Madsen Anne Marie Rosendahl, Schaltz-Buchholzer Frederik, Benfield Thomas, Bjerregaard-Andersen Morten, Dalgaard Lars Skov, Dam Christine, Ditlev Sisse Bolm, Faizi Gulia, Johansen Isik Somuncu, Kofoed Poul-Erik, Kristensen Gitte Schultz, Loekkegaard Ellen Christine Leth, Mogensen Christian Backer, Mohamed Libin, Ostenfeld Anne, Oedegaard Emilie Sundhaugen, Soerensen Marcus Kjaer, Wejse Christian, Jensen Aksel Karl Georg, Nielsen Sebastian, Krause Tyra Grove, Netea Mihai G, Aaby Peter, Benn Christine Stabell
Bandim Health Project, OPEN, Department of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.
Center of Research & Disruption of Infectious Diseases (CREDID), Department of Infectious Diseases, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark.
Trials. 2020 Sep 17;21(1):799. doi: 10.1186/s13063-020-04714-3.
The Bacille Calmette-Guérin (BCG) vaccine against tuberculosis is associated with non- specific protective effects against other infections, and significant reductions in all-cause morbidity and mortality have been reported. We aim to test whether BCG vaccination may reduce susceptibility to and/or the severity of COVID-19 and other infectious diseases in health care workers (HCW) and thus prevent work absenteeism.The primary objective is to reduce absenteeism due to illness among HCW during the COVID-19 pandemic. The secondary objectives are to reduce the number of HCW that are infected with SARS-CoV-2, and to reduce the number of hospital admissions among HCW during the COVID-19 pandemic.
BCG vaccination of HCW will reduce absenteeism by 20% over a period of 6 months.
Placebo-controlled, single-blinded, randomised controlled trial, recruiting study participants at several geographic locations. The BCG vaccine is used in this study on a different indication than the one it has been approved for by the Danish Medicines Agency, therefore this is classified as a phase III study.
The trial will recruit 1,500 HCW at Danish hospitals.To be eligible for participation, a subject must meet the following criteria: Adult (≥18 years); Hospital personnel working at a participating hospital for more than 22 hours per week.A potential subject who meets any of the following criteria will be excluded from participation in this study: Known allergy to components of the BCG vaccine or serious adverse events to prior BCG administration Known prior active or latent infection with Mycobacterium tuberculosis (M. tuberculosis) or other mycobacterial species Previous confirmed COVID-19 Fever (>38 C) within the past 24 hours Suspicion of active viral or bacterial infection Pregnancy Breastfeeding Vaccination with other live attenuated vaccine within the last 4 weeks Severely immunocompromised subjects. This exclusion category comprises: a) subjects with known infection by the human immunodeficiency virus (HIV-1) b) subjects with solid organ transplantation c) subjects with bone marrow transplantation d) subjects under chemotherapy e) subjects with primary immunodeficiency f) subjects under treatment with any anti-cytokine therapy within the last year g) subjects under treatment with oral or intravenous steroids defined as daily doses of 10 mg prednisone or equivalent for longer than 3 months h) Active solid or non-solid malignancy or lymphoma within the prior two years Direct involvement in the design or the execution of the BCG-DENMARK-COVID trial Intervention and comparator: Participants will be randomised to BCG vaccine (BCG-Denmark, AJ Vaccines, Copenhagen, Denmark) or placebo (saline). An adult dose of 0.1 ml of resuspended BCG vaccine (intervention) or 0.1 ml of sterile 0.9% NaCl solution (control) is administered intradermally in the upper deltoid area of the right arm. All participants will receive one injection at inclusion, and no further treatment of study participants will take place.
Main study endpoint: Days of unplanned absenteeism due to illness within 180 days of randomisation.Secondary study endpoints: The cumulative incidence of documented COVID-19 and the cumulative incidence of hospital admission for any reason within 180 days of randomisation.Randomisation: Randomisation will be done centrally using the REDCap tool with stratification by hospital, sex and age groups (+/- 45 years of age) in random blocks of 4 and 6. The allocation ratio is 1:1.Blinding (masking): Participants will be blinded to treatment. The participant will be asked to leave the room while the allocated treatment is prepared. Once ready for injection, vaccine and placebo will look similar, and the participant will not be able to tell the difference.The physicians administering the treatment are not blinded.Numbers to be randomised (sample size): Sample size: N=1,500. The 1,500 participants will be randomised 1:1 to BCG or placebo with 750 participants in each group.Trial Status: Current protocol version 5.1, from July 6, 2020.Recruitment of study participants started on May 18, 2020 and we anticipate having finished recruiting by the end of December 2020.
