Primary objective:To compare the effect of multiple dose atazanavir/cobicistat on the multiple dose phar-macokinetics of daclatasvir with the effect of atazanavir/ritonavir on the multiple dose of daclatasvir by intra-subject comparison in healthy…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To compare the effect of multiple dose atazanavir/cobicistat (300/150mg QD) on
the multiple dose pharmacokinetics (AUC, Cmax, Ctrought) of daclatasvir (30mg)
with the effect of atazanavir/ritonavir on the multiple dose of 30mg
daclatasvir, by intra-subject com-parison, in healthy subjects. The endpoints
are geometric mean ratio*s (GMR) of daclatasvir AUC, Cmax, Ctrought with
atazanavir/cobicistat compared to atazanavir/ritonavir co-treatment.
GMR of atazanavir AUC, Cmax, Ctrought with daclatasvir + cobicistat compared to
daclatasvir + ritonavir co-treatment
Secondary outcome
Adverse events will be described and compared (including clinically relevant
laboratory abnormalities) of the control treatments (atazanavir/ritonavir) and
of the intervention treatment (atazanavir/cobicistat).
Background summary
Approximately 20-25% of the total number of HIV-infected pa-tients is
co-infected with HCV which translates to 6-8 million per-sons worldwide.
Combined treatment of HIV and HCV is compli-cated by the risk of drug-drug
interactions as both the direct act-ing 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
recom-mended 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 objective
Primary objective:
To compare the effect of multiple dose atazanavir/cobicistat on the multiple
dose phar-macokinetics of daclatasvir with the effect of atazanavir/ritonavir
on the multiple dose of daclatasvir by intra-subject comparison in healthy
subjects.
Secondary objective:
To evaluate the safety and tolerability of co administration of daclatasvir
with atazanavir/cobicistat and atazanavir/ritonavir in healthy subjects.
Study design
This is a prospective open-label, 2-period, randomized, cross-over,
single-centre, phase-I, multiple dose trial in 16 healthy volunteers.
Treatment period Group 1:
A Daclatasvir 30 mg QD + atazanavir/ritonavir 300/100mg QD from Day 1 to 10
(refer-ence ATV/r)
Day 11-21 wash-out
B Daclatasvir 30mg QD + atazanavir/cobicistat 300/150mg QD from Day 22-31 (test
ATV/c)
Treatment period Group 2:
B Daclatasvir 30 mg QD + atazanavir/cobicistat 300/150mg QD from Day 1 to 10
(test ATV/c)
Day 11-21 wash-out
A Daclatasvir 30mg QD + atazanavir/ritonavir 300/100mg QD from Day 22-31
(reference ATV/r)
Intervention
See study design:
Daclatasvir 30 mg QD + atazanavir/ritonavir 300/100mg QD from Day 1 to 10
(reference ATV/r)
Daclatasvir 30mg QD + atazanavir/cobicistat 300/150mg QD from Day 22-31
(intervention ATV/c)
Study burden and risks
This study will be performed in healthy volunteers instead of HCV-infected
patients. The study participants will not benefit from the participation in
this clinical trial. The study participants are healthy subjects between 18 and
55 years, these subjects are repre-sentative for HCV-infected patients. In our
opinion it is not ethical to perform this study in patients, as we are going to
study an unknown interaction and we potentially do not give optimal HCV
treatment.
On the other hand one could argue that a study in healthy volunteers might be
unethical if severe adverse events cannot be excluded. However, as mentioned
before, daclatasvir, atazanavir, cobicistat, and ritonavir are authorized
products which are well tolerated by both patients and healthy volunteers.
Participants will visit the clinical research centre for a screening visit, 2
full day visits and 10 short visits. Eight short visits are scheduled to
control safety/adverse events, and two for PK-sampling. The duration of the
entire trial (excluding screening period) is 32 days. Duration of treatment
with study medication is 20 days.
The overall risk is judged to be minimal.
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is at least 18 and not older than 55 years at screening.
2. Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to Day 1.
3. Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
4. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
5. 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.
6. Subject has a normal blood pressure and pulse rate, according to the Investigator's judgment.
Exclusion criteria
1. Creatinine clearance below 60mL/min.
2. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
3. Positive HIV test.
4. Positive hepatitis B or C test.
5. Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1) or breastfeeding 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.
6. Therapy with any drug (for two weeks preceding Day 1), except for acetaminophen (maximal 2 gram/day).
7. 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.
8. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
9. History of or current abuse of drugs, alcohol or solvents.
10. Inability to understand the nature and extent of the study and the procedures required.
11. Participation in a drug study within 60 days prior to Day 1.
12. Donation of blood within 60 days prior to Day 1.
13. Febrile illness within 3 days before Day 1.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-001354-15-NL |
| CCMO | NL53380.091.15 |
| Other | nog niet beschikbaar, wordt op Clinical trials.gov geregistreerd |