Clinical Trial Result Information

Protocol number
NV16054 (T20-301). 96 week combined analysis

Title of Study
A phase 3, open-label, randomized, active-controlled study assessing the efficacy and safety of T20/RO29-9800 (enfuvirtide [ENF]; HIV-1 Fusion Inhibitor) in combination with an optimized background regimen versus optimum background regimen alone in patients with prior experience and/or prior documented resistance to each of the three classes of approved antiretrovirals (nucleoside reverse transcriptase, non-nucleoside reverse transcriptase, and protease inhibitors).

Sponsor
Hoffmann-La Roche Inc; Trimeris Inc

Company division
Pharmaceutical

Product name
Fuzeon

Generic name
enfuvirtide

Therapeutic area
HIV Infections

Clinical study summary
NV16054 and BV16052 were randomized, open-label, active-controlled, parallel-group, multicenter, studies designed to assess the efficacy and safety of Fuzeon (90mg twice daily subcutaneously) in combination with an OB regimen of ARVs. The two studies were analysed separately up to 48 weeks. This report is a combined analysis of a 48 week optional treatment extension, to week 96.

Study center(s)
NV16054: 48 centers in Brazil, Canada, Mexico and the United States. BV16052: 67 centers in Australia, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, Switzerland and United Kingdom.

Phase of development
III

Objectives
The objective of the 48-week optional treatment extension to the study was to evaluate the long term safety and long term efficacy of Fuzeon in patients randomized to the Fuzeon + OB treatment group and in patients who switched to Fuzeon + OB during the study.

Methodology
Each study consisted of a 6 week screening period, a 48 week treatment period, an optional 48 week treatment-extension period, continuation beyond the 48-week extension period until 12 weeks after commercial availability of Fuzeon, plus a 4 week safety follow-up period.
In each study, qualifying patients were randomized to one of two treatment groups: Fuzeon + OB or OB in a 2:1 ratio. Patients initially randomized to the OB treatment group, who met the criteria for virological failure after Week 8 and who wished to start Fuzeon treatment, were to receive Fuzeon in combination with a revised OB regimen. Patients initially randomized to the OB regimen who wished to continue for the 48-week optional treatment extension phase were switched to the Fuzeon + OB regimen. Patients randomized to the Fuzeon + OB treatment group who met criteria for virological failure after Week 8 could continue to receive Fuzeon, if the patients and their physicians felt that there was sufficient benefit. These patients were encouraged to change their OB regimen at the time of virological failure, if they decided to continue Fuzeon.

Number of patients (planned/analyzed)
A total of 1013 patients, 673 Fuzeon + OB and 340 OB randomized into the 2 studies.

Diagnosis and main criteria for inclusion
HIV-1 infected males and females 16 years or older with plasma HIV-1 RNA ≥5000 copies/mL and prior experience and/or prior documented resistance to each of the three classes of approved ARVs, on a stable ARV regimen (could have been no ARV therapy) for ≥4 weeks prior to study entry.

Test product, dose and mode of administration or test procedure
Fuzeon, 90 mg/sc/bid.

Duration of treatment
96 weeks.

Reference therapy, dose and mode of administration or reference procedure
Individualized OB regimen based on patient’s treatment history and viral genotypic and phenotypic ARV resistance testing.

Criteria for evaluation (efficacy, safety)
Efficacy: Viral load. CD4+ Cell Counts. Quality of Life (physical function and mental health, scales of the MOS-HIV questionnaire).
Safety: Adverse events, deaths, serious adverse events, adverse events leading to withdrawal, AIDs defining events, local injection site reactions, clinical laboratory tests and vital signs.

Statistical methods
Efficacy: Three viral suppression categories (< 400 copies/mL HIV-1 RNA, < 50 copies/mL HIV-1 RNA, or ≥ 1.0 log drop from baseline), were used to analyze:
The proportions of patients with viral suppression; patients’ Week 48 and Week 96 viral suppression status; the duration of viral suppression for patients who responded prior to Week 24, and who responded prior to Week 48.
CD4+ T cell count improvements from baseline (in categories ≥ 50, ≥ 100, or ≥ 200 cells/μL) were provided over time.
Safety: Adverse events, SAEs, deaths, and ADEs were summarized by body system for the Fuzeon + OB, switch, and combined Fuzeon treatment groups. Laboratory results were summarized over time.

Summary (efficacy, safety, other results)
Summary of Results: Efficacy: Responder rates were calculated for virological and immunological response using a modified FDA algorithm. In both parameters, the percentage of patients in each response category decreased slightly from Week 48 to Week 96. However, the percentages of Fuzeon + OB patients in each response category at Week 96 were still approximately double those of OB patients at Week 48.

* The denominator for categorical analysis represents the Baseline population, not the actual population at that study visit (discontinued or missing are considered failures).

Mean HIV-1 RNA levels decreased continuously throughout the study, from 5.10 copies/mL at baseline to 2.93 copies/mL at Week 96. 
In most patients, maximum virological response was reached within 24 weeks of treatment; <1% of patients (≥ 1 log drop from baseline) to 17% of patients (< 50 copies/mL) took an additional 24 weeks to reach maximum response. Mean duration of suppression was a little over a year in each viral load category. However, additional data from patients who did not rebound prior to exiting the study was not captured. Thus, actual suppression may have been longer in some patients.

At week 96, the majority of patients (62% to 72%) had improved or maintained the virological response reached at Week 48.
Mean CD4⁺ T cell counts increased throughout the study, from 136.2 cells/μL at baseline to 325.5 cells/μL at Week 96, for a total mean increase of 166.3 cells/μL.

Generally, MOS-HIV questionnaire mean values showed improvement through Week 48. Following Week 48, most scores remained approximately the same while some (health transition, role function, social function, general health, and health distress domain mean values) continued to improve through Week 96.

Switch patients: Most patients who switched from OB treatment to Fuzeon + OB treatment (66%) did so due to virological failure. Although Switch baseline demographic values revealed a small decrease over baseline in mean viral load (4.85 log10 HIV-1 RNA vs 5.1 log10 HIV-1 RNA) and an increase over baseline in mean CD4⁺ T cell counts (145 cells/mm³ vs 115 cells/mm³), in many cases they also revealed a loss in genotypic sensitivity to 1 or more medications (47% switch patients), a loss in phenotypic sensitivity to 1 or more medications (56% switch patients), and/or an increase in the number of primary HIV-1 mutations (38% switch patients). Viral load and CD4⁺ T cell counts over time are summarized below.

* The denominator for categorical analysis represents the Baseline population, not the actual population at that study visit (discontinued or missing are considered failures).

Safety: The most commonly occurring AEs were diarrhea (34%), nausea (23%), and fatigue (23%). All other AEs occurred in less than 20% of the combined Fuzeon population.

The majority (89%) of adverse events reported during the study were mild or moderate in intensity, 9% were severe, and 2% were considered life threatening. Diarrhea and fatigue were the most frequently occurring severe AEs.
A total of 84% of patients in the combined Fuzeon treatment groups experienced at least one AE that was considered related to study medication. Diarrhea was the single most commonly reported treatment-related AE, occurring in 24% of the combined Fuzeon population. Nausea and fatigue occurred in 17% and 15% of the combined Fuzeon population, respectively.
Forty-four patients died in association with the study. The single most common cause of death was end stage AIDS. Twenty-nine (29) patients died within the 96-week study period or within 28 days of the last dose of study medication. Of these, only 2 (both occurring within the first 48 weeks of the study) were considered to be treatment-related (suicide and membranoproliferative glomerulonephritis).

SAEs were experienced by 39% of patients in each of the Fuzeon + OB and switch treatment groups. The most common of these were increase in blood CPK, increase in GGT, and neutropenia (in 3% of patients in both the switch and Fuzeon + OB treatment groups). Most SAEs occurred in only 1 or 2 patients (<1%) in any treatment group.

A total of 13% of patients who were exposed to Fuzeon treatment had adverse or AIDS-defining events leading to withdrawal. The most common events leading to withdrawal were vomiting and depression, each of which occurred in < 1% of the combined Fuzeon population.

Definitive or presumptive ADEs were experienced by 13.4% of the combined Fuzeon population. Candidiasis and cytomegalovirus were the most commonly occurring. Other ADEs (category C) were reported in 6.5% of the combined Fuzeon population; the most common was viral infection (3.6%).

There was no indication of an increase in the frequency or severity of ISR with prolonged dosing. Although the percentage of patients with injection site reactions did not decrease over time (63% to 75% at each visit), the individual signs and symptoms of injection site reactions generally decreased slightly or remained approximately the same, and most reactions were associated with only mild tenderness at the injection site. In addition, discomfort associated with injection site reactions was tolerable for most patients, as only 7% of patients in the Fuzeon + OB treatment group and 10% of patients in the switch group withdrew from the study due to injection site reactions.

Mean and median laboratory values were generally within standard reference ranges and showed little variation over time.
No clinically significant changes from baseline were observed in mean values for blood pressure, heart rate, temperature, or Karnofsky status score.

Conclusions
The results of this 48+ week extension study showed continued efficacy of Fuzeon beyond 48 weeks, with no new or increased safety signals. Overall, the results support a favourable risk/benefit ratio for long-term Fuzeon use.

Publications (references, if available)
Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in North and South America. New England Journal of Medicine, 2003; 348:2175-85.
Efficacy of Enfuvirtide in Patients Infected with Drug-Resistant HIV-1 in Europe and Australia. New England Journal of Medicine, 2003; 348:2186-95.
Nelson M, Keikawus A, Bonaventura C et al. Durable efficacy over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only. J Acquir Immune Defic Syndr 2005; 40:404-412.
Trottier B, Walmsley S, Reynes J et al. Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks. J Acquir Immune Defic Syndr 2005; 40:413-421.

Date of report
6/1/2005