Clinical trial NCT00001091: Safety and Effectiveness of Four Anti-HIV Drug Combinations in HIV-Infected Children and Teens
Official title: A Phase II Rolling Arm Master Protocol (PRAM) of Novel Antiretroviral Therapy in Stable Experienced HIV-Infected Children. PRAM-2: A Phase I/II Randomized, Multicenter Protocol Comparing Four Antiretroviral Regimens Containing Combinations of Protease Inhibitors, NRTIs and an NNRTI
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Drug Therapy, Combination
Nevirapine
Stavudine
HIV Protease Inhibitors
Ritonavir
Lamivudine
Nelfinavir
Reverse Transcriptase Inhibitors
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2001-08-31
Enrollment: 200
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to see if it is safe and effective to give HIV-infected children and teens 1 of 4 anti-HIV drug combinations.

Decreasing HIV levels in infected patients can slow down disease progression. Further study is needed to find out which drug combinations are most effective in doing this.

Detailed description: For PRAM 2: Evidence suggests that as a consequence of antiviral therapy, decreases in plasma HIV-1 RNA are strongly associated with a delay in clinical progression. Therefore, the drug regimens proposed in this study are designed to result in a much larger sustained drop in plasma HIV-1 RNA and greater clinical benefit. Further intent of this study is to evaluate the virologic and therapeutic potential of novel combinations of antiretrovirals and to better define the pharmacokinetics and drug-drug interactions of therapies included in this regimen.

The Master PRAM schema is designed to allow new therapeutic arms to be studied as "rolling screens" through multiple generations of PRAMs. There is a common, "linking" regimen between any 2 sequential PRAM generations that will permit an indirect comparison of included therapies. (NOTE: Due to significant changes in study design between PRAM 1 and PRAM 2, there is no "linking" arm between them. The linkage will be reinstated from PRAM 2 and subsequent PRAM generations.) The therapeutic potential of the treatment arms is assessed by their ability to decrease HIV copy numbers as defined by plasma HIV-1 RNA copy number. Once accrual to a PRAM is complete, a new treatment comparison will open for accrual.

For PRAM 2: This study will compare the following 4 treatment arms:

Arm A - stavudine (d4T)/nevirapine/ritonavir Arm B - d4T/lamivudine (3TC)/nelfinavir Arm C - d4T/nevirapine/nelfinavir Arm D - d4T/3TC/nevirapine/nelfinavir. Prior to randomization to 1 of the PRAM 2 treatment arms, patients are stratified based on their CD4% (less than 25% and greater than or equal to 25%) and by age (less than 24 months and greater than or equal to 24 months). The first 35 subjects/treatment arm are evaluated with special immunologic studies including lymphoproliferative assays and extended panel immunophenotyping. There is an interim analysis after all patients have completed 12 weeks of treatment. Patients are treated for 48 weeks. \[AS PER AMENDMENT 6/11/99: The study has been extended for an additional 48 weeks (96 weeks total) to permit long-term follow-up of clinically stable, HIV-infected children.\]

Eligibility criteria: Inclusion Criteria

Patients may be eligible for this study if they:

* Are HIV-positive.
* Have received the same continuous anti-HIV treatment for the past 16 weeks (missing no more than 6 weeks of treatment total during those 16 weeks).
* Are between 4 months and 17 years old (consent of parent or guardian required).

Exclusion Criteria

Patients will not be eligible if they:

* Have certain serious conditions such as cancer, an opportunistic (AIDS-related) infection, or other serious infection.
* Have ever taken any of the study drugs or any protease inhibitor.
* Are currently taking any anti-HIV drugs.
* Have taken an investigational drug within 14 days of entry into the study. (Co-enrollment in ACTG 219, ACTG 220 and certain ACTG opportunistic infection studies is allowed.)
* Are taking certain other drugs.
* Are pregnant.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham - Pediatric
state: Alabama
city: La Jolla
country: United States
facility: UCSD Med Ctr / Pediatrics / Clinical Sciences
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial (Pediatric)
state: California
city: Los Angeles
country: United States
facility: Children's Hosp of Los Angeles/UCLA Med Ctr
state: California
city: Los Angeles
country: United States
facility: Los Angeles County - USC Med Ctr
state: California
city: Los Angeles
country: United States
facility: UCLA Med Ctr / Pediatric
state: California
city: Los Angeles
country: United States
facility: Harbor - UCLA Med Ctr / UCLA School of Medicine
state: California
city: Oakland
country: United States
facility: Children's Hosp of Oakland
state: California
city: San Francisco
country: United States
facility: UCSF / Moffitt Hosp - Pediatric
state: California
city: Hartford
country: United States
facility: Connecticut Children's Med Ctr - Pediatric
state: Connecticut
city: New Haven
country: United States
facility: Yale Univ Med School
state: Connecticut
city: Washington
country: United States
facility: Children's Hosp of Washington DC
state: District of Columbia
city: Washington
country: United States
facility: Washington Hosp Ctr
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ Hosp
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: North Broward Hosp District
state: Florida
city: Gainesville
country: United States
facility: Univ of Florida Gainesville
state: Florida
city: Jacksonville
country: United States
facility: Univ of Florida Health Science Ctr / Pediatrics
state: Florida
city: Riviera Beach
country: United States
facility: Palm Beach County Health Dept
state: Florida
city: Atlanta
country: United States
facility: Emory Univ Hosp / Pediatrics
state: Georgia
city: Augusta
country: United States
facility: Med College of Georgia
state: Georgia
city: Chicago
country: United States
facility: Cook County Hosp
state: Illinois
city: Chicago
country: United States
facility: Univ of Illinois College of Medicine / Pediatrics
state: Illinois
city: Chicago
country: United States
facility: Chicago Children's Memorial Hosp
state: Illinois
city: Chicago
country: United States
facility: Univ of Chicago Children's Hosp
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ / Charity Hosp of New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: Univ of Maryland at Baltimore / Univ Med Ctr
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hosp - Pediatric
state: Maryland
city: Springfield
country: United States
facility: Baystate Med Ctr of Springfield
state: Massachusetts
city: Worcester
country: United States
facility: Univ of Massachusetts Med School
state: Massachusetts
city: Jackson
country: United States
facility: Univ of Mississippi Med Ctr
state: Mississippi
city: New Brunswick
country: United States
facility: UMDNJ - Robert Wood Johnson Med School / Pediatrics
state: New Jersey
city: Newark
country: United States
facility: Saint Joseph's Hosp and Med Ctr/UMDNJ - New Jersey Med Schl
state: New Jersey
city: Bronx
country: United States
facility: Bronx Lebanon Hosp Ctr
state: New York
city: Bronx
country: United States
facility: Bronx Municipal Hosp Ctr / Bronx Lebanon Hosp Ctr
state: New York
city: Bronx
country: United States
facility: Bronx Municipal Hosp Ctr/Jacobi Med Ctr
state: New York
city: Brooklyn
country: United States
facility: King's County Hosp Ctr / Pediatrics
state: New York
city: Brooklyn
country: United States
facility: SUNY - Brooklyn
state: New York
city: Great Neck
country: United States
facility: North Shore Univ Hosp
state: New York
city: New Hyde Park
country: United States
facility: Schneider Children's Hosp
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: Cornell Univ Med College
state: New York
city: New York
country: United States
facility: Metropolitan Hosp 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: Incarnation Children's Ctr / 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 Med Ctr
state: New York
city: Stony Brook
country: United States
facility: State Univ of New York at Stony Brook
state: New York
city: Philadelphia
country: United States
facility: Children's Hosp of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Saint Christopher's Hosp for Children
state: Pennsylvania
city: Charleston
country: United States
facility: Med Univ of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt Univ Med Ctr
state: Tennessee
city: Norfolk
country: United States
facility: Children's Hosp of the King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Children's Hospital & Medical Center / Seattle ACTU
state: Washington
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: Andrew Wiznia
role: STUDY_CHAIR
name: George Johnson
role: STUDY_CHAIR
name: Paul Krogstad
role: STUDY_CHAIR
References:
citation: Cunningham S, Ank B, Lewis D, Lu W, Wantman M, Dileanis JA, Jackson JB, Palumbo P, Krogstad P, Eshleman SH. Performance of the applied biosystems ViroSeq human immunodeficiency virus type 1 (HIV-1) genotyping system for sequence-based analysis of HIV-1 in pediatric plasma samples. J Clin Microbiol. 2001 Apr;39(4):1254-7. doi: 10.1128/JCM.39.4.1254-1257.2001.
citation: Eshleman SH, Krogstad P, Jackson JB, Lee S, Wang YG, Wei LJ, Cunningham S, Wantman M, Lindquist C, Nachman S, Palumbo P. Analysis of HIV-1 drug resistance in a randomized, controlled trial of a combination of nucleoside analog reverse transcriptase (RT) inhibitors plus nevirapine (NVP), nelfinavir (NFV), or ritonavir (RTV) in stable antiretroviral therapy-experienced HIV-infected children. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 468)
citation: Eshleman SH, Krogstad P, Jackson JB, Wang YG, Lee S, Wei LJ, Cunningham S, Wantman M, Wiznia A, Johnson G, Nachman S, Palumbo P. Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377). J Infect Dis. 2001 Jun 15;183(12):1732-8. doi: 10.1086/320728. Epub 2001 May 16.
citation: Krogstad P, Lee S, Johnson G, Stanley K, McNamara J, Moye J, Jackson JB, Aguayo R, Dieudonne A, Khoury M, Mendez H, Nachman S, Wiznia A; Pediatric AIDS Clinical Trials Group 377 Study Team. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis. 2002 Apr 1;34(7):991-1001. doi: 10.1086/338814. Epub 2002 Feb 27.
citation: Van Dyke RB, Lee S, Johnson GM, Wiznia A, Mohan K, Stanley K, Morse EV, Krogstad PA, Nachman S; Pediatric AIDS Clinical Trials Group Adherence Subcommittee Pediatric AIDS Clinical Trials Group 377 Study Team. Reported adherence as a determinant of response to highly active antiretroviral therapy in children who have human immunodeficiency virus infection. Pediatrics. 2002 Apr;109(4):e61. doi: 10.1542/peds.109.4.e61.
citation: Wiznia A, Stanley K, Krogstad P, Johnson G, Lee S, McNamara J, Moye J, Jackson JB, Mendez H, Aguayo R, Dieudonne A, Kovacs A, Bamji M, Abrams E, Rana S, Sever J, Nachman S. Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: week 24 results of a randomized controlled trial--PACTG 377. Pediatric AIDS Clinical Trials Group 377 Study Team. AIDS Res Hum Retroviruses. 2000 Aug 10;16(12):1113-21. doi: 10.1089/088922200414956.
citation: Jeremy RJ, Kim S, Nozyce M, Nachman S, McIntosh K, Pelton SI, Yogev R, Wiznia A, Johnson GM, Krogstad P, Stanley K; Pediatric AIDS Clinical Trials Group (PACTG) 338 & 377 Study Teams. Neuropsychological functioning and viral load in stable antiretroviral therapy-experienced HIV-infected children. Pediatrics. 2005 Feb;115(2):380-7. doi: 10.1542/peds.2004-1108.
citation: Rosenblatt HM, Song LY, Nachman SA, Stanley KE, Krogstad PA, Johnson GM, Wiznia AA; Pediatric Aids Clinical Trials Group 377 Study Team. Tetanus immunity after diphtheria, tetanus toxoids, and acellular pertussis vaccination in children with clinically stable HIV infection. J Allergy Clin Immunol. 2005 Sep;116(3):698-703. doi: 10.1016/j.jaci.2005.05.016.
citation: Saitoh A, Sarles E, Capparelli E, Aweeka F, Kovacs A, Burchett SK, Wiznia A, Nachman S, Fenton T, Spector SA. CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children. AIDS. 2007 Oct 18;21(16):2191-9. doi: 10.1097/QAD.0b013e3282ef9695.