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Minneapolis, Minnesota 55455

  • HIV Infections

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.


Study summary:

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.


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


Study is Available At:


Original ID:

ACTG A5175


NCT ID:

NCT00084136


Secondary ID:

1U01AI068636


Study Acronym:

PEARLS


Brief Title:

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


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 (PE


Overall Status:

Completed


Study Phase:

Phase 4


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

AIDS Clinical Trials Group


Oversight Authority:

United States: Federal Government


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

3


Number of Groups:

0


Total Enrollment:

1571


Enrollment Type:

Actual


Overall Contact Information

Official Name:Thomas B. Campbell, MD
Study Chair
University of Colorado, Denver

Study Dates

Start Date:May 2005
Completion Date:May 2010
Completion Type:Actual
Primary Completion Date:May 2010
Primary Completion Type:Actual
Verification Date:September 2018
Last Changed Date:September 11, 2018
First Received Date:June 7, 2004
First Results Date:July 13, 2011

Study Outcomes

Outcome Type:Primary Outcome
Measure:Time to Treatment Failure (PI Comparison)
Time Frame:Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks f
Safety Issues:False
Description: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
Outcome Type:Primary Outcome
Measure:Time to Treatment Failure (NRTI Comparison)
Time Frame:Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks f
Safety Issues:False
Description: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
Outcome Type:Secondary Outcome
Measure:Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison)
Time Frame:Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008)
Safety Issues:False
Description: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 rea
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description:Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3.
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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).
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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 ba
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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.
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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 con
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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 con
Outcome Type:Secondary Outcome
Measure:Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (NRTI Comparison)
Time Frame:Throughout follow-up until study closed (May 31,2010)
Safety Issues:False
Description: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 rea
Outcome Type:Secondary Outcome
Measure:Time to Immunologic Failure (NRTI Comparison)
Time Frame:At or after Week 48 (including all follow-up through study closure - May 31,2010)
Safety Issues:False
Description:Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3.
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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).
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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.
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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 con
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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 con
Outcome Type:Secondary Outcome
Measure: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
Safety Issues:False
Description: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 con
Outcome Type:Secondary Outcome
Measure: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
Safety Issues:False
Description: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
Outcome Type:Secondary Outcome
Measure: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)
Safety Issues:False
Description: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 ba

Study Interventions

Intervention Type:Drug
Name:Atazanavir
Description:400 mg taken orally daily
Arm Name:ddI+FTC+ATV
Other Name:ATV
Intervention Type:Drug
Name:Didanosine (enteric-coated)
Description:400 mg taken orally daily
Arm Name:ddI+FTC+ATV
Other Name:ddI
Intervention Type:Drug
Name:Efavirenz
Description:600 mg taken orally daily
Arm Name:ZDV/3TC+EFV
Other Name:EFV
Intervention Type:Drug
Name:Emtricitabine
Description:200 mg taken orally daily
Arm Name:ddI+FTC+ATV
Other Name:FTC
Intervention Type:Drug
Name:Emtricitabine/Tenofovir disoproxil fumarate
Description:200 mg/300 mg taken orally once daily
Arm Name:TDF/FTC+EFV
Other Name:FTC/TDF
Intervention Type:Drug
Name:Lamivudine/Zidovudine
Description:150 mg/300 mg taken orally twice daily
Arm Name:ZDV/3TC+EFV
Other Name:3TC/ZDV

Study Arms

Study Arm Type:Experimental
Arm Name:ZDV/3TC+EFV
Description:ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz
Study Arm Type:Experimental
Arm Name:ddI+FTC+ATV
Description:ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine
Study Arm Type:Experimental
Arm Name:TDF/FTC+EFV
Description:TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:AIDS Clinical Trials Group
Agency Class:NIH
Agency Type:Collaborator
Agency Name:National Institute of Allergy and Infectious Diseases (NIAID)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

Reference Type:Reference
Citation:Bartlett JA, Johnson J, Herrera G, Sosa N, Rodriguez A, Liao Q, Griffith S, Irlbeck D, Shaefer MS; Clinically Significant Long-Term Antiretroviral Sequential Sequencing Study (CLASS) Team. Long-term results of initial therapy with abacavir and Lamivudine combined with Efavirenz, Amprenavir/Ritonavir, or Stavudine. J Acquir Immune Defic Syndr. 2006 Nov 1;43(3):284-92.
PMID:16967040
Reference Type:Reference
Citation:Saag MS. Initiation of antiretroviral therapy: implications of recent findings. Top HIV Med. 2004 Jul-Aug;12(3):83-8. Review.
PMID:15310939
Reference Type:Reference
Citation:Tapper ML, Daar ES, Piliero PJ, Smith K, Steinhart C. Strategies for initiating combination antiretroviral therapy. AIDS Patient Care STDS. 2005 Apr;19(4):224-38. Review.
PMID:15857194

Data Source: ClinicalTrials.gov

Date Processed: April 03, 2020

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