Human Immunodeficiency Virus Type 1
Conditions
Keywords
Human Immunodeficiency Virus Type 1, HIV-1 infection, TMC125, Etravirine, Enfuvirtide, Antiretroviral therapy
Brief summary
The purpose of this study is to evaluate the long-term safety and tolerability of etravirine, administered as part of an individually optimized antiretroviral therapy (ART), in human immunodeficiency virus Type 1 (HIV-1) infected participants.
Detailed description
This is a Phase II, open-label (all people know the identity of the intervention), roll-over study (participants may go ahead and participate in another clinical study). Participants who were randomized (study medication is assigned by chance) to a etravirine (ETR) treatment arm in Phase II TMC125 feeder studies (TMC125-C203, TMC125-C209, TMC125-C223 and TMC125-C211), were treated for at least 48 weeks with etravirine, and who will derive continued benefit from etravirine therapy, as judged by the investigator, will be enrolled in this study. The final visit of the sponsor-selected Phase II ETR study will be the first (baseline) visit of this study. Approximately 300 participants will be enrolled in this study who will receive 800 mg twice daily of etravirine (formulation TF035) until the formulation 200 mg twice daily (formulation F060) is available. Once this formulation becomes available all the participants will be switched to receive F060 which will be given in combination with an investigator-selected, optimized underlying therapy (nucleotide reverse transcriptase \[NRTIs\] and/or allowed protease inhibitors and/or enfuvirtide). Participants will continue to receive ETR until they are no longer benefitted or this medication becomes commercially available. Safety evaluations will include assessment of adverse events, clinical laboratory tests, electrocardiogram, vital signs, and physical examination.
Interventions
DRUGEtravirine (ETR)
Participants will receive 800 mg of ETR (2 x 4 tablets of formulation TF035) twice daily and after the formulation switch they will receive 200 mg of ETR (2 x 2 tablets of formulation F060) twice daily until the participants benefitted from etravirine or it became comercially available.
DRUGNucleotide reverse transcriptase inhibitors (NRTIs)
Participants will receive 2 additonal approved antiretrovirals (ARVs) along with ETR. ARVs may be NRTIs and/or allowed protease inhibitors (PIs) and/or enfuvirtide (ENF).
DRUGProtease inhibitors (PIs)
Participants will receive 2 additonal approved antiretrovirals (ARVs) along with ETR. ARVs may be NRTIs and/or allowed protease inhibitors (PIs) and/or enfuvirtide (ENF).
DRUGEnfuvirtide (ENF)
Participants will receive 2 additonal approved antiretrovirals (ARVs) along with ETR. ARVs may be NRTIs and/or allowed protease inhibitors (PIs) and/or enfuvirtide (ENF).
Sponsors
Tibotec Pharmaceuticals, Ireland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Participants who were previously randomized to an etravirine (ETR) treatment arm and have completed at least 48 weeks of treatment with ETR * Participants who will be able to comply with the protocol requirements * Participants general medical condition should not interfere with the assessments and the completion of the study
Exclusion criteria
* Use of disallowed concomitant therapy unless a prior exemption had been granted * Participant with any treatment-emergent condition or exacerbation of underlying condition during original Phase II study * Agrees to protocol-defined use of effective contraception * Participant with a grade 3 elevation of amylase and/or lipase except for isolated grade 3 increases of amylase with lipase in normal range and no history of pancreatitis * Participant with any grade 4 toxicity according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) grading table; with the exception of grade 4 elevations of triglycerides or glucose asymptomatic or under non-fasting conditions; grade 4 elevation of glucose in participants with pre-existing diabetes * Participants with clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (International Normalized Ratio \[INR\] more than 1.5 or albumin less than 30g/l or bilirubin more than 2.5 x upper limit of normal)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Up to 3 years | Number of participants who reported at least 1 of the adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL) at Week 96 | Week 96 | Number of participants who had viral load more than or equal to 50 copies/mL and less than 50 copies/mL at TMC125-C229 baseline and who achieved virologic response (ie, viral load less than 50 copies/mL) at Week 96. The last visit of the TMC125 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies) was considered to be the TMC125-C229 baseline. |
| Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Less Than 400 Copies/mL; and Greater Than or Equal to 1 Log 10 Decrease From Baseline) at Week 96 | Week 96 | Baseline considered for this outcome is the baseline in the respective TMC125-C229 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies). |
| Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Viral Load Less Than 400 Copies/mL; and Greater Than or Equal to 1 log10 Decrease From Baseline) at Week 192 | Week 192 | Baseline considered for this outcome is the baseline in the respective TMC125-C229 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies). |
| Median Change From TMC125-C229 Basline in Cluster of Differentiation 4 (CD4+) Cell Count at Week 48 | Week 48 | The last visit of the TMC125 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies) was considered to be the TMC125-C229 baseline. |
| Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL) at Week 48 | Week 48 | Number of participants who had viral load more than or equal to 50 copies/mL and less than 50 copies/mL at TMC125-C229 baseline and who achieved virologic response (ie, viral load less than 50 copies/mL) at Week 48. The last visit of the TMC125 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies) was considered to be the TMC125-C229 baseline. |
| Median Change in Cluster of Differentiation 4 (CD4+) Cell Count From Baseline in TMC125-C229 Feeder Study at Week 96 | Week 96 | Baseline considered for this outcome is the baseline in the respective TMC125-C229 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies). |
| Median Change in Cluster of Differentiation 4 (CD4+) Cell Count From Baseline in TMC125-C229 Feeder Study at Week 192 | Week 192 | Baseline considered for this outcome is the baseline in the respective TMC125-C229 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies). |
| Number of Participants With Emerging Mutation (Reverse Transcriptase Mutation) | Baseline and Endpoint (ie, the last available time point during the treatment period) | Emerging mutations are the mutation which are not present at baseline (last visit of the TMC125 feeder study \[TMC125-C203 (NCT00412646), TMC125-C223 (NCT00081978), TMC125 C211 (NCT00111280) or TMC125-C209 feeder studies\]) and are present at endpoint (last available timepoint during treatment period for each individual participant). |
| Median Change From TMC125-C229 Baseline in Cluster of Differentiation 4 (CD4+) Cell Count at Week 96 | Week 96 | The last visit of the TMC125 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies) was considered to be the TMC125-C229 baseline. |
Participant flow
Recruitment details
In this study, 211 participants were enrolled in 12 different countries. The majority of participants (49%) were enrolled in the United States.
Pre-assignment details
In total, 211 participants (93 who rolled over from the etravirine arm of study TMC125-C203 (NCT00412646), 85 who rolled over from the etravirine arm of study TMC125-C223 (NCT00081978), 29 who rolled over from study TMC125-C211 (NCT00111280) and 4 who rolled over from study TMC125-C209) received treatment with etravirine.
Participants by arm
| Arm | Count |
|---|---|
| Etravirine 800 mg twice daily (formulation TF035), and after formulation switch, 200 mg twice daily (formulation F060) | 211 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 10 |
| Overall Study | Discontinued or ineligible for study | 2 |
| Overall Study | Lost to Follow-up | 4 |
| Overall Study | Non-compliant | 4 |
| Overall Study | Other | 9 |
| Overall Study | Reached a virologic endpoint | 29 |
| Overall Study | Withdrawal by Subject | 14 |
Baseline characteristics
| Characteristic | Etravirine |
|---|---|
| Age Continuous | 46.0 years FULL_RANGE 7.56 |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 24 Participants |
| Race/Ethnicity, Customized Hispanic | 16 Participants |
| Race/Ethnicity, Customized Other | 6 Participants |
| Race/Ethnicity, Customized White | 164 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 190 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 147 / 211 |
| serious Total, serious adverse events | 46 / 211 |
Outcome results
Primary
Number of Participants With Adverse Events
Number of participants who reported at least 1 of the adverse events.
Time frame: Up to 3 years
Population: Intent-to-treat population: Participants who received at least 1 dose of study medication were included
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants With Adverse Events | 195 Participants |
Secondary
Median Change From TMC125-C229 Baseline in Cluster of Differentiation 4 (CD4+) Cell Count at Week 96
The last visit of the TMC125 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies) was considered to be the TMC125-C229 baseline.
Time frame: Week 96
Population: Intent-to-treat participants who received at least one dose of study medication with evaluable data at Week 96
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Median Change From TMC125-C229 Baseline in Cluster of Differentiation 4 (CD4+) Cell Count at Week 96 | 18.50 x 1000000 cells/L |
Secondary
Median Change From TMC125-C229 Basline in Cluster of Differentiation 4 (CD4+) Cell Count at Week 48
The last visit of the TMC125 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies) was considered to be the TMC125-C229 baseline.
Time frame: Week 48
Population: Intent-to-treat participants who received at least one dose of study medication with evaluable data at Week 48
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Median Change From TMC125-C229 Basline in Cluster of Differentiation 4 (CD4+) Cell Count at Week 48 | 21.50 x 100000 cells/L |
Secondary
Median Change in Cluster of Differentiation 4 (CD4+) Cell Count From Baseline in TMC125-C229 Feeder Study at Week 192
Baseline considered for this outcome is the baseline in the respective TMC125-C229 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies).
Time frame: Week 192
Population: Intent-to-treat participants who received at least one dose of study medication with evaluable data at Week 192
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Median Change in Cluster of Differentiation 4 (CD4+) Cell Count From Baseline in TMC125-C229 Feeder Study at Week 192 | 149.50 x 1000000 cells/mL |
Secondary
Median Change in Cluster of Differentiation 4 (CD4+) Cell Count From Baseline in TMC125-C229 Feeder Study at Week 96
Baseline considered for this outcome is the baseline in the respective TMC125-C229 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies).
Time frame: Week 96
Population: Intent-to-treat participants who received at least one dose of study medication with evaluable data at Week 96
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Median Change in Cluster of Differentiation 4 (CD4+) Cell Count From Baseline in TMC125-C229 Feeder Study at Week 96 | 120.00 x 1000000 cells/mL |
Secondary
Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL) at Week 48
Number of participants who had viral load more than or equal to 50 copies/mL and less than 50 copies/mL at TMC125-C229 baseline and who achieved virologic response (ie, viral load less than 50 copies/mL) at Week 48. The last visit of the TMC125 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies) was considered to be the TMC125-C229 baseline.
Time frame: Week 48
Population: Intent-to-treat participants who received at least one dose of study medication with evaluable data at Week 48
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL) at Week 48 | 22 Participants |
| Viral Load Less Than 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL) at Week 48 | 80 Participants |
Secondary
Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL) at Week 96
Number of participants who had viral load more than or equal to 50 copies/mL and less than 50 copies/mL at TMC125-C229 baseline and who achieved virologic response (ie, viral load less than 50 copies/mL) at Week 96. The last visit of the TMC125 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies) was considered to be the TMC125-C229 baseline.
Time frame: Week 96
Population: Intent-to-treat participants who received at least one dose of study medication with evaluable data at Week 96
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL) at Week 96 | 28 Participants |
| Viral Load Less Than 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL) at Week 96 | 72 Participants |
Secondary
Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Less Than 400 Copies/mL; and Greater Than or Equal to 1 Log 10 Decrease From Baseline) at Week 96
Baseline considered for this outcome is the baseline in the respective TMC125-C229 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies).
Time frame: Week 96
Population: Intent-to-treat participants who received at least one dose of study medication with evaluable data at Week 96
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Less Than 400 Copies/mL; and Greater Than or Equal to 1 Log 10 Decrease From Baseline) at Week 96 | Viral load (VL) less than 50 copies/mL | 105 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Less Than 400 Copies/mL; and Greater Than or Equal to 1 Log 10 Decrease From Baseline) at Week 96 | Viral load less than 400 copies/mL | 124 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Less Than 400 Copies/mL; and Greater Than or Equal to 1 Log 10 Decrease From Baseline) at Week 96 | Viral load more than or equal to 1log10 | 132 Participants |
Secondary
Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Viral Load Less Than 400 Copies/mL; and Greater Than or Equal to 1 log10 Decrease From Baseline) at Week 192
Baseline considered for this outcome is the baseline in the respective TMC125-C229 feeder study (TMC125-C203 \[NCT00412646\], TMC125-C223 \[NCT00081978\], TMC125 C211 \[NCT00111280\] or TMC125-C209 feeder studies).
Time frame: Week 192
Population: Intent-to-treat participants who received at least one dose of study medication with evaluable data at Week 192
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Viral Load Less Than 400 Copies/mL; and Greater Than or Equal to 1 log10 Decrease From Baseline) at Week 192 | Viral load (VL) less than 50 copies/mL | 69 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Viral Load Less Than 400 Copies/mL; and Greater Than or Equal to 1 log10 Decrease From Baseline) at Week 192 | VL less than 400 copies/mL | 81 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants Who Achieved Virologic Response (ie, Viral Load Less Than 50 Copies/mL; Viral Load Less Than 400 Copies/mL; and Greater Than or Equal to 1 log10 Decrease From Baseline) at Week 192 | VL greater than or equal to 1log10 | 83 Participants |
Secondary
Number of Participants With Emerging Mutation (Reverse Transcriptase Mutation)
Emerging mutations are the mutation which are not present at baseline (last visit of the TMC125 feeder study \[TMC125-C203 (NCT00412646), TMC125-C223 (NCT00081978), TMC125 C211 (NCT00111280) or TMC125-C209 feeder studies\]) and are present at endpoint (last available timepoint during treatment period for each individual participant).
Time frame: Baseline and Endpoint (ie, the last available time point during the treatment period)
Population: Intent-to-treat population: Participants who received at least 1 dose of study medication were included
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants With Emerging Mutation (Reverse Transcriptase Mutation) | L100I | 8 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants With Emerging Mutation (Reverse Transcriptase Mutation) | Y181C | 7 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants With Emerging Mutation (Reverse Transcriptase Mutation) | A98G | 6 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants With Emerging Mutation (Reverse Transcriptase Mutation) | V179I | 6 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants With Emerging Mutation (Reverse Transcriptase Mutation) | K103N | 5 Participants |
| Viral Load More Than or Equal to 50 Copies/mL | Number of Participants With Emerging Mutation (Reverse Transcriptase Mutation) | H221Y | 5 Participants |