Tipranavir and Ritonavir vs. Saquinavir and Ritonavir Used With Two Nucleoside Reverse Transcriptase Inhibitors in Single Protease Inhibitor-experienced HIV-1 Patients

Study Overview
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Brief Summary
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Objectives of the study were to evaluate the efficacy and safety of two different doses of tipranavir (TPV) in combination with ritonavir (TPV/r) compared with a standard dual PI combination of saquinavir (SQV) and ritonavir (RTV) and to evaluate the dose response of two different doses of TPV in combination with RTV for efficacy and safety.

Official Title
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Tipranavir: An Open-label, Randomized Study Comparing Combination Therapy (Tipranavir and Ritonavir vs. Saquinavir and Ritonavir) Used With Two Nucleoside Reverse Transcriptase Inhibitors in Single Protease Inhibitor-experienced HIV-1 Patients

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Tipranavir (TPV) low dose
* Drug: Tipranavir (TPV) high dose
* Drug: Ritonavir low dose
* Drug: Ritonavir high dose
* Drug: Saquinavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical failure while on the current PI-containing regimen of indinavir, nelfinavir, or amprenavir In the investigator's opinion, adherence to the present PI-containing regimen Exposure of >=6 months to the current PI therapy Stable PI-containing regimen, i.e., receiving the current two reverse transcriptase inhibitors (RTIs) for at least 2 months prior to study entry HIV-1 RNA >=1000 copies/mL (assayed using the Amplicor polymerase chain reaction (PCR) method at the initial screening visit) No limit in CD4+ cell count at the initial screening At least two new nucleoside reverse transcriptase inhibitor (NRTI) options available Age >=18 years Acceptable screening laboratory test values that indicated adequate baseline organ function at the time of screening. Acceptable laboratory test values consisted of the following: severity <=Grade 1 (ACTG Grading Scale). Stable Grade 2 abnormalities were permitted if the values had been demonstrated and documented for at least >=2 months. All laboratory values >Grade 2 were subject to approval by the P&U Clinical Program Leader or designated personnel and subsequently by the BI designated personnel Acceptable medical history, physical examination, ECG, and chest radiograph prior to entry into the treatment phase of the study Use of a barrier contraceptive method of birth control for at least 30 days prior to study drug administration, during the study, and 30 days after study completion Ability to swallow numerous tablets and capsules without difficulty Ability to understand and provide informed consent. Minors had to have approval of a parent or legal guardian Exclusion Criteria: Treatment with more than one PI-containing regimen Clinically significant active or acute (onset within the month previous to study entry) medical problems, including the following: opportunistic infections, e.g., active cryptococcosis, Pneumocystis carinii pneumonia, herpes zoster, histoplasmosis, or cytomegalovirus; nonopportunistic diseases, including but not limited to the following: progressive multifocal leukoencephalopathy, lymphoma, or malignancy requiring systemic therapy Prior exposure (>7 days) to tipranavir, saquinavir, or ritonavir 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, saquinavir, or ritonavir Use of interferons, interleukins, HIV vaccines, or any active immunizations within 30 days of study entry Taking of any investigational medication with the exception of adefovir dipivoxil (Preveon™) 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 substance abuse, which in the investigator's opinion could affect adherence 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: 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPV low dose + RTV low dose<br> | Drug: Tipranavir (TPV) low dose<br> <br> Drug: Ritonavir low dose<br> <br> |
| Experimental: TPV high dose + RTV low dose<br> | Drug: Tipranavir (TPV) high dose<br> <br> Drug: Ritonavir low dose<br> <br> |
| Active Comparator: SQV + RTV high dose<br> | Drug: Ritonavir high dose<br> <br> Drug: Saquinavir<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in plasma HIV-1 RNA concentrations |  | Week 16, 24 and 48 | 
| Occurrence of HIV-1 RNA levels below the limit of quantitation (BLQ) | using the Roche Amplicor HIV Monitor™ Method [limit of detection (LD) 400 copies/mL] and the Roche Amplicor UltraSensitive Method™ (LD 50 copies/mL) | up to 96 weeks | 
| Number of patients with treatment-emergent and drug-related adverse events (AEs) |  | up to 96 weeks | 
| Number of patients with serious adverse events (SAEs) |  | up to 96 weeks | 
| Number of patients with grade 3 and 4 laboratory abnormalities |  | up to 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in cluster of differentiation (CD) 4+ cell count |  | Week 16, 24 and 48 | 
| Time to virologic failure | defined as plasma HIV-1 RNA values >400 copies/mL at two consecutive time points 2 to 4 weeks apart | after week 16 | 
| Occurrence of new or recurring AIDS-defining illnesses |  | up to 96 weeks | 
| Occurrence of HIV-1 related illness |  | up to 96 weeks | 
| Occurrence of death |  | up to 96 weeks | 
| Time to new or recurring AIDS-defining illnesses |  | up to 96 weeks | 
| Time to HIV-1 related illness |  | up to 96 weeks | 
| Time to death |  | up to 96 weeks | 
| Change from baseline in blood glucose |  | up to 96 weeks | 
| Change from baseline in cholesterol |  | up to 96 weeks | 
| Change from baseline in high density lipoprotein (HDL) |  | up to 96 weeks | 
| Change from baseline in triglycerides |  | up to 96 weeks | 
| Time to virologic response |  | up to 96 weeks | 
| Trough plasma tipranavir concentrations |  | up to week 24 | 
| Sequence-based HIV-1 analysis (genotyping) and drug susceptibility assays (phenotyping) |  | Baseline and week 24 |