Pharmacokinetics (PK) of Tipranavir/Ritonavir, Ribavirin, Pegylated Interferon (Peg INF) in Hepatitis C (HCV) Subjects With Mild Hepatic Impairment and in HCV, Hepatitis B (HBV), Hepatitis D Infected Subjects or Alcoholic Cirrhosis With Moderate Hepatic Impairment
Primary Purpose
Hepatic Insufficiency
Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Tipranavir
Ritonavir
Pegylated interferon
Ribavirin
Sponsored by
About this trial
This is an interventional treatment trial for Hepatic Insufficiency
Eligibility Criteria
Inclusion Criteria:
- Age ≥18 and Age ≤ 75 years
- BMI ≥18 and BMI ≤ 29 kg/m2 (Body Mass Index) at screening visit
- Signed and dated written informed consent prior to admission to the study in accordance with good clinical practice (GCP) and the local legislation
- Ability to swallow multiple large capsules without difficulty
- Serologic evidence of chronic hepatitis C infection by an antibody test and HCV branched DNA (bDNA) for subjects with mild hepatic impairment (Scheme A)
- Serologic evidence of chronic hepatitis C, B and/or delta infection by an antibody test and HCV bDNA, HBV RNA polymerase chain reaction (PCR) for subjects with moderate hepatic impairment (Child Pugh B)
- Alcoholic cirrhosis, for subjects with moderate hepatic impairment (Child Pugh B). Patients had to stop the alcohol consumption at least 1 month before the screening without any evidence of acute alcoholic hepatitis
- Subjects HCV positive with mild hepatic insufficiency were to be on stable treatment with PegIFN and ribavirin since at least 12 weeks prior to study entry
- Subjects with mild hepatic insufficiency were to be viral non-responders with less than a 2 log reduction in HCV RNA, compared to baseline (HCV treatment initiation) and have positive HCV RNA after 12 weeks therapy with PegIFN/RBV
Subjects with:
- stable mild hepatic insufficiency treated by PegIFN and RBV
- moderate hepatic insufficiency [Child-Pugh Class B (score 7-9)]
- All fertile males or females, and their respective partner(s) were to be using two forms of effective contraception during ribavirin treatment and during the 6 months after its end. All other women must agree to use an effective form of contraception during the entire duration of the study. This may include condoms, diaphragms or implants. This did not apply to those surgically sterilized or in a post menopausal state
Laboratory values that indicated adequate baseline organ function were required at the time of screening. All subjects with mild and moderate hepatic insufficiency should have all laboratory values less than or equal to grade 2, based on division of aids (DAIDS) Grading Scale. The following exceptions were made:
- Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) < 3 x upper limit of normal (ULN)
- Alkaline Phosphatase < 2 x ULN
- Haemoglobin > 10.0 g/dL
- Platelets > 50.000 / μl And all healthy control subjects should have all laboratory values < grade 1
- Willingness to abstain from alcohol starting 2 days prior to administration of study drug up to the end of the study, to abstain from over counter herbal medications for the duration of the trial
- Willingness to abstain from the following starting 14 days prior to administration of study medication up until the end of the study: Grapefruit or grapefruit juice, red wine, seville oranges (marmalade), St John's Wort or Milk Thistle
- Willingness to abstain from the following 72 h prior to PK sampling: Garlic supplements, Methylxanthine containing drinks (coffee, tea, cola, energy drinks, chocolate, etc.)
