Multiple Oral Doses of BI 207127 NA in Treatment naïve and Treatment-experienced Hepatitis C Virus (HCV)-Infected Patients

Safety, Antiviral Activity, and Pharmacokinetics of Multiple Oral Doses of BI 207127 NA Administered q8H for 5 Days as Monotherapy, a Randomised, Double-blind, Placebo Controlled Study

The purpose of this study was to investigate antiviral activity, safety and pharmacokinetics of 5 days of monotherapy with BI 207127 in HCV genotype 1 (GT1) infected patients. Both treatment-naïve patients and patients previously treated with peginterferon and ribavirin were included. In addition, the effect of study medication was examined in a group of patients with liver cirrhosis.

Study Overview

• Status: Completed
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Drug: Placebo; Drug: BI 207127 NA

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults from 18 - 70 years
• Male OR female with documented hysterectomy OR menopausal female with last menstrual period at least 12 months prior to screening
• Written informed consent consistent with International Conference on Harmonization/Good Clinical Practice and local legislation given prior to any study procedures
• Chronic HCV infection demonstrated by positive HCV immunoglobulin G Antibody
• HCV genotype 1 which has to be confirmed by central laboratory test before Visit 2
• For non-cirrhotic cohorts: Liver biopsy obtained within the last 36 months consistent with HCV infection showing minimal to mild liver fibrosis and without cirrhosis (Ishak or Metavir grade ≤ 2). For cirrhotic cohorts, previous liver biopsy or Fibroscan consistent with liver cirrhosis performed at any time before screening
• HCV RNA load > 100,000 IU RNA per ml serum at screening

Exclusion Criteria:

• All fertile males not willing to use an adequate form of contraception (condom, sterilisation at least 6 months post operation) in case their partner is of childbearing potential and is not using an adequate form of contraception (hormonal contraceptives, oral or injectable/ implantable, intra-uterine device)
• Patients who have been treated with at least one dose of any HCV-polymerase inhibitor for acute or chronic hepatitis C infection
• Any other or additional plausible cause for chronic liver disease, including the presence of other viruses known or suspected to cause hepatitis
• Decompensated liver disease within past 12 months, as indicated by variceal bleeding, ascites, encephalopathy, Prothrombin or International Normalized Ratio (INR) prolonged to >1.7 x upper limit of normal (ULN), serum bilirubin > 2 mg/dl or albumin < 3.5 g/dl (i.e. Child-Pugh grade B, score > 7)
• For non-cirrhotic cohorts: Any previous liver biopsy consistent with cirrhosis. For cirrhotic cohorts: Any liver biopsy or fibroscan result from last 2 years excluding liver cirrhosis.
• Positive test for human immunodeficiency virus (HIV) or hepatitis B antigen at screening
• Current alcohol or drug abuse, or history of the same, within the past six (6) months. Exception: Occasional use of cannabis is not an exclusion criterion. The investigator must however instruct the patient that consumption of cannabis is not allowed during the treatment period.
• Any concurrent disease (cardiovascular, pulmonary, renal, haematological, neurological, psychiatric, immunologic, metabolic or endocrine dysfunction) if clinically significant based on the investigator's medical assessment at screening. A clinically significant disease is defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or may influence the results of the study or the patient's ability to participate in the study. Exclusion is also necessary for any pre-existing cardiac abnormality by history.
• Clinically significant abnormalities at screening ECG, including but not limited to a QTc longer than 435 msec, Pulse Rate > 240 msec at baseline and any bundle branch block pattern, but not necessarily non-specific T wave abnormalities
• History of malignancy (except for previously cured squamous cell or basal cell carcinoma)
• Patients treated with any interferon (IFN) (approved or investigational) or Peg-IFN and/or Ribavirin within 3 months prior to screening
• Planned or concurrent usage of any other pharmacological therapy including any antiviral therapy or vaccination from 7 days before treatment and during treatment
• Usage of any investigational drug within thirty (30) days prior to enrolment or 5 halflives, whichever is longer; or the planned usage of an investigational drug during the course of the current study
• Known hypersensitivity to drugs or excipients

• Patients with any one of the following laboratory values at screening:

  • Alanine transaminase (ALT) > 3x ULN, local lab
  • Aspartate aminotransferase (AST) > 3x ULN, local lab
  • Total bilirubin > 1.5x ULN, local lab, unless predominantly conjugated and reflecting Gilbert's disease
  • Alkaline phosphatase > 1.5x ULN, local lab
  • Prothrombin time (INR) > 1.5x ULN, central lab
  • Creatinine > 1x ULN, local lab
  • Urine protein / creatinine ratio > 0.3 g protein / g creatinine, central lab
  • Alpha-1-microglobulin / creatinine in urine > 1x ULN, central lab
  • Platelet count < 100,000 / mm3, central lab
  • White Blood cell count < 2000 cells/mm3, central lab
  • Absolute neutrophile count < 1500 cells, central lab
  • Hemoglobin < 12 g/dL, central lab

  • For patients with liver cirrhosis:

    • ALT > 5x ULN, local lab
    • AST > 5x ULN, local lab
    • Platelet count < 70,000 / mm3, central lab
• Patients with any clinically significant laboratory abnormalities based on the investigator's medical assessment at screening
• Positive urine test for drug abuse at screening
• Prior randomisation into this trial
• Inability to comply with the protocol
• Patients with ongoing or historical photosensitivity or recurrent rash
• Alpha fetoprotein value (AFP) > 100 ng/ml; if AFP is > 20 and ≤ 100 ng/ml, patients can be included if liver cancer is excluded by a current imaging study (i.e. ultrasound, computer tomography scan or magnetic resonance imaging)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 207127 in patients with cirrhosis; multiple rising doses	Drug: BI 207127 NA
Experimental: BI 207127 in patients without cirrhosis; multiple rising doses	Drug: BI 207127 NA
Placebo Comparator: Placebo in patients without cirrhosis	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virologic Response (VR)	Virologic response was defined as a ≥ 1 log10 reduction in serum Hepatitis C virus (HCV) Ribonucleic acid (RNA) level from baseline at any time from the start of administration of treatment up to day 5. In this Outcome Measure the percentage of participants with virologic response is presented.	Baseline (Visit 2_2 at planned time 5 minutes prior to first administration of trial drug), up to day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time Dependent Change From Baseline in Viral Load (VL)	Change of VL from baseline to day 7 is presented (VL at timepoint minus VL at baseline). Acronym used within the categories: planned time (PTM). The number of participants analysed displays the number of participants included in the analysis set whereas the number of participants for each timepoint display the number of participants with available data at that timepoint.	Baseline, up to day 7
Cmax	Maximum measured concentration of Deleobuvir in plasma (Cmax) determined after the first dose.	5 minutes (min) prior to the first dose of study medication and 30 minutes and 1:00, 2:00, 3:00, 4:00, 6:00, 7:55, 10:00, 12:00, 15:55, 18:00 hours (h) thereafter on day 1
Cmin	Measured concentration of Deleobuvir in plasma determined immediately before the second dose (Cmin). The number of participants analysed displays the number of participants with available data at the timepoints of interest.	5 minutes (min) prior to the first dose of study medication and 30 minutes and 1:00, 2:00, 3:00, 4:00, 6:00, 7:55, 10:00, 12:00, 15:55, 18:00 hours (h) thereafter on day 1
Tmax	Time from dosing to maximum measured concentration (tmax) of Deleobuvir determined after the first dose.	5 minutes (min) prior to the first dose of study medication and 30 minutes and 1:00, 2:00, 3:00, 4:00, 6:00, 7:55, 10:00, 12:00, 15:55, 18:00 hours (h) thereafter on day 1
AUC0-τ	Area under the concentration-time curve of Deleobuvir in plasma over the interval 0 hour (h) to the next dose of trial medication (AUC0-τ) measured after first administration of trial drug.	5 minutes (min) prior to the first dose of study medication and 30 minutes and 1:00, 2:00, 3:00, 4:00, 6:00, 7:55, 10:00, 12:00, 15:55, 18:00 hours (h) thereafter on day 1
Cmax,ss	The maximum measured concentration of Deleobuvir in plasma at steady state after the last dose of study drug (Cmax,ss). more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only)	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
Cmin,ss	The minimum measured concentration of Deleobuvir in plasma at steady state (Cmin,ss). more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only). The number of participants analysed displays the number of participants with available data at the timepoints of interest.	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
Tmax,ss	Time from dosing to the maximum measured concentration of Deleobuvir at steady state after the last dose of study drug (tmax,ss) more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only)	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
AUCτ,ss	Area under the concentration-time curve of Deleobuvir in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) measured after last dose of trial drug. more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only). The number of participants analysed displays the number of participants with available data at the timepoints of interest.	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
