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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

Tracking Information
First Submitted Date  ICMJE February 16, 2018
First Posted Date  ICMJE February 27, 2018
Results First Submitted Date  ICMJE August 19, 2020
Results First Posted Date  ICMJE October 14, 2020
Last Update Posted Date May 13, 2021
Actual Study Start Date  ICMJE March 19, 2018
Actual Primary Completion Date July 19, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 18, 2020)
Number of Participants With Treatment-Emergent Adverse Events [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 26, 2018)
Incidence of Treatment-Emergent Adverse Events [ Time Frame: 80 days from study entry ]
Will be measured by assessing nature and frequency of AEs
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 18, 2020)
  • Number of Participants With Clearance of SYNB1020 From Feces [ Time Frame: 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 [ Time Frame: 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).
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability and Pharmacodynamics of SYNB1020
Official Title  ICMJE A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacodynamics of SYNB1020 in Hepatic Insufficiency and Cirrhosis Patients
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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
Condition  ICMJE Cirrhosis
Intervention  ICMJE
  • 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.
  • Other: Placebo
    Subjects received placebo orally in a chilled buffered solution (100 mL).
Study Arms  ICMJE
  • 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.
    Intervention: Drug: SYNB1020
  • 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.
    Intervention: Drug: SYNB1020
  • 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.
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: August 23, 2019)
23
Original Estimated Enrollment  ICMJE
 (submitted: February 26, 2018)
46
Actual Study Completion Date  ICMJE July 19, 2019
Actual Primary Completion Date July 19, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 74 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03447730
Other Study ID Numbers  ICMJE SYNB1020-CP-002
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Synlogic
Study Sponsor  ICMJE Synlogic
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Synlogic
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP