Hepatitis CPhase 1DATE-4NCT02565888
A Drug-drug Interaction Study Between Daclatasvir and Atazanavir/Ritonavir or Atazanavir/Cobicistat
A Phase 1 study testing Daclatasvir, Atazanavir and Ritonavir in people with Hepatitis C and HIV, run by Radboud University Medical Center at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Hepatitis C, HIV
- What is being tested?
- Daclatasvir, Atazanavir and Ritonavir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 1 siteNetherlands
- Study dates
- Nov 2015to Jan 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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.
- Conditions
- Hepatitis C, HIV
- Being tested
- Daclatasvir, Atazanavir, Ritonavir, Cobicistat
- Keywords
- Hepatitis C, HIV, atazanavir, ritonavir, daclatasvir, cobicistat
- Medical subject headings
- Hepatitis C
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DaclatasvirDrug
Also called Daklinza
AtazanavirDrug
Also called Reyataz
RitonavirDrug
Also called Norvir
CobicistatDrug
Also called Tybost
| Study group | Role | What they receive |
|---|---|---|
| Treatment A | Active comparator | Daclatasvir 30 mg QD film-coated tablet + atazanavir 300mg QD hard capsule + ritonavir 100mg QD from film-coated tablet for 10 days. Receives: Drug: Daclatasvir; Drug: Atazanavir; Drug: Ritonavir |
| Treatment B | Experimental | Daclatasvir 30 mg QD film-coated tablet + atazanavir 300mg QD hard capsule + cobicistat 150mg QD from film-coated tablet for 10 days. Receives: Drug: Daclatasvir; Drug: Atazanavir; Drug: Cobicistat |
What is being measured
The primary outcome is the main question the study is designed to answer.
AUC
Measured: up to 24 hours after administration
Secondary outcomes (1)
Adverse events
adverse events will be collected up to 4 weeks in total (entire study)
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Oct 2015 (estimated)
- Study startNov 2015
- Primary completionJan 2016
- Study completionJan 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Hepatitis CStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- David Burger, PharmD, PhD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02565888
- Sponsor's protocol ID
- UMCN-AKF 14.12
- Acronym
- DATE-4
- Status last verified
- Dec 2020
- First submitted
- 30 Sep 2015
- Last updated
- 7 Dec 2020
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 27798211Overbeek JK, van Erp NP, Burger DM, den Broeder AA, Koolen SLW, Huitema ADR, Ter Heine R. Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib. Clin Pharmacokinet. 2025 Mar;64(3):425-435. doi: 10.1007/s40262-025-01480-w. Epub 2025 Feb 5.
PubMed 39909979
Study at a glance
From the registry record, last updated by the sponsor on 7 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02565888
- Acronym / sponsor ID
- DATE-4 / UMCN-AKF 14.12
- Conditions
- Hepatitis C, HIV
- Keywords
- Hepatitis C, HIV, atazanavir, ritonavir, daclatasvir, cobicistat
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Nov 2015
- Primary completion
- Jan 2016 (actual)
- Study completion
- Jan 2016 (actual)
- First posted
- 1 Oct 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment A | Active comparator | Drug: Daclatasvir, Drug: Atazanavir, Drug: RitonavirDaclatasvir 30 mg QD film-coated tablet + atazanavir 300mg QD hard capsule + ritonavir 100mg QD from film-coated tablet for 10 days. |
| Treatment B | Experimental | Drug: Daclatasvir, Drug: Atazanavir, Drug: CobicistatDaclatasvir 30 mg QD film-coated tablet + atazanavir 300mg QD hard capsule + cobicistat 150mg QD from film-coated tablet for 10 days. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DaclatasvirAlso: Daklinza | Drug | Treatment A, Treatment B |
| AtazanavirAlso: Reyataz | Drug | Treatment A, Treatment B |
| RitonavirAlso: Norvir | Drug | Treatment A |
| CobicistatAlso: Tybost | Drug | Treatment B |
Primary outcome
AUC
Time frame: up to 24 hours after administration
1 secondary outcome
Adverse events
Time frame: 4 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Dec 2020.
- Results publication: PubMed 27798211Smolders 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.
- Derived from this study: PubMed 39909979Overbeek JK, van Erp NP, Burger DM, den Broeder AA, Koolen SLW, Huitema ADR, Ter Heine R. Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib. Clin Pharmacokinet. 2025 Mar;64(3):425-435. doi: 10.1007/s40262-025-01480-w. Epub 2025 Feb 5.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Burger, PharmD, PhD principal investigator
Radboud University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Daclatasvir, Atazanavir and Ritonavir in people with Hepatitis C and HIV, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
AUC (time frame: up to 24 hours after administration). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02565888, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Dec 2020.