A Study of Abacavir Plus Indinavir Sulfate Plus Efavirenz in HIV-Infected Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00001086
First received: November 2, 1999
Last updated: July 26, 2013
Last verified: July 2013
  Purpose

To compare the virologic response between abacavir (ABC, 1592U89) regimens (drug vs. placebo) and between the 2 dosing regimens (BID vs. TID) with respect to the proportion of patients with plasma HIV RNA levels below the limit of detection [AS PER AMENDMENT 8/27/97: < 500 copies/ml at week 16]. To evaluate the safety and tolerance of the study arms. [AS PER AMENDMENT 3/10/99: During the extension period, compare the time to detectable viremia (2 consecutive plasma HIV RNA levels greater than or equal to 500 copies/ml) between ABC and placebo.] Therapeutically, there is a need to explore potent alternative therapy for patients who have received, or are currently receiving, a double nucleoside analog combination including lamivudine (3TC), a regimen that was proven to be clinically inferior to indinavir (IDV) when combined with zidovudine/3TC in study ACTG 320. In order to produce and maintain a maximal antiviral response, all patients in this study will receive 2 or 3 potent, new agents; ABC, a nucleoside analog, EFV, a non-nucleoside reverse transcriptase inhibitor (NNRTI), and IDV, a protease inhibitor. Virologically, the major question this protocol seeks to answer is how prior 3TC exposure in a dual nucleoside regimen influences the response to subsequent treatment. It is unclear whether it is best to add a protease inhibitor either 1) an NNRTI at 1 of 2 doses, or 2) an NNRTI at 1 of 2 doses plus a new nucleoside analog to achieve plasma HIV RNA levels that are below the limits of detection.


Condition Intervention Phase
HIV Infections
Drug: Indinavir sulfate
Drug: Abacavir sulfate
Drug: Efavirenz
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Phase II, Placebo Controlled Trial of Abacavir (ABC, 1592U89) in Combination With Open-Label Indinavir Sulfate (IDV) and Efavirenz (EFV, DMP-266) in HIV-Infected Subjects With Nucleoside Analog Experience: A Rollover Study for ACTG 320

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 300
Study Completion Date: September 1999
Detailed Description:

Therapeutically, there is a need to explore potent alternative therapy for patients who have received, or are currently receiving, a double nucleoside analog combination including lamivudine (3TC), a regimen that was proven to be clinically inferior to indinavir (IDV) when combined with zidovudine/3TC in study ACTG 320. In order to produce and maintain a maximal antiviral response, all patients in this study will receive 2 or 3 potent, new agents; ABC, a nucleoside analog, EFV, a non-nucleoside reverse transcriptase inhibitor (NNRTI), and IDV, a protease inhibitor. Virologically, the major question this protocol seeks to answer is how prior 3TC exposure in a dual nucleoside regimen influences the response to subsequent treatment. It is unclear whether it is best to add a protease inhibitor either 1) an NNRTI at 1 of 2 doses, or 2) an NNRTI at 1 of 2 doses plus a new nucleoside analog to achieve plasma HIV RNA levels that are below the limits of detection.

Prior to randomization, patients are stratified by CD4 cell count (cells/mm3): less than or equal to 50 versus greater than 50 and by ACTG 320 participation: enrolled versus not enrolled. Patients with greater than 50 CD4 cells/mm3 are randomized to 1 of 4 treatment arms (Arms I, II, III, or IV) and patients with less than or equal to 50 CD4 cells/mm3 are randomized to 1 of 2 treatment arms (Arms I and II). All patients will be followed for 48 weeks beyond the enrollment of the last patient. The regimens for the treatment arms are as follows: Arm I - indinavir (IDV) plus EFV plus ABC placebo bid, Arm II - IDV (higher dose) plus EFV (lower dose) plus ABC, Arm III - IDV plus EFV plus ABC placebo, and Arm IV - IDV (higher dose) plus EFV (lower dose) plus ABC. If 15 week data indicates this is a reasonable dosing regimen, the sample size in Arms III and IV will be expanded to include additional patients with a CD4 count greater than 50 cells/mm3 and allow for equal enrollment across all 4 treatment arms. Those patients who roll over from ACTG 320 will be assigned to receive open-label treatment on Arm II and evaluated independently of the 4 treatment arms listed above.