AUC0-∞,ss	Area under the concentration-time curve of Deleobuvir in plasma over the interval 0 hour (h) extrapolated to infinity at steady state (AUC0-∞,ss) measured after last administration of trial drug. more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only). The number of participants analysed displays the number of participants with available data at the timepoints of interest.	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
λz,ss	Terminal rate of Deleobuvir constant in plasma at steady state (λz,ss) measured after last dose of study drug. more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only). The number of participants analysed displays the number of participants with available data at the timepoints of interest.	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
t1/2,ss	Terminal half-life of Deleobuvir in plasma at steady state (t1/2,ss) measured after the last dose of study drug. more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only). The number of participants analysed displays the number of participants with available data at the timepoints of interest.	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
CL/F,ss	Apparent clearance of Deleobuvir in plasma after oral administration at steady state (CL/F,ss) measured after the last dose of study drug. more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only). The number of participants analysed displays the number of participants with available data at the timepoints of interest.	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
Vz/F,ss	Apparent volume of Deleobuvir distribution during the terminal phase λz following an oral dose at steady state (Vz/F,ss) after the last dose of study drug. more detailed time frame information: 5 minutes (min) prior to the first dose of study medication of Day 5 (-0:05) and 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00 h thereafter; Assigned to the planned time points 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h (*At these time points, in patients with cirrhosis only). The number of participants analysed displays the number of participants with available data at the timepoints of interest.	5 min prior to the first dose of study medication of Day 5; 0:30, 1:00, 2:00, 3:00*, 4:00, 6:00, 8:00*, 10:00, 12:00, 16:00, 24:00, 48:00, 95:55, 96:30, 97:00, 98:00 99:00*, 100:00, 102:00, 104:00*, 106:00, 108:00, 112:00, 120:00, 144:00 h thereafter
Plasma Concentration Time Profiles	Individual drug plasma concentrations of Deleobuvir after multiple oral administration. Within the categories PTM means planned time. The number of participants analysed displays the number of participants included in the analysis data set whereas the number of participants for each timepoint displays the number of participants with available data at that timepoint. Below the limit of quantification (BLQ) is abbreviated.	up to day 7
Number of Patients With Clinically Significant Changes in Vital Signs (Pulse Rate, Systolic and Diastolic Blood Pressure).	Number of patients with clinically significant changes in vital signs (pulse rate, systolic and diastolic blood pressure) presents the number of patients with an reported adverse event which has a symptom in changes in vital signs. Vascular disorders was identified as changes in vital signs. The number of participant with vascular disorders is presented in this outcome measure	Baseline, up to day 14
Number of Patients With Abnormal Findings in 12-lead ECG (Electrocardiogram)	Number of patients with a new onset of an abnormal finding by central assessment are presented.	up to 14 days
Number of Patients With Abnormal Changes in Laboratory Tests	Number of patients with abnormal changes in safety laboratory tests including urine protein diagnostics, and adrenocorticotropic hormone (ACTH) and cortisol measurements resulted in adverse events.	Baseline, up to day 14
Number of Patients With Adverse Events	Number of patients with any adverse event (AE)	up to 14 days
Number of Patients With Abnormal Findings in Physical Examination	The number of patients with abnormal findings in physical examination presents the number of patients with any treatment-emergent adverse events in this study.	up to day 14
Assessment of Global Tolerability on a 4-point Scale	The global tolerability was presented on a four item scale: good, satisfactory, not satisfactory and bad. Rating was done by the investigator.	day 6
Body Temperature	The body temperature will be presented as the mean values in visit 1 and visit 7. The number of participants analysed displays the number of participants included in the analysis set whereas the numbers for each timepoint display the number of participants with available data at that timepoint.	Visit 1, Visit 7

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related links

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: June 26, 2014
• First Submitted That Met QC Criteria: June 26, 2014
• First Posted (Estimate): June 27, 2014

Study Record Updates

• Last Update Posted (Estimate): June 6, 2016
• Last Update Submitted That Met QC Criteria: April 28, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic
• Other Study ID Numbers: 1241.2