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A Drug-drug Interaction Study Between Daclatasvir and Atazanavir/Ritonavir or Atazanavir/Cobicistat (DATE-4)

Primary Purpose

Hepatitis C, HIV

Status

Completed

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Daclatasvir

Atazanavir

Ritonavir

Cobicistat

About this trial

This is an interventional other trial for Hepatitis C focused on measuring Hepatitis C, HIV, atazanavir, ritonavir, daclatasvir, cobicistat

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Subject is at least 18 and not older than 55 years at screening.
Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to Day 1.
Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
Subject is in good age-appropriate health condition as established by medical history, physical examination, and electrocardiography, results of biochemistry, hematology and urinalysis testing within 4 weeks prior to day 1. Results of biochemistry, hematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A). If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
Subject has a normal blood pressure and pulse rate, according to the Investigator's judgment.

Exclusion Criteria:

Creatinine clearance below 60mL/min.
Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
Positive HIV test.
Positive hepatitis B or C test.
Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the study.
Therapy with any drug (for two weeks preceding Day 1), except for acetaminophen (max 2 gram/day).
Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal and hepatic disorders (clinically relevant increased ALAT/ASAT or hyperbilirubinemia) hormonal disorders (especially diabetes mellitus), coagulation disorders.
Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
History of or current abuse of drugs, alcohol or solvents.
Inability to understand the nature and extent of the study and the procedures required.
Participation in a drug study within 60 days prior to Day 1.
Donation of blood within 60 days prior to Day 1.
Febrile illness within 3 days before Day 1.

Sites / Locations

CRCN, Radboud University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Treatment A

Treatment B

Arm Description

Daclatasvir 30 mg QD film-coated tablet + atazanavir 300mg QD hard capsule + ritonavir 100mg QD from film-coated tablet for 10 days.

Daclatasvir 30 mg QD film-coated tablet + atazanavir 300mg QD hard capsule + cobicistat 150mg QD from film-coated tablet for 10 days.

Outcomes

Primary Outcome Measures

AUC

Secondary Outcome Measures

Adverse events

adverse events will be collected up to 4 weeks in total (entire study)

Full Information

NCT ID

NCT02565888

First Posted

September 30, 2015

Last Updated

December 4, 2020

Sponsor

Radboud University Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT02565888

Brief Title

A Drug-drug Interaction Study Between Daclatasvir and Atazanavir/Ritonavir or Atazanavir/Cobicistat

Acronym

DATE-4

Official Title

A Drug-drug Interaction Study Between the Novel Anti-HCV Agent Daclatasvir and the Antiretroviral Agents Atazanavir/Ritonavir or Atazanavir/Cobicistat in Healthy Volunteers

Study Type

Interventional

2. Study Status

Record Verification Date

December 2020

Overall Recruitment Status

Completed

Study Start Date

November 2015 (undefined)

Primary Completion Date

January 2016 (Actual)

Study Completion Date

January 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Radboud University Medical Center

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This study aims to provide the evidence that 150mg of cobicistat will have the same effect on the pharmacokinetics of daclatasvir 30mg QD as 100mg of ritonavir, when given together with atazanavir 300mg.

Detailed Description

Approximately 20-25% of the total number of HIV-infected patients is co-infected with HCV which translates to 6-8 million persons worldwide. Combined treatment of HIV and HCV is complicated by the risk of drug-drug interactions as both the direct acting antiviral agents (DAAs) for HCV as the antiretroviral agents for HIV are substrates of cytochrome P450 (CYP450) or various membrane transporters, and also have the capacity to influence these systems. A careful selection of the appropriate regimens and if needed adjusted doses is key for optimal treatment of both viral infections. Daclatasvir is a recently approved anti-HCV agent that is a CYP3A4 substrate but does not affect CYP450 itself. It is also a moderate inhibitor of various membrane transporters such as organic anion-transporting polypeptide (OATP1B1), P-glycoprotein (P-gP), and organic cation transporters (OCT2). Atazanavir/ritonavir is one of the preferred antiretroviral agents in all international guidelines. Ritonavir is used as a boosting agents based on its inhibitory effects on CYP3A. This also inhibits CYP3A-mediated metabolism of daclatasvir and when atazanavir/ritonavir is combined with daclatasvir, it is recommended to reduce the dose of daclatasvir from 60mg QD to 30mg QD. Cobicistat has recently been approved as an alternative booster of atazanavir at a dose of 150mg QD. It is expected that cobicistat will inhibit CYP3A mediated metabolism of daclatasvir in a similar manner as ritonavir does, but there are no clinical data to support this. As cobicistat lacks some of the adverse events associated with ritonavir use, the use of cobicistat, including as a booster of atazanavir, is likely to increase. This study aims to provide the evidence that 150mg of cobicistat will have the same effect on the pharmacokinetics of daclatasvir 30mg QD as 100mg of ritonavir, when given together with atazanavir 300mg.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatitis C, HIV

Keywords

Hepatitis C, HIV, atazanavir, ritonavir, daclatasvir, cobicistat

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment A

Arm Type

Active Comparator

Arm Description

Daclatasvir 30 mg QD film-coated tablet + atazanavir 300mg QD hard capsule + ritonavir 100mg QD from film-coated tablet for 10 days.

Arm Title

Treatment B

Arm Type

Experimental

Arm Description

Daclatasvir 30 mg QD film-coated tablet + atazanavir 300mg QD hard capsule + cobicistat 150mg QD from film-coated tablet for 10 days.

Intervention Type

Drug

Intervention Name(s)

Daclatasvir

Other Intervention Name(s)

Daklinza

Intervention Type

Drug

Intervention Name(s)

Atazanavir

Other Intervention Name(s)

Reyataz

Intervention Type

Drug

Intervention Name(s)

Ritonavir

Other Intervention Name(s)

Norvir

Intervention Type

Drug

Intervention Name(s)

Cobicistat

Other Intervention Name(s)

Tybost

Primary Outcome Measure Information:

Title

AUC

Time Frame

up to 24 hours after administration

Secondary Outcome Measure Information:

Title

Adverse events

Description

adverse events will be collected up to 4 weeks in total (entire study)

Time Frame

4 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subject is at least 18 and not older than 55 years at screening. Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to Day 1. Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations. Subject is in good age-appropriate health condition as established by medical history, physical examination, and electrocardiography, results of biochemistry, hematology and urinalysis testing within 4 weeks prior to day 1. Results of biochemistry, hematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A). If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded. Subject has a normal blood pressure and pulse rate, according to the Investigator's judgment. Exclusion Criteria: Creatinine clearance below 60mL/min. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients. Positive HIV test. Positive hepatitis B or C test. Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the study. Therapy with any drug (for two weeks preceding Day 1), except for acetaminophen (max 2 gram/day). Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal and hepatic disorders (clinically relevant increased ALAT/ASAT or hyperbilirubinemia) hormonal disorders (especially diabetes mellitus), coagulation disorders. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion. History of or current abuse of drugs, alcohol or solvents. Inability to understand the nature and extent of the study and the procedures required. Participation in a drug study within 60 days prior to Day 1. Donation of blood within 60 days prior to Day 1. Febrile illness within 3 days before Day 1.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David Burger, PharmD, PhD

Organizational Affiliation

Radboud University Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

CRCN, Radboud University Medical Center

City

Nijmegen

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

27798211

Citation

Smolders EJ, Colbers EP, de Kanter CT, Velthoven-Graafland K, Drenth JP, Burger DM. Daclatasvir 30 mg/day is the correct dose for patients taking atazanavir/cobicistat. J Antimicrob Chemother. 2017 Feb;72(2):486-489. doi: 10.1093/jac/dkw429. Epub 2016 Oct 20.

Results Reference

result

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A Drug-drug Interaction Study Between Daclatasvir and Atazanavir/Ritonavir or Atazanavir/Cobicistat

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