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Safety and Effectiveness of Raltegravir Plus Darunavir/Ritonavir in Treatment-Naive HIV-Infected Adults

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00830804
First received: January 26, 2009
Last updated: December 7, 2011
Last verified: December 2011

January 26, 2009
December 7, 2011
April 2009
February 2010   (final data collection date for primary outcome measure)
Proportion of Participants With Virologic Failure After Initiating RAL Plus DRV/RTV at or Prior to Week 24 [ Time Frame: From start of study treatment to week 24 ] [ Designated as safety issue: No ]
Virologic failure is defined as: at week 12, confirmed plasma HIV-1 RNA >= 1000 copies/ml or confirmed rebound from the week 4 value by >0.5 log10 copies/ml (for subjects with week 4 value <= 50 copies/ml, confirmed rebound to >50 copies/ml); at week 24 or later, confirmed value > 50 copies/ml. Viral load confirmation was scheduled 7-35 days after initial virologic failure. The proportion was estimated using Kaplan-Meier method. An adaptation of Greenwood's variance estimate was used in constructing the confidence interval.
Proportion of ART-naive participants experiencing virologic failure after initiating RAL plus DRV/RTV [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00830804 on ClinicalTrials.gov Archive Site
  • Proportion of Participants With Virologic Failure or Off Study Treatment Regimen or Death at or Prior to Week 24 [ Time Frame: From start of study treatment to Week 24 ] [ Designated as safety issue: No ]
    The proportion of participants with virologic failure (see primary outcome measure for definition) and/or premature treatment discontinuation/modification and/or death was estimated using Kaplan-Meier method. An adaptation of Greenwood's variance estimate was used in constructing the confidence interval.
  • Change in Plasma HIV-1 RNA From Baseline to Week 1 [ Time Frame: Baseline and week 1 ] [ Designated as safety issue: No ]
    Results report the week 1 change from baseline (week 1 - baseline) in HIV-1 RNA. Baseline HIV-1 RNA was computed as the mean of the log10 HIV-1 RNA values at pre-entry and study entry.
  • Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/ml or <200 Copies/ml at Week 24 [ Time Frame: From start of study treatment to week 24 ] [ Designated as safety issue: No ]
    Results report the percentage of participants with plasma HIV-1 RNA < 50 copies/ml or <200 copies/ml at week 24.
  • Proportion of Participants With Plasma HIV-1 RNA <50 Copies/ml or <200 Copies/ml at Week 48 [ Time Frame: From start of study treatment to week 48 ] [ Designated as safety issue: No ]
    Results report the percentage of participants with plasma HIV-1 RNA <50 copies/ml or <200 copies/ml at week 48.
  • Proportion of Participants Who Experienced Signs/Symptoms or Laboratory Toxicities Grade 3 or Higher, or of Any Grade Which Led to a Permanent Change or Discontinuation of Study Treatment [ Time Frame: From start of study treatment to week 52 ] [ Designated as safety issue: Yes ]
    Signs, symptoms and laboratory values were graded according to the Division of AIDS Adverse Event Grading System. Results report the percentage of participants who had grade 3 or higher events, or events of any grade which led to a permanent change or discontinuation of study treatment, which occurred any time from start of treatment to end of treatment.
  • Number of Participants With Pretreatment Drug Resistance [ Time Frame: At screening ] [ Designated as safety issue: No ]
    Results report the number of participants who had resistance to non-nucleoside reverse transciptase inhibitors (NNRTI), nucleoside reverse transciptase inhibitors (NRTI) and protease inbitors (PI) based on genotypic resistance testing done prior to participant's entry into the study. Participants are classified into one (and only one category) based on the maximum number of drug class resistance seen for the participant.
  • Number of Participants With Integrase Drug Resistance at Virologic Failure [ Time Frame: From 12 weeks after starting study treatment to week 52 ] [ Designated as safety issue: No ]
    Results report the number of participants who had integrase resistance mutation(s) detected at the time of virologic failure.
  • Number of Participants With Protease Drug Resistance at Virologic Failure [ Time Frame: From 12 weeks after starting study treatment to week 52 ] [ Designated as safety issue: No ]
    Results report the number of participants who had protease resistance mutation(s) detected at the time of virologic failure.
  • Number of Participants With Perfect Overall Adherence by Self Report [ Time Frame: From one week after starting study treatment to week 52 ] [ Designated as safety issue: No ]
    At each study visit, adherence was measured in terms of the number of missed doses each participant had over a 4-day recall for each drug. Adherence for all study visit weeks were combined for an overall measure of adherence. Participants who had zero missed doses on all weeks in all drugs while on study were classified as having an overall "perfect" adherence.
  • Changes in Fasting Total Cholesterol, High-density Lipoprotein and Triglyceride at Week 24 [ Time Frame: From start of study treatment through week 24 ] [ Designated as safety issue: No ]
    Results report the week 24 change from week 0 (week 24 - week 0) fasting total cholesterol, high-density lipoprotein and triglyceride.
  • Change in Fasting Low-density Lipoprotein at Week 24 [ Time Frame: From start of study treatment through week 24 ] [ Designated as safety issue: No ]
    Results report the week 24 change from week 0 (week 24 - week 0) fasting low-density lipoprotein (LDL). For participants whose calculated fasting LDL and direct fasting LDL were both reported, only the calculated fasting LDL was used. Direct fasting LDL was reported when the participant had high fasting triglyceride.
  • Changes in Fasting Total Cholesterol, High-density Lipoprotein and Triglyceride at Week 48 [ Time Frame: From start of study treatment through week 48 ] [ Designated as safety issue: No ]
    Results report the week 48 change from week 0 (week 48 - week 0) fasting total cholesterol, high-density lipoprotein and triglyceride.
  • Change in Fasting Low-density Lipoprotein at Week 48 [ Time Frame: From start of study treatment through week 48 ] [ Designated as safety issue: No ]
    Results report the week 48 change from week 0 (week 48 - week 0) fasting low-density lipoprotein (LDL). For participants whose calculated fasting LDL and direct fasting LDL were both reported, only the calculated fasting LDL was used. Direct fasting LDL was reported when the participant had high fasting triglyceride.
  • Change in CD4 Count at Week 48 [ Time Frame: From start of study treatment through week 48 ] [ Designated as safety issue: No ]
    Results report the week 48 change from baseline (week 48 - baseline) in CD4 count. Baseline CD4 count was computed as the mean of CD4 count values at pre-entry and study entry.
  • Plasma Trough Concentration of Raltegravir [ Time Frame: From start of study treatment to week 52 ] [ Designated as safety issue: No ]
    Plasma trough concentrations (ng/ml) of Raltegravir (RAL) below the detection limit (10 ng/ml) were replaced by half the corresponding lower limit of quantitation. Geometric mean of trough concentrations obtained within the prescribed trough time (within 9-15 hours after the last RAL dose) was computed for each participant. For participants who experienced virologic failure (see primary outcome measure definition), only those concentrations on or before virologic failure confirmation were used in the geometric mean computation.
  • Plasma Trough Concentration of Darunavir [ Time Frame: From start of study treatment to week 52 ] [ Designated as safety issue: No ]
    Plasma trough concentrations (ng/ml) of Darunavir (DRV) below the detection limit (50 ng/ml) were replaced by half the corresponding lower limit of quantitation. Geometric mean of trough concentrations obtained within the prescribed trough time (within 20-28 hours after the last DRV dose) was computed for each participant. For participants who experienced virologic failure (see primary outcome measure definition), only those concentrations on or before virologic failure confirmation were used in the geometric mean computation.
  • Safety and tolerability of RAL plus DRV/RTV [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  • Virologic response [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Early virologic response to the combination of RAL plus DRV/RTV [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Pretreatment drug resistance [ Time Frame: At screening ] [ Designated as safety issue: No ]
  • Impact of transmitted drug resistance on virologic outcomes to RAL plus DRV/RTV [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Adherence by self report [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Associations between virologic and/or other efficacy responses and plasma trough concentrations of RAL and DRV [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Pretreatment drug resistant minority viral variants in participants with virologic failure and in a random sample of participants who do not experience virologic failure [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Changes in fasting lipids [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Changes in CD4 counts, CD4 naive, and memory subsets, CD4 and CD8 activation state, CD4 and CD8 turnover, and levels of bacterial 16s DNAs [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Association between virologic response, immune activation, and turnover in defined T-cell maturation subsets, bacterial 16s DNA level, and CD4 restoration [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Safety and Effectiveness of Raltegravir Plus Darunavir/Ritonavir in Treatment-Naive HIV-Infected Adults
A Pilot Efficacy and Safety Trial of Raltegravir Plus Darunavir/Ritonavir for Treatment-Naive HIV-1-Infected Subjects

The purpose of this study is to assess the effectiveness and safety of an antiretroviral therapy (ART) regimen consisting of raltegravir (RAL) and darunavir (DRV)/ritonavir (RTV) as first-line therapy in treatment-naïve participants.

Despite the remarkable strides made in the treatment of HIV-1-infected persons over the last decade, current first-line ART regimens are imperfect. The ideal combination, unlike some current first-line options, would have uncompromised efficacy in the presence of transmitted drug-resistant variants. The primary purpose of this study is to estimate the cumulative proportion of ART-naive participants experiencing virologic failure at or prior to week 24 after initiating raltegravir (RAL) plus darunavir/ritonavir (DRV/RTV).

The study will last 52 weeks. All participants will follow the same treatment schedule and take RAL plus DRV/RTV orally daily for the duration of the trial.

After entry, all participants will have scheduled visits at weeks 1, 4, 12, 24, 36, 48, and 52. Medical/medication history, blood and urine collection, and liver function tests will occur at screening. A targeted physical exam and concomitant medications history will occur at all study visits. Blood and urine collection and liver function tests will occur at most study visits. For females, a pregnancy test will occur at screening and study entry.

RAL and DRV were provided by the study. RTV was not provided by the study.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
HIV-1 Infections
  • Drug: Raltegravir
    400 mg tablet taken orally twice daily
    Other Name: RAL
  • Drug: Darunavir/Ritonavir
    800 mg Darunavir/100 mg Ritonavir tablet taken orally once daily
    Other Name: DRV/RTV
Experimental: RAL + DRV/RTV
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Interventions:
  • Drug: Raltegravir
  • Drug: Darunavir/Ritonavir

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
113
September 2010
February 2010   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-1-infected
  • Plasma HIV-1 RNA of at least 5,000 copies/mL within 90 days prior to study entry
  • HIV genotype (for reverse transcriptase and protease) performed at any time prior to study entry. More information on this criterion can be found in the protocol.
  • ARV drug-naive. More information on this criterion can be found in the protocol.
  • Negative result from a hepatitis B surface antigen test performed within 90 days prior to study entry
  • Agree to use one form of medically-accepted contraceptive throughout the study and for 60 days after stopping study treatment. More information on this criterion can be found in the protocol.

Exclusion Criteria:

  • Serious illness requiring systemic treatment and/or hospitalization for at least 7 days prior to study. More information on this criterion can be found in the protocol.
  • Screening HIV genotype obtained any time prior to study entry with more than one DRV resistance-associated mutation [RAM] (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, I84V, and L89V) or L76V alone
  • Known major integrase inhibitor RAM(s), including N155H, Q148H/R/K, Y143C/R, and G140S
  • Severe renal insufficiency requiring hemodialysis or peritoneal dialysis
  • Treatment with immunomodulators within 30 days prior to study entry. More information on this criterion can be found in the protocol.
  • Current medications that are prohibited with any study medications. More information on this criterion can be found in the protocol.
  • Known allergy/sensitivity to study drugs or their formulations. A history of sulfa allergy is not an exclusion.
  • Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with the study.
  • Certain abnormal laboratory results. More information on this criterion can be found in the protocol.
  • Pregnant or breastfeeding
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00830804
ACTG A5262, 1U01AI068636
Yes
AIDS Clinical Trials Group
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Study Chair: Joseph J. Eron, Jr., MD University of North Carolina, Chapel Hill
AIDS Clinical Trials Group
December 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP