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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Ritonavir; Drug: Tipranavir low dose; Drug: Tipranavir high dose; Drug: Nucleoside Reverse Transcriptase Inhibitor (NRTI); Drug: Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 1999
• Primary Completion (Actual): August 1, 2001

Study Registration Dates

• First Submitted: September 11, 2014
• First Submitted That Met QC Criteria: September 11, 2014
• First Posted (Estimate): September 12, 2014

Study Record Updates

• Last Update Posted (Estimate): September 12, 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; Nucleic Acid Synthesis Inhibitors; 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; Reverse Transcriptase Inhibitors
• Other Study ID Numbers: 1182.2