Clinical Trial Result Information

Protocol number
BV16052 (48 week analysis)

Title of Study
A Phase III, Open-Label, Randomized, Active-Controlled Study Assessing the Efficacy and Safety of T 20/Ro 29 9800 (enfuvirtide; HIV 1 Fusion Inhibitor) in Combination with an Optimized Background Regimen versus Optimized Background Regimen Alone in Patients with Prior Experience and/or Prior Documented Resistance to Each of the 3 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
Treatment of HIV-1 infection

Clinical study summary
This was a phase III, open-label, randomized, active controlled, parallel-group, multicenter study to assess the efficacy and safety of enfuvirtide (Fuzeon) in combination with an optimized background (OB) regimen of antiretroviral (ARV) therapy for 48 weeks.

Study center(s)
67 centers in Australia, Belgium, France, Germany, Italy, the Netherlands, Spain, Switzerland, Sweden, and the United Kingdom.

Phase of development
III

Objectives
Primary: To demonstrate the durability of efficacy of the Fuzeon + OB regimen as measured by the percentage of patients who responded with a decrease in viral load to meet 1 of 3 defined response categories (<50 copies/mL, 50 to 400 copies/mL, or >=1 log₁₀ decrease from baseline but >400 copies/mL) or had virological failure at Week 24, and maintained or improved their response in each category at Week 48.

Secondary: (1) To evaluate the percentage of patients in each response category (with a >=1.0-log₁₀ drop in log₁₀ HIV-1 RNA, HIV-1 RNA <400 copies/mL, and HIV-1 RNA <50 copies/mL); (2) To compare the safety of Fuzeon + OB to OB; (3) To evaluate the pharmacokinetics of Fuzeon in triple-class experienced and/or resistant patients; (4) To compare the health-related quality of life (QOL) scales derived from the Medical Outcomes Study (MOS)-HIV instrument of Fuzeon + OB with OB alone.

Methodology
After screening , eligible patients were randomized in a 2:1 ratio to receive either Fuzeon + OB or OB alone. Fuzeon was administered by subcutaneous (sc) injection at a dose of 90 mg twice daily (bid). All ARVs in the OB regimen were taken orally. Plasma HIV-1 RNA was measured at baseline, and at intervals throughout the 48-week treatment period. Patients in the OB treatment group with virological failure after Week 8 could switch to Fuzeon treatment in combination with a revised OB regimen. Patients in the Fuzeon + OB treatment group with virological failure after Week 8 were encouraged to change their OB regimen.

Number of patients (planned/analyzed)
512 randomized; 504 intent-to-treat (ITT); 506 safety

Diagnosis and main criteria for inclusion
Human Immunodeficiency Virus Type-1 (HIV-1) infected males and females (>=16 years of age) with plasma HIV 1 RNA >=5000 copies/mL; patients must have had prior experience and/or prior documented resistance to each of the 3 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
48 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)
Primary efficacy parameters: (1) Overall assessment of durability of response across 3 defined response categories (<50 copies/mL, >=50 copies/mL but <400 copies/mL, >400 copies/mL but >=1-log₁₀ decrease from baseline viral load) and within each response category from Week 24 to Week 48; (2) Time to virological failure by Week 48; and (3) Percentage of patients in each virological response category at Week 48.

Statistical methods
Efficacy was analyzed for intent-to-treat (ITT) population (ie, all patients who were randomized, received at least 1 dose of study medication, and had at least 1 post-treatment plasma HIV-1 RNA measurement). Change from baseline to Week 24 in log₁₀ HIV-1 RNA, CD4+ and CD8+ T cell counts, and physical function and mental health MOS-HIV scales were analyzed by analysis of covariance (ANCOVA). Virological responder categories were analyzed using a stratified Mantel-Haenszel test. Durability of the virological responder categories was tested using multinomial distributions and the chi-square test. Time to virological failure, time to rebound, and time to loss of virological response were analyzed using the Kaplan-Meier method and a log-rank test. Mean duration of viral suppression in the 3 defined mutually exclusive categories of virological response was analyzed using a 2-sample t-test.

