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

This study has been terminated.
Sponsor:
Information provided by:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00447902
First received: March 14, 2007
Last updated: April 25, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
HIV Infections
Drug: tipranavir
Drug: ritonavir
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
Official Title: Safety and Antiviral Activity of TPV in Hepatitis C or Hepatitis B HIV Coinfected Patients - TDM Randomised Pilot Evaluation

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Treatment Response at Week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    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. [ Time Frame: From the start of the study through 48 weeks. ] [ Designated as safety issue: Yes ]
    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:
  • Virologic Response Defined as Viral Load <50 Copies/mL at Each Visit [ Time Frame: After 4 weeks of treatment until the end of the trial ] [ Designated as safety issue: No ]
    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 [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: After 4 weeks of treatment until the end of the trial ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, 24 and 48 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: After 4 weeks of treatment until the end of the trial ] [ Designated as safety issue: No ]
    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 [ Time Frame: After Day 1 of treatment until the end of the trial ] [ Designated as safety issue: No ]
    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 [ Time Frame: After Day 1 of treatment until the end of the trial ] [ Designated as safety issue: No ]
    Time to new AIDS or AIDS related progression event or death as defined by AIDS defining and/or AIDS-related illnesses.

  • Change in CD4+ and CD8+ Cell Counts From Baseline to Week 48 [ Time Frame: after 2 weeks of treatment till Week 48 ] [ Designated as safety issue: No ]
    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.

  • Change in Ratio of CD38+/CD8+ From Baseline to Week 48 [ Time Frame: after 2 weeks of treatment till Week 48 ] [ Designated as safety issue: No ]
    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. [ Time Frame: after 2 weeks of treatment till Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: after 2 weeks of treatment till Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: After 4 weeks of treatment until the end of the trial ] [ Designated as safety issue: No ]
    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 [ Time Frame: After 2 weeks of treatment until the end of trial ] [ Designated as safety issue: No ]
    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 [ Time Frame: After 2 weeks of treatment until the end of trial ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
    Post-dose Tipranavir (TPV) and Ritonavir (RTV) plasma concentrations at Week 4

  • Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements [ Time Frame: Baseline through 48 weeks ] [ Designated as safety issue: Yes ]
    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)


Enrollment: 11
Study Start Date: March 2007
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00447902

Locations
United States, California
1182.99.32 Boehringer Ingelheim Investigational Site
Beverly Hills, California, United States
United States, Florida
1182.99.31 Boehringer Ingelheim Investigational Site
Fort Lauderdale, Florida, United States
United States, Rhode Island
1182.99.12 Boehringer Ingelheim Investigational Site
Providence, Rhode Island, United States
United States, Texas
1182.99.1 Boehringer Ingelheim Investigational Site
Austin, Texas, United States
1182.99.4 Boehringer Ingelheim Investigational Site
Houston, Texas, United States
Argentina
1182.99.54001
Capital Federal, Argentina
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, Brazil
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
1182.99.3310E Boehringer Ingelheim Investigational Site
Nice cedex 3, France
1182.99.3310D Boehringer Ingelheim Investigational Site
Nice cedex 3, France
1182.99.3310C 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, France
Germany
1182.99.4909 Boehringer Ingelheim Investigational Site
Düsseldorf, Germany
Italy
1182.99.3912 Boehringer Ingelheim Investigational Site
Ancona, Italy
1182.99.3916 Boehringer Ingelheim Investigational Site
Milano, Italy
1182.99.3911 Boehringer Ingelheim Investigational Site
Milano, Italy
1182.99.3901 Boehringer Ingelheim Investigational Site
Milano, Italy
1182.99.3906 Boehringer Ingelheim Investigational Site
Pavia, Italy
Spain
1182.99.3402
Barcelona, Spain
1182.99.3407
Madrid, Spain
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00447902     History of Changes
Other Study ID Numbers: 1182.99, EudraCT No.: 2005-005023-33
Study First Received: March 14, 2007
Results First Received: September 25, 2009
Last Updated: April 25, 2014
Health Authority: Argentina: A.N.M.A.T. (Administracion Nacional de Medicamentos, Alimentos Y Tecnología)
Brazil: Agência Nacional de Vigilância Sanitária - ANVISA
France: Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS)
Germany:
Italy: Comitato Etico Locale per la Sperimentazione Clinica Osp. L. Sacco - Milano
Portugal: INFARMED - Instituto Nacional da Farmácia e do Medicamento Parque da Saúde de Lisboa Av. do Brasil Lisboa
Spain:
United States: Food and Drug Administration

Keywords provided by Boehringer Ingelheim:
treatment experienced

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases

ClinicalTrials.gov processed this record on November 25, 2014