Dupilumab for the Treatment of Chronic Inducible Cold Urticaria in Patients Who Remain Symptomatic Despite the Use of H1-antihistamine (LIBERTY-CINDU CUrIADS)

Study Overview
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Brief Summary
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Primary Objective: To demonstrate the efficacy of dupilumab in adult and adolescent participants with primary acquired chronic inducible cold urticaria (ColdU) who remain symptomatic despite the use of an H1-antihistamine Secondary Objectives: To demonstrate the efficacy of dupilumab on primary acquired chronic inducible ColdU disease control To demonstrate the efficacy of dupilumab on primary acquired chronic inducible ColdU local signs and symptoms (hives/wheals, itch, burning sensation and pain) after provocation test To demonstrate the efficacy of dupilumab on primary acquired chronic inducible ColdU disease activity 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 participants who require rescue therapy To evaluate the proportion of participants with cold exposure triggered urticaria 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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A Randomized, Double-blind, Placebo-controlled, Multi-center, Parallel-group Study of Dupilumab in Patients With Chronic Inducible Cold Urticaria Who Remain Symptomatic Despite the Use of H1-antihistamine Treatment

Conditions
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Cold 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: Participant must be ≥12 years to 80 years of age inclusive at the time of signing the informed consent Participants who have a diagnosis of primary acquired chronic inducible ColdU defined as recurrence of itchy wheals and/or angioedema due to cold for longer than 6 weeks prior to screening visit (Visit 1) Participants with positive ice cube provocation test, ie, presenting at least a confluent hive/wheal on the exposed skin area, at the screening visit (Visit 1) and randomization visit (Visit 2) Participants meeting at least 1 of the following criteria despite regular/daily or as needed use of H1-antihistamine (AH): Urticaria Control Test (UCT) (4 item) <12 at the screening visit (Visit 1) and randomization visit (Visit 2) Within 6 months prior to the screening visit, documented medical history of cold exposure triggered anaphylaxis or oropharyngeal edema Within 6 months prior to the screening visit, documented medical history of cold exposure triggered urticaria requiring emergency medical care visit or treatment with epinephrine Participants using a study defined H1-antihistamine regularly/daily or as needed for primary acquired chronic inducible cold urticaria Body weight ≥30 kg Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Clearly defined underlying etiology for urticaria other than primary acquired chronic inducible ColdU Presence of skin morbidities other than cold urticaria 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 any other biologic therapy or any of its 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: 12 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: Dupilumab<br>Dose regimens, on top of regular or as needed 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<br>|
| Placebo Comparator: Matched Placebo<br>Placebo,on top of regular/as needed 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with negative ice cube provocation test at Week 24 compared with placebo | Negative ice cube provocation test is defined as the absence of a confluent hives/wheal at the entire skin site of exposure after ice cube provocation test. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in urticaria control test at Week 24 compared with placebo | The UCT is a PRO questionnaire for assessing urticaria control. It is comprised of 4 items (UCT-4). The UCT-4 total score is 0-16, with a score of 16 for complete disease control. | Baseline to Week 24 | 
| Proportion of well-controlled participants at Week 24 compared with placebo | The UCT is a PRO questionnaire for assessing urticaria control. It is comprised of 4 items (UCT-4). The UCT-4 total score is 0-16, with a score of 16 for complete disease control. Well-controlled is UCT-4 total score ≥12. | Week 24 | 
| Proportion of participants with an improvement of ≥3 in UCT-4 item from baseline to Week 24 compared with placebo | The UCT is a PRO questionnaire for assessing urticaria control. It is comprised of 4 items (UCT-4). The UCT-4 total score is 0-16, with a score of 16 for complete disease control. | Baseline to Week 24 | 
| Change from baseline in local wheal intensity at the provocation site at Week 12 and 24 using the wheal intensity Likert scale compared with placebo | The Wheal intensity Likert scale (ranging from 0 to 5) is a clinician-reported outcome measure comprised of a single item assessing the intensity of patients' cutaneous reaction rated as follows: 0=no wheals; 1=numerous small, noncoalescent wheals; 2= a large, regular, slightly edematous, coalescent wheal; 3=a large and moderately edematous wheal; 4=a large, regular, and significantly edematous wheal without pseudopodia; and 5=a large, very edematous wheal with pseudopodia. | Baseline to Week 12 and Week 24 | 
| Change from baseline in local itch severity at the provocation site at Week 12 and 24 using the Peak Pruritus Numerical Rating Scale (NRS) compared with placebo | The peak pruritus NRS is a patient-reported outcome (PRO) comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst itch imaginable). | Baseline to Week 12 and Week 24 | 
| Change from baseline in local skin burning sensation at the provocation site at Week 12 and Week 24 using the peak burning sensation NRS compared with placebo | The peak burning sensation NRS is a PRO comprised of a single item rated on a scale from 0 (No burning sensation) to 10 (Worst imaginable burning sensation). | Baseline to Week 12 and Week 24 | 
| Change from baseline in local pain severity at the provocation site at Week 12 and Week 24 using the peak pain sensation NRS compared with placebo | The peak pain NRS is a PRO comprised of a single item rated on a scale from 0 (No pain) to 10 (Worst imaginable pain). | Baseline to Week 12 and Week 24 | 
| Proportion of participants with negative ice cube provocation test at Week 12 compared with placebo | Negative ice cube provocation test is defined as the absence of a confluent hives/wheal at the entire skin site of exposure after ice cube provocation test. | Week 12 | 
| Change from baseline in cold urticaria signs and symptoms severity at Week 24 on cold exposure days as measured by ColdUAS compared with placebo | Cold Urticaria Activity Score (ColdUAS) is a disease specific PRO questionnaire designed to determine cold urticaria disease activity. | Baseline to Week 24 | 
| Change from baseline in the proportion of cold urticaria sign and symptom free days at Week 24 on cold exposure days as measured by ColdUAS, compared with placebo | ColdUAS is a disease specific PRO questionnaire designed to determine cold urticaria disease activity. | Baseline to Week 24 | 
| Change from baseline in health-related quality-of-life (HRQoL) as measured by Dermatology Life Quality Index (DLQI) at Week 24 compared with placebo | The DLQI is a PRO developed to measure dermatology-specific HRQoL in patients ≥16 years old. Overall scoring ranges from 0 to 30, with a high score indicative of a poor HRQoL. | Baseline to Week 24 | 
| Change from baseline in HRQoL as measured by Children's Dermatology Life Quality Index (CDLQI) at Week 24 compared with placebo | The CDLQI is a validated questionnaire designed to measure the impact of skin disease on children's (≥12 to <16 years old) HRQoL. The CDLQI total score is 0-30. The higher the score, the greater the impact is on the child's HRQoL. | Baseline to Week 24 | 
| Change from baseline in Cold Urticaria Quality of Life (ColdU QoL) at Week 24 compared with placebo | ColdU-QoL questionnaire is a disease-specific PRO questionnaire designed to assess the impact of cold urticaria on patients' health-related QoL. | Baseline to Week 24 | 
| Proportion of participants receiving rescue therapy for primary acquired chronic inducible ColdU during the planned treatment period compared with placebo |  | Baseline to Week 24 | 
| Proportion of participants with cold exposure urticaria requiring emergency medical care visit or treatment with epinephrine | At provocation test and/or at home. | Baseline to Week 24 | 
| Percentages of participants experiencing treatment--emergent adverse events (TEAEs) or serious adverse events (SAEs) |  | Throughout the study up to Week 36 | 
| Incidence of treatment-emergent antidrug antibodies (ADA) against dupilumab over time |  | Throughout the study up to Week 36 |