Safety, Tolerability and Pharmacodynamics of SYNB1020

• Sponsor: Synlogic (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03447730
• Collaborator: (none)
• Enrollment: 23
• Locations: 5
• Arms: 3
• Actual Duration (Months): 16
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Cirrhosis	Drug: SYNB1020; Other: Placebo	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Part 1 was open-label; Part 2 was double-blinded
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacodynamics of SYNB1020 in Hepatic Insufficiency and Cirrhosis Patients
• Actual Study Start Date: Mar 19, 2018
• Actual Primary Completion Date: Jul 19, 2019
• Actual Study Completion Date: Jul 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: 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.
Experimental: 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.	Drug: 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.
Placebo Comparator: 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.	Other: Placebo; Subjects received placebo orally in a chilled buffered solution (100 mL).

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events [Up to 70 days]

   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

1. Number of Participants With Clearance of SYNB1020 From Feces [Up to 65 days]

   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.

2. Daily Fasting Spot Venous Ammonia [Up to 9 days]

   Fasting spot venous ammonia was collected at baseline (Day -2) and at the time of discharge from the inpatient unit (Day 7).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southern California Research Center	Coronado	California	United States	92118
2	Inland Empire Liver Foundation	Rialto	California	United States	92377
3	Medical University of South Carolina	Charleston	South Carolina	United States	29425
4	Texas Liver Institute	San Antonio	Texas	United States	78006
5	McGuire VA Medical Center	Richmond	Virginia	United States	23249

Sponsors and Collaborators

• Synlogic

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Nov 27, 2018
• Statistical Analysis Plan - Apr 1, 2019

More Information

Publications

None provided.

• Responsible Party: Synlogic
• ClinicalTrials.gov Identifier: NCT03447730
• Other Study ID Numbers: SYNB1020-CP-002
• First Posted: Feb 27, 2018
• Last Update Posted: May 13, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Liver Cirrhosis; Fibrosis

Study Results

Participant Flow

Arm/Group Title	Part 1: SYNB1020	Part 2: SYNB1020	Part 2: Placebo
Arm/Group 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.
Period Title: Overall Study
STARTED	6	9	8
COMPLETED	6	7	8
NOT COMPLETED	0	2	0

Baseline Characteristics

Arm/Group Title	Part 1: SYNB1020	Part 2: SYNB1020	Part 2: Placebo	Total
Arm/Group 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 CFU 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.	Total of all reporting groups
Overall Participants	6	9	8	23
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54.5	57.0	59.5	58.0
Sex: Female, Male (Count of Participants)
Female	2 33.3%	4 44.4%	1 12.5%	7 30.4%
Male	4 66.7%	5 55.6%	7 87.5%	16 69.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 50%	4 44.4%	6 75%	13 56.5%
Not Hispanic or Latino	3 50%	5 55.6%	2 25%	10 43.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	6 100%	9 100%	8 100%	23 100%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	9 100%	8 100%	23 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of SYNB1020 or placebo

Arm/Group Title	Part 1: SYNB1020	Part 2: SYNB1020	Part 2: Placebo
Arm/Group 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 CFU 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.
Measure Participants	6	9	8
Any TEAE	4 66.7%	8 88.9%	4 50%
Maximum TEAE severity Grade 1	3 50%	3 33.3%	1 12.5%
Maximum TEAE severity Grade 2	1 16.7%	5 55.6%	2 25%
Maximum TEAE severity Grade 3	0 0%	0 0%	1 12.5%
Treatment-related TEAE	2 33.3%	4 44.4%	0 0%
TEAE leading to discontinuation	0 0%	2 22.2%	0 0%
Treatment-related TEAE leading to discontinuation	0 0%	0 0%	0 0%
Serious TEAE	0 0%	0 0%	1 12.5%
Treatment-related Serious TEAE	0 0%	0 0%	0 0%
TEAE leading to death	0 0%	0 0%	0 0%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of SYNB1020 or placebo

Arm/Group Title	Part 1: SYNB1020	Part 2: SYNB1020	Part 2: Placebo
Arm/Group 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 CFU 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.
Measure Participants	6	9	8
Cleared by 25 days after last dose	6 100%	9 100%	0 0%
SYNB1020 presence not detected	0 0%	0 0%	8 100%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of SYNB1020 or placebo, completed the study, and were considered evaluable for analysis of pharmacodynamic data

Arm/Group Title	Part 1: SYNB1020	Part 2: SYNB1020	Part 2: Placebo
Arm/Group 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 CFU 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.
Measure Participants	6	7	8
Baseline	64.7 (25.00)	82.0 (36.41)	55.6 (18.18)
End of Study/Day 7	62.3 (27.57)	97.7 (58.79)	67.9 (42.69)

Adverse Events

Time Frame	All AEs occurring from the time a subject signs informed consent through the safety follow-up period (i.e.,up to 70 days) were documented, regardless of the causal relationship to study drug. AEs that occurred or worsened in severity after the first dose of study treatment were considered treatment emergent (i.e., TEAEs).
Adverse Event Reporting Description	AE documentation included duration (onset and resolution dates), severity using the NCI CTCAE (version 4.03), assessment of causality, seriousness, and whether specific action or therapy was required. In summaries, preferred terms are counted only once per subject at the maximum reported grade.
Arm/Group Title	Part 1: SYNB1020		Part 2: SYNB1020		Part 2: Placebo
Arm/Group 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 CFU 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.
All Cause Mortality
	Part 1: SYNB1020		Part 2: SYNB1020		Part 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/9 (0%)		0/8 (0%)
Serious Adverse Events
	Part 1: SYNB1020		Part 2: SYNB1020		Part 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/9 (0%)		1/8 (12.5%)
Gastrointestinal disorders
Oesophageal varices haemorrhage	0/6 (0%)	0	0/9 (0%)	0	1/8 (12.5%)	1
Other (Not Including Serious) Adverse Events
	Part 1: SYNB1020		Part 2: SYNB1020		Part 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		8/9 (88.9%)		3/8 (37.5%)
Gastrointestinal disorders
Constipation	2/6 (33.3%)	2	4/9 (44.4%)	4	0/8 (0%)	0
Nausea	2/6 (33.3%)	2	4/9 (44.4%)	4	0/8 (0%)	0
Vomiting	3/6 (50%)	3	3/9 (33.3%)	3	0/8 (0%)	0
Diarrhoea	1/6 (16.7%)	1	2/9 (22.2%)	2	1/8 (12.5%)	1
Abdominal pain	0/6 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0
Abdominal pain upper	0/6 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0
Eructation	0/6 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0
Infections and infestations
Nasopharyngitis	0/6 (0%)	0	0/9 (0%)	0	1/8 (12.5%)	1
Upper respiratory tract infection	1/6 (16.7%)	1	0/9 (0%)	0	0/8 (0%)	0
Urinary tract infection	0/6 (0%)	0	0/9 (0%)	0	1/8 (12.5%)	1
Injury, poisoning and procedural complications
Limb injury	0/6 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0
Post-traumatic pain	0/6 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/6 (0%)	0	2/9 (22.2%)	2	0/8 (0%)	0
Nervous system disorders
Dizziness	1/6 (16.7%)	1	2/9 (22.2%)	2	0/8 (0%)	0
Headache	1/6 (16.7%)	1	2/9 (22.2%)	2	0/8 (0%)	0
Hepatic encephalopathy	0/6 (0%)	0	2/9 (22.2%)	2	0/8 (0%)	0
Tremor	0/6 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0
Psychiatric disorders
Insomnia	1/6 (16.7%)	1	0/9 (0%)	0	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/6 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0

Limitations/Caveats

Interim futility analyses identified a lack of SYNB1020 efficacy (plasma ammonia AUC) compared with placebo, resulting in study termination.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.