Efficacy and Safety of Subcutaneous Dupilumab for the Treatment of Adult Participants With Chronic Pruritus of Unknown Origin (CPUO) (LIBERTY-CPUO-CHIC)

Study Overview
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Brief Summary
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The main objective of the study is to assess efficacy and safety of dupilumab given up to 24 weeks in adults with CPUO. This is a master protocol which includes 2 parallel-treatment, double-blind, 2- arm Phase 3 staggered studies of similar design (Study A and Study B) in male and female participants aged 18 to 90 years with CPUO. Study B design may be adapted based on the results of Study A. For both Study A and B, after an up-to-4-week screening period, participants with severe pruritus (worst-itch numerical rating scale [WI-NRS ≥7) will enter a 4-week run-in period during with a non-sedative antihistamine and an emollient (moisturizer). Participants with severe pruritus (WI-NRS ≥7) at baseline will be randomized (1:1) to be treated for 24 weeks (Study A) or 12 weeks (Study B) with either dupilumab or matching placebo in addition to their antihistamine and emollient regimen. The treatment period for both study A and B will be followed by a 12-week follow-up period.

Detailed Description
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Study duration per participant will be up to 44 weeks (Study A) and 32 weeks (Study B).

Official Title
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Master Protocol of Two Randomized, Double Blind, Placebo-controlled, Multi-center, Parallel Group Studies to Evaluate the Efficacy and Safety of Dupilumab in Adult Patients With Chronic Pruritus of Unknown Origin (CPUO)

