Tipranavir/Ritonavir vs. Genotypically Defined Protease Inhibitor/Ritonavir in HIV Patients (RESIST-2)

Study Overview
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Brief Summary
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The objective of this study is to demonstrate the safety and efficacy of tipranavir/ritonavir versus an active control arm in highly treatment experienced Human immunodeficiency virus-1 infected patients. Patients must have a viral load > =1000 cells/mL, and genotype indicating at least one resistance conferring protease inhibitor-mutation as determined from a predefined panel of mutations. Any CD4+ count is acceptable.

Official Title
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Randomized, Open-label, Comparative Safety and Efficacy Study of Tipranavir Boosted With Low Dose Ritonavir (TPV/RTV) Versus Genotypically-defined Protease Inhibitor/Ritonavir (PI/RTV) in Multiple Antiretroviral Drug-experienced Patients (RESIST 2: Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients With Tipranavir)

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Tipranavir (with low dose ritonavir)
* Drug: Comparator protease inhibitor(CPI)/low dose ritonavir(r)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to trial participation. Human immunodeficiency virus-1 infected males or females >=18 years of age. Screening genotypic resistance report indicating both of the following: at least one primary protease 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. At least 3 consecutive months experience taking antiretrovirals from each of the classes of Nucleoside reverse transcriptase inhibitor(s), Non-nucleoside reverse transcriptase inhibitor(s), and Protease inhibitor(s) at some point in treatment history, with at least 2 Protease inhibitor-based regimens (minimum 3 months of exposure of each), one of which must be part of the current regimen, and current Protease inhibitor-based antiretroviral medication regimen for at least 3 months prior to randomisation. Human immunodeficiency virus-1 viral load >=1000 copies/mL at screening. Acceptable screening laboratory values that indicate adequate baseline organ function. Laboratory values are considered to be acceptable if the following apply: Total cholesterol <=400 mg/dl or 10,36 mm/L. Total triglycerides <=750 mg/dl or 8,5 mm/L. Alanine aminotransferase <=3x upper limit of normal and aspartate aminotransferase <=2.5x upper limit of normal. Any Grade gamma-glutamyl transpeptidase is acceptable. Any Grade creatinine kinase is acceptable as long as there is no concurrent myopathy. All other laboratory test values <= Grade 1(Division of Acquired immune deficiency syndrome, National Institute of Health grading scale). Acceptable medical history, as assessed by the investigator, with chest X-ray and electrocardiogram within 1 year of study participation. Willingness to abstain from ingesting substances during the study which may alter plasma study drug levels by interaction with the cytochrome P450 system. A prior Acquired immune deficiency syndrome-defining event is acceptable as long as it has resolved or the patient has been on stable treatment for at least 2 months (Acquired immune deficiency syndrome related complex is acceptable). Exclusion Criteria: Antiretroviral medication naïve. Patients on recent drug holiday, defined as off antiretroviral medications for at least 7 consecutive days within the last 3 months. Alanine aminotransferase >3x upper limit of normal and aspartate aminotransferase >2.5x upper limit of normal at either screening visit. Female patients of child-bearing potential who: have a positive serum pregnancy test at screening or during the study, are breast feeding are planning to become pregnant, or are not willing to use a barrier method of contraception, or require ethinyl estradiol administration Prior tipranavir use. Use of investigational medications within 30 days before study entry or during the trial. (T-20 [enfuvirtide] and Tenofovir (Viread), investigational at the time of writing of this protocol, will be allowed.) Use of immunomodulatory drugs within 30 days before study entry or during the trial (e.g. interferon, cyclosporin, hydroxyurea, interleukin 2). Inability to adhere to the requirements of the protocol, including active substance abuse as assessed by the investigator. In the opinion of the investigator, likely survival of less than 12 months because of underlying disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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 (with low dose ritonavir)<br> <br> |
| Other: Comparator protease inhibitor(CPI)/low dose ritonavir(r)<br> | Drug: Comparator protease inhibitor(CPI)/low dose ritonavir(r)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response at Week 48 | Patients who experienced treatment response. 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 | after 48 weeks of treatment | 
| 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 Log(baseline Viral Load) - Log(on-treatment Viral Load) < 1. | after 48 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response at Week 2 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 24 | Patients who experienced treatment response. 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 32 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 56 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 | Patients who experienced treatment response. 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 | after 96 weeks of treatment | 
| 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 Log(baseline Viral Load) - Log(on-treatment Viral Load) < 1. | after 96 weeks of treatment | 
| 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 where the Log(baseline viral load)-Log(on-treatment viral load)>1 before a 2 consecutive measurements where Log(baseline viral load)-Log(on-treatment viral load)<1. | after 48 weeks of treatment | 
| 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 where the Log(baseline viral load)-Log(on-treatment viral load)>1 before a 2 consecutive measurements where Log(baseline viral load)-Log(on-treatment viral load)<1. | after 96 weeks of treatment | 
| Virologic Response | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | Week 2 through Week 96 (at any point during trial) | 
| Virologic Response at Week 2 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | Week 2 | 
| Virologic Response at Week 4 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 4 | 
| Virologic Response at Week 8 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 8 | 
| Virologic Response at Week 16 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 16 | 
| Virologic Response at Week 24 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 24 | 
| Virologic Response at Week 32 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 32 | 
| Virologic Response at Week 40 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 40 | 
| Virologic Response at Week 48 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 48 | 
| Virologic Response at Week 56 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 56 | 
| Virologic Response at Week 64 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | week 64 | 
| Virologic Response at Week 72 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | Week 72 | 
| Virologic Response at Week 80 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | Week 80 | 
| Virologic Response at Week 88 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | Week 88 | 
| Virologic Response at Week 96 | Virologic response is defined as: Log(baseline viral load (VL))-Log(on-treatment VL)>=1 | Week 96 | 
| Median Change From Baseline in Viral Load (Week 2) |  | Baseline to Week 2 | 
| Median Change From Baseline in Viral Load (Week 4) |  | Baseline to Week 4 | 
| Median Change From Baseline in Viral Load (Week 8) |  | Baseline to Week 8 | 
| Median Change From Baseline in Viral Load (Week 16) |  | Baseline to Week 16 | 
| Median Change From Baseline in Viral Load (Week 24) |  | Baseline to Week 24 | 
| Median Change From Baseline in Viral Load (Week 32) |  | Baseline to Week 32 | 
| Median Change From Baseline in Viral Load (Week 40) |  | Baseline to Week 40 | 
| Median Change From Baseline in Viral Load (Week 48) |  | Baseline to Week 48 | 
| Median Change From Baseline in Viral Load (Week 56) |  | Baseline to Week 56 | 
| Median Change From Baseline in Viral Load (Week 64) |  | Baseline to Week 64 | 
| Median Change From Baseline in Viral Load (Week 72) |  | Baseline to Week 72 | 
| Median Change From Baseline in Viral Load (Week 80) |  | Baseline to Week 80 | 
| Median Change From Baseline in Viral Load (Week 88) |  | Baseline to Week 88 | 
| Median Change From Baseline in Viral Load (Week 96) |  | Baseline to Week 96 | 
| Virologic Response at Week 40 | Virologic response defined as Viral Load<400 copies/mL | Week 40 | 
| Virologic Response at Viral Load Nadir During Study Treatment Through 96 Weeks | Virologic response defined as Viral Load<400 copies/mL | Week 2 through Week 96 (at any point during trial) | 
| Virologic Response at Week 2 | Virologic response defined as Viral Load<400 copies/mL | Week 2 | 
| Virologic Response at Week 4 | Virologic response defined as Viral Load<400 copies/mL | Week 4 | 
| Virologic Response at Week 8 | Virologic response defined as Viral Load<400 copies/mL | Week 8 | 
| Virologic Response at Week 16 | Virologic response defined as Viral Load<400 copies/mL | Week 16 | 
| Virologic Response at Week 24 | Virologic response defined as Viral Load<400 copies/mL | Week 24 | 
| Virologic Response at Week 32 | Virologic response defined as Viral Load<400 copies/mL | Week 32 | 
| Virologic Response at Week 48 | Virologic response defined as Viral Load<400 copies/mL | Week 48 | 
| Virologic Response at Week 56 | Virologic response defined as Viral Load<400 copies/mL | Week 56 | 
| Virologic Response at Week 64 | Virologic response defined as Viral Load<400 copies/mL | Week 64 | 
| Virologic Response at Week 72 | Virologic response defined as Viral Load<400 copies/mL | Week 72 | 
| Virologic Response at Week 80 | Virologic response defined as Viral Load<400 copies/mL | Week 80 | 
| Virologic Response at Week 88 | Virologic response defined as Viral Load<400 copies/mL | week 88 | 
| Virologic Response at Week 96 | Virologic response defined as Viral Load<400 copies/mL | week 96 | 
| Virologic Response | Virologic response defined as Viral Load<50 copies/mL | Week 2 through Week 96 (at any point during trial) | 
| Virologic Response at Week 2 | Virologic response defined as Viral Load<50 copies/mL | Week 2 | 
| Virologic Response at Week 4 | Virologic response defined as Viral Load<50 copies/mL | Week 4 | 
| Virologic Response at Week 8 | Virologic response defined as Viral Load<50 copies/mL | Week 8 | 
| Virologic Response at Week 16 | Virologic response defined as Viral Load<50 copies/mL | Week 16 | 
| Virologic Response at Week 24 | Viral Load < 50 copies/mL | Week 24 | 
| Virologic Response at Week 32 | Virologic response defined as Viral Load<50 copies/mL | Week 32 | 
| Virologic Response at Week 40 | Virologic response defined as Viral Load<50 copies/mL | Week 40 | 
| Virologic Response at Week 48 | Virologic response defined as Viral Load<50 copies/mL | Week 48 | 
| Virologic Response at Week 56 | Virologic response defined as Viral Load<50 copies/mL | Week 56 | 
| Virologic Response at Week 64 | Virologic response defined as Viral Load<50 copies/mL | Week 64 | 
| Virologic Response at Week 72 | Virologic response defined as Viral Load<50 copies/mL | Week 72 | 
| Virologic Response at Week 80 | Virologic response defined as Viral Load<50 copies/mL | Week 80 | 
| Virologic Response at Week 88 | Virologic response defined as Viral Load<50 copies/mL | Week 88 | 
| Virologic Response at Week 96 | Virologic response defined as Viral Load<50 copies/mL | Week 96 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 2) |  | Baseline to Week 2 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 4) |  | Baseline to Week 4 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 8) |  | Baseline to Week 8 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 16) |  | Baseline to Week 16 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 24) |  | Baseline to Week 24 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 32) |  | Baseline to Week 32 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 40) |  | Baseline to Week 40 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 48) |  | Baseline to Week 48 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 56) |  | Baseline to Week 56 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 64) |  | Baseline to Week 64 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 72) |  | Baseline to Week 72 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 80) |  | Baseline to Week 80 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 88) |  | Baseline to Week 88 | 
| Mean Change From Baseline in CD4+ Cell Count (Week 96) |  | Baseline to Week 96 | 
| Time to New Centers for Disease Control (CDC) Class C Progression Event or Death. | Time to death or occurrence of AIDS-defining condition according to the US Centers for Disease Control and Prevention case definition. The median and quartiles are underestimated since more than 92% of the observations (in both treatment arms) were censored and the estimation was restricted to the largest observed event time. | up to 75 weeks of treatment |