HIV Infections
Conditions
Brief summary
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
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.
Interventions
DRUGEnfuvirtide
90 mg subcutaneous injection twice a day
DRUGHighly active antiretroviral treatment (HAART)
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.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Viral Suppression: HIV-1 RNA < 50 Copies/mL During the Induction Phase | From Baseline 1 to Week 28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Viral Suppression HIV-1 RNA < 400 Copies/mL During the Induction Phase | From Baseline 1 to Week 28 | 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. |
| Change From Baseline to Week 24 in Viral Load | Baseline and Week 24 | 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. |
| Change From Baseline to Week 24 in Cluster Differentiation Antigen Four Positive (CD4+) Cell Counts | Baseline and Week 24 | 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. |
| Percentage of Induction Phase Participants With Viral Load < 50 Copies/mL at 48 Weeks | Week 48 | 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. |
| Percentage of Maintenance Phase Participants With Viral Load < 50 Copies/mL at 48 Weeks | Week 48 | 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. |
| Change From Baseline to Week 48 in Cluster Differentiation Antigen Four Positive (CD4) Cell Counts | Baseline 1 and Week 48 | 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. |
| Time to Achieving HIV-1 RNA < 50 Copies/mL During the Induction Phase | Baseline 1 until Week 28. | 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. |
| Time to Virological Failure During the Maintenance Phase | From Baseline 2 to Week 48. | 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. |
| Number of Participants With Virological Failure During the Maintenance Phase | From Baseline 2 to Week 48. | Virological failure was defined by 2 consecutive HIV-1 RNA values ≥ 400 copies/mL during the Maintenance Phase. |
| Percentage of Participants Maintaining CD4+ Count During the Maintenance Phase | Baseline 2 to Week 48. | 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. |
| Percentage of Participants With Improvement in CD4+ Count During the Maintenance Phase | Baseline 2 to Week 48. | 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. |
| Number of Participants With Adverse Events (AEs) During the Induction Phase | Start of the study treatment until the end of the Induction Phase (Week 12 to Week 32) | 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. |
| Time to Loss of Viral Response During the Maintenance Phase | From Baseline 2 to Week 48. | 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. |
Countries
Canada, France, Germany, Israel, Italy, Mexico, Netherlands, Spain, Switzerland, United States
Participant flow
Recruitment details
A total of 47 patients were enrolled into the study at 20 investigational sites in France, Italy, Spain, Mexico, Germany and the US. Study starting 15NOV2005 and ending 5NOV2007.
Pre-assignment details
In the Induction Phase participants were randomized (2:1 ratio) to receive ENF + HAART or HAART. In the Maintenance Phase participants in the HAART group who responded (viral load \< 50 copies/mL) continued to receive HAART; those who responded in the ENF + HAART group were re-randomized (1:1 ratio) to receive ENF + HAART or HAART (ENF removed).
Participants by arm
| Arm | Count |
|---|---|
| ENF+HAART Participants received enfuvirtide 90 mg subcutaneously twice a day in combination with highly active antiretroviral treatment. | 29 |
| HAART Participants received highly active antiretroviral treatment. | 18 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Induction Phase | Abnormality of Laboratory Test | 0 | 1 | 0 |
| Induction Phase | Administrative | 0 | 1 | 0 |
| Induction Phase | Adverse Event | 5 | 0 | 0 |
| Induction Phase | Lack of Efficacy | 0 | 1 | 0 |
| Induction Phase | Lost to Follow-up | 2 | 2 | 0 |
| Induction Phase | Protocol Violation | 1 | 0 | 0 |
| Induction Phase | Refused Treatment | 1 | 2 | 0 |
| Maintenance Phase | Administrative | 0 | 0 | 1 |
| Maintenance Phase | Adverse Event | 1 | 0 | 0 |
| Maintenance Phase | Death | 1 | 0 | 0 |
| Maintenance Phase | Lost to Follow-up | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | ENF+HAART | HAART | Total |
|---|---|---|---|
| Age, Continuous | 44.1 years STANDARD_DEVIATION 7.04 | 41.9 years STANDARD_DEVIATION 10.57 | 43.3 years STANDARD_DEVIATION 8.52 |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 22 Participants | 15 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 29 | 11 / 18 | 2 / 10 | 4 / 9 | 3 / 8 |
| serious Total, serious adverse events | 3 / 29 | 3 / 18 | 2 / 10 | 3 / 9 | 0 / 8 |
Outcome results
Primary
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.
