A Study to Evaluate the Safety and Efficacy of Adding Enfuvirtide to Oral Highly Active Antiretroviral Therapy (HAART) in Human Immunodeficiency Virus (HIV) Patients With Prior Treatment Experience

Study Overview
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Brief Summary
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To assess the efficacy of enfuvirtide (Fuzeon) added to HAART compared to treatment with HAART alone in achieving and maintaining viral load suppression.

Detailed Description
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This study consisted of two phases. In the Induction phase patients were randomized at Baseline 1 (BL1) in a 1:2 ratio to receive: I1: HAART or I2: Enfuvirtide (90 mg twice a day) + HAART. Participants who achieved viral suppression < 50 copies/mL by week 24, confirmed by week 28 or earlier, qualified to enter the Maintenance Phase which started at Baseline 2 (BL2), four weeks after confirmation of response. The Maintenance Phase consisted of three treatment groups: M1: HAART continued (patients from I1) Patients on ENF+HAART (I2) were re-randomized (at a 1:1 ratio) at BL2 to: M2: Enfuvirtide stopped and HAART continued M3: Enfuvirtide + HAART continued. The duration of the Maintenance Phase was from BL2 up to 48 weeks after BL1. BL2 could start at the earliest at Week 12 and at the latest Week 32.

Official Title
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Phase IIIb/IV Randomized, Controlled Study Evaluating an Intensification Treatment Strategy of Adding Enfuvirtide (ENF) to an Oral Highly Active AntiRetroviral Therapy (HAART) in Treatment Experienced Patients

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Enfuvirtide
* Drug: Highly active antiretroviral treatment (HAART)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected adults >=18 years of age; currently on antiretroviral (ARV) therapy; previously treated with 2 or 3 different antiretroviral classes; HIV-1 Ribonucleic acid (RNA) >=1,000 copies/mL; Cluster differentiation antigen four (CD4) lymphocyte count >=200 cells/mm^3; females of childbearing potential must be willing to use a reliable form of effective barrier contraception for the duration of the study and for 30 days after the last dose of study drug. Exclusion Criteria: history of prior use of enfuvirtide or T-1249; women who are pregnant, breastfeeding or planning to become pregnant during the study; active, untreated opportunistic infection; patients on treatment interruption, or patients interrupting ARV therapy within 4 weeks of screening or during the screening period for reasons either than toxicity management.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ENF + HAART<br>Participants received Enfuvirtide (ENF) 90 mg administered by subcutaneous injection twice a day for up to 48 weeks in addition to an oral highly active antiretroviral treatment (HAART) regimen for up to 48 weeks. | Drug: Enfuvirtide<br>* 90 mg subcutaneous injection twice a day<br>* Other names: Fuzeon;Drug: Highly active antiretroviral treatment (HAART)<br>* An oral HAART regimen of 3-5 antiretrovirals was chosen by the physician and patient, based on the patient's prior treatment history and genotypic antiretroviral resistance testing.<br>|
| Active Comparator: HAART<br>Participants received an oral highly active antiretroviral treatment (HAART) regimen, consisting of 3-5 antivirals for up to 48 weeks. | Drug: Highly active antiretroviral treatment (HAART)<br>* An oral HAART regimen of 3-5 antiretrovirals was chosen by the physician and patient, based on the patient's prior treatment history and genotypic antiretroviral resistance testing.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Viral Suppression: HIV-1 RNA < 50 Copies/mL During the Induction Phase | Participants whose viral load achieved suppression (HIV-1 RNA < 50 copies/mL) at Week 24 at the latest, confirmed at Week 28 (2 consecutive assessments ≥ 28 days apart) were defined as responders. Patients who discontinued the study or did not respond to assigned treatment by week 28 were considered as non-responders. | From Baseline 1 to Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Achieving HIV-1 RNA < 50 Copies/mL During the Induction Phase | The time to achieving HIV-1 RNA <50 copies/mL was counted from Baseline 1 until the first of the two consecutive <50 copies/mL measurements. Patients who discontinued from the study or patients who did not have confirmed virological response by week 28 were classed as non-responders and censored at Week 24. | Baseline 1 until Week 28. | 
| Number of Participants With Viral Suppression HIV-1 RNA < 400 Copies/mL During the Induction Phase | Participants whose viral load achieved suppression (HIV-1 RNA < 400 copies/mL) by Week 24 at the latest, confirmed at Week 28 (2 consecutive assessments ≥ 28 days apart) were defined as responders. Patients who discontinued the study or did not respond to assigned treatment by Week 28 were considered as non-responders. | From Baseline 1 to Week 28 | 
| Change From Baseline to Week 24 in Viral Load | Change from Baseline in log10 HIV-1 RNA at Week 24. Least squares means were calculated from an analysis of covariance (ANCOVA) model with treatment, a flag variable removed ENF at re-randomization and Baseline viral load as independent variables. | Baseline and Week 24 | 
| Change From Baseline to Week 24 in Cluster Differentiation Antigen Four Positive (CD4+) Cell Counts | Change from Baseline in CD4+ Cell Counts at Week 24. Least squares means were calculated from an ANCOVA model with treatment as an independent variable. | Baseline and Week 24 | 
| Percentage of Induction Phase Participants With Viral Load < 50 Copies/mL at 48 Weeks | The percentage of participants from the Induction Phase who maintained HIV-1 RNA < 50 Copies/mL at Week 48. Patients who discontinued from the study, rebounded to ≥ 50 copies/mL (i.e., had two consecutive readings ≥ 50 copies/mL), had missing data or had virological failure by Week 48 were classed as non-responders. | Week 48 | 
| Percentage of Maintenance Phase Participants With Viral Load < 50 Copies/mL at 48 Weeks | The percentage of participants from the Maintenance Phase who maintained HIV-1 RNA < 50 copies/mL at Week 48. Patients who discontinued from the study, rebounded to ≥ 50 copies/mL (i.e., had two consecutive readings ≥ 50 copies/mL), had missing data or had virological failure by Week 48 were classed as non-responders. | Week 48 | 
| Change From Baseline to Week 48 in Cluster Differentiation Antigen Four Positive (CD4) Cell Counts | Change from Baseline in CD4 Cell Counts at Week 48. Least squares means were calculated from an ANCOVA model with treatment and baseline CD4 count as independent variables. | Baseline 1 and Week 48 | 
| Time to Loss of Viral Response During the Maintenance Phase | The time to loss of viral response (defined as HIV-1 RNA <50 copies/mL) was counted from Baseline 2 until the first of two consecutive ≥50 copies/mL measurements. Only patients who were qualified for entering the Maintenance Phase were included in the analysis. | From Baseline 2 to Week 48. | 
| Time to Virological Failure During the Maintenance Phase | Time to virological failure (defined as HIV-1 RNA ≥ 400 copies/mL) was counted from Baseline 2 until the first of the two consecutive ≥400 copies/mL measurements. Only patients who were qualified for entering the Maintenance Phase were included in the analyses. | From Baseline 2 to Week 48. | 
| Number of Participants With Virological Failure During the Maintenance Phase | Virological failure was defined by 2 consecutive HIV-1 RNA values ≥ 400 copies/mL during the Maintenance Phase. | From Baseline 2 to Week 48. | 
| Percentage of Participants Maintaining CD4+ Count During the Maintenance Phase | Maintenance of CD4+ count defined as having greater than or equal to 200 cells/mm^3 at Baseline 2 (BL2) and greater than or equal to 200 cells/mm^3 at Week 48. | Baseline 2 to Week 48. | 
| Percentage of Participants With Improvement in CD4+ Count During the Maintenance Phase | Improvement of CD4+ count defined as having from 100 to less than 200 CD4+ cells/mm^3 at Baseline 2 (BL2) and greater than or equal to 200 cells/mm^3 at Week 48. | Baseline 2 to Week 48. | 
| Number of Participants With Adverse Events (AEs) During the Induction Phase | A serious AE (SAE) is an event which: results in death, is life-threatening, disabling or incapacitating; is a congenital anomaly in the offspring of a patient who received study drug; requires or prolongs inpatient hospitalization; jeopardizes the patient or require medical or surgical intervention to prevent one of the outcomes above; any Grade 4 laboratory value considered by the investigator clinically significant or that requires an action; any injection site reaction that meets SAE criteria above. Non-serious AEs reported include pneumonia and non-serious AEs that led to discontinuation. | Start of the study treatment until the end of the Induction Phase (Week 12 to Week 32) |