HIV Infections
Conditions
Brief summary
The primary purpose of this study is to: 1. Demonstrate the safety and efficacy of tipranavir/ritonavir (TPV/r) among a racially diverse HIV+ population (males and females) who are three-class (nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI)) experienced with documented resistance to more than one PI. 2. Determine pharmacokinetic data in this racially and gender diverse population. 3. Determine the potential utility of using therapeutic drug monitoring (TDM) in improving efficacy outcomes.
Interventions
DRUGtipranavir
DRUGritonavir
Patients received between two and four active anti-retroviral medications based on resistance testing results, as background treatment, and remained on these for the duration of the trial.
Sponsors
Boehringer Ingelheim
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
Main inclusion criteria for the study are: 1. HIV-1 infected adults, men and women at least 18 years of age. 2. 3-class (nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI)) treatment-experienced (min of 3-months duration for each class) with resistance to more than one PI (on screening resistance testing). NNRTI-naïve patients who have genotypically documented NNRTI-resistance mutations on past or screening resistance testing would be eligible. 3. CD4+ T lymphocyte count \>=50 cells/mm3. 4. HIV-1 viral load \>=1,000 copies/mL at screening. 5. The antiretroviral (ARV) study treatment regimen must consist of TPV/r in combo with an optimized background regimen (OBR) of 2-4 agents: N(t)RTIs (NRTI or NtRTI), enfuvirtide (ENF), and/or, where available, a trial approved expanded access program (EAP) investigational agent. 6. Acceptable screening laboratory values that indicate adequate baseline organ function. 7. Acceptable medical history with a chest X-ray without evidence of active disease and an electrocardiogram (ECG) without clinically important abnormalities within one year of the study. 8. A reliable method of barrier contraception will be used by all female patients who are of childbearing potential.
Exclusion criteria
Main
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response at Week 48 | after 48 weeks of treatment | percentage of participants whose viral load \<50 copies/mL at Week 48 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Whose Viral Load <400 Copies/mL at Each Visit Including Visits at Weeks 24 and 48 | after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
| Percentage of Participants Whose ≥1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48 | after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
| Change in Viral Load From Baseline at Each Visit | after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
| Time to Treatment Failure | after Day 1 of treatment | For patients who never achieve a confirmed virologic response, time to treatment failure is defined as 0. For patients who achieve a confirmed virologic response, time to treatment failure is the earliest time of either: death, permanent discontinuation of the study drug or loss to follow-up, introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background drug, but not the study drug, or first occurrence of a VL \>50 copies/mL at two consecutive measurements after having achieved a VL \<50 copies/mL. |
| Time to New AIDS or AIDS Related Progression Event or Death | after Day 1 of treatment | — |
| Change in CD4+ and CD8+ Cell Counts From Baseline at Each Visit Including Visits at Week 24 and Week 48 | after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
| Percentage of Participants Whose Viral Load <50 Copies/mL at Each Visit Including Visits at Weeks 24 and 48 | after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
| Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48 | after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
| Patients Adherence With Study Medication Based on Pill Count | after 4 weeks of treatment | — |
| Occurrence of TPV Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured | after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
| Occurrence of TPV Trough Concentration >120 μM | after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
| Post-dose TPV and RTV Concentrations at Week 4 | Week 4 | — |
| Change in Ratio of CD38+/CD8+ From Baseline to Week 48 | after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48) | — |
Countries
Argentina, Brazil, Canada, Germany, Italy, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care (SoC) Standard of Care (SOC) Arm = Tipranavir/ritonavir (TPV/r) capsules taken orally at a dose of 500 mg/200 mg twice a day (BID) plus optimized background regimen (OBR). No TPV/r dose changes were permitted. | 15 |
| Therapeutic Drug Monitoring (TDM) Therapeutic Drug Monitoring (TDM) Arm = Patients began by receiving standard of care (SOC) tipranavir/ritonavir (TPV/r) capsules orally at a dose of 500 mg/200 mg twice a day (BID) plus optimized background regimen (OBR) followed, if needed, by TPV or ritonavir (RTV) dose adjustments at Week 4, 6, 10, 14, 18, 22, 26 and 30 based on viral response, phenotypic inhibitory quotient (IQ), and TPV trough concentrations. | 18 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Due to closure of trial | 8 | 10 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Standard of Care (SoC) | Therapeutic Drug Monitoring (TDM) | Total |
|---|---|---|---|
| Age, Continuous | 46.1 years STANDARD_DEVIATION 8.2 | 43.2 years STANDARD_DEVIATION 10.6 | 44.5 years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 15 | 15 / 18 |
| serious Total, serious adverse events | 0 / 15 | 0 / 18 |
Outcome results
Primary
Treatment Response at Week 48
percentage of participants whose viral load \<50 copies/mL at Week 48
Time frame: after 48 weeks of treatment
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Change in CD4+ and CD8+ Cell Counts From Baseline at Each Visit Including Visits at Week 24 and Week 48
Time frame: after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Change in Ratio of CD38+/CD8+ From Baseline to Week 48
Time frame: after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Change in Viral Load From Baseline at Each Visit
Time frame: after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Occurrence of TPV Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured
Time frame: after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Occurrence of TPV Trough Concentration >120 μM
Time frame: after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Patients Adherence With Study Medication Based on Pill Count
Time frame: after 4 weeks of treatment
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Percentage of Participants Whose ≥1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48
Time frame: after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Percentage of Participants Whose Viral Load <400 Copies/mL at Each Visit Including Visits at Weeks 24 and 48
Time frame: after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Percentage of Participants Whose Viral Load <50 Copies/mL at Each Visit Including Visits at Weeks 24 and 48
Time frame: after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Post-dose TPV and RTV Concentrations at Week 4
Time frame: Week 4
Secondary
Time to New AIDS or AIDS Related Progression Event or Death
Time frame: after Day 1 of treatment
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Time to Treatment Failure
For patients who never achieve a confirmed virologic response, time to treatment failure is defined as 0. For patients who achieve a confirmed virologic response, time to treatment failure is the earliest time of either: death, permanent discontinuation of the study drug or loss to follow-up, introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background drug, but not the study drug, or first occurrence of a VL \>50 copies/mL at two consecutive measurements after having achieved a VL \<50 copies/mL.
Time frame: after Day 1 of treatment
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.
Secondary
Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
Time frame: after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48)
Population: The study was terminated early due to low patient enrollment, and, therefore, no analysis was performed on the primary and secondary endpoints.