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    Summary
    EudraCT Number:2022-002605-26
    Sponsor's Protocol Code Number:SynAct-CS006
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-10-07
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2022-002605-26
    A.3Full title of the trial
    A two-part, randomized, double-blind, multi-center, placebo-controlled study of the dose-range, safety and efficacy of 4 and 12 weeks of treatment with AP1189 in adult rheumatoid arthritis (RA) patients with an inadequate response to Methotrexate (MTX) alone - RESOLVE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A two-part, randomized, double-blind, multi-center, placebo-controlled study of the dose-range, safety and efficacy of 4 and 12 weeks of treatment with AP1189 in adult rheumatoid arthritis (RA) patients with an inadequate response to Methotrexate (MTX) alone - RESOLVE
    A.3.2Name or abbreviated title of the trial where available
    RESOLVE
    A.4.1Sponsor's protocol code numberSynAct-CS006
    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 SponsorSynAct Pharma ApS
    B.1.3.4CountryDenmark
    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 supportSynAct Pharma ApS
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNBCD A/S
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressHerlev Hovedgade 82
    B.5.3.2Town/ cityHerlev
    B.5.3.3Post code2730
    B.5.3.4CountryDenmark
    B.5.6E-mailregulatory@nbcd.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.3.1Product nameAP1189 Tablet
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNA
    D.3.9.1CAS number 1809420-72-1
    D.3.9.2Current sponsor codeAP1189
    D.3.9.3Other descriptive name2-[(E)-[(E)-3-[1-(2-nitrophenyl)pyrrol-2-yl]prop-2-enylidene]amino]guanidine
    D.3.9.4EV Substance CodeSUB267518
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rheumatoid Arthritis
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10003268
    E.1.2Term Arthritis rheumatoid
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary safety Objective
    Part A: The primary safety objective is to evaluate the safety and tolerability of 4 weeks treatment with multiple doses AP1189 once daily to determine the suitable doses to be tested in Part B.
    Part B: The primary safety objective is to evaluate the safety and tolerability of 12 weeks treatment with multiple doses of AP1189 once daily.

    Primary efficacy Objective
    Part A: The primary efficacy objective is to evaluate the efficacy of 4 weeks treatment with multiple doses AP1189 once daily to help define the suitable doses to be tested in Part B.
    Part B: The primary efficacy objective is to evaluate the efficacy of 12 weeks treatment with multiple doses AP1189 once daily.
    E.2.2Secondary objectives of the trial
    Secondary efficacy Objectives
    The secondary efficacy objectives are to evaluate the efficacy of AP1189 on various responder criteria, composite endpoints, quality of life, fatigue and use of rescue medication.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Subjects participating in the Part B voluntary MRI sub-study will undergo dynamic contrast-enhanced MRI scanning procedures at Baseline and at Week 12.
    E.3Principal inclusion criteria
    Inclusion criteria are the same for the Part A and the Part B population:
    1. Written informed consent has been obtained prior to initiating any study specific
    procedures
    2. Male and female subjects, 18 to 85 years of age
    3. Confirmed diagnosis of RA according to the 2010 ACR/EULAR RA classification
    criteria and ACR class I-III
    a. ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on
    68 joint counts)
    b. Must meet at least one of the following parameters at Screening:
    i. A positive result for anti-CCP or RF,
    OR
    ii. Serum CRP ≥ 6 mg/L based on central laboratory value
    4. Ongoing methotrexate therapy ≥12 weeks in a stable dose of 7.5 to 25 mg/week for
    at least 4 weeks prior to the baseline visit
    5. Subject has an inadequate clinical response to maximally tolerated methotrexate
    therapy
    6. Subjects should be receiving an adequate and prescribed stable dose of folic acid
    (≥5 mg/week total dose or as per local clinical practice) which should be confirmed
    or initiated at screening and continued throughout the study
    7. Negative QuantiFERON-in-Tube test (QFG-IT) (Mantoux test can be used if QFGIT
    is not possible)
    8. Subjects should be able to complete (read and write) the Patient-Reported Outcome
    questionnaires (PRO questionnaires)
    9. Females of childbearing potential must have a negative pregnancy test at screening and again at baseline
    10. Sexually active females of childbearing potential and male participants are excluded
    if not practicing two different methods of birth control with their partner during the
    study and for at least 90 days after the last dose of study drug or who will not
    remain abstinent during the study and for 90 days after the last dose. If employing
    birth control, each couple must use two of the following precautions: vasectomy,
    tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth
    control implant, birth control depot injections, condom with spermicide, or sponge
    with spermicide.
