Clinical trial NCT00000841: A Study of Indinavir Sulfate Plus Zidovudine (AZT) Plus Lamivudine in HIV-Infected Patients Who Have Taken AZT for Six or More Months
Official title: A Randomized, Double-Blind, Phase III Study of Indinavir Sulfate With Open-Label Zidovudine (AZT) and Lamivudine (3TC) in Subjects With HIV Infection With CD4 Cell Counts <= 200 Cells/mm3 and >= 6 Months of Prior AZT Experience
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
Antiviral Agents
Zidovudine
Stavudine
HIV Protease Inhibitors
Lamivudine
Indinavir
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 1750
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To determine the clinical efficacy of indinavir sulfate or placebo in combination with zidovudine ( AZT ) and lamivudine ( 3TC ) in AIDS patients.

Protease inhibitors such as indinavir sulfate may be effective in patients with advanced HIV disease who have received prior AZT therapy. Since studies suggest that triple drug therapy may have an advantage over both monotherapy and two drug therapy, the combination of indinavir sulfate with AZT and 3TC should be evaluated.

Detailed description: Protease inhibitors such as indinavir sulfate may be effective in patients with advanced HIV disease who have received prior AZT therapy. Since studies suggest that triple drug therapy may have an advantage over both monotherapy and two drug therapy, the combination of indinavir sulfate with AZT and 3TC should be evaluated.

Patients are randomized to receive open-label AZT and 3TC with or without indinavir sulfate for at least 48 weeks. Patients who develop intolerance to AZT or have progressive disease after 24 weeks on study may substitute stavudine ( d4T ) for AZT. Patients are followed at weeks 4, 8, 16, 24, 32, 40, and 48 and every 8 weeks thereafter up to week 96. \[AS PER 02/25/97 AMENDMENT: Accrual has been halted because interim analysis has shown triple therapy superior to double-agent therapy. An open label extension phase has been added for the period through 06/30/97. Patients who had been randomized to AZT/3TC are given the option of continuing on assigned ACTG 320 study drugs, crossing over to open-label indinavir, or permanently discontinuing all study therapies and going off study. Patients who were randomized to AZT/3TC plus indinavir or who were crossed to such therapy are given the option of continuing their currently assigned therapies. It is strongly suggested that patients who were on AZT/3TC who wish to receive open-label indinavir consider changing the nucleoside analog component of their regimen if at all possible.\] \[ AS PER 06/06/97 AMENDMENT: The availability of the current ACTG 320 treatment has been further extended for approximately 12 additional weeks (but not beyond 09/30/97). This extension will allow patients to continue receiving study medications until ACTG 372 is open to accrual (the rollover protocol for subjects originally randomized to the triple drug component of ACTG 320 or who are crossed over due to a confirmed study endpoint is finalized).\] \[ AS PER 09/15/97 AMENDMENT: Open-label therapy will be provided for no more than 90 days beyond the enrollment of the first subject on ACTG 372.\]

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Required:

* PCP prophylaxis.

Allowed:

* Topical or oral antifungal agents (other than oral ketoconazole).
* Approved agents for opportunistic infections.
* Antibiotics unless specifically excluded.
* Systemic corticosteroids for no more than 21 days.
* Vitamins.
* Recombinant erythropoietin.
* G-CSF.
* Regularly prescribed medications such as allergy medications, antidepressants, antipyretics, analgesics, oral contraceptives, megestrol, and testosterone.

Concurrent Treatment:

Allowed:

* Acupuncture.
* Visualization techniques.

Patients must have:

* HIV infection.
* CD4 count \<= 200 cells/mm3.
* At least 6 months total prior AZT therapy.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Malignancy requiring systemic therapy other than minimal Kaposi's sarcoma.

Concurrent Medication:

Excluded:

* Antiretrovirals other than study drugs.
* Rifabutin and rifampin.
* Investigational drugs other than indinavir sulfate.
* Systemic cytotoxic chemotherapy.
* Oral ketoconazole.
* Chronic systemic corticosteroids.
* Herbal therapies.

Patients with the following prior conditions are excluded:

* Unexplained temperature \> 38.5 C for any 7 days within 30 days prior to study entry.
* Chronic diarrhea persisting for 15 days within 30 days prior to study entry.
* History of acute or chronic pancreatitis.
* Acute hepatitis within 30 days prior to study entry.
* Grade 2 or worse bilateral peripheral neuropathy within 60 days prior to study entry.
* Dose-limiting intolerance to prior AZT at 600 mg/day.

Prior Medication:

Excluded:

* More than 1 week of prior 3TC.
* Any prior protease inhibitors.
* Rifampin or rifabutin within 14 days prior to study entry.

