Effect of Dupilumab (Anti-IL4Rα) on the Host-Microbe Interface in Atopic Dermatitis

NCT03389893 | Terminated Phase 4 Results DMC FDA Drug

• 3 other identifiers: DAIT ADRN-09U19AI117673NIAID DAIT CRMS ID#: 38439
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 9

Brief Summary

The purpose of this study is to understand the effect that T helper 2 (Th2) blockade has on well-described pathophysiological features of Atopic Dermatitis (AD), for example: barrier, epidermal activation, dysbiosis and epidermal lipids.

Conditions

Atopic Dermatitis (AD)

Keywords

randomized double-masked (blind) placebo-controlled trial; T helper 2 (Th2) effect; cutaneous microbial community; skin barrier

Outcome Measures

Primary Outcomes (1)

• Staphylococcus Aureus Abundance on Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up

  Staphylococcus aureus (S. aureus) abundance was measured by microbial DNA (femA qPCR) on lesional skin at Day 28, measurement is expressed in relative Colony Forming Units (rCFU)/cm\^2). The abundance of S. aureus is summarized as the geometric mean ratio (and corresponding 95% confidence interval) between the dupilumab and placebo arms. The geometric mean ratio is reported from an ANCOVA model with fixed effects for clinical site, disease severity at Day 0 (as measured by EASI \>21.1 \[severe\] or ≤21.1 \[non-severe\]) and S. aureus abundance at Day 0.

  Day 28 (Post treatment initiation)

Secondary Outcomes (9)

• Staphylococcus Aureus Abundance on Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up

  Day 0 (Prior to treatment), 3, 7, 14, 21, 42, 77 and 112

• Staphylococcus Aureus Abundance on Non-lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up

  Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112

• Transepidermal Water Loss (TEWL) of Non-lesional and Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up

  Day 0 (Prior to treatment), 3, 7, 14, 21, 28, 42, 77 and 112

• Transepidermal Water Loss (TEWL) Area Under the Curve (AUC) on Non-Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up

  Day 0 (Prior to treatment), 7, 14, 21, 28, 42, 77 and 112

• Transepidermal Water Loss (TEWL) Slope on Non-Lesional Skin, Dupilumab+Open Label Extension and Follow-Up Versus Placebo+Open Label Extension and Follow-Up

  Day 0 (Prior to treatment), 7, 14, 21, 28, 42, 77 and 112

Other Outcomes (12)

• EXPLORATORY: Composition of Bacterial Taxa

  Day 0 (Prior to treatment), 16 weeks

• EXPLORATORY: Abundance of Bacterial Taxa in Lesional and Non-lesional Skin

  Day 0 (Prior to treatment), 16 weeks

• EXPLORATORY: Gene Expression in the Skin Transcriptome in Non-lesional Skin

  Day 0 (Prior to treatment) and 7

Study Arms (2)

Dupilumab w/OLE

EXPERIMENTAL

Participants will receive a loading dose of dupilumab (two 300 mg subcutaneous (subcut) injections (total of 600 mgs)) on Day 0, followed by 300 mg dose of dupilumab by subcut injection every 2 weeks (Days 14 and 28). Open Label Extension (OLE): Participants will begin a 10 week OLE on Day 42, beginning with a loading dose of two subcut administered injections (one 300 mg dose of dupilumab and one dose of placebo, in order to protect prior masking/blind).Participants will then maintain a regimen of 300 mg of dupilumab by subcut injection every two weeks through Day 98. The subcut injections will be administered in the abdomen (except for the 2 inches (5 cm) around the navel-not allowed), thighs, or upper arms. Injection sites will be rotated with each dose.

Drug: Dupilumab; Drug: Placebo

Placebo Comparator w/OLE

PLACEBO COMPARATOR

Participants will receive a loading dose of placebo (two placebo subcutaneous (subcut) injections) on Day 0 followed by one dose of placebo by subcut injections every 2 weeks (Days 14 and 28). Open Label Extension (OLE): Participants will begin a 10 week OLE on Day 42, beginning with a loading dose of dupilumab (two 300 mg subcut injections (total of 600 mgs)-protection of prior masking/blind maintained). Participants will then maintain a regimen of 300 mg of dupilumab by subcut injection every two weeks through Day 98. The subcut injections will be administered in the abdomen (except for the 2 inches (5 cm) around the navel-not allowed), thighs, or upper arms. Injection sites will be rotated with each dose.

Drug: Dupilumab; Drug: Placebo

Interventions

Dupilumab DRUG

Dupilumab, an interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist, is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. (FDA approved on March 28, 2017.)

Also known as: Dupixent®, IL4Ra mAb

Dupilumab w/OLE; Placebo Comparator w/OLE

Placebo DRUG

Placebo will contain the identical formulation as the dupilumab formulation without the active mAb and will be given by exactly the same route and schedule through Day 28.

