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Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.

ABSTRACT: INTRODUCTION:Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive inborn errors of metabolism characterized by hyperammonemia due to N-acetylglutamate synthase (NAGS) dysfunction. Carglumic acid (Carbaglu®; Orphan Europe Ltd.) is approved by the US Food and Drug Administration (USFDA) for the treatment of hyperammonemia due hepatic NAGS deficiency. Here we report the rationale and design of a phase IIIb trial that is aimed at determining the long-term efficacy and safety of carglumic acid in the management of PA and MMA. METHODS:This prospective, multicenter, open-label, randomized, parallel group phase IIIb study will be conducted in Saudi Arabia. Patients with PA or MMA (?15?years of age) will be randomized 1:1 to receive twice daily carglumic acid (50?mg/kg/day) plus standard therapy (protein-restricted diet, L-carnitine, and metronidazole) or standard therapy alone for a 2-year treatment period. The primary efficacy outcome is the number of emergency room visits due to hyperammonemia. Safety will be assessed throughout the study and during the 1?month follow-up period after the study. DISCUSSION:Current guidelines recommend conservative medical treatment as the main strategy for the management of PA and MMA. Although retrospective studies have suggested that long-term carglumic acid may be beneficial in the management of PA and MMA, current literature lacks evidence for this indication. This clinical trial will determine the long-term safety and efficacy of carglumic acid in the management of PA and MMA. TRIAL REGISTRATION:King Abdullah International Medical Research Center ( KAIMRC ): (RC13/116) 09/1/2014. Saudi Food and Drug Authority (SFDA) (33066) 08/14/2014. ClinicalTrials.gov (identifier: NCT02426775) 04/22/2015.

SUBMITTER: Nashabat M

PROVIDER: S-EPMC6563377 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.

Nashabat Marwan M Obaid Abdulrahman A Al Mutairi Fuad F Saleh Mohammed M Elamin Mohammed M Ahmed Hind H Ababneh Faroug F Eyaid Wafaa W Alswaid Abdulrahman A Alohali Lina L Faqeih Eissa E Aljeraisy Majed M Hussein Mohamed A MA Alasmari Ali A Alfadhel Majid M

BMC pediatrics 20190613 1

<h4>Introduction</h4>Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive inborn errors of metabolism characterized by hyperammonemia due to N-acetylglutamate synthase (NAGS) dysfunction. Carglumic acid (Carbaglu®; Orphan Europe Ltd.) is approved by the US Food and Drug Administration (USFDA) for the treatment of hyperammonemia due hepatic NAGS deficiency. Here we report the rationale and design of a phase IIIb trial that is aimed at determining the long-term eff ...[more]

PMID: 31196016

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Project description:IntroductionThis pilot study assessed instruments measuring relatively discrete neuropsychological domains to inform the selection of clinical outcome assessments that may be considered for interventional trials in methylmalonic acidemia (MMA) and propionic acidemia (PA).MethodsTests and questionnaires were selected for their possible relevance to MMA and PA and potential sensitivity to modest changes in functioning and behavior.ResultsTwenty-one patients (<18 years, n = 10;>18 years, n = 11) and/or their caregivers responded to video interviews and paper tests. Language deficits and significant motor deficits in some participants impacted scoring, especially in the verbal and processing speed sections of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) and the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV). However, all participants ≥12 years of age were able to complete the Cookie Theft Picture Task. Thus, verbal discourse remains a potentially useful endpoint for participants in this age group. The Vineland Adaptive Behavior Scales (VABS-3) Adaptive Behavior Composite and Communication Scores confirmed delayed or immature functioning in day-to-day activities in these participants. Significant motor deficits prevented completion of some tests. Computerized processing speed tasks, which require pressing a button or tapping a computer screen, may be easier than writing or checking off boxes on paper in this cohort. Sleep characteristics among MMA participants were within normative ranges of the Child and Adolescent Sleep Checklist (CASC), indicating that this measurement would not provide valuable data in a clinical trial. Despite their challenges, responses to the Metabolic Quality of Life Questionnaire indicated these patients and their caregivers perceive an overall high quality of life.ConclusionOverall, test and questionnaire results were notably different between participants with MMA and participants with PA. The study demonstrates that pilot studies can detect instruments that may not be appropriate for individuals with language or motor deficits and that may not provide a broad range of scores reflecting disease severity. It also provides a rationale for focusing on discrete neuropsychological domains since some aspects of functioning were less affected than others and some were more closely related to disease severity. When global measures are used, overall scores may mask specific deficits. A pilot study like this one cannot ensure that scores will change over time in response to a specific treatment in a clinical trial. However, it can avert the selection of instruments that do not show associations with severity or biomedical parameters likely to be the target of a clinical trial. A pilot study can also identify when differences in diagnoses and baseline functioning need to be addressed prior to developing the analytical plan for the trial.

Dataset Information

Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.

Publications

Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.

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