Excluded within 30 days prior to study entry:

* Erythropoietin.
* G-CSF or GM-CSF.
* Non-nucleoside reverse transcriptase inhibitors.
* Interferons.
* Interleukins.
* HIV vaccines.
* Any experimental therapy.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Children's Hosp of Los Angeles
state: California
city: Los Angeles
country: United States
facility: Univ of Southern California / LA County USC Med Ctr
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Ctr
state: California
city: San Diego
country: United States
facility: Univ of California / San Diego Treatment Ctr
state: California
city: San Francisco
country: United States
facility: San Francisco AIDS Clinic / San Francisco Gen Hosp
state: California
city: San Francisco
country: United States
facility: San Francisco Gen Hosp
state: California
city: San Francisco
country: United States
facility: Stanford at Kaiser / Kaiser Permanente Med Ctr
state: California
city: Stanford
country: United States
facility: San Mateo AIDS Program / Stanford Univ
state: California
city: Stanford
country: United States
facility: Stanford Univ Med Ctr
state: California
city: Torrance
country: United States
facility: Harbor UCLA Med Ctr
state: California
city: Denver
country: United States
facility: Kaiser Permanente Franklin Med Ctr
state: Colorado
city: Denver
country: United States
facility: Mountain States Reg Hemo Ctr / Univ of Colorado
state: Colorado
city: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
city: Washington
country: United States
facility: George Washington Univ / Hershey Med Ctr
state: District of Columbia
city: Washington
country: United States
facility: Georgetown Univ Hosp
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ
state: District of Columbia
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Miami
country: United States
facility: Univ of Miami (Pediatric)
state: Florida
city: Atlanta
country: United States
facility: Emory Univ
state: Georgia
city: Atlanta
country: United States
facility: Emory Hemo Comp Evaluation Clinic / East TN Comp Hemo Ctr
state: Georgia
city: Honolulu
country: United States
facility: Queens Med Ctr
state: Hawaii
city: Honolulu
country: United States
facility: Univ of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Univ Med School
state: Illinois
city: Chicago
country: United States
facility: Rush Presbyterian - Saint Luke's Med Ctr
state: Illinois
city: Chicago
country: United States
facility: Chicago Children's Memorial Hosp
state: Illinois
city: Chicago
country: United States
facility: Louis A Weiss Memorial Hosp
state: Illinois
city: Chicago
country: United States
facility: Illinois Masonic Med Ctr
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Division of Inf Diseases/ Indiana Univ Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp of Indiana / Life Care Clinic
state: Indiana
city: Iowa City
country: United States
facility: Univ of Iowa Hosp and Clinic
state: Iowa
city: New Orleans
country: United States
facility: Charity Hosp / Tulane Univ Med School
state: Louisiana
city: New Orleans
country: United States
facility: Tulane Med Ctr Hosp
state: Louisiana
city: New Orleans
country: United States
facility: Tulane Univ School of Medicine
state: Louisiana
city: Baltimore
country: United States
facility: State of MD Div of Corrections / Johns Hopkins Univ Hosp
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hosp
state: Maryland
city: Boston
country: United States
facility: Harvard (Massachusetts Gen Hosp)
state: Massachusetts
city: Boston
country: United States
facility: Boston Med Ctr
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - West Campus
state: Massachusetts
city: Worcester
country: United States
facility: Worcester Memorial Hosp / Med Ctr of Cntrl MA-Memorial
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Med Clinic
state: Minnesota
city: Minneapolis
country: United States
facility: Univ of Minnesota
state: Minnesota
city: Saint Paul
country: United States
facility: St Paul Ramsey Med Ctr
state: Minnesota
city: Saint Louis
country: United States
facility: St Louis Regional Hosp / St Louis Regional Med Ctr
state: Missouri
city: Omaha
country: United States
facility: Univ of Nebraska Med Ctr
state: Nebraska
city: Bronx
country: United States
facility: Montefiore Med Ctr Adolescent AIDS Program
state: New York
city: Bronx
country: United States
facility: Bronx Veterans Administration / Mount Sinai Hosp
state: New York
city: Buffalo
country: United States
facility: SUNY / Erie County Med Ctr at Buffalo
state: New York
city: Great Neck
country: United States
facility: North Shore Univ Hosp
state: New York
city: New York
country: United States
facility: Beth Israel Med Ctr
state: New York
city: New York
country: United States
facility: Bellevue Hosp / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Kaplan Cancer Ctr / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Manhattan Veterans Administration / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Saint Clare's Hosp and Health Ctr
state: New York
city: New York
country: United States
facility: Cornell Univ Med Ctr
state: New York
city: New York
country: United States
facility: Mem Sloan - Kettering Cancer Ctr
state: New York
city: New York
country: United States
facility: St Vincent's Hosp / Mem Sloan-Kettering Cancer Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr / Hemophilia Treatment Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr / Pediatrics
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr
state: New York
city: New York
country: United States
facility: Harlem Hosp Ctr
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY / State Univ of New York
state: New York
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Med Ctr
state: North Carolina
city: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
city: Greensboro
country: United States
facility: Moses H Cone Memorial Hosp
state: North Carolina
city: Raleigh
country: United States
facility: Central Prison/Women's Prison in Raleigh / NC
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Cincinnati
country: United States
facility: Univ of Kentucky Lexington
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve Univ
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hosp
state: Ohio
city: Columbus
country: United States
facility: Ohio State Univ Hosp Clinic
state: Ohio
city: Hershey
country: United States
facility: Milton S Hershey Med Ctr
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ Hosp
state: Pennsylvania
city: Charleston
country: United States
facility: Med Univ of South Carolina
state: South Carolina
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
city: Knoxville
country: United States
facility: Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
state: Tennessee
city: Nashville
country: United States
facility: Meharry Med College
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Univ Med Ctr
state: Tennessee
city: Galveston
country: United States
facility: Univ of Texas Galveston
state: Texas
city: Houston
country: United States
facility: Univ Texas Health Science Ctr / Univ Texas Med School
state: Texas
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
city: Wauwatosa
country: United States
facility: Great Lakes Hemophilia Foundation
state: Wisconsin
city: Bayamon
country: Puerto Rico
facility: Ramon Ruiz Arnau Univ Hosp / Pediatrics
city: San Juan
country: Puerto Rico
facility: Univ of Puerto Rico
Study officials:
name: Hammer SM
role: STUDY_CHAIR
name: Squires KE
role: STUDY_CHAIR
name: Fischl MA
role: STUDY_CHAIR
References:
citation: Reiter G, Wojnarowski C. Low rate of nelfinavir discontinuation in a clinic population. Int Conf AIDS. 1998;12:1049 (abstract no 60273)
citation: ACTG 320 trial halted as three-drug arm proves superior. AIDS Patient Care STDS. 1997 Jun;11(3):194. No abstract available.
citation: Conference updates show promising drug data. AIDS Alert. 1997 Nov;12(11):125-6.
citation: Baker R. 3-drug therapy reduces deaths and new AIDS-related illnesses by 50%. BETA. 1997 Mar:3-4.
citation: Demeter LM, Hughes MD, Coombs RW, Jackson JB, Grimes JM, Bosch RJ, Fiscus SA, Spector SA, Squires KE, Fischl MA, Hammer SM. Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. AIDS Clinical Trials Group Protocol 320. Ann Intern Med. 2001 Dec 4;135(11):954-64. doi: 10.7326/0003-4819-135-11-200112040-00007.
citation: Demeter LM, Bosch RJ, Coombs RW, Fiscus S, Bremer J, Johnson VA, Erice A, Jackson JB, Spector SA, Squires KM, Fischl MA, Hughes MD, Hammer SM. Detection of replication-competent human immunodeficiency virus type 1 (HIV-1) in cultures from patients with levels of HIV-1 RNA in plasma suppressed to less than 500 or 50 copies per milliliter. J Clin Microbiol. 2002 Jun;40(6):2089-94. doi: 10.1128/JCM.40.6.2089-2094.2002.
citation: Coplan P, Cook J, Carides G, Nguyen BY, Testa M. Impact of indinavir with zidovudine and lamivudine on quality of life for HIV patients with < or = 200 CD4 in ACTG 320. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:86 (abstract no 101)
citation: Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, Deyton LR, Chodakewitz JA, Fischl MA. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997 Sep 11;337(11):725-33. doi: 10.1056/NEJM199709113371101.
citation: Demeter LM, Degruttola V, Eshleman S, Jackson JB, Hughes M, Hammer SM. Baseline (BL) HIV-1 protease (PR) and reverse transcriptase (RT) genotype as a predictor of response to ZDV+3TC+indinavir (IDV). Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:92 (abstract no 131)
citation: Freedberg KA, Goldie SJ, Paltiel AD, Losina E, Cohen CJ, Seage GR, Craven DE, Zhang H, Kimmel AD, Sullivan LM, Weinstein MC. Combination antiretroviral therapy is both effective and cost-effective. 39th Intersci Conf Antimicrob Agents Chemother. 1999 Sept 26-29 (abstract no I-2070)
citation: Levine, AM. HPV Infection and Cervical/Anal Precursor Lesions in the HAART Era. http://www.medscape.com/viewarticle/440151
citation: Coplan PM, Cook JR, Carides GW, Heyse JF, Wu AW, Hammer SM, Nguyen BY, Meibohm AR, DiNubile MJ; AIDS Clinical Trials Group 320 Study Team. Impact of indinavir on the quality of life in patients with advanced HIV infection treated with zidovudine and lamivudine. Clin Infect Dis. 2004 Aug 1;39(3):426-33. doi: 10.1086/422520. Epub 2004 Jul 19.
citation: Mrus JM, Williams PL, Tsevat J, Cohn SE, Wu AW. Gender differences in health-related quality of life in patients with HIV/AIDS. Qual Life Res. 2005 Mar;14(2):479-91. doi: 10.1007/s11136-004-4693-z.
citation: Mrus JM, Schackman BR, Wu AW, Freedberg KA, Tsevat J, Yi MS, Zackin R. Variations in self-rated health among patients with HIV infection. Qual Life Res. 2006 Apr;15(3):503-14. doi: 10.1007/s11136-005-1946-4.
citation: Cole SR, Stuart EA. Generalizing evidence from randomized clinical trials to target populations: The ACTG 320 trial. Am J Epidemiol. 2010 Jul 1;172(1):107-15. doi: 10.1093/aje/kwq084. Epub 2010 Jun 14.