Clinical Trial Result Information

Protocol number
NV17658

Title of Study
A phase II open-label, randomized, active-controlled study comparing the efficacy and safety of once daily enfuvirtide dosing versus the currently recommended twice daily dosing in HIV-1 infected treatment-experienced patients.

Sponsor
Hoffmann-La Roche Inc. and Trimeris Inc.

Company division
Pharmaceutical

Product name
Fuzeon

Generic name
enfuvirtide

Therapeutic area
HIV Infections

Clinical study summary
This was a randomized, open-label, active-controlled, parallel group, multicenter trial, evaluating patients with prior experience and/or prior documented resistance to each of the three classes (NRTIs, NNRTIs, PIs) of approved ARVs.
Patients were randomized to one of the two treatment groups: Fuzeon (enfuvirtide) 180 mg, SC, QD + Optimized Background (OB) regimen or Fuzeon (enfuvirtide) 90 mg, SC, BID + OB.

Study center(s)
This study was conducted at 22 centers in the United States and Canada.

Phase of development
II

Objectives
Primary: To compare the antiviral activity of Fuzeon 180 mg QD in combination with an Optimized Background (OB) regimen with Fuzeon 90 mg BID in combination with an OB regimen, following 48 weeks of treatment.
Secondary: To compare the safety and tolerability of Fuzeon 180 mg QD in combination with an OB regimen and Fuzeon 90 mg BID in combination with an OB regimen following 24 and 48 weeks of treatment. To explore the relationship between the exposure parameters (C_trough, AUC and C_max) and antiviral effect (decline in viral load at Week 1 or 2 (PK visit), Week 8 and Week 24) for the two dosing regimens.

Methodology
Patients had to be on a current ‘pre-study’ antiretroviral regimen in which medications and doses remain unchanged for at least 4 weeks prior to Screen 1 visit and unchanged prior to baseline. Patients had documentation of a plasma HIV-1 RNA level ≥5,000 copies/mL measured at least 4 weeks after the initiation of their ‘pre-study’ antiretroviral regimen, but no more than 6 months prior to the first screening visit. Eligible patients were randomized at a ratio of 1:1 to one of the following two treatment groups: Fuzeon, 180 mg QD + OB or Fuzeon 90 mg BID + OB.
Safety and efficacy evaluations were conducted at weeks 1, 2, 4 and every 4 weeks through week 24, and every 8 weeks through week 48. Additional efficacy evaluations were carried out at any time if virological failure was suspected. Two pharmacokinetic assessments were done at (Week 1 or 2, 8, and 24) in all patients.

Number of patients (planned/analyzed)
Planned: 120 patients. Enrolled: 64 patients.

Diagnosis and main criteria for inclusion
HIV-1/AIDS adults or adolescents (≥16 years of age) with HIV-1 RNA ≥5,000 copies/mL. Prior experience or documented resistance to three classes of ARVs, (NRTIs, NNRTIs, PIs).

Test product, dose and mode of administration or test procedure
Fuzeon 180 mg, SC, QD (two injections once daily) + OB
OB – The investigator and patient selected the patient’s OB regimen which consisted of 3 to 5 antiretroviral drugs and could have included investigational drugs.

Duration of treatment
48 weeks

Reference therapy, dose and mode of administration or reference procedure
Fuzeon 90mg, SC, BID (one injection twice daily) + OB

Criteria for evaluation (efficacy, safety)
Efficacy: The primary efficacy parameter was the percentage of responders with an HIV-1 RNA level of <400 copies/mL, based on two consecutive HIV-1 RNA levels, at week 24 and week 48.

Secondary efficacy parameters included: number and percentage of patients with HIV-1 RNA <50 copies/mL or a ≥ 1-log10 decrease from baseline in HIV-1 RNA at week 24 and week 48; time to virological failure at week 24 and week 48; time to the first virologic response at week 24; change from baseline in viral load at week 24 and week 48; change from baseline in CD4⁺ T cell count at week 24 and week 48.

Pharmacokinetics: Assessment of steady state Bayesian estimates of PK parameters (Ctrough, AUC and Cmax) in all patients. Exploration of relationship between the exposure parameters (Ctrough, AUC and Cmax) and antiviral effect (decline in viral load at Week 1 or 2, Week 8 and Week 24) for the two dosing regimens.

Safety: Safety parameters included adverse events (including deaths and serious adverse events), premature withdrawals due to adverse events, AIDS defining events, local injection site reactions, clinical laboratory tests, electrocardiograms (ECGs), and vital signs.

Quality of Life: Subcutaneous-Injection Survey (SIS).

Statistical methods
Efficacy data was analyzed for all patients who were randomized and received at least one dose of study medication (Intent-to-Treat Population). Virological responder categories were analyzed using a stratified Mantel-Haenszel test. Change from baseline in HIV-1 RNA and CD4⁺ T cell counts were analyzed by analysis of covariance with the terms treatment, randomization stratum, treatment by stratum interaction, and covariates for baseline viral load, number of previous ARVs, and number of investigational ARVs. Time to virologic response and time to virologic failure were estimated using the Kaplan-Meier method.
Safety parameters were summarized descriptively.

Summary (efficacy, safety, other results)
Primary: The percentage of patients with HIV-1 RNA <400 copies/mL was similar between the 180 mg QD and 90 mg BID groups both at 24 weeks (26.7% and 32.3% respectively) and at 48 weeks (23.3% and 22.6% respectively).

Secondary: The percentage of patients with a virological response of HIV-1 RNA <50 copies/mL was lower in the 180 mg QD group (10.0%) compared with the 90 mg BID group (25.8%) at week 24 and at week 48 (13.3% and 22.6%, respectively). The percentage of patients with a virological response of ≥1-log₁₀ decrease from baseline in viral load was similar at week 24 in the 180 mg QD group (46.7%) and the 90 mg BID group (41.9%). However, at week 48, a lower percentage of patients in the 180 mg QD group (23.3%) compared with the 90 mg BID group (32.3%) had at least a ≥1-log₁₀ decrease. The mean change from baseline was -1.95 log₁₀ copies/mL and -1.55 log₁₀ copies/mL in the 180 mg QD and 90 mg BID groups respectively at week 24, and -2.21 log₁₀ copies/mL and -1.61 log₁₀ copies/mL in 180 mg QD and 90 mg BID groups, respectively.

The LSM change from baseline to week 24 in CD4+ T cell counts was 57.25 cells/µL and 44.98 cells/µL in the 180 mg QD and 90 mg BID groups respectively, and from baseline to week 48 was 47.0 cells/µL and 35.8 cells/µL in the 180 mg QD and 90 mg BID groups, respectively. If patients adhered to Fuzeon (≥95% by 4 day recall), virological responses of HIV-1 RNA <400 copies/mL were 25.0% in 180 mg QD and 27.8% in 90 mg BID groups. Virological responses of HIV-RNA <400 copies/mL in patients with ≥85% adherence by a 4 day recall were 21.4% in 180 mg QD and 28% in 90 mg BID groups.

Quality of Life: Results of the subcutaneous injection survey were similar for the 180 mg QD and 90 mg BID groups. Similar percentages of patients in both groups reported that the injections and the effects of the injections had little to no interference with their usual daily activities. Similar percentages of patients in both groups also reported little to no difficulty in preparing or administering the injection(s) or disposing of the needles and vials.

Pharmacokinetic: The mean predicted value of C_trough was approximately 65% lower for the QD regimen than the mean predicted value achieved with the BID regimen. The C_trough value was below 1 µg/mL in 15 of 30 patients under the QD regimen, and in none of 29 patients under the BID regimen.

The average predicted C_max was higher in the QD regimen compared to the BID regimen but the total mean AUC from the QD regimen was comparable to the BID regimen (after multiplying the AUC_0-τ value by 2 to account for the evening dose).
No apparent difference was observed between the QD and BID groups in the mean viral load decline from baseline to Weeks 1-2, 8 and 24 for patients with both PK and viral load data.

Safety: Overall, the percentage of patients experiencing AEs and SAEs in both groups was similar; the most common AEs (diarrhea, upper respiratory tract infection) were more frequent on BID treatment. Four patients had treatment-related SAEs (pneumonia, neutropenia and increased bilirubin in the 180 mg QD group, and injection site cellulitis in the 90 mg BID group). There was one death in the 180mg QD group (suicide-unrelated to treatment). Four patients withdrew from study due to adverse events (suicide, transaminase increases and an injection site reaction in the 180 QD group, and anxiety in the 90 mg BID group). Three patients, all in the 90 mg BID group, developed AIDS defining events (2 patients with candidiasis and 1 with herpes zoster). Most patients in both groups (180 mg, 93.3%; 90 mg BID, 93.5%) had at least one local injection site reaction during the study; Grade 3-4 injection site ecchymosis, indurations or erythema were more frequent on QD. No clinically significant changes were seen for ECGs, clinical laboratory tests, or vital signs in either treatment group.

A similar percentage of patients in the 180 mg QD and 90 mg BID groups were 100% adherent to the treatment regimen. However, adherence to Fuzeon (≥95% by 4 day recall) was 80% on 180 mg QD compared to 58% on 90 BID and for other adherence categories (≥90% and ≥85%), treatment adherence was higher in the 180 mg QD group than in the 90 mg BID group.

Conclusions
The primary efficacy endpoint, safety and tolerability were comparable between the 180 mg QD and 90 mg BID dosing regimens. Adherence was higher on 180mg QD. There was a trend favoring 90mg BID in the proportion of patients achieving <50 copies/mL. Total mean AUC from the QD regimen was comparable to that achieved for the BID regimen (after multiplying the AUC_0-τ value by 2 to account for the evening dose). The mean predicted value of C_trough was higher in the BID regimen and the mean predicted C_max was higher in the QD regimen.

Publications (references, if available)
Walmsley S, Wright D, Rodriguez A et al. A pilot study of enfuvirtide (ENF) once daily (180mg QD) vs twice daily (90mg BID) for 48 weeks. Abstract LB-23. 44th Annual Meeting IDSA, October 12-15, 2006. Toronto, Canada.

Date of report
8/1/2006

Click here for the protocol registry listing of this trial.