Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania.
Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania.
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DOI：
10.1186/s40814-023-01281-7
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发表时间：
2023-04-01
影响因子：
1.7
通讯作者：
Heysell, Scott K. K.
中科院分区：
文献类型：
--
作者：
Mpagama, Stellah G. G.;Mvungi, Happiness C. C.;Mbelele, Peter M. M.;Semvua, Hadija H. H.;Liyoyo, Alphonce A. A.;de Guex, Kristen Petros;Sloan, Derek;Kibiki, Gibson S. S.;Boeree, Martin;Phillips, Patrick P. J.;Heysell, Scott K. K.
关键词：
使用二线抗结核药物治疗耐多药结核病(MDR-TB)的患者经常发生药物不良反应(ADR)。ADR导致治疗中断，可能影响治疗反应，并有可能对贝达奎林等关键新药产生获得性耐药性，而严重的ADR具有相当高的发病率和死亡率。N-乙酰半胱氨酸(NAC)在减少与结核病相关的药物在病例系列或其他医疗条件下的随机对照试验中的不良反应方面表现出了希望，但在耐多药结核病患者中缺乏证据。结核病流行环境进行临床试验的能力有限。我们设计了一项概念验证临床试验，主要是为了探索NAC在接受二线抗结核药物治疗的耐多药结核病患者中保护作用的初步证据。这是一项概念验证的随机开放标签临床试验，包括3个治疗臂，包括对照组、NAC 900 mg/d的干预组和NAC 900 10 mg/d的干预组-在MDR-TB的强化治疗阶段每天两次。开始耐多药结核病治疗的患者将在坦桑尼亚乞力马扎罗地区的Kibong‘oto国家耐多药结核病英才中心登记。最小预期样本量为66个；每组参与者为22人。ADR监测将在基线和超过24周的每日随访中进行，包括采集血和尿样以检查肝肾功能和电解质异常，以及心电图。将在基线和此后每月收集痰，培养分枝杆菌，并检测结核分枝杆菌的其他分子靶标。随着时间的推移，将使用混合效应模型来分析药物不良事件。ARM与基线的ADR变化的平均差异(95%的可信区间)将从拟合的模型中得出。鉴于NAC促进谷胱甘肽的合成，谷胱甘肽是一种细胞内抗氧化剂，可以对抗氧化应激的影响，它可能会保护肝脏、胰腺、肾脏和免疫系统细胞等器官免受药物引起的氧化损伤。这项随机对照试验将确定NAC是否导致较少的ADR，以及这种保护是否具有剂量依赖性。耐多药结核病治疗患者的不良反应减少可能会显著改善需要延长疗程的多药方案的治疗结果。这项试验的进行将为临床试验建立所需的基础设施。2020年7月3日登记的PACTR202007736854169在线版本包含补充材料，可在10.1186/s40814-023-023-7查阅。
Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications. This is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900 mg daily, and an interventional arm of NAC 900 mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong’oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24 weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model. Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials. PACTR202007736854169 Registered 03 July 2020 The online version contains supplementary material available at 10.1186/s40814-023-01281-7.
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影响因子：
3.7
作者：
Mpagama SG;Houpt ER;Stroup S;Kumburu H;Gratz J;Kibiki GS;Heysell SK
通讯作者：
Heysell SK
影响因子：
11.8
作者：
Malik, Amyn A.;Fuad, Junaid;Hussain, Hamidah
通讯作者：
Hussain, Hamidah
影响因子：
2.9
作者：
Hwang, Thomas J.;Dotsenko, Svetlana;Wares, Douglas F.
通讯作者：
Wares, Douglas F.
DOI：
10.1093/cid/ciac511
发表时间：
2023-02-08
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
通讯作者：
--
影响因子：
10
作者：
Kranzer, Katharina;Elamin, Wael F.;Drobniewski, Francis
通讯作者：
Drobniewski, Francis