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Abstract：
OBJECTIVE: Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA.
METHODS: Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient\'s first month of life or >60 µmol/L thereafter, with an increased lactate level [> 1.8 mmol/L] and/or acidosis [pH < 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months\' and 18 months\' follow-up.
RESULTS: Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14-77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97-2569) before treatment to 103 µmol/L (range 97-171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of - 41% (range - 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated.
CONCLUSIONS: In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients.
BACKGROUND: ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04176523 .
METHODS: Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient\'s first month of life or >60 µmol/L thereafter, with an increased lactate level [> 1.8 mmol/L] and/or acidosis [pH < 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months\' and 18 months\' follow-up.
RESULTS: Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14-77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97-2569) before treatment to 103 µmol/L (range 97-171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of - 41% (range - 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated.
CONCLUSIONS: In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients.
BACKGROUND: ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04176523 .
摘要：
目的：甲基丙二酸尿症（MMA）和丙酸尿症（PA）是有机酸尿症，其特征是与继发性N-乙酰谷氨酸缺乏相关的毒性代谢物和高氨血症的积累。Carglumicacid,N-乙酰谷氨酸的合成类似物,通过恢复尿素循环的功能来降低氨水平。然而,关于卡洛米酸的长期安全性和有效性的数据有限.这里,我们对正在进行的，长期的,prospective,观察性保护研究(NCT04176523)，该研究正在研究在患有MMA和PA的儿童和成人中长期使用carglumic酸。
方法：来自法国的MMA或PA患者，德国,意大利,挪威,西班牙,作为常规护理的一部分，接受至少1年carglumic酸治疗的瑞典和英国有资格入选。主要目标是高氨血症急性代谢失代偿事件的数量和持续时间（患者生命的第一个月内氨水平>159µmol/L或此后>60µmol/L，乳酸水平升高[>1.8mmol/L]和/或酸中毒[pH<7.35]）在用海藻酸治疗前后。血浆氨水平峰值在最后一次失代偿事件之前和第一次失代偿事件之后开始，治疗开始前后的失代偿事件的年发生率也在评估中.次要目标包括与代偿失调事件相关的住院时间。在大约12个月和18个月的随访期间收集数据。
结果：在目前参加PROTECT研究的患者中，分析了10例MMA（n=4）和PA（n=6）患者的数据。患者接受甲磺酸治疗14-77个月（平均36个月）。Carglumicacid将总患者群体的氨中峰值水平从治疗前的250µmol/L（范围97-2569）降低到治疗后的103µmol/L（范围97-171）。高氨血症的急性代谢失代偿的年率在用海藻酸治疗后降低了中位数-41％（范围-100％至60％）。在治疗前经历过代偿失调事件的五名患者中，可以计算出治疗后的比率，4例患者接受卡洛米酸治疗后,年度失代偿事件发生率较低.在可以计算住院时间的五名患者中，有四名在代偿失调事件期间住院的平均持续时间比开始甲磺酸治疗之前短。
结论：在该组MMA和PA患者中，至少1年的金光酸治疗降低了总患者群体的血浆氨峰值水平，并降低了代谢失代偿事件的频率。以及部分患者因代谢代偿失调而住院的持续时间。
背景：ClinicalTrials.gov，NCT04176523。11月25日登记,2019年，追溯注册，https://clinicaltrials.gov/ct2/show/NCT04176523.
方法：来自法国的MMA或PA患者，德国,意大利,挪威,西班牙,作为常规护理的一部分，接受至少1年carglumic酸治疗的瑞典和英国有资格入选。主要目标是高氨血症急性代谢失代偿事件的数量和持续时间（患者生命的第一个月内氨水平>159µmol/L或此后>60µmol/L，乳酸水平升高[>1.8mmol/L]和/或酸中毒[pH<7.35]）在用海藻酸治疗前后。血浆氨水平峰值在最后一次失代偿事件之前和第一次失代偿事件之后开始，治疗开始前后的失代偿事件的年发生率也在评估中.次要目标包括与代偿失调事件相关的住院时间。在大约12个月和18个月的随访期间收集数据。
结果：在目前参加PROTECT研究的患者中，分析了10例MMA（n=4）和PA（n=6）患者的数据。患者接受甲磺酸治疗14-77个月（平均36个月）。Carglumicacid将总患者群体的氨中峰值水平从治疗前的250µmol/L（范围97-2569）降低到治疗后的103µmol/L（范围97-171）。高氨血症的急性代谢失代偿的年率在用海藻酸治疗后降低了中位数-41％（范围-100％至60％）。在治疗前经历过代偿失调事件的五名患者中，可以计算出治疗后的比率，4例患者接受卡洛米酸治疗后,年度失代偿事件发生率较低.在可以计算住院时间的五名患者中，有四名在代偿失调事件期间住院的平均持续时间比开始甲磺酸治疗之前短。
结论：在该组MMA和PA患者中，至少1年的金光酸治疗降低了总患者群体的血浆氨峰值水平，并降低了代谢失代偿事件的频率。以及部分患者因代谢代偿失调而住院的持续时间。
背景：ClinicalTrials.gov，NCT04176523。11月25日登记,2019年，追溯注册，https://clinicaltrials.gov/ct2/show/NCT04176523.
