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

Marwan Nashabat,Mohammed Elamin,Abdulrahman Alswaid,Mohammed Saleh,Hind Ahmed,Faroug Ababneh,Abdulrahman Obaid,Lina Alohali,Majed Aljeraisy,Fuad Al Mutairi,Mohamed A Hussein,Wafaa Eyaid,Ali Alasmari,Eissa Faqeih,Majid Alfadhel

doi:10.1186/s12887-019-1571-y

Abstract

IntroductionPropionic 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.MethodsThis 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.DiscussionCurrent 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 registrationKing 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.

Highlights

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
Since PA and MMA are rare debilitating inborn errors of metabolism that may have life-threatening consequences, early diagnosis, and management of these organic acidemias (OA) is of utmost importance
Guidelines on acute management of hyperammonemia in the middle east region recommend the use of nitrogen scavengers, carnitine, in cases where the plasma ammonia levels are > 100 μmol/L (> 150 μmol/L in neonates), and continuous renal replacement therapy for ammonia levels > 500 μmol/L

Summary

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. Propionic acidemia (PA; #606054 in the Online Mendelian Inheritance in Man [OMIM] database) and methylmalonic acidemia (MMA; OMIM #251000) are autosomal recessive inherited inborn errors of metabolism. These organic acidemias (OA) are characterized by recurrent episodes of hyperammonemic encephalopathy, which may be partially responsible for the cognitive delay seen in the majority of affected patients [1, 2]. Acyl CoA that has accumulated due to dysfunction of propionyl CoA carboxylase/methylmalonyl-CoA mutase inhibits the activity of N-acetylglutamate synthase (NAGS) resulting in a decrease in the production of N-acetylglutamate (NAG), a product of this enzyme. High levels of ammonia are a real emergency and should be treated promptly [6]

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