: Umhlanga
country: South Africa
facility: Umhlanga Hospital Medical Center
state: Kwazulu-Natal
city: Cape Town
country: South Africa
facility: Panorama Medical Centre
state: Western Cape
Study officials:
References: