Clinical Trial Result Information

Title of Study:
A Phase IIIb/IV randomized, controlled study evaluating an intensification treatment strategy of adding enfuvirtide (ENF) to an oral Highly Active AntiRetroviral Therapy (HAART) in treatment experienced patients (INTENSE Study).

Fast Facts:

Protocol number:	MV18406
Sponsor:	F. Hoffmann-La Roche Ltd.
Company division:	Pharmaceutical
Product name:	Fuzeon
Generic name:	enfuvirtide
Phase of development:	IV
Therapeutic area, approved indication:	Treatment of HIV-1 infection
Date of report:	4/1/2008

Clinical study summary:
This was an open-label, randomized, multicenter study, with 2 phases:
Induction phase: At baseline 1 patients were randomized 1:2 to I1) HAART or I2)Fuzeon (90mg sc bid) + HAART. Patients who achieved viral suppression <50 copies/mL by week 24, confirmed by week 28 at the latest, qualified for entering the Maintenance phase (starting at Baseline 2) with three treatment arms through 48 weeks (I2 patients randomized 1:1 to M2 or M3 four weeks after confirmation of response):
M1. HAART continued (patients from I1)
M2. Fuzeon stopped 4 weeks after confirmation of viral load <50 copies/mL and HAART continued
M3. Fuzeon + HAART continued.

Study center(s) :
20 centers in France, Germany, Italy, Mexico, Spain, and the USA.

Objectives:
Primary: To evaluate the induction strategy of HAART alone compared to Fuzeon (enfuvirtide) (90mg sc bid) in combination with HAART, as measured by the proportion of patients initially achieving viral suppression to <50 copies/mL by week 24 (confirmed by week 28 or earlier) while on originally randomized treatment.
Secondary: To determine the overall induction/maintenance treatment strategy (with or without Fuzeon) after 48 weeks of treatment as measured by the proportion of patients with viral load <50 copies/mL at 48 weeks from baseline 1; to compare different maintenance strategies for those patients who were qualified for entering the maintenance phase as measured by the time to loss of viral response (<50 copies/mL) from baseline 2; to assess the safety of induction phase and maintenance phase.

Methodology:
HIV-1 RNA copies were measured using the Amplicor HIV-1 Monitor (standard sample, diluted sample or ultrasensitive sample preparation, as applicable), active ARVs were determined on the basis of genotypic test results (GSS = Genotypic Sensitivity Scores). Deaths, AEs that led to discontinuation, were serious or both and any case of pneumonia were reported.

Number of patients (planned/analyzed):
300 patients planned, 47 enrolled and randomized.

Diagnosis and main criteria for inclusion:
HIV-1 infected adults (>18 years of age) previously treated with 2 or 3 different ARV classes with a CD4 lymphocyte count ≥200 cells/mm3 and HIV-1 RNA ≥1000 copies/mL, while on their current ‘pre-study’ ARV regimen. Patients had to be able to create a study HAART regimen with at lest 2 ARVs to which their virus showed sensitivity by genotypic testing at screening (Genotypic Sensitivity Score or GSS ≥2).

Test product, dose and mode of administration or test procedure:
SC injection of Fuzeon (enfuvirtide) 90mg bid, every 12 hours in addition to HAART.

Duration of treatment:
48 weeks

Reference therapy, dose and mode of administration or reference procedure:
HAART as per labelling of ARVs included in the HAART regimen.

Criteria for evaluation (efficacy, safety):
Efficacy: Percentage of patients initially achieving viral suppression to <50 copies/mL; time to achieving <50 copies/mL (from baseline to confirmed response); percentage of patients with viral load <50 copies/mL at week 48; percentage of patients initially achieving viral suppression to <400 copies/mL; change from baseline in log10 (HIV-1 RNA) and CD4 count at weeks 24 and 48; time to loss of viral response and time to virological failure; percentage of patients with viral load <400 copies/mL at week 48 (planned, but not carried out due to low patients numbers); change from baseline 2 in CD4 counts at week 48 (planned, but not carried out due to low patient numbers).

Safety: All pneumonias (whether meeting criteria as serious or not); Serious Adverse Events (SAEs) including deaths; AIDS-Defining Events (ADEs): Fatal ADEs and/or Category C that are considered serious; premature withdrawals due to adverse events; abnormal laboratory tests; local injection site reactions.

Statistical methods:
All efficacy analyses were based on the appropriate intent-to-treat populations (ITT, ITT1, ITT2). Stratified Cochran-Maentel-Haenszel tests were used to compare proportions of patients with confirmed viral loads <50 and <400 copies/mL in the induction phase and <50 copies/mL at the end of the maintenance phase between the two initial treatment groups. Change from baseline in HIV-1 RNA and CD4 cell counts at weeks 24 and 48 were analyzed by analysis of covariance (BLCF) providing least square means for the initial treatment groups and point and interval estimates of their differences. Safety parameters were summarized descriptively.

Summary (efficacy, safety, other results):
Efficacy: Due to a markedly reduced sample size the study was not sufficiently powered to yield confirmatory results. The proportion of responders was greater in the Fuzeon + HAART group (64.5%) than in the HAART group (50.0%). This difference almost reached the 15% difference in responder rates assumed for the sample size calculation. Median time to response was markedly shorter in the Fuzeon + HAART group (57 days) than in the HAART group (141 days, p-value = 0.048). The high drop out rate precluded a meaningful analysis of the combined induction/maintenance strategy (using ITT1 as denominator). During maintenance phase (using ITT2) maintenance of response till study end was more frequent in Fuzeon + HAART patients than in HAART patients (73.7% vs. 50%). To some extent advantages of adding Fuzeon to HAART were also discernible with respect to reduction of HIV-RNA copies and increase of CD4-cell counts.

Safety: During both the induction and maintenance phases, there was one death, (unrelated to study medication) and 5 SAEs in patients on Fuzeon + HAART and 8 SAEs in patients on a regimen with HAART alone (including events during the maintenance phase of patients who had Fuzeon removed at baseline 2). Of these one SAE was considered possibly causally related to Fuzeon (injection site reaction leading to withdrawal). In addition to the death, 5 patients in the Fuzeon + HAART group (including 2 cases of injection site pain or reaction) and one patient in the HAART group terminated the study early for safety reasons.

Conclusions:
Due to markedly reduced numbers of patients randomized and analyzed the study lacked sufficient power to yield confirmatory results. However, trends were noted in favour of treatment with Fuzeon + HAART vs. HAART alone with respect to a greater proportion of responders, shorter time to response and, once response was achieved, increased probability of response being maintained.
Treatment with Fuzeon + HAART was safe with only one SAE (ISR) that was considered possibly causally related to Fuzeon. Apart from local reactions/pain, treatment with Fuzeon + HAART was also well tolerated.
The results support a favourable risk/benefit ratio for the use of Fuzeon in addition to an optimized background therapy with HAART.

Publications (references, if available):
Clotet B, Capetti A, Soto-Ramirez LE, et al. An intensification treatment strategy of adding enfuvirtide to an oral HAART regimen: The INTENSE study 24 week induction phase analysis. 11th European AIDS Conference/EACS, Madrid, October 24-27, 2007, Poster P4.3/73.

Capetti A, Clotet B, Soto-Ramirez LD, et al. The INTENSE Study: An Intensification Strategy of Adding Enfuvirtide (ENF) to an Oral HAART Regimen. BHIVA 14th Annual Conference, Belfast, April 23-25, 2008, Poster P38

Click here for the protocol registry listing of this trial.