HIV Infections
Conditions
Keywords
Treatment Experienced
Brief summary
This study will investigate the safety and efficacy of raltegravir as a therapy for HIV-infected patients failing current therapy with 3-class antiviral resistance.
Detailed description
The primary double-blind study of raltegravir versus placebo was extended to 156 weeks and was followed by an open-label raltegravir phase in which continuing participants from both the raltegravir and placebo groups received open-label raltegravir for an additional 84 weeks for a maximum duration of up to 240 weeks. Participants who had viral failure after Week 16 may have received open-label raltegravir until Week 240.
Interventions
Raltegravir 400 mg twice daily (b.i.d.) by mouth (p.o.) with optimized background therapy. Treatment period of 48 weeks.
DRUGComparator: Placebo
Placebo b.i.d. p.o. with optimized background therapy. Treatment period of 48 weeks.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient must be HIV positive with HIV RNA values that are within ranges required by the study * Patient must have documented failure of certain antiretroviral therapy * Patient must be on the same antiretroviral therapy for at least the past two months
Exclusion criteria
* Patient is less than 16 years old * Additional study criteria will be discussed and identified by the study doctor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 48 | 48 Weeks | Percentage of participants who achieved HIV RNA \<400 copies/mL at Week 48 |
| Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <400 Copies/mL | 156 Weeks | Percentage of participants who achieved HIV RNA \<400 copies/mL at Week 156 |
| Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <400 Copies/mL | 240 Weeks | Percentage of participants who achieved HIV RNA \<400 Copies/mL at Week 240 |
| Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 16 | 16 Weeks | Percentage of participants who achieved HIV RNA \<400 copies/mL at Week 16 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double-Blind Extension - Week 156: Percentage of Participants Without Loss of Virologic Response | 156 weeks | For participants with confirmed HIV RNA levels \<50 copies/mL on 2 consecutive visits, loss of virologic response is the occurrence of the first value \>50 copies/mL or loss to follow-up; participants who never achieved HIV RNA \<50 copies/mL on 2 consecutive visits are also considered as having loss of virologic response. Events are the numbers of participants with loss of virologic response versus the numbers of participants with no loss of virologic response (event free). |
| Change From Baseline in HIV RNA (log10 Copies/mL) at Week 16 | Baseline and Week 16 | Mean change from baseline at Week 16 in HIV RNA (log10 copies/mL) |
| Change From Baseline in HIV RNA (log10 Copies/mL) at Week 48 | Baseline and Week 48 | Mean change from baseline at Week 48 in HIV RNA (log10 copies/mL) |
| Double-Blind Extension - Week 156: Change From Baseline in HIV RNA (log10 Copies/mL) | Baseline and Week 156 | Mean change from baseline at Week 156 in HIV RNA (log10 copies/mL) |
| Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 16 | 16 Weeks | Percentage of participants who achieved HIV RNA \<50 copies/mL at Week 16 |
| Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 16 | Baseline and Week 16 | Mean change from baseline at Week 16 in CD4 Cell Count (cells/mm\^3) |
| Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 48 | Baseline and Week 48 | Mean change from baseline at Week 48 in CD4 Cell Count (cells/mm\^3) |
| Double-Blind Extension - Week 156: Change From Baseline in CD4 Cell Count (Cells/mm^3) | Baseline and Week 156 | Mean change from baseline at Week 156 in CD4 Cell Count (cells/mm\^3) |
| Open-Label Extension - Week 240: Change From Baseline in CD4 Cell Count (Cells/mm^3) | Baseline and Week 240 | Mean change from baseline at Week 240 in CD4 Cell Count (cells/mm\^3) |
| Open-Label Extension - Week 240: Change From Baseline in HIV RNA (log10 Copies/mL) | Baseline and Week 240 | Mean change from baseline at Week 240 in HIV RNA (log10 copies/mL) |
| Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 48 | 48 Weeks | Percentage of participants who achieved HIV RNA \<50 copies/mL at Week 48 |
| Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <50 Copies/mL | 156 weeks | Percentage of participants who achieved HIV RNA \<50 copies/mL at Week 156 |
| Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <50 Copies/mL | 240 weeks | Percentage of participants who achieved HIV RNA \<50 copies/mL at Week 240 |
Participant flow
Recruitment details
Phase 3; First Patient In: Mar 2006; Last Patient Last Visit (LPLV) Week 48: Aug 2007; 61 of 63 sites in Australia, Belgium, Denmark, France, Germany, Italy, Peru, Portugal, Spain, Switzerland, Taiwan, Thailand randomized patients. Extension Study LPLV Week 240: June 2011
Pre-assignment details
Patients failed prior antiretroviral therapy (HIV RNA \>1000 copies/mL), and had documented resistance to at least one drug in each class of licensed oral antiretroviral therapy (Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase inhibitors and Protease Inhibitors). All patients must have met laboratory criteria.
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir 400 mg b.i.d. + OBT | 232 |
| Placebo + OBT | 118 |
| Total | 350 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension - Double-Blind Week 49-156 | Adverse Event | 1 | 4 |
| Extension - Double-Blind Week 49-156 | Death | 3 | 0 |
| Extension - Double-Blind Week 49-156 | Entered OLPVF Phase | 15 | 6 |
| Extension - Double-Blind Week 49-156 | Lack of Efficacy | 7 | 1 |
| Extension - Double-Blind Week 49-156 | Lost to Follow-up | 4 | 0 |
| Extension - Double-Blind Week 49-156 | Other Reason | 7 | 0 |
| Extension - Double-Blind Week 49-156 | Participant relocated or site terminated | 2 | 0 |
| Extension - Double-Blind Week 49-156 | Withdrawal by Subject | 13 | 4 |
| Extension - Open-Label Week 157-240 | Adverse Event | 5 | 0 |
| Extension - Open-Label Week 157-240 | Lack of Efficacy | 7 | 0 |
| Extension - Open-Label Week 157-240 | Lost to Follow-up | 1 | 0 |
| Extension - Open-Label Week 157-240 | Other Reason | 3 | 1 |
| Extension - Open-Label Week 157-240 | Participant relocated or site terminated | 2 | 0 |
| Extension - Open-Label Week 157-240 | Withdrawal by Subject | 2 | 1 |
| Open-Label Post Virologic Failure Phase | Adverse Event | 2 | 3 |
| Open-Label Post Virologic Failure Phase | Laboratory Adverse Event | 0 | 2 |
| Open-Label Post Virologic Failure Phase | Lack of Efficacy | 23 | 19 |
| Open-Label Post Virologic Failure Phase | Lost to Follow-up | 2 | 2 |
| Open-Label Post Virologic Failure Phase | Other Reason | 4 | 5 |
| Open-Label Post Virologic Failure Phase | Participant Moved or Site Terminated | 0 | 2 |
| Open-Label Post Virologic Failure Phase | Withdrawal by Subject | 2 | 4 |
| Primary Study - Double-Blind Week 0-48 | Adverse Event | 1 | 1 |
| Primary Study - Double-Blind Week 0-48 | Death | 3 | 3 |
| Primary Study - Double-Blind Week 0-48 | Entered OLPVF Phase | 33 | 60 |
| Primary Study - Double-Blind Week 0-48 | Lack of Efficacy | 0 | 2 |
| Primary Study - Double-Blind Week 0-48 | Lost to Follow-up | 1 | 1 |
| Primary Study - Double-Blind Week 0-48 | Never Treated | 2 | 0 |
| Primary Study - Double-Blind Week 0-48 | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo + OBT | Total | Raltegravir 400 mg b.i.d. + OBT |
|---|---|---|---|
| Age, Continuous | 43.7 Years | 45.3 Years | 46.1 Years |
| Cluster of Differentiation 4 (CD4) Cell Count | 153 cells/mm^3 | 155 cells/mm^3 | 156 cells/mm^3 |
| Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) | 31828 copies/mL | 37352 copies/mL | 40519 copies/mL |
| Race/Ethnicity, Customized Asian | 5 participants | 19 participants | 14 participants |
| Race/Ethnicity, Customized Black | 5 participants | 23 participants | 18 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants | 7 participants | 6 participants |
| Race/Ethnicity, Customized Other | 11 participants | 31 participants | 20 participants |
| Race/Ethnicity, Customized White | 96 participants | 270 participants | 174 participants |
| Sex: Female, Male Female | 15 Participants | 52 Participants | 37 Participants |
| Sex: Female, Male Male | 103 Participants | 298 Participants | 195 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 206 / 232 | 104 / 118 |
| serious Total, serious adverse events | 97 / 232 | 46 / 118 |
Outcome results
Primary
Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <400 Copies/mL
Percentage of participants who achieved HIV RNA \<400 copies/mL at Week 156
Time frame: 156 Weeks
Population: The analysis population was based on a non-completer equals failure approach where missing values for participants who discontinued the study for any reason were considered treatment failures.~Participants who experienced virologic failure after Week 16 are counted also as treatment failures for the subsequent virologic efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <400 Copies/mL | 57.3 Percentage of Participants |
| Placebo + OBT | Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <400 Copies/mL | 25.6 Percentage of Participants |
Primary
Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <400 Copies/mL
Percentage of participants who achieved HIV RNA \<400 Copies/mL at Week 240
Time frame: 240 Weeks
Population: The analysis population was based on a non-completer equals failure approach where missing values for participants who discontinued the study for any reason were considered treatment failures.~Participants who experienced virologic failure after Week 16 are also counted as treatment failures for the subsequent virologic efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <400 Copies/mL | 45.3 Percentage of Participants |
| Placebo + OBT | Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <400 Copies/mL | 20.3 Percentage of Participants |
Primary
Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 16
Percentage of participants who achieved HIV RNA \<400 copies/mL at Week 16
Time frame: 16 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 16 | 77.7 Percentage of Participants |
| Placebo + OBT | Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 16 | 41.0 Percentage of Participants |
Primary
Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 48
Percentage of participants who achieved HIV RNA \<400 copies/mL at Week 48
Time frame: 48 Weeks
Population: Participants who experienced virologic failure after Week 16 are also counted as treatment failures for the subsequent virologic efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 48 | 73.6 Percentage of Participants |
| Placebo + OBT | Percentage of Participants Achieving HIV RNA <400 Copies/mL at Week 48 | 36.4 Percentage of Participants |
Secondary
Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 16
Mean change from baseline at Week 16 in CD4 Cell Count (cells/mm\^3)
Time frame: Baseline and Week 16
Population: Observed failure approach assuming baseline-carry-forward for all failures, exclude other missing values. Baseline CD4 cell count (cells/mm\^3) was carried forward for participants who discontinued assigned therapy due to lack of efficacy.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 16 | 82.7 CD4 Cell Count (cells/mm^3) |
| Placebo + OBT | Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 16 | 31.3 CD4 Cell Count (cells/mm^3) |
Secondary
Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 48
Mean change from baseline at Week 48 in CD4 Cell Count (cells/mm\^3)
Time frame: Baseline and Week 48
Population: Observed failure approach assuming baseline-carry-forward for all failures, exclude other missing values. Baseline CD4 cell count (cells/mm\^3) was carried forward for participants who discontinued assigned therapy due to lack of efficacy.~Participants with virologic failure after Week 16 are treatment failures for virologic efficacy analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 48 | 120.2 CD4 Cell Count (cells/mm^3) |
| Placebo + OBT | Change From Baseline in CD4 Cell Count (Cells/mm^3) at Week 48 | 49.4 CD4 Cell Count (cells/mm^3) |
Secondary
Change From Baseline in HIV RNA (log10 Copies/mL) at Week 16
Mean change from baseline at Week 16 in HIV RNA (log10 copies/mL)
Time frame: Baseline and Week 16
Population: Observed mean change from baseline in log10 plasma HIV RNA calculated using conventional imputation (replace \<400 copies by 400 copies if signal detected; 200 copies if not detected); Missing values: baseline carry-~forward for all failures/discontinued due to lack of efficacy
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Change From Baseline in HIV RNA (log10 Copies/mL) at Week 16 | -1.85 HIV RNA (log10 copies/mL) |
| Placebo + OBT | Change From Baseline in HIV RNA (log10 Copies/mL) at Week 16 | -0.78 HIV RNA (log10 copies/mL) |
Secondary
Change From Baseline in HIV RNA (log10 Copies/mL) at Week 48
Mean change from baseline at Week 48 in HIV RNA (log10 copies/mL)
Time frame: Baseline and Week 48
Population: Observed mean change from baseline in log10 plasma HIV RNA calculated using conventional imputation (replace \<400 copies by 400 copies if signal detected; 200 copies if not detected); Missing values: baseline carry-forward for all failures/discontinued due to lack of efficacy~Participants with virologic failure after Week 16 = treatment failures
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Change From Baseline in HIV RNA (log10 Copies/mL) at Week 48 | -1.67 HIV RNA (log10 copies/mL) |
| Placebo + OBT | Change From Baseline in HIV RNA (log10 Copies/mL) at Week 48 | -0.68 HIV RNA (log10 copies/mL) |
Secondary
Double-Blind Extension - Week 156: Change From Baseline in CD4 Cell Count (Cells/mm^3)
Mean change from baseline at Week 156 in CD4 Cell Count (cells/mm\^3)
Time frame: Baseline and Week 156
Population: Observed failure approach assuming baseline-carry-forward for all failures, exclude other missing values. Baseline CD4 cell count (cells/mm\^3) was carried forward for participants who discontinued assigned therapy due to lack of efficacy.~Participants with virologic failure after Week 16 are treatment failures for virologic efficacy analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Double-Blind Extension - Week 156: Change From Baseline in CD4 Cell Count (Cells/mm^3) | 170.9 CD4 Cell Count (cells/mm^3) |
| Placebo + OBT | Double-Blind Extension - Week 156: Change From Baseline in CD4 Cell Count (Cells/mm^3) | 71.03 CD4 Cell Count (cells/mm^3) |
Secondary
Double-Blind Extension - Week 156: Change From Baseline in HIV RNA (log10 Copies/mL)
Mean change from baseline at Week 156 in HIV RNA (log10 copies/mL)
Time frame: Baseline and Week 156
Population: Observed mean change from baseline in log10 plasma HIV RNA calculated using conventional imputation (replace \<400 copies by 400 copies if signal detected; 200 copies if not detected); Missing values: baseline carry-forward for all failures/discontinued due to lack of efficacy~Participants with virologic failure after Week 16 = treatment failures
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Double-Blind Extension - Week 156: Change From Baseline in HIV RNA (log10 Copies/mL) | -1.44 HIV RNA (log10 copies/mL) |
| Placebo + OBT | Double-Blind Extension - Week 156: Change From Baseline in HIV RNA (log10 Copies/mL) | -0.51 HIV RNA (log10 copies/mL) |
Secondary
Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <50 Copies/mL
Percentage of participants who achieved HIV RNA \<50 copies/mL at Week 156
Time frame: 156 weeks
Population: Participants who experienced virologic failure after Week 16 are also counted as treatment failures for the subsequent virologic efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <50 Copies/mL | 53.4 Percentage of Participants |
| Placebo + OBT | Double-Blind Extension - Week 156: Percentage of Participants Achieving HIV RNA <50 Copies/mL | 25.6 Percentage of Participants |
Secondary
Double-Blind Extension - Week 156: Percentage of Participants Without Loss of Virologic Response
For participants with confirmed HIV RNA levels \<50 copies/mL on 2 consecutive visits, loss of virologic response is the occurrence of the first value \>50 copies/mL or loss to follow-up; participants who never achieved HIV RNA \<50 copies/mL on 2 consecutive visits are also considered as having loss of virologic response. Events are the numbers of participants with loss of virologic response versus the numbers of participants with no loss of virologic response (event free).
Time frame: 156 weeks
Population: Participants who experienced virologic failure after Week 16 are also counted as treatment failures for the subsequent virologic efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Double-Blind Extension - Week 156: Percentage of Participants Without Loss of Virologic Response | 47.4 Percentage of Participants |
| Placebo + OBT | Double-Blind Extension - Week 156: Percentage of Participants Without Loss of Virologic Response | 24.6 Percentage of Participants |
Secondary
Open-Label Extension - Week 240: Change From Baseline in CD4 Cell Count (Cells/mm^3)
Mean change from baseline at Week 240 in CD4 Cell Count (cells/mm\^3)
Time frame: Baseline and Week 240
Population: Observed failure approach assuming baseline-carry-forward for all failures, exclude other missing values. Baseline CD4 cell count (cells/mm\^3) was carried forward for participants who discontinued assigned therapy due to lack of efficacy.~Participants with virologic failure after Week 16 are treatment failures for virologic efficacy analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Open-Label Extension - Week 240: Change From Baseline in CD4 Cell Count (Cells/mm^3) | 193.6 CD4 Cell Count (cells/mm^3) |
| Placebo + OBT | Open-Label Extension - Week 240: Change From Baseline in CD4 Cell Count (Cells/mm^3) | 68.2 CD4 Cell Count (cells/mm^3) |
Secondary
Open-Label Extension - Week 240: Change From Baseline in HIV RNA (log10 Copies/mL)
Mean change from baseline at Week 240 in HIV RNA (log10 copies/mL)
Time frame: Baseline and Week 240
Population: Observed mean change from baseline in log10 plasma HIV RNA calculated using conventional imputation (replace \<400 copies by 400 copies if signal detected; 200 copies if not detected); Missing values: baseline carry-forward for all failures/discontinued due to lack of efficacy~Participants with virologic failure after Week 16 = treatment failures
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Open-Label Extension - Week 240: Change From Baseline in HIV RNA (log10 Copies/mL) | -1.24 HIV RNA (log10 copies/mL) |
| Placebo + OBT | Open-Label Extension - Week 240: Change From Baseline in HIV RNA (log10 Copies/mL) | -0.45 HIV RNA (log10 copies/mL) |
Secondary
Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <50 Copies/mL
Percentage of participants who achieved HIV RNA \<50 copies/mL at Week 240
Time frame: 240 weeks
Population: Participants who experienced virologic failure after Week 16 are also counted as treatment failures for the subsequent virologic efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <50 Copies/mL | 42.2 Percentage of Participants |
| Placebo + OBT | Open-Label Extension - Week 240: Percentage of Participants Achieving HIV RNA <50 Copies/mL | 18.6 Percentage of Participants |
Secondary
Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 16
Percentage of participants who achieved HIV RNA \<50 copies/mL at Week 16
Time frame: 16 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 16 | 61.6 Percentage of Participants |
| Placebo + OBT | Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 16 | 33.3 Percentage of Participants |
Secondary
Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 48
Percentage of participants who achieved HIV RNA \<50 copies/mL at Week 48
Time frame: 48 Weeks
Population: Participants who experienced virologic failure after Week 16 are also counted as treatment failures for the subsequent virologic efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir 400 mg b.i.d. + OBT | Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 48 | 64.5 Percentage of Participants |
| Placebo + OBT | Percentage of Participants Achieving HIV RNA <50 Copies/mL at Week 48 | 31.4 Percentage of Participants |