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Safety, Tolerability and Pharmacodynamics of SYNB1020

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ClinicalTrials.gov Identifier: NCT03447730
Recruitment Status : Terminated (Interim futility analyses identified a lack of SYNB1020 efficacy.)
First Posted : February 27, 2018
Results First Posted : October 14, 2020
Last Update Posted : May 13, 2021
Sponsor:
Information provided by (Responsible Party):
Synlogic

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Cirrhosis
Interventions Drug: SYNB1020
Other: Placebo
Enrollment 23
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Part 1: SYNB1020 Part 2: SYNB1020 Part 2: Placebo
Hide 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 [1] 6 7 8
Not Completed 0 2 0
Reason Not Completed
Adverse Event             0             2             0
[1]
Completed all 6 days of TID dosing
Arm/Group Title Part 1: SYNB1020 Part 2: SYNB1020 Part 2: Placebo Total
Hide 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 Number of Baseline Participants 6 9 8 23
Hide Baseline Analysis Population Description
All subjects who received at least 1 dose of study treatment
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 6 participants 9 participants 8 participants 23 participants
54.5
(35.0 to 68.0)
57.0
(38.0 to 74.0)
59.5
(45.0 to 74.0)
58.0
(35.0 to 74.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 9 participants 8 participants 23 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)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 9 participants 8 participants 23 participants
Hispanic or Latino
3
  50.0%
4
  44.4%
6
  75.0%
13
  56.5%
Not Hispanic or Latino
3
  50.0%
5
  55.6%
2
  25.0%
10
  43.5%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 9 participants 8 participants 23 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
6
 100.0%
9
 100.0%
8
 100.0%
23
 100.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 6 participants 9 participants 8 participants 23 participants
6 9 8 23
1.Primary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 6 9 8
Measure Type: Number
Unit of Measure: participants
Any TEAE 4 8 4
Maximum TEAE severity Grade 1 3 3 1
Maximum TEAE severity Grade 2 1 5 2
Maximum TEAE severity Grade 3 0 0 1
Treatment-related TEAE 2 4 0
TEAE leading to discontinuation 0 2 0
Treatment-related TEAE leading to discontinuation 0 0 0
Serious TEAE 0 0 1
Treatment-related Serious TEAE 0 0 0
TEAE leading to death 0 0 0
2.Secondary Outcome
Title Number of Participants With Clearance of SYNB1020 From Feces
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 6 9 8
Measure Type: Count of Participants
Unit of Measure: Participants
Cleared by 25 days after last dose
6
 100.0%
9
 100.0%
0
   0.0%
SYNB1020 presence not detected
0
   0.0%
0
   0.0%
8
 100.0%
3.Secondary Outcome
Title Daily Fasting Spot Venous Ammonia
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 6 7 8
Mean (Standard Deviation)
Unit of Measure: μmol/L
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)
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/6 (0.00%)      0/9 (0.00%)      0/8 (0.00%)    
Hide 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 (0.00%)      0/9 (0.00%)      1/8 (12.50%)    
Gastrointestinal disorders       
Oesophageal varices haemorrhage  1 [1]  0/6 (0.00%)  0 0/9 (0.00%)  0 1/8 (12.50%)  1
1
Term from vocabulary, MedDRA (20.1)
Indicates events were collected by systematic assessment
[1]
Severity Grade 3
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Part 1: SYNB1020 Part 2: SYNB1020 Part 2: Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/6 (66.67%)      8/9 (88.89%)      3/8 (37.50%)    
Gastrointestinal disorders       
Constipation  1 [1]  2/6 (33.33%)  2 4/9 (44.44%)  4 0/8 (0.00%)  0
Nausea  1 [2]  2/6 (33.33%)  2 4/9 (44.44%)  4 0/8 (0.00%)  0
Vomiting  1 [2]  3/6 (50.00%)  3 3/9 (33.33%)  3 0/8 (0.00%)  0
Diarrhoea  1 [2]  1/6 (16.67%)  1 2/9 (22.22%)  2 1/8 (12.50%)  1
Abdominal pain  1 [2]  0/6 (0.00%)  0 1/9 (11.11%)  1 0/8 (0.00%)  0
Abdominal pain upper  1 [2]  0/6 (0.00%)  0 1/9 (11.11%)  1 0/8 (0.00%)  0
Eructation  1 [1]  0/6 (0.00%)  0 1/9 (11.11%)  1 0/8 (0.00%)  0
Infections and infestations       
Nasopharyngitis  1 [1]  0/6 (0.00%)  0 0/9 (0.00%)  0 1/8 (12.50%)  1
Upper respiratory tract infection  1 [1]  1/6 (16.67%)  1 0/9 (0.00%)  0 0/8 (0.00%)  0
Urinary tract infection  1 [2]  0/6 (0.00%)  0 0/9 (0.00%)  0 1/8 (12.50%)  1
Injury, poisoning and procedural complications       
Limb injury  1 [2]  0/6 (0.00%)  0 1/9 (11.11%)  1 0/8 (0.00%)  0
Post-traumatic pain  1 [2]  0/6 (0.00%)  0 1/9 (11.11%)  1 0/8 (0.00%)  0
Metabolism and nutrition disorders       
Dehydration  1 [2]  0/6 (0.00%)  0 2/9 (22.22%)  2 0/8 (0.00%)  0
Nervous system disorders       
Dizziness  1 [2]  1/6 (16.67%)  1 2/9 (22.22%)  2 0/8 (0.00%)  0
Headache  1 [2]  1/6 (16.67%)  1 2/9 (22.22%)  2 0/8 (0.00%)  0
Hepatic encephalopathy  1 [2]  0/6 (0.00%)  0 2/9 (22.22%)  2 0/8 (0.00%)  0
Tremor  1 [1]  0/6 (0.00%)  0 1/9 (11.11%)  1 0/8 (0.00%)  0
Psychiatric disorders       
Insomnia  1 [1]  1/6 (16.67%)  1 0/9 (0.00%)  0 0/8 (0.00%)  0
Skin and subcutaneous tissue disorders       
Rash  1 [1]  0/6 (0.00%)  0 1/9 (11.11%)  1 0/8 (0.00%)  0
1
Term from vocabulary, MedDRA (20.1)
Indicates events were collected by systematic assessment
[1]
Maximum severity Grade 1
[2]
Maximum severity Grade 2
Interim futility analyses identified a lack of SYNB1020 efficacy (plasma ammonia AUC) compared with placebo, resulting in study termination.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Andrew Marsh, Head Clinical Operations
Organization: Synlogic
Phone: 617-401-9975 ext 9135
EMail: andrew.marsh@synlogictx.com
Layout table for additonal information
Responsible Party: Synlogic
ClinicalTrials.gov Identifier: NCT03447730    
Other Study ID Numbers: SYNB1020-CP-002
First Submitted: February 16, 2018
First Posted: February 27, 2018
Results First Submitted: August 19, 2020
Results First Posted: October 14, 2020
Last Update Posted: May 13, 2021