A Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (AD)

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study was to assess the ability of different Dupilumab dose regimens, administered as monotherapy, to maintain the treatment response achieved after 16 weeks of initial treatment with Dupilumab monotherapy compared to placebo.

Official Title
-----------------
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of Multiple Dupilumab Dose Regimens Administered as Monotherapy for Maintaining Treatment Response in Patients With Atopic Dermatitis

Conditions
-----------------
Atopic Dermatitis

Intervention / Treatment
-----------------
* Drug: Dupilumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Must have completed the treatment phase in 1 of the two 16-week initial treatment studies (R668-AD-1334 or R668-AD-1416). Must have achieved at least 1 of the following 2 treatment success criteria: Investigator Global Assessment (IGA) = 0 or 1 (clear or almost clear) at week 16 OR Eczema Area and Severity Index >= 75% (EASI-75) (at least 75% reduction in EASI score from baseline to week 16) Must be willing and able to comply with clinic visits and study-related procedures Must provide signed informed consent Must be able to understand and complete study-related questionnaires Key Exclusion Criteria: Receipt of rescue medication for AD in the initial treatment study Any conditions that require permanent discontinuation of study treatment in either initial treatment study Planned or anticipated major surgical procedure during the participants's participation in this study Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during this study Women unwilling to use adequate birth control, if of reproductive potential* and sexually active. Adequate birth control is defined as agreement to consistently practice an effective and accepted method of contraception, whenever engaging in heterosexual intercourse, throughout the duration of the study and for 120 days after last dose of study drug. These include hormonal contraceptives, intrauterine device, or double barrier contraception (e.g, condom + diaphragm), or a male partner with documented vasectomy. Additional requirements for acceptable contraception may apply in certain countries, based on local regulations. Investigators in these countries will be notified accordingly in a protocol clarification letter. (*For females, menopause is defined as at least 12 consecutive months without menses; if in question, a follicle stimulating hormone level of >= 25 milli units per milliliter (mU/mL) must be documented. Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented, as applicable; if documented, women with these conditions are not required to use additional contraception).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subcutaneous injection of Placebo (for Dupilumab) was administered once weekly (QW) from Week 1 (Day 1) to Week 36. | Drug: Placebo<br>* Subcutaneous injection of Placebo (for Dupilumab) was administered once weekly (QW).<br>|
| Experimental: Dupilumab 300 mg Q8W<br>Subcutaneous injection of Dupilumab 300 milligram (mg) alternatively with placebo (matched to Dupilumab) was administered once every eight week (Q8W) from Week 1 to Week 36. | Drug: Dupilumab<br>* Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) was administered.<br>* Other names: SAR231893;|
| Experimental: Dupilumab 300 mg Q4W<br>Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) was administered once every four week (Q4W) from Week 1 to Week 36. | Drug: Dupilumab<br>* Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) was administered.<br>* Other names: SAR231893;|
| Experimental: Dupilumab 300 mg Q2W/QW<br>Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) was administered once every week (QW) or twice a week (Q2W) from Week 1 to Week 36. | Drug: Dupilumab<br>* Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) was administered.<br>* Other names: SAR231893;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference Between Current Study Baseline and Week 36 in Percent Change in EASI From Parent Study Baseline (NCT02277743 and NCT02277769) | The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Difference of percent change in EASI between current study baseline and week 36 in from parent study baseline (NCT02277743 and NCT02277769) was reported. Values after first rescue treatment used were set to missing before multiple imputation (MI). | Baseline (Parent Study), Baseline (Current Study) and Week 36 (Current study) | 
| Percentage of Participants With Eczema Area and Severity Index >= 75% [EASI-75] at Baseline of Current Study Maintaining EASI-75 at Week 36 | The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-75 responders were the participants who achieved >=75% overall improvement in EASI score at Week 36. Values after first rescue treatment used were set to missing. Patients with missing value at week 36 were considered as a non-responder. | Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Maintaining Investigator Global Assessment (IGA) Response Within 1 Point of Baseline at Week 36 | IGA is an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response is an IGA score of 0 (clear) or 1 (almost clear). Participants with IGA score of 0 or 1 at baseline and maintaining within 1 point of baseline were reported as responders. Values after first rescue treatment used were set to missing. Participants with missing value at a visit were considered as a non-responder. | Baseline, Week 36 | 
| Percentage of Participants Maintaining Investigator Global Assessment (IGA) Response at 0 or 1 Point at Week 36 | IGA is an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response is an IGA score of 0 (clear) or 1 (almost clear). Participants with IGA score of 0 or 1 at week 36 were reported as responders. Values after first rescue treatment were set to missing and participants with missing IGA scores at Week 36 were considered as non-responders. | Week 36 | 
| Percentage of Participants With Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score Increased by 3 or More Points From Baseline to Week 35 | Pruritus NRS was an assessment tool that was used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Participants were asked the following question: how would a participant rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Values after first rescue treatment were set to missing and participants with missing peak NRS at Week 35 were considered as non-responders. | Baseline up to Week 35 | 
