Optimizing Treatment for Treatment-Experienced, HIV-Infected People

This study has been completed.
Sponsor:
Collaborator:
AIDS Clinical Trials Group
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00537394
First received: September 27, 2007
Last updated: September 8, 2014
Last verified: September 2014

September 27, 2007
September 8, 2014
January 2008
May 2012   (final data collection date for primary outcome measure)
Percent of Participants With Regimen Failure, Defined as a Confirmed Virologic Failure or Discontinuation of Randomized NRTI Component of Study Treatment [ Time Frame: From study entry to end of Week 48 evaluation window ] [ Designated as safety issue: No ]
Virologic failure defined as confirmed plasma HIV-1 RNA meeting 1 of the following 4 criteria: < 1.0 log10 copies/mL reduction from baseline level and >= 200 copies/mL at or after week 12 evaluation; >= 200 copies/mL after 1 measurement < 200 copies/mL; absence of any values < 200 copies/mL by and including week 24 evaluation; >= 200 copies/mL at week 48 evaluation. Discontinuation of Randomized NRTI component of Study Treatment is defined as permanently stopping all NRTIs among those randomized to add NRTIs, or starting any NRTI among those randomized to omit NRTIs. Subjects leaving the study for reasons other than death, relocation, incarceration, or site closure were reviewed for the discontinuation outcome by a blinded, independent panel. Additionally, any participant failing to start study treatment after randomization and prior to closure was also reviewed. Results report percent of participants reaching regimen failure outcome by week 48 evaluation using Kaplan-Meier method.
Time to regimen failure, as defined by the protocol [ Time Frame: Throughout study ]
Complete list of historical versions of study NCT00537394 on ClinicalTrials.gov Archive Site
  • Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality [ Time Frame: From treatment dispensation to week 96 study visit ] [ Designated as safety issue: Yes ]
    Events following permanent discontinuation of NRTI assignment are excluded (i.e. censoring at time of this event, if applicable).
  • Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable) [ Time Frame: From treatment dispensation to week 96 study visit ] [ Designated as safety issue: No ]
  • Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment [ Time Frame: From randomization to week 96 study visit ] [ Designated as safety issue: No ]
    Discontinuation of Randomized NRTI component of Study Treatment is defined as permanently stopping all NRTIs among those randomized to add NRTIs, or starting any NRTI among those randomized to omit NRTIs. Subjects leaving the study for reasons other than death, relocation, incarceration, or site closure were reviewed for meeting this outcome by a blinded, independent panel. Additionally, any participant failing to start study treatment after randomization and prior to closure was also reviewed.
  • Time From Randomization to Confirmed Virological Failure [ Time Frame: From randomization to week 96 study visit ] [ Designated as safety issue: No ]
    Virologic failure defined as confirmed (two consecutive) plasma HIV-1 RNA meeting 1 of the following 4 criteria: < 1.0 log10 copies/mL reduction from baseline level and >= 200 copies/mL at or after week 12 evaluation; >= 200 copies/mL after 1 measurement < 200 copies/mL; absence of any values < 200 copies/mL by and including week 24 evaluation; >= 200 copies/mL at week 48 evaluation.
  • Participants With Plasma HIV-1 Viral Load < 50 Copies/ml [ Time Frame: At Weeks 24, 48, 96 ] [ Designated as safety issue: No ]
    Number of participants with plasma HIV-1 Viral load < 50 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 30 weeks (for week 24), and between 42 and up to 54 (for week 48) used if multiple results available. Missing values excluded.
  • Change in Plasma HIV-1 Viral Load From Baseline to Week 1 [ Time Frame: From baseline to Week 1 evaluation ] [ Designated as safety issue: No ]
    Method of Kaplan and Meier used to accommodate left-censoring for those whose week 1 levels < 50 copies/mL.
  • Change in Summarized Quality of Life Score [ Time Frame: At study entry and Weeks 24, 48, 96 ] [ Designated as safety issue: No ]
    Quality-of-life score at each evaluation based upon a single question assessing participants' self-report of general health with a range of 0 (representing worst health status) to 100 (representing perfect health).
  • Number of Participants Self-reporting Non-adherence to Assigned Study ARVS (Excluding NRTIs, if Applicable) [ Time Frame: At Weeks 24 and 48 ] [ Designated as safety issue: No ]
    Results represent self-report of non-adherence during the 4-day period prior to the outcome evaluation visit. Participants in follow-up for whom these data are missing for any reason are inferred as not-adherent.
  • Change in Cardiovascular Risk Score From Baseline [ Time Frame: At Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
    Cardiovascular risk score defined by Framingham
  • Change in CD4 Count From Baseline [ Time Frame: From study entry to Weeks 48 and 96 ] [ Designated as safety issue: No ]
    Baseline CD4 calculated as average of pre-entry and entry values. Closest observed result between 42 and up to 54 weeks (for week 48), used if multiple results available.
  • Time From Randomization to Serious Non-AIDS-defining Events [ Time Frame: From randomization to week 96 study visit ] [ Designated as safety issue: Yes ]
  • Change in Virus Co-receptor Tropism Among Those With R5-only Tropic Virus at Study Entry [ Time Frame: From study entry to time of confirmed virological failure ] [ Designated as safety issue: No ]
    HIV Co-receptor tropism test result of either dual/mixed or evidence of X4 using virus from sample collected at confirmed virologic failure.
  • Change in Fasting Non-HDL Cholesterol From Baseline [ Time Frame: From study entry to Weeks 24, 48 ] [ Designated as safety issue: No ]
    Fasting non-HDL cholesterol calculated from difference between fasting total cholesterol and fasting HDL level. Missing values and non-fasting values excluded.
  • Percent of Participants With Newly Acquired HIV Drug Resistance Between Study Entry and Confirmed Virologic Failure [ Time Frame: Between baseline and confirmed virologic failure ] [ Designated as safety issue: No ]
    Defined among the subgroup of participants experiencing the outcome of confirmed virologic failure. Newly acquired HIV drug resistance is defined as one or more ARVs with partial resistance when pre-entry resistance was fully sensitive or resistant when pre-entry resistance was fully sensitive or partially sensitive.
  • Toxicity, as defined as time to first Grade 3 or higher (and one grade higher than baseline) signs/symptom or laboratory abnormality [ Time Frame: Throughout study ]
  • Tolerability, as defined as time to first dose modification, time to permanent discontinuation of all study drugs [ Time Frame: Throughout study ]
  • Time to "off-strategy" (time to permanent discontinuation of NRTIs in ARA; time to adding NRTIs in Arm B) [ Time Frame: Throughout study ]
  • Time to virological failure, as defined by the protocol [ Time Frame: Throughout study ]
  • Binary variable indication if viral load is less than 50 copies/ml [ Time Frame: At Weeks 24 and 48 ]
  • Change in viral load [ Time Frame: From study entry to Week 1 ]
  • Binary variable indicating acquisition of drug resistance mutations to any of the study agents [ Time Frame: At time of virologic failure ]
  • Change in summarized quality of life score [ Time Frame: From study entry to Weeks 24 and 48 of Step 2 ]
  • Binomial indicator of "perfect" adherence to assigned ARVs [ Time Frame: Throughout study ]
  • Change in cardiovascular risk score and fasting lipid values [ Time Frame: From study entry to Weeks 24 and 48 ]
  • Change in CD4 count [ Time Frame: From study entry to Week 48 ]
  • Time to new AIDS-defining condition, death, or targeted medical events [ Time Frame: Throughout study ]
  • Change in virus coreceptor tropism among those with R5-only tropic virus in Step 1 [ Time Frame: From study entry to time of virological failure and Weeks 24 and 48 ]
  • Resolution of diagnoses, signs/symptoms, and laboratory abnormalities present at baseline (during NRTI use) that resolve following Step 2 initiation [ Time Frame: Throughout Step 2 ]
Not Provided
Not Provided
 
Optimizing Treatment for Treatment-Experienced, HIV-Infected People
The Optimized Treatment That Includes or Omits NRTIs Trial: A Randomized Strategy Study for HIV-1-Infected Treatment-Experienced Subjects Using the cPSS to Select an Effective Regimen

The goal of anti-HIV therapy is to prevent HIV from replicating. Long-term control of HIV requires at least two anti-HIV drugs that are active against the virus. Drug resistance is a problem for many treatment-experienced, HIV-infected people. The purpose of this study was to determine the benefit of adding a nucleoside reverse transcriptase inhibitor (NRTI) to a new anti-HIV drug regimen for the suppression of HIV.

Two or more fully active antiretrovirals (ARVs) are recommended for successful suppression of HIV. In people infected with resistant HIV virus, finding two drugs that are fully active against HIV can be a challenge. However, the new generation of anti-HIV drugs has been designed to suppress drug-resistant HIV. These drugs include the FDA-approved protease inhibitors (PIs) darunavir and tipranavir, the investigational non-nucleoside transcriptase inhibitor (nNRTI) etravirine, the FDA-approved fusion inhibitor enfuvirtide, the recently FDA-approved CCR5 inhibitor maraviroc, and the investigational integrase inhibitor raltegravir. Also, it is not yet known whether multiple, partially-active drugs have the same rate of success in suppressing HIV. The purpose of this study was to use HIV resistance testing to predict the potency of a suggested ARV regimen using second generation ARVs and determine if the benefits of adding NRTIs to this new drug regimen outweigh the risks of drug toxicity and pill burden. All participants had treatment experience or resistance to NRTIs, nNRTIs, and PIs, and received novel agents.

An active screening period occurred for up to 75 days for all participants, and study participation lasted an additional 96 weeks for those who qualified for either randomization or assignment (i.e. not randomized), to the study intervention. During active screening, all participants remained on their current drug regimen. During screening, phenotypic and genotypic HIV resistance tests were performed on participants' blood samples, as well as a coreceptor tropism assay. Using this information and medication history, the study team determined the best new regimen options for each participant. Each clinician, along with the study participant, then chose a new regimen based on the recommendations of the study team and the participant's preference.

Evaluation for study outcomes began when participants started their new regimen as assigned by either randomization or determined assignment. Stratification between Arms A (Add NRTIs) and B (Omit NRTIs) or Arm C (Non-randomized to Add NRTIs) was based on predicted activity of the new regimen. Those assigned to a regimen with higher predicted activity were randomly assigned to Arm A (Add NRTIs) or B (Omit NRTIs); those assigned a regimen predicted to have lower activity were not randomized, but were assigned to Arm C (Add NRTIs).

Participants in Arms A and C will take their new assigned study regimen plus at least 2 NRTIs (personalized from expert recommendation and choice by local provider and participant) for 96 weeks. Participants in Arm B will take their new assigned study regimen with no NRTIs for 96 weeks. Participants in all arms who meet the primary efficacy outcome of regimen failure will remain in the study in order to be followed for important secondary outcomes.

All participants will have 13 clinical visits. At each visit, blood collection will occur. At some visits, urine collection and quality of life and adherence questionnaires will occur. A neurocognitive assessment will be done for all participants at time of starting the new study regimen. Participants may also consent to have cerebrospinal fluid collected via lumbar puncture following study treatment assignment and/or at Week 24. Those participants who consent to cerebrospinal fluid collection will also have neurocognitive assessments at the times of collections. Participants will be responsible for obtaining certain ARVs not provided by the study, including the ARVs they during the active screening period.

The primary study objectives and comparisons relate to the randomized arms, and therefore, results will not be initially provided for the non-randomized arm (C). The primary completion date of 5/31/12 reflects follow-up through study visit window for week 48, and therefore the initial results submission pertains to data from the randomized arms up to the primary outcome timepoint at week 48. All secondary outcomes and AE measured after week 48 will be reported when available.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
HIV Infections
  • Drug: Enfuvirtide
    90mg subcutaneously twice daily
  • Drug: Raltegravir
    400 mg twice daily
  • Drug: Darunavir
    Two 300-mg tablets twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)
  • Drug: Tipranavir
    Two 250-mg capsules twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)
  • Drug: Etravirine
    Two 100-mg tablets twice daily
  • Drug: Maraviroc
    Dosage dependent on regimen in which maraviroc is included
  • Experimental: A
    Regimen with higher predicted activity assigned by the study plus at least 2 NRTIs (personalized choice from expert recommendation) for 96 weeks. A 3-4 drug regimen will be selected from the drugs listed to the right.
    Interventions:
    • Drug: Enfuvirtide
    • Drug: Raltegravir
    • Drug: Darunavir
    • Drug: Tipranavir
    • Drug: Etravirine
    • Drug: Maraviroc
  • Experimental: B
    Regimen with higher predicted activity assigned by the study without NRTIs for 96 weeks. A 3-4 drug regimen will be selected from the drugs listed to the right.
    Interventions:
    • Drug: Enfuvirtide
    • Drug: Raltegravir
    • Drug: Darunavir
    • Drug: Tipranavir
    • Drug: Etravirine
    • Drug: Maraviroc
  • C
    Regimen with lower predicted activity assigned plus at least 2 NRTIs (personalized choice from expert recommendation) for 96 weeks. A 3-4 drug regimen will be selected from the drugs listed to the right.
    Interventions:
    • Drug: Enfuvirtide
    • Drug: Raltegravir
    • Drug: Darunavir
    • Drug: Tipranavir
    • Drug: Etravirine
    • Drug: Maraviroc

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
517
April 2013
May 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-1 infection
  • Triple-class drug experience or resistance. More information on this criterion can be found in the protocol.
  • Currently on a failing PI-containing regimen that includes 2 other ARVs with no regimen change for 8 weeks prior to study screening
  • HIV viral load of 1000 copies/ml or more
  • Hepatitis B surface antigen negative within 90 days of study entry
  • Able to obtain NRTIs and ritonavir and have required ARVs at time of starting study intervention
  • Willing to use acceptable forms of contraception
  • Parent or legal guardian willing to provide consent, if applicable
  • CD4 count result from a specimen drawn within 120 days prior to study entry
  • If any previous HIV-1 viral co-receptor tropism result is available, then most recent specimen date and the tropism result of that specimen AND specimen date and tropism result of any test with either X4 or D/M result, if different from the first specimen, must be available

Inclusion Criteria continued:

  • Receipt of successful phenotype/genotype resistance results within 105 days prior to study treatment intervention assignment
  • Study team identification of a study regimen and at least 2 NRTIs for participant to take
  • Certain abnormal laboratory values. More information on this criterion can be found in the protocol.

Exclusion Criteria:

  • Chronic, active hepatitis B virus infection (hepatitis B surface antigen positive or HBV DNA positive)
  • Taking certain medications. More information on this criterion can be found in the protocol.
  • Known allergy/sensitivity to components of two or more of the study-provided drugs or their formulations. For maraviroc, this includes hypersensitivity or history of allergy to soy lecithin or peanuts.
  • Active drug or alcohol use that, in the opinion of the investigator, may interfere with the study
  • Pregnancy or breastfeeding
  • Use of any immunomodulator (interferons, interleukins, systemic corticosteroids, or cyclosporine), vaccine, or investigational therapy within 30 days prior to study treatment allocation/assignment
  • Require certain medications prohibited with study treatment
  • Serious illness requiring systemic treatment or hospitalization. Participants who complete therapy or are clinically stable on therapy for at least 14 days prior to study treatment allocation are not excluded.
Both
16 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Puerto Rico
 
NCT00537394
A5241, 10395, ACTG A5241, OPTIONS
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
AIDS Clinical Trials Group
Study Chair: Karen T. Tashima, MD Brown University
Study Chair: Richard H. Haubrich, MD Division of Infectious Diseases, UCSD Antiviral Research Center
National Institute of Allergy and Infectious Diseases (NIAID)
September 2014

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