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    Summary
    EudraCT Number:2022-001828-15
    Sponsor's Protocol Code Number:SynAct-CS007
    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:2022-09-27
    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 number2022-001828-15
    A.3Full title of the trial
    A double-blind, multi-center, randomized, placebo-controlled study of the safety and efficacy of 12 weeks extended treatment with AP1189 in early rheumatoid arthritis (RA) patients naïve to DMARD treatment -EXPAND
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A double-blind, multi-center, randomized, placebo-controlled study of the safety and efficacy of 12 weeks extended treatment with AP1189 in early rheumatoid arthritis (RA) patients naïve to DMARD treatment -EXPAND
    A.4.1Sponsor's protocol code numberSynAct-CS007
    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 INNNot applicable
    D.3.9.1CAS number 1809420-72-1
    D.3.9.2Current sponsor codeAP1189
    D.3.9.3Other descriptive name N''-[(E)-[(2E)-3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-en-1-ylidene]amino]guanidinium acetate
    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
    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
    To evaluate the efficacy and safety of AP1189 combined with MTX over 12 weeks
    E.2.2Secondary objectives of the trial
    To compare the effects of 100 mg AP1189 against placebo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Participants at selected sites will be offered participation in a voluntary sub-study evaluating the effects of AP1189 on MRI-based markers of inflammation. Participants agreeing to participate in the sub-study will each undergo two dynamic contrast-enhanced MRI scans during the trial. The
    sub-study is expected to enroll a total of 30-60 participants, and enrollment into the sub-study may be halted prior to the completion of the main trial enrollment, if sufficient participants in the sub-study have been enrolled.
    E.3Principal inclusion criteria
    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 are ACR class I-III (See Section 22.1)
    4. ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts). For participants participating in the MRI sub-study, at least one affected joint must be in the hand/wrist.
    5. Candidate for MTX treatment
    6. Is about to begin treatment with MTX
    7. Must meet at least one of the following parameters at Screening:
    a) A positive result for anti-Cyclic Citrullinated Peptide (anti-CCP) or rheumatoid factor (RF)
    OR
    b) Serum CRP ≥ 6 mg/L
    8. Highly active RA (CDAI > 22) at screening and baseline
    9. Negative QuantiFERON-in-Tube test (QFG-IT) (Mantoux test can be used if QFG-IT is not possible)
    10. Subjects should be able to complete (read and write) the Patient-Reported Outcome questionnaires (PRO questionnaires)
    11. Females of child-bearing potential may only participate if using a highly effective method of contraception (for detailed information see section22.3) or are post-menopausal (menstrual periods stopped at least 12 months ahead of the enrolment in the trial) Surgically sterilized women at
    least 6 months prior to screening
    12. Females of childbearing potential must have a negative pregnancy test at screening and baseline.
    E.4Principal exclusion criteria
    1. Participation in any other study involving investigational drug(s) within 4 weeks prior to study entry
    2. Major surgery (including joint operation) within 8 weeks prior to screening or planned surgery within 1 month following randomization
    3. 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
    4. Functional class IV as defined by the ACR Criteria for Classification of Functional Status in RA or wheelchair/bedbound
    5. Prior history of or current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease)
    6. Subjects with fibromyalgia
    7. Use of hydroxychloroquine within 4 weeks prior the Screening Visit
    8. Initiation of, or change in existing NSAID treatment (including COX-2-inhibitors) within 2 weeks prior to the baseline visit
    9. Corticosteroids except inhaled or nasal formulations for seasonal allergy or asthma are prohibited within 2 weeks prior to screening
    10. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal,
    hepatic, endocrine (including uncontrolled diabetes mellitus), or gastrointestinal disease
    11. Have prior renal transplant, current renal dialysis, or severe renal insufficiency (determined by a derived glomerular filtration rate (GFR)
    using Cockcroft Gault formula of ≤30 ml/min/1,73m²)
    12. Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease where flares are commonly treated with oral or parenteral
    corticosteroids
    13. Evidence of active malignant disease (except basal cell carcinoma of the skin that has been excised and cured)
    14. Pregnant women or nursing (breastfeeding) women
    15. History of alcohol, drug, or chemical abuse within the 6 months prior to screening
    16. Neuropathies or other painful conditions that might interfere with pain evaluation
    17. Body weight of >150 kg
    18. 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.

    For participants in the MRI sub-study, additional exclusion criteria apply, as specified in the protocol text.
    E.5 End points
    E.5.1Primary end point(s)
    The objectives of the trial are to evaluate the efficacy and safety of AP1189 combined with MTX over 12 weeks.

    Primary safety endpoint:
    • To compare the safety of AP1189 against placebo. Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram (ECG), and clinical laboratory testing (hematology, biochemistry, and urinalysis).

    Primary efficacy endpoint:
    • Effect of 100 mg AP1189 against placebo in subjects with RA, evaluated by the American College of Rheumatology 20% (ACR20) response rate at week 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:

    To compare the effects of 100 mg AP1189 against placebo by assessing:

    • The American College of Rheumatology 50% (ACR50) response rate
    at week 12
    • The American College of Rheumatology 70% (ACR70) response rate
    at week 12
    • Time from baseline to subjects achieving American College of
    Rheumatology response criteria (ACR20, 50, and 70)
    • Change in Clinical disease activity index (CDAI) from baseline to
    weeks 2, 4, 8, and 12.
    • Change in DAS-28 (CRP) from baseline to weeks 2, 4, 8, and 12.
    • Percentage of subjects achieving moderate disease activity based on
    CDAI at weeks 2, 4, 8 and 12
    • Percentage of subjects achieving low disease activity based on CDAI
    at weeks 2, 4, 8 and 12
    • Percentage of subjects achieving disease remission based on CDAI at
    weeks 2, 4, 8 and 12
    • Percentage of participants achieving moderate disease Activity based
    on DAS28(CRP) ≤ 5.1 at weeks 2, 4, 8 and 12
    • Percentage of participants achieving Low Disease Activity based on
    DAS28(CRP) ≤ 3.2 at weeks 2, 4, 8 and 12
    • Percentage of participants achieving disease remission based on
    DAS28(CRP) < 2.6 at weeks 2, 4, 8 and 12
    • Proportion of patients treated with corticosteroids as rescue
    medication
    • Number of intra-articular corticosteroid injections given as rescue
    medication
    • Time from baseline to subject is treated with corticosteroid as rescue
    medication
    • Change in subject-reported quality of life (using Health Assessment
    Questionnaire – Disability Index (HAQ-DI)) from baseline to week 12
    • Change in subject-reported fatigue (using Functional Assessment of
    Chronic Illness Therapy [FACIT]-Fatigue) from baseline to week 12
    • Change in C-Reactive Protein (CRP) from baseline to weeks 2, 4, 8
    12.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 2,4, 8 and 12.
    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 No
    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 trial2
    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 concerned12
    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
    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 years
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months10
    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: 92
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state81
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 81
    F.4.2.2In the whole clinical trial 132
    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 Decision2022-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-07-20
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