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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

Tracking Information
First Submitted Date  ICMJE January 4, 2016
First Posted Date  ICMJE January 6, 2016
Last Update Posted Date August 22, 2016
Study Start Date  ICMJE December 2015
Actual Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 4, 2016)
  • 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) ]
  • 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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 4, 2016)
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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Open Label, Drug-Drug Interaction (DDI) Study of Dupilumab (REGN668/SAR231893) in Patients With Moderate to Severe Atopic Dermatitis (AD)
Official Title  ICMJE 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
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).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Atopic Dermatitis
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Period 1
    Patients will receive selected Cytochrome P450 substrates (Midazolam, Omeprazole, Warfarin, Caffeine, Metoprololin) in period 1 (day 1)
    Interventions:
    • Drug: Midazolam
    • Drug: Omeprazole
    • Drug: Warfarin
    • Drug: Caffeine
    • Drug: Metoprolol
  • 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).
    Interventions:
    • Drug: Dupilumab
    • Drug: Midazolam
    • Drug: Omeprazole
    • Drug: Warfarin
    • Drug: Caffeine
    • Drug: Metoprolol
Publications * Davis JD, Bansal A, Hassman D, Akinlade B, Li M, Li Z, Swanson B, Hamilton JD, DiCioccio AT. Evaluation of Potential Disease-Mediated Drug-Drug Interaction in Patients With Moderate-to-Severe Atopic Dermatitis Receiving Dupilumab. Clin Pharmacol Ther. 2018 Dec;104(6):1146-1154. doi: 10.1002/cpt.1058. Epub 2018 Apr 2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 18, 2016)
14
Original Estimated Enrollment  ICMJE
 (submitted: January 4, 2016)
18
Actual Study Completion Date  ICMJE July 2016
Actual Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02647086
Other Study ID Numbers  ICMJE R668-AD-1433
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Regeneron Pharmaceuticals
Study Sponsor  ICMJE Regeneron Pharmaceuticals
Collaborators  ICMJE Sanofi
Investigators  ICMJE
Study Director: Clinical Trial Management Regeneron Pharmaceuticals
PRS Account Regeneron Pharmaceuticals
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP