Addition of Efavirenz or Nelfinavir to a Lamivudine/Zidovudine/Indinavir HIV Treatment Regimen

May 17, 2012 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

A Phase III Randomized, Controlled Trial of Efavirenz (EFV) or Nelfinavir (NFV) in Combination With Fixed-Dose Combination Lamivudine/Zidovudine (3TC/ZDV) and Indinavir (IDV) in HIV-Infected Subjects With Less Than or Equal to 200 CD4 Cells/mm3 or Greater Than or Equal to 80,000 HIV RNA Copies/ml in Plasma

To compare time to a virologic failure (first of 2 consecutive plasma HIV RNA levels greater than or equal to 200 copies/ml at or after Week 24) of each 4-drug regimen vs the 3-drug regimen. To determine the safety, tolerance, and virologic benefits of either nelfinavir (NFV) or efavirenz (EFV) with indinavir/lamivudine/zidovudine (IDV/3TC/ZDV) vs IDV/3TC/ZDV alone, in the treatment of patients with advanced HIV disease who have received limited or no prior antiretroviral therapy.

Prior ACTG studies have shown that the 3-drug combination regimen (IDV/ZDV/3TC) resulted in improved clinical outcomes and therefore may prolong the effects of therapy. The enhanced effects seen with combination therapies are likely related to a greater suppression of RNA replication and alterations in resistance patterns. Due to the progressive success of combination regimens, it is possible that more potent regimens will further enhance viral suppression and provide more durable treatment responses. In light of the additive suppression of HIV replication determined by pharmacological, immunological, and virological results, nelfinavir (NFV) as an addition to IDV/ZDV/3TC will be evaluated. Based on the potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) to suppress viral replication and the effectiveness of 3-drug regimens containing NNRTIs, efavirenz (EFV) will also be evaluated as an addition to IDV/ZDV/3TC.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Prior ACTG studies have shown that the 3-drug combination regimen (IDV/ZDV/3TC) resulted in improved clinical outcomes and therefore may prolong the effects of therapy. The enhanced effects seen with combination therapies are likely related to a greater suppression of RNA replication and alterations in resistance patterns. Due to the progressive success of combination regimens, it is possible that more potent regimens will further enhance viral suppression and provide more durable treatment responses. In light of the additive suppression of HIV replication determined by pharmacological, immunological, and virological results, nelfinavir (NFV) as an addition to IDV/ZDV/3TC will be evaluated. Based on the potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) to suppress viral replication and the effectiveness of 3-drug regimens containing NNRTIs, efavirenz (EFV) will also be evaluated as an addition to IDV/ZDV/3TC.

Patients with HIV infection, CD4 cell count less than or equal to 200 cells/mm3 or plasma HIV RNA greater than or equal to 100,000 copies/ml, and limited (no prior 3TC, NNRTI, or protease inhibitor) or no prior antiretroviral treatment are randomized to 1 of 3 arms. Patients are stratified by CD4 cell count (less than or equal to 50 cells/mm3 vs greater than 50 cells/mm3), HIV-1 RNA copy number (less than or equal to 40,000 copies/ml vs greater than 40,000 copies/ml), and prior antiretroviral therapy (no therapy vs any therapy), and then randomly assigned to 1 of 3 treatment arms:

Arm 1: 3TC plus ZDV plus IDV. Arm 2: 3TC plus ZDV plus IDV plus EFV. Arm 3: 3TC plus ZDV plus IDV plus NFV. Patients are followed for at least 72 weeks [AS PER AMENDMENT 2/16/99: 96 weeks] beyond the enrollment of the last patient. Patients who experience virologic relapse will have the option of continuing randomized study medications, switching to Step 2 treatment, switching to another ACTG study, or seeking best available therapy for the remaining weeks of the study. Step 2 treatment consists of abacavir or 2 NNRTIs plus efavirenz plus amprenavir or another protease inhibitor. [AS PER AMENDMENT 4/3/00: Optimally, Step 2 treatment regimens should contain 3 or 4 drugs to which the virus is susceptible. If this is not possible, a drug to which the virus is partially susceptible is acceptable, but a drug to which the virus is resistant should not be included.]

Study Type

Interventional

Enrollment

444

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Puerto Rico
      • San Juan, Puerto Rico, 009365067
        • Puerto Rico-AIDS CRS
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • Alabama Therapeutics CRS
    • California
      • Los Angeles, California, United States, 90095
        • UCLA CARE Center CRS
      • Los Angeles, California, United States, 900331079
        • USC CRS
      • Palo Alto, California, United States
        • Stanford CRS
      • San Diego, California, United States, 92161
        • Ucsd, Avrc Crs
      • San Francisco, California, United States, 941102859
        • Ucsf Aids Crs
      • San Jose, California, United States, 951282699
        • Santa Clara Valley Med. Ctr.
      • San Mateo, California, United States
        • San Mateo County AIDS Program
      • San Rafael, California, United States
        • Marin County Dept. of Health & Human Services, HIV/AIDS Program & Specialty Clinic
      • Torrance, California, United States, 90502
        • Harbor-UCLA Med. Ctr. CRS
    • Colorado
      • Aurora, Colorado, United States, 80262
        • University of Colorado Hospital CRS
    • District of Columbia
      • Washington, District of Columbia, United States, 20059
        • Howard University Hosp., Div. of Infectious Diseases, ACTU
    • Florida
      • Miami, Florida, United States, 331361013
        • Univ. of Miami AIDS CRS
    • Georgia
      • Atlanta, Georgia, United States, 30308
        • The Ponce de Leon Ctr. CRS
    • Hawaii
      • Honolulu, Hawaii, United States, 96816
        • Univ. of Hawaii at Manoa, Leahi Hosp.
      • Honolulu, Hawaii, United States, 96816
        • Queens Med. Ctr.
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Cook County Hosp. CORE Ctr.
      • Chicago, Illinois, United States, 60611
        • Northwestern University CRS
      • Chicago, Illinois, United States, 60612
        • Rush Univ. Med. Ctr. ACTG CRS
      • Chicago, Illinois, United States, 60640
        • Weiss Memorial Hosp.
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
      • Indianapolis, Indiana, United States, 46202
        • Methodist Hosp. of Indiana
      • Indianapolis, Indiana, United States, 462025250
        • Indiana Univ. School of Medicine, Wishard Memorial
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • Univ. of Iowa Healthcare, Div. of Infectious Diseases
    • Louisiana
      • New Orleans, Louisiana, United States, 70112
        • Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Adult AIDS CRS
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deaconess Med. Ctr., ACTG CRS
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota, ACTU
    • Missouri
      • St Louis, Missouri, United States, 63112
        • St. Louis ConnectCare, Infectious Diseases Clinic
      • St. Louis, Missouri, United States
        • Washington U CRS
    • Nebraska
      • Omaha, Nebraska, United States, 681985130
        • Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
    • New York
      • Buffalo, New York, United States, 14215
        • SUNY - Buffalo, Erie County Medical Ctr.
      • New York, New York, United States, 10003
        • Beth Israel Med. Ctr., ACTU
      • New York, New York, United States
        • Weill Med. College of Cornell Univ., The Cornell CTU
      • New York, New York, United States, 10021
        • Cornell CRS
      • New York, New York, United States
        • NY Univ. HIV/AIDS CRS
      • New York, New York, United States, 10029
        • Beth Israel Med. Ctr. (Mt. Sinai)
      • New York, New York, United States
        • Cornell University A2201
      • Rochester, New York, United States, 14642
        • Univ. of Rochester ACTG CRS
    • North Carolina
      • Chapel Hill, North Carolina, United States, 275997215
        • Unc Aids Crs
      • Charlotte, North Carolina, United States, 28203
        • Carolinas HealthCare System, Carolinas Med. Ctr.
      • Durham, North Carolina, United States, 27710
        • Duke Univ. Med. Ctr. Adult CRS
      • Greensboro, North Carolina, United States, 27401
        • Regional Center for Infectious Disease, Wendover Medical Center CRS
    • Ohio
      • Cincinnati, Ohio, United States, 452670405
        • Univ. of Cincinnati CRS
      • Cleveland, Ohio, United States, 44106
        • Case CRS
      • Cleveland, Ohio, United States, 441091998
        • MetroHealth CRS
      • Columbus, Ohio, United States, 432101228
        • The Ohio State Univ. AIDS CRS
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Hosp. of the Univ. of Pennsylvania CRS
    • Washington
      • Seattle, Washington, United States, 981224304
        • University of Washington AIDS CRS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

13 years and older (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria

Concurrent Medication:

Allowed:

  • Chemoprophylaxis for Pneumocystis carinii pneumonia.
  • Topical and oral antifungal agents (except for oral ketoconazole and itraconazole).
  • All antibiotics as clinically indicated (unless otherwise excluded).
  • Treatment, maintenance, or chemoprophylaxis with approved agents for opportunistic infections as clinically indicated (unless otherwise excluded).
  • Systemic corticosteroids for 21 days or less for acute problems.
  • Recombinant erythropoietin (rEPO) and granulocyte colony-stimulating factor (G-CSF, filgrastim).
  • Regularly prescribed medications such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, megestrol acetate, testosterone.
  • Alternative therapies such as vitamins. Patients should report the use of these therapies.
  • [AS PER AMENDMENT 2/16/99: Rifabutin can be administered at a reduced dose.]
  • [AS PER AMENDMENT 4/3/00: Systemic cytotoxic chemotherapy. Study team should be notified.]
  • [AS PER AMENDMENT 4/3/00: Expanded access and compassionate use drugs are allowed as part of Step 2 treatment only.]

Allowed with caution:

  • [AS PER AMENDMENT 4/3/00: Viagra (sildenafil citrate) at a reduced dose unless otherwise approved by the protocol chair.]
  • [AS PER AMENDMENT 4/3/00: Lovastatin or simvastatin with PIs is not recommended. Caution should be exercised with the use of all other statins when used concomitantly with PIs.]

Concurrent Treatment:

Allowed:

  • Alternative therapies such as acupuncture and visualization techniques. Patients should report use of these therapies.

Patients must have:

  • Documented HIV-1 infection.
  • CD4 count less than or equal to 200 cells/mm3 or a plasma HIV RNA greater than or equal to 100,000 copies/ml [AS PER AMENDMENT 2/16/99:
  • 80,000 copies/ml] within 60 days prior to entry.
  • Other lab values performed within 14 days prior to entry.

Prior Medication:

Allowed:

  • Zidovudine (ZDV), didanosine (ddI), stavudine (d4T), or zalcitabine (ddC) therapy alone or in combination any time prior to study entry.

Exclusion Criteria

Concurrent Medication:

Excluded:

  • All antiretroviral therapies other than study medications. [AS PER AMENDMENT 4/3/00: Compassionate use and expanded access drugs are allowed as part of Step 2 treatment.]
  • Investigational drugs without specific approval from the Study Chair. [AS PER AMENDMENT 4/3/00: Compassionate use and expanded access drugs are allowed as part of Step 2 treatment.]
  • Systemic cytotoxic chemotherapy. [AS PER AMENDMENT 4/3/00: Systemic cytotoxic chemotherapy is allowed. Study team should be notified.]
  • Alprazolam, amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, encainide, ergot alkaloids and derivatives of ergot alkaloids, estazolam, flecainide, flurazepam, itraconazole , ketoconazole, meperidine, midazolam, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, rifampin, terfenadine, triazolam, or zolpidem. [AS PER AMENDMENT 2/16/99: Amiodarone, astemizole, cisapride, ergot alkaloids or drugs containing derivatives of ergot alkaloids, itraconazole, midazolam, triazolam, quinidine, rifampin, terfenadine.] [AS PER AMENDMENT 4/3/00: Amiodarone, astemizole, bepridil, cisapride, ergot alkaloids and derivatives of ergot alkaloids, Hypericum perforatum (St. John's wort), itraconazole, midazolam, quinidine, rifampin, terfenadine, triazolam.]
  • Vitamin E supplements. [AS PER AMENDMENT 4/3/00: Multivitamins containing vitamin E are allowed.]

Avoided:

  • Herbal medications. Patients should report use.

Patients with the following prior conditions are excluded:

  • Acute therapy for an infection or other medical illnesses within 14 days prior to study entry. [AS PER AMENDMENT 2/16/99: Acute therapy for a serious infection or other serious medical illnesses that are potentially life-threatening and require systemic therapy and/or hospitalization within 14 days of study entry.]

Prior Medication:

Excluded within 30 days prior to entry:

  • More than 1 day experience with lamivudine (3TC), nonnucleoside reverse transcriptase inhibitor, or protease inhibitor.
  • Erythropoietin, G-CSF, or GM-CSF.
  • Interferons, interleukins, HIV vaccines, or any experimental therapy.

Excluded within 14 days prior to entry:

  • Alprazolam (Xanax), amiodarone (Cordarone), astemizole (Hismanal), bepridil (Vascor), bupropion (Wellbutrin, Zyban), cisapride (Propulsid), clorazepate (Tranxene), clozapine (Clozaril), diazepam (Valium), encainide (Enkaid), ergot alkaloids or drugs containing derivatives of ergot alkaloids, estazolam (ProSom), flecainide (Tambocor), flurazepam (Dalmane), itraconazole (Sporanox), ketoconazole (Nizoral), meperidine (Demerol), midazolam (Versed), piroxicam (Feldene), propafenone (Rythmol), propoxyphene (Darvon, Darvocet), quinidine, rifabutin (Mycobutin), rifampin (Rifadin, Rifamate, Rifater, Rimactane), terfenadine (Seldane), triazolam (Halcion), or zolpidem (Ambien). [AS PER AMENDMENT 2/16/99: Agents excluded within 14 days prior to entry are now as follows:
  • amiodarone, astemizole, cisapride, ergot alkaloids or drugs containing derivatives of ergot alkaloids, itraconazole, midazolam, quinidine, rifampin, terfenadine, and triazolam.

Note:

  • Rifabutin can be administered at a reduced dose of 150 mg/day.]

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Masking: NONE

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

  • Study Chair: Stefano Vella

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Completion (Actual)

July 1, 2001

Study Registration Dates

First Submitted

November 2, 1999

First Submitted That Met QC Criteria

August 30, 2001

First Posted (Estimate)

August 31, 2001

Study Record Updates

Last Update Posted (Estimate)

May 21, 2012

Last Update Submitted That Met QC Criteria

May 17, 2012

Last Verified

May 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACTG 388
  • 11347 (DAIDS ES)
  • Substudy ACTG 734
  • Substudy ACTG A5060s
  • Substudy ACTG 732
  • Substudy ACTG 733
  • Substudy ACTG 735
  • Substudy ACTG 737
  • Substudy ACTG 746

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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