Carbamoyl-Phosphate Synthase I Deficiency Disease, Methylmalonic Acidemia, Ornithine Carbamoyltransferase Deficiency, Propionic Acidemia, Type I and/or Type II
Conditions
Keywords
Hyperammonemia, Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), Late-Onset CPS1 Deficiency (CPSD), Late-Onset Ornithine Transcarbamylase Deficiency (OTCD), Carbaglu
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.
Interventions
DRUGCarbaglu
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.
DRUGPlacebo
Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention
Sponsors
Children's National Research Institute
Boston Children's Hospital
University Hospitals Cleveland Medical Center
University of California, Los Angeles
Children's Hospital of Philadelphia
Stanford University
Icahn School of Medicine at Mount Sinai
University of Pittsburgh
Children's Hospital Colorado
Mendel Tuchman
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Weeks to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
There were 65 eligible patients, 35 were enrolled with a randomization of hyperammonemia. Eligible patients were randomized at each episode of hyperammonemia. To be enrolled, a patient had to have an eligible episode of hyperammonemia and was then randomized to either placebo or NCG at each randomization. 13 patients had multiple randomizations, 22 only had one.
Participants by arm
| Arm | Count |
|---|---|
| Episodes of N-carbamylglutamate (NCG) Total number of episodes of hyperammonemia where a patient was randomized to the NCG arm
A daily dose of 150 mg/kg/ day or 3.3 g/m2/day for patients \>15 kg administered for 7 days or until discharge, whichever is sooner. | 24 |
| Episodes of N-carbamylglutamate (NCG) Total number of episodes of hyperammonemia where a patient was randomized to the NCG arm
A daily dose of 150 mg/kg/ day or 3.3 g/m2/day for patients \>15 kg administered for 7 days or until discharge, whichever is sooner. | 52 |
| Episodes of Placebo Total number of episodes of hyperammonemia where a patient was randomized to the placebo arm
Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention | 23 |
| Episodes of Placebo Total number of episodes of hyperammonemia where a patient was randomized to the placebo arm
Placebo that looks/tastes the same as NCG and is administered on the same schedule as the NCG intervention | 54 |
| Total | 153 |
Baseline characteristics
| Characteristic | Episodes of N-carbamylglutamate (NCG) | Episodes of Placebo | Total |
|---|---|---|---|
| Age, Customized 0 - <5 years | 10 Episodes | 16 Episodes | 26 Episodes |
| Age, Customized 12 - <18 years | 1 Episodes | 4 Episodes | 5 Episodes |
| Age, Customized 18+ years | 14 Episodes | 12 Episodes | 26 Episodes |
| Age, Customized 5 - <12 years | 27 Episodes | 22 Episodes | 49 Episodes |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Episodes | 17 Episodes | 30 Episodes |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Episodes | 36 Episodes | 75 Episodes |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Episodes | 1 Episodes | 1 Episodes |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Episodes | 0 Episodes | 0 Episodes |
| Race (NIH/OMB) Asian | 21 Episodes | 19 Episodes | 40 Episodes |
| Race (NIH/OMB) Black or African American | 11 Episodes | 11 Episodes | 22 Episodes |
| Race (NIH/OMB) More than one race | 2 Episodes | 3 Episodes | 5 Episodes |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Episodes | 1 Episodes | 1 Episodes |
| Race (NIH/OMB) Unknown or Not Reported | 1 Episodes | 1 Episodes | 2 Episodes |
| Race (NIH/OMB) White | 17 Episodes | 19 Episodes | 36 Episodes |
| Sex: Female, Male Female | 33 Episodes | 34 Episodes | 67 Episodes |
| Sex: Female, Male Male | 19 Episodes | 20 Episodes | 39 Episodes |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 24 | 14 / 25 |
| other Total, other adverse events | 9 / 24 | 11 / 25 |
| serious Total, serious adverse events | 6 / 24 | 8 / 25 |
Outcome results
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.
Time frame: Average of all measurements of hyperammonemia, for up to 7 days
Population: Patients were randomized to either study drug or placebo at each episode of hyperammonemia analysed by diagnosis. Data presented as a hazard ratio based on the time to reach an ammonia level of ≤50 µmol/L. Higher ratios reflect an NCG advantage.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PA/MMA Episodes | Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge) | 1.37 Hazard Ratio |
| CPS1D/OTCD Episodes | Time to the Primary Outcome (Earlier of Ammonia <50 µmol/L or Hospital Discharge) | 0.79 Hazard Ratio |