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Open Label, Drug-Drug Interaction (DDI) Study of Dupilumab (REGN668/SAR231893) in Patients With Moderate to Severe Atopic Dermatitis (AD)

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ClinicalTrials.gov Identifier: NCT02647086
Recruitment Status : Completed
First Posted : January 6, 2016
Last Update Posted : August 22, 2016
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Regeneron Pharmaceuticals

Study Description
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Brief Summary:

This is an open-label, single-sequence DDI study designed to examine the effects of dupilumab on the pharmacokinetics of selected cytochrome P450 substrates in adult patients with moderate to severe AD.

The study consists of a screening period (day -35 to -2), study period 1 (day -1 to 7), study period 2 (day 8 to 50), and a follow-up period (day 51 to 135 [end of study]).

Following completion of study period 2 (Day 50), patients will be given the option to enroll into the Open-Label Extension (OLE) study R668-AD-1225. Patients who decline will be followed for the next 12 weeks (Day 135).


Condition or disease Intervention/treatment Phase
Atopic Dermatitis Drug: Dupilumab Drug: Midazolam Drug: Omeprazole Drug: Warfarin Drug: Caffeine Drug: Metoprolol Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: An Open-Label, Drug-Drug Interaction Study to Examine the Effects of Dupilumab on the Pharmacokinetics of Selected Cytochrome P450 Substrates in Adult Patients With Moderate to Severe Atopic Dermatitis
Study Start Date : December 2015
Actual Primary Completion Date : July 2016
Actual Study Completion Date : July 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Dupilumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Period 1
Patients will receive selected Cytochrome P450 substrates (Midazolam, Omeprazole, Warfarin, Caffeine, Metoprololin) in period 1 (day 1)
 Drug: Midazolam
Cytochrome P450 substrate

Drug: Omeprazole
Cytochrome P450 substrate

Drug: Warfarin
Cytochrome P450 substrate

Drug: Caffeine
Cytochrome P450 substrate

Drug: Metoprolol
Cytochrome P450 substrate
Experimental: Period 2
Patients will receive dupilumab starting in Period 2 (day 8) and continue weekly through day 50; Patients will receive selected Cytochrome P450 substrates (Midazolam, Omeprazole, Warfarin, Caffeine, Metoprolol) in period 2 (at day 36).
 Drug: Dupilumab
Other Name: REGN668/SAR231893

Drug: Midazolam
Cytochrome P450 substrate

Drug: Omeprazole
Cytochrome P450 substrate

Drug: Warfarin
Cytochrome P450 substrate

Drug: Caffeine
Cytochrome P450 substrate

Drug: Metoprolol
Cytochrome P450 substrate


Outcome Measures
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Primary Outcome Measures :
  1. Ratio of Area Under Curve last (AUClast) and maximum concentration (Cmax) for Cytochrome P450 substrates from pre-dupilumab administration at baseline (period 1, day 1) [ Time Frame: At Baseline (day 1) ]
  2. Ratio of AUClast and Cmax for CYP substrates 4 weeks after initiating a weekly regimen of dupilumab (period 2, day 36) [ Time Frame: At day 36 ]

Secondary Outcome Measures :
  1. Incidence of treatment-emergent adverse events (TEAEs) from day of first administration of dupilumab to end of study (day 50 for patients who enroll in the OLE study; day 134 for patients who decline participation in the OLE). [ Time Frame: Baseline up to day 134 ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female patient, aged 18 years or older
  2. Diagnosis of Chronic AD, defined as diagnosis of AD for at least 3 years before the screening visit
  3. Eczema Area Severity Index (EASI) score ≥16 at the screening and baseline visits
  4. Investigator's Global Assessment (IGA) score ≥3 (on the 0 to 4 IGA scale) at the screening and baseline visits
  5. ≥10% Body Surface Area (BSA) of AD involvement at the screening and baseline visits
  6. Patients with documented recent history (within 6 months before the screening visit) of inadequate response to outpatient treatment with topical medications, or for whom topical treatments are otherwise medically inadvisable (eg, because of important side effects or safety risks)
  7. Provide signed informed consent

Exclusion Criteria:

  1. Prior participation in a dupilumab clinical trial

  2. The use of any of the following treatments within 4 weeks before the baseline visit:

    • Systemic corticosteroids
    • Immunosuppressive/immunomodulating drugs
    • Phototherapy for AD
  3. Administration, within 14 days before baseline or within a period of 5 times the elimination half-life of the medication before baseline, whichever is longer, of any medication that is a known inducer or inhibitor of either one or more of the following CYP enzymes: CYP3A, CYP2C19, CYP2C9, CYD2D6, and CYP1A2. Patients who are on any of these medications at the time of screening and cannot be safely taken off these medications will be excluded from the study.

