Study design and objectives

This was a multicentre prospective observational study performed from 2010 to 2016 in 6 metabolic rare disease centres in France. Standardised data from patients’ medical charts were collected from 2010 until the end of the prospective cohort follow-up in December 2016. The study was prospective as outcomes (reduction in plasma leucine levels) following the intervention were not known at the time of data collection. Data collected after 2016 (one patient was added and additional amino acid data for 3 patients were completed) were analysed retrospectively as the outcome was already known. Patient medical charts were completed for each MSUD-associated metabolic decompensation by the patient’s physician or another attending healthcare professional closely involved in the patient’s care. Part of this cohort of rare MSUD patients attending hospitals in France have been described previously [16], and most recently, in a retrospective observational study including a control arm of patients from a centre in Germany who did not receive the IV BCAA-free solution and who experienced low numbers of decompensation episodes [19]. The current study provides an original analysis of data from the cohort of French patients receiving the IV BCAA-free solution between 2010 and 2016 (Table 1). This study provides information on 99 unique new episodes and 13 new patients not previously reported.

Table 1 Number of unique/new episodes from the French cohort of MSUD patients reported by each successive publication

As compared to our previous publications [16, 20], we report here data from 6 French centres for metabolic diseases. Given that the previous publications including French MSUD patients had been restricted to subpopulations, for example adult patients [16], or assessed long-term outcomes of a restricted subset of the cohort [17], or compared a subset of this cohort to other treatment groups, for example versus oral treatment [20], this research is intended to provide evidence of efficacy and safety of the IV BCAA-free solution in a full MSUD population cohort of all ages.

The study objective was to describe the overall management of MSUD decompensation episodes and confirm the safety and efficacy and time to normalise plasma leucine concentrations (defined as a plasma leucine concentration of < 381 μmol/L) when treated with IV BCAA-free solution. Time to leucine normalisation was analysed using the same dataset to corroborate the revised treatment algorithm for MSUD decompensation episodes [8].

Inclusion criteria

Inclusion criteria included biochemically confirmed MSUD diagnosis in patients, hospitalised at one of the 6 participating centres for a metabolic decompensation episode (defined as increased plasma leucine level > 381 μmol/L (5.0 mg/dL) and/or presence of clinical symptoms of metabolic decompensation) or in a condition of metabolic stress with a risk of decompensation (defined as presence of independent factors such as infection, injury, failure to eat (fasting) or psychological stress that lead to BCAA accumulation) requiring IV BCAA-free solution.

Treatment

The IV BCAA-free solution contained 16 amino acids for parental administration (Additional file 1: Table S1). The solution was manufactured and distributed by AGEPS from 2010 to 2016. This IV BCAA-free solution was the result of a multidisciplinary collaboration between physicians, dieticians and pharmacists from Necker Children’s University Hospital and AGEPS to define precise technical and practical aspects of the formula composition, dosage and recommendations for use [16]. The recommended intake and the volumes administered, over 24 h, per kg of body weight were 2–3 g/kg with 39–58 mL/kg of volume for newborns and infants (< 2 years) and 1–2 g/kg with 19–39 mL/kg for children (over 2 years), adolescents and adults. In addition to the IV BCAA-free solution, all patients received standard therapy including dextrose-lipids mixture, valine (50–800 mg/d in children; 200–1200 mg/d in adults) and isoleucine (100–800 mg/d in children; 300–1600 mg/d in adults).

Statistical analysis

Two sets of episodes were defined for analysis: The safety set (n = 126 episodes, 24 patients) corresponded to all episodes treated with IV BCAA-free solution during the study. This set was used to describe the profile of patients/episodes, the treatment exposure, clinical improvement, hospitalisation duration and safety. The efficacy set (n = 102 episodes, 16 patients) corresponded to all episodes treated with the IV BCAA-free solution which did not involve exogenous epuration, and with a documented leucine concentration at admission ≥ 381 µmol/L (5 mg/dL), and with at least one documented leucine level post-admission. This set was used to analyse normalisation of leucine concentrations. Episodes excluded from the efficacy set included: 8 for extracorporeal removal (7 episodes in children of whom 4 were younger than 2 years, and 1 episode in an adult), 8 with leucine level < 381 µmol/L at admission (6 admitted for nausea/vomiting, 1 for impaired consciousness, and 1 had no data), 5 without leucine levels at admission and 3 without post-admission leucine level available data.

Analyses were performed overall and by subgroups of age. Age categories for patients were defined as children < 15 years (including a sub-category of infants < 2 years) and adolescents or adult  > 15 years. The rationale for this latter group being that the metabolism of adolescents over 15 years is considered as similar to adults. To improve readability, the group of adolescents over 15 years and adults are referred to as ‘adults.’

Descriptive statistics were used to summarize the data in the study. For continuous variables, mean, standard deviation, median, quartiles and range may be included. For discrete variables N and frequency in percentage, a signed-rank test was used to compare the time of normalisation of leucine. A p-value of under 0.05 is considered statistically significant.

Data analysis was conducted using SAS software version 9.4 (SAS Institute Inc, Cary, North Carolina, USA).

Time to leucine normalisation algorithm

The predicted time (in days) to achieve normalisation of plasma leucine concentrations is calculated according to the authors’ own algorithm, previously published in 2013 [8]. This algorithm expresses the time needed to reach normal concentrations as equal to the amount of leucine accumulated in the body divided by the tolerance (see the calculation below). Leucine tolerance corresponds to the leucine quantity that can be absorbed (by extracorporeal removal or anabolism). The amount of leucine accumulated in the body is equal to: blood leucine concentration in mg/100 mL × 10 (in litres) x distribution volume (85–75% by weight in newborns to adolescents). For example, at 15 mg/l00 mL in a 4-year-old child weighing 16 kg: 15 × 10 × 12.8 (16 kg × 80%) = 1920 mg of accumulated leucine. The time (in days) it will take to achieve normal levels is equal to the amount of accumulated leucine in the body divided by the tolerance, where the tolerance is equal to the usual daily intake of leucine. In this case the tolerance would be 400 mg per day: 1,920 divided by 400 = 4.8 days. It will therefore take about 5 days for the levels to return to normal values if catabolism is controlled [8].

Ethical considerations

As this was a non-interventional study, patient consent was not required. As per French legal requirements all patients or their parents/caregivers were informed of the study. Any data was anonymised, stored in a secured password-protected database, and remained confidential. Study confidentiality was confirmed by the appropriate French authorities, the Comité consultatif sur le traitement de l’information en matière de recherche (CCTIRS) and the protocol was approved by the Commission nationale de l’informatique et des libertés (CNIL).

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