Safety parameters were summarized descriptively for the safety population (ie, all patients who received at least 1 dose of study medication and had at least 1 follow-up safety assessment). Two separate analyses were conducted for the safety data. The first analysis reported the percentage of patients with adverse events in each treatment group (ie, patients originally randomized to Fuzeon + OB, those remaining on OB, switch patients [originally on OB and switched to Fuzeon + OB], and combined Fuzeon patients [any patient who received Fuzeon at any time]). The second analysis was based on the incidence density for each adverse event or the number of patients with an event per 100 patient years of study drug exposure (events/100 Pt-Yrs).

Summary (efficacy, safety, other results)
Efficacy - The difference in distribution of durability of virological response based on the 4 defined categories was significant (P=.0007) between the 2 treatment groups. The overall percentage of patients who maintained or improved virological response from Week 24 to Week 48 was significantly (P<.0001) higher in the Fuzeon + OB group (30.1%) compared to the OB group (13.6%).

Median time to virological failure was significantly (P<.0001) longer in the Fuzeon + OB group (144 days) compared to the OB alone group (71 days). The percentage of patients reaching virological failure by Week 48 was lower in the Fuzeon + OB group (54.3%) compared to the OB group (81.1%).

For each category of virological response, the percentage of patients with a response was higher in the Fuzeon + OB (<50 copies/mL, 15.8%; <400 copies/mL, 28.4%; >=1-log₁₀ decrease from baseline, 36.1%) compared to the OB group (<50 copies/mL, 7.7%; <400 copies/mL, 11.2%; >=1-log₁₀ decrease from baseline, 16.0%). These treatment differences were statistically significant for each virological response category (P=.0079, P<.0001, and P<.0001 for the <50 copies/mL, <400 copies/mL, and >=1.0 log₁₀ decrease from baseline, respectively). The percentage of responders who maintained their 24-week response at Week 48 and the percentage of new responders who had a new virological response category at Week 48 compared with their response at Week 24 were higher in the Fuzeon + OB group compared to the OB group.

The effect of Fuzeon in suppressing viral load to Week 48 was also demonstrated in analyses of the least squares means (LSM) difference (-0.767 log₁₀ copies/mL; P<.0001) between the Fuzeon + OB and OB groups for viral load at Week 48.

Time-to-rebound curves were similar in the Fuzeon + OB and OB treatment groups for each category of virological response. Mean duration of viral suppression for patients with a virological response prior to Week 24 or Week 48 was longer in the Fuzeon + OB group compared to the OB group. For both treatment groups, greater viral suppression was associated with longer durations of suppression.

For mean CD4+ T cell count, the LSM increase for the Fuzeon + OB group over the OB group at Week 48 was statistically significant (P=.0359).

In general, patients in study BV16052 had advanced HIV infection, with a high risk of morbidity and mortality.The rates of confirmed ADEs (Fuzeon + OB, 12.4 patients with event/100 Pt-Yrs; OB, 13.1 patients with event/100 Pt-Yrs) and confirmed ADEs or deaths (Fuzeon + OB, 13.8 patients with event/100 Pt-Yrs; OB, 13.1 patients with event/100 Pt-Yrs) were similar in both treatment groups. The reported rate of deaths was 2.9 patients with event/100 Pt-Yrs in the Fuzeon + OB treatment group and 1.3 patients with event/100 Pt Yrs in the OB treatment group. None of these differences between treatment groups was statistically significant.

At Week 48, physical function and mental health scores from the MOS-HIV questionnaire were similar in the Fuzeon + OB and OB treatment groups. The 2 groups also had similar Karnofsky performance scores.

