Mpagama Stellah G, Mvungi Happiness C, Mbelele Peter M, Semvua Hadija H, Liyoyo Alphonce A, de Guex Kristen Petros, Sloan Derek, Kibiki Gibson S, Boeree Martin, Phillips Patrick P J, Heysell Scott K
Kibong'oto Infectious Diseases Hospital-Sanya Juu Siha/Kilimanjaro Clinical Research Institute, Mae Street, Lomakaa Road, Siha Kilimanjaro, Tanzania.
Kilimanjaro Christian Medical University College, Moshi, Kilimanjaro, Tanzania.
Pilot Feasibility Stud. 2023 Apr 1;9(1):55. doi: 10.1186/s40814-023-01281-7.
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.
使用二线抗结核药物治疗耐多药结核病（MDR-TB）的患者中，药物不良反应（ADR）频繁发生。ADR会导致治疗中断，这可能会影响治疗效果，并增加对诸如贝达喹啉等关键新型药物产生获得性耐药的风险，而严重的ADR会带来相当高的发病率和死亡率。在其他医疗状况的病例系列或随机对照试验中，N-乙酰半胱氨酸（NAC）已显示出有望减少与结核病相关药物的ADR，但耐多药结核病患者缺乏相关证据。结核病流行地区开展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对接受二线抗结核药物治疗的耐多药结核病患者的保护作用的初步证据。
这是一项概念验证随机开放标签临床试验，有3个治疗组，包括一个对照组、一个每天服用900毫克NAC的干预组，以及一个在耐多药结核病治疗强化期每天服用两次900毫克NAC的干预组。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基邦戈托耐多药结核病国家卓越中心入组。预计最小样本量为66例；每组22名参与者。将在基线时以及24周的每日随访中进行ADR监测，包括采集血液和尿液样本以检测肝肾功能和电解质异常情况，以及进行心电图检查。将在基线时以及此后每月采集痰液，进行分枝杆菌培养以及检测结核分枝杆菌的其他分子靶点。将使用混合效应模型对药物不良事件进行随时间分析。从拟合模型中得出各治疗组ADR从基线变化的平均差异（及其95%置信区间）。
鉴于NAC可促进谷胱甘肽的合成，谷胱甘肽是一种细胞内抗氧化剂，可对抗氧化应激的影响，它可能保护肝脏、胰腺、肾脏等器官以及免疫系统细胞免受药物诱导的氧化损伤。这项随机对照试验将确定NAC是否会导致更少的ADR，以及这种保护作用是否具有剂量依赖性。耐多药结核病患者中更少的ADR可能会显著改善需要长时间治疗的多药方案的治疗效果。开展这项试验将为临床试验建立所需的基础设施。
PACTR202007736854169 于2020年7月3日注册。
