Dupilumab for the Treatment of Chronic Spontaneous Urticaria in Patients Who Remain Symptomatic Despite the Use of H1 Antihistamine and Who Are naïve to, Intolerant of, or Incomplete Responders to Omalizumab (LIBERTY-CSU CUPID)

Study Overview
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Brief Summary
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Primary Objective: To demonstrate the efficacy of dupilumab in study participants with CSU who remain symptomatic despite the use of H1 antihistamine (Study A and C: omalizumab naïve; Study B: omalizumab intolerant or incomplete responders) Secondary Objectives: To demonstrate the efficacy of dupilumab on urticaria activity composite endpoint and itch or hives, separately, at various timepoints To demonstrate the efficacy of dupilumab on angioedema To demonstrate the efficacy of dupilumab on urticaria control To demonstrate improvement in health-related quality of life and overall disease status and severity To evaluate the ability of dupilumab in reducing the proportion of patients who require treatment with oral corticosteroids (OCS) To evaluate safety outcome measures To evaluate immunogenicity of dupilumab

Detailed Description
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The duration of study for each participant will include 2-4 weeks of screening period, 24 weeks of treatment period and 12 weeks of post treatment period.

Official Title
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Master Protocol of Three Randomized, Double-blind, Placebo Controlled, Multi-center, Parallel-group Studies of Dupilumab in Patients With Chronic Spontaneous Urticaria (CSU) Who Remain Symptomatic Despite the Use of H1 Antihistamine Treatment in Patients naïve to Omalizumab and in Patients Who Are Intolerant or Incomplete Responders to Omalizumab