Time frame: From Baseline 1 to Week 28
Population: Intent-to-Treat Population 1 (ITT1) population (patients evaluable for efficacy in the induction phase)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENF+HAART | Number of Participants With Viral Suppression: HIV-1 RNA < 50 Copies/mL During the Induction Phase | 20 Participants |
| HAART | Number of Participants With Viral Suppression: HIV-1 RNA < 50 Copies/mL During the Induction Phase | 8 Participants |
Secondary
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.
Time frame: Baseline and Week 24
Population: Intent-to-Treat Population 1 (ITT1) population (patients evaluable for efficacy in the Induction Phase). Baseline values were carried forward (i.e. the change from baseline set to zero) for patients with missing data at week 24 or who withdrew prior to the week 24 time window.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ENF+HAART | Change From Baseline to Week 24 in Cluster Differentiation Antigen Four Positive (CD4+) Cell Counts | 20.81 cells/mm^3 |
| HAART | Change From Baseline to Week 24 in Cluster Differentiation Antigen Four Positive (CD4+) Cell Counts | 17.88 cells/mm^3 |
Secondary
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.
Time frame: Baseline and Week 24
Population: Intent-to-Treat Population 1 (ITT1) population (patients evaluable for efficacy in the Induction Phase). Baseline values were carried forward (i.e. the change from baseline set to zero) for patients with missing data at week 24 or who withdrew prior to the week 24 time window.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ENF+HAART | Change From Baseline to Week 24 in Viral Load | -1.402 log10 copies/mL | 95% Confidence Interval 0.69 |
| HAART | Change From Baseline to Week 24 in Viral Load | -1.156 log10 copies/mL | 95% Confidence Interval 0.61 |
Secondary
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.
Time frame: Baseline 1 and Week 48
Population: Intent-to-Treat Population 2 (ITT2) population (patients evaluable for efficacy in the Maintenance Phase). Baseline values were carried forward (i.e. the change from baseline set to zero) for patients with missing data at week 48 or who withdrew prior to the week 48 time window.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ENF+HAART | Change From Baseline to Week 48 in Cluster Differentiation Antigen Four Positive (CD4) Cell Counts | 73.09 cells/mm^3 |
| HAART | Change From Baseline to Week 48 in Cluster Differentiation Antigen Four Positive (CD4) Cell Counts | 50.79 cells/mm^3 |
Secondary
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.
Time frame: Start of the study treatment until the end of the Induction Phase (Week 12 to Week 32)
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ENF+HAART | Number of Participants With Adverse Events (AEs) During the Induction Phase | Non-serious Adverse Event | 3 participants |
| ENF+HAART | Number of Participants With Adverse Events (AEs) During the Induction Phase | Adverse Events Leading to Withdrawal | 5 participants |
| ENF+HAART | Number of Participants With Adverse Events (AEs) During the Induction Phase | Serious Adverse Event | 3 participants |
| HAART | Number of Participants With Adverse Events (AEs) During the Induction Phase | Serious Adverse Event | 3 participants |
| HAART | Number of Participants With Adverse Events (AEs) During the Induction Phase | Non-serious Adverse Event | 1 participants |
| HAART | Number of Participants With Adverse Events (AEs) During the Induction Phase | Adverse Events Leading to Withdrawal | 1 participants |
Secondary
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.
Time frame: From Baseline 1 to Week 28
Population: ITT1 population (patients evaluable for efficacy in the induction phase)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENF+HAART | Number of Participants With Viral Suppression HIV-1 RNA < 400 Copies/mL During the Induction Phase | 21 Participants |
| HAART | Number of Participants With Viral Suppression HIV-1 RNA < 400 Copies/mL During the Induction Phase | 8 Participants |
Secondary
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.
Time frame: From Baseline 2 to Week 48.
Population: Maintenance Phase Intent-to-Treat Population 2 (ITT2)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENF+HAART | Number of Participants With Virological Failure During the Maintenance Phase | 3 Participants |
| HAART | Number of Participants With Virological Failure During the Maintenance Phase | 0 Participants |
Secondary
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.
Time frame: Week 48
Population: Induction Phase Intent-to-Treat Population 1 (ITT1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENF+HAART | Percentage of Induction Phase Participants With Viral Load < 50 Copies/mL at 48 Weeks | 45.2 percentage of participants |
| HAART | Percentage of Induction Phase Participants With Viral Load < 50 Copies/mL at 48 Weeks | 25.0 percentage of participants |
Secondary
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.
Time frame: Week 48
Population: Maintenance Phase Intent-to-Treat Population 2 (ITT2).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENF+HAART | Percentage of Maintenance Phase Participants With Viral Load < 50 Copies/mL at 48 Weeks | 73.7 percentage of participants |
| HAART | Percentage of Maintenance Phase Participants With Viral Load < 50 Copies/mL at 48 Weeks | 50.0 percentage of participants |
Secondary
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.
Time frame: Baseline 2 to Week 48.
Population: Maintenance Phase ITT2 population with a Baseline 2 CD4+ count of greater than or equal to 200 cells/mm\^3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ENF+HAART | Percentage of Participants Maintaining CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count ≥200 cells/mm^3 | 66.67 percentage of participants |
| ENF+HAART | Percentage of Participants Maintaining CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count Missing | 33.33 percentage of participants |
| HAART | Percentage of Participants Maintaining CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count ≥200 cells/mm^3 | 75.00 percentage of participants |
| HAART | Percentage of Participants Maintaining CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count Missing | 25.00 percentage of participants |
| HAART (ENF Removed) | Percentage of Participants Maintaining CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count ≥200 cells/mm^3 | 75.00 percentage of participants |
| HAART (ENF Removed) | Percentage of Participants Maintaining CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count Missing | 12.50 percentage of participants |
Secondary
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.
Time frame: Baseline 2 to Week 48.
Population: Maintenance Phase ITT2 population with a Baseline 2 CD4+ count of ≥100 to \<200 cells/mm\^3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ENF+HAART | Percentage of Participants With Improvement in CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count Missing | 0 percentage of participants |
| ENF+HAART | Percentage of Participants With Improvement in CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count ≥200 cells/mm^3 | 100.00 percentage of participants |
| HAART (ENF Removed) | Percentage of Participants With Improvement in CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count ≥200 cells/mm^3 | 100.00 percentage of participants |
| HAART (ENF Removed) | Percentage of Participants With Improvement in CD4+ Count During the Maintenance Phase | Week 48 CD4+ Count Missing | 0 percentage of participants |
Secondary
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.
Time frame: Baseline 1 until Week 28.
Population: Intent-to-Treat Population 1 (ITT1) population (patients evaluable for efficacy in the induction phase).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ENF+HAART | Time to Achieving HIV-1 RNA < 50 Copies/mL During the Induction Phase | 57.0 days |
| HAART | Time to Achieving HIV-1 RNA < 50 Copies/mL During the Induction Phase | 141.0 days |
Secondary
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.
Time frame: From Baseline 2 to Week 48.
Population: Maintenance Phase Intent-to-Treat Population 2 (ITT2)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ENF+HAART | Time to Loss of Viral Response During the Maintenance Phase | NA days |
| HAART | Time to Loss of Viral Response During the Maintenance Phase | NA days |
Secondary
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.
Time frame: From Baseline 2 to Week 48.
Population: Maintenance Phase Intent-to-Treat Population 2 (ITT2)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ENF+HAART | Time to Virological Failure During the Maintenance Phase | NA days |
| HAART | Time to Virological Failure During the Maintenance Phase | NA days |