Comparison of New Anti-HIV Drug Combinations in HIV-Infected Children Who Have Taken Anti-HIV Drugs

Condition(s) targeted: HIV Infections

Intervention: Indinavir sulfate (Drug); Ritonavir (Drug); Nevirapine (Drug); Lamivudine (Drug); Stavudine (Drug); Zidovudine (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Nachman S, Study Chair
Wiznia A, Study Chair

For PRAM-1: To evaluate zidovudine (ZDV) + lamivudine (3TC) vs. stavudine (d4T) + ritonavir vs. ZDV + 3TC + ritonavir with respect to the change in plasma HIV-1 RNA copy number from baseline to 48 weeks [AS PER AMENDMENT 1/5/98: 72 weeks; AS PER AMENDMENT 7/17/98: 48 weeks] in stable HIV-infected children with >= 16 weeks of prior continuous antiretroviral therapy. To evaluate the safety and tolerance of ZDV + 3TC vs. d4T + ritonavir vs. ZDV + 3TC + ritonavir based upon laboratory and clinical toxicities.

AS PER AMENDMENT 10/20/97: For PRAM-1, Step 2: To evaluate d4T + nevirapine + ritonavir with respect to change in plasma HIV-1 RNA copy number from baseline to 48 weeks in children who have received at least 12 weeks of therapy on the PRAM-1 ZDV/3TC arm and have over 10,000 viral copies at weeks 12, 24, or 36. To evaluate the safety and tolerance of d4T + nevirapine + ritonavir based upon laboratory and clinical toxicities. [AS PER AMENDMENT 10/23/98: To evaluate safety and tolerance of a switch from d4T + ritonavir vs. ZDV + 3TC + ritonavir to d4T + indinavir vs. ZDV + 3TC + indinavir in stable, HIV-infected children with RNA values <= 10,000 copies/ml.] For PRAM-1: Evidence supports combination therapy with 2 or more antiviral agents as beneficial in the long-term management of HIV. The possibility exists that combination therapy may result in a synergistic or additive activity over a prolonged period of time. Also hypothesized is that the development of resistance to individual agents will be developed if viral replication is significantly decreased.

AS PER AMENDMENT 10/20/97: For PRAM-1, Step 2: Interim analysis at 12 weeks on PRAM-1 indicates that the proportion of children reaching undetectable RNA levels on the ZDV + 3TC arm is significantly less than the other two arms. The protocol, therefore, has been modified (Step 2) to permit children in the ZDV + 3TC arm with RNA copy number >= 10,000 the opportunity to change to a novel therapeutic regimen (d4T + nevirapine + ritonavir).

Official title: A Phase II Rolling Arm Master Protocol (PRAM) of Novel Antiretroviral Therapy in Stable Experienced HIV- Infected Children; PRAM-1: ZDV+3TC vs. d4T+Ritonavir vs. ZDV+3TC+Ritonavir; PRAM-1, Step 2: d4T+Nevirapine+Ritonavir; PRAM-1, Step 3: d4T+Indinavir vs. ZDV+3TC+Indinavir

Study design: Treatment, Pharmacokinetics Study

Detailed description: For PRAM-1: Evidence supports combination therapy with 2 or more antiviral agents as beneficial in the long-term management of HIV. The possibility exists that combination therapy may result in a synergistic or additive activity over a prolonged period of time. Also hypothesized is that the development of resistance to individual agents will be developed if viral replication is significantly decreased.

AS PER AMENDMENT 10/20/97: For PRAM-1, Step 2: Interim analysis at 12 weeks on PRAM-1 indicates that the proportion of children reaching undetectable RNA levels on the ZDV + 3TC arm is significantly less than the other two arms. The protocol, therefore, has been modified (Step 2) to permit children in the ZDV + 3TC arm with RNA copy number >= 10,000 the opportunity to change to a novel therapeutic regimen (d4T + nevirapine + ritonavir).

The Master PRAM is a Phase II, multicenter, randomized, open-label trial of a standard therapeutic regimen in current use versus experimental therapies administered over 48 weeks. It is designed to allow new therapeutic arms to be studied as "rolling screens" through multiple generations of PRAM. Each PRAM generation compares 2 novel therapeutic arms with a linking arm that allows for an indirect comparison of included therapies. Once accrual to PRAM-1 is complete a new treatment comparison opens for accrual (PRAM-2). The linking arm to be used in PRAM-2 is decided by the Pediatric Primary Scientific Committee. PRAM-2 will continue to accrue patients while PRAM-1 patients continue therapy.

For PRAM-1: This study compares the following three treatment arms:

Arm I: ZDV plus 3TC Arm II: d4T plus ritonavir Arm III: ZDV plus 3TC plus ritonavir. Prior to randomization to one of the three arms, patients are stratified based on CD4 percents: either less than 15% or greater than or equal to 15%. The first 8 patients randomized to Arms II and III participate in a real-time Phase I pharmacokinetic study (16 patients total). After the first 45 (15 per arm) patients entered are followed for 24 weeks, an interim analysis is done. Patients are treated for 48 weeks [AS PER AMENDMENT 1/5/98: 72 weeks].

AS PER AMENDMENT 10/20/97:

PRAM-1, Step 2:

Patients initially assigned to Arm I (ZDV plus 3TC) who have RNA values greater than 10,000 copies at week 12, 24, or 36 are assigned to switch protocol treatment to d4T + ritonavir + nevirapine. Patients may enroll in Step 2 no later than week 38 of PRAM-1. [AS PER AMENDMENT 1/5/98: Patients initially assigned to Arm 1 with viral load greater than 100,000 copies may also switch to Step 2 or discontinue therapy. Patients originally assigned to Arms I or II with viral load greater than 10,000 may continue their current drugs or discontinue study therapy; those with viral load greater than 100,000 should discontinue study drugs.] [AS PER AMENDMENT 7/17/98: PRAM-1 has been extended to permit long-term follow-up of clinically stable, HIV-infected children for a total of 120 weeks. Patients still on initial treatment assignment for all three treatment arms are eligible for this extension, as are children from PRAM-1, Step 2. Step 2 is now closed to enrollment. Patients on 3TC/ZDV who reach virologic failure must discontinue study therapy].

[AS PER AMENDMENT 10/23/98: PRAM-1, Step 3: This amendment substitutes indinavir (IDV) capsules for ritonavir capsules in PRAM-1. The regimens will switch from d4T plus ritonavir versus ZDV plus 3TC plus ritonavir to d4T plus IDV versus ZDV plus 3TC plus IDV. All patients will be followed for 48 weeks. Patients eligible for this change in regimens are those taking ritonavir capsules who have RNA values less than or equal to 10,000 copies/ml (as demonstrated by the most recent viral load test) after at least 72 weeks on PRAM-1, Step I. Twelve patients with RNA values less than or equal to 400 copies/ml will immediately join the study; 6 will receive d4T plus IDV and 6 will receive ZDV plus 3TC plus IDV. Additional patients may be added based on toxicity and viral load results. A total sample size of 53 evaluable patients (37 with RNA values less than or equal to 400 copies/ml and 16 with RNA values of greater than 400 to 10,000 copies/ml) is anticipated. PRAM-1 Step 2 patients are not eligible for Step 3. PRAM-1, Step 2 patients currently taking liquid ritonavir should continue their study drug; those taking ritonavir capsules will switch to liquid ritonavir or go off study.

Minimum age: 2 Years. Maximum age: 17 Years. Gender(s): Both.

Criteria:

Inclusion Criteria

Concurrent Medication:

Allowed:

- IVIG and opportunistic infection prophylaxis will be allowed.

- Erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and

granulocyte-macrophage colony- stimulating factor (GM-CSF) will be allowed for the management of hematologic toxicity.

- Treatment with trimethoprim is allowed at the discretion of the principal

investigator.

Patients must have:

- Laboratory evidence (at least 2 viral tests) of HIV-1 infection.

- Clinical and immunological stability [maintained CDC category 1 or 2 immunologic

status for past 4 months and no new CDC category (diagnosis within the past year)].

- Patients must have received continuous antiretroviral therapy for the past 16 weeks

(missing no more than 6 weeks of therapy during the previous 16 weeks).

AS PER AMENDMENT 10/20/97: For PRAM-1, Step 2:

- Viral load >= 10,000 and < 100,000 copies/ml at week 12, 24, or 36 in children

initially assigned to Arm I (ZDV + 3TC) of PRAM-1 and currently on study.

Prior Medication:

Required:

- Patients must have received continuous antiretroviral therapy for the past 16 weeks.

Allowed:

- Patients who have received immunomodulator therapy as part of perinatal clinical

trials or in trials for HIV- exposed infants are eligible.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

- Current grade 3/4 clinical or laboratory toxicity and/or current grade 2 or higher

amylase/lipase toxicity.

- Active opportunistic infection and/or serious bacterial infection.

- Current diagnosis of malignancy.

Concurrent Medication:

Excluded:

- Current antiretroviral therapy identical to any of the following regimens:

- ZDV + 3TC, d4T + ritonavir and ZDV + 3TC + ritonavir.

- Concurrent therapy with any other anti-HIV-1 therapy, biologic response modifiers

(EPO, G-CSF and GM-CSF allowed), human growth hormone and megestrol acetate.

- Use of continuous systemic corticosteroids (>= 14 days duration) is not allowed.

- Medications that are incompatible with ritonavir.

- Probenecid and daily intravenous pentamidine.

[AS PER AMENDMENT 10/23/98: The following are excluded in patients receiving indinavir:

- terfenadine, astemizole, cisapride, rifampin, rifabutin, triazolam, ketoconazole,

clarithromycin, carbamazepine, phenobarbital, phenytoin, calcium channel blockers, midazolam, and ergot derivatives.]

Patients with the following prior conditions and symptoms are excluded:

- Documented hypersensitivity to a therapy included in any of the treatment arms.

Prior Medication:

Excluded:

Investigational drug therapy within 2 weeks prior to randomization.

NOTE:

- Co-enrollment in ACTG 219, ACTG 220 and certain ACTG opportunistic infection protocols

is allowed.

San Juan City Hosp, San Juan 009367344, Puerto Rico

Univ of Puerto Rico / Univ Children's Hosp AIDS, San Juan 009365067, Puerto Rico

Ramon Ruiz Arnau Univ Hosp / Pediatrics, Bayamon 00956, Puerto Rico

Univ of Alabama at Birmingham - Pediatric, Birmingham, Alabama 35233, United States

UCSF / Moffitt Hosp - Pediatric, San Francisco, California 941430105, United States

UCSD Med Ctr / Pediatrics / Clinical Sciences, La Jolla, California 920930672, United States

Harbor - UCLA Med Ctr / UCLA School of Medicine, Los Angeles, California 905022004, United States

Children's Hosp of Oakland, Oakland, California 946091809, United States

UCLA Med Ctr / Pediatric, Los Angeles, California 900951752, United States

Children's Hosp of Los Angeles/UCLA Med Ctr, Los Angeles, California 900276016, United States

Long Beach Memorial (Pediatric), Long Beach, California 90801, United States

Los Angeles County - USC Med Ctr, Los Angeles, California 90033, United States

Yale Univ Med School, New Haven, Connecticut 06504, United States

Univ of Connecticut / Farmington, Farmington, Connecticut 06032, United States

Howard Univ Hosp, Washington, District of Columbia 20060, United States

Children's Hosp of Washington DC, Washington, District of Columbia 200102916, United States

