NNRTI/PI Toxicity Switch to Darunavir Study

This study has been terminated.
(Difficulties in recruitment due to a change in the nature of practice.)
Sponsor:
Information provided by:
St Stephens Aids Trust
ClinicalTrials.gov Identifier:
NCT00765154
First received: October 1, 2008
Last updated: October 29, 2010
Last verified: October 2010
  Purpose

The purpose of the study is to examine the effects of switching from antiretroviral combinations that includes efavirenz (Sustiva®), lopinavir/ritonavir (Kaletra®) or atazanavir/ritonavir (Reyataz®/Norvir®) in individuals experiencing side effects from one of these agents, and replacing these with a new HIV medication called Darunavir also given with ritonavir (Norvir®).

The study will primarily investigate the effect of change in medication on the subjects viral load (the levels of the HIV virus in the blood), on immunological parameters (CD4 count) and on other safety parameters (such as cholesterol) and also quality of life.


Condition Intervention Phase
HIV
Drug: darunavir
Drug: ritonavir
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase IV, Two-arm, Open-label, Single-centre Randomised Pilot Study to Assess the Feasibility of Immediate or Deferred Switching of HIV-infected Individuals Intolerant of Efavirenz, Ritonavir-boosted Lopinavir or Ritonavir-boosted Darunavir

Resource links provided by NLM:


Further study details as provided by St Stephens Aids Trust:

Primary Outcome Measures:
  • The improvement of NNRTI/PI associated toxicity after 4 weeks of therapy with ritonavir boosted darunavir. [ Time Frame: 20 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Viral load suppression below 50 copies/ml post switch [ Time Frame: between 20 and 60 days ] [ Designated as safety issue: No ]
  • Viral load < 400 copies/ml post switch [ Time Frame: between 20 and 60 days ] [ Designated as safety issue: No ]
  • Toxicity [ Time Frame: 60 days ] [ Designated as safety issue: Yes ]
  • Health related quality of life questionnaires [ Time Frame: Baseline, 20 and 60 days ] [ Designated as safety issue: No ]
  • Changes in fasting triglycerides post switch [ Time Frame: 20 days and 60 days ] [ Designated as safety issue: No ]
  • Adherence as measured via questionnaire [ Time Frame: baseline, 20 days and 60 days ] [ Designated as safety issue: No ]
  • Tolerability as measured by tolerability index questionnaire (HIV patients symptoms profile [ Time Frame: baseline, 20 days and 40 days ] [ Designated as safety issue: No ]

Enrollment: 12
Study Start Date: October 2008
Study Completion Date: July 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group 1
Immediate switch from NNRTI/PI to DRV/r
Drug: darunavir
two 400mg tablets (800mg) once daily
Other Names:
  • TMC114
  • Trade Name: Prezista
Active Comparator: Group 2
Switch after 10 weeks from NNRTI/PI to DRV/r
Drug: ritonavir
one 100mg capsule once daily
Other Name: Trade Name: Norvir

Detailed Description:

The advent of highly active antiretroviral therapy (HAART) has revolutionised the treatment of HIV disease, with both patients and physicians enjoying the marked reductions in HIV related morbidity and mortality. However, as long term therapeutic success has become a realistic goal of treatment, there are increasing reports of toxicities associated with therapy.

Indeed since the advent of HAART the major reason for change in therapy has not been a lack of efficacy associated with drug regimens but the toxicity associated with individual agents. Although the potential adverse events associated with antiretrovirals are manifold there are signature treatment-limiting toxicities associated with particular agents such as EFV and CNS/neuropsychiatric adverse events, LPV/r and gastrointestinal toxicity and ATV/r and jaundice.

A recent study performed at the Chelsea and Westminster hospital showed that 61% of regimen switches were due to toxicity and the majority of these occurred after 12 weeks of therapy.

Darunavir is a recently licensed protease inhibitor which requires ritonavir boosting.Currently DRV/r is licensed for use in treatment-experienced individuals. In triple-class experienced patients ritonavir boosted darunavir has been associated with greater viral load reductions when combined with optimized background (OB) than OB alone. A study of PI experienced patients randomized to receive Kaletra or ritonavir boosted darunavir with optimised background therapy showed significantly higher rates of virological suppression in the DRV/r arm; rates of toxicities were similar overall but less diarrhoea in the DRV/r than the Kaletra arm. Darunavir is licensed twice daily and has a high barrier to the development of resistance. DRV/r dosed at 800/100mg once daily has been compared with LPV/r in treatment-naïve subjects. DRV/r was non-inferior to LPV/r overall and performed significantly better than LPV once daily and in subjects with a high baseline viral load. DRV/r and LPV/r have also been compared head to head in 'early'treatment-experienced patients (failing first or second line therapy but LPV-naive). Overall DRV/r exhibited superiority to LPV/r with 77% and 67% achieving viral suppression to less than 50 copies/ml by intent-to-treat analysis respectively (95% confidence interval for the difference 2-17%; p <0.0001). Animal studies have shown a low risk of teratogenesis associated with DRV.

This study aims to investigate whether substitution of NNRTI/PI with ritonavir boosted darunavir leads to resolution of toxicity associated with these drugs, continued virological suppression and immunological reconstitution and whether this is associated with an improvement in quality of life.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 infected as documented by a licensed HIV-1 antibody ELISA test
  • Subject is currently on an antiretroviral regimen comprising of at least three licensed antiretroviral agents including efavirenz, ritonavir-boosted lopinavir or ritonavir-boosted atazanavir
  • Subject is virologically suppressed with a viral load < 50 copies/ml
  • Subject has a CD4+ count above 50 cells/ml
  • If subject is a female of childbearing potential, she must agree to use a double barrier method of contraception
  • No previous exposure to darunavir

Exclusion Criteria:

  • Pregnant or lactating women
  • Any female of childbearing potential not using effective birth control methods or not willing to continue practicing these birth control methods during the trial and for at least 30 days after the end of the trial (or after last intake of investigational ARVs)
  • Heterosexually active male subject not using effective birth control methods or not willing to continue practicing these birth control methods during the trial and until 30 days after the end of the trial (or after last intake of investigational ARVs)
  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: NCT00765154

Locations
United Kingdom
Chelsea and Westminster Hospital
London, United Kingdom, SW10 9TH
Sponsors and Collaborators
St Stephens Aids Trust
Investigators
Principal Investigator: Mark Nelson St Stephen's AIDS Trust
  More Information

No publications provided

Responsible Party: Dr Mark Nelson, St Stephens Aids Trust
ClinicalTrials.gov Identifier: NCT00765154     History of Changes
Other Study ID Numbers: SSAT 028
Study First Received: October 1, 2008
Last Updated: October 29, 2010
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Ritonavir
Darunavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 16, 2014