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    The EU Clinical Trials Register currently displays   43976   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2021-000424-35
    Sponsor's Protocol Code Number:CLOU064A2302
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-09-13
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2021-000424-35
    A.3Full title of the trial
    A multicenter, randomized, double-blind, placebo-controlled Phase 3 study of remibrutinib (LOU064) to investigate the efficacy, safety and tolerability for 52 weeks in adult chronic spontaneous urticaria patients inadequately controlled by H1-antihistamines.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study of efficacy and safety of remibrutinib in the treatment of chronic spontaneous urticaria in adults inadequately controlled by H1-antihistamines
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberCLOU064A2302
    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 SponsorNovartis Pharma AG
    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 supportNovartis Pharma AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Healthcare A/S
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressEdvard Thomsens Vej 14
    B.5.3.2Town/ cityKøbenhavn S
    B.5.3.3Post code2300
    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 nameRemibrutinib
    D.3.2Product code LOU064
    D.3.4Pharmaceutical form Film-coated 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 INNRemibrutinib
    D.3.9.2Current sponsor codeLOU064
    D.3.9.4EV Substance CodeSUB204118
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboFilm-coated tablet
    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
    Chronic Spontaneous Urticaria
    E.1.1.1Medical condition in easily understood language
    Chronic Hives
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10072757
    E.1.2Term Chronic spontaneous urticaria
    E.1.2System Organ Class 10040785 - Skin and subcutaneous 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
    To demonstrate that remibrutinib is superior to placebo in CSU with respect to change from baseline in UAS7 at Week 12 (Scenario 1 with UAS7 as primary efficacy endpoint) or with respect to change from baseline in ISS7 and HSS7 at Week 12 (Scenario 2 with ISS7 and HSS7 as co-primary efficacy endpoints)
    E.2.2Secondary objectives of the trial
    To demonstrate:
    -that remibrutinib is superior to placebo in CSU with respect to change from baseline in UAS7 at Week 12 (only in scenario 2)
    -that a greater proportion of participants who are treated with remibrutinib compared to placebo-treated participants at Week 12:
    --achieve disease activity control (UAS7 ≤ 6)
    --achieve complete absence of hives and itch (UAS7 = 0)
    -superiority of remibrutinib treated compared to placebo-treated participants at Week 12 with respect to (only in scenario 1):
    --reduction from baseline in the ISS7
    --reduction from baseline in the HSS7
    -that a greater proportion of participants who are treated with remibrutinib compared to placebo-treated participants:
    --achieve UAS7 ≤ 6 at Week 2
    --achieve DLQI = 0-1 at Week 12
    -that remibrutinib treated compared to placebo treated participants over 12 weeks:
    --maintain disease activity control (defined as UAS7≤6) for more weeks
    --have more angioedema occurrence-free weeks
    -the safety and tolerability
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1) DNA sampling / Pharmacogenetics
    The study includes an optional genetic research component.
    The purpose of genetic research may be to better understand the safety and efficacy of remibrutinib, or to learn more about human diseases, or to help develop ways to detect, monitor and treat diseases.
    As technology changes over time, the most appropriate technology will be used at the time the exploratory genetic research is performed. This may include the study of the entire genome.
    The use of DNA to search for biomarkers of disease and drug action is exploratory.

    2) Additional biomarker assessments
    The study includes additional optional biomarker research components.
    Samples will be stored and analyzed depending on results of other biomarker assessments in this study, the overall study outcome, and/or other studies. Serum samples will be collected for autoantibodies assessment and the assessment of additional exploratory biomarkers.
    These serum samples may be used to better understand disease heterogeneity and for the identification of efficacy and/or stratification markers. Additionally, the effect of remibrutinib exposure on antibody titers may be assessed. The analyses may include but are not limited to IgE-autoantibodies. Detailed descriptions of the assays will be included in the bioanalytical data reports. It may also include targeted single or multiplex biomarkers panels (autoantibody, proteins, peptides or metabolites biomarkers) or hypothesis-free platforms (autoantibody, protein, peptide and metabolite biomarkers).
    The list may be changed or expanded further, as it is recognized that more relevant or novel biomarkers may be discovered during the conduct of the trial.
    E.3Principal inclusion criteria
    Participants eligible for inclusion in this study must meet all of the following criteria:
    - Signed informed consent must be obtained prior to participation in the study
    - Male and female adult participants ≥18 years of age
    - CSU duration for ≥ 6 months prior to screening (defined as the onset of CSU determined by the investigator based on all available supporting documentation)
    - Diagnosis of CSU inadequately controlled by second generation H1-antihistamines at the time of randomization defined as:
    --The presence of itch and hives for ≥6 consecutive weeks prior to screening despite the use of second generation H1-antihistamines during this time period
    --UAS7 score (range 0-42) ≥16, ISS7 score (range 0-21) ≥ 6 and HSS7 score (range 0-21) ≥ 6 during the 7 days prior to randomization (Day 1)
    - Documentation of hives within three months before randomization (either at screening and/or at randomization; or documented in the participants` medical history)
    - Willing and able to complete an Urticaria Patient Daily Diary (UPDD) for the duration of the study and adhere to the study protocol
    - Participants must not have had more than one missing UPDD entry (either morning or evening) in the 7 days prior to randomization (Day 1)

