Clinical Trial Result Information

Title of Study:
Phase I/II Pharmacokinetic and Safety Study of T-20 in Combination With an Optimized Antiretroviral Regimen in HIV Infected Children and Adolescents

Fast Facts:

Protocol number:	NV16056
Sponsor:	Hoffmann-La Roche Inc.; Trimeris Inc.
Company division:	Pharmaceutical
Product name:	Fuzeon
Generic name:	enfuvirtide
Phase of development:	II
Therapeutic area, approved indication:	Treatment of HIV-1 infection
Date of report:	6/18/2002

Clinical study summary:
This was a phase II, multicenter, open-label, nonrandomized, noncomparative study of enfuvirtide (Fuzeon) dosed subcutaneously (sc) at 2.0 mg/kg twice daily ( bid) (not to exceed 90 mg deliverable dose) for 48 weeks which evaluated the exposure of Fuzeon in children and adolescents with Human Immunodeficiency virus Type-1 ( HIV-1). (Interim study results are presented here.)

Study center(s) :
10 centers in the United States.

Objectives:
Primary: To evaluate the exposure of Fuzeon in a pediatric population.

Secondary: To determine the tolerability and safety of Fuzeon chronic dosing after 24 and 48 weeks of therapy.

Methodology:
Patients were stratified into 2 age groups; Group 1: children >=3 and <12 years of age; and Group 2: adolescents >=12 and <=16 years of age. Samples for HIV-1 genotype and phenotype resistance testing were to be obtained at screening to aid in the selection of the concomitant ARV agents. At the same time as Fuzeon initiation, patients were to start an optimized oral ARV regimen based on the patient's prior treatment history, previous resistance test results, and the results of genotype and phenotype testing performed at screening. The first 12 patients enrolled per age group were to be involved in intensive pharmacokinetic (PK) sampling at Week 1.

Number of patients (planned/analyzed):
25

Diagnosis and main criteria for inclusion:
HIV-1 infected children and adolescents 3 to 16 years of age; HIV-1 RNA >=5000 copies/mL; prior experience with at least 1 agent each from 2 of the 3 classes of approved oral antiretroviral (ARV) agents (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, or protease inhibitors) for >=3 months; on stable therapy (could have been no ARV therapy) for >=4 weeks prior to study entry; willingness and ability to take >=3 other ARV agents at therapeutic doses in addition to Fuzeon.

Test product, dose and mode of administration or test procedure:
Fuzeon, 2.0 mg/kg/sc/bid to a maximum of 90 mg.

Duration of treatment:
48 weeks

Reference therapy, dose and mode of administration or reference procedure:
Not applicable.

Criteria for evaluation (efficacy, safety):
PK: AUC_12h, C_max, C_trough, t_max (enfuvirtide only), ratio of AUC_12h of enfuvirtide metabolite/parent.

Safety and Tolerability: Clinical adverse events, laboratory abnormalities, local injection site reactions.

Statistical methods:
Standard noncompartmental techniques were used to assess AUC_12h, C_max, C_trough, and t_max from the intensive sampling data sets.

Safety: summaries of clinical adverse events, summaries of laboratory safety data, and summaries of marked laboratory abnormalities. Tolerability (based on summaries of premature withdrawals due to adverse events), and local injection site reactions were assessed.

Summary (efficacy, safety, other results):
PK (Interim): Fuzeon 2.0 mg/kg sc bid up to 90 mg deliverable exhibits a mean±SD AUC12h of 51.4±22.8 µg•hr/mL, derived from the values of 49.1±11.3 in children and 52.7±27.4 in adolescents, respectively. The PK data from this study supports the conclusion that consistent Fuzeon exposure in pediatric patients is achieved by body-weight-based dosing.

Safety (Interim): Overall, 15/25 (60%) patients (4 children and 11 adolescents) reported a total of 42 adverse events. The most commonly reported adverse events (>=3 patients) were injection site reactions, followed by diarrhea, nausea, and upper respiratory tract infection. Most of the adverse events reported (including injection site reactions) were mild to moderate in intensity. There were no deaths or withdrawals due adverse events reported in this study. One to 2 grade shifts in laboratory values were observed.

Conclusions:
Body-weight-based twice-daily dosing of Fuzeon at 2.0 mg/kg is appropriate in HIV-infected children and adolescents. Fuzeon added to a background oral ARV regimen was safe and well tolerated.

Publications (references, if available):
10) Bellibas SE, Siddique Z, Dorr A, et al. Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy. Pediatric Infectious Diseases Journal 2004; 23: 1137-1141