Clinical trial NCT00447902: Safety and Antiviral Activity of TPV in HCV and/or HBV HIV Coinfected Patients TDM Randomised Pilot Evaluation
Official title: Safety and Antiviral Activity of TPV in Hepatitis C or Hepatitis B HIV Coinfected Patients - TDM Randomised Pilot Evaluation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: HIV Infections
Keywords: treatment experienced
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2007-03-15
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main purposes of this study are: demonstrate the safety and efficacy of TPV/r among HCV or hepatitis B virus (HBV) co-infected HIV+population, three-class (NRTI, NNRTI, and PI) experienced, with documented resistance to more than one PI. Determine pharmacokinetic data in this co-infected population and potential utility of using therapeutic drug monitoring (TDM) in improving efficacy outcomes.


Eligibility criteria: Inclusion Criteria:

1. HIV-1 infected males or females at least 18 years of age.
2. Three-class (Nucleoside reverse transcriptase inhibitor (NRTI), Non nucleoside reverse transcriptase inhibitor (NNRTI), and Protease inhibitor (PI)) treatment-experienced (a minimum of 3-months duration for each class) with resistance to more than one PI (on the screening resistance testing). Patients that are NNRTI-naïve patients but who have genotypically documented NNRTI-resistance mutations on past or screening resistance testing would be eligible.
3. CD4+ T lymphocyte count ≥50 cells/µl and HIV-1 VL ≥1000 copies/mL at screening.
4. The ARV study treatment regimen must consist of new TPV/r in combination with an OBR of 2-4 agents of the following: N(t)RTIs (NRTI or NtRTI), enfuvirtide (ENF), and/or, where available, an Expanded Access Program (EAP) investigational agent (Section 3.3). In total, patients are to have an ARV study treatment regimen consisting of at least 3 agents (TPV/r and two OBRs).
5. Chronic hepatitis C Virus (HCV) infection demonstrated by HCV-ribonucleic acid (RNA) positivity or, Chronic hepatitis B (HB) infection demonstrated by anti HBc IgG Antibody and HB Surface Antigen positivity.
6. Acceptable screening laboratory values that indicate adequate baseline organ function.
7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< Division of AIDS (DAIDS) Grade 3.
8. Acceptable medical history, as assessed by the investigator.
9. Any AIDS defining illness listed in the Appendix 10.3.1 should be accepted as long as is resolved, asymptomatic or stable on treatment for at least 12 weeks before screening (Visit 1); the AIDS defining events listed below are not acceptable History of Progressive Multifocal Leukoencephalopathy (PML), Visceral Kaposi's Sarcoma (KS), and/or any malignancy.
10. A reliable method of barrier contraception will be used by all female patients who are of reproductive potential, for at least three months prior to Visit 3, during the trial, and 30 days after completion or termination from the trial.
11. Karnofsky performance score ≥70.

Exclusion Criteria:

1. Prior tipranavir use.
2. Known hypersensitivity to any of the ingredients to the tipranavir or ritonavir formulations.
3. ARV medication naive.
4. Genotypic resistance to Tipranavir (TPV) (defined as a TPV mutation score of more than 7).
5. Patients on recent drug holiday, defined as off ARV medications for at least 7 consecutive days within the month prior to screening.
6. Decompensated liver disease, including presence or history of ascites, variceal bleeding, or hepatic encephalopathy or having ever been diagnosed as having hepatic insufficiency of Child Pugh class B or C.
7. Female patients of childbearing potential who:

   * have a positive serum pregnancy test at screening,
   * are breast feeding,
   * are planning to become pregnant,
   * are not willing to use a barrier method of contraception, or
   * are only willing to use an estrogen-containing medication, e.g., ethinyl estradiol, as a method of contraception.
8. Use of investigational medications within 30 days before study entry or during the trial except for those investigational ARV drugs permitted during the trial as stated in inclusion criteria 6.
9. Use of concomitant drugs that may significantly reduce plasma levels of the study medications.
10. Use of immunomodulatory drugs or antineoplastic agents within 30 days before study entry or during the trial.
11. Inability to adhere to the requirements of the protocol, including active substance abuse, as defined by the investigator.
12. Anticipated need for an interferon-based regimen in the 48 weeks following the study entry.
13. Any other or additional plausible cause for chronic liver disease, including the presence of other viruses known or suspected to cause hepatitis.
14. Any active infection or neoplasm currently being treated.
15. Patients with history of hemorrhagic stroke or intracranial aneurysm.
16. Patients with history of ischemic stroke, neurosurgery, skull trauma and/or intracranial pathology (arteriovenous malformation, brain tumors and cerebral venous thrombosis) within 4 weeks prior to screening (Visit 1) as assessed by investigator.
17. Patients with current history of alcohol abuse defined as alcohol consumption that would interfere with patient's compliance or result in biological abnormalities.

