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

Methylmalonic Acidemia Clinical Trial

— STO  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01599286
• Other study ID #: NCGC0008
• Status: Completed
• Phase: Phase 2
• Start date: September 1, 2012
• Est. completion date: April 30, 2020

Study information

• Verified date: January 2021
• Source: Children's National Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: April 30, 2020
• Est. primary completion date: April 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 99 Years

Eligibility

Inclusion Criteria

o Aged older than 1 week with an established diagnosis of CPSD or OTCD (as follows):

• Diagnosed with late-onset CPSD confirmed by detection of pathogenic mutation(s), and/or decreased (<20% of control) CPS enzyme activity in liver OR

• Diagnosed with late-onset OTCD by detection of pathogenic OTC mutation, OR decreased (<20% of control) OTC enzyme activity in liver OR elevated urinary orotate (greater than 20 µM/mM) following allopurinol loading with the absence of argininosuccinic acid

AND: Subject or subject's first-degree relative had plasma ammonia level =100 µmol/L >1 week of age

OR

o An established diagnosis of PA or MMA (as follows):

• Diagnosed with PA by semi-quantitative urine organic acid analysis, defined as the presence of elevated Methylcitric acid and normal methylmalonic acid levels and no evidence of biotin related disorders in the organic acid analysis

OR

• Diagnosed with MMA by semi-quantitative urine organic acid analysis, defined as an elevation of methylmalonic acid and no evidence of vitamin B12 dependent disorder on plasma amino acid analysis (B12 dependency is defined by documented B12 responsiveness)

AND: Subject or subject's first-degree relative had plasma ammonia level at any time =100 µmol/L

• Able to receive medications orally, by nasogastric (NG)-tube or by gastric (G)-tube

• No concomitant illness which would preclude safe participation as judged by the investigator

• If post-menarcheal must have a negative pregnancy test prior to administration of study drug at each episode

• Signed informed consent by the subject or the subject's legally acceptable representative

Exclusion Criteria

• Administration of NCG within 7 days of participation in the study

• Use of any other investigational drug, biologic, or therapy

• Planned participation in any other clinical trial

• Diagnosis of any medical condition causing hyperammonemia which is not PA/MMA, CPSD or OTCD. Other urea cycle disorders will be excluded from this study

• Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at additional risk by participating in this study

• Has had a liver transplant

• Is not expected to be compliant with this study in terms of returning to the site for subsequent episodes of hyperammonemia crises

• Is pregnant

Related Conditions & MeSH terms

• Acidosis
• Carbamoyl-Phosphate Synthase I Deficiency Disease
• Deficiency Diseases
• Hyperammonemia
• Methylmalonic Acidemia
• Ornithine Carbamoyltransferase Deficiency
• Propionic Acidemia
• Propionic Acidemia, Type I and/or Type II

Intervention

Drug:
• Carbaglu
Carbaglu Chemical Composition: N-carbamoyl-L-glutamic acid (NCG) The daily dose will be 150 mg/kg/ day or 3.3 g/m2/day for patients >15 kg and will be administered for 7 days or until discharge, whichever is sooner. The doses are to be divided into 2 equal doses and administered orally or enterally by nasogastric or gastrostomy tube. Standard of care will prevail when choosing the mode of drug administration. The tablets must be dispersed in a minimum of 2.5-10 ml of water and ingested immediately or administered by fast-push through a syringe via a nasogastric or gastrostomy tube. The suspension has a slightly acidic taste.
• Placebo
Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention

Locations

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

Sponsors (10)

Lead Sponsor	Collaborator
Mendel Tuchman	Boston Children's Hospital, Children's Hospital Colorado, Children's Hospital of Philadelphia, Children's National Research Institute, Icahn School of Medicine at Mount Sinai, Stanford University, University Hospitals Cleveland Medical Center, University of California, Los Angeles, University of Pittsburgh

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge)	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.	Average of all measurements of hyperammonemia, for up to 7 days