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Study to Assess the Efficacy and Long-term Safety of Dupilumab (REGN668/SAR231893) in Adult Participants With Moderate-to-Severe Atopic Dermatitis (CHRONOS)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02260986
First Posted: October 9, 2014
Last Update Posted: October 17, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Sanofi
Information provided by (Responsible Party):
Regeneron Pharmaceuticals
Results First Submitted: April 30, 2017  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Atopic Dermatitis
Interventions: Drug: Dupilumab
Drug: Placebo (for Dupilumab)
Other: Topical Corticosteroid (TCS)

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted in 14 countries between 16 Sep 2014 and 19 Oct 2016. A total of 957 participants were screened in the study.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Out of 957 participants, 740 participants were randomized and treated in the study. Participants were randomized in 3:1:3 ratio to receive Dupilumab 300 mg once weekly (qw) or Dupilumab 300 mg every 2 weeks (q2w) or placebo (for Dupilumab) qw.

Reporting Groups
  Description
Placebo qw Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 51.
Dupilumab 300 mg q2w Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab q2w from Week 1 to Week 51. During weeks in which Dupilumab was not administered, participants received placebo.
Dupilumab 300 mg qw Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection of Dupilumab qw from Week 1 to Week 51.

Participant Flow:   Overall Study
    Placebo qw   Dupilumab 300 mg q2w   Dupilumab 300 mg qw
STARTED   315   106   319 
Safety Population   315   110 [1]   315 [2] 
COMPLETED   225   93   278 
NOT COMPLETED   90   13   41 
Adverse Event                24                0                11 
Lack of Efficacy                27                3                0 
Protocol Violation                14                5                16 
Car accident                0                0                1 
Withdrawal by Subject                17                4                9 
Incorrect randomization                0                1                0 
Lack of investigation product supply                2                0                1 
Lost to Follow-up                4                0                3 
Pregnancy                2                0                0 
[1] 4 participants from Dupilumab 300 mg qw arm analyzed in Dupilumab 300 mg q2w arm
[2] 4 participants received fewer injections of Dupilumab 300 mg (analyzed in Dupilumab 300 mg q2w arm)



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Baseline population included all randomized participants.

Reporting Groups
  Description
Placebo qw Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 51.
Dupilumab 300 mg q2w Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab q2w from Week 1 to Week 51. During weeks in which Dupilumab was not administered, participants received placebo.
Dupilumab 300 mg qw Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection of Dupilumab qw from Week 1 to Week 51.
Total Total of all reporting groups

Baseline Measures
   Placebo qw   Dupilumab 300 mg q2w   Dupilumab 300 mg qw   Total 
Overall Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Age 
[Units: Years]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
   36.6  (13.01)   39.6  (13.98)   36.9  (13.67)   37.1  (13.46) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Female      122  38.7%      44  41.5%      128  40.1%      294  39.7% 
Male      193  61.3%      62  58.5%      191  59.9%      446  60.3% 
Ethnicity (NIH/OMB) 
[Units: Participants]
Count of Participants
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Hispanic or Latino      10   3.2%      2   1.9%      5   1.6%      17   2.3% 
Not Hispanic or Latino      299  94.9%      103  97.2%      309  96.9%      711  96.1% 
Unknown or Not Reported      6   1.9%      1   0.9%      5   1.6%      12   1.6% 
Race (NIH/OMB) 
[Units: Participants]
Count of Participants
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
American Indian or Alaska Native      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Asian      83  26.3%      29  27.4%      89  27.9%      201  27.2% 
Native Hawaiian or Other Pacific Islander      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Black or African American      19   6.0%      2   1.9%      13   4.1%      34   4.6% 
White      208  66.0%      74  69.8%      208  65.2%      490  66.2% 
More than one race      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Unknown or Not Reported      5   1.6%      1   0.9%      9   2.8%      15   2.0% 
Region of Enrollment 
[Units: Participants]
       
