Clinical Trial Result Information

Protocol number
NV16390 (T20-304)

Title of Study
A phase III, open-label, uncontrolled, ‘roll over’ safety study of T-20/RO 29-9800 (HIV-1 fusion inhibitor) in combination with free choice of background antiretrovirals, in patients who have participated in prior T-20 clinical studies.

Sponsor
Hoffmann-La Roche Inc.

Company division
Pharmaceutical

Product name
Fuzeon

Generic name
enfuvirtide

Therapeutic area
HIV Infections

Clinical study summary
This was an open-label, uncontrolled, single-arm roll-over safety study for patients who were actively participating in or had completed Fuzeon clinical studies. No restriction was placed on concurrent background antiretroviral regimen and the background regimen was not provided by the study. Adult patients received 90 mg of Fuzeon twice daily by subcutaneous (sc) injection in addition to the background regimen chosen by the investigator. Pediatric patients received 2.0 mg/kg of Fuzeon up to the adult maximum of 90 mg twice daily by sc injection in addition to the background regimen chosen by the investigator.

Study center(s)
44 centers in Belgium, Brazil, Canada, France, Italy, Mexico, Thailand and USA.

Phase of development
III

Objectives
To collect additional safety data (local injection site reactions, discontinuations, serious adverse events, serious AIDS defining events) on Fuzeon (enfuvirtide/T-20) in HIV injected patients who had already received Fuzeon while participating in clinical studies.

Methodology
Screening was performed on eligible patients between Days -14 to -1. Dosing started on Day 1. Patients returned to the clinic at week 2 for study assessments. Subsequent visits occurred at intervals up to week 48, and every 12 weeks until the end of the study.

Number of patients (planned/analyzed)
209 patients (202 adult and 7 pediatric patients) were enrolled; 208 patients (201 adults and 7 pediatric patients) were included in the safety analysis population.

Diagnosis and main criteria for inclusion
HIV-1/AIDS-infected male and female adults, adolescents or children (>=6 months of age). Patients must have been actively participating in or have completed a Fuzeon clinical study within the last 12 months.

Test product, dose and mode of administration or test procedure
Fuzeon (enfuvirtide). Adult dose: 90 mg sc injection bid (deliverable dose). Pediatric dose: 2 mg/kg sc injection bid up to a maximum of 90 mg deliverable.

Reference therapy, dose and mode of administration or reference procedure
No restriction was made on concurrent background antiretroviral regimen nor was it provided through the study. The protocol required the investigator to select antiretrovirals for concomitant administration with Fuzeon based on the patient’s prior history and prior/current antiretroviral resistance testing.

Criteria for evaluation (efficacy, safety)
Safety: Safety assessments included deaths, serious adverse events (SAEs) and withdrawals due to adverse events (AEs) or injection site reactions (ISRs). Only laboratory abnormalities that were serious or led to discontinuation were recorded as AEs. The overall grading of local ISRs was based on pain and discomfort at every visit. Grade 4 local ISRs based on overall pain and discomfort were reported as SAEs. AIDS defining events were collected; fatal AIDS defining events were reported as SAEs.

Statistical methods
Analyses were performed for the safety analysis population, defined as all patients who were enrolled into the trial and received at least one dose of study drug and a post-baseline safety assessment.

Summary (efficacy, safety, other results)
A total of 209 patients enrolled in this study and 208 (99.5%) qualified for inclusion in the SAP. A total of 46 (22.9%) adult patients prematurely discontinued from the study. Nineteen (9.5%) adult patients withdrew for safety reasons: 7 (3.5%) withdrew due to an adverse event, 10 (5.0%) withdrew because of a local ISR and 2 (1.0%) withdrew due to death. The remaining 27 (13.4%) adult patients discontinued for non-safety reasons. No pediatric patients prematurely discontinued the study. A total of 17 (8.5%) adult patients experienced SAEs, but only 2 patients (1.0%) had a SAE (bacterial pneumonia and injection site infection) considered by the investigator as being related to Fuzeon. The most common SAEs occurring in adults were appendicitis (1.0%), pneumonia (1.0%), bacterial pneumonia (1.0%) and acute renal failure (1.0%). Two SAEs led to death; one patient discontinued study treatment due to bacterial pneumonia and subsequently died, and a second experienced pneumonia and died. No pediatric patients experienced a SAE. A total of 16 (8.0%) adult patients experienced at least one AE which resulted in discontinuation from the study. Local ISR (4.5%) was the most common AE occurring in adults which led to study discontinuation. No pediatric patients discontinued the study due to AEs or SAEs. A total of 5 (2.5%) adult patients died during this study. The reasons for death were as follows: pneumonia, progressive multifocal leukoencephalopathy, septic shock, coronary disease and renal failure. One patient discontinued study treatment due to bacterial pneumonia and subsequently died. No pediatric patients died during this study. Nine (4.5%) adult patients discontinued treatment due to a local ISR reported as AEs. Of those, only one of these events (an injection site abscess) was serious. No pediatric patients discontinued treatment due to an ISR. Eleven (5.5%) adult patients experienced an overall grading for pain and discomfort of Grade 4 and/or an ISR that led to discontinuation or hospitalization. The majority of these patients experienced local ISR signs and symptoms with a maximum severity of Grade 3 (2.0%) or Grade 4 (2.5%). The majority of individually reported local ISR signs and symptoms were Grade 1 (31.3%) and Grade 2 (31.3%). No pediatric patients experienced an overall grading for pain and discomfort of Grade 4 and/or an ISR that led to discontinuation. Five (2.5%) adult patients reported pneumonia, but only 1 case was considered by the investigator to be related to Fuzeon treatment. Two patients experienced pneumonia that led to study discontinuation. No pediatric patients experienced pneumonia. A total of 5 (2.5%) adult patients experienced at least one serious AIDS defining event, all of which were considered to be unrelated to study treatment. Only 1 patient discontinued Fuzeon treatment due to a serious AIDS defining event. The most common serious AIDS defining event was candidiasis (1.0%). No pediatric patients experienced an AIDS defining event.

Conclusions
Fuzeon added to a background oral antiretroviral regimen was well tolerated. The majority (78%) of patients completed the study. All deaths were considered unrelated to study treatment. The majority of SAEs were considered unrelated to study treatment. No pattern in the types of serious and non-serious adverse events reported was observed.

Date of report
11/1/2005

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