SPRING: Safety, Efficacy, Pharmacokinetics of tipRanavir/r IN Race/Gender HIV+ Patients Randomized to TDM or SoC

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study is to: 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. Determine pharmacokinetic data in this racially and gender diverse population. Determine the potential utility of using therapeutic drug monitoring (TDM) in improving efficacy outcomes.

Official Title
-----------------
SPRING: Safety, Efficacy, Pharmacokinetics of tipRanavi/r IN Race/Gender HIV+ Patients Randomized to Therapeutic Drug Monitoring or Standard of Care

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Drug: tipranavir
* Drug: ritonavir
* Drug: Optimized Background Regimen (OBR)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Main inclusion criteria for the study are: HIV-1 infected adults, men and women at least 18 years of age. 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. CD4+ T lymphocyte count >=50 cells/mm3. HIV-1 viral load >=1,000 copies/mL at screening. 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. Acceptable screening laboratory values that indicate adequate baseline organ function. 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. A reliable method of barrier contraception will be used by all female patients who are of childbearing potential. Exclusion Criteria: Main exclusion criteria for the study are: Known hypersensitivity to the tipranavir (TPV) or ritonavir (RTV). ARV medication naïve. Genotypic resistance to TPV (defined as a TPV mutation score >7). Patients on recent drug holiday, defined as off antiretroviral (ARV) medications for at least 7 consecutive days within the month prior to screening. Prior tipranavir use. Inability to adhere to the requirements of the protocol. Patients with prior history of hemorrhagic stroke or intracranial aneurysm. Patients with a history of ischemic stroke, neurosurgery or skull trauma within 4 weeks prior to screening. History of Progressive Multifocal Leukoencephalopathy, Visceral Kaposi's Sarcoma, and/or any malignancy. Any acquired immunodeficiency syndrome (AIDS) defining illness that is unresolved, symptomatic or not stable on treatment for at least 12 weeks at screening visit.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard of Care (SoC)<br>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. | Drug: tipranavir<br> <br> Drug: ritonavir<br> <br> Drug: Optimized Background Regimen (OBR)<br>* 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.<br>* Other names: Raltegravir;|
| Other: Therapeutic Drug Monitoring (TDM)<br>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. | Drug: tipranavir<br> <br> Drug: ritonavir<br> <br> Drug: Optimized Background Regimen (OBR)<br>* 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.<br>* Other names: Raltegravir;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response at Week 48 | percentage of participants whose viral load <50 copies/mL at Week 48 | after 48 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 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. | after Day 1 of treatment | 
| 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) | 
| 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) | 
| 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 |