key: cord-0965788-cnzai57z
authors: Moore, Hunter B.; Barrett, Christopher D.; Moore, Ernest E.; Jhunjhnuwala, Rashi; McIntyre, Robert C.; Moore, Peter K; Wang, Janice; Hajizadeh, Negin; Talmor, Daniel S.; Sauaia, Angela; Yaffe, Michael B.
title: STudy of Alteplase for Respiratory failure in SARS‐Cov2/COVID‐19: Study Design of the Phase IIa STARS Trial
date: 2020-05-21
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12395
sha: 13f0145ef769bf60277ec0c1fd4868cea97ba8e6
doc_id: 965788
cord_uid: cnzai57z

BACKGROUND: The COVID‐19 pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non COVID‐19) demonstrated improvement in pulmonary function in ARDS patients using fibrinolytic therapy. A follow‐up trial using the widely available tissue‐plasminogen activator (alteplase) is now needed to assess optimal dosing and safety in this critically ill patient population. OBJECTIVE: To describe the design and rationale of a Phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID‐19‐induced ARDS. PATIENTS/METHODS: A rapidly adaptive, pragmatic, open label, randomized, controlled, phase IIa clinical trial will be conducted with three groups: intravenous(IV) alteplase 50mg, IV alteplase 100mg, and control (standard‐of‐care). Inclusion criteria are known/suspected COVID‐19 infection with PaO2/FiO2 ratio<150mmHg for >4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50mg or 100mg followed by heparin infusion for systemic anticoagulation, with alteplase re‐dosing if there is a >20% PaO2/FiO2 improvement not sustained by 24 hours. RESULTS: The primary outcome is improvement in PaO2/FiO2 at 48 hours post‐randomization. Other outcomes include: ventilator‐ and ICU‐free‐days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifity eligible patients will be enrolled in a rapidly adaptive, modified stepped‐wedge design with four looks at the data. CONCLUSION: Findings will provide timely information on the safety, efficacy and optimal dosing of tPA to treat moderate/severe COVID‐19‐induced ARDS, which can be rapidly adapted to a phase III trial. (NCT04357730; FDA IND 149634)

The world-wide incidence of COVID-19 continues to rise, taxing the health care and economic resources of countries throughout the developed world. Based on the clinical experience in China and

This article is protected by copyright. All rights reserved Italy, it is estimated that 5-27% of hospitalized COVID-19 patients will require prolonged intensive care (1) (2) (3) (4) (5) (6) , with 50-99% requiring mechanical ventilation (MV) for viral-induced pneumonitis progressing to acute hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS) (2, 7, 8) . In patients requiring MV , the reported mortality exceeds 50% (7, 9) and approached 90% in a recent report from New York City (10) . There is no specific treatment for COVID-19 ARDS other than routine mechanical ventilation, although prone positioning seems to be particularly effective in this population(11), either as a consequence of enhanced alveolar drainage or redistribution of perfusion to better aerated portions of the lungs.

A remarkable feature of the pulmonary pathophysiology in COVID-19 ARDS is the preservation of relatively normal lung compliance and a low incidence of barotrauma (12) suggesting extensive shunting, V/Q mismatch, and loss of regulation of alveolar perfusion. Autopsy and surgical specimens in these patients show a range of pathologic findings including diffuse alveolar damage, fibrin accumulation in the alveoli, the presence of mononuclear cell infiltrates and megakaryocytes, as well as fibrin-platelet microthrombi in the pulmonary vasculature (1, 3) . The concept of accumulation of micro pulmonary thrombi leading to death dates back to 1845 (13) . The angiographic appearance of filling defects of the pulmonary vasculature in ARDS patients has associated with a high mortality rates for decades (14) (15) (16) (17) . Animal models of irreversible shock have demonstrated clots in organs driving organ failure (18, 19) . This can be reversed with pre emptive heparin (20, 21) or post shock fibrinolytics (22) . Autopsies of critically ill patients also demonstrated clots in the organ of patients in the intensive care unit that died from organ failure (19, 23) These observations were eventually translated to two separate phase I human trial ARDS (24, 25), which were not followed up.

Given these vascular and hematological findings and the distinct nature of the COVID-19 ARDS, with preserved pulmonary mechanics, we postulate that this advanced ARDS this is due to the microthrombosis and resistance to clot lysis in the pulmonary circulation. We believe these factors are directly contribute to the high shunt type of hypoxemic respiratory failure seen in COVID-19 ARDS.

We hypothesized that administration of alteplase, a tissue plasminogen activator (tPA) followed by systemic anticoagulation will improve the PaO2/FiO2 ratio 48 hours after treatment.

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To describe the design and rationale of a Phase IIa trial (NCT04357730) that will evaluate the safety and efficacy of tPA (alteplase) treatment for moderate to severe ARDS in the setting of COVID-19 infection.

This is a Phase IIa clinical trial, open label, with a modified stepped-wedge design, testing systemic administration of fibrinolytic therapy with alteplase (using Activase ® manufactured by Genentech, Inc.) versus standard-of-care for patients infected with COVID-19 resulting in severe ARDS. The study is registered at clinicaltrials.gov (NCT04357730), has received approval to proceed by the Food and Drug Administration (IND 149634), and by all institutions Institutional Review Boards. The design is a rapidly adaptive, pragmatic clinical trial, with three interim analyses and one final look at the data. Pre-planned adaptations described below will be contemplated at each interim analysis or earlier if recommended by the Data Safety Monitoring Board (DSMB).

Inclusion Criteria: We will include patients ages 18 to 75 years, with known or suspected COVID-19 infection, with a normal neurological exam at time of enrollment (if patient is on paralytics, the patient has been awaken and showed no new neurological deficits in a complete neurological exam or had MRI/CT scan in the last 4.5 hours with no evidence of stroke), with a PaO2/FiO2 ratio < 150mmHg (at sea level or adjusted for altitude) persisting for longer than 4 hours despite maximal mechanical ventilation management according to each institution's ventilation protocols (FiO2>60% and PEEP>10cmH2O). If obtaining arterial blood gases is not possible due to a surge-related shortage of blood gas syringes, as we have experienced previously, we will infer the PaO2/FiO2 ratio from percent saturation of hemoglobin with oxygen as measured by pulse oximetry (Spo2), using the nonlinear imputation developed by the National Heart, Lung and Blood Institute (NHLBI) PETAL (Prevention and Early Treatment of Acute Lung Injury) Network Collaborators (26) A normal neurological exam or CT/MRI scan to demonstrate no evidence of an acute stroke is needed due to recent reports of large-vessel stroke as a presenting feature of covid-19 in young individuals. (27) 

This article is protected by copyright. All rights reserved Patients will be enrolled based on clinical characteristics, without consideration of language (using hospital interpreters and translated consent), race/ethnicity, or sex/gender. Patients are eligible to participate even if they are concurrently enrolled in other COVID-19 therapeutic trials. Exclusion criteria are listed in Table 1 .

There are three treatment arms: 1) Group tPA50 (n=20) will receive 50 mg of alteplase intravenous bolus administration over 2 hours, given as a 10mg push followed by the remaining 40mgs over a total time of 2 hrs.

Immediately following the alteplase infusion, 5000U of unfractionated heparin (UFH) will be delivered; the heparin drip will be continued to maintain the activated partial thromboplastin time (PTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). This tPA protocol is a modification of the GUSTO I to III trials. (28, 29) 2) Group tPA100 Group tPA100 (n=20) will receive 100 mg of tPA intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 90 mgs over a total time of 2 hrs. Immediately following the tPA infusion, 5000 U of UFH will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time at 60-80sec (2.0 to 2.5 times the upper limit of normal). This tPA protocol is similar to that used by Konstantinides et al. (30) 3) Control: institution's standard-of-care protocol for ARDS Re-bolusing of tPA is permitted in the first two intervention groups, particularly in those patients who show an initial transient response, but is not sustained (less than 50% PaO2/FiO2 improvement by 24 hours). All exclusion criteria (Table 1 ) also apply to the second tPA (alteplase) bolus.

Other modifications of the alteplase dosing are as follows:

Fibrinogen monitoring: For all tPA administration groups, fibrinogen levels will be measured before and after tPA IV bolus, 6 hours after the start of the infusion, then every 6 hours for first 24 hours, and once a day for 6 days following treatment intervention in all the groups (see detailed lab testing schedule below). If fibrinogen levels fall below 300 mg/dl, the second bolus of tPA (alteplase) will not be given.

This article is protected by copyright. All rights reserved 2.

Heparin dosing: An infusion of unfractionated heparin infusion will be continued for up to 7 days or until the patient is extubated and has an O2 requirement of < 4L/min by nasal cannula, and titrated to maintain the activated partial thromboplastin time to 60-80sec (2.0 to 2.5 times the upper limit of normal). The goal of this treatment is to prevent recurrent microvascular thrombotic hypoxemia or macrovascular complications (stroke, myocardial infarction or venous thromboembolism) due to possible rebound tPA effects causing hypercoagulability. If necessary, an infusion of anti-thrombin concentrate will be administered in heparin-resistant patients.

Diverse positioning and/or paralytic agents for ventilation: If the position or use of paralytics must be changed before the 24-and 48-hours post-randomization, the PaO2/FiO2 measured immediately before these changes (within <6 hours of the 48 hours post-randomization endpoint) will be used as primary outcome.

Outcomes: The primary outcome of interest is change in PaO2/FiO2 at 48 hours from randomization.

Secondary outcomes are listed in Table 2 .

Rapidly Adaptive Design ( Figure 1 ): The design is a rapidly adaptive, pragmatic clinical trial, with three interim analyses and one final look at the data, with test boundaries determined by the Pocock method to maintain overall experiment error at <0.05. Pre-planned adaptations described below will be contemplated at each interim analysis or earlier if recommended by the Data Safety Monitoring Board (DSMB). For rapid efficacy assessment to isolate the arm(s) with the highest likelihood of success and lowest bleeding risk, we will deploy each intervention arm sequentially up to each interim analysis, in a modified stepped-wedge fashion (31) , with pre-planned adaptations(below) at each interim analysis.

Data collection and storage: Study data will be collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted by the University of Colorado Anschutz Medical Campus. (32) Randomization: All randomizations will be conducted intra-hospital (i.e., no cluster randomization) to avoid the confounding effect of practice variation, in blocks of 10 to allow better distribution between Accepted Article groups at each interim analysis. It will be done by the Data Coordinating Center (DCC) and automated in a REDCap instrument. Upon confirmed eligibility and consent, the REDCap instrument will reveal the assignment (Group tPA50, Group tPA100, Control) to the pharmacy of the enrolling institution, which will then release the drug if the patient was assigned to one of the intervention groups. Time zero is assigned as the time of randomization. We anticipate that each of the five centers will enroll 5-10 patients.

Sample Size Rationale: the sample size was fixed at n=50 (with 20 patients in each intervention group and 10 patients in the control group) due to budgetary and feasibility constraints. The minimum detectable difference was then calculated using PASS vs 14.0 (NCSS, LLC, Kaysville, Utah, USA), focusing on the primary outcome (PaO2/FiO2 improvement) and assuming: 1)power=80%, confidence=95%, and 4 sequential tests(3 interim+1 final), using the Pocock method to determine test boundaries; 2) potential improvement assumptions based on a previous study (25) as well as a more favorable scenario with mean baseline PaO2/FiO2=149 with an overestimated standard deviation of 100, 3) design effect=1.12 due to the study's multicenter nature (intra-class correlation coefficient=0.03 (33, 34) , average cluster=5); and 4) 20% inflation to account for premature death or withdrawal for any reasons.

A sample size of 50 (20 in each intervention group and 10 in the control group) patients would detect a >68% improvement in PaO2/FiO2 between the two intervention groups and >73% improvement between intervention groups and controls. While balanced group sizes will maximize a study's statistical power, unequal randomization ratios will only significantly reduce the power of a study if the ratio is 3:1 or more. The reasons for the unequal randomization: 1) more safety information, an essential component of a Phase IIa study; and 2) experience with dosing of tPA; and 3) to allow three equal sequential phases that would inform the remainder of the trial. (35) The initial two phases (tPA 50mg vs control; tPA 100mg vs control) will provide a signal that allows the termination of the control arm.

Recruitment will assume at least 30% increase to account for refusal or inability to consent. We anticipate enrolling enough individuals to result in a sample of 50 eligible patients, to be re-evaluated during each of the interim analyses. Legally authorized representative (LAR), as defined by each state

This article is protected by copyright. All rights reserved and each institution's legislation and policies, will be able to consent.

Criteria for stopping the clinical trial early for efficacy or harm: These include reaching adjusted pvalue for the primary outcome and at least one of the secondary outcomes at all follow-up time points or DSMB deemed harm profile unacceptable.

Criteria for stopping for futility: we will follow the guidelines established by Jitlal et al (36) .These criteria are: 1) low conditional power (<15%), calculated using bootstrapping simulations, based on the target minimum differences for all primary and secondary outcomes; 2) Observed difference size in the primary or secondary outcomes favor the control group (<5%); 3) the DSMB and trial team agree that enough patients and events have been observed so far to produce a reliable effect; 4) only one center interested in continuing enrollment; and 4) no evidence of an effect in any pre-specified subgroups. If the DSMB deemed the adverse events profile acceptable, we may wish to continue to ensure that a modest effect is not missed.

Pre-planned adaptations at each interim analysis: The study interim analyses will be used to propose pre-planned modifications based on observed effects, recruitment, eligibility and other aspects of the study as determined below. 

This article is protected by copyright. All rights reserved • Sample size: the current sample size is defined by budget and feasibility constrains, and may prove insufficient if the effect detected is substantial but there is low power to detect it. A larger sample size may be recommended by the trial team and the DSMB, in which case we will pursue additional resources to increase enrollment;

• Cessation rules: based on interim analyses, coagulation and oxygenation variables may become important determinants of benefit/risk for the subjects as explained above, thus these variables may be proposed as further determinants for cessation rules;

• Enrollment/refusal rates: modifications on enrollment and consent procedure may be proposed to remedy low enrollment and high refusal rate. One potential alternative is the addition of an observational arm as done by Pieracci et al (37) .

• Crossover: if one treatment arm shows a signal of benefit (as defined in our proposed outcomes), we are under the ethical mandate to offer it to patients who were enrolled in the other arms but did not show improvement. These patients "crossover" to the alternative arm.

The analysis will be conducted as an intent-to-treat approach (patients are analyzed according to their initial assigned group) and subsequently in a separate as-treated analysis considering the combination of the two treatments. 

This article is protected by copyright. All rights reserved (only baseline for controls), then every 6 hours for first 24 hours, and once a day for 7 days (or earlier if patient is extubated) following treatment intervention in all the groups. Table 3 .

Follow-up: Patients will be followed to death or discharge up to 28 days. Laboratory measurements related to the research study, however, will end at day 7 after randomization.

Statistical analysis: The statistical analysis plan followed the recently published guidelines (40) and is

This article is protected by copyright. All rights reserved available as SDC. All outcome variables will be examined for distribution. If very skewed, we will attempt log and Box-Cox power transformations to approximate normality. If those are unsuccessful, the outcomes will be categorized using the median or previously defined cutoff. All outcomes will also be analyzed as relative change from baseline. Effectiveness of the randomization to determine baseline comparability of the groups will be done using the absolute standardized mean difference (SMD<0.20 defined as acceptable balance). Any differences deemed clinically relevant or with absolute SMD >0.2 will be adjusted for using inverse probability weighting methods as described below.

All outcome comparisons analyses will be conducted initially as an intent-to-treat (patients are analyzed in the group they were randomized to), followed by an as-treated analysis. The primary outcome will be assessed within group and between groups. Differences in the primary outcome will be evaluated using linear mixed models, with appropriate transformations if normality departure of residuals is detected. Linear mixed models allows: 1) adjustment for potential confounders detected in the comparison of the groups at baseline using inverse probability weighting by a propensity score;

and 2) change in the covariance structure to account for repeated measures and the intra-hospital correlation (as this is a multicenter study). In addition, it tolerates missing observations. We will also compare percent change over baseline, using t-tests with the appropriate adjustment for heteroscedasticity if needed. Categorical outcomes will be compared using generalized estimating equations to account for confounders (as above), covariance structure and intra-hospital correlation. In addition, we will compare the "dose" of the intervention (i.e., how much of the treatment the patient received) as an effect of interest, as premature death and withdrawals are expected. Survival analysis with inverse probability weighted Cox proportional hazards model and robust sandwich variance estimate to account for clustering for hospitals will be used for mortality as well as for survivor-bias subject outcomes (e.g., pulmonary embolism) censoring for death. As all outcomes are in-hospital, loss to follow-up is not likely. The pre-planned comparisons include within group (improvement over baseline) and between groups, all two-tailed with significance declared as defined by the Pocock spending method.

There will be no adjustment for multiple outcomes, as all were pre-planned. Adjustments for multiple comparisons in pre-planned hypotheses leads to more type II errors. (41, 42)

This article is protected by copyright. All rights reserved Pre-planned subgroup analyses: We anticipate the following subgroup analyses, which will assist in determining whether there is a subgroup of patients for whom the intervention is more beneficial/harmful: 1) baseline PaO2/FiO2 <100 and <50; 2) hemodynamic instability with Additional subgroup analyses may be defined at an interim analysis and will be added for the subsequent interim analyses. This will be documented by filing another version of this SAP with the IRBs, DSMB, funder and FDA.

Missing data: Missing data are expected to be minimal. If less than 15% and non-differential between study groups, we will proceed with analyses of complete data. If greater than 15% or differential between groups (possibly missing not at random), we will add two strategies to the complete dataset analyses: 1) Multiple imputation by chained equations (MICE), recognizing that MICE is better for missing at random data; and 2) Sensitivity analyses: we will assume worst and best clinical scenarios and compare the results with the complete dataset.

The COVID-19 has a clear association with thrombotic complications, which predominantly occur in the lungs (46) . Coagulation biomarkers have been associated with poor prognosis (52) . Functional coagulation measurements have further supported the hypercoagulable state of these patients (43) .

While the mechanism of thrombosis and hypercoagulability remains unclear, inflammation driving cytokine release is believed to be the initiator of coagulation changes based on prior work in sepsis (53) . Cytokine production is believed to drive tissue factor product resulting in systemic activation of coagulation (54) . Tissue factor expression is upregulated on macrophages and endothelial cells in response to elevated TNF-alpha, IL-6 and IL-1 (55) . At the same time the cytokine storm damages the endothelium reducing the antithrombic capacity of the systemic circulation via suppression of protein C, protein S, antithrombin, and tissue factor pathway inhibitor (TFPI) (56) . This is compounded by the SARS-COV-2 virus directly infecting the endothelium of the lungs, heart and small bowel (57) . COVID also is commonly associated with a high fibrinogen level that correlates with IL-6 levels(45). IL-6 has previously been reported to be the main stimulator of fibrinogen synthesis(58). With the combination of coagulation activation and hyperfibrinogenemia it is not surprising that this population is prone to thrombosis.

Endotoxin leading to cytokine production has also been demonstrated to activate of the fibrinolytic system 2 hours following infusion, followed by a shutdown of fibrinolysis within the following hour due to elevated plasminogen activator inhibitor -1 (PAI-1) levels (59) . Fibrinolysis activation with rapid suppression from PAI-1 was appreciated with endotoxin infusion in non-human primates, with concurrent increases in thrombin generation (60) . Pentoxifylline attenuates these fibrinolytic changes in this animal model, whereas IL-6 and TNF-alpha inhibitors have no effect (61) .

These experiments were followed up with the hypothesis that an antifibrinolytic (e.g., tranexamic acid) would prevent progression to DIC by blocking plasmin activation, however tranexamic acid had no impact on the prothrombic component of endotoxin infusion in healthy subjects and did not alter

