Randomized Evaluation of Strategic Intervention in Multidrug Resistant Patients With Tipranavir (RESIST)

Study Overview
=================
Brief Summary
-----------------
Demonstrate the safety and efficacy of Tipranavir/Ritonavir versus an active treatment regimen in highly treatment experienced Human Immunodeficiency virus 1(HIV-1) infected patients.

Official Title
-----------------
Randomized, Open-label, Comparative Safety and Efficacy Study of Tipranavir Boosted With Low-dose Ritonavir (TPV/RTV) Verses Genotypically-defined Protease Inhibitor/Ritonavir (PI/RTV) in Multiple Antiretroviral Drug-experienced Patients.

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

Intervention / Treatment
-----------------
* Drug: Tipranavir
* Drug: Ritonavir(r)
* Drug: Comparator Protease Inhibitor (CPI)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients meeting the following criteria will be eligible for participation in th is study: Human Immunodeficiency virus 1 (HIV-1) infected males or females >=18 years of age. Screening genotypic resistance report indicating both of the following: at least one primary protease Inhibitor (PI) mutation at the following sites: 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V or 90M, and no more than two protease mutations on codons 33, 82, 84, or 90. 3. At least 3 consecutive months experience taking antiretrovirals (ARVs) from each of the classes of nucleoside reverse transcriptase inhibitors(NRTI(s)), non-nucleoside reverse transcriptase inhibitors(NNRTI(s)), and protease inhibitors (PIs) at some point in treatment history,with at least 2 protease inhibitor (PI)-based regimens, one of which must be the current regimen, and current protease inhibitor (PI)-based antiretroviral (ARV) medication regimen for at least 3 months prior to randomization. 4. Human Immunodeficiency Virus 1 (HIV-1) viral load >=1,000 copies/mL at screening. Exclusion criteria: Patients with any of the following criteria are excluded from participation in t he study: Antiretroviral (ARV) medication naïve. Patients on recent drug holiday, defined as off antiretroviral (ARV) medications for at least 7 consecutive days within the last 3 months. alanine aminotransferase (ALT) >=3.0x upper limit of normal (ULN) and aspartate aminotransferase(AST) >=2.5x upper limit of normal (ULN) (>=Division of AIDS(DAIDS) Grade 1) at either 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
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Tipranavir(TPV)/low dose ritonavir(r)<br> | Drug: Tipranavir<br> <br> Drug: Ritonavir(r)<br> <br> |
| Other: Comparator protease inhibitor(CPI)/low dose ritonavir(r)<br> | Drug: Ritonavir(r)<br> <br> Drug: Comparator Protease Inhibitor (CPI)<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response at Week 48 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | At week 48 | 
| Time to Treatment Failure Through 48 Weeks of Treatment | Time to treatment failure is defined as 0 for patients who never achieve TR otherwise time to treatment failure is the earliest time of death, discontinuation of the study drug or 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, or the first of two consecutive visits with VL measurements <1 log10 below baseline. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response at Week 24 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | Week 24 | 
| Treatment Response at Week 2 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | week 2 | 
| Treatment Response at Week 4 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | week 4 | 
| Treatment Response at Week 8 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | week 8 | 
| Treatment Response at Week 16 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | week 16 | 
| Treatment Response at Week 32 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | Week 32 | 
| Treatment Response at Week 40 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | Week 40 | 
| Treatment Response at Week 48 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | Week 48 | 
| Treatment Response at Week 56 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | week 56 | 
| Treatment Response at Week 64 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | week 64 | 
| Treatment Response at Week 72 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | Week 72 | 
| Treatment Response at Week 80 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | Week 80 | 
| Treatment Response at Week 88 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | Week 88 | 
| Treatment Response at Week 96 | Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound | Week 96 | 
| Time to Treatment Failure Through 96 Weeks of Treatment | time to treatment failure is defined as 0 for patients who never achieve TR otherwise time to treatment failure is the earliest time of death, discontinuation of the study drug or 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, or the first of two consecutive visits with VL measurements <1 log10 below baseline. | Week 96 | 
| Time to Confirmed Virologic Failure Through 48 Weeks of Treatment | Time to virologic failure is defined as the time from the start of treatment to the last measurement with a viral load reduction greater than 1.0 log before a confirmed drop of viral load reduction below 1.0 log. | Week 48 | 
| Time to Confirmed Virologic Failure Through 96 Weeks of Treatment | Time to virologic failure is defined as the time from the start of treatment to the last measurement with a viral load reduction greater than 1.0 log before a confirmed drop of viral load reduction below 1.0 log. | Week 96 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Viral Load Nadir, LOCF | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 2 through Week 96 (at any point during trial) | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 2 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 2 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 4 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 4 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 8 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 8 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 16 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 16 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 24 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 24 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 32 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 32 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 40 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 40 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 48 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 48 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 56 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 56 | 
| Virologic Response (Viral Load >= 1 Log Drop) at Week 64 | Percentage of participants with Viral Load (VL) >= 1 log reduction from baseline | Week 64 | 
| Median Change From Baseline in Viral Load to Week 2 |  | Baseline to Week 2 | 
| Median Change From Baseline in Viral Load to Week 4 |  | Baseline to Week 4 | 
| Median Change From Baseline in Viral Load to Week 8 |  | Baseline to Week 8 | 
| Median Change From Baseline in Viral Load to Week 16 |  | Baseline to Week 16 | 
| Median Change From Baseline in Viral Load to Week 24 |  | Baseline to Week 24 | 
| Median Change From Baseline in Viral Load to Week 32 |  | Baseline to Week 32 | 
| Median Change From Baseline in Viral Load to Week 40 |  | Baseline to Week 40 | 
| Median Change From Baseline in Viral Load to Week 48 |  | Baseline to Week 48 | 
| Median Change From Baseline in Viral Load to Week 56 |  | Baseline to Week 56 | 
| Median Change From Baseline in Viral Load to Week 64 |  | Baseline to Week 64 | 
| Median Change From Baseline in Viral Load to Week 72 |  | Baseline to Week 72 | 
| Median Change From Baseline in Viral Load to Week 80 |  | Baseline to Week 80 | 
| Median Change From Baseline in Viral Load to Week 88 |  | Baseline to Week 88 | 
| Median Change From Baseline in Viral Load to Week 96 |  | Baseline to Week 96 | 
| Mean Change From Baseline to Week 2 in CD4+ Cell Count |  | Baseline to Week 2 | 
| Mean Change From Baseline to Week 4 in CD4+ Cell Count |  | Baseline to Week 4 | 
| Mean Change From Baseline to Week 8 in CD4+ Cell Count |  | Baseline to Week 8 | 
| Mean Change From Baseline to Week 16 in CD4+ Cell Count |  | Baseline to Week 16 | 
| Mean Change From Baseline to Week 24 in CD4+ Cell Count |  | Baseline to Week 24 | 
| Mean Change From Baseline to Week 32 in CD4+ Cell Count |  | Baseline to Week 32 | 
| Mean Change From Baseline to Week 40 in CD4+ Cell Count |  | Baseline to Week 40 | 
| Mean Change From Baseline to Week 48 in CD4+ Cell Count |  | Baseline to Week 48 | 
| Mean Change From Baseline to Week 56 in CD4+ Cell Count |  | Baseline to Week 56 | 
| Mean Change From Baseline to Week 64 in CD4+ Cell Count |  | Baseline to Week 64 | 
| Mean Change From Baseline to Week 72 in CD4+ Cell Count |  | Baseline to Week 72 | 
| Mean Change From Baseline to Week 80 in CD4+ Cell Count |  | Baseline to Week 80 | 
| Mean Change From Baseline to Week 88 in CD4+ Cell Count |  | Baseline to Week 88 | 
| Mean Change From Baseline to Week 96 in CD4+ Cell Count |  | Baseline to Week 96 | 
| Time to New CDC Class C Progression Event or Death. | Time to new Centers for Disease Control and Prevention (CDC) class C progression event (i.e., new AIDS defining illness) or death | after 48 weeks of treatment | 
| Virologic Response (VL < 400 Copies/ml) at Viral Load Nadir, LOCF | Percentage of participants with Viral Load < 400 copies/mL | Week 2 through Week 96 (at any point during trial) | 
| Virologic Response (VL < 400 Copies/ml) at Week 2 | Percentage of participants with Viral Load < 400 copies/mL | Week 2 | 
| Virologic Response (VL < 400 Copies/ml) at Week 4 | Percentage of participants with Viral Load < 400 copies/mL | Week 4 | 
| Virologic Response (VL < 400 Copies/ml) at Week 8 | Percentage of participants with Viral Load < 400 copies/mL | Week 8 | 
| Virologic Response (VL < 400 Copies/ml) at Week 16 | Percentage of participants with Viral Load < 400 copies/mL | Week 16 | 
| Virologic Response (VL < 400 Copies/ml) at Week 24 | Percentage of participants with Viral Load < 400 copies/mL | Week 24 | 
| Virologic Response (VL < 400 Copies/ml) at Week 32 | Percentage of participants with Viral Load < 400 copies/mL | week 32 | 
| Virologic Response (VL < 400 Copies/ml) at Week 40 | Percentage of participants with Viral Load < 400 copies/mL | Week 40 | 
| Virologic Response (VL < 400 Copies/ml) at Week 48 | Percentage of participants with Viral Load < 400 copies/mL | Week 48 | 
| Virologic Response (VL < 400 Copies/ml) at Week 56 | Percentage of participants with Viral Load < 400 copies/mL | Week 56 | 
| Virologic Response (VL < 400 Copies/ml) at Week 64 | Percentage of participants with Viral Load < 400 copies/mL | Week 64 | 
| Virologic Response (VL < 400 Copies/ml) at Week 72 | Percentage of participants with Viral Load < 400 copies/mL | Week 72 | 
| Virologic Response (VL < 400 Copies/ml) at Week 80 | Percentage of participants with Viral Load < 400 copies/mL | Week 80 | 
| Virologic Response (VL < 400 Copies/ml) at Week 88 | Percentage of participants with Viral Load < 400 copies/mL | week 88 | 
| Virologic Response (VL < 400 Copies/ml) at Week 96 | Percentage of participants with Viral Load < 400 copies/mL | week 96 | 
| Virologic Response (VL < 50 Copies/ml) at Viral Load Nadir, LOCF | Percentage of participants with Viral Load < 50 copies/mL | Week 2 through Week 96 (at any point during trial) | 
| Virologic Response (VL < 50 Copies/ml) at Week 2 | Percentage of participants with Viral Load < 50 copies/mL | Week 2 | 
| Virologic Response (VL < 50 Copies/ml) at Week 4 | Percentage of participants with Viral Load < 50 copies/mL | Week 4 | 
| Virologic Response (VL < 50 Copies/ml) at Week 8 | Percentage of participants with Viral Load < 50 copies/mL | Week 8 | 
| Virologic Response (VL < 50 Copies/ml) at Week 16 | Percentage of participants with Viral Load < 50 copies/mL | Week 16 | 
| Virologic Response (VL < 50 Copies/ml) at Week 24 | Percentage of participants with Viral Load < 50 copies/mL | Week 24 | 
| Virologic Response (VL < 50 Copies/ml) at Week 32 | Percentage of participants with Viral Load < 50 copies/mL | Week 32 | 
| Virologic Response (VL < 50 Copies/ml) at Week 40 | Percentage of participants with Viral Load < 50 copies/mL | Week 40 | 
| Virologic Response (VL < 50 Copies/ml) at Week 48 | Percentage of participants with Viral Load < 50 copies/mL | Week 48 | 
| Virologic Response (VL < 50 Copies/ml) at Week 56 | Percentage of participants with Viral Load < 50 copies/mL | Week 56 | 
| Virologic Response (VL < 50 Copies/ml) at Week 64 | Percentage of participants with Viral Load < 50 copies/mL | Week 64 | 
| Virologic Response (VL < 50 Copies/ml) at Week 72 | Percentage of participants with Viral Load < 50 copies/mL | Week 72 | 
| Virologic Response (VL < 50 Copies/ml) at Week 80 | Percentage of participants with Viral Load < 50 copies/mL | Week 80 | 
| Virologic Response (VL < 50 Copies/ml) at Week 88 | Percentage of participants with Viral Load < 50 copies/mL | Week 88 | 
| Virologic Response (VL < 50 Copies/ml) at Week 96 | Percentage of participants with Viral Load < 50 copies/mL | Week 96 | 
| Percentage of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 Laboratory Abnormalities | NIH Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | 240 Weeks |