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

Phase 1

Completed

• Conditions: Hepatitis C, Chronic
• Interventions: Drug: BI 207127 NA; Drug: Placebo

• Registration Number: NCT02176525
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2007-12
• Primary Completion: 2009-12
• Study First Submitted: 2014-06-26
• Study First Submitted QC: 2014-06-26
• Study First Posted: 2014-06-27
• Results First Submitted: 2016-01-21
• Status Verified: 2016-04
• Results First Submitted QC: 2016-04-28
• Last Update Submitted: 2016-04-28
• Results First Posted: 2016-06-06
• Last Update Posted: 2016-06-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 75

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BI 207127 in patients with cirrhosis	BI 207127 NA	multiple rising doses
Placebo in patients without cirrhosis	Placebo	-
BI 207127 in patients without cirrhosis	BI 207127 NA	multiple rising doses

Primary Outcome Measures

Name	Time	Method
Virologic Response (VR)	Baseline (Visit 2_2 at planned time 5 minutes prior to first administration of trial drug), up to day 5	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.

Secondary Outcome Measures

Name	Time	Method
Cmax	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	Maximum measured concentration of Deleobuvir in plasma (Cmax) determined after the first dose.
Time Dependent Change From Baseline in Viral Load (VL)	Baseline, up to day 7	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.
Cmin	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	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.
Tmax	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	Time from dosing to maximum measured concentration (tmax) of Deleobuvir determined after the first dose.
AUC0-τ	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	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.
Cmax,ss	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	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)
Cmin,ss	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	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.
Tmax,ss	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	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)
AUCτ,ss	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	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.
AUC0-∞,ss	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	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.
λz,ss	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	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.
t1/2,ss	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	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.
CL/F,ss	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	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.
Vz/F,ss	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	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.
Plasma Concentration Time Profiles	up to day 7	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.
Number of Patients With Clinically Significant Changes in Vital Signs (Pulse Rate, Systolic and Diastolic Blood Pressure).	Baseline, up to day 14	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
Number of Patients With Abnormal Findings in 12-lead ECG (Electrocardiogram)	up to 14 days	Number of patients with a new onset of an abnormal finding by central assessment are presented.
Number of Patients With Abnormal Changes in Laboratory Tests	Baseline, up to day 14	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.
Number of Patients With Adverse Events	up to 14 days	Number of patients with any adverse event (AE)
Number of Patients With Abnormal Findings in Physical Examination	up to day 14	The number of patients with abnormal findings in physical examination presents the number of patients with any treatment-emergent adverse events in this study.
Assessment of Global Tolerability on a 4-point Scale	day 6	The global tolerability was presented on a four item scale: good, satisfactory, not satisfactory and bad. Rating was done by the investigator.
Body Temperature	Visit 1, Visit 7	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.