Clinical Trial Result Information

Title of Study:
Prospective, open-label, multicenter, cohort study to assess HIV-1 patient QUAlity of LIfe and Tolerability after administration of Enfuvirtide-containing HAART (QUALITE study).

Fast Facts:

Protocol number:	ML18018
Sponsor:	Roche Laboratories Inc.
Company division:	Pharmaceutical
Product name:	Fuzeon
Generic name:	enfuvirtide
Phase of development:	IV
Therapeutic area, approved indication:	HIV infection
Date of report:	3/1/2006

Clinical study summary:
This was a prospective, 12 week, multicenter, open-label study to assess the effect of Fuzeon–containing HAART on quality of life in HIV-infected, treatment-experienced patients.

Study center(s) :
80 centers in the United States

Objectives:
Primary: To identify potentially important factors that predict quality-of-life (QoL) improvement at 12 weeks in clinically stable, HIV-1-infected, treatment-experienced patients receiving a highly active antiretroviral therapy (HAART) that included Fuzeon (enfuvirtide) administered using a syringe with a 31-gauge, 8mm needle.
Secondary: To determine the change from baseline in QoL after 12 weeks of Fuzeon therapy using the MOS-HIV survey; to determine the change from baseline in HIV-1 RNA viral load (log10 copies/mL) and in CD4+ lymphocyte count at Week 12; to investigate the association between clinical improvement and QoL improvement; to determine the incidence of significant (≥Grade 2) injection site reactions (ISRs) in patients using a syringe with a 31-gauge, 8mm needle when administering Fuzeon therapy; to describe the characteristics of ISRs, based on an ISR-grading tool; to assess patient ease of injection and impact on daily functioning and activities of daily living; to assess patient adherence to Fuzeon therapy; to assess serious adverse events (SAEs), any adverse events (AEs) leading to study discontinuation, and all events resulting in death, including those up to 28 days after treatment.

Methodology:
After screening and eligibility were confirmed, patients were switched to a Fuzeon containing ARV regimen. Choice of the ARV regimen to be used with Fuzeon was at the discretion of the investigator, based on the patient’s treatment history and resistance testing, if available. Fuzeon was administered as a 90 mg subcutaneous injection given twice daily (total daily dose of 180 mg) using a syringe with a 31-gauge, 8-mm needle.
Patients returned to the clinic for assessments at Weeks 1, 4, 8 and 12/early termination. A follow up visit was scheduled to occur at least 4 weeks after the patient’s final visit.

Number of patients (planned/analyzed):
Planned: 325. Enrolled: 361.

Diagnosis and main criteria for inclusion:
HIV-1-infected, treatment-experienced adults and adolescents (≥16 years of age) who were clinically stable with CD4+ counts >50 cells/mm³ and fusion inhibitor naïve. Patients had to be willing to change their current antiretroviral (ARV) regimen to a Fuzeon-containing ARV regimen and consent to clinical assessments.

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

Duration of treatment:
12 weeks.

Criteria for evaluation (efficacy, safety):
Primary: Assessment of disease severity and demographics as predictors of improvement in quality of life as measured by improvement in MOS-HIV physical function score >3. Quality of life was assessed using MOS-HIV scores at baseline and at week 12 or at premature study discontinuation.
Secondary: Change from baseline in MOS-HIV physical and mental health summary scores at Week 12 or premature discontinuation; change from baseline in the MOS-HIV Item 1 (general health) and Item 12 (QoL) scores at Weeks 4 and 8; change from baseline in HIV-1 RNA viral load (log10 copies/mL) and CD4+ lymphocyte count at Week 12 or at premature study drug discontinuation; number and percentage of patients with ≥1 ongoing/present ISRs through Week 12; number and percentage of patients discontinuing Fuzeon due to a local ISR or who experienced a serious ISR; mean patient count for ongoing/present ISRs by severity grade of pain/discomfort or other ISR signs and symptoms by visit; number and percentage of local ISRs by severity grade of immediate or reactive pain since last visit by week of study; number and percentage of most frequent type of pain experienced since the last visit by week of study; assessment of ease of injection, and performance of daily activities at Week 12 or at premature study drug discontinuation, using SIS scales; patient adherence.
Safety: Incidence of SAEs, AEs leading to premature study drug discontinuation, and all AEs resulting in death, including those up to 28 days after treatment discontinuation.

Statistical methods:
The primary study parameter was assessment of disease severity and demographics as predictors of improvement in quality of life (assessed by MOS-HIV scores). Improvement in QoL was defined as (0/1), derived from the MOS-HIV 6-item physical function scale. The derived score could take 2 possible values: 1 for positive change scores (>3.0) in MOS-HIV physical function scale and 0 (zero) for otherwise.
Logistic regression models were used to identify potentially important factors that predicted that the binary QoL improvement outcome. The significance of the predictor variables was determined after adjusting for potential confounding variables: age, gender, race, BMI, marital status, level of education, and baseline disease status (HIV-1 RNA viral load, CD4+ count, and number of prior ARVs).
The following secondary analyses were planned: MOS-HIV mean change score: descriptive statistics and 95% confidence interval; HIV-1 RNA viral load and CD4+ lymphocyte count: descriptive statistics; HIV-1 RNA viral load, CD4+ lymphocyte count, and MOS-HIV score: exploratory analysis using analysis of covariance (ANCOVA); association between improved QoL and clinical outcome: multiple regression model; interaction between demographics and patient characteristics, disease status and outcomes: regression tree model; injection site reaction analysis: descriptive statistics; subcutaneous injection survey: descriptive statistics and 95% confidence interval; patient adherence to Fuzeon: descriptive statistics.
Descriptive statistics of safety data were reported.

Summary (efficacy, safety, other results):
Efficacy: Primary: The primary objective of this study was to evaluate potential predictors of improvement in quality of life, including change in disease severity and demographics. There were statistically significant improvements from baseline in disease severity and demographics. There were statistically significant improvements from baseline at Week 12 in both the physical function (P=0.0002) and mental health (P=0.0006) domains of the MOS-HIV health survey. However, none of the baseline variables were strong predictors for the binary quality-of-life improvement outcome. In the ITT population, baseline CD4+ count was identified as the potential predictor of binary quality-of-life improvement outcome. This factor, however, was not statistically significant when applying a stepwise model selection in logistic regression analysis. For the per-protocol population, baseline CD4+ count and marital status were identified as potential predictors. Neither variable was statistically significant. Therefore, no statistically significant predictors of quality-of-life improvement were identified in this study.

Secondary: The results of the analysis of change from baseline to Week 12 in the MOS-HIV health survey showed statistically significant improvement for both the physical function and mental health domains of the MOS-HIV questionnaire. For physical function, the least squares mean (LSM) mean change from baseline to Week 12 was 4.932 (95% CI [2.374, 7.490]; P=0.0002). For mental health, the LSM mean change from baseline to Week 12 was 3.636 (95% CI [1.571, 5.701]; P=0.0006). Statistically significant improvement was also shown for the 2 aggregate summary scales: physical function and mental health (P<0.0001). Most of the other domain scores of the MOS-HIV also showed statistically significant improvement. Only social function and role function were not statistically significantly improved.
Clinical outcome in this study was measured by viral load and CD4+ count at Week 12 relative to baseline. The mean change (±SD) in log10 HIV-1 RNA (copies/mL) for the 292 patients in the ITT population with values at both baseline and Week 12/early termination was -1.10 (±1.211) (range, -5.10 to 2.33). At Week 12, 53.1% of patients had a viral load of <400 copies/mL and 18.2% had a viral load <50 copies/mL; 63.9% of patients had at least a 0.5 log10 decrease from baseline in viral load, and 49.4% of patients had at least a 1.0 log10 decrease from baseline in viral load. The mean change (±SD) in CD4+ count (cells/mm³) for the 305 patients in the ITT population with values at both baseline and Week 12/early termination was 46 (±117.4) (range, -511 to 526).
Most (86.8%) patients experienced at least 1 local reaction associated with Fuzeon injection. A total of 210 (59.2%) patients had at least 1 ISR whose worst pain/discomfort grade was ≤1, and 98 (27.6%) had at least 1 ISR whose worst pain/discomfort grade was ≥2. There were no ISRs that met the criteria for a serious adverse event in this study, and the proportion of patients who discontinued Fuzeon due to ISRs was small (10[2.8%] patients).
In the SIS questionnaire, the majority of patients assessed all 5 items on the ease of injection subscale as ‘very easy’ or ‘easy’ ( range 69.7% to 89.5%). Most patients reported that Fuzeon injections had little impact on their daily functioning. The proportion of patients who rated the 9 items on the daily functioning subscale as limiting their ability ‘not at all’ or ‘a little’ ranged from 76.0% to 90.4%. Nearly all patients assessed the 3 items on the activities of daily living subscale as limiting their ability ‘not at all’ or ‘a little’( range, 94.9% to 97.4%).
Overall, the patients in this study demonstrated good adherence, considering that the treatment was self-administered. More than 90% of patients reported ≥85% adherence at Weeks 1 through 8, and approximately 80% of patients reported ≥85% adherence at Week 12.
Safety: Twenty-six patients experienced 41 SAEs during treatment or up to 28 days after discontinuing treatment. Sixteen patients had SAEs associated with infections and infestations. All other SAEs occurred in less than 1% of the study population. Of the 41 SAEs reported, 36 SAEs were judged by the investigator to be unrelated to trial treatment. One SAE (hepatic failure) was judged by the investigator to be remotely related to treatment, 2 SAEs (pneumonia and bacterial pneumonia) were assessed as possibly related to treatment, and 2 SAEs (pneumonia and immune reconstitution syndrome) were assessed as probably related to treatment.
Six deaths were reported; 3 deaths occurred during the treatment period and 3 occurred after treatment was discontinued. Most deaths were associated with HIV disease, ie hepatic failure, drug toxicity, Pneumocystis jiroveci pneumonia and pneumonia. The other 2 deaths were accidental deaths (gun shot wound, traffic accident). All deaths were rated by the investigator as unrelated to treatment, with the exception of the death caused by hepatic failure (rated remotely related to treatment).
Eight patients discontinued trial treatment due to a nonserious adverse event. Of these 8 AEs, 1 (urticaria) was judged by the investigator to be unrelated to trial treatment, 1 (abdominal pain) was rated remotely related to trial treatment, 5 (skin rash, peripheral edema, herpes simplex, pain in extremity, and dizziness) were rated possibly related to trial treatment, and 1 (palpitations) was rated probably related to trial treatment.

Conclusions:
Statistically significant improvement from baseline in physical function and mental health was observed in HIV-1-infected patients treated with a Fuzeon-containing ARV regimen for up to 12 weeks. However, none of the baseline variables were statistically significant predictors for the binary quality-of-life improvement outcome.
Patients in the study achieved statistically significant and clinically meaningful improvement in viral load and CD4+ cell count.
The prevalence of any ISR symptom ≥Grade 2 was low with an average of <1 ISR per visit and the majority of patients experiencing either no or minor ISRs at Week 12. The discontinuation rate due to ISRs was low and there were no serious ISRs.
The majority of patients reported that self-injection of Fuzeon was ‘easy’ or ‘very easy’; the self-injection process had little impact on their daily function.
Treatment with a Fuzeon (90 mg BID)-containing ARV regimen for up to 12 weeks was generally safe and well tolerated in treatment-experienced HIV-1 patients, and adherence was good. The thin-walled, 31-gauge/8mm needles were generally well tolerated and represent a viable Fuzeon administration option.

Publications (references, if available):
Shalit P, True A, Thommes JA, on behalf of the QUALITE Investigators. Quality of Life and Tolerability After Administration of Enfuvirtide With a Thin-Walled Needle. HIV Clin Trials. 2007;8:24-35.

Click here for the protocol registry listing of this trial.