Clinical Trial Result Information

Title of Study:
Fuzeon® Biojector® 2000 Open-Label Safety Study (BOSS).

Fast Facts:

Protocol number:	ML19849
Sponsor:	Hoffmann-La Roche
Company division:	Pharmaceutical
Product name:	Fuzeon
Generic name:	enfuvirtide
Phase of development:	IV
Therapeutic area, approved indication:	HIV Infections
Date of report:	6/1/2007

Clinical study summary:
This was a prospective, 8-week, multicenter, open-label, randomized trial to compare injection site reactions associated with 2 injection devices for administration of Fuzeon. Patients were randomized to receive Fuzeon (enfuvirtide) via either a needle/syringe, or a needle-free injection device. After 4 weeks, all patients received Fuzeon via the needle-free injection device for the remainder of the study.

Study center(s) :
42 centers in the United States.

Objectives:
Primary: To compare injection site reaction (ISR) signs and symptoms associated with Fuzeon  injection using needle/syringe (NS) versus Biojector 2000 (B2000) needle-free injection device (NFID) based on a composite endpoint of grade 1-3 ongoing pain and either (a) grade 3-4 induration (≥25mm)  or (b) grade 2-4 nodules/cysts (>20mm); to compare the incidence and severity of individual clinical signs and symptoms of ISR associated with Fuzeon injection using NS versus B2000 NFID.
Secondary: To evaluate the following during self-administration of Fuzeon using the B2000; Fuzeon safety/tolerability based on frequency  and severity of ISR signs and symptoms; overall Fuzeon exposure and time to discontinuation; Fuzeon adherence, patient satisfaction, and preference.

Methodology:
At the baseline, prior to randomization, eligible patients were stratified into 1 of 4 groups based on previous/current Fuzeon use, and presence of an ISR (characterized by grade 1-3 ongoing pain and either grade 3-4 induration or grade 2-4 nodules/cysts). After stratification patients were randomized 2:1 to B2000 NFID or standard 27G½" NS. Patients randomized to B2000 self-administered Fuzeon using B2000 beginning at the baseline visit through the end of the study. Patients randomized to standard NS self-administered Fuzeon using NS at the baseline visit through week 4. At the week 4 visit after IRS assessments, patients randomized to standard NS switched to B2000 through the end of the study.
Patient safety monitoring by the investigator was per standard of care. Patients returned to the clinic for assessments at week 4 and week 8. In-clinic ISR evaluations were made at baseline, week 4 and week 8. The clinician conducting the in-clinic ISR evaluations was blinded to the injection device through week 4.

Number of patients (planned/analyzed):
Planned: Up to 300 patients. Analyzed: 317 patients.

Diagnosis and main criteria for inclusion:
HIV-1 infected, Fuzeon-experienced males and females ≥16 years of age who had difficulty tolerating long-term (>4 weeks) administration of Fuzeon with standard needle and syringe and who could benefit from needle-free administration of Fuzeon.

Test product, dose and mode of administration or test procedure:
Fuzeon (enfuvirtide) 90mg / SC / BID (total daily dose 180mg).

Duration of treatment:
8 weeks

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

Criteria for evaluation (efficacy, safety):
Tolerability: Primary: Signs and symptoms associated with Fuzeon injection based on a composite endpoint of grade 1-3 ongoing pain and either (a) grade 3-4 induration (≥25mm) or (b) grade 2-4 nodules/cysts (>20mm); incidence and severity of individual clinical signs and symptoms of ISR. This composite endpoint had not been clinically validated.
Secondary: Overall ISR score based on in-clinic signs and symptoms of ISRs; incidence of patients discontinuing the study due to clinical adverse events (AEs) and ISRs.

Safety: Incidence of serious adverse events (SAEs), serious AIDs-defining events, and AEs of special interest defined as any device-related AE other than the expected signs or symptoms of localized ISRs; incidence of AEs leading to discontinuation; incidence of death.

Statistical methods:
Tolerability: The dichotomous response indication whether or not a patient met the composite primary endpoint at week 4 on each assigned device was analyzed using a Cochran-Mantel-Haenszel chi squared test with 4 strata (combinations of current/interrupted Fuzeon usage, and with/without painful bumps at the screening visit).
The difference in maximum severity grades associated with NS administration during the first 4 weeks of the study versus administration with the B2000 during the second 4 weeks was calculated. These difference scores were further collapsed into mutually exclusive categories as 'improved', 'worsened' and 'no change'.
Frequency and severity was combined into an overall ISR score, calculated for each individual sign/symptom. The individual scores were summed to give an overall total ISR score for each visit. The ISR scores were summarized by device, and statistical significance was determined using the Wilcoxon signed rank test and Wilcoxon ranked sum test for within-subject and between-subject comparison, respectively.
Where applicable, analysis of other parameters was conducted in a similar fashion to that of the primary ISR tolerability endpoints.

Summary (efficacy, safety, other results):
αTolerability: The percentage of patients meeting composite primary endpoint criteria (painful induration or nodules/cysts) at week 4 was statistically significantly lower in the B2000 group (25.4%) than the NS→B2000 group (45.1%) (P=0.0003). In the B2000 group, the percentage of patients meeting the composite endpoint decreased from baseline (40.1%) to week 4 (25.4%) and remained relatively stable at week 8 (21.2%). In the NS→B2000 group, the percentage of patients meeting the composite endpoint increased from baseline (36.5%) to week 4 (45.1%) when patients were using NS for Fuzeon injections and decreased from week 4 (45.1%) to week 8 (26.1%) after the switch when patients were using B2000 for Fuzeon injections.
With the exception of ecchymosis, the percentage of patients with each individual sign and symptom (any severity grade) at week 4 was modestly lower when using B2000 than when using NS for Fuzeon injections. For ecchymosis, the percentage of patients experiencing any severity grade reaction at week 4 was similar when using B2000 (28.8%) versus NS (26.5%).

Evaluation of individual ISR signs and symptoms by maximum severity grade showed that with the exception of ecchymosis, a higher percentage of patients in the B2000 group relative to the NS→B2000 group did not experience individual ISR signs and symptoms (ie grade 0) at week 4. For ecchymosis, the percentage of patients who did not experience this reaction at week 4 was similar in the B2000 group (71.2%) and the NS→B2000 group (73.5%). Except for ecchymosis, the percentage of patients with grade 3/4 ISR signs and symptoms at week 4 was lower in the B2000 group than in the NS→B2000 group: ongoing pain/discomfort (2.4% vs 4.9%, respectively), erythema (15.6% vs 23.5% respectively), induration (39.5% vs 52.9%, respectively), nodules/cysts (16.6% vs 18.6%, respectively). For ecchymosis, the percentage of patients with grade 3/4 reaction at week 4 was higher in the B2000 group than in the NS→B2000 group (9.3% vs 3.9%, respectively).

The mean number of ISRs decreased from baseline to week 4 and from baseline to week 8 in the B2000 group for all ISRs combined and for each individual sign/symptom, except ecchymosis. In the NS→B2000 group, for all ISRs combined and for each individual sign/symptom except ecchymosis, the mean number of ISRs decreased from week 4 to week 8 after the switch when patients were using B2000 for Fuzeon injections. From baseline to week 4 when patients were using NS, the mean number of ISRs either increased or decreased to a lesser extent relative to the B2000 group. For ecchymosis, there was no consistent trend with either device in the change from baseline to week 4 or to week 8 in the mean number of ISRs.

Secondary Tolerability Endpoints: The between-patient comparison (B2000 group versus NS→B2000 group) showed a statistically significantly greater mean decrease from baseline to week 4 in overall ISR score when administering Fuzeon with B2000 (5.3) relative to NS (-0.4) (P=0.003). The within-patient comparison (NS→B2000 group, week 4 vs. week 8 assessment) also showed a statistically significantly greater mean decrease from baseline to the post-use endpoint in overall ISR score when administering Fuzeon with B2000 (-7.5) relative to NS (0.0) (P<0.0001).
Thirteen (13) patients using B2000 to administer Fuzeon discontinued the study due to 1 or more ISRs. There were no discontinuations due to ISRs among patients using NS. Data collected for B2000 was pooled from both device groups and therefore reflects a longer time period of use than NS. There were no serious ISRs during the study.

Safety: Adverse events resulting in discontinuation of Fuzeon, all judged to be unrelated to trial medication, occurred in 3 (0.9%) patients administering Fuzeon with B2000 and 1 (1.0%) patient administering Fuzeon with NS.
Adverse events of special interest for this study were defined as any device-related AE other than the expected signs or symptoms of localized ISRs. Ten patients experienced 14 AEs of special interest, all while administering Fuzeon with B2000. The most common AE of special interest was bleeding (hemorrhage/hematoma in 5 patients). Pain (pain in extremities/neuralgia) was reported as an AE of special interest in 2 patients. None of these AEs of special interest met the criteria for an SAE.
Six (1.9%) patients administering Fuzeon with B2000 and 4 (3.8%) patients administering Fuzeon with NS had 1 or more SAEs during the study. Headache was the only SAE that occurred in more than 1 patient. No patients met the criteria for a serious AIDS-defining event. All SAEs were judged by the investigator to be unrelated to trial medication.
There were 2 unrelated deaths during the study, 1 when Fuzeon was being administered with B2000 and 1 when Fuzeon was being administered with NS. None of the AEs leading to death were considered by the investigator to be related to the trial medication.

Conclusions:
At week 4, a statistically significantly lower percentage of patients had painful injection site induration or nodules/cysts (primary composite endpoint; not clinically validated) when Fuzeon was administered with B2000 than when Fuzeon was administered with NS.
With the exception of ecchymosis, the incidence and severity of individual ISRs at week 4 was lower when Fuzeon was administered with B2000 than when Fuzeon was administered with NS. For ecchymosis, incidence and severity were similar when using B2000 versus NS. However, the percentage of patients with grade 3/4 ecchymosis at week 4 was higher when using B2000 versus NS (9.3% versus 3.9%, respectively).
Both between-patient and within patient comparisons showed a statistically significant greater mean decrease in overall ISR score from baseline to the post-use endpoint when using B2000 relative to administer Fuzeon.
Thirteen patients using B2000 to administer Fuzeon discontinued the study due to ISRs. There were no discontinuations due to ISRs among patients using NS, which could be due to the lack of an alternative device after the use of NS. There were no serious ISRs during the study.
Adverse events of special interest, defined as any device-related AE other than the expected signs or symptoms of localized ISRs, were reported in 10 patients, all of whom were administering Fuzeon with B2000.

Publications (references, if available):
Lalezari J, Saag M, Walworth C et al. Injection site reactions in the BOSS study: enfuvirtide injection with a needle-free injection device or standard needle-syringe. Abstract accepted at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

http://www.liebertonline.com/doi/abs/10.1089/aid.2007.0251

Lalezari J, Saag M, Walworth C, Larson P . An Open-Label Safety Study of Enfuvirtide Injection with a Needle-Free Injection Device or Needle/Syringe: the Biojector 2000 Open-label Safety Study (BOSS) . AIDS Res Hum Retroviruses. 2008;24:805-813.

Click here for the protocol registry listing of this trial.