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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
  Purpose

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.


Condition Intervention Phase
HIV-1 Infections
Drug: Raltegravir
Drug: Darunavir/Ritonavir
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Efficacy and Safety Trial of Raltegravir Plus Darunavir/Ritonavir for Treatment-Naive HIV-1-Infected Subjects

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 113
Study Start Date: April 2009
Study Completion Date: September 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: RAL + DRV/RTV
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
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

Detailed Description:

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.

  Eligibility

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

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
  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: NCT00830804

Locations
United States, Alabama
AlabamaTherapeutics CRS
Birmingham, Alabama, United States, 35294
United States, California
Stanford CRS
Palo Alto, California, United States, 94304
Ucsd, Avrc Crs
San Diego, California, United States, 92103
Ucsf Aids Crs
San Francisco, California, United States, 94110
United States, Colorado
University of Colorado Hospital CRS
Aurora, Colorado, United States, 80045
United States, District of Columbia
Georgetown University CRS
Washington, District of Columbia, United States, 20007
United States, Illinois
Northwestern University CRS
Chicago, Illinois, United States, 60611
United States, Massachusetts
Beth Israel Deaconess Med Center
Boston, Massachusetts, United States, 02115
Brigham and Women's Hosp. ACTG CRS
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington U CRS
St.Louis, Missouri, United States, 63110
United States, New York
AIDS Community Health Ctr. ACTG CRS
Rochester, New York, United States, 14604
United States, North Carolina
Unc Aids Crs
Chapel Hill, North Carolina, United States, 27599
Duke Univ. Med. Ctr. Adult CRS
Durham, North Carolina, United States, 27710
United States, Ohio
Univ. of Cincinnati CRS
Cincinnati, Ohio, United States, 45267-0405
Case CRS
Cleveland, Ohio, United States, 44106
MetroHealth CRS
Cleveland, Ohio, United States, 44109
The Ohio State Univ. AIDS CRS
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Hosp. of the Univ. of Pennsylvania CRS
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh CTU
Pittsburgh, Pennsylvania, United States, 15213
United States, Rhode Island
The Miriam Hospital
Providence, Rhode Island, United States, 02906
United States, Tennessee
Vanderbilt Therapeutics CRS
Nashville, Tennessee, United States, 37203
United States, Texas
Houston AIDS Research Team
Houston, Texas, United States, 77030
Sponsors and Collaborators
AIDS Clinical Trials Group
Investigators
Study Chair: Joseph J. Eron, Jr., MD University of North Carolina, Chapel Hill
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT00830804     History of Changes
Other Study ID Numbers: ACTG A5262, 1U01AI068636
Study First Received: January 26, 2009
Results First Received: September 7, 2011
Last Updated: December 7, 2011
Health Authority: United States: Federal Government

Keywords provided by AIDS Clinical Trials Group:
Treatment Naive

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

ClinicalTrials.gov processed this record on November 27, 2014