Clinical trial NCT00001045: Comparison of Three Anti-HIV Drug Combinations in HIV-Infected Patients With No Symptoms of the Disease
Official title: A Double-Blinded, Randomized Trial Comparing Zidovudine (AZT) Versus AZT Plus Didanosine (ddI) Versus AZT Plus ddI Plus Nevirapine in Asymptomatic Patients on AZT Monotherapy Who Develop a Mutation at Codon 215 of HIV Reverse Transcriptase in Serum/Plasma Viral RNA
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Didanosine
Drug Therapy, Combination
Zidovudine
Nevirapine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Bristol-Myers Squibb
name: Glaxo Wellcome
First posted: 2001-08-31
Enrollment: 300
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To validate that the alteration of codon 215 of reverse transcriptase in plasma virus precedes the increase in viral burden as measured in the peripheral blood and the decline in CD4 count that have been observed in association with clinical failure on zidovudine (AZT). To determine whether alternative regimens of antiretroviral agents alter the course of viral burden as measured in the peripheral blood and CD4 changes in patients with HIV infection. To obtain further data on the safety and immunologic and virologic response to AZT/didanosine/nevirapine.

Of the HIV-1 mutations reported to be associated with zidovudine resistance, the mutation at codon 215 of the reverse transcriptase gene is the most commonly occurring and has the greatest impact on susceptibility. When this mutation appears, a change in drugs may prevent further immunologic and virologic deterioration.

Detailed description: Of the HIV-1 mutations reported to be associated with zidovudine resistance, the mutation at codon 215 of the reverse transcriptase gene is the most commonly occurring and has the greatest impact on susceptibility. When this mutation appears, a change in drugs may prevent further immunologic and virologic deterioration.

Initially, all patients receive AZT alone. After detection of a 215 mutation in plasma RNA, patients are randomized to one of three treatment arms: AZT alone, AZT plus ddI, or AZT/ddI plus nevirapine. Patients are followed every 8 weeks and receive treatment for up to 4 years.

AS PER AMENDMENT 5/9/96: All AZT monotherapy options have been eliminated. Patients will be randomized to either Arm II or Arm III, regardless of their codon 215 status. All patients who were randomized to Arm I following a mutation at codon 215 will be rerandomized to Arm II or Arm III. All patients who were randomized to either Arm II or Arm III following a mutation at codon 215 will remain on their initial randomized assignment.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Allowed:

* Chemoprophylaxis for Pneumocystis carinii pneumonia.
* Antibiotics, antifungals, and antiviral medications, as clinically indicated.
* Regularly prescribed medication such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, or any other medications deemed appropriate by the primary care provider.

Concurrent Treatment:

Allowed:

* Limited localized radiation therapy to the skin.

Prior Medication: Required:

* AZT (minimum 300 mg/day) for at least 1 month (uninterrupted) but no more than 2 years immediately prior to study entry.

Patients must have:

* Asymptomatic HIV infection.
* CD4 count 300-600 cells/mm3.
* No plasma/serum PCR for codon 215 mutation at screening.
* Prior AZT monotherapy.

NOTE:

* All Department of Defense (DOD)-eligible patients must be at least 18 years of age. Enrollment of women is encouraged.

AS PER AMENDMENT 04/03/95:

* DOD female patients must have a negative pregnancy test within 48 hours prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Symptomatic grade 2 or worse peripheral neuropathy.
* Unable to swallow capsules and tablets.
* Other medical condition that contraindicates study participation.

Concurrent Medication:

Excluded:

* Systemic cytotoxic chemotherapy.
* Biologic response modifiers (such as interferon, ampligen, or PEG-IL2).
* Anti-HIV agents other than study drugs.
* Other investigational agents.
* Foscarnet unless clinically indicated for unresponsive herpes virus infection.
* Chronic antacid or H-2 blocker use.
* Rifampin or rifamycin class agents.
* Antibiotics containing clavulanic acid.

Concurrent Treatment:

Excluded:

* Radiation therapy other than limited localized therapy to skin.

Patients with the following prior condition are excluded:

* History of pancreatitis.

