Clinical Trial Result Information

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)

Fast Facts:

Protocol number:	NV16054 (48 week analysis)
Sponsor:	Hoffmann-La Roche Inc.; Trimeris Inc.
Company division:	Pharmaceutical
Product name:	Fuzeon
Generic name:	enfuvirtide
Phase of development:	III
Therapeutic area, approved indication:	Treatment of HIV-1 infection
Date of report:	8/15/2003

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) :
48 centers in Brazil, Canada, Mexico, and the United States.

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):
501 randomized; 491 intent to treat (ITT); 491 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.

Secondary efficacy parameters: (1) Change in viral load (2) duration of viral suppression for each virological response category assessed by time to rebound, mean duration of viral suppression, and time to loss of virological response; (3) Change from baseline to Week 48 in CD4+ and CD8+ T cell counts; (4) Percentage of patients with either an AIDS defining event (ADE) or death by Week 48; (5) Time to either an ADE or death at Week 48; (6) Change from baseline to Week 48 in physical function and mental health scales of the MOS-HIV questionnaire; and (7) Change from baseline to Week 48 in Karnofsky performance score.

Safety parameters: Adverse events, deaths, serious adverse events, adverse events leading to withdrawal, local injection site reactions, clinical laboratory tests, and vital signs.

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 are 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<.0001) 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 (31.6%) compared to the OB group (15.2%).

Median time to virological failure was significantly (P<.0001) longer on Fuzeon + OB group (275 days) compared to the OB alone group (99 days). The percentage of patients reaching virological failure by Week 48 was lower in the Fuzeon + OB group (50.3%) compared to the OB group (74.5%).

For each category of virological response, the percentage of patients with a response was higher in the Fuzeon + OB group (<50 copies/mL, 20.7%; <400 copies/mL, 36.2%; >=1-log₁₀ decrease from baseline, 49.1%) compared to the OB group (<50 copies/mL, 8.5%; <400 copies/mL, 14.5%; >=1-log₁₀ decrease from baseline, 20.6%). These treatment differences were statistically significant (P<.0001) for each response category. 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.

The effect of Fuzeon in suppressing viral load to Week 48 was also demonstrated in analyses of the least squares means (LSM) difference (-0.964 log₁₀ copies/mL; P<.0001) for viral load between the Fuzeon + OB and OB groups at Week 48.

The time-to-rebound curves were significantly in favor of the Fuzeon + OB treatment group for the <50 copies/mL and >=1.0-log₁₀ decrease from baseline categories of virological response (P=.02 and P=.0011, respectively). Kaplan Meier curves for <400 copies/mL were similar for both treatment groups. 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 OB group at Week 48 was statistically significant (P<.0001).

The rates of confirmed ADEs (Fuzeon + OB, 8.9 patients with events/100 Pt-Yrs; OB, 9.3 patients with events/100 Pt-Yrs) and confirmed ADEs or deaths (Fuzeon + OB, 10.3 patients with events/100 Pt-Yrs; OB, 10.5 patients with events/100 Pt-Yrs) were similar in both treatment groups. The rate of death in the Fuzeon + OB group was 2.8 patients with event/100 Pt-Yrs compared to 4.7 patients with event/100 Pt-Yrs the OB group. None of these differences between treatment groups were statistically significant.

At Week 48, both the physical function and mental health scales were higher (better QOL) in the Fuzeon + OB treatment group compared to the OB treatment group. Although the LSM difference was not significant in the physical function scale, the LSM differences between treatments were significant (P=.0494) in the mental health scale. The 2 groups had similar Karnofsky performance scores.

Safety - The overall rate of adverse events was lower in the Fuzeon + OB (113.4 events/100 Pt-Yrs) and combined Fuzeon (122.8 events/100 Pt-Yrs) groups than in the OB group (180.9 events/100 Pt-Yrs). The most frequently reported adverse event for all 3 groups was diarrhea, which was reported at a higher rate in the OB group (79.3 events/100 Pt-Yrs) than in the Fuzeon + OB (40.7 events/100 Pt-Yrs) and combined Fuzeon (39.8 events/100 Pt-Yrs) groups.

Adverse events reported at a 3-times higher risk ratio in the combined Fuzeon group compared to the OB group included lymphadenopathy, pneumonia, weakness, asthma, and hypertriglyceridemia.

Eight patients on ENF+OB (2.8 per 100 Pt-Yrs) and 4 patients on OB (4.7 per 100 Pt-Yrs) and one patient on switch died before 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 incidence of serious adverse events was lower in the Fuzeon + OB (35.8 events/100 Pt-Yrs) and combined Fuzeon (36.2 events/100 Pt-Yrs) groups than in the OB group (47.8 events/100 Pt-Yrs). The most frequently reported serious adverse event in the combined Fuzeon group was an increase in blood creatine phosphokinase, whereas the most frequently reported serious adverse event in the OB group was neutropenia. The overall rate/100 Pt-Yrs of adverse events (not including ADEs or local injection site reactions) leading to study withdrawal was similar in the Fuzeon + OB, combined Fuzeon, and the OB groups.

Nearly all patients (99%) in the Fuzeon + OB treatment group had at least 1 local injection site reaction, with most experiencing their first reaction during Week 1. Overall, 96.9% 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 46.2%, moderate without limitation of usual activities for 44.9%, and severe requiring analgesics or limiting usual activities for 8.9%. Few Fuzeon-treated patients (2.5%) experienced infection at the injection site and a small percentage of patients (3.5%) discontinued Fuzeon treatment because of local injection site reactions.

Treatment-emergent eosinophilia occurred at a higher rate in the Fuzeon + OB treatment group (13.5 patients/100 Pt-Yrs) compared to the OB treatment group (7.0 patients/100 Pt-Yrs). 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, as well as the percentage of responders for each category of virological response at Week 48, was significantly higher in the Fuzeon + OB group compared to the OB group (P<.0001 for both). 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. Time to virological failure was significantly longer (P<.0001) and a lower percentage of patients had confirmed virological failure through Week 48, on Fuzeon + OB compared to OB alone.

The Fuzeon + OB group had significantly (P<.0001) greater decreases in viral load and a significantly (P<.0001) greater increase in CD4+ T cell count than the OB group at Week 48. The need for twice daily injections of Fuzeon had no apparent negative effect on either mental health or physical function as evidenced by the similarity in the scores for these functions between the Fuzeon + OB and OB treatment groups. Local injection site reactions are the most common adverse event associated with Fuzeon treatment and are 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