Comparison of New Anti-HIV Drug Combinations in HIV-Infected Children Who Have Taken Anti-HIV Drugs
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 2

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).
    

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.
    

Intervention name(s): Indinavir sulfate; Ritonavir; Nevirapine; Lamivudine; Stavudine; Zidovudine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention MeSH terms: Ritonavir; Indinavir; Lamivudine; Zidovudine; Nevirapine; Stavudine
Primary purpose: Treatment
Keywords: HIV-1; Drug Therapy, Combination; Zidovudine; Nevirapine; Stavudine; HIV Protease Inhibitors; Ritonavir; Lamivudine; Indinavir; RNA, Viral; Reverse Transcriptase Inhibitors; Anti-HIV Agents