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Trial record 3 of 84 for:    HIV AND GS9350

Clinical Trial to Evaluate Drug-drug Interactions Between Darunavir/Cobicistat and Etravirine in Hiv- Infected Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Fundacio Lluita Contra la SIDA
ClinicalTrials.gov Identifier:
NCT02818348
First received: June 20, 2016
Last updated: December 5, 2016
Last verified: December 2016
  Purpose
This study aims to provide information about the safety and pharmacokinetic drug-drug interactions between darunavir/cobicistat (800/150mg QD) and etravirine (400mg QD) in HIV-infected patients, as well as evaluate the efficacy of concomitant administration of darunavir/cobicistat and etravirine.

Condition Intervention Phase
HIV-1 Infection
Drug: darunavir/cobicistat
Drug: etravirine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Clinical Trial to Evaluate Drug-drug Interactions Between Darunavir/Cobicistat and Etravirine in Hiv- Infected Patients

Resource links provided by NLM:


Further study details as provided by Fundacio Lluita Contra la SIDA:

Primary Outcome Measures:
  • Darunavir, cobicistat and etravirine concentrations in plasma [ Time Frame: on day 7 (PK1) ] [ Designated as safety issue: No ]
  • Darunavir, cobicistat and etravirine concentrations in plasma [ Time Frame: on day 14 (PK2) ] [ Designated as safety issue: No ]
  • Darunavir, cobicistat and etravirine concentrations in plasma [ Time Frame: on day 21 (PK2) ] [ Designated as safety issue: No ]
  • Grade ≥3 adverse events and serious adverse events [ Time Frame: From baseline to 28 days follow-up (ETR cohort) ] [ Designated as safety issue: Yes ]
  • Grade ≥3 adverse events and serious adverse events [ Time Frame: From baseline to 35 days follow-up (DRV/c cohort) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • HIV-1 RNA load in plasma [ Time Frame: baseline ] [ Designated as safety issue: No ]
  • HIV-1 RNA load in plasma [ Time Frame: on day 28 (ETR cohort) ] [ Designated as safety issue: No ]
  • HIV-1 RNA load in plasma [ Time Frame: on day 35 (DRV/c cohort) ] [ Designated as safety issue: No ]

Enrollment: 30
Study Start Date: June 2016
Study Completion Date: November 2016
Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DRV cohort
Darunavir/Cobicistat 800/150 mg, once daily during 35 days + etravirine 400 mg, once daily during 14 days
Drug: darunavir/cobicistat
800/150 mg, once daily during 35 days + etravirine 400 mg, once daily during 14 days
Other Name: Rezolsta
Drug: etravirine
400 mg, once daily during 28 days + darunavir/cobicistat 800/150 mg, once daily during 7 days
Other Name: Intelence
Experimental: ETR cohort
Etravirine 400 mg, once daily during 28 days + darunavir/cobicistat 800/150 mg, once daily during 7 days
Drug: darunavir/cobicistat
800/150 mg, once daily during 35 days + etravirine 400 mg, once daily during 14 days
Other Name: Rezolsta
Drug: etravirine
400 mg, once daily during 28 days + darunavir/cobicistat 800/150 mg, once daily during 7 days
Other Name: Intelence

Detailed Description:

Toxicity associated with use of nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of VIH-infection has prompted increasing interest in new antiretroviral treatment strategies without NRTIs (nuc-sparing regimens).

Ritonavir boosted protease inhibitors (PI/r) like, lopinavir, atazanavir, saquinavir and darunavir may be candidates for maintenance mono-therapy due to their high potency and genetic barrier for drug resistance and possibility for once daily dosing. However, although several controlled and uncontrolled studies have been conducted to examine the safety and tolerance of PI/r monotherapy for maintenance in HIV-infected patients, many of these studies were small or did not use controls; and evidence on the efficacy and safety of PI/r monotherapy is therefore limited. Moreover, several trials have reported a higher rate of intermittent viremia in patients with PI/r monotherapy. A metaanalysis including 10 randomised controlled clinical trials reported an absolute increase in the risk of virological failure at one year with PI/r monotherapy of roughly 10% to 13%. Therefore, PI/r monotherapy is not an option for clinicians and patients who do not want to accept such a risk.

If a nuc-sparing regimen is to be used, dual regimens may be an alternative to PI/r monotherapy. This approach could be able to prevent NRTI-derived toxicity while maintaining antiviral efficacy. Consequently, a growing interest in this strategy has emerged during recent years.

Ideally, a dual antiretroviral regimen should be efficacious and safe, it should permit once-daily administration with a low pill burden, and it should have a high genetic barrier towards the development of drug resistance mutations in patients who might eventually develop virological failure. The combination of the boosted PI darunavir plus the non-nucleoside reverse transcriptase inhibitor etravirine fulfills most of these requirements, and it may be an attractive dual antiretroviral treatment regimen. Although clinical experience with this combination is still limited, promising results from previous studies support current interest on the use of this dual therapy in clinical practice. Moreover, a fixed-dose combination (FDC) tablet containing darunavir and the new pharmacokinetic enhancer cobicistat (Rezolsta®) has been recently launched on the market. Among potential advantages, this FDC may contribute to decrease pill burden as well as to avoid medication errors. However, according to prescribing information, darunavir/cobicistat and etravirine should not be combined due to potential drug-drug interactions.

Darunavir and cobicistat are both metabolized by the isoenzyme CYP3A4 of the cytochrome P450, which is inhibited by cobicistat. On the other hand, etravirine, which is mainly metabolized by 2C19 (but also by CYP3A4 in a minor extent), is a CYP3A4 inducer. Based on this rationale, etravirine could decrease the exposure to cobicistat, eventually leading to concentrations of cobicistat which might be insufficient to boost darunavir.

Although no clinically relevant changes in drug concentrations were evidenced in specific trials evaluating the presence of drug-drug interactions between darunavir/ritonavir and etravirine, the combination of darunavir/cobicistat with etravirine might be more sensitive to the CYP3A inducing effect of etravirine. However, specific data on this potential drug-drug interaction are still lacking. Consequently, the combination of darunavir/cobicistat with etravirine is currently not recommended per prescribing until formal pharmacokinetic data supporting this combination are generated.

  Eligibility

Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 years old
  2. Documented HIV infection (western blot)
  3. Stable antiretroviral treatment including darunavir/cobicistat 800/150mg QD (cohort DRV) or etravirine 400mg QD (cohort ETR) for at least 4 weeks. Plasma HIV-1 RNA load <50 copies/mL for at least 12 weeks
  4. In women of childbearing age*, commitment to use at least one of these birth control methods: male or female condom with or without spermicide, cap, diaphragm or sponge with or without spermicide, intrauterine device, bilateral tubal occlusion, vasectomised partner, sexual abstinence during the study.
  5. Signed Informed Consent

    • According to recommendations of Clinical Trial Facilitation Group (CTFG), a woman is considered of childbearing potential: fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

Exclusion Criteria:

  1. Inadequate adherence to antiretroviral treatment (<90% during the last week)
  2. Patients who are taking or have been taking any other medication within the last two weeks prior to be recruited in the study, including herbal medicines and food supplements, with known interactions with darunavir, cobicistat or etravirine (i.e St. John's wort, grapefruit juice, some antibiotics such as erythromycin or rifampicin; antiepileptics such as phenytoin, phenobarbital or carbamazepine; antifungals such as itraconazole or ketoconazole; antiretrovirals such as ritonavir, efavirenz or nevirapine, among others.)
  3. Acute illness that could interfere with darunavir, cobicistat or etravirine pharmacokinetics (acute hepatitis…) within the prior 4 weeks
  4. Active AIDS-defining illness within the prior 4 weeks
  5. In women, pregnancy or breastfeeding.
  6. Evidence or clinical suspicion that the patient will not be able to complete the study treatment and protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02818348

Locations
Spain
Fundació Lluita contra la SIDA
Badalona, Barcelona, Spain, 08916
Sponsors and Collaborators
Fundacio Lluita Contra la SIDA
  More Information

Responsible Party: Fundacio Lluita Contra la SIDA
ClinicalTrials.gov Identifier: NCT02818348     History of Changes
Other Study ID Numbers: DRV/c-ETR 
Study First Received: June 20, 2016
Last Updated: December 5, 2016
Health Authority: Spain: Ministry of Health

Keywords provided by Fundacio Lluita Contra la SIDA:
HIV infection
Darunavir/cobicistat
Etravirine, drug-drug interactions
Population PK analysis

Additional relevant MeSH terms:
Cobicistat
Anti-HIV Agents
HIV Protease Inhibitors
Darunavir
Etravirine
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Protease Inhibitors

ClinicalTrials.gov processed this record on December 09, 2016