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 (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 (24 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:	6/27/2002

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 that Fuzeon 90 mg twice daily ( bid ) added to an OB regimen provides an additional drop in plasma HIV-1 RNA ≥0.5 log₁₀ copies/mL compared with the OB regimen alone, as measured by the difference in the mean changes from baseline value in plasma HIV-1 RNA at Week 24.

Secondary: (1) To evaluate the percentage of patients with a ≥1.0-log₁₀ drop in HIV-1 RNA, HIV-1 RNA <400 copies/mL, and HIV-1 RNA <50 copies/mL; (2) To compare the safety of Fuzeon + OB with OB alone; (3) To evaluate the pharmacokinetics of Fuzeon in triple-class experienced and/or resistant/intolerant patients; and (4) To compare health-related quality of life (QOL) scales derived from the Medical Outcomes Study (MOS)-HIV instrument for Fuzeon + OB and 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 bid. All ARVs in the OB regimen were taken orally. Plasma HIV-1 RNA was measured at baseline, and at intervals throughout the 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 or 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 parameter: Change from baseline to Week 24 in viral load.

Secondary efficacy parameters: (1) Change from baseline to Week 8 in viral load; (2) Categorical virological responder analysis at Week 8 and Week 24; (3) Time to virological response; (4) Time to virological failure; (5) Changes from baseline to Week 8 and Week 24 in CD4+ and CD8+ T cell counts; (6) Percentage of patients with either an AIDS-defining event (ADE) or death by Week 24; (7) Changes from baseline to Week 24 in physical function and mental health scales of the MOS-HIV questionnaire; and (8) Change from baseline to Week 24 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 the 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). Selected efficacy parameters were also analyzed for the restricted-treated (RT) population (ie, all patients in the ITT population who, in addition, had no major protocol violations). Change from baseline to Week 24 in log₁₀ HIV-1 RNA, CD4+ and CD8+ T cell counts, and MOS-HIV scores were analyzed by analysis of covariance (ANCOVA). Virological responder categories were analyzed by a stratified Mantel-Haenszel test. Time to virological response was estimated using Kaplan-Meier method. Time-to-event curves for each category of virological response and for virological failure were compared between treatment groups using a stratified log-rank statistic.

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).

Summary (efficacy, safety, other results):
Efficacy - The primary efficacy endpoint was met (least squares means [LSM] difference ENF+OB minus OB=-0.93, P<.0001). Similar results were obtained in an analysis in the RT population (LSM difference=-1.13, P<.0001), in sensitivity analyses, and at Week 8 in the ITT population (LSM difference=-0.83, P<.0001). The effect of Fuzeon + OB versus OB alone in suppressing viral load was further demonstrated in analyses of percentages of patients with virological responses (table), and confirmed in sensitivity analyses.

Kaplan-Meier curves of time to virological response differed between treatment groups (P<.0001, log-rank test) for HIV-1 RNA <400 copies/mL and for =1.0-log₁₀ decrease from baseline HIV-1 RNA, with higher proportions of patients achieving virological responses in the Fuzeon + OB treatment group than in the OB treatment group over time.

The percentage of patients reaching virological failure was 16% in the Fuzeon + OB treatment group as compared to 33.3% in the OB alone treatment group at Week 8 and remained lower in the Fuzeon + OB treatment group at Week 24 (Fuzeon + OB, 41.7%; OB, 64.2%). Kaplan-Meier curves of time to virological failure differed between treatment groups (P<.0001, log-rank test).

At Week 24, the increases over baseline in CD4+ and CD8+ T cell counts were significantly greater in the Fuzeon + OB treatment group than in the OB treatment group (LSM difference at Week 24 for CD4⁺=44.1 cells/µL, P=.0001; for CD8+=158.9 cells/µL, P=.0027). At Week 24, physical function and mental health scores in the MOS-HIV questionnaire tended to be higher in the Fuzeon + OB treatment group than in the OB treatment group, but the difference between treatment groups was not statistically significant. The 2 treatment groups were similar in Karnofsky performance scores.

