Cirrhosis
Conditions
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.
Interventions
DRUGSYNB1020
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.
OTHERPlacebo
Subjects received placebo orally in a chilled buffered solution (100 mL).
Sponsors
Synlogic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Part 1 was open-label; Part 2 was double-blinded
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 CFU TID given immediately after meals from Days 1 through 6. | 6 |
| 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. | 9 |
| 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. | 8 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Part 1: SYNB1020 | Total | Part 2: Placebo | Part 2: SYNB1020 |
|---|---|---|---|---|
| Age, Continuous | 54.5 years | 58.0 years | 59.5 years | 57.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 13 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 10 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 23 Participants | 8 Participants | 9 Participants |
| Region of Enrollment United States | 6 participants | 23 participants | 8 participants | 9 participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 16 Participants | 7 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 9 | 0 / 8 |
| other Total, other adverse events | 4 / 6 | 8 / 9 | 3 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 9 | 1 / 8 |
Outcome results
Primary
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
Population: All subjects who received at least 1 dose of SYNB1020 or placebo
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Any TEAE | 4 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 1 | 3 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 2 | 1 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 3 | 0 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related TEAE | 2 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | TEAE leading to discontinuation | 0 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related TEAE leading to discontinuation | 0 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related Serious TEAE | 0 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | TEAE leading to death | 0 participants |
| Part 1: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Serious TEAE | 0 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 3 | 0 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | TEAE leading to death | 0 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related TEAE | 4 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | TEAE leading to discontinuation | 2 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 1 | 3 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Serious TEAE | 0 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related TEAE leading to discontinuation | 0 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Any TEAE | 8 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related Serious TEAE | 0 participants |
| Part 2: SYNB1020 | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 2 | 5 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 3 | 1 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 2 | 2 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | Any TEAE | 4 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related TEAE | 0 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | TEAE leading to death | 0 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related TEAE leading to discontinuation | 0 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | TEAE leading to discontinuation | 0 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | Maximum TEAE severity Grade 1 | 1 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | Treatment-related Serious TEAE | 0 participants |
| Part 2: Placebo | Number of Participants With Treatment-Emergent Adverse Events | Serious TEAE | 1 participants |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: SYNB1020 | Daily Fasting Spot Venous Ammonia | Baseline | 64.7 μmol/L | Standard Deviation 25 |
| Part 1: SYNB1020 | Daily Fasting Spot Venous Ammonia | End of Study/Day 7 | 62.3 μmol/L | Standard Deviation 27.57 |
| Part 2: SYNB1020 | Daily Fasting Spot Venous Ammonia | Baseline | 82.0 μmol/L | Standard Deviation 36.41 |
| Part 2: SYNB1020 | Daily Fasting Spot Venous Ammonia | End of Study/Day 7 | 97.7 μmol/L | Standard Deviation 58.79 |
| Part 2: Placebo | Daily Fasting Spot Venous Ammonia | Baseline | 55.6 μmol/L | Standard Deviation 18.18 |
| Part 2: Placebo | Daily Fasting Spot Venous Ammonia | End of Study/Day 7 | 67.9 μmol/L | Standard Deviation 42.69 |
Secondary
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
Population: All subjects who received at least 1 dose of SYNB1020 or placebo
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: SYNB1020 | Number of Participants With Clearance of SYNB1020 From Feces | Cleared by 25 days after last dose | 6 Participants |
| Part 1: SYNB1020 | Number of Participants With Clearance of SYNB1020 From Feces | SYNB1020 presence not detected | 0 Participants |
| Part 2: SYNB1020 | Number of Participants With Clearance of SYNB1020 From Feces | Cleared by 25 days after last dose | 9 Participants |
| Part 2: SYNB1020 | Number of Participants With Clearance of SYNB1020 From Feces | SYNB1020 presence not detected | 0 Participants |
| Part 2: Placebo | Number of Participants With Clearance of SYNB1020 From Feces | SYNB1020 presence not detected | 8 Participants |
| Part 2: Placebo | Number of Participants With Clearance of SYNB1020 From Feces | Cleared by 25 days after last dose | 0 Participants |