  4. Any contraindication to one or more of the following drugs, according to the applicable labeling:

    • Midazolam
    • Omeprazole
    • Warfarin
    • Caffeine
    • Metoprolol

  5. Consumption of any 1 or more of the following food items and/ or beverages within 1 week prior to baseline:

    • Grapefruit or grapefruit juice, apple or apple juice, orange or orange juice, lemons or lemon juice, limes or lime juice
    • Vegetables from the mustard green family (eg, broccoli)
    • Charbroiled meats
    • Caffeinated beverages, foods or drugs containing caffeine Patients who are not willing to abstain from the consumption of these food items and/or beverages for certain periods during the study will also be excluded
  6. History of excessive consumption of beverages containing caffeine (more than 4 cups or glasses per day). Patients who are not willing to abstain from the consumption of caffeine during certain periods of the study will also be excluded
  7. History or presence of alcohol or drug abuse within last 2 years
  8. History of smoking within last 2 years
  9. Poor metabolizers for CYP2C9, CYP2C19, or CYP2D6 based on genotyping

  10. Presence of any one or more of the following lab abnormalities at screening:

    • Platelet count ≤100 x 10^3/µL
    • Neutrophils ≤1 x 10^3/µL
    • Creatinine phosphokinase (CPK) >10 x upper limit of normal (ULN)
    • International normalized ratio (INR) ≥2
  11. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the screening visit, or superficial skin infections within 1 week before the screening visit
  12. Known or suspected immunodeficiency, including history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency or prolonged duration suggesting an immune compromised status, as judged by the investigator
  13. History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening
  14. Positive with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody (Hep C Ab) at the screening visit. NOTE: Patients who are HBsAg negative and HBsAb positive are considered immune after a natural infection has cleared or they have been vaccinated against hepatitis B. Therefore, they are acceptable for the study.
  15. 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
  16. History of clinical endoparasitosis (ie, helminth infection) within 12 months before the baseline visit, or high risk of helminth infection, such as residence within or recent travel (within 12 months before the baseline visit) to areas endemic for endoparasitoses, where the circumstances are consistent with parasite exposure (eg, extended stay, rural or slum areas, lack of running water, consumption of uncooked, undercooked, or otherwise potentially contaminated food, close contact with carriers and vectors, etc), unless subsequent medical assessments (eg, stool exam, blood tests, etc) have ruled out the possibility of parasite infection/infestation
  17. Female patients who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study
  18. Women who are using any form of hormonal contraceptives (eg, oral, injectables, implants, patches, rings, hormone-impregnated intrauterine devices [IUDs]) for birth control
  19. Women unwilling to use adequate birth control, if of reproductive potential and sexually active.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02647086


Locations
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United States, Arkansas
Regeneron Study Site
Little Rock, Arkansas, United States
United States, Colorado
Regeneron Study Site
Centennial, Colorado, United States
United States, Minnesota
Regeneron Study Site
Minneapolis, Minnesota, United States
United States, New Jersey
Regeneron Study Site
Berlin, New Jersey, United States
United States, North Carolina
Regeneron Study Site
Raleigh, North Carolina, United States
Sponsors and Collaborators
Regeneron Pharmaceuticals
Sanofi
Investigators
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Study Director: Clinical Trial Management Regeneron Pharmaceuticals
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Regeneron Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02647086    
Other Study ID Numbers: R668-AD-1433
First Posted: January 6, 2016    Key Record Dates
Last Update Posted: August 22, 2016
Last Verified: August 2016
Keywords provided by Regeneron Pharmaceuticals:
Eczema
Additional relevant MeSH terms:
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Dermatitis, Atopic
Dermatitis
Eczema
Skin Diseases
Skin Diseases, Genetic
Genetic Diseases, Inborn
Skin Diseases, Eczematous
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Metoprolol
Midazolam
Caffeine
Omeprazole
Warfarin
 Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticoagulants