PK and PD Study of IDN-6556 in Subjects With Hepatic Impairment and Matched Healthy Volunteers

An Open-Label Pharmacokinetic and Pharmacodynamic Study of a Single Dose of IDN-6556 in Subjects With Hepatic Impairment and in Matched Healthy Volunteers

This is an open-label, parallel-group study to compare the pharmacokinetics and pharmacodynamics of IDN-6556 following a single 50 mg oral dose of IDN-6556 in subjects with mild, moderate, and severe hepatic impairment (defined as Child-Pugh A, B, and C, respectively) and matched healthy volunteers with normal hepatic function.

Study Overview

• Status: Completed
• Conditions: Liver Diseases; Digestive System Diseases; Hepatic Impairment
• Intervention / Treatment: Drug: IDN-6556

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • DeLand, Florida, United States, 32720
      • Avail Clinical Research
    • Miami, Florida, United States, 33136
      • University of Miami
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All Subjects:

• Male or female subjects 18 years of age or older, able to provide written informed consent, understand and comply with all scheduled visits, and other requirements of the study
• Body mass index (BMI) 18.0 - 40.0 kg/m2 and body weight >45 kg
• Willingness to utilize two reliable forms of contraception (for both males and females of childbearing potential) from Screening to one month after the last dose of study drug

Matched Healthy Volunteers:

• Medically healthy as determined by the Investigator
• Supine blood pressure ≤145/90 mmHg
• No significant uncontrolled systemic or major illness that, in the opinion of the Investigator, would preclude the subject from participating in and completing the study

• Demographically comparable to subjects with hepatic impairment as follows:

  1. Mean body weight within ±15 kg
  2. Mean age within ±10 years
  3. Similar gender ratio

Subjects with Hepatic Impairment:

• Evidence of hepatic disease

  1. Score ≥ 2 on one of the Child-Pugh parameters, or
  2. Histological or imaging diagnosis of cirrhosis, or
  3. Presence of esophageal varices, or
  4. Abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels

• Meet one of the following criteria for Child-Pugh classification for hepatic impairment during Screening

  1. Mild hepatic impairment: Class A (Child-Pugh Scores 5-6 points)
  2. Moderate hepatic impairment: Class B (Child-Pugh Scores 7-9 points)
  3. Severe hepatic impairment: Class C (Child Pugh Scores 10-15 points)
• Supine blood pressure ≤160/100 mmHg

Exclusion Criteria:

All Subjects:

• Known infection with human immunodeficiency virus (HIV) upon serological testing
• Evidence of clinically significant uncontrolled hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, renal, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing)
• Disorders or surgery of the gastrointestinal tract which may interfere with drug absorption or may otherwise influence the pharmacokinetics of the investigational medicinal product (e.g., inflammatory bowel disease, resections of the small or large intestine, etc.)
• History of febrile illness within 5 days prior to dosing Note: Subjects can be rescreened once afebrile and more than 5 days have elapsed since the febrile illness.
• Known ongoing drug abuse within one month prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during Screening and/or at Day -1
• Subjects with active or history of malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas)
• Dosing in another clinical trial within 30 days prior to the study drug administration
• If female: known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding

Matched Healthy Volunteers:

• Evidence of clinically significant liver disease or liver damage (e.g., hepatitis B or C, autoimmune hepatitis, primary biliary cirrhosis, non-alcoholic fatty liver disease, elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) that is considered clinically significant by the Investigator, etc.)
• Screening creatinine clearance <80 mL/min using the Cockcroft-Gault equation
• History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of >450 milliseconds (msec)
• History of regular alcohol consumption exceeding 28 drinks/week (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of spirits) within 6 months of Screening

Subjects with Hepatic Impairment:

• Fluctuating or rapidly deteriorating hepatic function, as indicated by strongly varying or worsening of clinical and/or laboratory signs of hepatic impairment during Screening period and up to Day -1 (e.g., advanced ascites, infection of ascites, fever, active gastrointestinal bleeding)
• History of liver transplant, or have a transjugular intrahepatic portosystemic shunt, and/or have undergone portacaval shunting
• History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of >480 milliseconds (msec)
• Screening creatinine clearance <50 mL/min using the Cockcroft-Gault equation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chil-Pugh Class A; All subjects with mild hepatic impairment received a single 50 mg oral dose of IDN-6556	Drug: IDN-6556; Other Names: emricasan; PF-03491390
Experimental: Chil-Pugh Class B; All subjects with moderate hepatic impairment received a single 50 mg oral dose of IDN-6556	Drug: IDN-6556; Other Names: emricasan; PF-03491390
Experimental: Chil-Pugh Class C; All subjects with severe hepatic impairment received a single 50 mg oral dose of IDN-6556	Drug: IDN-6556; Other Names: emricasan; PF-03491390
Experimental: Normal Hepatic Function; All healthy volunteers subjects received a single 50 mg oral dose of IDN-6556	Drug: IDN-6556; Other Names: emricasan; PF-03491390

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC	Area under the plasma concentration curve (AUC) to 12 hours post-dose (AUC0-12); AUC to the last observed plasma concentration (AUClast);	48 Hours
Cmax	Maximum concentration (Cmax)	48 Hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of cCK18/M30	Caspase-cleaved cytokeratin levels (cCK18M30)	predose, 0.5, 1,2,3,4,5,8,12,24, and 48 hours post dose
Levels of Caspase 3/7 RLU	Concentration of Caspase 3/7 Relative Light Units	predose, 0.5, 1,2,3,4,5,8,12,24, and 48 hours post dose

Collaborators and Investigators

• Sponsor: Conatus Pharmaceuticals Inc.
• Investigators: Study Chair: Dave Hagerty, MD, Conatus Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: April 18, 2014
• First Submitted That Met QC Criteria: April 22, 2014
• First Posted (Estimate): April 24, 2014

Study Record Updates

• Last Update Posted (Estimate): February 24, 2016
• Last Update Submitted That Met QC Criteria: January 27, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Pharmacodynamics; Hepatic Impairment
• Additional Relevant MeSH Terms: Liver Diseases; Gastrointestinal Diseases; Digestive System Diseases
• Other Study ID Numbers: IDN-6556-08