Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis
- Conditions
- Rheumatoid arthritis (RA)MedDRA version: 23.1Level: PTClassification code 10039073Term: Rheumatoid arthritisSystem Organ Class: 10028395 - Musculoskeletal and connective tissue disordersTherapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]
- Registration Number
- EUCTR2022-000169-42-DE
- Lead Sponsor
- Kiniksa Pharmaceuticals, Ltd.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 131
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 study specific procedures.
2. Adult male or female, age 18 to 80 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
- vasecto
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 antiinflammatory 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 (eg, 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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method