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: | BV16052 (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: | 7/30/2002 |
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) :
67 centers in Australia, Belgium, France, Germany, Italy, the Netherlands, Spain, Switzerland, Sweden, and the United Kingdom.
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):
512 randomized; 504 intent-to-treat (ITT); 506 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 (NB Analyses were performed at 24 and 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 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=-0.78, P<.0001. Similar results were obtained in an analysis in the RT population (LSM difference= 0.70, P<.0001), in sensitivity analyses, and at Week 8 in the ITT population (LSM difference=-0.71, 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.
| |
HIV-1 RNA <50 Copies/mL |
|
HIV-1 RNA <400 Copies/mL |
|
>=1.0-Log10 Decrease from Baseline HIV-1 RNA |
| Week 8 |
Week 24 |
Week 8 |
Week 24 |
Week 8 |
Week 24 |
| Fuzeon + OB |
1.8% |
12.2% |
17.9% |
28.4% |
56.4% |
42.7% |
| OB |
0.6% |
5.3% |
7.1% |
13.6% |
28.4% |
20.7% |
| P Value |
.2796 |
.0099 |
.0005 |
<.0001 |
<.001 |
<.0001 |
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 19.1% in the Fuzeon + OB treatment group as compared to 40.2% in the OB alone treatment group at Week 8 and remained lower in the Fuzeon + OB treatment group at Week 24 (Fuzeon + OB, 49.3%; OB, 76.9%). Kaplan-Meier curves of time to virological failure differed between treatment groups (P<.0001, log-rank test).
At Week 24, the increase over baseline in CD4+ T cell count was significantly greater in the Fuzeon + OB treatment group than in the OB treatment group (LSM difference at Week 24=27.5 cells/µL, P=.0236). The increases over baseline in CD8+ T cell count were not significantly greater in the Fuzeon + OB treatment group than in the OB treatment group.
At Week 24, there were no significant differences between treatment groups in QOL as measured by physical function and mental health scales of the MOS-HIV questionnaire. Karnofsky performance scores were similar in the 2 treatment groups.
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, 24.3%; OB, 27.2%) and nausea (Fuzeon + OB, 15.1%; OB, 16.6%). Most adverse events were mild or moderate, and none had a >=5% difference in frequency between treatment groups. Cutaneous hypersensitivity was reported by a higher percentage of patients in the Fuzeon + OB treatment group than in the OB treatment group (Fuzeon + OB, 16.3%; OB, 10.1%).
In general patients in study BV16052 had advanced HIV infection with a high risk of morbidity and mortality. Six deaths (1.8%) were reported in the Fuzeon + OB treatment group, 1 death (0.6%) in the OB treatment group and one death in the switch group occurred within the first 24 weeks of the study. The percentage of patients with serious adverse events (Fuzeon + OB, 23.7%; OB, 24.3%) and the percentage with treatment-related serious adverse events (Fuzeon + OB, 11.3%; OB, 8.3%) were similar for the 2 treatment groups. The percentage of patients with adverse events leading to withdrawal was higher in the Fuzeon + OB treatment group (7.7%) than in the OB treatment group (1.2%). Depression led to withdrawal in 6 patients (1.8%, including 1 suicide) in the Fuzeon + OB treatment group and none in the OB treatment group.
Nearly all patients (97.6%) 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 (38.1%) or moderate pain without limitation of usual activities (51.7%). Frequent signs and symptoms of local injection site reactions included induration (94.4%), erythema (90.8%), and nodules and cysts (70.3%). Small percentages of patients (3.3% randomized to Fuzeon + OB, 2.6% of switch patients) discontinued treatment with Fuzeon because of local injection site reactions. Clinical laboratory tests, vital signs, and ECGs showed no evidence of toxicity associated with the addition of Fuzeon to an OB regimen.
Conclusions:
Patients receiving Fuzeon + OB demonstrated an increased viral suppression compared with patients receiving OB alone. A higher proportion of patients achieved virological response and fewer patients experienced virological failure with Fuzeon + OB treatment in comparison with OB alone. The efficacy findings of this study are robust, as demonstrated by several sensitivity analyses that confirmed the benefits of Fuzeon + OB over OB treatment alone.
Local injection site reactions were the most common adverse events associated with Fuzeon treatment, but 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. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant human immunodeficiency virus type 1 in Europe and Australia. N Engl J Med 2003; 348:2186-95
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)
