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

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ClinicalTrials.gov Identifier: NCT00001083
Recruitment Status : Completed
First Posted : August 31, 2001
Last Update Posted : February 16, 2012
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
HIV Infections Drug: Indinavir sulfate Drug: Ritonavir Drug: Nevirapine Drug: Lamivudine Drug: Stavudine Drug: Zidovudine Phase 2

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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.


Study Type : Interventional  (Clinical Trial)
Enrollment : 240 participants
Primary Purpose: Treatment
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
Actual Study Completion Date : June 2001

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS





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Ages Eligible for Study:   2 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00001083


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Locations
United States, Alabama
Univ of Alabama at Birmingham - Pediatric
Birmingham, Alabama, United States, 35233
United States, California
UCSD Med Ctr / Pediatrics / Clinical Sciences
La Jolla, California, United States, 920930672
Long Beach Memorial (Pediatric)
Long Beach, California, United States, 90801
Children's Hosp of Los Angeles/UCLA Med Ctr
Los Angeles, California, United States, 900276016
Los Angeles County - USC Med Ctr
Los Angeles, California, United States, 90033
UCLA Med Ctr / Pediatric
Los Angeles, California, United States, 900951752
Harbor - UCLA Med Ctr / UCLA School of Medicine
Los Angeles, California, United States, 905022004
Children's Hosp of Oakland
Oakland, California, United States, 946091809
UCSF / Moffitt Hosp - Pediatric
San Francisco, California, United States, 941430105
United States, Connecticut
Univ of Connecticut / Farmington
Farmington, Connecticut, United States, 06032
Yale Univ Med School
New Haven, Connecticut, United States, 06504
United States, District of Columbia
Children's Hosp of Washington DC
Washington, District of Columbia, United States, 200102916
Howard Univ Hosp
Washington, District of Columbia, United States, 20060
United States, Florida
North Broward Hosp District
Fort Lauderdale, Florida, United States, 33311
Univ of Florida Gainesville
Gainesville, Florida, United States, 32610
Univ of Florida Health Science Ctr / Pediatrics
Jacksonville, Florida, United States, 32209
Univ of Miami (Pediatric)
Miami, Florida, United States, 33161
Palm Beach County Health Dept
Riviera Beach, Florida, United States, 33404
United States, Georgia
Emory Univ Hosp / Pediatrics
Atlanta, Georgia, United States, 30306
United States, Illinois
Univ of Illinois College of Medicine / Pediatrics
Chicago, Illinois, United States, 60612
Chicago Children's Memorial Hosp
Chicago, Illinois, United States, 606143394
Univ of Chicago Children's Hosp
Chicago, Illinois, United States, 606371470
United States, Louisiana
Tulane Univ / Charity Hosp of New Orleans
New Orleans, Louisiana, United States, 701122699
United States, Maryland
Univ of Maryland at Baltimore / Univ Med Ctr
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Children's Hosp of Boston
Boston, Massachusetts, United States, 021155724
Boston City Hosp / Pediatrics
Boston, Massachusetts, United States, 02118
Baystate Med Ctr of Springfield
Springfield, Massachusetts, United States, 01199
Univ of Massachusetts Med School
Worcester, Massachusetts, United States, 016550001
United States, Mississippi
Univ of Mississippi Med Ctr
Jackson, Mississippi, United States, 39213
United States, New Jersey
UMDNJ - Robert Wood Johnson Med School / Pediatrics
New Brunswick, New Jersey, United States, 089030019
Univ of Medicine & Dentistry of New Jersey / Univ Hosp
Newark, New Jersey, United States, 071032714
Saint Joseph's Hosp and Med Ctr/UMDNJ - New Jersey Med Schl
Newark, New Jersey, United States, 07103
United States, New York
Children's Hosp at Albany Med Ctr
Albany, New York, United States, 12208
Bronx Lebanon Hosp Ctr
Bronx, New York, United States, 10457
Bronx Municipal Hosp Ctr/Jacobi Med Ctr
Bronx, New York, United States, 10461
King's County Hosp Ctr / Pediatrics
Brooklyn, New York, United States, 11203
SUNY - Brooklyn
Brooklyn, New York, United States, 11203
North Shore Univ Hosp
Great Neck, New York, United States, 11021
Schneider Children's Hosp
New Hyde Park, New York, United States, 11040
Bellevue Hosp / New York Univ Med Ctr
New York, New York, United States, 10016
Cornell Univ Med College
New York, New York, United States, 10021
Metropolitan Hosp Ctr
New York, New York, United States, 10029
Mount Sinai Med Ctr / Pediatrics
New York, New York, United States, 10029
Columbia Presbyterian Med Ctr
New York, New York, United States, 10032
Incarnation Children's Ctr / Columbia Presbyterian Med Ctr
New York, New York, United States, 10032
Harlem Hosp Ctr
New York, New York, United States, 10037
Univ of Rochester Med Ctr
Rochester, New York, United States, 146420001
State Univ of New York at Stony Brook
Stony Brook, New York, United States, 117948111
SUNY Health Sciences Ctr at Syracuse / Pediatrics
Syracuse, New York, United States, 13210
Westchester Hosp
Valhalla, New York, United States, 10595
United States, North Carolina
Duke Univ Med Ctr
Durham, North Carolina, United States, 277103499
United States, Ohio
Columbus Children's Hosp
Columbus, Ohio, United States, 432052696
United States, Pennsylvania
Saint Christopher's Hosp for Children
Philadelphia, Pennsylvania, United States, 191341095
United States, South Carolina
Med Univ of South Carolina
Charleston, South Carolina, United States, 294253312
United States, Texas
Children's Med Ctr of Dallas
Dallas, Texas, United States, 75235
Texas Children's Hosp / Baylor Univ
Houston, Texas, United States, 77030
United States, Virginia
Med College of Virginia
Richmond, Virginia, United States, 23219
United States, Washington
Children's Hospital & Medical Center / Seattle ACTU
Seattle, Washington, United States, 981050371
Puerto Rico
Ramon Ruiz Arnau Univ Hosp / Pediatrics
Bayamon, Puerto Rico, 00956
Univ of Puerto Rico / Univ Children's Hosp AIDS
San Juan, Puerto Rico, 009365067
San Juan City Hosp
San Juan, Puerto Rico, 009367344
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Nachman S
Study Chair: Wiznia A

Publications of Results:
Nachman S. Lack of improvement in growth in HIV-infected children on HAART 39th Intersci Conf Antimicrob Agents Chemother. 1999 Sept 26-29 (abstract no 120)

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00001083     History of Changes
Other Study ID Numbers: ACTG 338
11309 ( Registry Identifier: DAIDS ES )
First Posted: August 31, 2001    Key Record Dates
Last Update Posted: February 16, 2012
Last Verified: February 2012

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
HIV-1
Drug Therapy, Combination
Zidovudine
Nevirapine
Stavudine
HIV Protease Inhibitors
Ritonavir
Lamivudine
Indinavir
RNA, Viral
Reverse Transcriptase Inhibitors
Anti-HIV Agents

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Indinavir
Lamivudine
Zidovudine
Nevirapine
Stavudine
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Antimetabolites
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers