Clinical trial NCT00000912: A Study on Amprenavir in Combination With Other Anti-HIV Drugs in HIV-Positive Patients
Official title: A Phase II, Randomized Trial of Amprenavir as Part of Dual Protease Inhibitor Regimens (Placebo-Controlled) in Combination With Abacavir, Efavirenz, and Adefovir Dipivoxil Versus Amprenavir Alone in HIV-Infected Subjects With Prior Exposure to Approved Protease Inhibitors and Loss of Virologic Suppression as Reflected by a Plasma HIV-1 RNA Concentration >= 1,000 Copies/ml
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Placebos
Drug Therapy, Combination
HIV Protease Inhibitors
VX 478
Anti-HIV Agents
Viral Load
efavirenz
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 475
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare 4 different combinations of anti-HIV drugs and to determine the number of people whose HIV blood levels decrease to 200 copies/ml or less while on the treatment. This study evaluates the safety of these drug combinations, which include an experimental protease inhibitor (PI), amprenavir.

Despite the success that many patients have had with PI treatment regimens, there is still a possibility that patients receiving PIs may continue to have high HIV blood levels. Because of this possibility, alternative drug combinations containing PIs are being studied. It appears that amprenavir, when taken with 3 or 4 other anti-HIV drugs, may be effective in patients with prior PI treatment experience.

Detailed description: A number of studies both within and outside the ACTG have been initiated or are in development to try to address the issue of alternative treatments for patients who either do not achieve or lose virologic control while receiving protease inhibitors (PIs). Amprenavir (APV) is an attractive candidate to investigate as part of salvage regimens because: 1) it has substantial antiretroviral activity; 2) there are preliminary in vitro and in vivo data that suggest that resistance to this agent may be mediated in part by a unique mutation (I50V); and 3) its cross-resistance profile to the approved PIs is uncertain.

Patients are selectively randomized to 1 of 4 study arms based on prior PI experience. Those randomized to Arms A, B, or C receive 2 PIs, 1 of which is amprenavir (APV), and those randomized to Arm D receive a single PI (APV) as part of their treatment regimen, as follows:

Arm A: APV plus saquinavir soft gel capsule (SQVsgc) plus abacavir (ABC) plus efavirenz (EFV) plus adefovir (ADV).

Arm B: APV plus indinavir (IDV) plus ABC plus EFV plus ADV. Arm C: APV plus nelfinavir (NFV) plus ABC plus EFV plus ADV. Arm D: APV plus placebo (NFV, IDV, or SQVsgc) plus ABC plus EFV plus ADV. All patients receive L-carnitine supplementation. All patients receive clinical physical assessments and laboratory testing during study as follows: Weeks 2, 4, and every 4 weeks thereafter. A primary analysis is performed after the last patient has reached 24 weeks. \[AS PER AMENDMENT 3/2/00: At that time, all patients are unblinded to their original treatment assignment.\] Patients who experience virologic failure are unblinded and may choose 1 of the following 3 options: Continue study medications open-label, permanently discontinue study medications, or selectively continue study medications \[AS PER AMENDMENT 3/2/00: from the arm the patient was originally randomized to\] and combine with other approved antiretroviral agents. \[AS PER AMENDMENT 3/2/00: For patients adding didanosine (ddI) to their regimens, monitoring for the development of pancreatitis is crucial.\] Final evaluations are required for those patients who are off drug during the immediate 8-week period following the last dose of study treatment. Beyond 8 weeks, they are followed for incidence of death, cancer, congenital anomalies, and permanent disabilities. \[AS PER AMENDMENT 3/2/00: Gilead Sciences has terminated its U.S. development of ADV for HIV infection. Gilead will continue to supply ADV for patients in ACTG 398 until the study closes. Patients who are receiving ADV at the completion of the study may continue to access ADV through the Expanded Access Program, provided that the physician and patient have determined that continued use of ADV is beneficial.\]

Eligibility criteria: Inclusion Criteria

Patients may be eligible for this study if they:

* Are HIV-positive.
* Have current virologic failure (2 consecutive HIV blood levels above 1,000 copies/ml) while on PIs.
* Are over 13 years of age (consent of parent or guardian required if under 18).
* Agree to practice abstinence or use effective methods of birth control during the study and for 90 days after.