Eight patients (2.9 per 100 Pt-Yrs) on Fuzeon+OB and 1 patient (1.3 per 100 Pt-Yrs) on OB and one patient on switch died prior to week 48, or for patients who withdrew before completing 48 weeks of treatment, within 28 days of the last dose of study medication The overall rate of serious adverse events was lower in the Fuzeon + OB (35.3 events/100 Pt-Yrs) and combined Fuzeon (37.0 events/100 Pt-Yrs) groups than in the OB group (58.9 events/100 Pt-Yrs). A higher rate of adverse events leading to study withdrawal was seen in the Fuzeon + OB treatment group (11.7 events/100 Pt-Yrs) compared to the OB treatment group (2.6 events/100 Pt-Yrs). This difference between treatment groups was not due to a specific adverse event.

Nearly all patients (97.9%) in the Fuzeon + OB treatment group had at least 1 local injection site reaction, with most experiencing their first reaction during Week 1. Overall, 95.3% of patients with these reactions experienced some measure of pain and discomfort. For patients randomized to the Fuzeon + OB treatment group, the worst pain and discomfort experienced with local injection site reactions was mild for 31.2%, moderate without limitation of usual activities for 55.8%, and severe requiring analgesics or limiting usual activities for 13.1%. Few Fuzeon-treated patients (1.5%) experienced infection at the injection site and a small percentage of patients (5.1%) discontinued Fuzeon treatment because of local injection site reactions.

Treatment-emergent eosinophilia occurred at a higher rate in the Fuzeon + OB treatment group (12.4 patients/100 patient-years) compared to the OB treatment group (3.9 patients/100 patient-years). Vital signs and electrocardiograms (ECGs) showed no evidence of toxicity associated with the addition of Fuzeon to an OB regimen.

Conclusions
The addition of Fuzeon to an OB regimen provided a durable virological response at 48 weeks of treatment. The overall percentage of patients who maintained or improved virological response from Week 24 to Week 48 was significantly (P<.0001) higher in the Fuzeon + OB group compared to the OB group. For each category of virological response, the percentage of responders was significantly higher in the Fuzeon + OB group compared to the OB group at Week 48. Also at Week 48, the percentage of 24-week responders who maintained their response and the percentage of new responders were both higher on Fuzeon + OB compared to OB alone. Time to virological failure was significantly longer (P<.0001), and the percentage of patients with confirmed virological failure through Week 48 was lower in patients receiving Fuzeon + OB compared to OB alone.

The Fuzeon + OB group had greater decreases in viral load and greater increases in CD4+ T cell count as compared to OB alone. Twice daily injections of Fuzeon had no apparent negative effect on either mental health or physical functions. Local injection site reactions were the most common adverse events associated with Fuzeon treatment and were seldom treatment limiting.

The safety profile identified at Week 24 was maintained at Week 48 with no new safety concerns.

Publications (references, if available)
1) Katlama C, Arastéh K, Clotet B, et al. Enfuvirtide TORO studies: 48 week results confirm 24 week findings. 2nd IAS Conference on HIV Pathogenesis and Treatment; Paris, France; July 13–16, 2003 abstract LB2) 2) Eron JJ, Delfraissy JF, Kuritzkes D, et al. Safety of enfuvirtide ENF) through 48 weeks of therapy in the TORO trials. 43rd Interscience Conference on Antimicrob. Agents Chemother. Chicago, IL, USA (2003). Abstract H-836 3) Clumeck N, Cohen CJ, Thompson M et al. Impact of enfuvirtide on health-related quality of life at 48 weeks. 9th European AIDS Conference. Warsaw, Poland (2003). Abstract 7.3/19 4) Trottier B, Arastéh K, Henry K, et al. Durability of response to enfuvirtide through 48 weeks in the TORO trials. 43rd Interscience Conference on Antimicrob. Agents Chemother. Chicago, IL, USA (2003). Abstract H-835

Date of report
8/15/2003