Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis

• Register: EUCTR
• Last refreshed on: 15 July 2024
• Main ID: EUCTR2022-000169-42-CZ
• Date of registration: 18/07/2022
• Prospective Registration: Yes
• Primary sponsor: Kiniksa Pharmaceuticals, Ltd.
• Public title: Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis
• Scientific 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
• Date of first enrolment: 18/07/2022
• Target sample size: 131
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2022-000169-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 9
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Czech Republic, Czechia, Georgia, Germany, Hungary, Poland, Serbia, South Africa, United States

Contacts

• Name: Erica Boswell
• Affiliation: Kiniksa Pharmaceuticals, Ltd.

• Name: Erica Boswell
• Affiliation: Kiniksa Pharmaceuticals, Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Voluntarily sign and date an informed consent form, approved by an Independent Ethics Committee/Institutional Review Board, prior to the initiation of any screening or studyspecific procedures.
2. Adult male or female, age 18 to 70 years of age (inclusive) at the time of signing the informed consent form.
3. Body weight = 40 to = 140 kg for all cohorts.
4. 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.
5. 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.
6. Currently receiving csDMARD therapy = 3 months and on a stable dose for = 4 weeks before the first dose of investigational product.
a. 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).
b. A combination of up to 2 background csDMARDs is allowed, except the combination of MTX and leflunomide.
7. Meets all of the following disease activity criteria: a. Six or more swollen joints (based on 66 joint counts) and = 6 tender joints (based on 68 joint counts) at screening and baseline visits;
b. Level of high-sensitivity C-reactive protein = 3 mg/L (= 0.3 mg/dL) by central laboratory;
c. Documented seropositivity for serum RF and/or ACPA (> ULN) at Screening or by prior laboratory evaluation.
8. Has completed a locally approved authorized COVID-19 vaccine regimen according to local guidance at least 3 weeks before the first dose of investigational product.
9. 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:
a. = 4 weeks for etanercept;
b. = 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, tocilizumab, and sarilumab;
c. = 1 year for rituximab;
d. = 2 weeks for JAKi (either investigational or commercially available treatment).
10. For potential participants already receiving opiate analgesia, the dose must be limited to no greater than 50 mg oral-morphine-equivalents per day (50 MME/day).
11. If female, must be either postmenopausal (defined as no menses for 12 months without other medical cause), permanently surgically sterile, or, for women of childbearing potential, must practice at least one highly effective method of contraception that is effective from study Day 1 through at least 30 days after the EOS visit (additional local requirements may apply). Sexually active female subjects must be:
• Nonpregnant, nonlactating, and having agreed to use a highly effective method of contraception from the screening visit until 30 days after EOS visit.
o Note: highly effective methods of contraception include: hormonal contraceptives associated with inhibition of ovulation (stable dose for at least 4 weeks prior to first dose of investigational product)
?intrauterine device
?intrauterine system
?bilateral tubal occlusion
?vasectomized m
Exclusion criteria:
1. Prior exposure to any other anti-CD40/CD40L agent.
2. 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.
3. Injectable corticosteroids (including intra-articular) or treatment with > 10 mg/day dose oral prednisone or equivalent within 8 weeks prior to randomization. (Note: Concomitant treatment with nonsteroidal anti-inflammatory drugs, acetaminophen, oral corticosteroids [equivalent to prednisone = 10 mg/day], or inhaled corticosteroids at a stable dose = 4 weeks prior to baseline for stable medical conditions is allowed and should be kept at a stable dose throughout the study.)
4. Has received any investigational product within 30 days or 5 half-lives, if the half-life is known, of the investigational product (whichever is longer) before the first dose of investigational product.
8. Receipt of live (attenuated) vaccine within the 4 weeks before baseline or expected need of live vaccination during study participation including 4 weeks after the last dose of investigational product.
9. History of any arthritis with onset prior to age 16 years or current diagnosis of inflammatory joint disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis and nonradiographic axial spondyloarthritis, reactive arthritis, overlap
connective tissue diseases, scleroderma, polymyositis, dermatomyositis, fibromyalgia [currently with active symptoms]). Current diagnosis of secondary Sjogren's syndrome is permitted.
10. Clinically significant active infection, including signs/symptoms suggestive of infection, any significant recurrent or chronic infection (including positive hepatitis C virus antibody), or any episode of infection requiring hospitalization or treatment with IV antibiotics within 12 weeks before screening, or treatment with oral anti-infectives within 14 days prior to the first dose of investigational product. Subjects with any opportunistic infection within 6 months before screening will be excluded from the study.
12. Subjects at a high risk of infection (e.g., history of hereditary or acquired immune deficiency disorder), a history of an infected joint prosthesis at any time with that
prosthesis still in situ, leg ulcers, indwelling urinary catheter, or persistent or recurrent chest infections.
13. Subjects testing positive for human immunodeficiency virus infection. HIV test will not be required if a subject had a previously documented negative HIV result within 8 weeks screening.
14. Subjects with chronic active hepatitis B infection as defined below will be excluded from the study:
a. Hepatitis B surface antigen positive.
b. Hepatitis B anti-core antibody positive but anti-surface antibody negative.
15. Positive (or 2 indeterminate) QuantiFERON® test results unless confirmation of prior completion of appropriate treatment for latent TB and no evidence of active TB (when possible, test should be performed at least 4 weeks after receiving an mRNA COVID-19 vaccine).
16. History of thromboembolic event, a significant risk of future thromboembolic events (defined as a definitive diagnosis of thrombophilia OR an unstable condition associated with an increased incidence of thrombosis, such as atrial fibrilla

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Rheumatoid arthritis (RA)
MedDRA version: 23.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Code: KPL-404
Pharmaceutical Form: Solution for injection
Current Sponsor code: KPL-404
Other descriptive name: Human IgG4 monoclonal antibody against CD40
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: Cohorts 1 and 2: To evaluate the efficacy of multiple SC doses of KPL-404 versus placebo for the treatment of RA.
Cohorts 3 and 4: To evaluate the safety, tolerability, and PK of KPL-404 versus placebo.

Primary end point(s): Cohorts 1, 2:
• Incidence of treatment-emergent adverse events (TEAEs)
• Maximum serum concentration (Cmax)
• Area under the serum concentration time curve from 0 to the end of the dosing interval (AUC0-t)
Cohorts 3 and 4:
•Change from baseline in disease activity score of 28 joints using C-reactive protein (DSA28-CRP) at Week 12.

Main Objective: Cohorts 1 and 2: To evaluate the dose response relationship as measured by safety, tolerability, and pharmacokinetics (PK) of multiple subcutaneous (SC) doses of KPL-404 versus placebo.
Cohorts 3 and 4: To evaluate the efficacy of KPL-404 versus placebo for the treatment of rheumatoid arthritis (RA).

Timepoint(s) of evaluation of this end point: At various time points as defined in the protocol

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: At various time points as defined in the protocol.

Secondary end point(s): Cohorts 1 and 2:
• Change from baseline in DAS28-CRP at Week 12 Cohort 3 and 4:
• Incidence of TEAEs
• Cmax
• AUC0-t

Secondary ID(s)

2022-000169-42-DE

155,963

KPL-404-C211

NCT05198310

Source(s) of Monetary Support

Kiniksa Pharmaceuticals, Ltd.

Ethics review

Status: Approved
Approval date: 13/07/2022
Contact: