Safety, Tolerability, and Anti-HIV Activity of DMP 266 (Efavirenz) in Combination With Nelfinavir in HIV-Positive Children

A Phase I/II, Open-Label, AUC-Controlled Study to Determine the Pharmacokinetics, Safety, Tolerability, and Antiviral Activity of DMP 266 (Efavirenz) in Combination With Nelfinavir in Children

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Nelfinavir mesylate; Drug: Efavirenz

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.

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 1

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 009365067
    • Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS
  • San Juan, Puerto Rico, 009367344
    • San Juan City Hosp. PR NICHD CRS
• United States
  • California
    • Long Beach, California, United States, 90801
      • Long Beach Memorial Med. Ctr., Miller Children's Hosp.
    • Los Angeles, California, United States
      • UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS
    • Los Angeles, California, United States
      • Usc La Nichd Crs
    • Oakland, California, United States
      • Children's Hosp. & Research Ctr. Oakland, Ped. Clinical Research Ctr. & Research Lab.
    • San Diego, California, United States
      • UCSD Maternal, Child, and Adolescent HIV CRS
    • Torrance, California, United States
      • Harbor - UCLA Med. Ctr. - Dept. of Peds., Div. of Infectious Diseases
  • District of Columbia
    • Washington, District of Columbia, United States, 20060
      • Howard Univ. Washington DC NICHD CRS
  • Florida
    • Jacksonville, Florida, United States, 32209
      • Univ. of Florida Jacksonville NICHD CRS
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane/LSU Maternal/Child CRS
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Univ. of Maryland Med. Ctr., Div. of Ped. Immunology & Rheumatology
  • Massachusetts
    • Boston, Massachusetts, United States, 021155724
      • HMS - Children's Hosp. Boston, Div. of Infectious Diseases
    • Worcester, Massachusetts, United States, 016550001
      • WNE Maternal Pediatric Adolescent AIDS CRS
  • Mississippi
    • Jackson, Mississippi, United States, 39213
      • Univ. of Mississippi Med. Ctr Children's Hosp.
  • New York
    • Bronx, New York, United States, 10457
      • Bronx-Lebanon Hosp. IMPAACT CRS
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Med. Ctr., Children's Hosp. at Downstate NICHD CRS
    • New York, New York, United States, 10037
      • Harlem Hosp. Ctr. NY NICHD CRS
    • New York, New York, United States
      • NYU Med. Ctr., Dept. of Medicine
    • New York, New York, United States, 10029
      • Metropolitan Hosp. Ctr.
    • New York, New York, United States
      • Nyu Ny Nichd Crs
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • St. Christopher's Hosp. for Children
    • Philadelphia, Pennsylvania, United States, 191044318
      • The Children's Hosp. of Philadelphia IMPAACT CRS
  • Tennessee
    • Memphis, Tennessee, United States
      • St. Jude/UTHSC CRS
  • Texas
    • Houston, Texas, United States
      • Texas Children's Hosp. CRS
  • Washington
    • Seattle, Washington, United States
      • Seattle Children's Hospital CRS
    • Seattle, Washington, United States
      • UW School of Medicine - CHRMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Children may be eligible for this study if they:

• Are HIV-positive.
• Are between 3 months and 16 years old (consent of parent or legal guardian required). (These age requirements reflect a change.)
• Have a plasma viral load of at least 400 copies/ml at screening.
• Agree to practice abstinence or use effective methods of birth control during the study.
• Are able to take oral medication and comply with study requirements.
• Are taking at least 1 nucleoside reverse transcriptase inhibitor (NRTI), such as zidovudine (ZDV) or stavudine (d4T). Patients can begin taking NRTIs at the beginning of the study.

Exclusion Criteria

Children will not be eligible for this study if they:

• Have had more than 2 episodes of moderate to severe diarrhea or vomiting lasting more than 4 days within 3 months prior to study entry.
• Are allergic to EFZ or NFV.
• Have any disease, including hepatitis, cancer, or an active opportunistic (HIV-associated) infection.
• Are pregnant or breast-feeding.
• Are taking any other experimental drugs or certain medications.
• Have ever taken protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Study Chair: Stuart Starr; Study Chair: Courtney Fletcher

Publications and helpful links

General Publications

• Brundage RC, Fletcher CV, Fiske WD, Kornhauser DM, McNamara J, Mofenson L, Starr SE. Pharmacokinetics of an efavirenz suspension in children. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:147 (abstract no 424)
• Fletcher CV, Fenton T, Powell C, Anderson PL, Brundage RC, Spector SA, Starr SE. Pharmacologic characteristics of efavirenz (EFV) and nelfinavir (NFV) associated with virologic response in HIV-infected children. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 259)
• Saitoh A, Hsia K, Fenton T, Powell CA, Christopherson C, Fletcher CV, Starr SE, Spector SA. Persistence of human immunodeficiency virus (HIV) type 1 DNA in peripheral blood despite prolonged suppression of plasma HIV-1 RNA in children. J Infect Dis. 2002 May 15;185(10):1409-16. Epub 2002 Apr 30.
• Fletcher CV, Brundage RC, Fenton T, Fiske WD, Kornhauser D, McNamara J, Mofenson L, Starr SE. Efavirenz (EFV) and nelfinavir (NFV) pharmacokinetics (PK) in HIV-infected children participating in an area under the curve (AUC) controlled trial. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:136 (abstract no 366)
• Starr SE, Fletcher CV, Spector SA, Yong FH, Fenton T, Brundage RC, Manion D, Ruiz N, Gersten M, Becker M, McNamara J, Mofenson LM, Purdue L, Siminski S, Graham B, Kornhauser DM, Fiske W, Vincent C, Lischner HW, Dankner WM, Flynn PM. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team. N Engl J Med. 1999 Dec 16;341(25):1874-81. doi: 10.1056/NEJM199912163412502.
• Spector SA, Hsia K, Yong FH, Cabral S, Fenton T, Fletcher CV, McNamara J, Mofenson LM, Starr SE. Patterns of plasma human immunodeficiency virus type 1 RNA response to highly active antiretroviral therapy in infected children. J Infect Dis. 2000 Dec;182(6):1769-73. doi: 10.1086/317621. Epub 2000 Oct 26.
• Saitoh A, Singh KK, Powell CA, Fenton T, Fletcher CV, Brundage R, Starr S, Spector SA. An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. AIDS. 2005 Mar 4;19(4):371-80. doi: 10.1097/01.aids.0000161766.13782.2f.
• Saitoh A, Fenton T, Alvero C, Fletcher CV, Spector SA. Impact of nucleoside reverse transcriptase inhibitors on mitochondria in human immunodeficiency virus type 1-infected children receiving highly active antiretroviral therapy. Antimicrob Agents Chemother. 2007 Dec;51(12):4236-42. doi: 10.1128/AAC.00893-07. Epub 2007 Sep 24.

Study record dates

Study Major Dates

• Study Start: October 1, 1997
• Study Completion (Actual): December 1, 2002

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): October 29, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Reverse Transcriptase Inhibitors; HIV Protease Inhibitors; Nelfinavir; Dose-Response Relationship, Drug; efavirenz; Area Under Curve
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Nelfinavir; Efavirenz
• Other Study ID Numbers: ACTG 382; 10105 (DAIDS ES); PACTG 382