E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Spontaneous Urticaria |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10072757 |
E.1.2 | Term | Chronic spontaneous urticaria |
E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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) |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full 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.
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E.3 | Principal 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. |
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E.4 | Principal 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 anti-platelet 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. |
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E.5 End points |
E.5.1 | Primary 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)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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 |
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E.5.2.1 | Timepoint(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)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Malaysia |
Switzerland |
Taiwan |
Brazil |
Canada |
China |
India |
Russian Federation |
South Africa |
Thailand |
United Kingdom |
United States |
Viet Nam |
Austria |
Denmark |
Germany |
Poland |
Slovakia |
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E.8.7 | Trial 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
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LVLS (last visit of the last subject) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |