A Study to Assess Plasma Ammonia Time-Normalized Area Under the Curve and Rate of Ureagenesis in Healthy Adult Subjects

Study Overview
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Brief Summary
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The objective of the study is to characterize 24-hour plasma ammonia levels, characterize urea production rates in healthy normal subjects.

Detailed Description
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During Part 1, eligible subjects will be asked to participate in 3 inpatient visits, each lasting up to 3 days (Day -1 to Day 2). Each visit will assess 24-hour ammonia levels in plasma and rate of urea production for 4 hours following ingestion of [1-13C]sodium acetate. Sodium acetate is used as a tracer to measure the rate of ureagenesis. During Part 2, eligible subjects will be asked to participate in 1 inpatient visit, lasting up to 3 days (Day -1 to Day 2). The visit will assess 24-hour ammonia levels in plasma and rate of urea production for 4 hours following ingestion of [1-13C]sodium acetate. Sodium acetate is used as a tracer to measure the rate of ureagenesis.

Official Title
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A Single-Center Study to Assess Plasma Ammonia Time-Normalized Area Under the Curve From Time Zero to 24 Hours and Rate of Ureagenesis in Healthy Adult Subjects

Conditions
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Ornithine Transcarbamylase Deficiency

Intervention / Treatment
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* Other: No Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index between 18 and 30 kg/m2, inclusive. Exclusion Criteria: History of liver disease as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage 3 fibrosis. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than the upper limit of normal (ULN), total bilirubin >1.5 × ULN, alkaline phosphatase >2.5 × ULN. NOTE: the ALT and/or AST levels may be repeated. Subject has a history of gout. Plasma ammonia level that is not within normal limits at Screening in the opinion of the Investigator or Sponsor. Received any vaccine within 14 days prior to Screening. Pregnant, lactating, or intending to become pregnant at any time during the study. Blood transfusion within 8 weeks prior to Screening.diuretics, cyclophosphamide and other cytotoxic agents, tolbutamide, chlorpropamide, diazoxide, dichlorphenamide, pyrazinamide, probenecid, theophylline/aminophylline, riluzole, warfarin and other antithrombotic agents, supplements containing aluminum hydroxide, or iron supplements within 30 days of Part 1or Part 2.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Part 1<br>30 eligible subjects will be asked to participate in 3 inpatient visits, each lasting up to 3 days (Day -1 to Day 2). Each visit will assess 24-hour ammonia levels in plasma and rate of urea production for 4 hours following ingestion of [1-13C]sodium acetate. Sodium acetate is used as a tracer to measure the rate of ureagenesis. | Other: No Intervention<br>* No intervention<br>|
| Part 2<br>90 eligible subjects will be asked to participate in 1 inpatient visit, each lasting up to 3 days (Day -1 to Day 2). Each visit will assess 24-hour ammonia levels in plasma and rate of urea production for 4 hours following ingestion of [1-13C]sodium acetate. Sodium acetate is used as a tracer to measure the rate of ureagenesis. | Other: No Intervention<br>* No intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Ammonia Area Under the Curve (AUC0-24) | Characterization of ammonia production over 24hr | Part 1, Day 1 (Visits 1-3) and Part 2, Day 1:Predose (0hour) up to 24 hours post dose | 
| Rate of Ureagenesis Based On Presence of [1-13C] In Urea | Characterization of nitrogen flux as determined by production of urea. Sodium acetate is used as a tracer to measure the rate of ureagenesis. | Part 1, Day 1 (Visits 1-3) and Part 2, Day 1: Predose (0hour) up to 4 hours post dose | 
| Intra- and inter-subject coefficient of variation (CV) of AUC0-24 and Rate of Ureagenesis | Comparative analysis of both parameters | Part 1 Treatment Period: 17 days; Part 2 Treatment Period: 3 days |