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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00000893

Collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)

103

Enrollment

Locations

Duration (Months)

3.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Nelfinavir mesylate Drug: Efavirenz	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

103 participants

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

Study Start Date :

Oct 1, 1997

Actual Study Completion Date :

Dec 1, 2002

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Months to 16 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

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