Exclusion Criteria

Patients will not be eligible for this study if they:

* Have hepatitis within 90 days prior to study entry.
* Have a history of a peripheral neuropathy within 60 days of study entry.
* Have an unexplained temperature for a 7-day period.
* Have chronic diarrhea within 30 days prior to study entry.
* Have cancer requiring chemotherapy.
* Received any therapy for infection or other illness within 30 days prior to study entry.
* Have received certain other medications.
* Are pregnant or breast-feeding.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
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: USC Univ Hosp & Ambulatory Hlth Care Ctr / USC Med Ctr
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Ctr
state: California
city: Menlo Park
country: United States
facility: Willow Clinic
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 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: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
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: 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: Tripler AMC
country: United States
facility: Tripler Army Med Ctr
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Univ Med School
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp
state: Illinois
city: Chicago
country: United States
facility: Rush Presbyterian - Saint Luke's Med Ctr
state: Illinois
city: New Orleans
country: United States
facility: Charity Hosp / Tulane Univ Med School
state: Louisiana
city: New Orleans
country: United States
facility: Tulane Univ School of Medicine
state: Louisiana
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: Minneapolis
country: United States
facility: Univ of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: St Louis Regional Hosp / St Louis Regional Med Ctr
state: Missouri
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: Chelsea 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: Mount Sinai Med Ctr
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
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: Cincinnati
country: United States
facility: Univ of Cincinnati
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: Univ of Pennsylvania at Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Univ of Pittsburgh Med Ctr
state: Pennsylvania
city: Galveston
country: United States
facility: Univ of Texas Galveston
state: Texas
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
city: San Juan
country: Puerto Rico
facility: Univ of Puerto Rico
Study officials:
name: Scott Hammer
role: STUDY_CHAIR
name: John Mellors
role: STUDY_CHAIR
References:
citation: Pfister M, Labbe L, Hammer SM, Mellors J, Bennett KK, Rosenkranz S, Sheiner LB; Adult AIDS Clinical Trial Group Study 398. Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398. Antimicrob Agents Chemother. 2003 Jan;47(1):130-7. doi: 10.1128/AAC.47.1.130-137.2003.
citation: Pfister M, Labbe L, Lu JF, Hammer SM, Mellors J, Bennett KK, Rosenkranz S, Sheiner LB; AIDS Clinical Trial Group Protocol 398 Investigators. Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir. Clin Pharmacol Ther. 2002 Aug;72(2):133-41. doi: 10.1067/mcp.2002.126183.
citation: Hammer SM, Vaida F, Bennett KK, Holohan MK, Sheiner L, Eron JJ, Wheat LJ, Mitsuyasu RT, Gulick RM, Valentine FT, Aberg JA, Rogers MD, Karol CN, Saah AJ, Lewis RH, Bessen LJ, Brosgart C, DeGruttola V, Mellors JW; AIDS Clinical Trials Group 398 Study Team. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA. 2002 Jul 10;288(2):169-80. doi: 10.1001/jama.288.2.169.
citation: Sun J, Nagaraj HN, Reynolds NR. Discrete stochastic models for compliance analysis based on an AIDS Clinical Trial Group (ACTG) study. Biom J. 2007 Aug;49(5):731-41. doi: 10.1002/bimj.200610368.
citation: Ghosh P, Ghosh K, Tiwari RC. Joint modeling of longitudinal data and informative dropout time in the presence of multiple changepoints. Stat Med. 2011 Mar 15;30(6):611-26. doi: 10.1002/sim.4119. Epub 2010 Nov 30.