HIV-1
Conditions
Keywords
HIV-1, TMC125-TiDP35-C213, TMC125-C213
Brief summary
The purpose of this study is to determine the safety and antiviral activity of etravirine in treatment-experienced human immunodeficiency virus (HIV) infected children and adolescents.
Detailed description
The study design is a single arm treatment (all patients assigned to receive etravirine), open label (patients will know the identity of the treatments they are receiving) safety and antiviral activity of Etravirine (TMC125) in treatment-experienced, HIV infected children and adolescents 6 to 17 years of age. Etravirine is a new drug belonging to the NNRTI (a non-nucleoside reverse transcriptase inhibitor) drug class that slows down the growth of the human immunodeficiency virus (HIV). This drug has been tested for safety and effectiveness in adults, however, there is no data on the drug's long-term safety and antiviral activity in children and adolescents. This study will last for a maximum of 48 weeks. A total of 100 ptients will receive etravirine tablets based on body weight and an investigator selected optimized background regimen (OBR) of at least 2 antiretrovirals (ARVs), consisting of a boosted protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor(s) (NRTI\[s\]). Use of enfuvirtide is optional. Safety will be monitored throughout the study.
Interventions
DRUGEtravirine (TMC125)
Patients will be dosed by body weight , i.e. 5.2 mg/kg twice daily (b.i.d.) up to a maximum of 200 mg b.i.d. for 48 weeks.
An investigator-selected optimized background regimen (OBR) comprising of a low-dose ritonavir (rtv)-boosted protease inhibitor (PI) (either lopinavir \[LPV\], darunavir \[DRV\], atazanavir \[ATV\] or saquinavir \[SQV\]) in combination with nucleos(t)ide reverse transcriptase inhibitor(s) (N\[t\]RTIs) to be dosed according to the drugs individual package inserts for 48 weeks.
Sponsors
Tibotec Pharmaceuticals, Ireland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* HIV-1 infected * Body weight according to age within the 10-90th percentile of CDC growth chart * On steady antiretroviral therapy regimen for at least 8 weeks at screening and willing to remain on that regimen until baseline * HIV viral load of 1,000 copies/ml or greater at study entry * Parent or legal guardian willing to provide informed consent, if necessary
Exclusion criteria
* The Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | 48 weeks | A treatment-emergent adverse event (TEAE) was defined as an event that occurred in the 48-week treatment period during which it emerged (i.e. started or worsened in severity, relation, or other attribute), and not in the subsequent study periods, even if the event continued to be present. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen |
| The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | 48 weeks | The percentage of patients with a treatment-emergent adverse event (TEAE) (defined as an event that occurred in the 48-week treatment period during which it emerged \[i.e. started or worsened in severity, relation, or other attribute\], and not in the subsequent study periods, even if the event continued to be present\] are provided below. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax) | Week 4 | Etravirine/TMC125 (ETR) Cmax was approximated for each individual using the median value of plasma ETR concentrations taken 4 hours postdose (± 1 hour), when available, on the day of the Week 4 visit as shown in the table below. |
| Percentage of Patients With Virologic Response at Week 24 | Week 24 | Virologic response was defined as the percentage of patients with plasma viral load \< 50 copies/mL at Week 24 calculated according to the non-completer=failure (NC=F) imputation method. |
| Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h) | Weeks 4-48 | The AUC12h is a Bayesian estimation based on a population pharmacokinetic model and sparse samples collected at each visit over the duration of trial. For each sparse sample taken, the time blood sample was recorded as well as the time of etravirine intake just prior to the time of blood sample. |
| The Change From Baseline in CD4 Cell Counts Over Time | Baseline, Week 48 | — |
| The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures | Baseline and Endpoint (up to Week 48) | Virologic failure (lack of response) was defined as: plasma viral load decline of \< 0.5 log10 from Baseline by Week 8 and/or plasma viral load decline of \<1.0 log10 from Baseline by Week 12. Virologic failure (loss of response) was defined as 2 consecutive measurements of plasma viral load \> 0.5 log10 above the nadir after a minimum of 12 weeks of treatment. The table below provides data for 41 viologic failures of which 30 had mutation data available. In the table below, only the 4 most frequently emerging mutations are presented (emerging in at least 3 patients). |
| Change From Baseline in Human Immunodeficiency Virus - Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time | Baseline, Week 48 | — |
| Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h) | Week 48 | — |
Countries
Argentina, Brazil, Canada, France, Netherlands, Portugal, Puerto Rico, Romania, South Africa, Spain, Thailand, United Kingdom, United States
Participant flow
Recruitment details
In total, 41 investigators in 13 countries enrolled patients in study TMC125-C213. A total of 103 patients were documented as being enrolled in the study, however 2 patients were randomized in error. Therefore, 101 patients were enrolled and treated with etravirine (ETR) also known as TMC125 and included in the intent-to-treat (ITT) population.
Participants by arm
| Arm | Count |
|---|---|
| TMC125 TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day | 101 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Resistance to TMC125 | 1 |
| Overall Study | Subject ineligible to continue the trial | 1 |
| Overall Study | Subject non-compliant | 8 |
| Overall Study | Subject reached a virologic endpoint | 4 |
| Overall Study | Switch to Commercial Medication | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | TMC125 |
|---|---|
| Age, Continuous | 12.2 years STANDARD_DEVIATION 2.99 |
| Age Customized >=12 to <18 years | 60 participants |
| Age Customized >=6 to <12 years | 41 participants |
| Sex: Female, Male Female | 64 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 70 / 101 |
| serious Total, serious adverse events | 5 / 101 |
Outcome results
Primary
The Number of Patients With Treatment-emergent Adverse Events (TEAEs)
A treatment-emergent adverse event (TEAE) was defined as an event that occurred in the 48-week treatment period during which it emerged (i.e. started or worsened in severity, relation, or other attribute), and not in the subsequent study periods, even if the event continued to be present. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen
Time frame: 48 weeks
Population: The safety analysis was done on the intent-to-treat (ITT) population, which included all patients who received at least one dose of investigational medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 89 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs that were fatal | 0 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs that were serious | 5 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs that were grade 3 or 4 in severity | 14 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to temporary ETR discontinuation | 8 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to permanent ETR discontinuation | 8 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs possibly related to ETR | 23 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs probably related to ETR | 14 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs very likely related to ETR | 3 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs at least possibly related to ETR | 33 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs possibly related to OBR | 27 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs probably related to OBR | 12 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs very likely related to OBR | 5 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs at least possibly related to OBR | 36 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of at least grade 2 in severity | 21 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of at least grade 3 in severity | 3 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: Skin event | 31 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: Rash | 23 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: severe cutaneous reactions | 7 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: angioedema | 4 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: neuropsychiatric events | 2 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: hepatic events | 0 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: cardiac events | 0 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: pancreatic events | 1 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: lipid-related events | 6 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: neoplasms | 1 Patients |
| TMC125 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: bleeding events | 0 Patients |
Primary
The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs)
The percentage of patients with a treatment-emergent adverse event (TEAE) (defined as an event that occurred in the 48-week treatment period during which it emerged \[i.e. started or worsened in severity, relation, or other attribute\], and not in the subsequent study periods, even if the event continued to be present\] are provided below. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen
Time frame: 48 weeks
Population: The safety analysis was done on the intent-to-treat (ITT) population, which included all patients who received at least one dose of investigational medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 88.1 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs that were fatal | 0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs that were serious | 5.0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs that were grade 3 or 4 in severity | 13.9 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to temporary ETR discontinuation | 7.9 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to permanent ETR discontinuation | 7.9 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs possibly related to ETR | 22.8 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs probably related to ETR | 13.9 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs very likely related to ETR | 3.0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs at least possibly related to ETR | 32.7 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs possibly related to OBR | 26.7 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs probably related to OBR | 11.9 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs very likely related to OBR | 5.0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs at least possibly related to OBR | 35.6 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of at least grade 2 in severity | 20.8 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of at least grade 3 in severity | 3.0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: Skin event | 30.7 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: Rash | 22.8 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: severe cutaneous reactions | 6.9 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: angioedema | 4.0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: neuropsychiatric events | 2.0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: hepatic events | 0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: cardiac events | 0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: bleeding events | 0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: pancreatic events | 1.0 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: lipid-related events | 5.9 Percentage of patients |
| TMC125 | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | TEAEs of interest: neoplasms | 1.0 Percentage of patients |
Secondary
Change From Baseline in Human Immunodeficiency Virus - Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time
Time frame: Baseline, Week 48
Population: The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC125 | Change From Baseline in Human Immunodeficiency Virus - Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time | -1.53 log10 copies/mL | Standard Error 0.132 |
Secondary
Percentage of Patients With Virologic Response at Week 24
Virologic response was defined as the percentage of patients with plasma viral load \< 50 copies/mL at Week 24 calculated according to the non-completer=failure (NC=F) imputation method.
Time frame: Week 24
Population: The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMC125 | Percentage of Patients With Virologic Response at Week 24 | 52.5 Percentage of Patients |
95% CI: [42.7, 62.2]
Secondary
Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h)
The AUC12h is a Bayesian estimation based on a population pharmacokinetic model and sparse samples collected at each visit over the duration of trial. For each sparse sample taken, the time blood sample was recorded as well as the time of etravirine intake just prior to the time of blood sample.
Time frame: Weeks 4-48
Population: The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken ETR at least once, regardless of their compliance with the protocol was used for this analysis. The table below shows results for Overall (children and adolescents combined).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC125 | Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h) | 5216 ng.h/mL | Standard Deviation 4305 |
Secondary
Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax)
Etravirine/TMC125 (ETR) Cmax was approximated for each individual using the median value of plasma ETR concentrations taken 4 hours postdose (± 1 hour), when available, on the day of the Week 4 visit as shown in the table below.
Time frame: Week 4
Population: The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC125 | Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax) | 589 ng/mL | Standard Deviation 486 |
Secondary
Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h)
Time frame: Week 48
Population: The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken ETR at least once, regardless of their compliance with the protocol was used for this analysis. The table below shows results for Overall (children and adolescents combined).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC125 | Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h) | 346 ng/mL | Standard Deviation 342 |
Secondary
The Change From Baseline in CD4 Cell Counts Over Time
Time frame: Baseline, Week 48
Population: The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC125 | The Change From Baseline in CD4 Cell Counts Over Time | 156 10E6 cells/L | Standard Error 22.7 |
Secondary
The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures
Virologic failure (lack of response) was defined as: plasma viral load decline of \< 0.5 log10 from Baseline by Week 8 and/or plasma viral load decline of \<1.0 log10 from Baseline by Week 12. Virologic failure (loss of response) was defined as 2 consecutive measurements of plasma viral load \> 0.5 log10 above the nadir after a minimum of 12 weeks of treatment. The table below provides data for 41 viologic failures of which 30 had mutation data available. In the table below, only the 4 most frequently emerging mutations are presented (emerging in at least 3 patients).
Time frame: Baseline and Endpoint (up to Week 48)
Population: The patients in the intent-to-treat (ITT) population classified as virologic failures were used for this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TMC125 | The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures | V90I | 3 Patients |
| TMC125 | The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures | L100I | 3 Patients |
| TMC125 | The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures | E138A | 3 Patients |
| TMC125 | The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures | Y181C | 8 Patients |