Also known as: Dupilumab placebo

Dupilumab w/OLE; Placebo Comparator w/OLE

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must be able to understand and provide informed consent
• Chronic AD, (according to the Atopic Dermatitis Research Network \[ADRN\] Standard Diagnostic Criteria), that has been present for at least 3 years before the Screening Visit
• EASI score ≥12 at the Screening Visit and ≥16 at the Treatment Initiation Visit
• Investigator Global Assessment (IGA) score ≥3 (on the 0-4 IGA scale) at the Screening and Treatment Initiation Visits
• ≥10% body surface area of AD involvement at the Screening and Treatment Initiation Visits
• Must have active lesions (minimum of 3 of at least 4x4 cm\^2 each on the upper or lower extremities, excluding the palms of the hands and soles of the feet) at the Screening and Treatment Initiation Visits
• Documented recent history (within 6 months before the Screening Visit) of inadequate response to outpatient treatment with topical corticosteroids of medium to high potency (± topical calcineurin inhibitors as appropriate), or for whom topical treatments are otherwise inadvisable
• Must agree to apply a stable dose of a topical emollient (moisturizer) at least twice daily for at least 7 days before the Treatment Initiation Visit, and must confirm application at the Treatment Initiation Visit
• Individuals with asthma must adhere to asthma controller medication(s) for the duration of the study including the open-label and follow-up portions
• Females of childbearing potential must have a negative pregnancy test at the Screening and Treatment Initiation Visits
• Females with reproductive potential\* and sexually active must agree to use FDA approved methods of birth control for the duration of the study, including during the open-label and follow-up portions of the study:
• FDA approved methods of birth control include hormonal contraceptives, intrauterine device, double barrier contraception (i.e., condom plus diaphragm), or male partner with documented vasectomy.
• \*Menopause is defined as at least 12 consecutive months without menses; if in question, a follicle stimulating hormone of ≥25 U/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.
• Willing and able to comply with all clinic visits and study-related procedures
• Able to understand and complete study-related questionnaires

You may not qualify if:

• Inability or unwillingness of an individual to give written informed consent or comply with study protocol
• Known systemic hypersensitivity to any of the excipients of the dupilumab or placebo study products
• Known or suspected immunosuppression, including history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent immune-compromised status, as judged by the investigator
• Known history of human immunodeficiency virus (HIV) infection
• Ocular disorder that, in the opinion of the investigator, could adversely affect the individual's risk for study participation. Examples include, but are not limited to, individuals with a history of or active case of:
• herpes keratitis,
• Sjogren's Syndrome,
• keratoconjunctivitis sicca or Dry Eye Syndrome that requires daily use of supplemental lubrication, or
• ocular condition(s) requiring the regular use of ocular corticosteroids or cyclosporine.
• Parasitic infection, except for vaginal trichomoniasis, within 12 months of the Treatment Initiation Visit, or high risk for contracting parasitic infections (e.g., living in or traveling to endemic areas)
• Presence of skin comorbidities that may interfere with study assessments
• History of malignancy within 5 years before the Treatment Initiation 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 or melanoma in situ
• History of non-malignant lymphoproliferative disorders
• History of alcohol or drug abuse within 2 years before the Screening Visit
• Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect the individual's participation in the study. Examples include, but are not limited to, individuals with short life expectancy, uncontrolled diabetes (HbA1c ≥9%), cardiovascular conditions (e.g., stage III or IV cardiac failure according to the New York Heart Association classification), severe renal conditions (e.g., individuals on dialysis), hepato-biliary conditions (e.g., Child-Pugh class B or C), neurological conditions (e.g., demyelinating diseases), active major autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic diseases.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Regeneron Pharmaceuticals: collaborator
• Sanofi: collaborator
• Atopic Dermatitis Research Network: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (9)

University of California San Diego

La Jolla, California, 92093, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

University of Florida

Gainesville, Florida, 32611, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Oregon Health Sciences University

Portland, Oregon, 97239, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Links

• National Institute of Allergy and Infectious Disease (NIAID) Website
• Division of Allergy, Immunology, and Transplantation (DAIT) website

MeSH Terms

Conditions

Dermatitis, Atopic

Interventions

dupilumab

Condition Hierarchy (Ancestors)

Skin Diseases, Genetic; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Dermatitis; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Eczematous; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Limitations and Caveats

One randomized participant did not meet criteria to be in the modified intent-to-treat (mITT) population because they withdrew prior to Day 28. Ten participants had 23 modified visits due to the coronavirus disease 2019 (COVID-19) pandemic.

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

240-669-5064

Study Officials

• Lisa A. Beck, MD

  University of Rochester

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 27, 2017
• First Posted: January 4, 2018
• Study Start: July 25, 2018
• Primary Completion: April 3, 2020
• Study Completion: September 9, 2020
• Last Updated: October 4, 2021
• Results First Posted: June 14, 2021

Record last verified: 2021-09

Locations

US (9)