Exploratory Study of Tipranavir and Ritonavir in Multiple Protease Inhibitor-experienced HIV Patients

Study Overview
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Brief Summary
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The primary objective was to evaluate the antiviral activity and safety of two regimens of tipranavir (500 mg BID or 1000 mg BID) plus ritonavir (100 mg BID) administered in combination with 1 new nucleoside reverse transcriptase inhibitor (NRTI) + efavirenz in multiple protease-inhibitor-experienced HIV-1 positive patients.

Official Title
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Tipranavir Disodium: An Open-Label ExploratorySstudy of Tipranavir and Ritonavir in Combination With One Nucleoside Reverse Transcriptase Inhibitor and One Non-Nucleoside Reverse Transcriptase Inhibitor in Multiple Protease Inhibitor-Experienced HIV Patients

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Tipranavir low dose
* Drug: Tipranavir high dose
* Drug: Ritonavir
* Drug: Nucleoside Reverse Transcriptase Inhibitor (NRTI)
* Drug: Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Multiple (two or more) PI-experience. Eligible patients must have had exposure to at least two antiretroviral regimens containing a single protease inhibitor or a regimen containing dual protease inhibitors In the investigator's opinion, the patient had adhered to PI-containing regimens Exposure of ≥ 3 months to the current PI therapy Exposure of ≥ 4 months to the prior PI therapy with single PI-containing regimens Stable PI-containing regimen for at least 2 months prior to study entry HIV-1-RNA ≥ 5,000 copies/mL Cluster of differentiation (CD)4+ cell count ≥ 50 cells/mm**3 At least one new NRTI option available Age ≥ 13 years Acceptable screening laboratory values that indicated adequate baseline organ function at the time of screening. Laboratory values were considered acceptable if the severity was ≤ Grade 1 (AIDS Clinical Trial Group (ACTG) Grading Scale). Stable Grade 2 abnormalities were permitted if the values had been demonstrated and documented for at least ≥ 2 months. Acceptable medical history, physical examination, electrocardiogram, and chest X-ray prior to entry into the treatment phase of the study Agreement to use a barrier contraceptive method of birth control for at least 30 days prior to study drug administration, during the study, and 30 days after the end of the study Ability to swallow numerous tablets and capsules without difficulty Ability to understand and provide informed consent. Minors were required to have approval of a parent or legal guardian Exclusion Criteria: Prior exposure, defined as > 7 treatment days, to nonnucleoside reverse transcriptase inhibitor (NNRTIs) including, but not limited to: nevirapine, efavirenz, delavirdine, atevirdine, MKC-442, loviride, and HBY-097 Clinically significant active or acute (onset within the month previous to study entry) medical problems, including the following: opportunistic infections, such as active cryptococcosis, Pneumocystis carinii pneumonia, herpes zoster, histoplasmosis, or cytomegalovirus or nonopportunistic diseases, including, but not limited to, progressive multifocal leukoencephalopathy, lymphoma, or malignancy requiring systemic therapy Prior exposure (> 7 days) to tipranavir History of clinically significant nervous system or muscle diseases, seizure disorder, or psychiatric disorder that might impair adherence to the protocol Taking of any known P450 3A enzyme-inducing drugs within 30 days of study entry and including the following: rifabutin, rifampin, carbamazepine, dexamethasone, phenobarbital, phenytoin, sulfadimidine, sulfinpyrazone, or troleandomycin Hypersensitivity to tipranavir and/or ritonavir Use of interferons, interleukins, HIV vaccines, or any active immunizations within 30 days prior to study entry Taking of any investigational medication with the exception of adefovir dipivoxil (Preveon™) and amprenavir (Agenerase™) within 30 days of study entry Pregnancy or lactation (serum β-human chorionic gonadotrophin test had to have been negative within 14 days of study entry) Evidence of active substance abuse, which in the investigator's opinion, could affect compliance to the protocol In the investigator's judgment, inability to comply with the protocol requirements for reasons other than those specified

Ages Eligible for Study
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Minimum Age: 13 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tipranavir low dose<br> | Drug: Tipranavir low dose<br> <br> Drug: Ritonavir<br> <br> Drug: Nucleoside Reverse Transcriptase Inhibitor (NRTI)<br> <br> Drug: Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)<br> <br> |
| Experimental: Tipranavir high dose<br> | Drug: Tipranavir high dose<br> <br> Drug: Ritonavir<br> <br> Drug: Nucleoside Reverse Transcriptase Inhibitor (NRTI)<br> <br> Drug: Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in HIV-1 RNA concentrations |  | weeks 16, 24, 48 and 80 | 
| Occurrence of HIV-1 RNA levels below the limit of quantitation (BLQ) (400 copies/mL) | measured by the Roche Amplicor HIV-1 Monitor™ polymerase chain reaction (PCR) Method | up to 112 weeks | 
| Occurrence of HIV-1 RNA levels BLQ (50 copies/mL) | measured by the Roche Amplicor UltraSensitive™ PCR Method | up to 112 weeks | 
| Number of patients with treatment-emergent and drug-related adverse events (AEs) |  | up to 115 weeks | 
| Number of patients with serious adverse events (SAEs) |  | up to 115 weeks | 
| Number of patients with grade 3 and 4 laboratory abnormalities |  | up to 115 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in cluster of differentiation (CD) 4+ cell count responses |  | weeks 24, 48 and 80 | 
| Change from baseline in CD8+ cell count responses |  | weeks 24, 48 and 80 | 
| Time to new or recurring AIDS-defining illness |  | up to 115 weeks | 
| Time to new or recurring HIV-related illness |  | up to 115 weeks | 
| Time to death |  | up to 115 weeks | 
| Occurrence of AIDS-defining illness, |  | up to 115 weeks | 
| Occurrence of HIV-related illness, |  | up to 115 weeks | 
| Occurrence of death |  | up to 115 weeks | 
| Time to virologic failure | defined as plasma HIV-1 RNA values >400 copies/mL or a 0.5 log reduction from baseline at two consecutive time points | up to 115 weeks | 
| Change from baseline in cholesterol |  | up to 115 weeks | 
| Change from baseline in HDL |  | up to 115 weeks | 
| Change from baseline in triglycerides |  | up to 115 weeks | 
| Change from baseline in blood glucose |  | up to 115 weeks | 
| Steady-state plasma concentrations |  | up to week 24 | 
| Fold-change in concentration required to produce 50% of inhibition (IC 50) | sequence-based HIV-1 analysis (genotyping) and drugs susceptibility assays (phenotyping) | Baseline, weeks 24, 48 and 80 |