This article is protected by copyright. All rights reserved cytokine production (62) . Our groups recent work has demonstrated that COVID-19 patients with a thrombelastography LY30 of 0% and D-Dimer level greater than 2600 ng/ml have a venous thrombosis rate of 50% (63) . Due to D-dimers having a half-life that exceeds 12 hours (64) , this lab is reflective of the cumulative amount of polymerized fibrin present over the past day, or longer. While low fibrinolytic activity measures the current fibrinolytic systemic state of the patient. Therefore, an elevated D-dimer with low fibrinolytic activity is consistent with prior activation of fibrinolysis with current low fibrinolytic activity, fulfilling the definition of fibrinolysis shutdown, which has been described for the past half century (65, 66) . This fibrinolytic phenotype has been associated with poor outcomes in trauma(67-71). Elevated D-dimer and low fibrinolytic state has previously been mis termed overt hyperfibrinolysis (72) , however, the "overt hyperfibrinolytic" phenotype in trauma does not commonly bleed to death, and received significantly fewer transfusions compared to patients with elevated D-Dimes and elevated LY30s that represents true hyperfibrinolysis. Hyperfibrinolytic trauma patients have the hall mark signs of excessive fibrinolysis with excessive bleeding and low fibrinogen levels, that can be reversed with an antifibrinolytic medication (73) . COVID-19 patients have elevated fibrinogen are not bleeding to death, and should not be classified as hyperfibrinolytic, which has already been proposed (74) . The combination of prothrombotic and lack of fibrinolysis poses a major logistical challenge in treating COVID-19 as both ends of coagulation likely require treatment for effective outcomes. There is a potential that a combination of IL-6 blockage to attenuate hyperfibrinogenemia in combination of tPA could provide a more durable response, which can be adapted from this phase II trial.

The 48-hour assessment of PaO2/FiO2 in patients after tPA treatment will also have limitation in quantifying pulmonary dysfunction improvement. There a numerous ventilator adjuncts to improve oxygenation in the setting of severe ARDS including proning the patient(11), paralytics(75), nitric oxide(76) and prostonoids(77). Prolonged use of these interventions is associated with adverse events (78) . Therefore, getting the patients off of these medications or prone positioning would be considered a beneficial outcome with tPA regardless of change in PaO2/FiO2 over 48 hours. This also includes reducing toxic levels of oxygen (FiO2 >80%) and reducing PEEP. In addition to assessing improvements in each of these individual variables, a composite score of each adjunctive

This article is protected by copyright. All rights reserved measure will also be conducted to represent a global change in requirement of adjuncts for improving oxygenation at 48 hours.

Due to different treatment practices at the five enrolling centers we anticipate that there will be variability in the techniques used prior to patient enrollment to optimize oxygenation, an acknowledged limitation. This in line with the pragmatic nature of the trial. Moreover, the crisis created by the pandemic without available treatments precluded the development of agreed upon standard operating procedures for ventilation as well as other intensive care procedures.

During the current pandemic, there has been a call for rigorous trials with concurrent control groups to allow (79) . However, randomized controlled trials bring ethical dilemmas, especially when no current treatment exists. Thus, it is imperative that creativity and the rigorous application of the scientific method are combined to produce an innovative, efficient study design. Our design uses the adaptive framework (80, 81) , which allows pre-planned modifications to improve the efficiency the trial and detect effect or harm more promptly, and a modified stepped-wedge design. More recently, the stepped-wedge randomized trials have gained popularity have been proposed. (82, 83) . The modified stepped-wedge pragmatic design is different than the usual parallel randomized controlled trials RCTs, in which the intervention and control groups run, as the name implies, in parallel. The traditional stepped-wedged approach involves a sequential roll-out of an intervention to participants (individuals or clusters) over a number of time periods, such that at the end of the study, all participants will have received the intervention. The name of the design (stepped-wedged) comes from the schematic illustration of the design. The 1987 Gambia hepatitis intervention study (84) was the pioneer stepped wedge study, and tested the effectiveness of a hepatitis B vaccine. We modified the stepped wedge design to deploy the intervention groups sequentially to more quickly accrue the sample size with one of the intervention groups with a parallel control. In a traditional parallel design, the first interim analyses would require sufficient number in three (as opposed to two) groups, thus increasing the efficiency of the trial and increasing the likelihood of isolating the more successful arm.

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It should be noted that using the traditional (yet arbitrary) confidence level of 95% (alpha=0.05) is overly stringent for the current circumstances. The rigid cutoff of 95% level of certainty, as eloquently summarized by Nuzzo in one of the most cited Nature articles (85) should not be applied without regard to the conditions in which the study is conducted. Is it appropriate or necessary to be 95% certain when the condition in question has high lethality and morbidity, threatening to exceed the healthcare system capacity, and has no known prevention (except for isolation) or treatment? While we do not believe this is the precise time to re-ignite a discussion about the traditional p<0.05, we will, in our study, for all comparisons present the effect size with 

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