Department of Internal Medicine 1, University Hospital Tübingen, Tübingen, Germany.
Department Internal Medicine 2, University Hospital Tübingen, Tübingen, Germany.
Trials. 2020 Jul 10;21(1):635. doi: 10.1186/s13063-020-04556-z.
The aim of this trial is to identify the effect of ambulatory treatment in early COVID-19 disease with hydroxychloroquine on the rate of hospitalization or death in older patients above the age of 64.
Parallel, 2:1 randomization, double blind, placebo-controlled, multi-center trial.
Male and female patients above the age of 64 (i.e. ≥65 years of age) with COVID-19 diagnosis confirmed by SARS-CoV2 positive throat swab (PCR). Patients can only be included within 3 days of symptom onset in ambulatory care if they consent to the study procedure and are able to adhere to the study visit schedule and protocol requirements (including telephone visits concerning symptoms and side effects). Severity of disease at inclusion is mild to moderate defined as not requiring hospital admission: SpO2 >94%, respiratory rate <20, mental state alert, no signs of septic shock. Cardiac risk is minimised by requiring a Tisdale score ≤ 6. Patients are recruited in the two german cities of Ulm and Tübingen in various ambulatory care settings.
Each patient will be given a first dose of 600 mg Hydroxychloroquine or the equivalent number of placebo capsules (3 capsules) at the day of inclusion. From the 2 day on, each patient will get 200 mg or the equivalent number of placebo capsules twice a day (400mg/day) until day 7 (6 more does of 400 mg); a cumulative dose of 3 g.
Rate of hospitalization or death at day 7 after study inclusion RANDOMISATION: All consenting adult patients having confirmed COVID-19 are randomly and blindly allocated in a 2:1 ratio to either IMP or placebo. The biostatistical center produced a randomization list (block randomization) with varying block length and stratified for the study center. This list is provided for packaging to the pharmaceutical unit which is providing encapsulated placebo and IMP. Only the pharmaceutical unit is aware of group allocation according to the randomization list.
BLINDING (MASKING): Patients and investigators, as well as treating physicians are blinded to the treatment- allocation.
NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the first stage of an adaptive design 120 patients in a 2:1 ration: 72 Verum and 36 Placebo, plus an increase for 10% drop outs. After interim analysis, the total sample size will be calculated based on the effect seen in the first stage. Total sample size is estimated approximately n = 300-400 patients.
Protocol version number: V3, 19.05.2020 Recruitment not yet started but is anticipated to begin by June 2020 and be complete by December 2020 TRIAL REGISTRATION: ClinicalTrials.gov: NCT04351516 , date: 17 April 2020 EudraCT: 2020-001482-37, date: 30 March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (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.
本试验旨在确定在 64 岁以上的 COVID-19 早期患者中使用羟氯喹进行门诊治疗对住院或死亡的影响。
平行、2:1 随机分组、双盲、安慰剂对照、多中心试验。
年龄在 64 岁以上（即≥65 岁）的男性和女性 COVID-19 患者，通过 SARS-CoV2 阳性咽喉拭子（PCR）确诊。如果患者同意研究程序并能够遵守研究就诊时间表和方案要求（包括有关症状和副作用的电话就诊），则可以在门诊护理中在症状出现后 3 天内纳入。纳入时疾病严重程度为轻度至中度，定义为无需住院：SpO2>94%，呼吸频率<20，精神状态警觉，无脓毒性休克迹象。通过要求 Tisdale 评分为≤6 来最大限度地降低心脏风险。患者在德国乌尔姆和图宾根的各种门诊护理环境中招募。
每位患者在纳入当天将给予 600mg 羟氯喹或等效数量的安慰剂胶囊（3 粒）的首剂量。从第 2 天开始，每位患者将每天服用 200mg 或等效数量的安慰剂胶囊两次（每天 400mg），直到第 7 天（共 6 次 400mg）；累计剂量为 3g。
纳入研究后第 7 天的住院或死亡率
所有同意的成年患者均随机且盲法分为 IMP 组或安慰剂组，比例为 2:1。生物统计学中心根据不同的分组长度和分层为研究中心生成了一个随机分组列表（分组随机分组）。该列表提供给提供封装安慰剂和 IMP 的制药单位。只有制药单位根据随机分组列表知道分组分配。
盲法（掩蔽）：患者和研究者以及治疗医生对治疗分配均不知情。
随机分组的人数（样本量）：在适应性设计的第一阶段，以 2:1 的比例随机分配 120 名患者：72 名接受治疗，36 名接受安慰剂，加上 10%的脱落率增加。在中期分析后，将根据第一阶段的效果计算总样本量。总样本量估计约为 300-400 名患者。
方案版本号：V3，2020 年 5 月 19 日，尚未开始招募，但预计于 2020 年 6 月开始，2020 年 12 月完成。临床试验注册：ClinicalTrials.gov：NCT04351516，日期：2020 年 4 月 17 日，EudraCT：2020-001482-37，日期：2020 年 3 月 30 日。完整方案：完整方案作为附加文件附加，可从试验网站访问（附加文件 1）。为了加快传播这一材料，已省略了熟悉的格式；本函是对完整方案主要内容的总结。
