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Clinical Trial Result Information
Title of Study:
A randomized, open-label, two-way, crossover study to assess the tolerability of the B2000 needle-free injection device (NFID) for administration of enfuvirtide (ENF).
Fast Facts:
| Protocol number: | ML18596 |
| Sponsor: | Roche Laboratories Inc. and Trimeris Inc. |
| Company division: | Pharmaceutical |
| Product name: | Fuzeon |
| Generic name: | enfuvirtide |
| Phase of development: | IV |
| Therapeutic area, approved indication: | HIV infection |
| Date of report: | 11/1/2006 |
Clinical study summary:
This was an open-label, blinded injection site reaction (ISR) evaluator, randomized two period (28 days each) crossover trial evaluating the B2000 needle-free injection device and a standard 27G ½" needle/syringe for administration of Fuzeon (enfuvirtide).
Study center(s) :
12 centers in the United States.
Objectives:
Primary: To evaluate the tolerability of the B2000 NFID based on signs and symptoms associated with any Fuzeon injection. The primary endpoint is Painful Nodules/Induration (composite endpoint of grade 1-3 ongoing pain and either (a) grade 3-4 induration (≥25 mm) or (b) grade 2-4 nodules/cysts (>20 mm) when using the B2000 NFID, in comparison to a standard 27G ½” needle/syringe (NS), during chronic self-administration).
Secondary: To determine the adherence, overall satisfaction, and preference for chronic self-administration of Fuzeon between the B2000 NFID and a 27G ½” needle/syringe. To determine and compare the pre-dose steady-state Ctrough levels of Fuzeon following chronic self-administration with the B2000 NFID vs. the 27G ½” needle/syringe for abdominal injections.
Methodology:
During the 28-day evaluation period, subjects self-administered 56 injections with each assigned device. For consistency, it was recommended that subject give injections while in a similar body position (always sitting, always standing, etc). Any ISR present at the in-clinic evaluations (ongoing ISR) were evaluated and recorded by severity grade and body location by a treatment-blinded clinician. Four pre-AM blood samples per dosing period were drawn for the determination of Ctrough.
Number of patients (planned/analyzed):
58 randomized. 48 in safety analysis. 28 in ISR analysis.
Diagnosis and main criteria for inclusion:
Fuzeon-naïve HIV-1 infected adults (≥18) with no active untreated opportunistic infections.
Test product, dose and mode of administration or test procedure:
Fuzeon 90 mg/mL sc bid with either a 27G ½" needle/syringe (NS) or Biojector 2000 (B2000) device for 28 days each.
Duration of treatment:
56 days.
Reference therapy, dose and mode of administration or reference procedure:
N/A
Criteria for evaluation (efficacy, safety):
Efficacy: No efficacy parameters were evaluated in this trial.
Pharmacodynamics: No pharmacodynamic parameters were evaluated in this trial.
Pharmacokinetics: Steady-state Ctrough assessments only for abdominal injections with each device.
Safety: Treatment-emergent Adverse Events, AIDS-defining events, graded laboratory toxicities, and injection site reactions (ISR).
Subject preference/satisfaction: After completing dosing periods with both devices, subjects were asked to state which device they preferred and with which they were more satisfied.
Statistical methods:
Forty evaluable subjects treated with each device would allow estimation with 95% confidence of the difference in responses between devices of less than 15% (half-width of 95% CI), assuming an observed response rate of 45% for the incidence of subjects having the painful ISRs primary endpoint. Based on an expected binary endpoint of 45% with NS administration of Fuzeon, an assumed discordant pairs rate of 27%, and employing a 2-sided exact McNemar's test for paired binary data at a 5% significance level, 40 subjects would allow for detection of a statistically significant difference of 23% with 80% probability.
Summary (efficacy, safety, other results):
Safety: Mean subject adherence was similar between the two devices (97.7% B2000 and 98.3% NS). A similar number of subjects experienced AEs on the B2000 (22/44) as compared to the needle/syringe (22/46). Four subjects experienced SAEs during this trial, 2 in the B2000 arm and 2 in the needle/syringe arm. None of the SAEs was considered related to Fuzeon. One SAE (hematoma) was considered related to the B2000 device but the subject elected to continue dosing with the B2000 for the remainder of the trial and thereafter. One subject withdrew from the trial due to an ISR experienced while dosing with the NS.
ISR results:A total of 40 patients were dosed with both devices. Of these, 12 patients from one site were excluded from the ISR analysis due to flawed ISR evaluations, leaving an ISR population of 28 patients.
Across all injection locations, fewer subjects on the B2000 experienced Painful ISRs (31%) compared to those on the needle/syringe (59%, p=0.004).
Fewer subjects experienced any Grade 2-4 ISR in the abdomen or the arm/thigh on the B2000 (68%) vs. NS (86%; p=0.025). Fewer subjects experienced any grade (G1-3) of ongoing abdominal pain/discomfort on the B2000 (75%) compared to those on the NS (96%; p=0.014). Fewer subjects experienced any grade (G1-3) ongoing pain/discomfort in all injection locations on the B2000 compared to the NS (79% B2000 vs. 96% NS; p=0.025).
Fewer subjects experienced any grade of abdominal ecchymosis on the B2000 (36%) compared to the NS (61%; p=0.020). More subjects experienced G2-4 ecchymosis on the B2000 (29%) vs. NS (11%; p=0.025) in the arm/thigh with abdomen as an optional site. Fewer subjects experienced abdominal G2-3 pruritus on the B2000 (7%) than the NS (21%; p=0.046).
A weighted overall ISR severity summary score was derived by totalling the severity grades for each individual sign/symptom, and dividing by the total number of individual ISRs present. Across all injection sites, the median weighted overall ISR severity summary score was lower on the B2000 (2.6, range 0.3-5.9) compared to the needle/syringe (3.6 , range 0.4-7.9; p=0.0183).
Overall subject preference/satisfaction: 31 subjects (83.8%) preferred and were more satisfied with the B2000 for administration of Fuzeon compared to 6 subjects (16.2%) who preferred and were more satisfied with the needle/syringe.
Pharmacokinetics: The ratio of the LS means for Ctrough between the two devices was 0.817 (B2000/27G NS), which fell within the 90% CI of 0.612, 1.092.
Conclusions:
The B2000 constitutes a safe, viable and preferred option for the chronic self-administration of Fuzeon and may offer significant improvements in Painful ISRs, ongoing pain/discomfort, ecchymosis and pruritus in comparison to a standard needle/syringe.
Publications (references, if available):
Needle-free Administration Of Enfuvirtide Significantly Reduces Incidence Of Painful Injection Site Reactions: Results From A Single Blind, Randomized, Controlled Study. Abstract #1905b, 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA, USA, Sept 27-30, 2006.
