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HIV InfectionsPhase 1NCT00000893

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

A Phase 1 study testing Nelfinavir mesylate and Efavirenz in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 27 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 3 months to 16 years
Conditions the study is for
HIV Infections
What is being tested?
Nelfinavir mesylate and Efavirenz
How many people
103 participants
Where
27 sitesin 2 countries
Study dates
Oct 1997to Dec 2002
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 months to 16 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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.

Who cannot join

  • 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).

Trial locations and contacts

27 sites in 2 countries.

27 sites in 2 countries

United States25 sites

  • Univ. of Maryland Med. Ctr., Div. of Ped. Immunology & Rheumatology

    Baltimore, Maryland, 21201

  • HMS - Children's Hosp. Boston, Div. of Infectious Diseases

    Boston, Massachusetts, 021155724

  • SUNY Downstate Med. Ctr., Children's Hosp. at Downstate NICHD CRS

    Brooklyn, New York, 11203

  • Texas Children's Hosp. CRS

    Houston, Texas

  • Univ. of Mississippi Med. Ctr Children's Hosp.

    Jackson, Mississippi, 39213

  • Univ. of Florida Jacksonville NICHD CRS

    Jacksonville, Florida, 32209

  • Long Beach Memorial Med. Ctr., Miller Children's Hosp.

    Long Beach, California, 90801

  • UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS

    Los Angeles, California

  • Usc La Nichd Crs

    Los Angeles, California

  • St. Jude/UTHSC CRS

    Memphis, Tennessee

  • Tulane/LSU Maternal/Child CRS

    New Orleans, Louisiana, 70112

  • Metropolitan Hosp. Ctr.

    New York, New York, 10029

  • Harlem Hosp. Ctr. NY NICHD CRS

    New York, New York, 10037

  • NYU Med. Ctr., Dept. of Medicine

    New York, New York

  • Nyu Ny Nichd Crs

    New York, New York

  • Children's Hosp. & Research Ctr. Oakland, Ped. Clinical Research Ctr. & Research Lab.

    Oakland, California

  • The Children's Hosp. of Philadelphia IMPAACT CRS

    Philadelphia, Pennsylvania, 191044318

  • St. Christopher's Hosp. for Children

    Philadelphia, Pennsylvania

  • UCSD Maternal, Child, and Adolescent HIV CRS

    San Diego, California

  • Seattle Children's Hospital CRS

    Seattle, Washington

  • UW School of Medicine - CHRMC

    Seattle, Washington

  • Bronx-Lebanon Hosp. IMPAACT CRS

    The Bronx, New York, 10457

  • Harbor - UCLA Med. Ctr. - Dept. of Peds., Div. of Infectious Diseases

    Torrance, California

  • Howard Univ. Washington DC NICHD CRS

    Washington D.C., District of Columbia, 20060

  • WNE Maternal Pediatric Adolescent AIDS CRS

    Worcester, Massachusetts, 016550001

Other trials in United States

Puerto Rico2 sites

  • Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS

    San Juan, 009365067

  • San Juan City Hosp. PR NICHD CRS

    San Juan, 009367344

Other trials in Puerto Rico

About this study

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

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.

Read the 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.

Conditions
HIV Infections
Being tested
Nelfinavir mesylate, Efavirenz
Keywords
Dose-Response Relationship, Drug, Drug Therapy, Combination, HIV Protease Inhibitors, Nelfinavir, Reverse Transcriptase Inhibitors, Area Under Curve, efavirenz
Medical subject headings
HIV Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nelfinavir mesylateDrug

  • EfavirenzDrug

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Aug 2001 (estimated)
  2. Study startOct 1997
  3. Study completionDec 2002

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Enrolment
103 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00000893
Sponsor's protocol ID
ACTG 382
Other IDs
10105, PACTG 382
Status last verified
Oct 2021
First submitted
2 Nov 1999
Last updated
29 Oct 2021
Results posted
No

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)

  • 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.

    PubMed 10601506

  • 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.

    PubMed 11069252

  • 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.

    PubMed 15750390

  • 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.

    PubMed 17893156

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Nelfinavir mesylate and Efavirenz in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 27 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 27 sites in United States, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00000893, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2021.

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