    E.4Principal exclusion criteria
    Exclusion criteria are the same for the Part A and the Part B populations:
    1. Use of all other biologic or nonbiologic DMARDs and immunosuppressive therapy
    within 4 weeks or five half-lives (whichever is longer) prior to administration of the
    first dose of study drug
    2. Oral steroids at a dose >10 mg/day of prednisone (or equivalent) or a prescription
    for oral steroids which has changed within 4 weeks of baseline
    3. Receipt of an intra-articular or parenteral corticosteroid injection within 4 weeks
    prior to baseline
    4. Participation in any other study involving investigational drug(s) within 4 weeks
    prior to baseline
    5. Major surgery (including joint operation) within 8 weeks prior to screening or
    planned surgery within the period of the study participation
    6. Rheumatic autoimmune disease other than RA, including systemic lupus
    erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma,
    polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis,
    pulmonary fibrosis or Felty’s syndrome). Sjögren’s syndrome with RA is allowable
    7. Functional class IV as defined by the ACR Criteria for Classification of Functional
    Status in RA or wheelchair/bedbound
    8. Prior history of or current inflammatory joint disease other than RA (e.g., gout,
    reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme
    disease)
    9. Subjects with fibromyalgia
    10. Initiation or change in dose for NSAIDs (including low-dose aspirin and COX-2
    inhibitors) within 2 weeks prior to baseline
    11. Evidence of serious uncontrolled concomitant cardiovascular (including clinically
    significantly prolonged QTc interval), nervous system, pulmonary (including
    obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled
    diabetes mellitus), or gastrointestinal disease
    12. Serum Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)
    higher than 1.5 x the upper limit of normal (ULN) and alkaline phosphatase (ALP)
    and/or bilirubin values above the ULN at the screening visit.
    13. Prior renal transplant, current renal dialysis, or moderate to severe renal
    insufficiency (determined by a derived glomerular filtration rate (GFR) using
    Cockcroft Gault formula of ≤60 ml/min/1,73m²)
    14. Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel
    disease where flares are commonly treated with oral or parenteral corticosteroids
    15. Evidence of active malignant disease (except basal cell carcinoma of the skin that
    has been excised and cured)
    16. Pregnant women or nursing (breastfeeding) mothers
    17. History of alcohol, drug, or chemical abuse within the 6 months prior to screening
    18. Neuropathy or other painful, chronic conditions that might interfere with pain
    evaluation
    19. Body weight of >150 kg
    20. HBsAg positive and/or Anti-HBc with sign of current infection. Participants with
    positive Anti-HBc should be tested for IgM anti-HBc - if IgM anti-HBc is positive
    the patient will be excluded.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Safety Endpoint
    • Adverse events (AE), physical examinations, vital sign measurements, electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry, and urinalysis)

    Primary Efficacy Endpoint
    • Effect of AP1189 compared to placebo in subjects with RA, evaluated by American College of Rheumatology 20% (ACR20) response rate at Week 4 (Part A) and Week 12 (Part B)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 4 (Part A) and week 12 (Part B)
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints
    The secondary efficacy endpoints are to compare the effects of multiple doses AP1189 against placebo by assessing:
    Response rates evaluated by the American College of Rheumatology 50% (ACR50) at Week 4 (Part A) and Week 12 (Part B)
    • Response rates evaluated by the American College of Rheumatology 70% (ACR70) at Week 4 (Part A) and Week 12 (Part B)Time from Baseline to when subjects achieve American College of Rheumatology response criteria (ACR20, 50 and 70)
    • Changes in clinical disease activity evaluated by a reduction in the Clinical Disease Activity Index (CDAI) from Baseline to Week 4 (Part A) or Week 12 (Part B).
    • Changes in clinical disease activity evaluated by reduction in DAS-28 (CRP) from Baseline to Week 4 (Part A) or Week 12 (Part B).
    • Proportion of subjects achieving Moderate Disease Activity based on CDAI at Weeks 2 and 4 (Part A) or Weeks 2, 4, 8 and 12 (Part B)
    • Proportion of subjects achieving Low Disease Activity based on CDAI at Weeks 2 and 4 (Part A) or Weeks 2, 4, 8 and 12 (Part B)
    • Proportion of subjects achieving disease remission based on CDAI at Weeks 2 and 4 (Part A) or Weeks 2, 4, 8 and 12 (Part B)
    • Proportion of subjects achieving Moderate Disease Activity based on DAS28(CRP) ≤ 5.1 at Weeks 2 and 4 (Part A) or Weeks 2, 4, 8 and 12 (Part B)
    • Proportion of subjects achieving Low Disease Activity based on DAS28(CRP) ≤ 3.2 at Weeks 2 and 4 (Part A) or Weeks 2, 4, 8 and 12 (Part B)
    • Proportion of subjects achieving disease remission based on DAS28(CRP) < 2.6 at Weeks 2 and 4 (Part A) or Weeks 2, 4, 8 and 12 (Part B)
    • Proportion of subjects treated with corticosteroids as rescue medication
    • Number of intra-articular corticosteroid injections given as rescue medication
    • Time from Baseline to rescue medication use
    • Change in subject-reported quality of life (using Health Assessment Questionnaire – Disability Index (HAQ-DI)) from Baseline to Week 4 (Part A) or Week 12 (Part B)
    • Change in subject-reported fatigue (using Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue) from Baseline to week 4 (Part A) or weeks 12 (Part B)
    • Change in CRP from Baseline to Weeks 2, 4 (Part A) or to Weeks 2, 4, 8 12 (Part B).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 4 (Part A) and week 12 (Part B)
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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 Yes
    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 trial4
    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 concerned10
    E.8.5The trial involves multiple Member States No
    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
    United States
    Moldova, Republic of
    Bulgaria
    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 years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    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: 280
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 140
    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 state55
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 420
    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)
    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 Decision2022-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-12-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-01-24
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