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

HIV Infections Clinical Trial

Official title:

Safety and Antiviral Activity of TPV in Hepatitis C or Hepatitis B HIV Coinfected Patients - TDM Randomised Pilot Evaluation

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00447902
• Other study ID #: 1182.99
• Secondary ID: EudraCT No.: 200
• Status: Terminated
• Phase: Phase 3
• First received: March 14, 2007
• Last updated: April 25, 2014
• Start date: March 2007

Study information

• Verified date: April 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: A.N.M.A.T. (Administracion Nacional de Medicamentos, Alimentos Y Tecnología)Brazil: Agência Nacional de Vigilância Sanitária - ANVISAFrance: Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS)Germany:Italy: Comitato Etico Locale per la Sperimentazione Clinica Osp. L. Sacco - MilanoPortugal: INFARMED - Instituto Nacional da Farmácia e do Medicamento Parque da Saúde de Lisboa Av. do Brasil LisboaSpain:United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 11
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• tipranavir

• ritonavir

Locations

Country	Name	City	State
Argentina	1182.99.54001	Capital Federal
Brazil	1182.99.55002 Hospital DIA	Sacomã - São Paulo
Brazil	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
France	1182.99.3301A Boehringer Ingelheim Investigational Site	Garches
France	1182.99.3306G Boehringer Ingelheim Investigational Site	Nantes
France	1182.99.3306K Boehringer Ingelheim Investigational Site	Nantes
France	1182.99.3310C Boehringer Ingelheim Investigational Site	Nice cedex 3
France	1182.99.3310D Boehringer Ingelheim Investigational Site	Nice cedex 3
France	1182.99.3310E Boehringer Ingelheim Investigational Site	Nice cedex 3
France	1182.99.3310F 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	1182.99.3302A Boehringer Ingelheim Investigational Site	Perpignan
Germany	1182.99.4909 Boehringer Ingelheim Investigational Site	Düsseldorf
Italy	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	1182.99.3916 Boehringer Ingelheim Investigational Site	Milano
Italy	1182.99.3906 Boehringer Ingelheim Investigational Site	Pavia
Spain	1182.99.3402	Barcelona
Spain	1182.99.3407	Madrid
United States	1182.99.1 Boehringer Ingelheim Investigational Site	Austin	Texas
United States	1182.99.32 Boehringer Ingelheim Investigational Site	Beverly Hills	California
United States	1182.99.31 Boehringer Ingelheim Investigational Site	Fort Lauderdale	Florida
United States	1182.99.4 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1182.99.12 Boehringer Ingelheim Investigational Site	Providence	Rhode Island

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  France,  Germany,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment Response at Week 48	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	48 weeks	No
Primary	The Primary Safety Endpoint Was the Occurrence of Dose-limiting Hepatotoxicity During the Study.	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.	From the start of the study through 48 weeks.	Yes
Secondary	Virologic Response Defined as Viral Load <50 Copies/mL at Each Visit	Virologic response defined as viral load less than 50 copies/mL	After 4 weeks of treatment until the end of the trial	No
Secondary	Occurrence of Viral Load Less Than 400 Copies/mL at Weeks 24 and 48	Patients with a viral load of less than 400 copies/mL at Weeks 24 and 48 as measured from a plasma sample.	24 and 48 weeks	No
Secondary	Occurrence of Viral Load Less Than 400 Copies/mL at Each Visit	Patients with a viral load of less than 400 copies/mL at each visit as measured from a plasma sample.	After 4 weeks of treatment until the end of the trial	No
Secondary	Occurrence of =1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48	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	Baseline, 24 and 48 weeks	No
Secondary	Change in Viral Load From Baseline at Each Visit	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 .	After 4 weeks of treatment until the end of the trial	No
Secondary	Time to Treatment Failure	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.	After Day 1 of treatment until the end of the trial	No
Secondary	Time to New AIDS or AIDS Related Progression Event or Death	Time to new AIDS or AIDS related progression event or death as defined by AIDS defining and/or AIDS-related illnesses.	After Day 1 of treatment until the end of the trial	No
Secondary	Change in CD4+ and CD8+ Cell Counts From Baseline to 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.	after 2 weeks of treatment till Week 48	No
Secondary	Change in Ratio of CD38+/CD8+ From Baseline to 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.	after 2 weeks of treatment till Week 48	No
Secondary	Change in Ratio of CD3+ CD8+ CD38+ HLA DR From Baseline to 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.	after 2 weeks of treatment till Week 48	No
Secondary	Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and 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	after 2 weeks of treatment till Week 48	No
Secondary	Patients Adherence With Study Medication Based on Pill Count	number of pills actually taken divided by the planned number of pills the patient should take	After 4 weeks of treatment until the end of the trial	No
Secondary	Occurrence of Tipranavir (TPV) Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured	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.	After 2 weeks of treatment until the end of trial	No
Secondary	Occurrence of Tipranavir (TPV) Trough Concentration >120 µM	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.	After 2 weeks of treatment until the end of trial	No
Secondary	Post-dose Tipranavir (TPV) and Ritonavir (RTV) Concentrations at Week 4	Post-dose Tipranavir (TPV) and Ritonavir (RTV) plasma concentrations at Week 4	Week 4	No
Secondary	Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements	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)	Baseline through 48 weeks	Yes

External Links

•   Link