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首页> 外文期刊>EBioMedicine >Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12?h regimen of N-acetylcysteine for paracetamol overdose (POP trial)
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Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12?h regimen of N-acetylcysteine for paracetamol overdose (POP trial)

机译：使用N-乙酰半胱氨酸治疗对乙酰氨基酚过量的12？h方案中的患者使用Calmanafodipir进行的随机开放标签探索性，安全性和耐受性研究的主要结果（POP试验）

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Background The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n -acetylcysteine (NAC) for paracetamol overdose. Methods Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24?h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n?=?6) or NAC alone (n?=?2). Calmangafodipir doses were 2, 5, or 10?μmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). ( Clinicaltrials.gov : NCT03177395 ). Findings All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC?+?calmangafodipir (2?μmol/kg), 4/6; NAC?+?calmangafodipir (5 μmol/kg), 2/6; NAC?+?calmangafodipir (10?μmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT??100?U/L; with NAC?+?calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20?h fold change, NAC?+?calmangafodipir (5?μmol/kg) compared to NAC alone: 0.48 (95%CI 0.28–0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. Interpretation Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.
机译：背景POP试验是一项1期，开放标签，剂量递增的随机研究，探讨了对乙酰氨基半胱氨酸过量使用卡马古非地吡（超氧化物歧化酶模拟物）与正乙酰半胱氨酸（NAC）共同治疗的安全性和耐受性。方法在爱丁堡皇家医院（2017年6月8日至2018年5月10日）招募患者。纳入标准：对乙酰氨基酚过量的24小时内需要NAC的成年人。在3个连续队列中的每一个队列中，参与者均被隐式分配给NAC和单次静脉注射卡伦加非地尔剂量（n？=？6）或单独使用NAC（n？=？2）。 Calmangafodipir的剂量为2、5或10？μmol/ kg。参加者，研究和临床团队没有盲目。主要结果是安全性和耐受性。次要结果是丙氨酸转氨酶（ALT），国际标准化比率（INR），角蛋白18，胱天蛋白酶切割的角蛋白18（ccK18），microRNA-122和谷氨酸脱氢酶（GLDH）。 （Clinicaltrials.gov：NCT03177395）。结果所有24名参与者均接受了分配的药物剂量并进行了分析。主要终点：所有参与者均发生≥1次不良事件（AE），最常见的是胃肠道疾病。发生≥1次严重不良事件（SAE）的患者：仅NAC，2/6; NAC +钙锰福地吡（2？μmol/ kg），4/6; NAC +钙锰福地吡（5μmol/ kg），2/6; NAC +钙锰福地吡（10？μmol/ kg），3/6。没有AE或SAE可能是或肯定是与calmanafodipir相关的。次要安全性结果显示两组之间无差异。仅使用NAC，2/6的ALT？>？100？U / L。使用NAC？+？calmangafodipir，0/18。没有INR差异。与单独使用NAC相比，单独使用NAC的组中角蛋白18和ccK18的增加要多于卡那非地吡（基线变化20？h，NAC？+？钙锰福地吡（5？μmol/ kg）：0.48（95％CI 0.28–0.83） ）。 microRNA-122的变化与K18相似，但经常未检测到GLDH。解释与NAC联合使用时，可耐受Calmangafodipir，可能会降低对乙酰氨基酚毒性的生物标志物。

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