Safety and Antiviral Activity of TPV in HCV and/or HBV HIV Coinfected Patients TDM Randomised Pilot Evaluation

Phase 3

Terminated

• Conditions: HIV Infections

• Registration Number: NCT00447902
• Lead Sponsor: Boehringer Ingelheim

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2007-03
• Study First Submitted: 2007-03-14
• Study First Submitted QC: 2007-03-14
• Study First Posted: 2007-03-15
• Primary Completion: 2008-10
• Results First Submitted: 2009-09-25
• Results First Submitted QC: 2009-11-18
• Results First Posted: 2009-12-23
• Status Verified: 2014-04
• Last Update Submitted: 2014-04-25
• Last Update Posted: 2014-05-14

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 11

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Treatment Response at Week 48	48 weeks	Treatment response is a confirmed virologic response, defined as a viral load less than 50 copies/mL at two consecutive measurements at least 5 days apart, without death, permanent discontinuation, or introduction of a new antiretroviral
The Primary Safety Endpoint Was the Occurrence of Dose-limiting Hepatotoxicity During the Study.	From the start of the study through 48 weeks.	Dose-limiting hepatotoxicity was defined as Grade 4 ALT or AST elevation confirmed in 48h or any evocative symptoms or signs of hepatitis, if it not clearly attributable to another cause. Patients who experienced dose-limiting hepatotoxicity stopped TPV/r and were considered treatment failures for the analysis.

Secondary Outcome Measures

Name	Time	Method
Change in CD4+ and CD8+ Cell Counts From Baseline to Week 48	after 2 weeks of treatment till Week 48	Change from baseline to Week 48 for CD4+ and CD8+ cell counts. Samples were obtained for CD4+ and CD8+ as measurements of viral suppression during antiretroviral therapy.
Virologic Response Defined as Viral Load <50 Copies/mL at Each Visit	After 4 weeks of treatment until the end of the trial	Virologic response defined as viral load less than 50 copies/mL
Occurrence of Viral Load Less Than 400 Copies/mL at Weeks 24 and 48	24 and 48 weeks	Patients with a viral load of less than 400 copies/mL at Weeks 24 and 48 as measured from a plasma sample.
Occurrence of Viral Load Less Than 400 Copies/mL at Each Visit	After 4 weeks of treatment until the end of the trial	Patients with a viral load of less than 400 copies/mL at each visit as measured from a plasma sample.
Occurrence of ≥1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48	Baseline, 24 and 48 weeks	Occurrence of greater than or equal to 1 log10 drop in viral load from baseline at all visits, including visits at Weeks 24 and 48
Change in Viral Load From Baseline at Each Visit	After 4 weeks of treatment until the end of the trial	Change in viral load (measured from a plasma sample) from baseline at each visitPatients with a viral load of less than 400 copies/mL at each visit as .
Time to Treatment Failure	After Day 1 of treatment until the end of the trial	For patients who never achieve a confirmed virologic response, time to treatment failure is defined as 0. For patients who achieve a confirmed virologic response, time to treatment failure is the earliest time of either: death, permanent discontinuation of the study drug or loss to follow-up, introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background drug, but not the study drug, or first occurrence of a VL \>50 copies/mL at two consecutive measurements after having achieved a VL \<50 copies/mL.
Time to New AIDS or AIDS Related Progression Event or Death	After Day 1 of treatment until the end of the trial	Time to new AIDS or AIDS related progression event or death as defined by AIDS defining and/or AIDS-related illnesses.
Change in Ratio of CD38+/CD8+ From Baseline to Week 48	after 2 weeks of treatment till Week 48	Change from baseline to Week 48 for the ratio of CD38+ to CD8+ cell counts. Samples were obtained for CD38+ and CD8+ as measurements of viral suppression during antiretroviral therapy.
Change in Ratio of CD3+ CD8+ CD38+ HLA DR From Baseline to Week 48.	after 2 weeks of treatment till Week 48	Change from baseline to Week 48 for the ratio of CD3+ CD8+ CD38+ HLA DR . Samples were obtained for CD3+ CD8+ CD38+ HLA DR as measurements of viral suppression during antiretroviral therapy.
Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48	after 2 weeks of treatment till Week 48	Tipranavir (TPV) and Ritonavir (RTV) trough concentrations from plasma samples at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
Patients Adherence With Study Medication Based on Pill Count	After 4 weeks of treatment until the end of the trial	number of pills actually taken divided by the planned number of pills the patient should take
Occurrence of Tipranavir (TPV) Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured	After 2 weeks of treatment until the end of trial	A high inhibitory quotient (IQ), the ratio of trough plasma drug concentration to the protein-adjusted viral IC50, is a useful indicator of the potential efficacy margin of antiretroviral drugs. The IQ for TPV is calculated by the formula IQ = TPV Ctrough / (3.75 x Z x fold change of the patients virus), where Z = wild type control IC50 IIIB.
Occurrence of Tipranavir (TPV) Trough Concentration >120 μM	After 2 weeks of treatment until the end of trial	Patients with TPV trough above 120 μM are at high risk of developing a Grade 3 or 4 ALT or AST elevations. The risk of Grade 3 or greater transaminase elevations appeared to be uniform at TPV trough concentration below 120 μM. Hence, for this study the TPV trough should be maintained below 120 μM.
Post-dose Tipranavir (TPV) and Ritonavir (RTV) Concentrations at Week 4	Week 4	Post-dose Tipranavir (TPV) and Ritonavir (RTV) plasma concentrations at Week 4
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements	Baseline through 48 weeks	Frequency of patients (%) with possible clinically significant abnormalities of laboratory measurements (haematology, differentials (automatic and absolute), coagulation, electrolytes, enzymes, substrates, urinalysis, serology and T-cells)

Trial Locations

Locations (30)

1182.99.31 Boehringer Ingelheim Investigational Site; 🇺🇸 Fort Lauderdale, Florida, United States

1182.99.3306K Boehringer Ingelheim Investigational Site; 🇫🇷 Nantes, France

1182.99.4909 Boehringer Ingelheim Investigational Site; 🇩🇪 Düsseldorf, Germany

1182.99.3912 Boehringer Ingelheim Investigational Site; 🇮🇹 Ancona, Italy

1182.99.3901 Boehringer Ingelheim Investigational Site; 🇮🇹 Milano, Italy

1182.99.3911 Boehringer Ingelheim Investigational Site; 🇮🇹 Milano, Italy

1182.99.1 Boehringer Ingelheim Investigational Site; 🇺🇸 Austin, Texas, United States

1182.99.3402; 🇪🇸 Barcelona, Spain

1182.99.54001; 🇦🇷 Capital Federal, Argentina

1182.99.55002 Hospital DIA; 🇧🇷 Sacomã - São Paulo, Brazil

1182.99.32 Boehringer Ingelheim Investigational Site; 🇺🇸 Beverly Hills, California, United States

1182.99.4 Boehringer Ingelheim Investigational Site; 🇺🇸 Houston, Texas, United States

1182.99.3302A Boehringer Ingelheim Investigational Site; 🇫🇷 Perpignan, France

1182.99.3407; 🇪🇸 Madrid, Spain

1182.99.12 Boehringer Ingelheim Investigational Site; 🇺🇸 Providence, Rhode Island, United States

1182.99.55004 Unidade de Referência em doenças Infecciosas Preveníveis; 🇧🇷 Santo André, Brazil

1182.99.55001 Universidade Federal de Sao Paulo; 🇧🇷 Sao Paulo, Brazil

1182.99.55003 Centro de Referência e Treinamento - DST/AIDS; 🇧🇷 Vila Mariana - Sao Paulo, Brazil

1182.99.3301A Boehringer Ingelheim Investigational Site; 🇫🇷 Garches, France

1182.99.3306G Boehringer Ingelheim Investigational Site; 🇫🇷 Nantes, France

1182.99.3310F Boehringer Ingelheim Investigational Site; 🇫🇷 Nice cedex 3, France

1182.99.3310C Boehringer Ingelheim Investigational Site; 🇫🇷 Nice cedex 3, France

1182.99.3310E Boehringer Ingelheim Investigational Site; 🇫🇷 Nice cedex 3, France

1182.99.3310D Boehringer Ingelheim Investigational Site; 🇫🇷 Nice cedex 3, France

1182.99.3310G Boehringer Ingelheim Investigational Site; 🇫🇷 Nice cedex 3, France

1182.99.3310H Boehringer Ingelheim Investigational Site; 🇫🇷 Nice cedex 3, France

1182.99.3304A Boehringer Ingelheim Investigational Site; 🇫🇷 Paris, France

1182.99.3304C Boehringer Ingelheim Investigational Site; 🇫🇷 Paris, France

1182.99.3906 Boehringer Ingelheim Investigational Site; 🇮🇹 Pavia, Italy

1182.99.3916 Boehringer Ingelheim Investigational Site; 🇮🇹 Milano, Italy