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    Summary
    EudraCT Number:2022-000169-42
    Sponsor's Protocol Code Number:KPL-404-C211
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-07-18
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2022-000169-42
    A.3Full title of the trial
    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
    Multicentrická, randomizovaná, dvojitě zaslepená, placebem kontrolovaná studie fáze 2 hodnotící bezpečnost, farmakokinetiku a účinnost přípravku KPL-404 u subjektů se středně závažnou až závažnou aktivní revmatoidní artritidou s nedostatečnou odpovědí nebo s nesnášenlivostí nejméně jednoho biologického chorobu modifikujícího antirevmatického léku nebo inhibitoru Janusovy kinázy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis
    Studie fáze 2 hodnotící bezpečnost, snášenlivost, farmakokinetiku, farmakodynamiku a účinnost přípravku KPL-404 u subjektů se středně závažnou až závažnou revmatoidní artritidou.
    A.4.1Sponsor's protocol code numberKPL-404-C211
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05198310
    A.5.4Other Identifiers
    Name:INDNumber:155,963
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorKiniksa Pharmaceuticals, Ltd.
    B.1.3.4CountryBermuda
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportKiniksa Pharmaceuticals, Ltd.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKiniksa Pharmaceuticals, Ltd.
    B.5.2Functional name of contact pointErica Boswell
    B.5.3 Address:
    B.5.3.1Street AddressClarendon House, 2 Church Street
    B.5.3.2Town/ cityHamilton
    B.5.3.3Post codeHM 11
    B.5.3.4CountryBermuda
    B.5.4Telephone number+15599061057
    B.5.6E-mailClinicalTrials@Kiniksa.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code KPL-404
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeKPL-404
    D.3.9.3Other descriptive nameHuman IgG4 monoclonal antibody against CD40
    D.3.9.4EV Substance CodeSUB261005
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rheumatoid arthritis (RA)
    E.1.1.1Medical condition in easily understood language
    Rheumatoid arthritis (RA)
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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).
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 male partner
    abstinence from heterosexual intercourse
    12. Sexually active male subjects must have documented vasectomy or must agree to use a condom or highly effective method of contraception as defined above with their partners of childbearing potential from first dose of investigational product until 30 days after EOS visit.
    13. Male subjects must agree to refrain from donating sperm from first dose until 30 days after the last study drug administration. Female subjects must agree to refrain from donating eggs from first dose of investigational product until 30 days after EOS visit.
    14. Female subjects of childbearing potential must have a negative serum β-human chorionic gonadotropin (β-hCG) test at the screening visit and negative urine pregnancy test on Day 1.
    E.4Principal 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 fibrillation or presence of antiphospholipid antibodies). All history of thrombosis should be approved by the medical monitor.
    17. Laboratory values meeting the following criteria within the screening period (prior to randomization) of investigational product:
    a. Serum aspartate aminotransferase > 3 × upper limit of normal (ULN);
    b. Serum alanine aminotransferase > 3 × ULN;
    c. Total bilirubin > 2 × ULN;
    d. Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease formula < 40 mL/min/1.73 m2 ;
    e. Absolute neutrophil count < 1,500/μL;
    f. Hemoglobin < 9 g/dL;
    g. Total white blood cell count < 2,500/μL;
    h. Platelet count < 150,000/μL;
    i. Absolute lymphocyte count < 800/μL.
    19. 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.
    21. History of any of the following cardiovascular conditions:
    a. Moderate to severe congestive heart failure (New York Heart Association class III or IV);
    b. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting;
    c. Uncontrolled hypertension as defined by a confirmed systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
    22. Clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG with QT interval corrected for heart rate (QTc) > 500 msec.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At various time points as defined in the protocol
    E.5.2Secondary 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    At various time points as defined in the protocol.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial9
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA28
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Georgia
    Serbia
    South Africa
    United States
    Bulgaria
    Czechia
    Germany
    Hungary
    Poland
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 99
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 65
    F.4.2.2In the whole clinical trial 131
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Local Standard of Care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-07-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-13
    P. End of Trial
    P.End of Trial StatusOngoing
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