The trial was registered with EudraCT on April 16, 2020, EudraCT number: 2020-001888-90, and with ClinicalTrials.gov on May 1, 2020, registration number NCT04373291.Full protocol: The full protocol is attached as an additional file, accessible from the Trialswebsite (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
卡介苗（BCG）用于预防结核病，还具有针对其他感染的非特异性保护作用，且有报告称其可显著降低全因发病率和死亡率。我们旨在测试卡介苗接种是否可以降低医护人员（HCW）对2019冠状病毒病（COVID-19）和其他传染病的易感性及/或感染后的严重程度，从而防止缺勤。主要目标是在COVID-19大流行期间减少医护人员因病缺勤的情况。次要目标是减少感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的医护人员数量，并减少COVID-19大流行期间医护人员的住院人数。
对医护人员进行卡介苗接种将在6个月内使缺勤率降低20%。
安慰剂对照、单盲、随机对照试验，在多个地理位置招募研究参与者。本研究中使用的卡介苗的适应症与丹麦药品管理局批准的不同，因此本研究归类为III期研究。
该试验将在丹麦医院招募1500名医护人员。符合以下标准的受试者才有资格参与：成年人（≥18岁）；在参与研究的医院每周工作超过22小时的医院工作人员。符合以下任何一项标准的潜在受试者将被排除在本研究之外：已知对卡介苗成分过敏或既往接种卡介苗后出现严重不良事件；已知既往有活动性或潜伏性结核分枝杆菌（结核杆菌）或其他分枝杆菌感染；既往确诊感染COVID-19；过去24小时内发热（>38℃）；疑似活动性病毒或细菌感染；怀孕；哺乳期；在过去4周内接种过其他减毒活疫苗；严重免疫功能低下的受试者。该排除类别包括：a）已知感染人类免疫缺陷病毒（HIV-1）的受试者；b）实体器官移植受者；c）骨髓移植受者；d）接受化疗的受试者；e）原发性免疫缺陷受试者；f）在过去一年内接受任何抗细胞因子治疗的受试者；g）接受口服或静脉注射类固醇治疗（定义为每日剂量10mg泼尼松或等效药物，持续超过3个月）的受试者；h）在前两年内患有活动性实体或非实体恶性肿瘤或淋巴瘤；直接参与卡介苗-丹麦-COVID试验的设计或实施。干预措施和对照：参与者将被随机分配接受卡介苗（丹麦卡介苗，AJ疫苗公司，丹麦哥本哈根）或安慰剂（生理盐水）。将0.1ml复溶的卡介苗疫苗（干预组）或0.1ml无菌0.9%氯化钠溶液（对照组）成人剂量皮内注射到右臂的上臂三角肌区域。所有参与者在入选时接受一次注射，且不再对研究参与者进行进一步治疗。
主要研究终点：随机分组后180天内因病计划外缺勤的天数。次要研究终点：随机分组后180天内确诊COVID-19的累积发病率以及因任何原因住院的累积发病率。随机分组：将使用REDCap工具进行集中随机分组，按医院、性别和年龄组（±45岁）分层，随机分组块大小为4和6。分配比例为1:1。盲法（遮蔽）：参与者对治疗方案不知情。在准备分配的治疗时，会要求参与者离开房间。一旦准备好注射，疫苗和安慰剂看起来相似，参与者无法区分。实施治疗的医生不设盲。随机分组的数量（样本量）：样本量：N = 1500。1500名参与者将按1:1随机分配到卡介苗组或安慰剂组，每组750名参与者。试验状态：当前方案版本5.1，自2020年7月6日起。研究参与者的招募于2020年5月18日开始，预计在2020年12月底完成招募。
该试验于2020年4月16日在欧洲临床试验数据库（EudraCT）注册，EudraCT编号：2020-001888-90，并于2020年5月1日在美国国立医学图书馆临床试验注册库（ClinicalTrials.gov）注册，注册号为NCT04373291。完整方案：完整方案作为附加文件附上，可从试验网站获取（附加文件1）。为了加快传播此材料，已去除了常见的格式；本信函作为完整方案关键要素的摘要。
