Clinical Trial Result Information
Protocol number
ML19712
Title of Study
A multicenter, open-label study evaluating the safety and efficacy of a new protease inhibitor (Darunavir) with Fuzeon (enfuvirtide) plus background antiretroviral regimen in HIV-1 infected, triple-class treatment experienced patients (BLQ Study).
Sponsor
Hoffmann-La Roche
Company division
Pharmaceutical
Product name
Fuzeon
Generic name
enfuvirtide
Therapeutic area
HIV Infections
Clinical study summary
This was a prospective, multicenter, single-arm, open-label, 24-week study to assess the efficacy and safety of treatment with darunavir/ritonavir + Fuzeon + a background antiretroviral regimen in Fuzeon-naive HIV-1 infected patients.
Study center(s)
28 centers in the United States.
Phase of development
IV
Objectives
Primary: To evaluate the efficacy of a new PI (darunavir) with Fuzeon in HIV-1 infected, triple-class treatment experienced, Fuzeon naive adults.
Secondary: To evaluate the safety, adherence, and tolerability of Fuzeon with a new PI (darunavir) in HIV-1 infected, triple-class treatment-experienced, Fuzeon-naive adults.
Methodology
After the baseline visit, eligible patients started treatment on the following regimen: Fuzeon 90mg sc bid + new PI (darunavir/ritonavir) + other investigator-choice ARVs. Darunavir/ritonavir was administered according to the procedures of the early access program or, post-approval and post-termination of the early access program at a dosage of 600mg/100mg po bid. Patients selected their preferred injection device among the following 3 options: 27G½" needle/syringe, 31G 8mm needle/syringe or Biojector 2000 (B2000) needle-free injection device (NFID). Patients self-administered injections as outpatients.
Efficacy, tolerability, and safety assessments took place at clinic visits at the end of weeks 1, 4, 12, 16 and 24. Patients returned for a follow-up safety visit 4 weeks after the end of treatment.
Number of patients (planned/analyzed)
Planned: 120 patients. Enrolled: 137 patients.
Diagnosis and main criteria for inclusion
HIV-1 infected, triple-class treatment experienced, Fuzeon-naive, darunavir-naive adults (≥18 years of age) with an HIV-1 RNA viral load >2,000 copies/mL.
Test product, dose and mode of administration or test procedure
Fuzeon (enfuvirtide) 90mg sc bid + darunaivr/ritonavir 600mg/100mg bid + other investigator choice ARV regimen.
Duration of treatment
24 weeks
Reference therapy, dose and mode of administration or reference procedure
N/A.
Criteria for evaluation (efficacy, safety)
Primary: Number and percentage of patients with plasma HIV-1 RNA <50 copies/mL at week 24.
Secondary: Number and percentage of patients with plasma HIV-1 RNA <50 copies/mL at weeks 4 and 12; number and percentage of patients with plasma HIV-1 RNA <400 copies/mL at weeks 4, 12 and 24; change from baseline in plasma HIV-1 RNA and CD4+ lymphocyte count at weeks 4, 12 and 24; number and percentage of patients meeting virologic failure criteria at week 12 and week 24; number and percentage of patients adhering to Fuzeon at weeks 4, 12, and 24; descriptive summary of injection site reactions (ISRs).
Safety: Serious adverse events (SAEs), including all deaths, serious AIDs-defining events, premature discontinuations, localized ISRs.
Statistical methods
Primary efficacy: For the primary efficacy endpoint, a statistical test of the null hypothesis of responder rate less than or equal to the predefined rate was conducted, where the predefined responder rate was set as 43% of patients achieving HIV-1 RNA ≤50 copies/mL at week 24.
A 1-sided 97.5% CIs was constructed for the proportion of patients with viral load <50% copies/mL at week 24 using the normal approximation to the binomial distribution. The null hypothesis would be rejected if the lower limit of the CI was greater than the predefined rate.
Secondary Efficacy: The proportion of patients with viral load <50 copies/mL and <400 copies/mL at weeks 4, 12 and 24 were summarized with 2-sided 95% CIs using the normal approximation to the binomial distribution. Changes from baseline in log10 plasma HIV-1 RNA viral load and CD4+ lymphocycte count were summarized.
Tolerability: The number and percentage of patients adhering to the Fuzeon regimen were tabulated. The correlation of cumulative adherence with patient characteristics and clinical outcome was assessed by Pearson correlation coefficients.
The number and percentage of patients with ISRs were summarized by device. The number and percentage of patients who experienced serious ISRs or who discontinued Fuzeon due to 1 or more local ISRs during the study were summarized by device.
Safety: All deaths, SAEs and adverse events leading to premature discontinuation were tabulated by severity and relationship to study medication.
Summary (efficacy, safety, other results)
Efficacy: Seventy-nine (60.3%) patients had an HIV-1 RNA viral load <50 copies/mL at week 24. The lower limit of the 1-sided 97.5% CI (CI=51.5%) was greater than 43%; therefore, the study null hypothesis of responder rate less than or equal to the predefined rate was rejected.
Week 24 virologic and immunologic response data (ITT population) were as follows:
| No (%) patients with an HIV-1 RNA <50 copies/mL
|
79 (60.3%)
|
| No. (%) patients with an HIV-1 RNA <400 copies/mL
|
95 (72.5%)
|
| Mean (SD) change from baseline in log10 HIV-1 RNA (copies/mL)1
|
-2.61 (1.099)
|
| Mean (SD) change from baseline in CD4+ count (/mm3)1
|
89 (103.4)
|
1 P<0.0001 based on analysis of covariance
Virologic response rates (both HIV-1 RNA <50 copies/mL and <400 copies/mL) were similar for the ITT and per-protocol analyses. For all analyses, the data showed a progressive increase from week 2 to week 24 in the percentage of patients achieving virologic response. A statistically significant mean decrease from baseline in log10 HIV-1 RNA and a statistically significant mean increase from baseline in CD4+ count were observed at all weeks in all analyses (ie ITT, LOCF and per-protocol).
Twenty-one (16.0%) and 55 (42.0%) patients met protocol-defined virological failure criteria at week 12 and week 24, respectively. Of the 110 patients who achieved virologic success at week 12, 67.3% (74/110) remained virologic success at week 24.
Tolerability: Of the 131 patients with available information, the mean cumulative adherence (SD) was 95.7% (10.54%) with a median (range) of 100.0% (20.8% to 100.0%). No statistically significant correlation was found between patient cumulative adherence and age, BMI, change in HIV-1 RNA, or change in CD4+ count.
The majority (109 [83.2%] at week 1) of patients selected Biojector 2000 NFID; 20 (15.3%) patients selected the 31G 8mm insulin needle/syringe and 2 (1.5%) patients selected the 27G ½” needle/syringe. There were no serious ISRs. One patient discontinued treatment at week 1 due to ISRs during use of B2000. In total, 107 (78.1%) patients had 1 or more ISR. The median time to first ISR was 8 days.
Significant (grade ≥2) ISRs were reported by 79/119 (66.4%) patients who used B2000, 26/30 (86.7%) patients who used the 31G 8mm insulin needle/syringe, and 2/2 (100%) patients who used the 27G ½” needle syringe. In general, erythema and induration were the most common signs and symptoms observed overall and at each week. The percentages of patients with grade ≥2 ISRs were generally comparable between the 31G 8mm needle/syringe and the B2000. Since only 2 patients used the 27G ½” needle/syringe, comparison of the results from this device with the other 2 devices is not meaningful.
For most ISRs, the worst grade during the 24-week treatment period was grade 1 or grade 2 for all signs and symptoms and for all injection devices. In general, induration, followed by nodules/cysts and ecchymosis were the most common signs and symptoms with worst grade 3/4 at each week. The percentages of patients with worst grade 3/4 ISRs were generally comparable between the 31G 8mm insulin needle/syringe and the B2000.
Safety: There was 1 unrelated death (due to sepsis) during the study. Thirteen patients had a total of 19 SAEs. Cellulitis, pneumonia, sepsis, and renal failure were the only SAEs that occurred in more than 1 patient. Of the 19 SAEs, only 1 (decreased neutrophil count) was judged to be remotely related to study medication. Two patients had serious AIDS-defining events (pneumonia and Pneumocystis jiroveci pneumonia).
Three patients had AEs that caused discontinuation of treatment (both Fuzeon and the new PI). Adverse events resulting in discontinuation included non-serious rash judged by the investigator as possibly related to the trial treatment and upper gastrointestinal hemorrhage (SAE) judged by the investigator as unrelated to the trial treatment.
One patient developed non-serious cellulitus while administering Fuzeon with B2000. The investigator considered the cellulitis to be possibly related to the injection and possibly related to Fuzeon.
Conclusions
The addition of Fuzeon to treatment regimens containing darunavir/ritonavir plus ARV background therapy yielded high 24-week virologic and immunologic responses in HIV-1 infected, triple-class treatment-experienced, Fuzeon-naive patients.
The Fuzeon-containing treatment regimens used in this study were generally well tolerated.
There were no serious ISRs during this study. One patient had ISRs during the use of B2000 that resulted in discontinuation of treatment at week 1. Erythema and induration were the most common signs and symptoms. For most ISRs, the worst grade was grade 1 or grade 2.
Of the 19 SAEs, only 1 was judged to be remotely related to study medication. Three patients had AEs that caused discontinuation of treatment, including 1 death from sepsis that was considered unrelated to study drug.
Publications (references, if available)
DeJesus E, Farthing C, Gottlieb M et al. Response to darunavir/ritonavir (DRV/r) combined with enfuvirtide (ENF)-containing ARV in triple-class experienced patients was not predicted by baseline darunavir (DRV) sensitivity or viral tropism (VT): The BLQ Study Final Results. Abstract for the 47th ICAAC, 2007; 291, H-367.
Date of report
9/3/2007
Click here for the protocol registry listing of this trial.
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