Trial record 2 of 2 for:    ACTG 5175

Prospective Evaluation of Anti-retroviral Combinations for Treatment Naive, HIV Infected Persons in Resource-limited Settings (PEARLS)

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00084136
First received: June 7, 2004
Last updated: August 10, 2011
Last verified: August 2011
  Purpose

This study compared 3 different three-drug combinations in HIV infected individuals starting their first HIV treatment regimens. Participants were recruited from resource-limited areas in Africa, Asia, South America, Haiti, and also from the United States. The study hypothesis was each of the once daily combinations (PI based, or NNRTI based) would not have inferior efficacy compared to the twice daily NNRTI based combination.


Condition Intervention Phase
HIV Infections
Drug: Atazanavir
Drug: Didanosine (enteric-coated)
Drug: Efavirenz
Drug: Emtricitabine
Drug: Emtricitabine/Tenofovir disoproxil fumarate
Drug: Lamivudine/Zidovudine
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: Randomized, Open-Label Evaluation of Efficacy of Once-Daily Protease Inhibitor and Once-Daily Non-Nucleoside Reverse Transcriptase Inhibitor-Containing Therapy Combinations for Initial Treatment of HIV-1 Infected Persons From Resource-Limited Settings (PEARLS) Trial

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Time to Treatment Failure (PI Comparison) [ Time Frame: Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up until ddI+FTC+ATV arm closed (May 22, 2008). ] [ Designated as safety issue: No ]
    Time from randomization to the earliest of: scheduled week of first plasma sample meeting virologic failure (two consecutive plasma HIV-1 RNA values 1,000 copies/mL or higher, regardless of whether ARV medications being taken at the time); scheduled week of first AIDS defining diagnosis (WHO Stage 4 (2005), plus microsporidiosis, cyclospora gastroenteritis and Chaga's disease), not attributed to Immune Reconstitution Inflammatory Syndrome (reviewed by chairs); date of death (due to any cause). Plasma drawn every 8 weeks (except confirmation samples could be drawn earlier).

  • Time to Treatment Failure (NRTI Comparison) [ Time Frame: Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up through study closure (May 31, 2010). ] [ Designated as safety issue: No ]
    Time from randomization to the earliest of: scheduled week of first plasma sample meeting virologic failure (two consecutive plasma HIV-1 RNA values 1,000 copies/mL or higher, regardless of whether ARV medications being taken at the time); scheduled week of first AIDS defining diagnosis (WHO Stage 4 (2005) plus microsporidiosis, cyclospora gastroenteritis and Chaga's disease), not attributed to Immune Reconstitution Inflammatory Syndrome (reviewed by chairs); date of death (due to any cause). Plasma drawn every 8 weeks (except confirmation samples could be drawn earlier).


Secondary Outcome Measures:
  • Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison) [ Time Frame: Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008) ] [ Designated as safety issue: No ]
    Time is measured from date of treatment initiation to earliest of the following: date of last participant contact (premature discontinuation of study follow-up); date all ARV medications were held (if all medications held for at least 8 weeks, for any reason); date that any ARV medication was changed (excluding the following single ARV substitutions: stavudine or tenofovir for zidovudine, nevirapine for efavirenz, or didanosine for tenofovir).

  • Time to Immunologic Failure (PI Comparison) [ Time Frame: At or after Week 48 (including only follow-up until ddI+FTV+ATV arm closed - May 22,2008) ] [ Designated as safety issue: No ]
    Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3.

  • Change in CD4 Count From Screening to Weeks 24, 48, 96 (PI Comparison) [ Time Frame: weeks 24, 48 and 96 (including follow-up until ddI+FTC+ARV arm closed - May 22, 2008) ] [ Designated as safety issue: No ]
    Available pre-randomization CD4 cell counts were limited to the single CD4 cell count used for study eligibility (and therefore must have been fewer than 300 cells/mm3).

  • Time to First Dose Modification or Grade 3 or 4 Adverse Event (PI Comparison) [ Time Frame: Throughout study follow-up until ddI+FTC+ATV arm closed (May 22, 2008) ] [ Designated as safety issue: Yes ]
    Time from treatment dispensation to the first occurring of the following: week of first ARV medication change; week of first grade 3 or higher sign/symptom or laboratory abnormality (total bilirubin was excluded) that was at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables.

  • Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (PI Comparison) [ Time Frame: At Weeks 24 and 48 (including only follow-up until ddI+FTC+ARV arm closed - May 22, 2008) ] [ Designated as safety issue: No ]
    Number of participants with plasma HIV-1 Viral load fewer than 400 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 28 weeks (for week 24), and between 44 and up to 52 (for week 48) used if multiple results available. Missing values excluded, and both study treatment status and history ignored.

  • Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(PI Comparison) [ Time Frame: Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) ] [ Designated as safety issue: No ]
    Time from randomization to any of the following events occurring prior to week 48: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression.

  • Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison) [ Time Frame: Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) ] [ Designated as safety issue: No ]
    Time from randomization to any of the following events occurring prior to week 48: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression.

  • Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (NRTI Comparison) [ Time Frame: Throughout follow-up until study closed (May 31,2010) ] [ Designated as safety issue: No ]
    Time is measured from date of treatment initiation to earliest of the following: date of last participant contact (premature discontinuation of study follow-up); date all ARV medications were held (if all medications held for at least 8 weeks, for any reason); date that any ARV medication was changed (excluding the following single ARV substitutions: stavudine or tenofovir for zidovudine, nevirapine for efavirenz, or didanosine for tenofovir).

  • Time to Immunologic Failure (NRTI Comparison) [ Time Frame: At or after Week 48 (including all follow-up through study closure - May 31,2010) ] [ Designated as safety issue: No ]
    Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3.

  • Change in CD4 Count From Screening to Weeks 24, 48, 96 (NRTI Comparison) [ Time Frame: weeks 24, 48 and 96 (including all follow-up through to study closure on May 31, 2010) ] [ Designated as safety issue: No ]
    Available pre-randomization CD4 cell counts were limited to the single CD4 cell count used for study eligibility (and therefore must have been fewer than 300 cells/mm3).

  • Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (NRTI Comparison) [ Time Frame: At Weeks 24 and 48 (including follow-up through to study closure on May 31, 2010) ] [ Designated as safety issue: No ]
    Number of participants with plasma HIV-1 Viral load fewer than 400 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 28 weeks (for week 24), and between 44 and up to 52 (for week 48) used if multiple results available. Missing values excluded, and both study treatment status and history ignored.

  • Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison) [ Time Frame: Week 48 (using follow-up through study closure on May 31,2010) ] [ Designated as safety issue: No ]
    Time from randomization to any of the following events occurring prior to week 48: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression.

  • Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison) [ Time Frame: Week 96 (using follow-up through to study closure on May 31,2010) ] [ Designated as safety issue: No ]
    Time from randomization to any of the following events occurring prior to week 96: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression.

  • Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison) [ Time Frame: Week 48 using follow-up through study closure on May 31,2010 ] [ Designated as safety issue: No ]
    Time from randomization to any of the following events occurring prior to week 48: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression.

  • Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison) [ Time Frame: Week 96 using follow-up through study closure on May 31,2010 ] [ Designated as safety issue: No ]
    Time to any of the following events occurring prior to week 96: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression.

  • Time to First Dose Modification or Grade 3 or 4 Adverse Event (NRTI Comparison) [ Time Frame: Throughout study follow-up until study closure (May 31, 2010) ] [ Designated as safety issue: Yes ]
    Time from treatment dispensation to the first occurring of the following: week of first ARV medication change; week of first grade 3 or higher sign/symptom or laboratory abnormality (total bilirubin was excluded) that was at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables.


Enrollment: 1571
Study Start Date: May 2005
Study Completion Date: May 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ZDV/3TC+EFV
ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz
Drug: Efavirenz
600 mg taken orally daily
Other Name: EFV
Drug: Lamivudine/Zidovudine
150 mg/300 mg taken orally twice daily
Other Name: 3TC/ZDV
Experimental: ddI+FTC+ATV
ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine
Drug: Atazanavir
400 mg taken orally daily
Other Name: ATV
Drug: Didanosine (enteric-coated)
400 mg taken orally daily
Other Name: ddI
Drug: Emtricitabine
200 mg taken orally daily
Other Name: FTC
Experimental: TDF/FTC+EFV
TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz
Drug: Efavirenz
600 mg taken orally daily
Other Name: EFV
Drug: Emtricitabine/Tenofovir disoproxil fumarate
200 mg/300 mg taken orally once daily
Other Name: FTC/TDF

Detailed Description:

In developed countries, standard effective antiretroviral (ARV) therapy for treatment-naive HIV infected people includes three-drug combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). However, direct comparisons of ARV efficacy in persons that more closely reflect the worldwide demographics of HIV-1 infection are needed.

>

> Trial participants were recruited in Africa (Malawi, South Africa, Zimbabwe), Asia (India, Thailand), South America (Brazil, Peru), Haiti, and the United States.

>

> All participants were randomly assigned to one of three arms, and random allocation was stratified by 2 factors: country, and screening plasma HIV-1 RNA level (< 100,000 copies/mL versus >= 100,000 copies/mL). Participants assigned to the ZDV/3TC+EFV arm received lamivudine/zidovudine twice daily and efavirenz once daily. Participants assigned to the ddI+FTC+ATV arm received emtricitabine, atazanavir, and enteric-coated didanosine once daily. Participants assigned to the TDF/FTC+EFV arm received emtricitabine, tenofovir disoproxil fumarate, and efavirenz once daily.

>

>

> Physical exam and blood collection occurred at entry and at most study visits. Participants experiencing virologic failure were offered a switch to another regimen.

>

> On May 23, 2008, the ddI+FTC+ATV was closed following a planned interim review by the study's independent Data and Safety Monitoring Board (DSMB). The DSMB recommendation was based upon compelling evidence that this arm had significantly more virologic failure (and therefore was inferior when) compared to the ZDV/3TC+EFV arm . Participants still receiving ddI+FTC+ATV were offered alternative medications, and all participants continued to be followed.

>

> On November 3, 2009, the DSMB recommended that the study close to all follow-up on May 31, 2010, before the designed termination (based on 30% of participants meeting the primary outcome) was met. The board observed that the recent accumulation of primary efficacy events (i.e. regimen failures) was very slow. Therefore, if the study were to continue another 1-2 years, the precision gained for treatment comparisons would likely be small.

  Eligibility

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

Inclusion Criteria :

  • HIV-1 infected
  • CD4 count fewer than 300 cells/mm3
  • Viral load test result
  • Absolute Neutrophil Count at least 750mm3
  • Hemoglobin at least 7.5 g/dL
  • Platelet count at least 50,000/mm3
  • Calculated creatinine clearance at least 60 mL/min
  • A , A, and alkaline phosphatase <= 5 times upper limit of normal
  • total bilirubin <= 2.5 times upper limit of normal
  • Karnofsky performance score of 70 or higher
  • Plans to stay in the area for the duration of the study
  • Agrees to use acceptable forms of contraception for the duration of the study

Exclusion Criteria:

  • More than 7 days exposure to ARVs (except for single-dose NVP or ZDV for any period for the purpose of pMTCT)
  • Acute therapy for serious medical illnesses within 14 days prior to study entry
  • Certain abnormal laboratory values
  • Radiation therapy or chemotherapy within 45 days prior to study entry.
  • Any immunomodulator, HIV vaccine, or other investigational therapy within 30 days prior to study entry.
  • Current alcohol or drug abuse that, in the opinion of the site investigator, would interfere with study participation
  • Inflamed pancreas within 3 years prior to study entry
  • Allergy/sensitivity to any of the study drugs or their formulations
  • Heart rate less than 40 beats/min
  • History of untreated, active second- or third-degree heart block
  • Currently detained in jail or for treatment of a psychiatric or physical illness
  • Vomiting or inability to swallow medications
  • Pregnancy
  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: NCT00084136

  Hide Study Locations
Locations
United States, California
UCLA CARE Center CRS
Los Angeles, California, United States, 90095-1793
University of Southern California
Los Angeles, California, United States, 90033-1079
Harbor General/UCLA
Torrance, California, United States, 90502-2052
United States, Colorado
Univ. of Colorado Health Sciences Center, Denver
Denver, Colorado, United States
United States, Hawaii
Univ. of Hawaii at Manoa, Leahi Hosp.
Honolulu, Hawaii, United States, 96816-2396
United States, Illinois
Rush-Presbyterian/St. Lukes (Chicago)
Chicago, Illinois, United States, 60612-3806
Cook County Hospital Core Center
Chicago, Illinois, United States, 60612
Northwestern University
Chicago, Illinois, United States, 60611-3015
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455-0392
United States, Missouri
Washington University (St. Louis)
St. Louis, Missouri, United States, 63108-2138
United States, New York
Cornell CRS
119 West 24th Street, Ground Floor, New York, New York, United States, 10011
NY Univ. HIV/AIDS CRS
550 First Avenue BCD 5, Room 558, New York, United States, NY 10016
HIV Prevention & Treatment CRS
HVTN 722 West 168th Street MSPH Bldg., New York, United States, 10032
Beth Israel Medical Center
New York, New York, United States, 10003
Community Health Network, Inc.
Rochester, New York, United States, 14642-0001
Univ. of Rochester ACTG CRS
Rochester, New York, United States, 14642-0001
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27514
Wake County Health and Human Services Clinical Research Site
Chapel Hill, North Carolina, United States, 27514
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
University of Cincinnati
Cincinnati, Ohio, United States, 45267-0405
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
United States, Rhode Island
The Miriam Hosp. ACTG CRS
Providence, Rhode Island, United States, 02906
Stanley Street Treatment and Resource
Providence, Rhode Island, United States, 02906
United States, Tennessee
Vanderbilt Therapeutics CRS
719 Thompson Lane, Suite 47183, Nashville, Tennessee, United States, 37204
United States, Texas
University of Texas, Galveston
301 University Boulevard, Galveston, Texas, United States, 77555-0435
University of Texas, Southwestern Medical Center
Dallas, Texas, United States
University of Texas, Galveston
Galveston, Texas, United States, 77555-0435
Brazil
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
Manguinhos, Rio de Janeiro, Brazil
Hospital Nossa Senhora da Conceicao
Porto Alegre, RS, Brazil, 91350-200
Haiti
Les Centres GHESKIO CRS
33 Boulevard Harry Truman, Bicentenaire Port-au-Prince, Haiti, HT-6110
India
YRG CARE Medical Ctr., VHS Chennai CRS
Rajiv Gandhi Salai Taramani, Chennai, India, 600113
NARI Pune CRS
Pune, Maharashtra, India
NARI Clinic at NIV CRS
Maharashtra State, Pune, India
Dr. Kotnis Dispensary
Pune, India, 411026
Malawi
College of Med. JHU CRS
P.O. Box 1131, Blantyre, Malawi
University of North Carolina Lilongwe CRS
Mzimba Road, Lilongwe, Malawi
Peru
Asociacion Civil Impacta Salud y Educacion - Miraf CRS
Barranco, Lima, Peru
San Miguel CRS
San Miguel, Lima, Peru
South Africa
Wits HIV CRS
Helen Joseph Hospital, Perth Road, Westdene Themba Lethu Clinic, Johannesburg, Gauteng, 2092, South Africa, South Africa
Durban Adult HIV CRS
Durban, KwaZulu Natal, South Africa, 4001
Thailand
Chiang Mai Univ. ACTG CRS
P.O. Box 80, Chiang Mai, Thailand, 50200
Zimbabwe
UZ-Parirenyatwa CRS
AIDS Research Unit P.O. Box A178, Harare, Zimbabwe
Sponsors and Collaborators
AIDS Clinical Trials Group
Investigators
Study Chair: Thomas B. Campbell, MD University of Colorado, Denver
Study Chair: Timothy Flanigan, MD The Miriam Hospital
Study Chair: James Hakim, MscClinEpi, FRCP Department of Medicine, University of Zimbabwe
Study Chair: Nagalingeswaran Kumarasamy, MD Centre for AIDS Research and Education
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Daniel R. Kuritzkes, M.D., Social & Scientific Systems, Inc.
ClinicalTrials.gov Identifier: NCT00084136     History of Changes
Other Study ID Numbers: ACTG A5175, 1U01AI068636, PEARLS, A5185s, 5-K24-AI051966-03
Study First Received: June 7, 2004
Results First Received: July 13, 2011
Last Updated: August 10, 2011
Health Authority: United States: Federal Government

Keywords provided by AIDS Clinical Trials Group:
Treatment Naive
Adherence
Drug Resistance
Treatment Failure

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Didanosine
Zidovudine
Lamivudine
Reverse Transcriptase Inhibitors
Tenofovir
Tenofovir disoproxil
Efavirenz
Lamivudine, zidovudine drug combination
Atazanavir
Emtricitabine
Protease Inhibitors
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on August 28, 2014