Conditions
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Pruritus

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo
* Drug: Fexofenadine (loratadine if not available)
* Drug: Moisturizer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 (or the legal age of consent in the jurisdiction in which the study is taking place) to 90 years of age inclusive, at the time of signing the informed consent. Participants with chronic pruritus for at least 6 months before the screening visit. Chronic pruritus considered of unknown origin as assessed by the investigator at baseline (excluding chronic pruritus secondary to dermatological or systemic conditions, of neuropathic or psychogenic origin or secondary to drugs). Chronic pruritus must affect at least 2 of the following body areas: legs, arms, or trunk. History of insufficient control of the chronic pruritus with prior treatment. Participants should receive optimal treatment for concomitant conditions that could impact pruritus (eg, diabetes, iron deficiency). Participants must have a history of severe itch and a worst itch score of ≥7 at screening on the WI-NRS (score scale ranges from 0 to 10; higher score indicates worse itch) and Patient global impression of severity (PGIS) of pruritus scored severe at screening. Participants must have an average worst itch score of ≥7 in the 7 days prior to run-in visit and in the 7 days prior to Day 1 on the WI-NRS. Participants scored severe in the PGIS of pruritus on Day 1. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the patient's participation in the study. Patients with active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis, unless it is well documented by a specialist that the participant has been adequately treated and can now start treatment with a biologic agent. Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of antiparasitic drug within 2 weeks before the screening visit. HIV infection. Severe renal failure (dialysis). Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the run-in visit. 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 and completely treated and resolved non metastatic squamous or basal cell carcinoma of the skin. History of hypersensitivity or intolerance to non-sedative antihistamines. 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: 18 Years
Maximum Age: 90 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>Loading dose administered subcutaneous (SC), followed by SC once every 2 weeks (Q2W) on top of non-sedative antihistamine and moisturizer | Drug: Dupilumab<br>* Injection solution subcutaneous<br>Drug: Fexofenadine (loratadine if not available)<br>* Tablet or capsule Oral<br>Drug: Moisturizer<br>* Topical<br>|
| Placebo Comparator: Placebo<br>Loading dose administered SC, followed by SC Q2W on top of non-sedative antihistamine and moisturizer | Drug: Placebo<br>* Injection solution SC<br>Drug: Fexofenadine (loratadine if not available)<br>* Tablet or capsule Oral<br>Drug: Moisturizer<br>* Topical<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study A: Proportion of participants with improvement (reduction) in weekly average of daily worst-itch numerical rating scale (WI-NRS) by ≥4 from baseline to Week 24 | WI-NRS is a patient reported outcome (PRO) comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 24 | 
| Study B: Proportion of participants with improvement (reduction) in weekly average of daily WI-NRS by ≥4 from baseline to Week 12 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study A; Proportion of participants with improvement (reduction) in weekly average of daily WI-NRS by ≥4 from baseline to Week 12 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 12 | 
| Study A: Proportion of participants who scored none or mild in Patient Global Impression of Severity (PGIS) of pruritus at Week 24 | The PGIS of pruritus is a one-item categorical scale that asks participants to provide the overall self-assessment of their pruritus severity on a 4-point scale for the past week. Response choices are: None, Mild, Moderate, Severe. | Week 24 | 
| Study A: Proportion of participants with improvement (reduction) in weekly average of daily WI-NRS by ≥4 from baseline over time until Week 24 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 24 | 
| Study A: Time to first response of WI-NRS ≥4 points reduction from baseline by Week 24 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 24 | 
| Study A: Absolute change from baseline in weekly average of daily WI-NRS at Week 24 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 24 | 
| Study A: Percent change from baseline in weekly average of daily WI-NRS at Week 24 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 24 | 
| Study A: Proportion of participants who scored none or mild in PGIS of pruritus at Week 12 | The PGIS of pruritus is a one-item categorical scale that asks participants to provide the overall self-assessment of their pruritus severity on a 4-point scale for the past week. Response choices are: None, Mild, Moderate, Severe. | Week 12 | 
| Study A: Absolute change from baseline in weekly average of daily WI-NRS at Week 12 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 12 | 
| Study A: Percent change from baseline in weekly average of daily WI-NRS at Week 12 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 12 | 
| Study A: Absolute change from baseline in weekly average of daily sleep disturbances numerical rating scale (NRS) at Week 24 | The sleep disturbance NRS is to be used by the participants to report the degree of their sleep loss related to itch over the past 24 hours. Participants will rate their sleep disturbance from 0 ('no sleep loss related to itch') to 10 ('I cannot sleep at all due to itch') once daily in the morning. | Baseline to Week 24 | 
| Study A: Percent change from baseline in weekly average of daily sleep disturbances NRS at Week 24 | The sleep disturbance NRS is to be used by the participants to report the degree of their sleep loss related to itch over the past 24 hours. Participants will rate their sleep disturbance from 0 ('no sleep loss related to itch') to 10 ('I cannot sleep at all due to itch') once daily in the morning. | Baseline to Week 24 | 
| Study A: Change from baseline in Dermatology Life Quality Index (DLQI) score at Week 24 | The DLQI is a validated 10-item questionnaire to measure dermatology-specific quality of life (QoL) in adult patients. Overall scoring ranges from 0 to 30, with a higher score indicating a poorer QoL. | Baseline to Week 24 | 
| Study A: Change from baseline in the Itchy quality of life (ItchyQoL) score at Week 24 | ItchyQoL is a pruritus-specific QoL instrument that measures specifically disease burden in pruritus patients. | Baseline to Week 24 | 
| Study A: Change from baseline in Hospital Anxiety and Depression Scale (HADS) total score at Week 24 | The HADS is a validated questionnaire for screening anxiety and depression in non-psychiatric populations. The total score ranges from 0 to 42. 0 to 7= normal; 8 to 10= borderline abnormal; 11 to 21= abnormal. | Baseline to Week 24 | 
| Study A: Absolute change from baseline in weekly average of daily sleep disturbances NRS at Week 12 | The sleep disturbance NRS is to be used by the participants to report the degree of their sleep loss related to itch over the past 24 hours. Participants will rate their sleep disturbance from 0 ('no sleep loss related to itch') to 10 ('I cannot sleep at all due to itch') once daily in the morning. | Baseline to Week 12 | 
| Study A: Percent change from baseline in weekly average of daily sleep disturbances NRS at Week 12 | The sleep disturbance NRS is to be used by the participants to report the degree of their sleep loss related to itch over the past 24 hours. Participants will rate their sleep disturbance from 0 ('no sleep loss related to itch') to 10 ('I cannot sleep at all due to itch') once daily in the morning. | Baseline to Week 12 | 
| Study A: Change from baseline in DLQI score at Week 12 | The DLQI is a validated 10-item questionnaire to measure dermatology-specific quality of life (QoL) in adult patients. Overall scoring ranges from 0 to 30, with a higher score indicating a poorer QoL. | Baseline to Week 12 | 
| Study A: Change from baseline in the ItchyQoL score at Week 12 | ItchyQoL is a pruritus-specific QoL instrument that measures specifically disease burden in pruritus patients. It is a 22-item instrument that measures the degree to which pruritus affects quality-of-life for the past week. The overall score is the average of the 22 items ranging from 1 to 5. A higher score corresponds to a more adverse impact on QoL. | Baseline to Week 12 | 
| Study A: Change from baseline in HADS total score at Week 12 | The HADS is a validated questionnaire for screening anxiety and depression in non-psychiatric populations. The total score ranges from 0 to 42. 0 to 7= normal; 8 to 10= borderline abnormal; 11 to 21= abnormal. | Baseline to Week 12 | 
| Study A: Percentage of participants experiencing treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) from baseline through end of study (EOS) | Percentage of participants experiencing TEAEs or SAEs from baseline through EOS | Baseline to Week 36 | 
| Study A: Incidence of treatment-emergent antidrug antibodies (ADA) against dupilumab | Incidence of treatment-emergent ADA against dupilumab | Baseline to Week 36 | 
| Study B: Proportion of participants who scored none or mild in PGIS of pruritus at Week 12 | The PGIS of pruritus is a one-item categorical scale that asks participants to provide the overall self-assessment of their pruritus severity on a 4-point scale for the past week. Response choices are: None, Mild, Moderate, Severe. | Week 12 | 
| Study B: Absolute change from baseline in weekly average of daily WI-NRS at Week 12 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 12 | 
| Study B: Percent change from baseline in weekly average of daily WI-NRS at Week 12 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 12 | 
| Study B: Proportion of participants with improvement (reduction) in weekly average of daily WI-NRS by ≥4 from baseline over time until Week 12 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 12 | 
| Study B: Time to first response of WI-NRS ≥4 points reduction from baseline by Week 12 | WI-NRS is a PRO comprised of a single item rated on a scale from 0 (No itch) to 10 (Worst imaginable itch). | Baseline to Week 12 | 
| Study B: Absolute change from baseline in weekly average of daily sleep disturbances NRS at Week 12 | The sleep disturbance NRS is to be used by the participants to report the degree of their sleep loss related to itch over the past 24 hours. Participants will rate their sleep disturbance from 0 ('no sleep loss related to itch') to 10 ('I cannot sleep at all due to itch') once daily in the morning. | Baseline to Week 12 | 
| Study B: Percent change from baseline in weekly average of daily sleep disturbances NRS at Week 12 | The sleep disturbance NRS is to be used by the participants to report the degree of their sleep loss related to itch over the past 24 hours. Participants will rate their sleep disturbance from 0 ('no sleep loss related to itch') to 10 ('I cannot sleep at all due to itch') once daily in the morning. | Baseline to Week 12 | 
| Study B: Change from baseline in DLQI score at Week 12 | The DLQI is a validated 10-item questionnaire to measure dermatology-specific quality of life (QoL) in adult patients. Overall scoring ranges from 0 to 30, with a higher score indicating a poorer QoL. | Baseline to Week 12 | 
| Study B: Change from baseline in the ItchyQoL score at Week 12 | ItchyQoL is a pruritus-specific QoL instrument that measures specifically disease burden in pruritus patients. It is a 22-item instrument that measures the degree to which pruritus affects quality-of-life for the past week. The overall score is the average of the 22 items ranging from 1 to 5. A higher score corresponds to a more adverse impact on QoL. | Baseline to Week 12 | 
| Study B: Change from baseline in HADS total score at Week 12 | The HADS is a validated questionnaire for screening anxiety and depression in non-psychiatric populations. The total score ranges from 0 to 42. 0 to 7= normal; 8 to 10= borderline abnormal; 11 to 21= abnormal. | Baseline to Week 12 | 
| Study B: Percentage of participants experiencing TEAEs or SAEs from baseline through EOS | Percentage of participants experiencing TEAEs or SAEs from baseline through EOS | Baseline to Week 24 | 
| Study B: Incidence of treatment-emergent ADA against dupilumab | Incidence of treatment-emergent ADA against dupilumab | Baseline to Week 24 |