Open-label Study of Dupilumab in Patients With Atopic Dermatitis

• ClinicalTrials.gov Identifier: NCT01949311
• Recruitment Status: Completed
• First Posted: September 24, 2013
• Results First Posted: October 17, 2023
• Last Update Posted: October 17, 2023
• Sponsor: Regeneron Pharmaceuticals
• Collaborator: Sanofi
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Tracking Information

• First Submitted Date: September 20, 2013
• First Posted Date: September 24, 2013
• Results First Submitted Date: June 23, 2023
• Results First Posted Date: October 17, 2023
• Last Update Posted Date: October 17, 2023
• Actual Study Start Date: October 10, 2013
• Actual Primary Completion Date: June 27, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 16, 2023)

• Number of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Up to 272 weeks ]
• OPTIONAL SUB-STUDY: Number of Adverse Events of Special Interest (AESIs) Through the Last Study Visit After Switching to the New Dupilumab Drug Product [ Time Frame: Up to 24 Weeks ]
  Adverse events of special interest in this study include: Anaphylactic reactions, Systemic hypersensitivity reactions, Helminthic infections, Any severe type of conjunctivitis or blepharitis, Keratitis, Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms)

Original Primary Outcome Measures (submitted: September 20, 2013)

Number of TEAEs [ Time Frame: At week 52 and at week 116 ]

The primary endpoint in the study is the incidence and rate (events per patient-year) of treatment-emergent adverse events (TEAEs) through the last study visit.

Current Secondary Outcome Measures (submitted: October 16, 2023)

