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

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 to blinding.

To limit the potential for bias in this open-label trial, randomization will use a web-based system with variable block size. Variable block randomization was selected to ensure that the study groups were balanced, given the small number of patients. In addition, the endpoint criteria are objective and not influenced by investigator’s or patient’s knowledge.

The study population will be children ≤15 years of age, since adult patients with PA and MMA generally have mild enzyme deficiency and better treatment outcomes that may not significantly change the number of ER admissions, and thus not demonstrate any potential differences between the two treatment groups.

The main exclusion criteria include patients with other OAs or with hyperammonemia due to other causes, receiving other investigational therapy for PA or MMA, and PA or MMA plus other inherited genetic conditions or congenital anomalies.

All patients who meet the study inclusion criteria and whose parents/guardians provide a written informed consent will be included in the study. Since all patients will need to receive the minimum standard of care for obvious ethical reasons, randomization during this study will compare standard therapy for PA or MMA plus carglumic acid versus standard therapy alone. Standard therapy is defined as protein-restricted diet, L-carnitine (150 mg/kg/day divided every 8 h), metronidazole (15 mg/kg/day divided every 8 h for 1 week each month) [9]. The principal investigator will conduct a protocol training session in other participating centers to ensure that the co-investigators follow the same plan. Additionally, a written management protocol including standard treatment, emergency management protocol, and nutritional management will be distributed for all participating centers. A detailed emergency card will be given for all the patients, to be shown during any emergency visit within or outside the participating centers. This card includes the patient’s chronic medications, the study arm and the standard emergency management of the patient.

All patients will be randomized (1:1) to receive carglumic acid (50 mg/kg/day) plus standard therapy or standard therapy alone for a period of 2 years. Carglumic acid will be administered twice daily in equally divided doses immediately before or with meals enterally via mouth, gastrostomy or a feeding tube depending on the clinical status of the patient (patients with PA and MMA may have a gastrostomy tube/feeding tube due to poor pharyngo-oesophageal coordination caused by neurological complications). Each 200 mg tablet of carglumic acid is dissolved in 4 mL of water to yield a concentration of 50 mg/mL, to be given as 1 mL/kg/day. Tablets should not be swallowed whole or crushed.

All patients will be instructed to keep the unopened bottle of carglumic acid (Carbaglu® 60 tablets) refrigerated at 2–8 °C, to store it at room temperature (≤30 °C) once opened, to tightly close the container after each use to protect the tablets from moisture, and to discard the bottle 1 month after opening. To monitor the patients’ compliance on the study medication, the parents and care givers will be asked about the compliance directly in the interview of each visit, which will be documented in the case report form. Additionally, the parents will be asked to bring all the medication containers, including the empty ones, to the pharmacy each visit to further monitor the compliance.

Patients will remain on medications that he/she has been taking prior to the study, except for other nitrogen scavenging drugs such as sodium benzoate, which must be discontinued at least 30 days before randomization and not taken throughout the study. Episodes of hyperammonemia during the study period may be treated with rescue medication such as intravenous sodium phenylacetate and/or sodium benzoate, with or without hemodialysis, at the clinician’s discretion. If carglumic acid is suspended during the management of an acute episode, it should be reintroduced as soon as the episode is managed.

The study is approved by the IRB at the two participating centers: King Abdulaziz Medical City, King Abdullah International Medical Research Center IRB: (RC13/116) and King Fahad Medical City IRB (14–165). The trial has been reviewed and approved by the Saudi Food and Drug Authority (SFDA) (33066), and is registered at ClinicalTrials.​gov (identifier: NCT02426775). The study will be conducted in accordance with the laws and regulations of Saudi Arabia and in line with the ICH harmonized tripartite guidelines for Good Clinical Practice 1996 and the declaration of Helsinki.

The primary efficacy outcome is the number of ER visits due to hyperammonemia above the age dependent reference range during the study period. Secondary efficacy outcomes include time to first ER visit due to hyperammonemia after treatment initiation, plasma ammonia levels and levels of biochemical markers (acylcarnitine profile, urine organic acid, and plasma amino acid levels) during the study, and the number of hospitalization days during the 2-year study period.

Safety will be assessed by monitoring and recording all adverse events (AEs) and serious AEs observed during regular monitoring of hematology and blood chemistry, urinalysis, vital signs, and physical and neurological examinations.

All patients will be evaluated at the screening visit followed by baseline, and at 3, 6, 12, 18 and 24 months during the study. The baseline visit can be combined with the screening visit, or held within 30 days of screening. During each clinic visit, treating physicians will conduct a physical examination, blood tests and complete medical history of the patients in order to collect information on AEs and treatment compliance between the scheduled study visits. Parents/legal guardians of the patients will provide the required information to the treating physician during each clinic visit. The investigators will be asked to use the same laboratory throughout the study period for each individual patient.

All patients will receive a follow-up call 30 ± 7 days after the end of the study to ensure post-treatment safety. Any AEs reported during this period will be noted. In addition to the data collected at each visit, any acute decompensated episodes between scheduled visits will be recorded in a separate section in the electronic case report form (eCRF).

A specialized diet will be chosen for each study participant dependent on their age and residual enzyme activity. All patients will be required to adhere to the low protein diet and the prescribed amino acid supplements, and compliance will be assessed at each visit by a metabolic nutritionist experienced in PA and MMA who is aware of the study protocol.

Patients will stop receiving the study drug at any time during the study if any of the following criteria are met: allergy or hypersensitivity reaction to study drug (of any grade), liver transplantation, inability to tolerate study drug (to be decided by the treating physician), acute life-threatening event related to study drug, > 30% increase in liver enzymes or long QT interval or cardiac arrhythmias, and patient or caregiver wishes to discontinue the study drug.

All patients who withdraw from the study will be included in the intention to treat analysis (ITT) based on the treatment arm they were allocated to. It will be the duty of the investigator to record the primary reason(s) and the date of the premature discontinuation of the treatment using the eCRF. Each discontinuation will be categorized as an AE (defined as any clinical or laboratory event that requires treatment discontinuation for the best interest of the patient, as diagnosed by the study investigator); withdrawal of consent (defined as patient’s desire to withdraw from further participation in the study in the absence of a medical reason to withdraw); a major protocol deviation (if the parameters recorded at each visit or the patient conduct failed to meet the protocol requirements); loss to follow-up (if the patient does not return for one or more scheduled visit(s) after treatment initiation and does not contact the investigator); other reasons such as an administrative problem, including termination of study by the sponsor.

A research assistant who has expertise in data entry will enter data into a password-protected database. Data will be entered and double checked for accuracy. After resolution of any discrepancies and a combination of manual and automated data- review procedures, the final data set will be subject to a quality assurance audit.

To ensure the quality of the clinical data across all participants and sites, a clinical data management review will be performed on all subject data every 6 months. During this review, subject data will be checked for consistency, omissions and any apparent discrepancies. In addition, the data will be reviewed for adherence to protocol. To resolve any questions arising from the clinical data review process, data queries will be sent to the site for completion.

It is the responsibility of the Investigators to record all observations and other data pertinent to the clinical investigation. For this study an electronic CRF (eCRF) will be used.

Data on subjects during the trial will be documented in an anonymous fashion and the subject will only be identified by the subject number, and his/her initials. The Investigator must maintain source documents for each patient in the study. All information in the study database must be traceable to these source documents, which are generally maintained in the patient’s file. The source documents should contain all demographic and medical information, including laboratory data, and a copy of the signed informed consent form, which should indicate the study number and title of the trial.

An interim analysis will be performed after 1 year of treatment. A data and safety monitoring board (DSMB) will be convened to review the unblinded efficacy and safety data to determine whether the study can be continued for the total study duration of 2 years. Using the Haybittle-Peto stopping rules [13, 14], the study will be terminated prematurely if the treatment arm shows significant inferiority compared with the control group (p-value < 0.01). Inferiority will be defined as an estimated rate ratio (RR) significantly > 1.