Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia

Phase 2

Completed

Conditions: Methylmalonic Acidemia
Propionic Acidemia, Type I and/or Type II
Carbamoyl-Phosphate Synthase I Deficiency Disease
Ornithine Carbamoyltransferase Deficiency

Interventions: Drug: Carbaglu
Drug: Placebo

Registration Number: NCT01599286

Lead Sponsor: Mendel Tuchman

Brief Summary: The overall objective of this drug trial is to determine whether the treatment of acute hyperammonemia with N-carbamyl-L-glutamate (NCG, Carglumic acid) in propionic acidemia (PA), methylmalonic acidemia (MMA), late-onset CPS1 deficiency (CPSD) and late-onset Ornithine transcarbamylase deficiency (OTCD) accelerates the resolution of hyperammonemia efficiently and safely.

The primary goal is to determine if the study drug (NCG) efficiently reduces ammonia levels following a hyperammonemia episode(s).

Secondly, the investigators want to know if treatment with this study drug (NCG) efficiently improves neurologic function, reduces plasma glutamine levels and lessens the duration of hospitalization after each episode of hyperammonemia.

Detailed Description: This is a double-blind, placebo-controlled, randomized clinical drug trial to evaluate the efficacy of NCG in the treatment of two organic acidemias (severe PA and MMA), and two urea-cycle disorders (late-onset CPSD and OTCD).

Primarily, the investigators want to determine whether NCG treatment of acute hyperammonemia in severe, neonatal-onset PA, MMA, CPSD, and OTCD is efficacious and whether it is safe. The investigators will approach this task in two ways.

1. Assess Whether NCG Treatment is Effective

The objective of this study is to assess whether NCG is efficacious in treating hyperammonemia and improving outcome:

The investigators will realize this goal by randomizing each hyperammonemic episode from every subject to NCG (NCG)+standard treatment (NCG-STD) versus placebo+standard treatment (PLBO-STD) and subsequently gauging response with the primary outcome of plasma ammonia levels, in addition to the plasma glutamine, the Functional Status Scale, and the length of hospitalization.

2. Safety

The primary safety outcome of the study will be the assessed via the rate of Serious Adverse Events (SAEs), defined in this study as death or substantial prolongation of hospitalization, as patients are hospitalized as part of the entry to the study.

Safety tests consisting of complete blood count (CBC), liver and kidney function tests, and coagulation profile (PTT/INR) will be performed before treatment, between days 3-5 of treatment, and just prior to discontinuation of NCG. An electrocardiogram will be performed before treatment and on the third day of treatment or before discharge if earlier.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active Comparator	Carbaglu	Parallel Trial Comparing NCG + Standard of Care Treatment
Placebo Comparator	Placebo	Placebo and Standard of Care Therapy

Primary Outcome Measures

Name	Time	Method
Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge)	Average of all measurements of hyperammonemia, for up to 7 days	The composite primary intention to treat (ITT) outcome of the earlier of time to reach an ammonia level of ≤50 µmol/L or hospital discharge. Data presented as a hazard ratio based on the time to reach an ammonia level of ≤50 µmol/L. The outcome measure was a survival analysis based on time to reach the earlier of an ammonia level of ≤50 µmol/L or time to discharge, which was considered to be a point where the patient was no longer at risk of neurological injury from ammonia. The outcome of survival analysis was a hazard ratio reflecting the ratio of probabilities in each group (drug vs placebo) of reaching the earlier of an ammonia level of ≤50 µmol/L or discharge. We measured multiple post-treatment ammonia levels at uncontrolled times during an episode, so it is difficult to compute a meaningful average that would not be biased by the frequency and timing of ammonia testing during episodes.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (9): Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
The Children's Hospital of Colorado
🇺🇸
Aurora, Colorado, United States
Children's Hospital Boston
🇺🇸
Boston, Massachusetts, United States
University of California Los Angeles
🇺🇸
Los Angeles, California, United States
Lucile Packard Children's Hospital at Stanford
🇺🇸
Palo Alto, California, United States
University Hospitals Cleveland Medical Center
🇺🇸
Cleveland, Ohio, United States
Mount Sinai School of Medicine
🇺🇸
New York, New York, United States
The Children's Hospital of Philadelphia (CHOP)
🇺🇸
Philadelphia, Pennsylvania, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States