    Other protocol-defined inclusion criteria may apply.
    E.4Principal exclusion criteria
    - Participants having a clearly defined predominant or sole trigger of
    their chronic urticaria (chronic inducible urticaria) including urticaria
    factitia (symptomatic dermographism), cold-, heat-, solar-, pressure-,delayed pressure-, aquagenic-, cholinergic-, or contact-urticaria
    - Other diseases with symptoms of urticaria or angioedema, including
    but not limited to urticaria vasculitis, urticaria pigmentosa, erythema
    multiforme, mastocytosis, hereditary urticaria, or drug-induced urticaria
    - Any other skin disease associated with chronic itching that might
    influence in the investigator's opinion the study evaluations and results, e.g. atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus or psoriasis
    - Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 12 months prior to Visit 1), neurological, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, hematological disorders, gastrointestinal disease or immunodeficiency that, in the investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the participant
    - Significant bleeding risk or coagulation disorders
    - History of gastrointestinal bleeding, e.g. in association with use of
    nonsteroidal anti-inflammatory drugs (NSAID), that was clinically
    relevant (e.g., where intervention was indicated or requiring
    hospitalization or blood transfusion)
    - Requirement for anti-platelet medication, except for acetylsalicylic acid up to 100 mg/d or clopidogrel up to 75 mg/d. The use of dual antiplatelet therapy (e.g. acetylsalicylic acid + clopidogrel) is prohibited.
    - Requirement for anticoagulant medication (for example, warfarin or
    Novel Oral Anti-Coagulants (NOAC))
    - History or current hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure or Aspartate
    Aminotransferase (AST)/ Alanine Aminotransferase (ALT) levels of more than 1.5 x upper limit of normal (ULN) or International Normalized Ratio (INR) of more than 1.5 at screening

    Other protocol-defined exclusion criteria may apply.
    E.5 End points
    E.5.1Primary end point(s)
    Absolute change from baseline in UAS7 (only in scenario 1)
    Absolute change from baseline in ISS7 (only in scenario 2)
    Absolute change from baseline in HSS7 (only in scenario 2)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary end point(s)
    - Absolute change from baseline in UAS7 (only in scenario 2)
    - Achievement of UAS7≤ 6 (yes/no) at Week 12;
    - Achievement of UAS7 = 0 (yes/no) at Week 12;
    - Improvement of severity of itch, assessed as absolute change from baseline in ISS7 score at Week 12 (only in scenario 1);
    - Improvement of severity of hives, assessed as absolute change from baseline in HSS7 score at Week 12 (only in scenario 1);
    - Achieving early onset of disease activity control, as defined as achievement of UAS7≤ 6 (yes/no) at Week 2;
    - No impact on participants' dermatology-quality of life, as defined by achievement of DLQI = 0-1 (yes/no) at Week 12;
    - Achieving sustained disease activity control, assessed as cumulative number of weeks with an UAS7≤6 response between baseline and Week 12;
    - Number of weeks without angioedema, assessed by the cumulative number of weeks with an AAS7= 0 response between baseline and Week 12;
    - Occurrence of treatment emergent adverse events and serious adverse events during the study
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 12;
    Week 2 for achieving early onset of disease activity control, defined as achievement of UAS7≤ 6 (yes/no)
    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 No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA31
    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
    South Africa
    United States
    Viet Nam
    Russian Federation
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    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 (last visit of the last subject)
    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 months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    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: 405
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 107
    F.4.2.2In the whole clinical trial 450
    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)
    Participants who complete 52 week treatment period of this trial may be eligible to receive remibrutinib as part of an extension study. For participants not willing or ineligible to roll over into extension study and who want to continue receiving remibrutinib every effort will be made to continue provision of study treatment prior to the IMP becoming available in the respective country, if in the opinion of the investigator, they are still deriving clinical benefit from remibrutinib.
    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 Decision2021-10-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-02-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-01-05
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