• Number of Serious Adverse Events (SAEs) of Special Interest [ Time Frame: Up to 272 weeks ]
  Adverse events of special interest in this study include: Anaphylactic reactions, Systemic hypersensitivity reactions, Helminthic infections, Any severe type of conjunctivitis or blepharitis, Keratitis, Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms)
• Rate of AESIs [ Time Frame: Up to 272 weeks ]
  Rate (events per patient-year) of AESIs Adverse events of special interest in this study include: Anaphylactic reactions, Systemic hypersensitivity reactions, Helminthic infections, Any severe type of conjunctivitis or blepharitis, Keratitis, Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms)
• Number of AESIs [ Time Frame: Up to 272 weeks ]
  Adverse events of special interest in this study include: Anaphylactic reactions, Systemic hypersensitivity reactions, Helminthic infections, Any severe type of conjunctivitis or blepharitis, Keratitis, Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms)
• Percentage of Participants With Investigator's Global Assessment (IGA) Score = 0-1 at Each Visit [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 272 (End of Study) ]
  IGA is an assessment scale used to determine severity of hand and foot 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.
• Percentage of Participants With Eczema Area and Severity Index (EASI)-75 (≥75% Reduction in EASI Scores From Baseline of the Parent Study) at Each Visit [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 272 (End of Study)" ]
  The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, induration, 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.
• Percentage of Participants With Low Disease Activity State (eg, IGA ≤2) at Each Visit [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 272 (End of Study)" ]
  Low disease activity state is defined as an IGA score of ≤2 [mild = 2, almost clear = 1, or clear = 0]
• Change From Baseline in EASI Score at Each Visit [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 272 (End of Study)" ]
  The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, induration, 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.
• Percent Change From Baseline in EASI Score at Each Visit [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 272 (End of Study)" ]
  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 range from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD.
• Percentage of Participants With EASI-50 (≥50% Reduction in EASI Scores From Baseline of the Parent Study) at Each Visit [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 272 (End of Study)" ]
  EASI-50 was defined as >=50% reduction in EASI scores from baseline of the parent study
• Percentage of Participants With EASI-90 (≥90% Reduction in EASI Scores From Baseline of the Parent Study) at Each Visit [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 272 (End of Study)" ]
  EASI-90 was defined as >=90% reduction in EASI scores from baseline of the parent study
• Change From Baseline in Pruritus Numerical Rating Scale (NRS) in Parent Study [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 1, 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 252, 272 (End of Study)" ]
  The Pruritus NRS is an assessment tool for patients to report the intensity of their pruritus (itch), using a scale from 0-10, where 0 is no itch and 10 is the worst itch imaginable. Daily peak pruritus NRS score is the worst one between morning and evening scores of the day. Baseline Pruritus NRS is determined based on average of daily peak NRS scores during the 7 days immediately preceding randomization. A minimum of 4 daily scores out of 7 days is required to calculate baseline average score. Weekly worst score is calculated by taking the worst score within the week
• Percent Change From Baseline in Pruritus NRS [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 1, 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 252, 272 (End of Study)" ]
  The Pruritus NRS is an assessment tool for patients to report the intensity of their pruritus (itch), using a scale from 0-10, where 0 is no itch and 10 is the worst itch imaginable. Daily peak pruritus NRS score is the worst one between morning and evening scores of the day. Baseline Pruritus NRS is determined based on average of daily peak NRS scores during the 7 days immediately preceding randomization. A minimum of 4 daily scores out of 7 days is required to calculate baseline average score. Weekly worst score is calculated by taking the worst score within the week
• Percentage of Participants With Improvement (Reduction) of Pruritus NRS ≥3 From Baseline [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 1, 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 252, 272 (End of Study)" ]
  The Pruritus NRS is an assessment tool for patients to report the intensity of their pruritus (itch), using a scale from 0-10, where 0 is no itch and 10 is the worst itch imaginable. Daily peak pruritus NRS score is the worst one between morning and evening scores of the day. Baseline Pruritus NRS is determined based on average of daily peak NRS scores during the 7 days immediately preceding randomization. A minimum of 4 daily scores out of 7 days is required to calculate baseline average score. Weekly worst score is calculated by taking the worst score within the week
• Percentage of Participants With Improvement (Reduction) of Pruritus NRS ≥4 From Baseline [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 1, 4, 16, 36, 52, 100, 124, 156, 172, 188, 204, 220, 236, 252, 272 (End of Study)" ]
  The Pruritus NRS is an assessment tool for patients to report the intensity of their pruritus (itch), using a scale from 0-10, where 0 is no itch and 10 is the worst itch imaginable. Daily peak pruritus NRS score is the worst one between morning and evening scores of the day. Baseline Pruritus NRS is determined based on average of daily peak NRS scores during the 7 days immediately preceding randomization. A minimum of 4 daily scores out of 7 days is required to calculate baseline average score. Weekly worst score is calculated by taking the worst score within the week
• Percentage of Participants Requiring Rescue Treatment: Overall [ Time Frame: Up to 272 weeks ]
• Percentage of Participants Requiring Rescue Treatment: Systemic Treatment [ Time Frame: Up to 272 weeks ]
• Percentage of Participants Requiring Rescue Treatment: Phototherapy [ Time Frame: Up to 272 weeks ]
• Changes From Current Study Baseline to Prespecified Time Points Through the End of the Study: Dermatology Life Quality Index (DLQI) [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 12, 24, 36, 48, 76, 100, 124, 148, 272 (End of Study)" ]
  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 format is a simple response to 10 items, which assess QOL over the past week, with an overall scoring system of 0 to 30; a high score is indicative of a poor QOL
• Changes From Current Study Baseline to Prespecified Time Points Through the End of the Study: Patient Oriented Eczema Measure (POEM) [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 12, 24, 36, 48, 76, 100, 124, 148, 272 (End of Study)" ]
  The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess disease symptoms in children and adults. The format is a response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) with a scoring system of 0 to 28; a high score is indicative of a poor QOL.
• Changes From Parent Study Baseline to Prespecified Time Points Through the End of the Study: EuroQol-5D (EQ-5D) [ Time Frame: Up to 272 weeks (End of Study), "Baseline, Weeks 12, 24, 36, 48, 76, 100, 124, 148, 272 (End of Study)" ]
  The EuroQOL 5-Dimension Health Questionnaire (EQ-5D) is a standardized measure of health status developed by the EuroQOL Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The minimum value for the single index utility score is -0.594 (Best imaginable health state) and the maximum value for the single index utility score is 1 (Worst imaginable health state).
• OPTIONAL SUB-STUDY: Ctrough of Functional Dupilumab in Serum Before and After Switching to the New Dupilumab Drug Product [ Time Frame: Up to week 12 ]
• OPTIONAL SUB-STUDY: Incidence of Treatment-emergent Anti-drug Antibody (ADA) Response in Patients Receiving the New Dupilumab Drug Product [ Time Frame: Up to 24 Weeks ]
  For participants receiving dupilumab from a new manufacturing process, ADA baseline was defined as the baseline visit in the sub-study, or at the end of the main study, dependent on available data.