Romania         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Romania   2   0   2   4 
Hungary         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Hungary   11   5   11   27 
United States         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
United States   61   19   59   139 
Japan         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Japan   54   16   47   117 
United Kingdom         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
United Kingdom   17   4   15   36 
Spain         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Spain   4   2   4   10 
New Zealand         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
New Zealand   1   1   3   5 
Canada         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Canada   47   17   51   115 
Czech Republic         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Czech Republic   7   7   6   20 
Netherlands         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Netherlands   17   7   19   43 
Korea, Republic of         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Korea, Republic of   8   4   14   26 
Poland         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Poland   63   17   64   144 
Italy         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Italy   5   1   7   13 
Australia         
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
Australia   18   6   17   41 
Eczema Area and Severity Index (EASI) Score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
   32.6  (12.93)   33.6  (13.30)   32.1  (12.76)   32.5  (12.90) 
[1] The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures 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.
Investigator Global Assessment (IGA) Score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
   3.5  (0.50)   3.5  (0.50)   3.5  (0.50)   3.5  (0.50) 
[1] IGA was 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 was an IGA score of 0 (clear) or 1 (almost clear).
Weekly Peak Averaged Pruritus Numeric Rating Scale (NRS) [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
   7.3  (1.84)   7.4  (1.66)   7.1  (1.90)   7.3  (1.84) 
[1] Pruritus NRS was an assessment tool that was used to report the intensity of 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 worst moment during previous 24 hours (for maximum itch intensity on a scale of 0–10 [0=no itch;10=worst itch imaginable]).
Body Surface Area (BSA) Involvement with Atopic Dermatitis [1] 
[Units: Percentage of body surface area]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
   56.9  (21.69)   59.5  (20.84)   54.1  (21.76)   56.1  (21.66) 
[1] Body surface area 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.
SCORing Atopic Dermatitis (SCORAD) Score [1] [2] 
[Units: Units on a scale]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 313   105   316   734 
   66.0  (13.53)   69.3  (15.24)   65.9  (13.63)   66.4  (13.86) 
[1] SCORAD is a clinical tool for assessing the severity of atopic dermatitis 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).
[2] Number of participants analyzed = participants with available data for this baseline parameter.
Dermatology Life Quality Index (DLQI) Total Score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
   14.7  (7.37)   14.5  (7.31)   14.4  (7.17)   14.5  (7.27) 
[1] 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.
Patient Oriented Eczema Measure (POEM) [1] [2] 
[Units: Units on a scale]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 314   106   319   739 
   20.0  (5.99)   20.3  (5.68)   20.1  (6.05)   20.1  (5.95) 
[1] The POEM was a 7-item questionnaire that assessed 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]).
[2] Number of participants analyzed = participants with available data for this baseline parameter.
Global Individual Signs Score (GISS) [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
   8.7  (1.84)   8.9  (2.04)   8.9  (1.80)   8.8  (1.85) 
[1] Individual components of the AD lesions (erythema, infiltration/ papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0 = none, 1 = mild, 2 = moderate and 3 = severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease).
Total Hospital Anxiety Depression Scale (HADS) [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
       
Participants Analyzed 
[Units: Participants]
 315   106   319   740 
   12.6  (8.06)   12.9  (7.73)   12.8  (8.01)   12.7  (7.98) 
[1] The HADS is a fourteen item scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 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.


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Participants With Investigator’s Global Assessment (IGA) Score of “0” or “1” and Reduction From Baseline of ≥2 Points at Week 16   [ Time Frame: Baseline to Week 16 ]

2.  Secondary:   Percentage of Participants With Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 16   [ Time Frame: Baseline to Week 16 ]

3.  Secondary:   Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 16   [ Time Frame: Baseline to Week 16 ]

4.  Secondary:   Percentage of Participants With Improvement (Reduction ≥3 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 16   [ Time Frame: Baseline to Week 16 ]

5.  Secondary:   Percentage of Participants With Investigator’s Global Assessment (IGA) Score of “0” or “1” and Reduction From Baseline of ≥2 Points at Week 52   [ Time Frame: Baseline to Week 52 ]

6.  Secondary:   Percentage of Participants With Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 52   [ Time Frame: Baseline to Week 52 ]

7.  Secondary:   Percent Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 16   [ Time Frame: Baseline to Week 16 ]

8.  Secondary:   Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 52   [ Time Frame: Baseline to Week 52 ]

9.  Secondary:   Percentage of Participants With Improvement (Reduction ≥3 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 52   [ Time Frame: Baseline to Week 52 ]

10.  Secondary:   Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 24   [ Time Frame: Baseline to Week 24 ]

11.  Secondary:   Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 4   [ Time Frame: Baseline to Week 4 ]

12.  Secondary:   Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 2   [ Time Frame: Baseline to Week 2 ]

13.  Secondary:   Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 16   [ Time Frame: Baseline to Week 16 ]

14.  Secondary:   Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score to Week 16   [ Time Frame: Baseline to Week 16 ]

15.  Secondary:   Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis to Week 16   [ Time Frame: Baseline to Week 16 ]

16.  Secondary:   Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score to Week 16   [ Time Frame: Baseline to Week 16 ]

17.  Secondary:   Change From Baseline in Dermatology Life Quality Index (DLQI) to Week 16   [ Time Frame: Baseline to Week 16 ]

18.  Secondary:   Change From Baseline in Patient Oriented Eczema Measure (POEM) to Week 16   [ Time Frame: Baseline to Week 16 ]

19.  Secondary:   Change From Baseline in Hospital Anxiety Depression Scale (HADS) to Week 16   [ Time Frame: Baseline to Week 16 ]

20.  Secondary:   Percent Change From Baseline in Total Global Individual Signs Score (GISS) to Week 16   [ Time Frame: Baseline to Week 16 ]

21.  Secondary:   Proportion of Topical Atopic Dermatitis Medication-Free Days Through Week 52   [ Time Frame: Baseline to Week 52 ]

22.  Secondary:   Percent Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 2   [ Time Frame: Baseline to Week 2 ]

23.  Secondary:   Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score to Week 52   [ Time Frame: Baseline to Week 52 ]

24.  Secondary:   Change From Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis to Week 52   [ Time Frame: Baseline to Week 52 ]

25.  Secondary:   Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score to Week 52   [ Time Frame: Baseline to Week 52 ]

26.  Secondary:   Percent Change From Baseline in Global Individual Signs Score (GISS) to Week 52   [ Time Frame: Baseline to Week 52 ]

27.  Secondary:   Change From Baseline in Dermatology Life Quality Index (DLQI) to Week 52   [ Time Frame: Baseline to Week 52 ]

28.  Secondary:   Change From Baseline in Patient Oriented Eczema Measure (POEM) to Week 52   [ Time Frame: Baseline to Week 52 ]

29.  Secondary:   Change From Baseline in Hospital Anxiety Depression Scale (HADS) to Week 52   [ Time Frame: Baseline to Week 52 ]

30.  Secondary:   Number of Flares Through Week 52   [ Time Frame: Baseline up to Week 52 ]

31.  Secondary:   Number of Serious Treatment Emergent Adverse Events (TEAEs) Leading to Study Drug Discontinuation Through Week 52   [ Time Frame: Baseline up to Week 52 ]

32.  Secondary:   Percentage of Participants With Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) From Baseline Through Week 52   [ Time Frame: Baseline up to Week 52 ]

33.  Secondary:   Number of Skin Infection TEAEs (Excluding Herpetic Infections) From Baseline Through Week 52   [ Time Frame: Baseline up to Week 52 ]

34.  Secondary:   Percentage of Participants With Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) Requiring Systemic Treatment From Baseline Through Week 52   [ Time Frame: Baseline up to Week 52 ]

35.  Secondary:   Number of Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) Requiring Systemic Treatment From Baseline Through Week 52   [ Time Frame: Baseline up to Week 52 ]

36.  Other Pre-specified:   Change From Baseline in Sinonasal Outcome Test (SNOT-22) Score to Week 16   [ Time Frame: Baseline to Week 16 ]

37.  Other Pre-specified:   Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Score to Week 16   [ Time Frame: Baseline to Week 16 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Clinical Trial Management
Organization: Regeneron Pharmaceuticals, Inc.
e-mail: clinicaltrials@regeneron.com



Responsible Party: Regeneron Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02260986     History of Changes
Other Study ID Numbers: R668-AD-1224
First Submitted: October 6, 2014
First Posted: October 9, 2014
Results First Submitted: April 30, 2017
Results First Posted: October 17, 2017
Last Update Posted: October 17, 2017