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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00000893
First received: November 2, 1999
Last updated: May 17, 2012
Last verified: May 2012
  Purpose

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.


Condition Intervention Phase
HIV Infections
Drug: Nelfinavir mesylate
Drug: Efavirenz
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Enrollment: 103
Study Completion Date: December 2002
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.

  Eligibility

Ages Eligible for Study:   3 Months to 16 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00000893

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

Additional Information:
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 C, Christopherson C, Fletcher CV, Starr SE, Spector SA. HIV-1 DNA persists in PBMC of children on HAART despite prolonged suppression of plasma HIV-1 RNA. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 685B)
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)

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00000893     History of Changes
Other Study ID Numbers: ACTG 382, 10105, PACTG 382
Study First Received: November 2, 1999
Last Updated: May 17, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Dose-Response Relationship, Drug
Drug Therapy, Combination
HIV Protease Inhibitors
Nelfinavir
Reverse Transcriptase Inhibitors
Area Under Curve
efavirenz

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Efavirenz
Reverse Transcriptase Inhibitors
Nelfinavir
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
HIV Protease Inhibitors
Protease Inhibitors
Anti-HIV Agents

ClinicalTrials.gov processed this record on September 18, 2014