目标:截至12月,1st,2020年,由SARS-CoV-2引起的2019年冠状病毒病(COVID-19)导致全球超过1472917人死亡,死亡人数仍呈指数增长。许多COVID-19感染者无症状或出现中度症状,无需医疗干预即可康复。然而,老年人和患有高血压的人,糖尿病,肥胖,或者心脏病死亡的风险更高。因为目前对COVID-19患者的治疗选择仅限于有风险的老年人群,Biophitis正在发展BIO101(20-羟基蜕皮激素,aMas受体激活剂)作为在严重阶段管理SARS-CoV-2感染患者的新治疗选择。血管紧张素转换酶2(ACE2)充当SARS-CoV-2的受体。ACE2与SARS-CoV2刺突蛋白之间的相互作用似乎改变了ACE2的功能,ACE2是肾素-血管紧张素系统(RAS)的关键参与者。COVID-19的临床表现包括急性呼吸窘迫综合征(ARDS),心肌病,多器官功能障碍和休克,所有这些都可能是由于RAS的不平衡造成的。我们建议通过ACE2活性下游的MasR激活可以在COVID-19患者中恢复RAS平衡,20-羟基蜕皮激素(BIO101)是一种非肽Mas受体(MasR)激活剂。的确,20-羟基蜕皮激素的MasR激活具有抗炎作用,抗血栓,和抗纤维化特性。BIO101,一种97%的药物级20-羟基蜕皮激素,可以通过改善呼吸功能并最终促进COVID-19患者的生存,从而提供一种新的治疗选择,这些患者患上了这种严重的破坏性疾病。因此,这项COVA研究的目的是评估BIO101的安全性和有效性,其活性成分是20-羟基蜕皮激素,COVID-19重症肺炎患者。
方法:随机化,双盲,安慰剂对照,多中心,组顺序和适应性,将分2部分进行。第1部分:确定BIO101的安全性和耐受性,并获得BIO101在预防目标人群呼吸恶化方面的活性的初步指示。第2部分:重新评估确认部分2所需的样本量,并确认在第1部分中观察到的BIO101在目标人群中的作用。这项研究被设计为小组顺序,以允许有效的贯穿,从获得活动的早期指示到最终确认。和适应性-允许在第2部分中积累早期数据并调整样本量,以告知试验验证部分的最终设计。
方法:纳入标准1.年龄:45岁及以上2.确诊为COVID-19感染,在过去的14天内,在随机化之前,通过PCR或其他批准的商业或公共卫生检测确定,在所使用的试验规定的试样中。3.住院治疗,因COVID-19感染症状观察或计划住院,预计住院时间≥3天4.肺炎的证据基于以下所有方面:a.体格检查的临床发现b.在过去7天内出现呼吸道症状5.有呼吸代偿失调的证据在研究药物开始前不超过4天开始,并在筛查时出现,符合以下标准之一,经医护人员评估:a.呼吸急促:每分钟≥25次呼吸b.动脉血氧饱和度≤92%c.如果怀疑COVID-19相关心肌炎或心包炎,应特别注意,因为这些的存在是一个分层标准6。肝功能检查无明显恶化:a.ALT和AST≤5x正常上限(ULN)b.γ-谷氨酰转移酶(GGT)≤5xULNc.总胆红素≤5×ULN7.愿意参加并能够签署知情同意书(ICF)。或者,当相关时,合法授权代表(LAR)可以代表研究参与者签署ICF8.女性参与者应:绝经后至少5年(即,在没有其他医学原因的情况下持续闭经5年)或手术无菌;ORa.在筛查时尿液妊娠试验为阴性b.愿意使用纳入标准9中概述的避孕方法,从筛查到最后一次给药后30天。9.与女性伴侣性活跃的男性参与者必须同意在整个研究中使用有效的节育方法,直到最后一次服用研究产品后3个月。(注意:参与者和/或伴侣可能使用的医学上可接受的避孕方法包括联合口服避孕药,避孕阴道环,避孕注射,宫内节育器,依托孕烯植入,每个都补充了避孕套,以及灭菌和输精管切除术)。10.哺乳期的女性参与者必须同意在研究期间和干预后14天内不母乳喂养。11.男性参与者必须同意在整个研究过程中以及在最后一次施用研究产品后3个月之前不捐赠精子用于生殖目的。12.仅适用于法国:隶属于欧洲社会保障。排除标准1.在研究期间不需要或不愿意留在医疗机构2.由于其他和非COVID-19相关的疾病3.通过气管内导管参与有创机械通气,或体外膜氧合(ECMO),或高流量氧气(以≥16L/min的流量输送氧气。).4.参与者不能口服药物(如胶囊或粉末,混合在水中)。5.不允许的伴随用药:食用任何含有20-羟基蜕皮激素和来自Leuzeacarthamoides的草药产品;不允许使用阴道炎或鼠尾草炎(例如性能增强剂)。6.任何已知的对任何成分的超敏反应,或研究药物的赋形剂,BIO101.7.需要透析的肾脏疾病,或已知肾功能不全(eGFR≤30mL/min/1.73m2,基于Cockcroft&Gault公式)。8.仅在法国:a。不属于法国强制性社会保障计划(受益人或权利持有人)。b.受监护或法定监护。参与者将从比利时大约30个临床中心招募,法国,英国,美国和巴西。参与研究的最大患者将持续28天。出院的参与者的随访将在14(±2)天和60(±4)天通过干预后电话进行。
■在这项研究中将测试两个治疗组:BIO101(AP20-羟基蜕皮激素)的介入组350mgb.i.d和安慰剂比较组350mgb.i.d。每日剂量的施用在整个治疗期间是相同的。参与者将在住院期间接受研究药物治疗长达28天或直到达到临床终点(即,\'负\'或\'正\'事件)。正式出院的参与者将不再接受研究药物治疗。
结果:主要研究终点:28天内出现“阴性”事件的参与者比例。“阴性”事件定义为呼吸恶化和全因死亡率。出于本研究的目的,呼吸恶化将被定义为以下任何一种:需要机械通气(包括由于资源限制和分诊而不会插管的病例)。需要体外膜氧合(ECMO)。需要高流量氧气,定义为在≥16L/min的流量下输送氧气。只有当主要终点在主要最终分析中具有显著性时,以下关键次要终点才将按该顺序进行测试:在第28天有呼吸衰竭事件的参与者的比例在第28天有“阳性”事件的参与者的比例。在第28天时出现全因死亡事件的参与者比例A“阳性”事件定义为由于参与者病情改善而由科室正式出院。次要和探索性终点:此外,各种功能测量和生物标志物(包括SpO2/FiO2比,病毒载量和与炎症相关的标志物,肌肉,组织和RAS/MAS途径)也将被收集。
■在基线访视期间使用IBM临床开发IWRS系统进行随机化。分组置换随机化将用于以1:1的比例分配符合条件的参与者。在第1部分中,随机化将通过RAS途径调节剂的使用(是/否)和合并症(无与1及以上)。在第2部分中,随机化将按中心分层,性别,RAS通路调节剂使用(是/否),合并症(无vs.1及以上),在研究进入时接受持续气道正压/双水平气道正压(CPAP/BiPAP)(是/否),并怀疑COVID-19相关心肌炎或心包炎(存在或不存在)。
■参与者,看护者,评估结果的研究团队对小组分配视而不见。所有治疗单位(TU),BIO101b.i.d.或安慰剂b.i.d.,不能按照双盲过程进行区分。一个独立的数据监测委员会(DMC)将进行2个中期分析。第一个基于来自第1部分的数据,第二个基于来自第1部分和第2部分的数据。第一个将告知BIO101的安全性,为了允许开始招募进入第二部分,然后分析疗效数据,以获得活动的指示。第二个中期分析将告知第2部分所需的样本量,以实现足够的统计能力。要随机分配的人数(样本量)随机分配的参与者人数:最多465人,总计第1部分:50(以获得COVID-19患者的概念证明)。第2部分:310,可能增加了50%(基于中期分析2,高达465)(以确认第1部分中观察到的BIO101的作用)。
■当前协议版本为V10.0,日期为2020年9月24日。从2020年9月1日开始的招聘正在进行中,预计将在2021年3月完成整个研究。
背景:该试验在试验登记处开始之前进行了登记:EudraCT,不。2020-001498-63,注册于2020年5月18日;和Clinicaltrials.gov,标识符NCT04472728,2020年7月15日注册。
■完整协议作为附加文件附加,可从试验网站访问(附加文件1)。为了加快这一材料的传播,熟悉的格式已被删除;这封信作为完整协议的关键要素的摘要。
OBJECTIVE: As of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia.
METHODS: Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The
study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the
trial.
METHODS: Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the
study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients\' participation in the
study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days.
UNASSIGNED: Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., \'negative\' or \'positive\' event). Participants who are officially discharged from hospital care will no longer receive study medication.
RESULTS: Primary study endpoint: The proportion of participants with \'negative\' events up to 28 days. \'Negative\' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with \'positive\' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A \'positive\' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected.
UNASSIGNED: Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not).
UNASSIGNED: Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacy data, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients). Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1).
UNASSIGNED: The current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021.
BACKGROUND: The
trial was registered before
trial start in
trial registries: EudraCT , No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 2020.
UNASSIGNED: 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.