Safety, Tolerability, and Anti-HIV Activity of DMP 266 (Efavirenz) in Combination With Nelfinavir in HIV-Positive Children
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      Cohort I: The purpose of this study is to see how safe it is to combine 2 anti-HIV
      medications, efavirenz (EFZ) and nelfinavir (NFV) to treat HIV-positive children and to find
      an appropriate dose of EFZ to use in combination with NFV. Cohort II: The purpose of this
      study is to see how safe it is to give EFZ syrup combined with NFV and to measure the levels
      of EFZ and NFV in the blood. (This purpose reflects a change from the original since there
      are now 2 different cohorts of patients.) EFZ is an effective anti-HIV medication that easily
      can be combined with other drugs to treat HIV. This is an early study to determine a safe and
      effective dose for HIV-positive children. This study also will examine the correct dose of
      NFV to use in combination with EFZ.
    

Detailed description: 
      The demonstrated antiviral activity, tolerability, and pharmacokinetic properties of DMP 266
      and its utility in combination with other agents make DMP 266 an attractive agent for use in
      HIV-infected pediatric patients. However, the tolerability of DMP 266 in the pediatric
      population must be evaluated, and appropriate dosing instructions need to be developed. By
      following the patients over time, the antiviral activity of DMP 266-containing regimens will
      be documented. Dosage guidelines for children can then be developed following analysis of the
      results.

      This is a 48-week [AS PER AMENDMENT (APA) 12/21/98:104-week] [APA 5/8/00: 208-week] study. It
      is designed to minimize the chance that ineffective therapy is provided (short
      dose-escalation phase) and utilizes an area under the concentration time curve (AUC) to
      establish plasma levels of DMP 266 and nelfinavir in the pediatric population that are both
      tolerable and efficacious. [APA 5/26/98: Patients are stratified by age into Cohorts I and
      II] and receive EFV concurrently with NFV.

      [APA 5/26/98: The initial starting dose of DMP 266 for patients in Cohort II is higher than
      the initial starting dose for patients in Cohort I.] [APA 12/21/98: The initial starting dose
      for patients in Stratum 1 of Cohort II is higher than the initial starting dose for patients
      in Cohort I and Stratum 2 of Cohort II.] The initial target AUC for DMP 266 is between 190
      and 380 micromoles/h (uM/h). The initial starting dose (based on a 70 kg patient and adjusted
      for each patient's weight) for the first 6 patients is adjusted on the basis of tolerability
      and plasma concentrations of DMP 266 after 2 weeks of daily doses. If at least 4 of the first
      6 patients attain a tolerable dose (dose at which no more than 2 of 6 patients experience
      Grade 3 or worse toxicity) and target AUC, additional patients may continue to be accrued.
      However, if any of the initial 6 patients experience life-threatening toxicity, further
      accrual is suspended. [APA 5/26/98: An assessment of the tolerability and plasma
      concentrations of EFV is not required in an initial group of Cohort II patients. Individual
      dose is based on pharmacokinetic sampling.] Patients receive a given starting dose of DMP 266
      and continue on that dose until individual dose adjustments are needed. If a patient's
      starting dose is tolerated but the target AUC is not achieved, the dose is increased. If the
      starting dose is well tolerated and target AUC achieved, no adjustment in starting dose is
      given to future patients. If no tolerated dose achieving at least an AUC of 150 micromoles/h
      is reached in 4 of 6 patients, the study is suspended and alternative dosing regimens, e.g.,
      twice-daily dosing, are considered.

      A patient's current dose of DMP 266 is adjusted based on how the dose is tolerated and
      whether the target AUC is achieved. If a patient does not achieve an AUC of greater than 110
      micromoles/h and experiences Grade 3 or worse toxicity, the patient is discontinued from the
      study.

      [APA 12/21/98: The dose of NFV is the same for patients in Cohort I and Stratum 2 of Cohort
      II; the dose for patients in Stratum 1 of Cohort II is higher.] The minimum target AUC for
      NFV is 10 mg x h/L. Doses are adjusted for an individual child if AUC falls below threshold
      at Week 2 or 6. Children with weight no greater than 30 kg receive a lower dose than children
      with weight greater than 30 kg or Tanner Stage IV. [APA 5/8/00: The first group of 6 patients
      receives the initial dose of NFV. If none of the 6 patients falls below the target AUC, the
      remainder of the sample is accrued and treated at this dose. If more than 1 of the 6 patients
      fall below the target AUC, then another group of 6 patients is accrued and treated at the
      next higher dose. If exactly 1 of the 6 patients falls below the target AUC, 2 more patients
      are accrued and treated at the same dose. If 1 of these 2 patients falls below the target
      AUC, another group of 6 patients is tested on the next higher dose. If neither of these 2
      patients falls below the target AUC, then the remainder of the sample is accrued and treated
      at this dose. The dose is escalated until a dose that meets the above criteria is achieved or
      further dose escalation is prohibited due to toxicity.] The duration of therapy is 48 [APA
      12/21/98:104] [APA 5/8/00: 208] weeks.
    

Intervention name(s): Nelfinavir mesylate; Efavirenz
Intervention type(s): Drug; Drug
Intervention MeSH terms: Efavirenz; Nelfinavir
Primary purpose: Treatment
Keywords: Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Protease Inhibitors; Nelfinavir; Reverse Transcriptase Inhibitors; Area Under Curve; efavirenz