- Acceptable medical history, physical examination were required prior to entering the treatment phase of the trial
- Reasonable probability for completion of the study, including dosing requirements of TPV/r and acceptance of the risk for hepatic decompensation
Exclusion Criteria:
- Use of any medication listed in the protocol within 30 days prior to Day 1
- Participation in another trial with an investigational medicine within 2 months prior to Day 1
- Absolute neutrophil count (ANC) < 750 cells/mm³ at screening
- Serum creatine level > 1.5 times upper the limit of normal at screening
- History of acute illness within 60 days prior to Day 1
- Subject with mild hepatic impairment (scheme A), HIV, HBV, hepatitis Delta positive and/or alcoholic cirrhosis
- Subject with moderate hepatic impairment (CPB), HIV positive
- Subject control, HIV hepatitis positive and alcoholic cirrhosis
- Subjects HIV positive, HBV positive and, for subjects controls HCV positive
- Active bleeding from oesophageal varices or other conditions consistent with active decompensated liver disease, active spontaneous bacterial peritonitis, active oesophageal variceal disease or active liver encephalopathy
- Subjects with Child-Pugh Class C (score > 9)
- Alcohol abuse within 1 month prior to screening or during the study
- Other substance abuse within 6 months prior to screening or during the study
- Subjects with a history of any illness or allergy (including drug allergy) that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering TPV and RTV
- Subjects who have taken (within 7 days prior to Day 1) any over-the-counter or prescription medication that, in the opinion of the investigator in consultation with the Boehringer Ingelheim France (BIF) clinical monitor, might interfere with absorption, distribution, or metabolism of the study medications
- Known hypersensitivity to sulphonamide class of drugs
- Known hypersensitivity to TPV, RTV or antiretroviral drugs (marketed or experimental use as part of clinical research studies)
- Known elevated liver enzymes in past clinical trials with any compounds
- Inability to adhere to the protocol
- Cautions or warnings in the RTV, PegIFN and RBV package insert which, in the opinion of the investigator, constituted grounds for subject exclusion
- History or other evidence of severe illness, malignancy or any other conditions which would have made the patients, in the opinion of the investigator, unsuitable for the trial
- History of any systemic antineoplasic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) ≤ 6 months prior to study entry or expectation that such treatment would be needed at any time during the study
- Use of hormone replacement therapy with oestrogen-based preparations for at least 1 month prior to screening and for the duration of the study
- Administration of antimicrobial agents within 10 days prior to Day 1 (Visit 2)
- Subjects with evidence of hepatocellular carcinoma, or who tested positive for serum alpha foeto protein > 5μg/l or suspected tumour based on ultrasonography examination, - Patients with history of stroke, intracranial aneurysm, neurosurgery and skull traumatism within 4 weeks prior to screening
- History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intraarticular bleeding
- Gastrointestinal hemorrhage within the past year
- Endoscopically documented gastro-duodenal ulcer disease in the previous 30 days
- Hemorrhagic disorder or bleeding diathesis
- Need for anticoagulant treatment for disorders
- Uncontrolled hypertension (systolic blood pressure (SBP) >180 mmHg and/or diastolic blood pressure (DBP) >100 mmHg)
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Mild hepatic insufficiency
Moderate hepatic insufficiency
Healthy subjects
Arm Description
Outcomes
Primary Outcome Measures
Area under the concentration-time curve from 0 to 12 hours of ribavirin (RBV), tipranavir (TPV) and ritonavir (RTV) in the plasma (AUC0-12h)
Area under the concentration-time curve from 0 to 24 hours of pegylated interferon (Peg IFN) in the plasma (AUC0-24h)
Maximum measured concentration of RBV, Peg INF, TPV and RTV in the plasma (Cmax)
Measured concentration of RBV, TPV and RTV in the plasma at 12 hours (Cp12h)
Measured concentration of Peg INF in the plasma at 24 hours (Cp24h)
Area under the concentration-time curve from 0 extrapolated to infinity of TPV and RTV in the plasma (AUC0-∞)
Secondary Outcome Measures
Time from dosing to the maximum concentration of the analytes in the plasma (tmax)
Terminal half-life of the analytes in the plasma (t1/2)
Apparent clearance of the analytes in the plasma after extra vascular administration (CL/F)
Apparent volume of distribution of the analytes in the plasma (Vz/F)
Number of patients with clinically significant changes in laboratory values
Number of patients with adverse events
Number of patients with clinically significant changes in vital signs (seated blood pressure, pulse rate)
Number of patients with clinically significant changes from baseline in 12-lead ECG
Assessment of tolerability by the investigator
verbal rating scale
Full Information
NCT ID
NCT02259855
First Posted
September 24, 2014
Last Updated
October 7, 2014
Sponsor
Boehringer Ingelheim
1. Study Identification
Unique Protocol Identification Number
NCT02259855
Brief Title
Pharmacokinetics (PK) of Tipranavir/Ritonavir, Ribavirin, Pegylated Interferon (Peg INF) in Hepatitis C (HCV) Subjects With Mild Hepatic Impairment and in HCV, Hepatitis B (HBV), Hepatitis D Infected Subjects or Alcoholic Cirrhosis With Moderate Hepatic Impairment
Official Title
Open Label, Study to Determine the Pharmacokinetic Interactions of Steady State Tipranavir/Ritonavir (500/200 mg) and Steady State Ribavirin and Pegylated Interferon Alfa 2a in HIV Negative, HCV Infected Subjects With Mild Hepatic Impairment and the Pharmacokinetic Properties of Tipranavir/Ritonavir in HIV Negative, HCV, HBV, Hepatitis Delta Infected Subjects or Alcoholic Cirrhosis Subjects With Moderate Hepatic Impairment
Study Type
Interventional
2. Study Status
Record Verification Date
October 2014
Overall Recruitment Status
Completed
Study Start Date
January 2006 (undefined)
Primary Completion Date
October 2008 (Actual)
Study Completion Date
undefined (undefined)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim
4. Oversight
5. Study Description
Brief Summary
The primary objectives were:
To determine the effects of steady state TPV co-administered with low dose RTV on steady state PegIFN and RBV in HIV negative subjects with mild hepatic impairment (scheme A)
To determine the effects of steady state of pegylated interferon (PegIFN) and RBV on steady state pharmacokinetics of TPV co-administered with low dose RTV in HIV negative subjects with mild hepatic impairment (scheme A)
To determine the pharmacokinetics of single dose and steady state TPV/r 500/200 mg in subjects with moderate hepatic insufficiency (scheme B)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatic Insufficiency
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Mild hepatic insufficiency
Arm Type
Experimental
Arm Title
Moderate hepatic insufficiency
Arm Type
Experimental
Arm Title
Healthy subjects
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Tipranavir
Intervention Type
Drug
Intervention Name(s)
Ritonavir
Intervention Type
Drug
Intervention Name(s)
Pegylated interferon
Intervention Type
Drug
Intervention Name(s)
Ribavirin
Primary Outcome Measure Information:
Title
Area under the concentration-time curve from 0 to 12 hours of ribavirin (RBV), tipranavir (TPV) and ritonavir (RTV) in the plasma (AUC0-12h)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Area under the concentration-time curve from 0 to 24 hours of pegylated interferon (Peg IFN) in the plasma (AUC0-24h)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Maximum measured concentration of RBV, Peg INF, TPV and RTV in the plasma (Cmax)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Measured concentration of RBV, TPV and RTV in the plasma at 12 hours (Cp12h)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Measured concentration of Peg INF in the plasma at 24 hours (Cp24h)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Area under the concentration-time curve from 0 extrapolated to infinity of TPV and RTV in the plasma (AUC0-∞)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Secondary Outcome Measure Information:
Title
Time from dosing to the maximum concentration of the analytes in the plasma (tmax)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Terminal half-life of the analytes in the plasma (t1/2)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Apparent clearance of the analytes in the plasma after extra vascular administration (CL/F)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Apparent volume of distribution of the analytes in the plasma (Vz/F)
Time Frame
Pre-dose, up to 120 hours after start of treatment
Title
Number of patients with clinically significant changes in laboratory values
Time Frame
up to 3 weeks after start of treatment
Title
Number of patients with adverse events
Time Frame
Up to 7 weeks
Title
Number of patients with clinically significant changes in vital signs (seated blood pressure, pulse rate)
Time Frame
up to 3 weeks after start of treatment
Title
Number of patients with clinically significant changes from baseline in 12-lead ECG
Time Frame
3 weeks after start of treatment
Title
Assessment of tolerability by the investigator
Description
verbal rating scale
Time Frame
Up to 3 weeks after start of treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Age ≥18 and Age ≤ 75 years
BMI ≥18 and BMI ≤ 29 kg/m2 (Body Mass Index) at screening visit
Signed and dated written informed consent prior to admission to the study in accordance with good clinical practice (GCP) and the local legislation
Ability to swallow multiple large capsules without difficulty
Serologic evidence of chronic hepatitis C infection by an antibody test and HCV branched DNA (bDNA) for subjects with mild hepatic impairment (Scheme A)
Serologic evidence of chronic hepatitis C, B and/or delta infection by an antibody test and HCV bDNA, HBV RNA polymerase chain reaction (PCR) for subjects with moderate hepatic impairment (Child Pugh B)
Alcoholic cirrhosis, for subjects with moderate hepatic impairment (Child Pugh B). Patients had to stop the alcohol consumption at least 1 month before the screening without any evidence of acute alcoholic hepatitis
Subjects HCV positive with mild hepatic insufficiency were to be on stable treatment with PegIFN and ribavirin since at least 12 weeks prior to study entry
Subjects with mild hepatic insufficiency were to be viral non-responders with less than a 2 log reduction in HCV RNA, compared to baseline (HCV treatment initiation) and have positive HCV RNA after 12 weeks therapy with PegIFN/RBV
Subjects with:
stable mild hepatic insufficiency treated by PegIFN and RBV
moderate hepatic insufficiency [Child-Pugh Class B (score 7-9)]
All fertile males or females, and their respective partner(s) were to be using two forms of effective contraception during ribavirin treatment and during the 6 months after its end. All other women must agree to use an effective form of contraception during the entire duration of the study. This may include condoms, diaphragms or implants. This did not apply to those surgically sterilized or in a post menopausal state
Laboratory values that indicated adequate baseline organ function were required at the time of screening. All subjects with mild and moderate hepatic insufficiency should have all laboratory values less than or equal to grade 2, based on division of aids (DAIDS) Grading Scale. The following exceptions were made:
Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) < 3 x upper limit of normal (ULN)
Alkaline Phosphatase < 2 x ULN
Haemoglobin > 10.0 g/dL
Platelets > 50.000 / μl And all healthy control subjects should have all laboratory values < grade 1
Willingness to abstain from alcohol starting 2 days prior to administration of study drug up to the end of the study, to abstain from over counter herbal medications for the duration of the trial
Willingness to abstain from the following starting 14 days prior to administration of study medication up until the end of the study: Grapefruit or grapefruit juice, red wine, seville oranges (marmalade), St John's Wort or Milk Thistle
Willingness to abstain from the following 72 h prior to PK sampling: Garlic supplements, Methylxanthine containing drinks (coffee, tea, cola, energy drinks, chocolate, etc.)
