Clinical Trial Result Information

Protocol number
MV18220

Title of Study
A 24 week, open label, single arm study to evaluate the safety and efficacy of switching a toxicity causing antiretroviral (ARV) to enfuvirtide (ENF) and to assess resolution or improvement of ARV toxicities in patients with current, historical treatment-limiting toxicities.

Sponsor
F. Hoffmann-La Roche Ltd.

Company division
Pharmaceutical

Product name
Fuzeon

Generic name
enfuvirtide

Therapeutic area
HIV Infections

Clinical study summary
Open-label, single-arm, multicenter study.

Study center(s)
28 centers in Canada, Germany, Italy, Poland, Romania and Spain.

Phase of development
IV

Objectives
Primary: To assess the resolution and change in severity of the primary offending ARV toxicity over 24 weeks, after the toxicity-causing ARV was switched to Fuzeon (enfuvirtide) at baseline.
Secondary: To assess the safety and tolerability of a Fuzeon-based regimen over 24 weeks after the toxicity-causing ARV was switched at baseline; to assess the maintenance of efficacy of a Fuzeon-based regimen at 24 weeks after the toxicity-causing ARV was switched to Fuzeon at baseline; adherence: 4-day recall questionnaire.

Methodology
Primary and non-primary ARV associated toxicities were identified at baseline and followed for changes in intensity during the study, after the primary offending ARV was discontinued and replaced by Fuzeon at the baseline visit. Although graded using the same intensity scales as for AEs, ARV-associated toxicities were tracked and analyzed separately from AEs.

Number of patients (planned/analyzed)
300 patients planned, 91 enrolled

Diagnosis and main criteria for inclusion
Human Immunodeficiency virus type 1 (HIV-1) infected patients with prior experience and/or prior documented resistance to each of the 3 classes of approved ARV agents. All patients were experiencing treatment-limiting toxicity to a component of their ARV regimen.

Test product, dose and mode of administration or test procedure
Fuzeon (enfuvirtide) 90 mg twice daily by subcutaneous injection.

Duration of treatment
24 weeks

Reference therapy, dose and mode of administration or reference procedure
N/A.

Criteria for evaluation (efficacy, safety)
Safety: Change from baseline in ARV-associated toxicities; treatment-emergent adverse events (AEs); AIDS-defining events; abnormal laboratory tests; deaths; changes from baseline in vital signs; discontinuations due to injection-site reaction (ISRs) or other AEs.
Efficacy: Proportion of patients who maintain or improve viral load response from baseline to Week 24; proportion of patients who maintain or improve CD4 counts from baseline to Week 24.
Other: Mean score changes from baseline in MOS-HIV scores; adherence to Fuzeon and the background ARV regimen; relationship between improvement/resolution in the primary ARV-associated toxicity and 1) adherence or 2) Medical Outcomes Study (MOS)-HIV scores.

Statistical methods
All data from this study were summarized descriptively. No statistical hypothesis testing was performed.

Summary (efficacy, safety, other results)
Safety: Of the 91 enrolled patients, 38 (42%) had no change in the primary ARV-associated toxicity, while 26 (29%) had resolution, 24 (26%) had improvement and 3 (3%) had worsening. Compared with primary ARV-associated toxicities, non-primary ARV-associated toxicities were more likely to remain unchanged during the study. Of the 60 non-primary ARV-associated toxicities at baseline, 41 (68%) had no change in the toxicity, while 16 (27%) had resolution, 2 (3%) had improvement and 1 (2%) had worsening.
A total of 58 patients (64%) experienced AEs during the study. The only individual AEs reported in more than 3 patients were nasopharyngitis (10 patients [11%]), ISR (6 patients [7%]) and diarrhea (4 patients [4%]).
No treatment-emergent laboratory abnormalities were serious adverse events, or resulted in discontinuation from the study. Six patients were discontinued from the study for ISRs.
There were no deaths, no treatment-emergent AIDS-defining events and only one treatment-related serious adverse event (exacerbation of chronic bronchitis considered remotely related).
There were no clinically relevant changes in vital signs.

Efficacy: Overall, 60% of patients maintained or improved their viral load category and 73% of patients maintained or improved their CD4 count category during the study. Eleven patients shifted to a higher viral load category during the study, and 3 patients shifted to a lower CD4 count category.
Stability or improvement in virological and immunologic parameters was demonstrated by stable HIV-1 RNA levels (-0.18 [1.38] log₁₀ copies/mL at Week 24) and increases in CD4 counts (18.87 cells/mm³ at Week 24).

Other: Mean increases were observed during the study for all MOS-HIV scale scores, indicating improvement in health-related quality of life. Quality of life improvements were similar at Weeks 12 and 24, indicating that perceived increases in quality of life were maintained throughout the treatment period.
Most patients reported excellent adherence to the background regimen (91.21% of patients reported ≥95% adherence). Reported adherence to Fuzeon was somewhat lower (79.12% of patients reported ≥95% adherence and 85.71 reported ≥90% adherence).
For all MOS-HIV scales except cognitive functioning, the mean increases from baseline at Weeks 12 and 24 were greater among patients with improved or resolved toxicity compared with those who had no change or worsening toxicity.

Conclusions
Results of this open-label, single-arm study in HIV-infected patients experiencing treatment-limiting toxicity to a component of their ARV regimens demonstrate that switching from the toxic ARV medication to Fuzeon improved or resolved toxicities in a majority of patients over a 24-week treatment period. Safety and tolerability results were favorable, and efficacy (virological and immunological response and quality of life) was similar to or improved over baseline. Overall, the results support a favourable risk/benefit ratio for Fuzeon.

Publications (references, if available)
Stoll M, Muller M, Staszewski S, et al. Switching a Toxicity-Causing Antiretroviral (ARV) to Enfuvirtide (ENF) in Patients with Treatment-Limiting Toxicities. 8th International Congress on Drug Therapy in HIV-1 Infection. Glasgow, 12-16 November 2006 (Poster P56).

Date of report
4/2/2007

Click here for the protocol registry listing of this trial.