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

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

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.

Study Overview

• Status: Terminated
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Saquinavir; Drug: Ritonavir high dose; Drug: Ritonavir low dose; Drug: Tipranavir (TPV) low dose; Drug: Tipranavir (TPV) high dose

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TPV low dose + RTV low dose	Drug: Ritonavir low dose; Drug: Tipranavir (TPV) low dose
Experimental: TPV high dose + RTV low dose	Drug: Ritonavir low dose; Drug: Tipranavir (TPV) high dose
Active Comparator: SQV + RTV high dose	Drug: Saquinavir; Drug: Ritonavir high dose

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 1999
• Primary Completion (Actual): November 1, 2001

Study Registration Dates

• First Submitted: September 11, 2014
• First Submitted That Met QC Criteria: September 11, 2014
• First Posted (Estimate): September 15, 2014

Study Record Updates

• Last Update Posted (Estimate): September 15, 2014
• Last Update Submitted That Met QC Criteria: September 11, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Tipranavir; Saquinavir
• Other Study ID Numbers: 1182.4