[AS PER AMENDMENT 8/27/97: Patients with 2 consecutive HIV RNA measurements at least 500 copies/ml at week 16 or anytime thereafter are given the option to receive open-label treatment with IDV plus EFV plus ABC, or to seek the best available therapy outside of the study. NOTE: Patients who choose the open-label combination may take other prescribed nucleoside analogs provided outside the study.] [AS PER AMENDMENT 12/17/97: It is strongly recommended that patients who reach a confirmed endpoint and elect to receive open-label therapy consider adding additional approved (and novel, if possible) antiretroviral agents to their open-label regimen.] [AS PER AMENDMENT 1/12/98: Patients who choose the open-label combination may receive other approved antiretrovirals obtained outside the study provided the ACTG 368 team approves the combination.] [AS PER AMENDMENT 8/7/98: Subjects will take study medications for a maximum of 96 weeks, depending on their time of study enrollment.] [AS PER AMENDMENT 3/10/99: A 24-week extension, which will end July 30, 1999, has been added to the study. The extension applies to subjects currently on blinded Step 1 treatment, on open-labeled Step 2, or on study but off treatment. Subjects are to be unblinded in their study treatment and followed for the remainder of the extension. Subjects continue on their current study drug schedule. Subjects on blinded IDV plus EFV who, upon unblinding (not failure) decide to add prescription ABC to their regimen, will be considered off study treatment and will be followed for the duration of the extension; those already registered on Step 2 will continue their Step 2 therapy. Any subject who does not wish to continue on the study extension will be unblinded to their original randomized regimen. Subjects who experience virologic failure during the extension should seek best available treatment following current recommendations to use as many approved, novel antiretroviral agents as possible. The new drug regimen may incorporate any or all of the study drugs.]

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Concurrent Medication:

Allowed:

  • Chemoprophylaxis for Pneumocystis carinii pneumonia is required for all patients who have a CD4 cell count <= 200 cells/mm3.
  • Topical and/or oral antifungal agents are permitted except for oral ketoconazole.
  • Treatment, maintenance or chemoprophylaxis with approved agents for opportunistic infections as clinically indicated, except for rifabutin.
  • All antibiotics as clinically indicated.
  • Systemic corticosteroid use for <= 21 days for acute problems is permitted as medically indicated; chronic systemic corticosteroid use is not permitted, unless it is within physiologic replacement levels.
  • Recombinant erythropoietin and granulocyte colony-stimulating factor are permitted as medically indicated.
  • Regularly prescribed medications such as antipyretics, analgesics, allergy medications (except for terfenadine (Seldane) and astemizole (Hismanal)), antidepressants, sleep medications, oral contraceptives, megestrol acetate, testosterone or any other medications are permitted as medically indicated.

NOTE:

  • Due to the possibility that EFV or ABC may alter the effectiveness of oral contraceptives or depo-progesterone, oral contraceptives or depo-progesterone must not be used as the sole form of birth control. [AS PER AMENDMENT 8/7/98: adequate birth control is hormonal plus barrier method or two barrier methods].
  • Alternative therapies such as vitamins, acupuncture, and visualization techniques will be permitted. Herbal medications should be avoided. Patients should report the use of these therapies; alternative therapies will be recorded. [AS PER AMENDMENT 8/7/98: Due to the likelihood of IDV increasing the concentrations of sildenafil (Viagra) when coadministered, it is suggested that subjects who use viagra take the lowest dose (25 mg, i.e., half the typical dose).]

Both NIAID ACTG 320 participants and non-ACTG 320 patients must have:

  • Documented HIV-1 infection.
  • Written informed consent from parent or legal guardian for those patients < 18 years old.

Non-ACTG 320 patients must have:

  • Documented CD4 cell count <= 200 cells/mm3 at the time of initiation of ZDV (or d4T) plus 3TC therapy [AS PER AMENDMENT 12/17/97:
  • Documented CD4 cell count <= 250 cells/mm3 within 3 months of initiation of ZDV (or d4T) plus 3TC therapy].

Prior Medication:

Required:

For ACTG 320 patients:

  • Patients must have participated in ACTG 320 with original randomization to the double-nucleoside combination arm, and maintenance of that treatment (on-study/on-treatment in ACTG 320) until enrollment into ACTG 368.

For non-ACTG 320 patients:

  • Greater than or equal to 3 months [2 months AS PER AMENDMENT 12/17/97] of therapy with ZDV (or d4T) + 3TC and receiving ZDV (or d4T) + 3TC at the time of entry.

Exclusion Criteria

Co-existing Condition:

Non-ACTG 320 patients with the following symptoms and conditions are excluded:

Malignancy that requires systemic therapy other than minimal Kaposi's sarcoma.

NOTE:

  • Minimal Kaposi's sarcoma, defined as <= 5 cutaneous lesions and no visceral disease or tumor-associated edema, allowed, provided systemic therapy not required.

Non-ACTG 320 patients with the following prior conditions or symptoms are excluded:

  • Unexplained temperature > 38.5 degrees C for 7 consecutive days.
  • Chronic diarrhea defined as > 3 liquid stools per day persisting for 15 days, within 30 days prior to entry.
  • Proven or suspected acute hepatitis within 30 days prior to entry, even if AST (SGOT) and ALT (SGPT) are <= 5 X ULN.

Concurrent Medication: Excluded:

  • All antiretroviral therapies other then study medications.
  • Rifabutin and rifampin.
  • Investigational drugs without specific approval from the protocol chair.
  • Systemic cytotoxic chemotherapy.
  • Oral ketoconazole (Nizoral), terfenadine (Seldane), astemizole (Hismanal), cisapride (Propulsid), triazolam (Halcion), and midazolam (Versed).
  • Caution should be taken in the consumption of alcoholic beverages with study medications.
  • Itraconazole.

Prior Medication: Excluded: For ACTG 320 patients:

  • Those who opted to receive open-label IDV while on ACTG 320, or if they switched to open label IDV during the study.

For non-ACTG 320 patients:

  • Acute therapy for an infection or other medical illness within 14 days prior to entry.
  • Prior protease inhibitor therapy.
  • Prior NNRTI therapy (approved or experimental).
  • Erythropoietin, G-CSF or GM-CSF within 30 days prior to entry.
  • Interferons, interleukins or HIV vaccines within 30 days prior to entry.
  • Any experimental therapy within 30 days prior to entry.
  • Rifampin or rifabutin within 14 days prior to entry.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00001086

  Hide Study Locations
Locations
United States, California
Univ of Southern California / LA County USC Med Ctr
Los Angeles, California, United States, 900331079
UCLA CARE Ctr
Los Angeles, California, United States, 90095
San Francisco Gen Hosp
San Francisco, California, United States, 941102859
Stanford at Kaiser / Kaiser Permanente Med Ctr
San Francisco, California, United States, 94115
Stanford Univ Med Ctr
Stanford, California, United States, 943055107
United States, Colorado
Univ of Colorado Health Sciences Ctr
Denver, Colorado, United States, 80262
United States, District of Columbia
Howard Univ
Washington, District of Columbia, United States, 20059
Georgetown Univ Hosp
Washington, District of Columbia, United States, 20037
United States, Florida
Univ of Miami School of Medicine
Miami, Florida, United States, 331361013
United States, Hawaii
Queens Med Ctr
Honolulu, Hawaii, United States, 96816
Univ of Hawaii
Honolulu, Hawaii, United States, 96816
United States, Illinois
Louis A Weiss Memorial Hosp
Chicago, Illinois, United States, 60640
Rush Presbyterian - Saint Luke's Med Ctr
Chicago, Illinois, United States, 60612
Northwestern Univ Med School
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana Univ Hosp
Indianapolis, Indiana, United States, 462025250
Division of Inf Diseases/ Indiana Univ Hosp
Indianapolis, Indiana, United States, 46202
United States, Iowa
Univ of Iowa Hosp and Clinic
Iowa City, Iowa, United States, 52242
United States, Louisiana
Tulane Med Ctr Hosp
New Orleans, Louisiana, United States, 70112
Tulane Univ School of Medicine
New Orleans, Louisiana, United States, 70112
Charity Hosp / Tulane Univ Med School
New Orleans, Louisiana, United States, 70112
United States, Maryland
Johns Hopkins Hosp
Baltimore, Maryland, United States, 21287
State of MD Div of Corrections / Johns Hopkins Univ Hosp
Baltimore, Maryland, United States, 212052196
United States, Massachusetts
Harvard (Massachusetts Gen Hosp)
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Med Ctr
Boston, Massachusetts, United States, 02215
Beth Israel Deaconess - West Campus
Boston, Massachusetts, United States, 02215
Boston Med Ctr
Boston, Massachusetts, United States, 02118
United States, Minnesota
Univ of Minnesota
Minneapolis, Minnesota, United States, 55455
Hennepin County Med Clinic
Minneapolis, Minnesota, United States, 55415
St Paul Ramsey Med Ctr
St Paul, Minnesota, United States, 55101
United States, Missouri
St Louis Regional Hosp / St Louis Regional Med Ctr
St Louis, Missouri, United States, 63112
United States, Nebraska
Univ of Nebraska Med Ctr
Omaha, Nebraska, United States, 681985130
United States, New York
SUNY / Erie County Med Ctr at Buffalo
Buffalo, New York, United States, 14215
Mount Sinai Med Ctr
New York, New York, United States, 10029
St Vincent's Hosp / Mem Sloan-Kettering Cancer Ctr
New York, New York, United States, 10021
Bellevue Hosp / New York Univ Med Ctr
New York, New York, United States, 10016
Cornell Univ Med Ctr
New York, New York, United States, 10021
Beth Israel Med Ctr
New York, New York, United States, 10003
Saint Clare's Hosp and Health Ctr
New York, New York, United States, 10019
Univ of Rochester Medical Center
Rochester, New York, United States, 14642
United States, North Carolina
Univ of North Carolina
Chapel Hill, North Carolina, United States, 275997215
Duke Univ Med Ctr
Durham, North Carolina, United States, 27710
Moses H Cone Memorial Hosp
Greensboro, North Carolina, United States, 27401
Central Prison/Women's Prison in Raleigh / NC
Raleigh, North Carolina, United States, 276260540
United States, Ohio
Univ of Cincinnati
Cincinnati, Ohio, United States, 452670405
Univ of Kentucky Lexington
Cincinnati, Ohio, United States, 45267
Case Western Reserve Univ
Cleveland, Ohio, United States, 44106
Ohio State Univ Hosp Clinic
Columbus, Ohio, United States, 432101228
United States, Pennsylvania
Milton S Hershey Med Ctr
Hershey, Pennsylvania, United States, 170330850
Univ of Pennsylvania at Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Julio Arroyo
West Columbia, South Carolina, United States, 29169
United States, Tennessee
Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
Knoxville, Tennessee, United States, 37920
Vanderbilt Univ Med Ctr
Nashville, Tennessee, United States, 37203
United States, Texas
Univ of Texas Galveston
Galveston, Texas, United States, 775550435
United States, Washington
Univ of Washington
Seattle, Washington, United States, 981224304
United States, Wisconsin
Great Lakes Hemophilia Foundation
Wauwatosa, Wisconsin, United States, 532130127
Puerto Rico
Univ of Puerto Rico
San Juan, Puerto Rico, 009365067
Sponsors and Collaborators
Investigators
Study Chair: Squires KE
Study Chair: Hammer SM
Study Chair: Fischl MA
  More Information

Additional Information:
Publications:
Squires K, Hammer S, Degruttola V, Fischl M, Grimes J, Demeter L, Morse G. Randomized trial of abacavir (ABC) in combination with indinavir (IDV) and efavirenz (EFV) in HIV-infected patients (pts) with nucleoside analog experience (NRTI exp). Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:207 (abstract no LB15)
Dicenzo R, Forrest A, Smith P, Squires K, Hammer S, Fischl M, Degruttola V, Morse G. Comparing intensive and sparse sampling for estimating the population pharmacokinetics (PK) of indinavir (IDV) in efavirenz (EFV)containing regimens. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 751)

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00001086     History of Changes
Other Study ID Numbers: ACTG 368, 11331
Study First Received: November 2, 1999
Last Updated: July 26, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Placebos
HIV-1
Drug Therapy, Combination
HIV Protease Inhibitors
Indinavir
RNA, Viral
Reverse Transcriptase Inhibitors
Anti-HIV Agents
Viral Load
efavirenz

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
HIV Protease Inhibitors
Indinavir
Efavirenz
Abacavir
Reverse Transcriptase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on April 16, 2014