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

• ClinicalTrials.gov Identifier: NCT05198310
• Recruitment Status: Active, not recruiting
• First Posted: January 20, 2022
• Last Update Posted: March 12, 2024
• Sponsor: Kiniksa Pharmaceuticals, Ltd.
• Information provided by (Responsible Party): Kiniksa Pharmaceuticals, Ltd.

Tracking Information

• First Submitted Date: January 3, 2022
• First Posted Date: January 20, 2022
• Last Update Posted Date: March 12, 2024
• Actual Study Start Date: December 14, 2021
• Actual Primary Completion Date: February 8, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 20, 2023)

• Cohorts 1 and 2: Incidence of Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Up to 24 weeks ]
• Cohorts 1 and 2: Maximum Serum Concentration (Cmax) [ Time Frame: Predose on Days 1-169 ]
• Cohorts 1 and 2: Area Under the Curve from Time 0 to the Last Measurable Concentration (AUC0-t) [ Time Frame: 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 [ Time Frame: Baseline, Week 12 ]

Original Primary Outcome Measures (submitted: January 3, 2022)

• Cohorts 1, 2, and 3: Incidence of Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Up to 24 weeks ]
• Cohorts 1, 2, and 3: Maximum Serum Concentration (Cmax) [ Time Frame: Predose on Days 1-169 ]
• Cohorts 1, 2, and 3: Area Under the Curve from Time 0 to the Last Measurable Concentration (AUC0-t) [ Time Frame: Predose on Days 1-169 ]
• Cohort 4 in conjunction with data from Cohorts 1 (placebo only), 2, and 3: Change from Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 [ Time Frame: Baseline, Week 12 ]

Current Secondary Outcome Measures (submitted: September 20, 2023)

• Cohorts 1 and 2: Change from Baseline in DAS28-CRP at Week 12 [ Time Frame: Baseline, Week 12 ]
• Cohort 3 and 4: Incidence of TEAEs [ Time Frame: Up to 24 weeks ]
• Cohort 3 and 4: Cmax [ Time Frame: Predose on Days 1-169 ]
• Cohort 3 and 4: AUC0-t [ Time Frame: Predose on Days 1-169 ]

Original Secondary Outcome Measures (submitted: January 3, 2022)

• Cohorts 1, 2, and 3: Change from Baseline in DAS28-CRP at Week 12 [ Time Frame: Baseline, Week 12 ]
• Cohort 4: Change from Baseline in DAS28-CRP at Week 12 [ Time Frame: Baseline, Week 12 ]
• Cohort 4: Incidence of TEAEs [ Time Frame: Up to 24 weeks ]
• Cohort 4: Cmax [ Time Frame: Predose on Days 1-169 ]
• Cohort 4: AUC0-t [ Time Frame: Predose on Days 1-169 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Arthritis, Rheumatoid

Intervention

• Drug: KPL-404
  Humanized monoclonal antibody
• Drug: Placebo
  Matching placebo

Study Arms

• Experimental: Cohort 1 KPL-404
  KPL-404 2mg/kg Subcutaneous (SC) q2wk for 12 weeks
  Intervention: Drug: KPL-404
• Placebo Comparator: Cohort 1 Placebo
  Placebo for KPL-404 SC q2wk for 12 weeks
  Intervention: Drug: Placebo
• Experimental: Cohort 2 KPL-404
  KPL-404 5mg/kg SC q2wk for 12 weeks
  Intervention: Drug: KPL-404
• Placebo Comparator: Cohort 2 Placebo
  Placebo for KPL-404 SC q2wk for 12 weeks
  Intervention: Drug: Placebo
• Experimental: Cohort 3 KPL-404
  KPL-404 5mg/kg SC qwk for 12 weeks
  Intervention: Drug: KPL-404
• Experimental: Cohort 3 KPL-404 and Placebo
  KPL-404 5mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks
  Interventions:

  • Drug: KPL-404
  • Drug: Placebo
• Placebo Comparator: Cohort 3 Placebo
  Placebo for KPL-404 SC qwk for 12 weeks
  Intervention: Drug: Placebo
• Experimental: Cohort 4 KPL-404
  KPL-404 SC q4wk for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at weeks 4 and 8.
  Intervention: Drug: KPL-404
• Placebo Comparator: Cohort 4 Placebo
  Placebo for KPL-404 SC q4wk for 12 weeks
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 8, 2024): 145
• Original Estimated Enrollment (submitted: January 3, 2022): 84
• Estimated Study Completion Date: May 2024
• Actual Primary Completion Date: February 8, 2024 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Czechia, Georgia, Hungary, Poland, South Africa, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT05198310
• Other Study ID Numbers: KPL-404-C211; 2022-000169-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Kiniksa Pharmaceuticals, Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: Kiniksa Pharmaceuticals, Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Kiniksa Pharmaceuticals, Ltd.
• Verification Date: March 2024