Acceptable medical history, physical examination were required prior to entering the treatment phase of the trial
Reasonable probability for completion of the study, including dosing requirements of TPV/r and acceptance of the risk for hepatic decompensation
Exclusion Criteria:
Use of any medication listed in the protocol within 30 days prior to Day 1
Participation in another trial with an investigational medicine within 2 months prior to Day 1
Absolute neutrophil count (ANC) < 750 cells/mm³ at screening
Serum creatine level > 1.5 times upper the limit of normal at screening
History of acute illness within 60 days prior to Day 1
Subject with mild hepatic impairment (scheme A), HIV, HBV, hepatitis Delta positive and/or alcoholic cirrhosis
Subject with moderate hepatic impairment (CPB), HIV positive
Subject control, HIV hepatitis positive and alcoholic cirrhosis
Subjects HIV positive, HBV positive and, for subjects controls HCV positive
Active bleeding from oesophageal varices or other conditions consistent with active decompensated liver disease, active spontaneous bacterial peritonitis, active oesophageal variceal disease or active liver encephalopathy
Subjects with Child-Pugh Class C (score > 9)
Alcohol abuse within 1 month prior to screening or during the study
Other substance abuse within 6 months prior to screening or during the study
Subjects with a history of any illness or allergy (including drug allergy) that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering TPV and RTV
Subjects who have taken (within 7 days prior to Day 1) any over-the-counter or prescription medication that, in the opinion of the investigator in consultation with the Boehringer Ingelheim France (BIF) clinical monitor, might interfere with absorption, distribution, or metabolism of the study medications
Known hypersensitivity to sulphonamide class of drugs
Known hypersensitivity to TPV, RTV or antiretroviral drugs (marketed or experimental use as part of clinical research studies)
Known elevated liver enzymes in past clinical trials with any compounds
Inability to adhere to the protocol
Cautions or warnings in the RTV, PegIFN and RBV package insert which, in the opinion of the investigator, constituted grounds for subject exclusion
History or other evidence of severe illness, malignancy or any other conditions which would have made the patients, in the opinion of the investigator, unsuitable for the trial
History of any systemic antineoplasic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) ≤ 6 months prior to study entry or expectation that such treatment would be needed at any time during the study
Use of hormone replacement therapy with oestrogen-based preparations for at least 1 month prior to screening and for the duration of the study
Administration of antimicrobial agents within 10 days prior to Day 1 (Visit 2)
Subjects with evidence of hepatocellular carcinoma, or who tested positive for serum alpha foeto protein > 5μg/l or suspected tumour based on ultrasonography examination, - Patients with history of stroke, intracranial aneurysm, neurosurgery and skull traumatism within 4 weeks prior to screening
History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intraarticular bleeding
Gastrointestinal hemorrhage within the past year
Endoscopically documented gastro-duodenal ulcer disease in the previous 30 days
Hemorrhagic disorder or bleeding diathesis
Need for anticoagulant treatment for disorders
Uncontrolled hypertension (systolic blood pressure (SBP) >180 mmHg and/or diastolic blood pressure (DBP) >100 mmHg)
12. IPD Sharing Statement
Links:
URL
http://trials.boehringer-ingelheim.com
Description
Related Info
Learn more about this trial
Pharmacokinetics (PK) of Tipranavir/Ritonavir, Ribavirin, Pegylated Interferon (Peg INF) in Hepatitis C (HCV) Subjects With Mild Hepatic Impairment and in HCV, Hepatitis B (HBV), Hepatitis D Infected Subjects or Alcoholic Cirrhosis With Moderate Hepatic Impairment
We'll reach out to this number within 24 hrs