| Time to First Event of Investigator's Global Assessment (IGA) >= 2 for Participants With IGA 0 or 1 at Baseline | IGA is an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response is an IGA score of 0 (clear) or 1 (almost clear). | Baseline up to Week 36 | 
| Percentage of Participants With Increased Investigator's Global Assessment (IGA) Score 3 or 4 at Week 36 | IGA is an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response is an IGA score of 0 (clear) or 1 (almost clear). Values after first rescue treatment were set to missing and participants with missing IGA scores at Week 36 were considered as responders (i.e. having a increase 3 or 4 of IGA value). | Week 36 | 
| Percentage of Participants With Eczema Area and Severity Index-50 (EASI-50) (>= 50% Reduction in EASI Score) at Week 36 | The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-50 responders were the participants who achieved >= 50% overall improvement in EASI score from baseline to Week 36. Values after first rescue treatment were set to missing and participants with missing EASI-50 scores at Week 36 were considered as non-responders. | Week 36 | 
| Absolute Change From Baseline in Eczema Area and Severity Index (EASI) at Week 36 | The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Values after first rescue treatment were set to missing and participants with missing Values at Week 36 were imputed by using multiple imputation method. | Baseline, Week 36 | 
| Absolute Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 36 | SCORAD is a clinical tool for assessing the severity of AD developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23-31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) are assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). Values after first rescue treatment used were set to missing (censoring) before MI. | Baseline, Week 36 | 
| Absolute Change From Baseline in Peak Daily Pruritus Numerical Rating Scale (NRS) Score at Week 35 | Pruritus NRS was an assessment tool that was used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Participants were asked the following question: how would a participant rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Values after first rescue treatment used were set to missing before MI. | Baseline, Week 35 | 
| Absolute Change From Baseline in Body Surface Area (BSA) Through Week 36 | BSA affected by AD was assessed for each section of the body (the possible highest score for each region was: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]). It was reported as a percentage of all major body sections combined. Values after first rescue treatment used were set to missing (censoring) before MI. | Baseline through Week 36 | 
| Absolute Change From Baseline Through in Patient Oriented Eczema Measure (POEM) Through Week 36 | The POEM is a 7-item questionnaire that assesses disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding and weeping) with a scoring system of 0 (absent disease) to 28 (severe disease) (high score indicative of poor quality of life [QOL]). Values after first rescue treatment used were set to missing (censoring) before MI. | Baseline through Week 36 | 
| Absolute Change From Baseline in Dermatology Life Quality Index (DLQI) Through Week 36 | The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The 10 questions assessed QOL over the past week, with an overall scoring of 0 (absent disease) to 30 (severe disease); a high score was indicative of a poor QOL. Values after first rescue treatment used were set to missing before MI. | Baseline through Week 36 | 
| Absolute Change From Baseline in Hospital Anxiety Depression Scale (HADS) Through Week 36 | HADS is a fourteen item scale. Seven of the items relate to anxiety and seven items relate to depression. Each item on the questionnaire is scored from 0 (minimum score) - 3 (maximum score) and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression. Values after first rescue treatment used were set to missing before MI. | Baseline through Week 36 | 
| Difference Between Current Study Baseline and Week 36 in Percent Change in SCORAD From Parent Study Baseline | SCORAD is a clinical tool for assessing the severity of AD developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23-31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) are assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). Values after first rescue treatment used were set to missing before MI. | Baseline (Parent Study), Baseline (Current Study) and Week 36 (Current study) | 
| Difference Between Current Study Baseline and Week 35 in Percent Change in Peak Weekly Pruritus NRS From Parent Study Baseline | Pruritus NRS was an assessment tool that was used to report the intensity of a participant's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Participants were asked the following question: how would a participant rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 - 10 [0 = no itch; 10 = worst itch imaginable]). Values after first rescue treatment used were set to missing before MI. | Baseline (Parent Study), Baseline (Current Study) and Week 35 (Current study) | 
| Annualized Event Rate of Skin Infection Treatment- Emergent Adverse Events (TEAEs) | Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment- emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during on- treatment period (time from the first dose of study drug up to the end of study [Week 36]). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life- threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs. | Baseline through Week 36 | 
| Annualized Event Rate of Flares | Rate of Flares defined as worsening of disease requiring initiation or escalation of rescue treatment. | Baseline through week 36 | 
| Percentage of Well-Controlled Weeks During the On-treatment Period | Well-controlled weeks are those in which participants during their weekly IVRS call completion has their eczema been well-controlled over the last week during which no rescue treatments were administered. Percentage of well-controlled weeks during the on-treatment period were reported. | Baseline through Week 36 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Eczema