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

Study protocol Open Access Open Peer Review 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 Nashabat1, Abdulrahman Obaid1, Fuad Al Mutairi1, Mohammed Saleh2, Mohammed Elamin2, Hind Ahmed1, Faroug Ababneh1, Wafaa Eyaid1, Abdulrahman Alswaid1, Lina Alohali1, Eissa Faqeih2, Majed Aljeraisy3, Mohamed A. Hussein4, Ali Alasmari2 and Majid Alfadhel1Email authorView ORCID ID profile BMC Pediatrics201919:195 https://doi.org/10.1186/s12887-019-1571-y ©  The Author(s). 2019 Received: 12 July 2018Accepted: 4 June 2019Published: 13 June 2019 Open Peer Review reports 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. Keywords Carbaglu®Carglumic acidHyperammonemiaMethylmalonic acidemiaPropionic acidemia Background 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]. Death can occur quickly in this population mainly owing to secondary hyperammonemia, infections, cardiomyopathy or basal ganglia stroke [3]. From an epidemiological standpoint, both OAs are very rare diseases. However, PA appears to be more common in Saudi Arabia (estimated frequency of about 1 in 3000) than in other parts of the world (1 in 100,000) [4]. The main mechanism of hyperammonemia in PA and MMA is related to the effect of acyl CoA esters on the urea cycle. Briefly, 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. NAG is an activator of carbamoyl phosphate synthetase (CPS), and the lack of NAG results in decreased CPS activity causing hyperammonemia [5]. High concentrations of ammonia may partially saturate the “enzymatic detoxifier” of the astrocytes, impeding the brain’s capacity for self-protection and contributing to neurological dysfunction. Therefore, high levels of ammonia are a real emergency and should be treated promptly [6]. N-carbamylglutamate or carglumic acid (Carbaglu®; Orphan Europe Ltd.) is a synthetic analog of NAG that activates carbamoyl-phosphate synthetase I (CPS-I), an enzyme involved in the first and rate-limiting step of the urea cycle [7]. It is approved by the US Food and Drug Administration (USFDA) for acute and chronic treatment of hyperammonemia due to the deficiency of hepatic NAGS [8]. However, there is no current evidence supporting the use of carglumic acid for chronic management of PA and MMA. Here, we report the design and rationale of a randomized, multicenter, prospective phase IIIb study which aims primarily to compare the long-term efficacy and safety of carglumic acid (50 mg/kg/day) plus standard therapy with standard therapy alone, in decreasing the number of emergency room (ER) visits due to hyperammonemia in patients with PA and MMA. Methods Study aim, design and setting The main aim of the study is to evaluate whether the long-term use of carglumic acid can reduce the frequency of metabolic decompensations and ER visits of PA and MMA patients due to hyperammonemia. This prospective, multicenter, open-label, randomized, parallel group phase IIIb study will be conducted at two centers in Riyadh, Saudi Arabia, (King Abdulaziz Medical City and King Fahad Medical City) and may be extended regionally and/or internationally. The study will be conducted over a 2-year period followed by a 1-month follow-up period. Since PA and MMA are rare disorders, a multicenter design has been chosen for the study in order to allow for better recruitment of eligible patients and the subsequent generalization of the study findings. Although a crossover design would have been appropriate for a rare and chronic disease such as PA and MMA, a parallel arm design was chosen as the investigators decided that the benefits of a crossover study will be limited owing to the varying nature of PA and MMA. The use of a crossover design may lead to small, less representative and less homogenous patient groups, which might affect the interpretation of results. Furthermore, the study duration for a crossover design would have been 4 years (versus 2 years for the present parallel group design), which in turn would increase the risk of patient loss to follow-up, thereby further reducing the benefit of a crossover design. And most importantly, the parents of the patients might refuse to switch their kids to standard care arm if they have observed marked improvement due to treatment. This issue might compromise the trial midway and lead to unsuccessful outcome. Similarly, although a placebo-controlled study would have been ideal, the emergency management of acute crises using carglumic acid as a rescue medication would be difficult due (...truncated)