Primary outcomes:
measure: Treatment Response at Week 48
timeFrame: 48 weeks
measure: The Primary Safety Endpoint Was the Occurrence of Dose-limiting Hepatotoxicity During the Study.
timeFrame: From the start of the study through 48 weeks.
Secondary outcomes:
measure: Virologic Response Defined as Viral Load <50 Copies/mL at Each Visit
timeFrame: After 4 weeks of treatment until the end of the trial
measure: Occurrence of Viral Load Less Than 400 Copies/mL at Weeks 24 and 48
timeFrame: 24 and 48 weeks
measure: Occurrence of Viral Load Less Than 400 Copies/mL at Each Visit
timeFrame: After 4 weeks of treatment until the end of the trial
measure: Occurrence of ≥1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48
timeFrame: Baseline, 24 and 48 weeks
measure: Change in Viral Load From Baseline at Each Visit
timeFrame: After 4 weeks of treatment until the end of the trial
measure: Time to Treatment Failure
timeFrame: After Day 1 of treatment until the end of the trial
measure: Time to New AIDS or AIDS Related Progression Event or Death
timeFrame: After Day 1 of treatment until the end of the trial
measure: Change in CD4+ and CD8+ Cell Counts From Baseline to Week 48
timeFrame: after 2 weeks of treatment till Week 48
measure: Change in Ratio of CD38+/CD8+ From Baseline to Week 48
timeFrame: after 2 weeks of treatment till Week 48
measure: Change in Ratio of CD3+ CD8+ CD38+ HLA DR From Baseline to Week 48.
timeFrame: after 2 weeks of treatment till Week 48
measure: Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
timeFrame: after 2 weeks of treatment till Week 48
measure: Patients Adherence With Study Medication Based on Pill Count
timeFrame: After 4 weeks of treatment until the end of the trial
measure: Occurrence of Tipranavir (TPV) Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured
timeFrame: After 2 weeks of treatment until the end of trial
measure: Occurrence of Tipranavir (TPV) Trough Concentration >120 μM
timeFrame: After 2 weeks of treatment until the end of trial
measure: Post-dose Tipranavir (TPV) and Ritonavir (RTV) Concentrations at Week 4
timeFrame: Week 4
measure: Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements
timeFrame: Baseline through 48 weeks
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: 1182.99.32 Boehringer Ingelheim Investigational Site
state: California
city: Fort Lauderdale
country: United States
facility: 1182.99.31 Boehringer Ingelheim Investigational Site
state: Florida
city: Providence
country: United States
facility: 1182.99.12 Boehringer Ingelheim Investigational Site
state: Rhode Island
city: Austin
country: United States
facility: 1182.99.1 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1182.99.4 Boehringer Ingelheim Investigational Site
state: Texas
city: Capital Federal
country: Argentina
facility: 1182.99.54001
city: Sacomã - São Paulo
country: Brazil
facility: 1182.99.55002 Hospital DIA
city: Santo André
country: Brazil
facility: 1182.99.55004 Unidade de Referência em doenças Infecciosas Preveníveis
city: Sao Paulo
country: Brazil
facility: 1182.99.55001 Universidade Federal de Sao Paulo
city: Vila Mariana - Sao Paulo
country: Brazil
facility: 1182.99.55003 Centro de Referência e Treinamento - DST/AIDS
city: Garches
country: France
facility: 1182.99.3301A Boehringer Ingelheim Investigational Site
city: Nantes
country: France
facility: 1182.99.3306G Boehringer Ingelheim Investigational Site
city: Nantes
country: France
facility: 1182.99.3306K Boehringer Ingelheim Investigational Site
city: Nice cedex 3
country: France
facility: 1182.99.3310C Boehringer Ingelheim Investigational Site
city: Nice cedex 3
country: France
facility: 1182.99.3310D Boehringer Ingelheim Investigational Site
city: Nice cedex 3
country: France
facility: 1182.99.3310E Boehringer Ingelheim Investigational Site
city: Nice cedex 3
country: France
facility: 1182.99.3310F Boehringer Ingelheim Investigational Site
city: Nice cedex 3
country: France
facility: 1182.99.3310G Boehringer Ingelheim Investigational Site
city: Nice cedex 3
country: France
facility: 1182.99.3310H Boehringer Ingelheim Investigational Site
city: Paris
country: France
facility: 1182.99.3304A Boehringer Ingelheim Investigational Site
city: Paris
country: France
facility: 1182.99.3304C Boehringer Ingelheim Investigational Site
city: Perpignan
country: France
facility: 1182.99.3302A Boehringer Ingelheim Investigational Site
city: Düsseldorf
country: Germany
facility: 1182.99.4909 Boehringer Ingelheim Investigational Site
city: Ancona
country: Italy
facility: 1182.99.3912 Boehringer Ingelheim Investigational Site
city: Milano
country: Italy
facility: 1182.99.3901 Boehringer Ingelheim Investigational Site
city: Milano
country: Italy
facility: 1182.99.3911 Boehringer Ingelheim Investigational Site
city: Milano
country: Italy
facility: 1182.99.3916 Boehringer Ingelheim Investigational Site
city: Pavia
country: Italy
facility: 1182.99.3906 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1182.99.3402
city: Madrid
country: Spain
facility: 1182.99.3407
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References: