Roche trials database

Protocol number:

NV16391

Title of Study:

A phase III, open-label, safety study of enfuvirtide (HIV-1 fusion inhibitor) in combination with oral antiretrovirals in patients who are unable to construct a viable regimen.

Sponsor:

Hoffmann-La Roche Inc.

Company division:

Pharmaceutical

Product name:

Fuzeon

Generic name:

enfuvirtide

Therapeutic area:

• HIV Infections

Clinical study summary:

This was a multi-center, open-label, uncontrolled, single arm safety and tolerability study for patients with advanced HIV disease who were unable to construct a viable regimen from among approved antiretroviral agents. No restriction was placed on concurrent background antiretroviral regimen and background regimen was not provided by the study. Adult patients received 90 mg of Fuzeon (enfuvirtide/T-20) 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.

Study center(s):

180 centers in Australia, Belgium, Brazil, Canada, France, Germany, Italy, Mexico, Netherlands, Portugal, Spain, Sweden, Switzerland, UK and USA.

Phase of development:

III

Objectives:

To assess safety and tolerability of Fuzeon (enfuvirtide) in patients with advanced HIV disease who were unable to construct a viable regimen from among approved antiretroviral agents.

Methodology:

This was a Phase III, multi-center, open-label, uncontrolled safety and tolerability study of Fuzeon administered to HIV-I infected adults, adolescents, or children by sc injection. 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):

708 patients (687 adult and 21 pediatric patients) were enrolled and included in the safety analysis population.

Diagnosis and main criteria for inclusion:

HIV-1/AIDS-infected male and female adults, adolescents or children (≥ 6 years of age) with HIV-1 RNA viral load ≥ 10,000 copies/mL and CD4+ lymphocyte count ≤ 100 cells/mm³, both while on HAART, who were unable to construct a viable regimen from among approved antiretroviral agents.

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 grade 4 laboratory abnormalities or those otherwise meeting criteria for "serious" were reported as SAEs. 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. Serious 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 had at least one post-baseline safety assessment.

Summary (efficacy, safety, other results):

A total of 708 patients enrolled in this study and all (100%) qualified for inclusion in the analysis. A total of 343 (49.9%) adult patients discontinued from the study. One hundred fifty-one (22.0%) adult patients withdrew for safety reasons: 57 (8.3%) withdrew due to an adverse event, 1 (0.1%) withdrew due to a laboratory abnormality, 34 (4.9%) withdrew because of a local ISR and 59 (8.6%) withdrew due to death. The remaining 192 (27.9%) adult patients discontinued for non-safety reasons. A total of 4 (19.0%) pediatric patients withdrew from the study, three due to an adverse event and 1 due to an insufficient therapeutic response. A total of 204 (29.7%) adult and 4 (19.0%) pediatric patients experienced SAEs, but only 30 (4.4%) adult patients and 1 (4.8%) pediatric patient experienced SAEs related to Fuzeon. The most common SAEs occurring in adults were AIDS (2.5%) and pancreatitis (2.6%). No SAE was reported by more than one pediatric patient. A total of 80 (11.6%) adult and 2 (9.5%) pediatric patients experienced at least one adverse event which resulted in discontinuation from the study. Local ISR (2.9%) was the most common AE in adults which led to study discontinuation. The 2 pediatric patients discontinued due to pneumonia and renal failure, respectively. A total of 73 (10.6%) adult patients and 1 pediatric patient died during the study. The most common reason for the deaths occurring in the adult population were AIDS (1.5%) and multi-organ failure (1.2%). The pediatric patient died from cachexia. Twenty (2.9%) adult patients discontinued treatment due to a local ISR reported as an AE. Two of these events (abdominal abscess, and injection site abscess) were considered serious. No pediatric patients discontinued treatment due to an ISR. Thirty-seven (5.4%) adult patients experienced an overall grading for pain and discomfort of Grade 4 and/or an ISR that led to discontinuation. The majority (62.2%) of these patients experienced local ISR signs and symptoms with a maximum severity of Grade 3. Fourteen (2.0%) adult patients and 1 pediatric patient reported pneumonia AEs. Three patients experienced pneumonia AEs that were considered by the investigator to be related to Fuzeon treatment. Two patients (one adult and one pediatric) experienced pneumonia AEs, considered related to Fuzeon treatment, that led to study discontinuation. A total of 99 (14.4%) adult patients experienced at least one serious AIDS defining event; of these only 7 patients discontinued Fuzeon treatment as a result. The most common serious AIDS defining events were candidiasis (4.1%) and cytomegalovirus (2.9%). No pediatric patients experienced an AIDS defining event.

Conclusions:

Fuzeon added to a background oral ARV regimen was well tolerated. The majority (96%) of patients did not experience SAEs that were considered related to study treatment. The majority (89%) of patients did not discontinue Fuzeon treatment due to AEs. No pattern in the types of serious and non-serious adverse events reported was observed.

Date of report:

01.11.2005

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