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Drug: Dupilumab SAR231893
* Drug: Placebo
* Drug: non sedating H1-antihistamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study A and C: Participant must be ≥6 years to 80 years of age at the time of signing the informed consent. Study B: Participant must be ≥12 years (or the minimum legal age for adolescents in the country of the investigational site) to 80 years of age at the time of signing the informed consent Participants who have a diagnosis of CSU refractory to H1 antihistamines (H1-AH) at the time of randomization defined by Diagnosis of CSU>6 months prior to screening visit Presence of itch and hives for >6 consecutive weeks at any time prior to screening visit despite the use of H1-AH during this time period Using a study defined H1-antihistamine for CSU treatment During the 7 days before randomization: UAS7≥16 ISS7≥ 8 Study A and C: omalizumab naïve, Study B; intolerant or incomplete responder to omalizumab Participants must be willing and able to complete a daily symptom e-Diary for the duration of the study Exclusion Criteria: Participants are excluded from any of the studies if any of the following criteria apply: Weight is less than 30 kg in adults and adolescents and 15 kg in children aged 6 to<12years Clearly defined underlying etiology for chronic urticarias other than CSU Presence of skin morbidities other than CSU that may interfere with the assessment of the study outcomes Active atopic dermatitis Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect the patient's participation in the study Active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis unless documented adequately treated. Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the screening visit and during the screening period Known or suspected immunodeficiency Active malignancy or history of malignancy within 5 years before the baseline visit, except completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin History of systemic hypersensitivity or anaphylaxis to omalizumab or any biologic therapy, including any excipients Participation in prior dupilumab clinical study, or have been treated with commercially available dupilumab. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study A Dupilumab<br>dose regimens, on top of non-sedating H1-antihistamine | Drug: Dupilumab SAR231893<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>Drug: non sedating H1-antihistamine<br>* Pharmaceutical form:Tablet Route of administration: oral administration<br>|
| Placebo Comparator: Study A Matched Placebo<br>placebo, on top of non-sedating H1-antihistamine | Drug: Placebo<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>Drug: non sedating H1-antihistamine<br>* Pharmaceutical form:Tablet Route of administration: oral administration<br>|
| Experimental: Study B Dupilumab<br>dose regimens, on top of non-sedating H1-antihistamine | Drug: Dupilumab SAR231893<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>Drug: non sedating H1-antihistamine<br>* Pharmaceutical form:Tablet Route of administration: oral administration<br>|
| Placebo Comparator: Study B Matched Placebo<br>placebo, on top of non-sedating H1-antihistamine | Drug: Placebo<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>Drug: non sedating H1-antihistamine<br>* Pharmaceutical form:Tablet Route of administration: oral administration<br>|
| Experimental: Study C Dupilumab<br>dose regimens, on top of non-sedating H1-antihistamine | Drug: Dupilumab SAR231893<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>Drug: non sedating H1-antihistamine<br>* Pharmaceutical form:Tablet Route of administration: oral administration<br>|
| Placebo Comparator: Study C Matched Placebo<br>placebo, on top of non-sedating H1-antihistamine | Drug: Placebo<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>Drug: non sedating H1-antihistamine<br>* Pharmaceutical form:Tablet Route of administration: oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in weekly itch severity score (except EU and EU reference countries) | Change from baseline in weekly itch severity score (ISS7) at Week 24. | Baseline to Week 24 | 
| For EU and EU reference countries only: change from baseline in weekly urticaria activity score | Change from baseline in weekly urticaria activity score (UAS7, composite patient reported itch and hive score) at Week 24. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in weekly urticaria activity score | Change from baseline in weekly urticaria activity score (UAS7, composite patient reported itch and hive score) at Week 12 and Week 24 (except EU and EU reference countries). | Baseline to Week 12 and Week 24 | 
| Change from baseline in ISS7 | Change from baseline in ISS7 at Week 12 and Week 24 (in EU and EU reference countries). | Baseline to Week 12 and Week 24 | 
| Change from baseline in weekly hives severity score | Change from baseline in weekly hives severity score (HSS7) at Week 12 and Week 24. | Baseline to Week 12 and Week 24 | 
| 4. Time to ISS7 minimally important (MID) (ISS7 ≥5) response | 4. Time to ISS7 minimally important (MID) (ISS7 ≥5) response. | 4. Baseline over time until Week 24 | 
| Proportion of ISS7 MID (≥5 points) responders | Proportion of ISS7 MID (≥5 points) responders at Week 12 and Week 24. | Week 12 and Week 24 | 
| Change from baseline in ISS7 at all time points | Change from baseline in ISS7 at all time points (onset of action is assessed by the first p<0.05 that remains significant at subsequent measures until Week 24). | Baseline to Week 24 | 
| Proportion of patients with UAS7 ≤6 | Proportion of patients with UAS7 ≤6 at Week 12 and Week 24. | Week 12 and Week 24 | 
| Proportion of patients with UAS7=0 | Proportion of patients with UAS7=0 at Week 12 and Week 24. | Week 12 and Week 24 | 
| Change from baseline in angioedema activity score over 7 days (AAS7) | Change from baseline in angioedema activity score over 7 days (AAS7) at Week 12 and Week 24. | Baseline to Week 12 and Week 24 | 
| Change from baseline in urticaria control test (UCT) | Change from baseline in urticaria control test (UCT) at Week 12 and Week 24. | Baseline to Week 12 and Week 24 | 
| Proportion of well controlled patients (UCT ≥12) | Proportion of well controlled patients (UCT ≥12) at Week 12 and Week 24. | Week 12 and Week 24 | 
| Change from baseline in health-related quality-of-life - DLQI | Change from baseline in health-related quality-of-life (HRQoL) as measured by Dermatology Life Quality Index (DLQI) in patients ≥16 years old. | Baseline to Week 12 and Week 24 | 
| Change from baseline in health-related quality-of-life - CDLQI | Change from baseline in health-related quality-of-life (HRQoL) as measured by Children's Dermatology Life Quality Index (CDLQI) in patients ≥6 - <16 years old at Week 12 and Week 24. | Baseline to Week 12 and Week 24 | 
| Patient Global Assessment of Change (PGIC) of CSU | Patient Global Assessment of Change (PGIC) of CSU at Week 12 and Week 24. | Week 12 and Week 24 | 
| Change from baseline in Patient Global Impression of Severity (PGIS) of CSU | Change from baseline in Patient Global Impression of Severity (PGIS) of CSU at Week 12 and Week 24. | Baseline to Week 12 and Week 24 | 
| Proportion of patients receiving OCS for CSU during the planned treatment period | Proportion of patients receiving OCS for CSU during the planned treatment period. | Baseline over time to Week 24 | 
| Time to event of patients receiving OCS for CSU during the planned treatment period | Tme to event of patients receiving OCS for CSU during the planned treatment period. | Baseline over time to Week 24 | 
| Percentage of participants experiencing treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) | Percentage of participants experiencing treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs). | Baseline to Week 24 | 
| Incidence of treatment-emergent ADA against dupilumab over time | Incidence of treatment-emergent ADA against dupilumab over time. | Baseline to Week 24 |