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

Atopic Dermatitis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02647086
• Other study ID #: R668-AD-1433
• Status: Completed
• Phase: Phase 1
• First received: January 4, 2016
• Last updated: August 18, 2016
• Start date: December 2015
• Est. completion date: July 2016

Study information

• Verified date: August 2016
• Source: Regeneron Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: July 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Atopic Dermatitis
• Dermatitis
• Dermatitis, Atopic
• Eczema

Intervention

Drug:
• Dupilumab

• Midazolam
Cytochrome P450 substrate
• Omeprazole
Cytochrome P450 substrate
• Warfarin
Cytochrome P450 substrate
• Caffeine
Cytochrome P450 substrate
• Metoprolol
Cytochrome P450 substrate

Locations

Country	Name	City	State
United States	Regeneron Study Site	Berlin	New Jersey
United States	Regeneron Study Site	Centennial	Colorado
United States	Regeneron Study Site	Little Rock	Arkansas
United States	Regeneron Study Site	Minneapolis	Minnesota
United States	Regeneron Study Site	Raleigh	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals	Sanofi

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)		At Baseline (day 1)	No
Primary	Ratio of AUClast and Cmax for CYP substrates 4 weeks after initiating a weekly regimen of dupilumab (period 2, day 36)		At day 36	No
Secondary	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).		Baseline up to day 134	Yes