Back to resultsSafety, Tolerability and Pharmacodynamics of SYNB1020
Primary Purpose
Cirrhosis
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
SYNB1020
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Cirrhosis
Eligibility Criteria
Key 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)
Key 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
Sites / Locations
- Southern California Research Center
- Inland Empire Liver Foundation
- Medical University of South Carolina
- Texas Liver Institute
- McGuire VA Medical Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Part 1: SYNB1020
Part 2: SYNB1020
Part 2: Placebo
Arm Description
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.
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.
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.
Outcomes
Primary Outcome Measures
Number of Participants With Treatment-Emergent Adverse Events
Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, as follows: Grade 1 (mild/asymptomatic; no intervention); Grade 2 (moderate; minimal intervention); Grade 3 (severe/medically significant; hospitalization indicated; disabling); Grade 4 (life-threatening; urgent intervention required). Adverse events (AEs) were reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent was signed through the end of the safety follow-up period. AEs were considered to be treatment emergent adverse events (TEAEs) if they occurred or worsened in severity after the first dose of study treatment. TEAEs were considered treatment-related if relationship to study drug was possibly related, probably related, definitely related, or a missing relationship.
Secondary Outcome Measures
Number of Participants With Clearance of SYNB1020 From Feces
SYNB1020 transit through the gastrointestinal tract was measured with qualitative and quantitative polymerase chain reaction (PCR) fecal assays from fecal samples collected at baseline, daily during the dosing period (Days 1 through 6), at the time of discharge from the inpatient unit (Day 7), and at follow-up visits beginning 7±1 days after the last dose and continuing biweekly until a subject had a negative SYNB1020 fecal test. SYNB1020 clearance reflects a test value of below the limit of quantitation (BLQ) occurring after the indicated number of days following the last dose of study treatment.
Daily Fasting Spot Venous Ammonia
Fasting spot venous ammonia was collected at baseline (Day -2) and at the time of discharge from the inpatient unit (Day 7).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03447730
Brief Title
Safety, Tolerability and Pharmacodynamics of SYNB1020
Official Title
A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacodynamics of SYNB1020 in Hepatic Insufficiency and Cirrhosis Patients
Study Type
Interventional
2. Study Status
Record Verification Date
May 2021
Overall Recruitment Status
Terminated
Why Stopped
Interim futility analyses identified a lack of SYNB1020 efficacy.
Study Start Date
March 19, 2018 (Actual)
Primary Completion Date
July 19, 2019 (Actual)
Study Completion Date
July 19, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Synlogic
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Part 1 was open-label; Part 2 was double-blinded
Allocation
Randomized
Enrollment
23 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part 1: SYNB1020
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 2: SYNB1020
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 2: Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
SYNB1020
Intervention Description
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
Other
Intervention Name(s)
Placebo
Intervention Description
Subjects received placebo orally in a chilled buffered solution (100 mL).
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events
Description
Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, as follows: Grade 1 (mild/asymptomatic; no intervention); Grade 2 (moderate; minimal intervention); Grade 3 (severe/medically significant; hospitalization indicated; disabling); Grade 4 (life-threatening; urgent intervention required). Adverse events (AEs) were reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent was signed through the end of the safety follow-up period. AEs were considered to be treatment emergent adverse events (TEAEs) if they occurred or worsened in severity after the first dose of study treatment. TEAEs were considered treatment-related if relationship to study drug was possibly related, probably related, definitely related, or a missing relationship.
Time Frame
Up to 70 days
Secondary Outcome Measure Information:
Title
Number of Participants With Clearance of SYNB1020 From Feces
Description
SYNB1020 transit through the gastrointestinal tract was measured with qualitative and quantitative polymerase chain reaction (PCR) fecal assays from fecal samples collected at baseline, daily during the dosing period (Days 1 through 6), at the time of discharge from the inpatient unit (Day 7), and at follow-up visits beginning 7±1 days after the last dose and continuing biweekly until a subject had a negative SYNB1020 fecal test. SYNB1020 clearance reflects a test value of below the limit of quantitation (BLQ) occurring after the indicated number of days following the last dose of study treatment.
Time Frame
Up to 65 days
Title
Daily Fasting Spot Venous Ammonia
Description
Fasting spot venous ammonia was collected at baseline (Day -2) and at the time of discharge from the inpatient unit (Day 7).
Time Frame
Up to 9 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key 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)
Key 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
Facility Information:
Facility Name
Southern California Research Center
City
Coronado
State/Province
California
ZIP/Postal Code
92118
Country
United States
Facility Name
Inland Empire Liver Foundation
City
Rialto
State/Province
California
ZIP/Postal Code
92377
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Texas Liver Institute
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78006
Country
United States
Facility Name
McGuire VA Medical Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23249
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Safety, Tolerability and Pharmacodynamics of SYNB1020
We'll reach out to this number within 24 hrs