HIV-1
Conditions
Keywords
HIV-1, treatment experienced, virologic failure
Brief summary
The purpose of this trial is to evaluate the long-term safety and tolerability of TMC125 200 mg twice daily as part of an antiretroviral therapy including TMC114/rtv and an investigator selected optimized background in HIV-1 infected patients who have participated in a DUET trial (TMC125-C206 or TMC125 C216) and have met the definition of virologic failure at Week 24 or later in these trials.
Detailed description
This is a Phase III open-label, roll-over trial to evaluate the long term tolerability, safety, antiviral and immunological effect of TMC125 as part of an individually optimized antiretroviral therapy including TMC114/rtv in HIV-1 infected patients who participated in one of the DUET (TMC125-C206 or TMC125-C216) trials. Also the change in HIV-1 resistance over time will be evaluated. This trial offers patients meeting the definition of virologic failure at Week 24 or beyond the option to roll-over to an open-label trial where they will receive TMC125 and TMC114/rtv. Three hundred patients are estimated to enroll into this trial. The withdrawal visit of the DUET trial will be the first visit of this trial. From this visit onward, all patients will receive 200 mg twice daily TMC125 and 600/100 mg twice daily TMC114/rtv until both TMC114 and TMC125 are commercially available or the therapy is no longer of clinical benefit to the patient. Patients will receive an antiretroviral therapy consisting of TMC125 as the only non-nucleoside reverse transcriptase inhibitor (NNRTI), TMC114/rtv as the only protease inhibitor (PI) and an optimized background, which will be selected by the investigator according to the local standard of care, the patient's experience with previous therapies and most recent resistance testing. The most recent HIV-1 genotype-analysis system report results from the DUET trial will be made available. TMC125 will be dosed at 200 mg twice daily, administered orally as 2 tablets twice daily with food.TMC114/rtv will be dosed at 600/100 mg twice daily, administered orally as 2 tablets TMC114 and 1 capsule ritonavir twice daily with food.The optimized background will comprise of at least 1 approved ARV drug: 1 or more NRTI(s), with or without ENF. Administration will continue until both TMC114 and TMC125 are commercially available or therapy is no longer of clinical benefit to the patient.
Interventions
DRUGTMC125
200 mg twice daily until commercially available
Sponsors
Tibotec Pharmaceuticals, Ireland
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient was previously randomized in a DUET (TMC125-C206 or TMC125-C216) trial and completed at least 24 weeks of treatment * Patient was virologically failing in a DUET trial.
Exclusion criteria
* Use of disallowed concomitant therapy * Any grade 4 toxicity according to the Division of AIDS (DAIDS) grading table * Patients who had to be withdrawn from the DUET (TMC125-C206 or TMC125-C216) trials because of any of the mandatory withdrawal criteria of that trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants Experiencing Adverse Events | 1 week to 180 weeks, with a median of 62 weeks | The table below provides the number of participants who experienced Serious Adverse Events (SAEs) and Other Adverse Events (except SAEs) that started or worsened in severity during the overall TMC125-C217 treatment period. The duration of treatment ranged per patient from 1 week to 180 weeks, with a median of 62 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With Virologic Outcomes Over Time | Weeks 24, 48, and 96 | The table below shows the percentage of participants with virologic suppression (\< 50 copies/mL), the percentage of participants who were virologic failures (VF) (\>50 copies/mL, discontinued prior to time X for reasons of VF or for other reasons, except for VF or adverse event, with a last viral load \>50 copies/mL), and the percentage of participants with no viral load (VL) data available over time (ie, at Weeks 24, 48, and 96). |
| Change in Plasma Viral Load Versus Baseline (ie, Mean Change in log10 Plasma Viral Load From Baseline Over Time) | Baseline, Week 24, Week 48, and Week 96 | In the table below, the total number of participants analyzed in the Duet Placebo and Duet TMC125 groups, respectively at each time point were: Baseline (256;247 participants), Week 24 (251;240 participants), Week 48 (235;192 participants), and Week 96 (123;69 participants). |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, France, Germany, Mexico, Panama, Puerto Rico, Spain, Thailand, United States
Participant flow
Pre-assignment details
Participants with human immunodeficiency virus - type 1 (HIV-1) infection were enrolled in this study from DUET Study TMC125-C206 or TMC125-C216 and met the definition of virologic failure at Week 24 or later in these studies, or who completed one of the DUET studies after 96 weeks of treatment.
Participants by arm
| Arm | Count |
|---|---|
| DUET PLACEBO Participants who received Placebo in a previous DUET study and received open-label treatment with 200 mg twice daily etravirine, also known as TMC125 (ETR) and 600/100 mg twice daily darunavir (DRV)/low-dose ritonavir (rtv) were referred to as ETR-naïve participants. | 256 |
| DUET TMC125 Participants who received etravirine, also known as TMC125 (ETR) in a previous DUET study and received open-label treatment with 200 mg twice daily ETR and 600/100 mg twice daily darunavir (DRV)/low-dose ritonavir (rtv) were referred to as ETR-experienced participants. | 247 |
| Total | 503 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 26 | 8 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 4 | 1 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Subject Ineligible To Continue The Trial | 1 | 0 |
| Overall Study | Subject Non-Compliant | 1 | 2 |
| Overall Study | Subject Reached A Virologic Endpoint | 45 | 32 |
| Overall Study | Withdrawal by Subject | 2 | 9 |
Baseline characteristics
| Characteristic | DUET PLACEBO | DUET TMC125 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 252 Participants | 245 Participants | 497 Participants |
| Age, Continuous | 46.9 years STANDARD_DEVIATION 8.28 | 46.6 years STANDARD_DEVIATION 7.01 | 46.7 years STANDARD_DEVIATION 7.68 |
| Sex: Female, Male Female | 27 Participants | 37 Participants | 64 Participants |
| Sex: Female, Male Male | 229 Participants | 210 Participants | 439 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 160 / 256 | 137 / 247 | 297 / 503 |
| serious Total, serious adverse events | 46 / 256 | 42 / 247 | 88 / 503 |
Outcome results
Primary
The Number of Participants Experiencing Adverse Events
The table below provides the number of participants who experienced Serious Adverse Events (SAEs) and Other Adverse Events (except SAEs) that started or worsened in severity during the overall TMC125-C217 treatment period. The duration of treatment ranged per patient from 1 week to 180 weeks, with a median of 62 weeks.
Time frame: 1 week to 180 weeks, with a median of 62 weeks
Population: The safety analysis was carried out on the ITT population, which included all participants who received at least one dose of investigational medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DUET PLACEBO | The Number of Participants Experiencing Adverse Events | Serious Adverse Events (SAEs) | 46 Participants |
| DUET PLACEBO | The Number of Participants Experiencing Adverse Events | Other Adverse Events (AEs) | 160 Participants |
| DUET TMC125 | The Number of Participants Experiencing Adverse Events | Serious Adverse Events (SAEs) | 42 Participants |
| DUET TMC125 | The Number of Participants Experiencing Adverse Events | Other Adverse Events (AEs) | 137 Participants |
| All Participants | The Number of Participants Experiencing Adverse Events | Serious Adverse Events (SAEs) | 88 Participants |
| All Participants | The Number of Participants Experiencing Adverse Events | Other Adverse Events (AEs) | 297 Participants |
Secondary
Change in Plasma Viral Load Versus Baseline (ie, Mean Change in log10 Plasma Viral Load From Baseline Over Time)
In the table below, the total number of participants analyzed in the Duet Placebo and Duet TMC125 groups, respectively at each time point were: Baseline (256;247 participants), Week 24 (251;240 participants), Week 48 (235;192 participants), and Week 96 (123;69 participants).
Time frame: Baseline, Week 24, Week 48, and Week 96
Population: The intent-to-treat (ITT) population was used as the primary analysis population for the efficacy analysis and included all participants who took at least one dose of etravirine (ETR) (also known as TMC125) in the TMC125-C217 study.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| DUET PLACEBO | Change in Plasma Viral Load Versus Baseline (ie, Mean Change in log10 Plasma Viral Load From Baseline Over Time) | Week 24 | -0.8 log10 copies/mL |
| DUET PLACEBO | Change in Plasma Viral Load Versus Baseline (ie, Mean Change in log10 Plasma Viral Load From Baseline Over Time) | Week 48 | -0.7 log10 copies/mL |
| DUET PLACEBO | Change in Plasma Viral Load Versus Baseline (ie, Mean Change in log10 Plasma Viral Load From Baseline Over Time) | Week 96 | -0.5 log10 copies/mL |
| DUET TMC125 | Change in Plasma Viral Load Versus Baseline (ie, Mean Change in log10 Plasma Viral Load From Baseline Over Time) | Week 24 | 0 log10 copies/mL |
| DUET TMC125 | Change in Plasma Viral Load Versus Baseline (ie, Mean Change in log10 Plasma Viral Load From Baseline Over Time) | Week 48 | -0.1 log10 copies/mL |
| DUET TMC125 | Change in Plasma Viral Load Versus Baseline (ie, Mean Change in log10 Plasma Viral Load From Baseline Over Time) | Week 96 | -0.2 log10 copies/mL |
Secondary
The Percentage of Participants With Virologic Outcomes Over Time
The table below shows the percentage of participants with virologic suppression (\< 50 copies/mL), the percentage of participants who were virologic failures (VF) (\>50 copies/mL, discontinued prior to time X for reasons of VF or for other reasons, except for VF or adverse event, with a last viral load \>50 copies/mL), and the percentage of participants with no viral load (VL) data available over time (ie, at Weeks 24, 48, and 96).
Time frame: Weeks 24, 48, and 96
Population: The intent-to-treat (ITT) population was used as the primary analysis population for the efficacy analysis and included all participants who took at least one dose of etravirine (ETR) (also known as TMC125) in the TMC125-C217 study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 24 - Virologic Response (<50 cop/mL) | 43.0 Percentage of Participants |
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 48 - No VL Data available | 14.5 Percentage of Participants |
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 48 - Virologic Response (<50 cop/mL) | 35.2 Percentage of Participants |
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 96 -Virologic Response (<50 cop/mL) | 7.4 Percentage of Participants |
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 24 - No VL Data available | 10.2 Percentage of Participants |
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 96 - Virologic Failure | 48.0 Percentage of Participants |
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 48 - Virologic Failure | 50.4 Percentage of Participants |
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 96 - No VL Data available | 44.5 Percentage of Participants |
| DUET PLACEBO | The Percentage of Participants With Virologic Outcomes Over Time | Week 24 - Virologic Failure | 46.9 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 96 - No VL Data available | 68.0 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 24 - Virologic Response (<50 cop/mL) | 62.3 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 24 - Virologic Failure | 31.6 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 24 - No VL Data available | 6.1 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 48 - Virologic Response (<50 cop/mL) | 44.5 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 48 - Virologic Failure | 31.2 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 48 - No VL Data available | 24.3 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 96 -Virologic Response (<50 cop/mL) | 4.5 Percentage of Participants |
| DUET TMC125 | The Percentage of Participants With Virologic Outcomes Over Time | Week 96 - Virologic Failure | 27.5 Percentage of Participants |