Original Secondary Outcome Measures (submitted: September 20, 2013)

• Number of TEAEs of special interest [ Time Frame: At week 52 and at week 116 ]
  Incidence and rate (events per patient-year) of serious adverse events (SAEs) and adverse events (AEs) of special interest
• Proportion of participants with IGA score of 0 to 1 [ Time Frame: day 1 to week 116 ]
  Proportion of patients who achieve and maintain a score of 0 to 1 on the Investigator's Global Assessment (IGA) scale [(a 6-point scale ranging from 0 (clear) to 5 (very severe)]
• Number of disease free days per patient-year [ Time Frame: At week 52 and at week 116 ]
• EASI scores [ Time Frame: day 1 to week 116 ]
  Proportion of patients achieving and maintaining at least 50% reduction in EASI (Eczema Area and Severity Index) scores over time

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Open-label Study of Dupilumab in Patients With Atopic Dermatitis
• Official Title: An Open-label Study of Dupilumab in Patients With Atopic Dermatitis Who Participated in Previous Dupilumab Clinical Trials

Brief Summary

The primary objective is to assess the long-term safety of dupilumab administered in adult participants with atopic dermatitis (AD).

The secondary objective of the study is to assess the immunogenicity of dupilumab in adult participants with AD, in the context of re-treatment, and to monitor efficacy parameters associated with long-term treatment.

Optional Sub-Study:

The primary objective of the sub-study is to assess the safety of the new dupilumab drug product in adult patients with AD after switching from the current dupilumab drug product.

The secondary objectives of the sub-study are to evaluate systemic exposure and immunogenicity of the new dupilumab drug product in adult patients with AD.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Atopic Dermatitis

Intervention

Drug: Dupilumab

Other Names:

• DUPIXENT®
• REGN668
• SAR231893

Study Arms

Experimental: Dupilumab

Participants will receive repeat doses of dupilumab

Intervention: Drug: Dupilumab

Publications *

• Blauvelt A, Wollenberg A, Eichenfield LF, Zhang H, Sierka D, Khokhar FA, Vakil J, Shabbir A, Marco AR, Cyr SL. No Increased Risk of Overall Infection in Adults with Moderate-to-Severe Atopic Dermatitis Treated for up to 4 Years with Dupilumab. Adv Ther. 2023 Jan;40(1):367-380. doi: 10.1007/s12325-022-02322-y. Epub 2022 Nov 1.
• Wechsler ME, Klion AD, Paggiaro P, Nair P, Staumont-Salle D, Radwan A, Johnson RR, Kapoor U, Khokhar FA, Daizadeh N, Chen Z, Laws E, Ortiz B, Jacob-Nara JA, Mannent LP, Rowe PJ, Deniz Y. Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis. J Allergy Clin Immunol Pract. 2022 Oct;10(10):2695-2709. doi: 10.1016/j.jaip.2022.05.019. Epub 2022 May 28.
• Beck LA, Deleuran M, Bissonnette R, de Bruin-Weller M, Galus R, Nakahara T, Seo SJ, Khokhar FA, Vakil J, Xiao J, Marco AR, Levit NA, O'Malley JT, Shabbir A. Dupilumab Provides Acceptable Safety and Sustained Efficacy for up to 4 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis. Am J Clin Dermatol. 2022 May;23(3):393-408. doi: 10.1007/s40257-022-00685-0. Epub 2022 May 3.
• Armstrong A, Blauvelt A, Simpson EL, Smith CH, Herranz P, Kataoka Y, Seo SJ, Ferrucci SM, Chao J, Chen Z, Rossi AB, Shumel B, Tomondy P. Continued Treatment with Dupilumab is Associated with Improved Efficacy in Adults with Moderate-to-Severe Atopic Dermatitis Not Achieving Optimal Responses with Short-Term Treatment. Dermatol Ther (Heidelb). 2022 Jan;12(1):195-202. doi: 10.1007/s13555-021-00643-4. Epub 2021 Dec 13.
• Yosipovitch G, de Bruin-Weller M, Armstrong A, Wu JJ, Herranz P, Thaci D, Delevry D, Bagousse GB, Zhang R, Shumel B, Rossi AB, Chao J. Dupilumab Treatment Provides Sustained Improvements Over 2 Years in Symptoms and Quality of Life in Adults with Atopic Dermatitis. Dermatol Ther (Heidelb). 2021 Dec;11(6):2147-2157. doi: 10.1007/s13555-021-00630-9. Epub 2021 Oct 29.
• Beck LA, Thaci D, Deleuran M, de Bruin-Weller M, Chen Z, Khokhar FA, Zhang M, Ozturk ZE, Shumel B. Laboratory safety of dupilumab for up to 3 years in adults with moderate-to-severe atopic dermatitis: results from an open-label extension study. J Dermatolog Treat. 2022 May;33(3):1608-1616. doi: 10.1080/09546634.2020.1871463. Epub 2021 Feb 8.
• Beck LA, Thaci D, Deleuran M, Blauvelt A, Bissonnette R, de Bruin-Weller M, Hide M, Sher L, Hussain I, Chen Z, Khokhar FA, Beazley B, Ruddy M, Patel N, Graham NMH, Ardeleanu M, Shumel B. Dupilumab Provides Favorable Safety and Sustained Efficacy for up to 3 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis. Am J Clin Dermatol. 2020 Aug;21(4):567-577. doi: 10.1007/s40257-020-00527-x.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 22, 2021): 2733
• Original Estimated Enrollment (submitted: September 20, 2013): 800
• Actual Study Completion Date: June 27, 2022
• Actual Primary Completion Date: June 27, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

1. Participation in a prior clinical trial of dupilumab for AD and met one of the following:

   1. Received study treatment and adequately completed the assessments required for both the treatment and follow-up periods of the parent studies (except studies listed in b) as defined in the parent protocols
   2. Received study treatment in one the studies that have completed last patient, last visit irrespective of duration of participation, provided that patients completed with the instructions received during the study.
   3. Underwent screening in R668-AD-1334 (Liberty AD SOLO 1) or R668-AD-1416 (Liberty AD SOLO 2) but could not be randomized due to randomization closure.
2. Willing and able to comply with all clinic visits and study-related procedures
3. Able to understand and complete study-related questionnaires
4. Provide signed informed consent

Optional Sub-Study:

1. Provide separate informed consent
2. Continuing in the treatment period of the main OLE study
3. Demonstrated compliance with dupilumab therapy, as defined in the protocol

Key Exclusion Criteria:

1. Patients who, during their participation in a previous dupilumab clinical trial, developed a serious adverse event (SAE) deemed related to dupilumab*, which in the opinion of the investigator or of the medical monitor could indicate that continued treatment with dupilumab may present an unreasonable risk for the patient.
2. Patients who, during their participation in a previous dupilumab clinical trial, developed an AE that was deemed related to dupilumab* and led to study treatment discontinuation, which in the opinion of the investigator or of the medical monitor could indicate that continued treatment with dupilumab may present an unreasonable risk for the patient.

3. Conditions in the previous dupilumab study consistent with protocol-defined criteria for permanent study drug discontinuation, if deemed related to dupilumab* or led to investigator - or sponsor-initiated withdrawal of patient from the study (eg, non-compliance, inability to complete study assessments, etc.).

   *Note for exclusion criteria # 1, 2, and 3: In studies that are still blinded, conditions deemed related to the study treatment will be considered related to dupilumab.

4. Treatment with an investigational drug, other than dupilumab, within 8 weeks or within 5 half-lives (if known), whichever is longer, before the baseline visit
5. Pregnant or breastfeeding women, or planning to become pregnant or breastfeed during the patient's participation in this study

Optional Sub-Study:

1. Patients who have already completed the end of treatment visit (ie, visit 44) for the main study R668-AD-1225

Note: Other Protocol Defined Inclusion / Exclusion Criteria Apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Bulgaria, Canada, China, Czechia, Denmark, Estonia, Finland, France, Germany, Hungary, Ireland, Italy, Japan, Korea, Republic of, Lithuania, Netherlands, New Zealand, Poland, Romania, Russian Federation, Singapore, Slovakia, Spain, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01949311
• Other Study ID Numbers: R668-AD-1225; 2013-001449-15 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Regeneron Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Regeneron Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Sanofi

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

• PRS Account: Regeneron Pharmaceuticals
• Verification Date: October 2023