Safety - The adverse event profiles of the 2 randomized treatment groups were similar and generally consistent with ARV side effects and/or underlying HIV infection. The most frequently reported adverse events in both treatment groups were diarrhea (Fuzeon + OB, 29.4%; OB, 40.0%), nausea (Fuzeon + OB, 25.2%; OB, 30.9%), and fatigue (Fuzeon + OB, 23.3%; OB, 26.7%). The only adverse events reported with a >=5% difference in frequency between treatment groups were peripheral neuropathy (Fuzeon + OB, 12.3%; OB, 6.1%) and decreased appetite (Fuzeon + OB, 8.9%; OB, 3.6%).

Most adverse events were mild or moderate. Similar percentages of patients in the 2 treatment groups had adverse events that were related to study medication (Fuzeon + OB, 77.6%; OB, 74.5%).

The following adverse events were reported by higher percentages of patients in the Fuzeon + OB treatment group than in the OB treatment group: hypersensitivity (Fuzeon + OB, 4%; OB, 1%), peripheral neuropathy (Fuzeon + OB, 12.3%; OB, 6.1%), pancreatitis (Fuzeon + OB, 13%; OB, 6%), and lipid disorders (Fuzeon + OB, 7%; OB, 5%). Cutaneous hypersensitivity was reported by a higher percentage of patients in the OB treatment group (Fuzeon + OB, 16%; OB, 19%).

In general patients in study NV16054 had advanced HIV infection with a high risk of morbidity and mortality. Four patients (1.2%) in the Fuzeon + OB arm, 4 patients (2.4%) in the OB arm, and one switch patient died within the first 24 weeks of the study. The percentages of patients who had a serious adverse event (Fuzeon + OB, 25.8%; OB, 21.2%), a treatment-related serious adverse event (Fuzeon + OB, 8.6%; OB, 6.1%), or an adverse event leading to withdrawal (Fuzeon + OB, 6.7%; OB, 4.8%) were similar between treatment groups.

Nearly all patients (98.2%) in the Fuzeon + OB treatment group had at least 1 local injection site reaction, with most experiencing their first reaction during Week 1. Among patients who experienced pain or discomfort from local injection site reactions, most had either mild tenderness at the injection site (49.7%) or moderate pain without limitation of usual activities (41.7%). Only small percentages of patients (2.8% in the Fuzeon + OB treatment group and 1.2% of switch patients) discontinued treatment with Fuzeon because of local injection site reactions. Clinical laboratory tests, vital signs, and electrocardiograms ( ECGs) showed no evidence of toxicity associated with Fuzeon treatment.

Conclusions:
In comparison with OB ARV therapy alone, Fuzeon + OB demonstrated increased viral suppression at 24 weeks. Fuzeon + OB increased the proportion of patients achieving a virological response and decreased the proportion of virological failures. The efficacy findings of this study are robust, as demonstrated by several sensitivity analyses that confirmed the benefits of Fuzeon + OB treatment over OB treatment alone.

Local injection site reactions were the most common adverse events associated with Fuzeon treatment and were seldom treatment limiting. The addition of Fuzeon to ARV therapy in treatment experienced patients generally did not exacerbate the toxicities known to be associated with ARV therapy.

Publications (references, if available):
1. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003; 348:2175-85

2. Mould DR, Zhang X, Nieforth K, et al. Population pharmacokinetics and exposure–response relationship of enfuvirtide in triple class-experienced HIV-1-infected patients. Clinical Pharmacology and Therapeutics. In press

3. Cohen CJ, Clumeck N, Molina JM, et al. Health-related quality of life with enfuvirtide (ENF; T-20) in combination with an optimized background regimen. J Acquir Immune Defic Syndr 2004 Sep 1; 37 (No. 1): 1140-6

4. Battegay M, DeMasi R, Delehanty J, Analysis of virological failure through 24 weeks of treatment in the TORO 1 and TORO 2 studies. 2nd IAS Conference on HIV Pathogenesis and Treatment; Paris, France; July 13–16, 2003 abstract 574)