A Phase 1/2 interventional study of SYNB1020 and Placebo in Cirrhosis, sponsored by Synlogic. Terminated at 5 sites in United States. Open to participants aged 18 Years to 74 Years. Per ClinicalTrials.gov, last updated 2021-05-13.
Sponsored by Synlogic · Phase 1/2, Interventional, and Treatment
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.
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.
Key Inclusion Criteria:
Key Exclusion Criteria:
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
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
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
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.
Subjects received placebo orally in a chilled buffered solution (100 mL).
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.
Time frame: Up to 70 days
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.
Time frame: Up to 65 days
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).
Time frame: Up to 9 days
| Milestone | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo |
|---|---|---|---|
| Started | 6 | 9 | 8 |
| Completed | 6 | 7 | 8 |
| Not completed | 0 | 2 | 0 |
| Withdrew: Adverse event | 0 | 2 | 0 |
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.
| participants | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo |
|---|---|---|---|
| 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 |
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.
| Participants | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo |
|---|---|---|---|
| Cleared by 25 days after last dose | 6 | 9 | 0 |
| SYNB1020 presence not detected | 0 | 0 | 8 |
Fasting spot venous ammonia was collected at baseline (Day -2) and at the time of discharge from the inpatient unit (Day 7).
| μmol/L | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo |
|---|---|---|---|
| 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 |
Collected over 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).. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part 1: SYNB1020 | 0/6 (0%) | 0/6 (0%) | 4/6 (66.7%) |
| Part 2: SYNB1020 | 0/9 (0%) | 0/9 (0%) | 8/9 (88.9%) |
| Part 2: Placebo | 0/8 (0%) | 1/8 (12.5%) | 3/8 (37.5%) |
| Event | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo |
|---|---|---|---|
| Oesophageal varices haemorrhageGastrointestinal disorders | 0/6 | 0/9 | 1/8 |
| Event | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo |
|---|---|---|---|
| VomitingGastrointestinal disorders | 3/6 | 3/9 | 0/8 |
| ConstipationGastrointestinal disorders | 2/6 | 4/9 | 0/8 |
| NauseaGastrointestinal disorders | 2/6 | 4/9 | 0/8 |
| DiarrhoeaGastrointestinal disorders | 1/6 | 2/9 | 1/8 |
| DizzinessNervous system disorders | 1/6 | 2/9 | 0/8 |
| HeadacheNervous system disorders | 1/6 | 2/9 | 0/8 |
| Hepatic encephalopathyNervous system disorders | 0/6 | 2/9 | 0/8 |
| DehydrationMetabolism and nutrition disorders | 0/6 | 2/9 | 0/8 |
| Upper respiratory tract infectionInfections and infestations | 1/6 | 0/9 | 0/8 |
| InsomniaPsychiatric disorders | 1/6 | 0/9 | 0/8 |
All subjects who received at least 1 dose of study treatment
| Age, Continuous(years) | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo | Total |
|---|---|---|---|---|
| Median | 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(Participants) | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo | Total |
|---|---|---|---|---|
| Female | 2 | 4 | 1 | 7 |
| Male | 4 | 5 | 7 | 16 |
| Ethnicity (NIH/OMB)(Participants) | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo | Total |
|---|---|---|---|---|
| Hispanic or Latino | 3 | 4 | 6 | 13 |
| Not Hispanic or Latino | 3 | 5 | 2 | 10 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 |
| White | 6 | 9 | 8 | 23 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Region of Enrollment(participants) | Part 1: SYNB1020 | Part 2: SYNB1020 | Part 2: Placebo | Total |
|---|---|---|---|---|
| United States | 6 | 9 | 8 | 23 |
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