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

Arthritis, Rheumatoid Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05198310
• Other study ID #: KPL-404-C211
• Secondary ID: 2022-000169-42
• Status: Completed
• Phase: Phase 2
• Start date: December 14, 2021
• Est. completion date: May 6, 2024

Study information

• Verified date: June 2024
• Source: Kiniksa Pharmaceuticals, Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: May 6, 2024
• Est. primary completion date: February 8, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid

Intervention

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

Locations

Country	Name	City	State
Bulgaria	Medical center "Artmed" LTD	Plovdiv
Czechia	Vesalion s.r.o.	Ostrava
Czechia	Revmatologicky Utsav	Praha 2
Czechia	Medical Plus S.R.O.	Uherské Hradište
Georgia	Aleksandre Aladashvili Clinic LLC	Tbilisi
Georgia	JSC Evex Hospitals	Tbilisi
Georgia	LTD Georgian-Dutch Hospital	Tbilisi
Georgia	LTD Israel-Georgian Medical Research Clinic Helsicore	Tbilisi
Hungary	Magyar Honvedseg Egeszsegugyi Kozpont	Budapest
Hungary	Qualiclinic Ltd (Qualiclinic Inc)	Budapest
Hungary	Porcika Klinika	Hódmezovásárhely
Hungary	Szabolcs-Szatmar-Bereg Megyei Korhazak es Egyetemi Oktatokorhaz	Nyíregyháza
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged	Csongrád
Hungary	Vita Verum Medical Egeszsegugy	Székesfehérvár
Poland	Centrum Kliniczno-Badawcze	Elblag
Poland	Silmedic sp. z o.o.	Katowice
Poland	Prywatna Praktyka Lekarska Prof. UM dr hab.med. Pawel Hrycaj	Poznan
Poland	RCMed Oddzial Sochaczew	Sochaczew
Poland	Centrum Medyczne Reuma Park	Warszawa
South Africa	Panorama Medical Centre	Cape Town	Western Cape
South Africa	Clinresco Centres (Pty) Ltd	Kempton Park	Gauteng
South Africa	Jacaranda Hospital	Pretoria	Gauteng
South Africa	Umhlanga Hospital Medical Center	Umhlanga	Kwazulu-Natal
United States	Arthritis and Rheumatology Research Institute	Allen	Texas
United States	Carewell Arthritis Center	Apple Valley	California
United States	Rheumatology and Pulmonary Clinic	Beckley	West Virginia
United States	Trinity Universal Research Assoc	Carrollton	Texas
United States	Arthritis & Osteoporosis Center of Coastal Bend	Corpus Christi	Texas
United States	Medvin Clinical Research	Covina	California
United States	International Medical Research	Daytona Beach	Florida
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Sweet Hope Research Specialty, Inc.	Hialeah	Florida
United States	Saint Francis Hospital- Memphis	Memphis	Tennessee
United States	Southwest Rheumatology Research LLC	Mesquite	Texas
United States	San Marcus Research Clinic, Inc.	Miami Lakes	Florida
United States	Paramount Medical Research & Consulting, LLC	Middleburg Heights	Ohio
United States	Millennium Research	Ormond Beach	Florida
United States	West Broward Rheumatology Associates, Inc.	Tamarac	Florida
United States	DM Clinical Research	Tomball	Texas
United States	Rheumatology Clinic of Houston	Tomball	Texas
United States	Inland Rheumatology Clinical Trials	Upland	California
United States	Medvin Clinical Research	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
Kiniksa Pharmaceuticals, Ltd.

Countries where clinical trial is conducted

United States,  Bulgaria,  Czechia,  Georgia,  Hungary,  Poland,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohorts 1 and 2: Incidence of Treatment-Emergent Adverse Events (TEAEs)		Up to 24 weeks
Primary	Cohorts 1 and 2: Maximum Serum Concentration (Cmax)		Predose on Days 1-169
Primary	Cohorts 1 and 2: Area Under the Curve from Time 0 to the Last Measurable Concentration (AUC0-t)		Predose on Days 1-169
Primary	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	Cohorts 1 and 2: Change from Baseline in DAS28-CRP at Week 12		Baseline, Week 12
Secondary	Cohort 3 and 4: Incidence of TEAEs		Up to 24 weeks
Secondary	Cohort 3 and 4: Cmax		Predose on Days 1-169
Secondary	Cohort 3 and 4: AUC0-t		Predose on Days 1-169