Univ of Miami (Pediatric), Miami, Florida 33161, United States

Univ of Florida Health Science Ctr / Pediatrics, Jacksonville, Florida 32209, United States

North Broward Hosp District, Fort Lauderdale, Florida 33311, United States

Univ of Florida Gainesville, Gainesville, Florida 32610, United States

Palm Beach County Health Dept, Riviera Beach, Florida 33404, United States

Emory Univ Hosp / Pediatrics, Atlanta, Georgia 30306, United States

Chicago Children's Memorial Hosp, Chicago, Illinois 606143394, United States

Univ of Illinois College of Medicine / Pediatrics, Chicago, Illinois 60612, United States

Univ of Chicago Children's Hosp, Chicago, Illinois 606371470, United States

Tulane Univ / Charity Hosp of New Orleans, New Orleans, Louisiana 701122699, United States

Univ of Maryland at Baltimore / Univ Med Ctr, Baltimore, Maryland 21201, United States

Children's Hosp of Boston, Boston, Massachusetts 021155724, United States

Boston City Hosp / Pediatrics, Boston, Massachusetts 02118, United States

Baystate Med Ctr of Springfield, Springfield, Massachusetts 01199, United States

Univ of Massachusetts Med School, Worcester, Massachusetts 016550001, United States

Univ of Mississippi Med Ctr, Jackson, Mississippi 39213, United States

Univ of Medicine & Dentistry of New Jersey / Univ Hosp, Newark, New Jersey 071032714, United States

UMDNJ - Robert Wood Johnson Med School / Pediatrics, New Brunswick, New Jersey 089030019, United States

Saint Joseph's Hosp and Med Ctr/UMDNJ - New Jersey Med Schl, Newark, New Jersey 07103, United States

King's County Hosp Ctr / Pediatrics, Brooklyn, New York 11203, United States

Harlem Hosp Ctr, New York, New York 10037, United States

SUNY - Brooklyn, Brooklyn, New York 11203, United States

Cornell Univ Med College, New York, New York 10021, United States

North Shore Univ Hosp, Great Neck, New York 11021, United States

Westchester Hosp, Valhalla, New York 10595, United States

Schneider Children's Hosp, New Hyde Park, New York 11040, United States

Bellevue Hosp / New York Univ Med Ctr, New York, New York 10016, United States

Columbia Presbyterian Med Ctr, New York, New York 10032, United States

Mount Sinai Med Ctr / Pediatrics, New York, New York 10029, United States

Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx, New York 10461, United States

Metropolitan Hosp Ctr, New York, New York 10029, United States

Children's Hosp at Albany Med Ctr, Albany, New York 12208, United States

SUNY Health Sciences Ctr at Syracuse / Pediatrics, Syracuse, New York 13210, United States

Bronx Lebanon Hosp Ctr, Bronx, New York 10457, United States

Incarnation Children's Ctr / Columbia Presbyterian Med Ctr, New York, New York 10032, United States

State Univ of New York at Stony Brook, Stony Brook, New York 117948111, United States

Univ of Rochester Med Ctr, Rochester, New York 146420001, United States

Duke Univ Med Ctr, Durham, North Carolina 277103499, United States

Columbus Children's Hosp, Columbus, Ohio 432052696, United States

Saint Christopher's Hosp for Children, Philadelphia, Pennsylvania 191341095, United States

Med Univ of South Carolina, Charleston, South Carolina 294253312, United States

Children's Med Ctr of Dallas, Dallas, Texas 75235, United States

Texas Children's Hosp / Baylor Univ, Houston, Texas 77030, United States

Med College of Virginia, Richmond, Virginia 23219, United States

Children's Hospital & Medical Center / Seattle ACTU, Seattle, Washington 981050371, United States

Click here for more information about zidovudine

Click here for more information about stavudine

Click here for more information about nevirapine

Click here for more information about lamivudine

Click here for more information about indinavir sulfate

Click here for more information about ritonavir

Last updated: February 28, 2007