Prior Medication:

Excluded:

* Prior therapy with nucleoside or non-nucleoside antiretroviral agents other than AZT.
* Immune modulating therapies (e.g., IFN-alpha, gp160) within 60 days prior to screening.

Prior Treatment:

Excluded:

* Blood transfusion within the preceding 2 weeks.

Illicit drug or alcohol abuse.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA CARE Ctr
state: California
city: San Francisco
country: United States
facility: Stanford at Kaiser / Kaiser Permanente Med Ctr
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium
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: Univ of Colorado Health Sciences Ctr
state: Colorado
city: Washington
country: United States
facility: Georgetown Univ Med Ctr
state: District of Columbia
city: Washington
country: United States
facility: Children's Hosp of Washington DC
state: District of Columbia
city: Washington
country: United States
facility: George Washington Univ / Hershey Med Ctr
state: District of Columbia
city: Washington
country: United States
facility: Walter Reed Army Med Ctr
state: District of Columbia
city: Atlanta
country: United States
facility: Emory Univ Hosp / Pediatrics
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: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Iowa City
country: United States
facility: Univ of Iowa Hosp and Clinic
state: Iowa
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: Bethesda
country: United States
facility: Natl Naval Med Ctr
state: Maryland
city: Rockville
country: United States
facility: Fitzsimmons Army Med Ctr
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Med Ctr
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: Omaha
country: United States
facility: Univ of Nebraska Med Ctr
state: Nebraska
city: Albany
country: United States
facility: Adirondack Med Ctr at Saranac Lake
state: New York
city: Albany
country: United States
facility: Albany Med College / Division of HIV Medicine A158
state: New York
city: Albany
country: United States
facility: Mid - Hudson Care Ctr
state: New York
city: Bronx
country: United States
facility: Bronx Municipal Hosp Ctr/Jacobi Med Ctr
state: New York
city: Bronx
country: United States
facility: Comprehensive Health Care Ctr / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Montefiore Family Health Ctr / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Jack Weiler Hosp / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Montefiore Med Ctr / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Montefiore Med Ctr Adolescent AIDS Program
state: New York
city: Bronx
country: United States
facility: North Central Bronx Hosp / Bronx Municipal Hosp
state: New York
city: Buffalo
country: United States
facility: SUNY / Erie County Med Ctr at Buffalo
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: Columbia Presbyterian 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: Raleigh
country: United States
facility: Wake County Dept of Health
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve Univ
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Med Ctr
state: Ohio
city: Columbus
country: United States
facility: Ohio State Univ Hosp Clinic
state: Ohio
city: Toledo
country: United States
facility: Med College of Ohio
state: Ohio
city: Hershey
country: United States
facility: Milton S Hershey Med Ctr
state: Pennsylvania
city: Philadelphia
country: United States
facility: Univ of Pennsylvania at Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ Hosp
state: Pennsylvania
city: Knoxville
country: United States
facility: Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
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: Lackland Air Force Base
country: United States
facility: Wilford Hall Med Ctr
state: Texas
city: San Antonio
country: United States
facility: Brooke Army Med Ctr
state: Texas
city: Bayamon
country: Puerto Rico
facility: Ramon Ruiz Arnau Univ Hosp / Pediatrics
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp
Study officials:
name: Merigan TC
role: STUDY_CHAIR
name: Mayers DL
role: STUDY_CHAIR
References:
citation: Slade DE, Vavro CL, Stapleton JT, Swack N, StClair MH. A novel mutation at codon 215 of HIV RT. Int Conf AIDS. 1993 Jun 6-11;9(1):239 (abstract no PO-A26-0625)
citation: Mayers D, Merigan T, Gilbert P. T215Y/F mutation associated with zidovudine (ZDV) resistance leads to poor response to ZDV+ddI or ZDV+ddI+NVP: ACTG244/RV79. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:91 (abstract no 129)
citation: Holodniy M, Katzenstein D, Mole L, Winters M, Merigan T. Human immunodeficiency virus reverse transcriptase codon 215 mutations diminish virologic response to didanosine-zidovudine therapy in subjects with non-syncytium-inducing phenotype. J Infect Dis. 1996 Oct;174(4):854-7. doi: 10.1093/infdis/174.4.854.