Clinical Trial Result Information

Title of Study:
An open-label, randomized, crossover study in HIV-positive subjects to determine and compare the single-dose pharmacokinetics of enfuvirtide (Fuzeon) after a single 90 mg sc administration with the Biojector 2000 Needle-Free Injection System and a 27G ½-inch (12.7 mm) needle/syringe

Fast Facts:

Protocol number:	ML19235 (T20-405)
Sponsor:	Hoffmann-La Roche Inc; Trimeris Inc.
Company division:	Pharmaceutical
Product name:	Fuzeon
Generic name:	enfuvirtide
Phase of development:	IV
Therapeutic area, approved indication:	HIV infection
Date of report:	4/11/2005

Clinical study summary:
This was an open-label, randomized, 2-period, crossover, single-center study of the pharmacokinetics (PK), safety, and tolerability of enfuvirtide (Fuzeon) in HIV-positive patients involving 2 single-dose treatments using 2 different injection devices, with a 7-day washout phase between treatments.

Study center(s) :
1 center in the United States.

Objectives:
Primary: To determine the relative bioavailability of Fuzeon after a single sc 90 mg (1.0 mL) administration using 2 different injection devices: the B2000 Needle-Free Injection System and a 27G ½-inch (12.7 mm) needle/syringe. Secondary: To compare the safety and tolerability of single doses of the 2 injection devices.

Methodology:
Subject screening took place 7 to 30 days prior to the first dose of Fuzeon. Patients were scheduled to receive the following treatments: Treatment A: a single dose of 90mg (1.0mL) Fuzeon, delivered subcutaneously using a 27 gauge ½ inch (12.7mm) needle/syringe (Reference Treatment) Treatment B: a single dose of 90mg (1.0mL) Fuzeon, delivered by one 1.0mL subcutaneous injection, using needle-free Biojector ® 2000 injection system and No. 2 needle-free syringe (Test Treatment). Subjects received the 2 treatments according to a balanced randomization sequence. Each dose was administered as a single subcutaneous injection into the abdomen. A 1 week washout interval occurred between the two treatment periods.

Number of patients (planned/analyzed):
27

Diagnosis and main criteria for inclusion:
HIV-1 infected adult patients who were treatment-naïve or patients who were on stabilized antiretroviral therapy (ARV) with HIV-1 viral loads <1000 copies/mL for 3 months prior to screening and at screening.

Test product, dose and mode of administration or test procedure:
A single sc dose of 90mg (1.0mL) Fuzeon using a Biojector 2000 Needle-Free Injection System (B2000)

Duration of treatment:
2 single doses, 7 days apart.

Reference therapy, dose and mode of administration or reference procedure:
A single sc dose of 90 mg (1.0 mL) Fuzeon using a 27G ½-inch (12.7 mm) needle/syringe.

Criteria for evaluation (efficacy, safety):
Single-dose PK parameters, determined by noncompartmental methods for each treatment, included: C_max, t_max, AUC_0-t, and AUC_0-¥. Ratios of C_max, AUC_0-t, and AUC_0-¥ served as criteria for bioequivalence determination.

Safety: (1) Incidence of AEs, SAEs, and graded laboratory toxicities; (2) Specific signs and symptoms associated with local ISRs, including pain/discomfort during and following injection. Fuzeon tolerability analyses were based on assessments of clinical adverse events (including clinically significant laboratory abnormalities, graded laboratory toxicities, and local ISRs) leading to discontinuation from the study. A brief questionnaire was administered to patients at the end of the trial to determine their perception and preference regarding injection with the needle/syringe and B2000.

Statistical methods:
All PK parameters were analyzed using a 2-way analysis of variance model (ANOVA). The primary analysis was based on logarithmic transformations of PK parameters. The model included sequence, period, and treatment as fixed effects, and subject within sequence as a random effect. The 90% confidence interval (CI) for the ratio of least squares means between test and reference treatment, derived from the ANOVA model, was used to assess bioequivalence. The two treatments were considered bioequivalent if the 90% CI for the ratios of log-transformed area under the serum concentration-time curve (AUC), AUC 0-τ. AUC 0-∞, and C_max between treatments were within 80%-125%. Adverse events, (AEs), selected clinical safety laboratory test results, vital signs, physical examination findings, and local injection-site reactions (ISRs) were summarized.

Summary (efficacy, safety, other results):
PK – Similar values for all calculated PK parameters were achieved between the 27G needle and B2000. A total of 26 patients had plasma PK data from both devices and served as the basis for the analysis of bioequivalence. Results of ANOVA bioequivalence testing indicated that the ratio of geometric least squares means of B2000 to 27G needle for log-transformed values of both AUC 0-∞ and AUC 0-τ were 0.99 with a 90% CI (93%, 105%),within the equivalence region (80%–125%). The ratio of geometric least squares means of B2000 to 27G needle for log-transformed values of C_max was 0.95 with a 90% CI (84%, 109%), which was also within the equivalence region (80%–125%). Thus, the 2 devices were bioequivalent based on the transformed values of AUC 0-∞, AUC 0-τ, and C_max. Although not defined as part of the bioequivalence criteria in the analysis plan, the ratio for the plasma concentration of enfuvirtide at 12 hours post-dose (C₁₂) for the 27G needle and the B2000 was also determined. The ratio of geometric least squares means of B2000 to 27G needle for log-transformed values of C₁₂ was 0.97 with a 90% CI (86%, 109%). Thus, both devices were also bioequivalent based on C12. The AUCs for the devices were nearly identical.

Safety – All AEs were considered possibly related to Fuzeon by the investigator. Excluding ISRs, a total of 3 patients and 4 patients experienced AEs following injection of Fuzeon with the 27G needle and B2000, respectively. The only AE occurring in >1 patient was headache, occurring in 2 patients during the B2000 period. AEs in other body systems were experienced by single patients only. There was 1 drug-related serious adverse event (Grade 4 absolute neutrophil count [ANC]), noted during the follow-up period of the trial in a patient who had neutropenia on study entry. All treatment-emergent laboratory abnormalities (15 patients), were of Grade 1 severity, with the exception of the patient who experienced the Grade 4 ANC.

Injection Events and Local ISRs – No injection malfunctions or injection anomalies (ie, wet injections, partial dose delivered, leak-back etc) were noted with any injection for either device. The majority of patients reported no pain/discomfort during the injection for either the 27G needle (24/26) or the B2000 (22/27). During the B2000 period, all pain/discomfort experienced was reported as “mild tenderness at injection site” (14.8%, Grade 1), except for 1 patient during the B2000 period, who reported “moderate pain without limitation of usual activities” (Grade 2). In general, the majority of ISRs reported during the trial were mild and infrequent with both injection devices. No severity greater than Grade 2 was noted for any sign/symptom with either device.

Conclusions:
Bioequivalence was achieved between the B2000 and 27G ½-inch needle for AUC0-∞, AUC 0-τ, C_max, and C₁₂. There were no clinically significant local ISRs for the B2000 or 27G needle. There was a comparable safety profile between the B2000 and 27G needle. Patients had a favorable overall opinion of the B2000 device, which constitutes a suitable alternative for sc delivery of Fuzeon.

Publications (references, if available):
True AL, Zhang Y, Chiu YY et al. Needle-free administration of enfuvirtide with Biojector TM 2000 (B2000) demonstrates pharmacokinetic bioequivalence to a standard needle administration. Proceedings DART 2004 (7th International Congress on Drug Therapy in HIV Infection)