A Phase 2 interventional study of Carbaglu and Placebo in Propionic Acidemia, Type I and/or Type II, Methylmalonic Acidemia and Carbamoyl-Phosphate Synthase I Deficiency Disease, sponsored by Mendel Tuchman. Completed at 9 sites in United States. Open to participants aged 1 Week to 99 Years. Per ClinicalTrials.gov, last updated 2021-02-15.
Sponsored by Mendel Tuchman · Phase 2, Interventional, and Treatment
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.
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.
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.
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.
o Aged older than 1 week with an established diagnosis of CPSD or OTCD (as follows):
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):
OR
AND: Subject or subject's first-degree relative had plasma ammonia level at any time ≥100 μmol/L
Exclusion Criteria
Parallel Trial Comparing NCG + Standard of Care Treatment
Drug: Carbaglu
Placebo and Standard of Care Therapy
Drug: Placebo
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.
Also known as: Carglumic Acid
Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention
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.
Time frame: Average of all measurements of hyperammonemia, for up to 7 days
| Milestone | Episodes of N-Carbamylglutamate | Episodes of Placebo |
|---|---|---|
| Started | 24 | 23 |
| Completed | 24 | 23 |
| Not completed | 0 | 0 |
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.
| Hazard Ratio | PA/MMA Episodes | CPS1D/OTCD Episodes |
|---|---|---|
| Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge) | 1.37 (0.88 to 2.13) | 0.79 (0.22 to 2.81) |
Collected over During each hospitalization, once per day, up to 7 days.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 10/24 (41.7%) | 6/24 (25%) | 9/24 (37.5%) |
| N-carbamylglutamate (NCG) | 14/25 (56%) | 8/25 (32%) | 11/25 (44%) |
| Event | Placebo | N-carbamylglutamate (NCG) |
|---|---|---|
| Gastrointestinal DisordersGastrointestinal disorders | 4/24 | 5/25 |
| Infections and InfestationsInfections and infestations | 2/24 | 4/25 |
| Nervous SystemNervous system disorders | 0/24 | 3/25 |
| InjuryInjury, poisoning and procedural complications | 1/24 | 1/25 |
| Metabolic and NutritionalMetabolism and nutrition disorders | 1/24 | 1/25 |
| RespiratoryRespiratory, thoracic and mediastinal disorders | 0/24 | 1/25 |
| Event | Placebo | N-carbamylglutamate (NCG) |
|---|---|---|
| MetabolismMetabolism and nutrition disorders | 4/24 | 6/25 |
| GastrointestinalGastrointestinal disorders | 4/24 | 4/25 |
| Blood/LymphaticBlood and lymphatic system disorders | 3/24 | 4/25 |
| Nervous SystemNervous system disorders | 2/24 | 4/25 |
| GeneralGeneral disorders | 3/24 | 1/25 |
| InfectionsInfections and infestations | 3/24 | 1/25 |
| InvestigationsInvestigations | 0/24 | 3/25 |
| CardiacCardiac disorders | 1/24 | 1/25 |
| Injury/Procedure ComplicationsInjury, poisoning and procedural complications | 1/24 | 1/25 |
| Product IssuesProduct Issues | 1/24 | 0/25 |
65 participants were eligible based on diagnosis. There were 35 individual participants enrolled due to a hyperammonemia episode. 24 individuals had episodes where they were randomized to the NCG arm, and 23 had episodes where they were randomized to the placebo arm. 13 participants had multiple randomizations to both arms throughout the study, while 22 participants only had a single randomization to either placebo of NCG. 35 unique participants were randomized providing 106 randomized episodes.
| Age, Customized(Episodes) | Episodes of N-carbamylglutamate (NCG) | Episodes of Placebo | Total |
|---|---|---|---|
| 0 - <5 years | 10 | 16 | 26 |
| 5 - <12 years | 27 | 22 | 49 |
| 12 - <18 years | 1 | 4 | 5 |
| 18+ years | 14 | 12 | 26 |
| Sex: Female, Male(Episodes) | Episodes of N-carbamylglutamate (NCG) | Episodes of Placebo | Total |
|---|---|---|---|
| Female | 33 | 34 | 67 |
| Male | 19 | 20 | 39 |
| Ethnicity (NIH/OMB)(Episodes) | Episodes of N-carbamylglutamate (NCG) | Episodes of Placebo | Total |
|---|---|---|---|
| Hispanic or Latino | 13 | 17 | 30 |
| Not Hispanic or Latino | 39 | 36 | 75 |
| Unknown or Not Reported | 0 | 1 | 1 |
| Race (NIH/OMB)(Episodes) | Episodes of N-carbamylglutamate (NCG) | Episodes of Placebo | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 21 | 19 | 40 |
| Native Hawaiian or Other Pacific Islander | 0 | 1 | 1 |
| Black or African American | 11 | 11 | 22 |
| White | 17 | 19 | 36 |
| More than one race | 2 | 3 | 5 |
| Unknown or Not Reported | 1 | 1 | 2 |
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Ornithine Carbamoyltransferase Deficiency Disease→