Companion Protocol for Methacetin Breath Test (MBT) in Conatus Protocol IDN-6556-14

Companion Protocol for the ¹³C-Methacetin Breath Test Using the BreathID® MCS System for Conatus Phase 2 Study of Emricasan, an Oral Caspase Inhibitor, Under Protocol IDN-6556-14 (NCT02960204)

To validate the ability of the Methacetin Breath Test (MBT) to detect clinically significant portal hypertension (CSPH)/severe portal hypertension (SPH) defined as hepatic venous pressure gradient (HVPG) ≥ 10 mmHg and HVPG ≥ 12 mmHg respectively, in patients with non-alcoholic steatohepatitis (NASH) during the course of treatment with Conatus's investigational product emricasan/placebo.

Study Overview

• Status: Completed
• Conditions: Cirrhosis; Portal Hypertension; NASH - Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Emricasan; Drug: Placebo oral capsule; Combination product: Methacetin Breath Test

Detailed Description

This study is a companion protocol that will use the data generated by Conatus' study of emricasan under protocol IDN-6556-14 (NCT02960204).The IDN-6556-14 study is a Phase 2, multicenter, double-blind, randomized, placebo-controlled trial in subjects with non-alcoholic steatohepatitis (NASH) cirrhosis and severe portal hypertension.

As one of the Conatus' study exploratory objectives, this companion protocol is designed to assess whether emricasan compared to placebo improves liver metabolic function at Weeks 24 and 48 as assessed by the methacetin breath test (at select sites), if relevant.

• Study Type: Interventional
• Enrollment (Actual): 343

Contacts and Locations

Study Locations

• France
  • Clichy, France, 92118
    • Hopital Beaujon

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female subjects 18 years or older, able to provide written informed consent and able to understand and willing to comply with the requirements of the study.
2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.)
3. Compensated cirrhosis OR Decompensated cirrhosis with no more than 1 prior significant decompensating event.
4. Severe portal hypertension defined as HVPG ≥12 mmHg
5. Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a stable dose for at least 3 months prior to Day 1
6. Willingness to utilize effective contraception (for both males and females of childbearing potential) from Screening to 4 weeks after the last dose of study drug

Exclusion Criteria:

1. Evidence of severe decompensation
2. Severe hepatic impairment defined as a Child-Pugh score ≥10
3. ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening
4. Estimated creatinine clearance <30 mL/min
5. Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure
6. Known portal vein thrombosis
7. Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy, other definitive treatment (e.g. sphincterotomy), or medical management (e.g. ursodeoxycholic acid)
8. Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 transporters
9. Alpha-fetoprotein >50 ng/mL
10. History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of >500 msec
11. History of or active malignancies, other than those successfully treated with curative intent and believed to be cured
12. Prior liver transplant
13. Change in diabetes medications or vitamin E within 3 months of screening
14. Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening
15. Significant systemic or major illness other than liver disease
16. HIV infection
17. Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening
18. If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding
19. Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Emricasan 5mg; Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day. The MBT will be performed at screening, at week 24/week 48/at early termination.	Drug: Emricasan; Investigational drug for NASH treatment in Main Conatus protocol; Combination product: Methacetin Breath Test; A breath analyzer will be used to measure changes in carbon-12 to carbon-13 ratio as a result of metabolism of the Methacetin substrate before and after treatment.
Experimental: Emricasan 25mg; Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day. The MBT will be performed at screening, at week 24/ week 48/ at early termination.	Drug: Emricasan; Investigational drug for NASH treatment in Main Conatus protocol; Combination product: Methacetin Breath Test; A breath analyzer will be used to measure changes in carbon-12 to carbon-13 ratio as a result of metabolism of the Methacetin substrate before and after treatment.
Experimental: Emricasan 50mg; Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day. The MBT will be performed at screening, at week 24/ week 48/ at early termination.	Drug: Emricasan; Investigational drug for NASH treatment in Main Conatus protocol; Combination product: Methacetin Breath Test; A breath analyzer will be used to measure changes in carbon-12 to carbon-13 ratio as a result of metabolism of the Methacetin substrate before and after treatment.
Placebo Comparator: Placebo; Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day. The MBT will be performed at screening, at week 24/week 48/at early termination.	Drug: Placebo oral capsule; Placebo versus emricasan in Conatus NASH treatment trial; Combination product: Methacetin Breath Test; A breath analyzer will be used to measure changes in carbon-12 to carbon-13 ratio as a result of metabolism of the Methacetin substrate before and after treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Matched Clinically Significant Portal Hypertension Based on Hepatic Venous Pressure Gradient (HVPG) and Methacetin Breath Test (MBT)	Binary diagnosis of clinically significant portal hypertension (CSPH) as determined by HVPG, defined as HVPG ≥ 10mmHg and by the MBT derived from an algorithm developed under other Exalenz clinical studies	1 hour for MBT related to assessment of this diagnostic primary outcome assesses during screening

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Matched Subjects With Significant Portal Hypertension (Defined as HVPG>=12mmHg) Based on HVPG and MBT	Binary diagnosis of HVPG>=12mmHg and by the MBT derived from an algorithm developed under other Exalenz clinical studies	1 hour for MBT for assessment of this diagnostic secondary outcome assessed during screening

Collaborators and Investigators

• Sponsor: Meridian Bioscience, Inc.
• Collaborators: Conatus Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2016
• Primary Completion (Actual): April 8, 2019
• Study Completion (Actual): May 13, 2019

Study Registration Dates

• First Submitted: January 29, 2018
• First Submitted That Met QC Criteria: February 13, 2018
• First Posted (Actual): February 20, 2018

Study Record Updates

• Last Update Posted (Actual): December 20, 2022
• Last Update Submitted That Met QC Criteria: December 19, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypertension, Portal
• Other Study ID Numbers: CON-EX-0616

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No