Safety, Tolerability and Pharmacodynamics of SYNB1020

NCT ID: NCT03447730

Last Updated: 2021-05-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 23 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-19
• Study Completion Date: 2019-07-19

Brief Summary

This Phase 1b/2a, randomized, double-blind, placebo-controlled study was designed to evaluate the safety, tolerability, and pharmacodynamics of SYNB1020 in hepatic insufficiency and cirrhosis patients with hyperammonemia, with dosing of the investigational medicinal product (IMP) administered in an inpatient unit and subsequent outpatient follow-up for SYNB1020 clearance in two study parts.

Detailed Description

In Part 1, a sentinel open-label cohort of subjects with cirrhosis and Model for End-Stage Liver Disease (MELD) score <12 was admitted to an inpatient facility for a run-in diet, baseline assessments, IMP administration, safety monitoring, and collection of blood, urine, and stool samples for evaluation of safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations. Subjects in Part 1 were enrolled sequentially to receive SYNB1020. Once the safety and tolerability were established in Part 1, enrollment was opened to subjects in Part 2.

Part 2 comprised a randomized, double-blind, placebo-controlled study in subjects with cirrhosis and hyperammonemia. Subjects were permitted to be pre-screened for eligibility based on medical history and a single fasting spot venous ammonia measurement. Eligible subjects with elevated fasting spot venous ammonia then underwent full screening within 7 days of pre-screening. Eligible subjects were admitted to an inpatient facility for a run-in diet and 24-hour ammonia profile, and those with an elevated 24-hour ammonia area under the curve (AUC) (>1.2 × the upper limit of normal [ULN]) proceeded with computer-generated randomization in a 1:1 ratio to receive either SYNB1020 or matching placebo. Randomization was followed by IMP administration, safety monitoring, and collection of blood, urine, and stool samples for PK and PD evaluations.

Conditions

Cirrhosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Part 1: SYNB1020

Part 1 comprised a sentinel open-label cohort of subjects enrolled sequentially to receive SYNB1020, which was administered orally at a dose of 5 × 10\^11 colony-forming units (CFU) 3 times daily (TID) given immediately after meals from Days 1 through 6.

Group Type: EXPERIMENTAL

SYNB1020

Intervention Type: DRUG

SYNB1020 was supplied at a concentration of approximately 1 × 10\^11 CFU/mL in a buffered solution in 5 mL cryovials with a nominal 5 mL fill volume, administered with 100 mL of masking buffer solution.

Part 2: SYNB1020

Subjects randomized to receive SYNB1020 in Part 2 received SYNB1020 administered orally at a dose of 5 × 10\^11 CFU TID given immediately after meals from Days 1 through 6.

Group Type: EXPERIMENTAL

SYNB1020

Intervention Type: DRUG

SYNB1020 was supplied at a concentration of approximately 1 × 10\^11 CFU/mL in a buffered solution in 5 mL cryovials with a nominal 5 mL fill volume, administered with 100 mL of masking buffer solution.

Part 2: Placebo

Subjects randomized to receive control in Part 2 received matching placebo (100 mL masking solution) administered orally TID given immediately after meals from Days 1 through 6.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Subjects received placebo orally in a chilled buffered solution (100 mL).

Interventions

SYNB1020

SYNB1020 was supplied at a concentration of approximately 1 × 10\^11 CFU/mL in a buffered solution in 5 mL cryovials with a nominal 5 mL fill volume, administered with 100 mL of masking buffer solution.

Intervention Type: DRUG

Placebo

Subjects received placebo orally in a chilled buffered solution (100 mL).

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18 to < 75 years
• Females must have been of non-childbearing potential
• Able and willing to complete informed consent process
• Available for and agreed to all study procedures
• Screening laboratory evaluations within defined acceptable limits or judged to be not clinically significant by the Investigator
• Diagnosis of chronic, stable, hepatic insufficiency with features of cirrhosis due to any etiology
• Evidence of elevated portal hypertension by either liver stiffness measurement, the presence of abdominal or esophageal varices, splenomegaly or ascites (Part 2 only)
• Elevated venous ammonia (Part 2 only)

Exclusion Criteria

• Body mass index < 18.5 or ≥ 40 kg/m^2
• Administration or ingestion of an investigational drug within 8 weeks or 5 half-lives, whichever was longer, prior to screening or current enrollment in an investigational study
• Allergy to ranitidine or intolerance to any of the excipients (glycerol, CS Health Easy Fiber)
• Any condition, prescription medication or over-the-counter product that may possibly have affected absorption of medications or nutrients
• Dependence on drugs of abuse
• Apart from chronic liver disease, any acute or chronic medical, surgical, psychiatric, or social condition including history of cerebrovascular disease (stroke, transient ischemic attack) or dementia, or laboratory abnormality that may have increased the subject risk associated with study participation, compromised adherence to study procedures and requirements, confounded interpretation of the safety, kinetics, or PD results, and, in the judgment of the Investigator, made the subject inappropriate for enrollment
• Current or past hepatic encephalopathy of Grade 2 or higher requiring hospitalization
• Child-Turcotte-Pugh score > 9
• History of liver transplant

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Synlogic

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Southern California Research Center

Coronado, California, United States

Inland Empire Liver Foundation

Rialto, California, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Texas Liver Institute

San Antonio, Texas, United States

McGuire VA Medical Center

Richmond, Virginia, United States

Countries

United States

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

SYNB1020-CP-002

Identifier Type: -

Identifier Source: org_study_id