Primary objective:To assess the pharmacokinetics of the alternative maintenance QD regimen combining atazanavir, dolutegravir and lamivudine in HIV infected patients. Secondary objectives:To asses short term efficacy of the combination of atazanavir…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetic parameters (AUC0-24h, Cmax, Ct, C24h, Tmax, T1/2) for
atazanavir, dolutegravir en lamivudine. Values will be compared to historical
data.
Secondary outcome
HIV viral load and CD4 count (efficacy) and adverse events (safety).
Background summary
During the past years the treatment of HIV-1 infection has transformed towards
chronic treatment. Patients are being treated with antiretroviral drugs for
many years and become older. The risk of developing side-effects due to long
term antiretroviral therapy is therefore more and more likely. New alternative
once-daily maintenance regimes are needed for those who are extensively
pre-treated and experience side-effects or toxic-ity on standard treatment
combinations. A possible once-daily, fully active maintenance regimen, with a
mild side-effect profile is the combination of atazanavir (unboosted),
dolutegravir and lamivudine (PRADA II regimen). Dolutegravir has shown to be
highly potent in reducing the HIV-1 RNA viral load and was generally safe and
well tolerated. Compared to other inte-grase inhibitors dolutegravir has a
higher barrier to resistance. Dolutegravir showed low rates of discontinuation
due to adverse events and has a low potency to cause drug interactions. The use
of once daily unboosted atazanavir leads to improved safety without
compromising virological efficacy in patients having achieved virological
suppression on other combination therapies. Combining dolutegravir and
atazanavir with lamivudine adds a third fully active agent to the regimen. The
combination of unboosted atazanavir, dolutegravir and lamivudine would thus be
expected to be a safe, once-daily maintenance regimen with a favorable
side-effect profile. This combination suits patients with intolerance and/or
resistance to NRTIs, NNRTIs and ritonavir, who have a suppressed viral load.
However, for this new combination the pharmacokinetic profile is unknown and
there are no data on short-term and long-term safety and efficacy.
Study objective
Primary objective:
To assess the pharmacokinetics of the alternative maintenance QD regimen
combining atazanavir, dolutegravir and lamivudine in HIV infected patients.
Secondary objectives:
To asses short term efficacy of the combination of atazanavir, dolute-gravir
and lamivudine as maintenance regimen in HIV infected patients.
To evaluate the safety and tolerability of the combination of atazanavir,
dolutegravir and lamivudine as maintenance regimen in HIV infected patients.
Study design
Pilot, open-label, multi-centre, phase IIA, prospective longitudinal
observational pharmacokinetic study in 20 HIV-infected patients.
Treatment: once daily maintenance regimen containing atazanavir 400 mg /
dolute-gravir 50 mg / lamivudine 300 mg.
Treatment period: 2 weeks until pharmacokinetic sampling. Total duration of
treatment will be 12 weeks.
Intervention
HIV therapy will be adapted.
Study burden and risks
The study participants are HIV infected patients in need for a switch of
medication regimen, for example due to side-effects or toxicities. Switching to
the combination of atazanavir, dolutegravir and lamivudine could possibly
relief or prevent progression of troublesome or unpleasant side-effects.
A potential risk due to switching to the combination of atazanavir,
dolutegravir and lamivudine is treatment failure, resulting in a detectable
viral load. Patients can develop side-effects after switching to the
combination of atazanavir, dolutegravir and lamivudine.
Participants will visit the clinical research centre for a screening visit, 3
short visits (approximately 1 hour) and 1 full day (9-10 hours). Short visits
at week 6 and week 12 after switching to a new regimen are part of standard
care. The duration of the entire trial (excluding screening period) and
duration of treatment with study medication is 84 days.
For pharmacokinetic purposes 10 blood samples will be taken in total. For
safety assessment (haematology and clinical chemistry), hCG blood test, blood
glucose, pharmacogenetic testing and determination of VL and CD4-count a total
of 30 blood samples will be collected. The total blood volume taken will be
approximately 195.5-205.5 mL. During the day that blood samples will be
collected for a pharmacokinetic curve an intravenous cannula will be inserted
to facilitate blood sampling and limit the amount of venous punctions.
Risk assessment is 'moderate'.
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. HIV-infected as documented by positive HIV antibody test and confirmed by Western Blot.
2. Subject is in need for a switch in maintenance regimen due to adverse effects, toxicities, simplification and/or resistance.
3. Subject is at least 18 years of age at the day of screening.
4. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
5. HIV-1 RNA < 40 copies/mL for at least 6 months on antiretroviral therapy prior to inclusion.
6. Subject has no documented resistance mutations to PIs, INSTIs or lamivudine.
Exclusion criteria
1. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
2. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
3. Inability to understand the nature and extent of the trial and the procedures required.
4. Pregnant female (as confirmed by an HCG test performed less than 3 weeks before the first dose) or breast-feeding female.
5. Abnormal serum transaminases determined as levels being > 5 times upper limit of normal (see Appendix A for normal ranges of clinical laboratory values).
6. Renal failure determined as an estimated Glomerular Filtration Rate (eGFR) < 50 ml/min (MDRD-based).
7. Concomitant use of medications that interfere with atazanavir, dolutegravir or lamivudine pharmacokinetics: oxcarbamazepine, phenytoin, phenobarbital, carbamazepine, St. John*s wort, rifampicin, clarithromycin, H2 receptor antagonists, proton pump inhibitors, irinotecan, midazolam, triazolam, buprenorfine, aprepitant, modafinil, imatinib, co-trimoxazole, other antiretroviral drugs.
8. Concomitant use of medications that are contraindicated for use with atazanavir, dolutegravir or lamivudine: alfuzosin, pimozide, quetiapine, kinidine, bepridil, simvastatin, atorvastatin, lovastatin, sildenafil (as for use in pulmonary arterial hypertension), cladribine.
9. Active hepatobiliary or hepatic disease (including chronic hepatitis B or C infection).
10. Alcohol abuse.
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 | EUCTR2014-004488-19-NL |
| CCMO | NL52048.091.14 |