Peer orenaccess Atorvastatin versus placebo in patients with covid-19 in intensive (@ check tor updates INSPIRATIONS Investigators FAST TRACK ‘Correspondence to: ABSTRACT Sateghipu, OBJECTIVE ale Clovscuar Maciea nd Research Cnt, Tehran ran peaeghipour@botrat.com {Reid o000-0001'96020513) -edtona matali published ‘nine ont To ew pease vis the ural nine To assess the effect of statin treatment versus placebo ‘on clinical outcomes in patients with covid-19 ‘admitted tothe intensive cate unt (ICU). DESIGN INSPIRATION/INSPIRATION-S was 2 multicenter, randomized controlled wal with a 2«2 factorial Ciethisa:0i/2022376<06e407 design. Results for the anticoagulation randomization pfecbiow 10.1367 have been reported previously. Results for the double bo2tasss07 blind randomization to atorvastatin versus placebo Accepted:7 Decne: 2021 are reported here. SETTING 11 hospitals in Iran. PARTICIPANTS ‘Adults aged 218 years with covid-19 admitted tothe ICU. INTERVENTION Atorvastatin 20 mg orally once dally versus placebo, to.be continued for 30 days from randomization inespective of hospital discharge status. (MAIN OUTCOME MEASURES The primary efficacy outcome was a composite ‘of venaus or arterial thrombosis, reatment with extracorporeal membrane oxygenation, oF all cause mortality within 30 days from randomization. Prespecified safety outcomes included increase in Liver enzyme levels more than three times the upper \imit of normal and clinically diagnosed myopathy. Aclinical events committe blinded to treatment assignment adjudicated the efficacy and safety ‘outcomes. WHAT IS ALREADY KNOWN ON THIS TOPIC Studies have shown that statins might have ant-inflammatary, antithrombotic, and antiibrotic properties Some clinical studies before covid-19 indicated that statin treatment might be associated with reduced mortality in patients with hyperinlammatory acute respiratory distress syndrome Some observational studies have suggested an association between a history of statin use or continued use of statins during hospital admission and improved outcomes in patients with covide WHAT THIS STUDY ADDS In this randomized trial, atorvastatin compared with placebo was not associated witha significant reduction in the primary outcome, a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, of all cause mortality Because the event rates were lower than expected, a smaller treatment effect cannot be excluded Results within subgroups, including patients who presented within seven days of symptom onset, ae hypothesis generating and require additional confiemation inthe ongoing studies ‘elms 1472022376 0068407 | dol 101126/bu) 2021 068407 care: randomized controlled trial esutrs ‘01605 patients randomized between 29 July 2020 and 4 Apri 2021 for statin randomization in the INSPIRATION’ tal, 343 were coxandomized to intermediate dose versus standard dose prophylactic anticoagulation with heparin based regimens, \hereas 262 were randomized after completion ofthe anticoagulation study. 587 of the 605 participants were incluced in te primary analysis of INSPIRATIONS, reported here: 290 were assigned to atorvastatin and 297 to placebo (median age $7 years Gnterquatile range 45-68 years); 256 (44%) women) The primary outcome occurred in 95 (33%) patients assigned to atowastatin and 108 (36%) assigned to placebo (ods ratio 0.84, 95% confidence interval 10.58 to 1.21). Death occurred in 90 (31%) patients in the atorvastatin group and 103 (35%) in the placebo ‘10Up (odds ratio 0.84, 95% confidence interval 0.5810 1.22). Rates fr venous thromboembolism in the atorvastatin group and 3% in the placebo group (odds ratio 0.71, 95% confidence interval 0.24 to 2.06). Myopathy was not clinically diagnosed in either group. Liver enayme levels were increased in five (2%) patients assigned to atorvastatin and six (2%) assigned to placebo (odds tatio 0.85, 95% confidence interval 0.25 10 2.81). CONCLUSIONS In adults with covid-19 admitted to the ICU, atorvastatin was not associated with a significant reduction in the composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation or all Cause mortality compared with placebo. Treatment as, however, found 1 be safe. As the overall event rates were lower than expected, acinicallyimportant treatment effect cannot be excluded. TRIAL REGISTRATION Clnicatals gov NCTO4486508, Introduction Covid-19 can result in multiorgan manifestations.' ? ‘The overactive immuneresponse can ead to pulmonary and extrapulmonary injury.’ Pulmonary parenchymal ‘injury, which can progress to acute respiratory distress syndrome, is the most common and sinister feature of severe covid-19. Vascular endothelial activation, 2 hypercoagulable state, and immobility because of severe illness or medical instrumentation might increase the risk of microthrombosis and macrothrombosis, particularly venous thrombo- embolism in patients with covid-19."® The rates of thrombosis and mortality are highest among patients. with covid-19 who are admitted to the intensive care unit (icv)? Hydroxymethyiglutaryl coenzyme A reductase inhibitors, or statins, have antiinflammatory and warget'01 se paysiand isiy sre, quBuxdoo hq payoa}0%d 1S9N6 Aq ZzOZ YOHEHY GI Uo /usoo fwug'mMM/-cy WOH papeojUMo “Zzoz AUENUEr J UO Lo¥Ee90-1Z0%antithrombotic properties." "* Stains inhibit the nuclear factor kappa light chain enhancer of activated B cells (NF-KB) pathway and reduce inlammation.*"” Statins might also exert antioxidant and ant-apoptotic effects. Inthe HydroxymethyslutaryCoA Reductase Inhibition with Simvastatin in Acute Lung Injury Reduce Pulmonary Dysfunction-2 Study (HARP-2), simvastatin compared with placebo was not associated with a reduced mortality in the overall population.” In the subset of patients with a hyperinlammatory phenotype, however, simvastatin was shown (0 reduce all cause morality.” In addition to reducing inflammation, statins might exert endothelial stabilizing properties, such as increased nitric oxide production.” Moreover, statins are known to have antithrombotic and modest profibrinolytic activites. In pre-covid-19 studies, statins have been shown 10 reduce plasminogen activator inhibitor, platelet aggregation," and the risk of vascular events" such a5 venous thromboembolism.” Statins might also interfere with viral entry through the disruption ofthe membrane lipid raft Therefore, we hypothesized that statin treatment might be of benefit to adults with covid-19** admitted to the ICU by reducing the risk of thrombotic events or death related to worsening inflammation or respiratory status. The Intermediate vs Standard-Dose Prophylactic Anticoagulation in Critically Patients With COVID.19: An Open Label Randomised Contolled Trial (INSPIRATION) and INSPIRATION stain (INSPIRATIONS) studies were part of a randomized clinical trial witha 22 factorial design in patients with covid-19 admitted to the ICU. The first randomization tested the effect of intermediate dose versus standard dose prophylactic anticoagulation with heparin based regimens. The results are reported elsewhere.” ® The second randomization tested the effet of atonvastatin 20 mg orally once daily versus placebo in patents ‘with covid-19 admitted to the ICU. This manuscript reports the results of this second randomization {INSPIRATIONS ‘Methods INSPIRATION/INSPIRATION-S were part of a multicenter, randomized controlled tial with a 2<2 factorial design created by an international committee and conducted in 11 Iranian hospitals in. Tehran, ‘Tabriz, and Kara The rationale and design ofthe trial have been described previously.”””” Patients or thelr healthcare proxies provided written informed consent for participation. An Independent data and safety ‘monitoring committee, not part of the authorship team, monitored the trial esults. Participants: We recruited adults aged 218 years with reverse transcription polymerase chain reaction confirmed covid-19 who were admitted to an ICU and had no efinite indication for therapeutic anticoagulation or baseline statin use, Adults were excluded if their estimated survival was less than 24 hours, they sere weighed <40 kg, they had major bleeding or serious bleeding diathesis within 30 days from enrollment, their liver enzyme test results were greater than five times the upper limit of normal, they had active liver disease (liver function test results greater than three times the upper limit of normal with histological ‘evidence of costs, inflammation, or necrosis), and their creatine kinase concentration was >500 U/L. Supplementary appendix 3 provides a full list of the inclusion and exclusion criteria. Site clinicians at the enrolling centers screened patients inthe ICU for eligibility Eligible patients who agreed to participate were randomized and followed- up for 30 days from the time of randomization. While the patients were in hospital, their follow-up was performed by the ite clinicians who enrolled them. Site clinicians were responsible for collecting the baseline ‘linical information and clinical outcomes. Follow- up on Hospital discharge was done through weekly telephone calls either by the same site clinicians, of, if needed, by the trial coordinating center, Randomization and blinding Eligible adults were randomly assigned to atorvastatin or matching placebo in a 1:1 ratio, A centralized computer based system with a block size of 4 was used. for randomization. The site clinicians who enrolled patients received a unique tial registration number for each randomized patient, Access to the allocation sequence was concealed from the site clinicians. The ‘study drug and placebo were identical in appearance and given to treatment teams (in the hospital) or the patients or thelr caregivers on hospital discharge. ‘The boxes of drugs contained three 10-pill blister ppacks and had distinct codes for the randomization ‘sequence and study drug. The study investigators and participants remained blinded to assigned treatments, ‘until completion of the analyses. Intervention ‘The study intervention was atorvastatin 20 mg orally ‘once daily compared with placebo. For patients who were mechanically ventilated, atorvastatin was delivered through a nasogastric or orogasttic tube. The plan was for the study drug to be continued for 30 days from randomization or until the primary outcome was reached within the ist 30 days post-randomization, outcomes ‘Theprimaryefficacy outcomewasacompositeofvenous or arterial thrombosis, weatment with extracorporeal ‘membrane oxygenation, or all cause mortality within 30 days from randomization. Secondary efficacy outcomes included the individual components of the primary outcome (venous thromboembolism, arterial ‘turombosis, and all cause mortality)and ventilator free days (the difference between total number of days alive postenrollment and total number of days receiving invasivemechanical ventilation). Exploratory outcomes. included objectively clinically diagnosed type I acute myocardial infarction, stroke, and acute peripheral do 101136 /bmy) 2001 068407 | 472022375.068407 | heb warget'01 se paysiand isiy sre, quBuxdoo hq payoa}0%d 1S9N6 Aq ZzOZ YOHEHY GI Uo /usoo fwug'mMM/-cy WOH papeojUMo “Zzoz AUENUEr J UO Lo¥Ee90-1Z0%arterial thrombosis, the proportion of patients. discharged alive from the ICU, length of hospital stay in the ICU, incident arial brillation, and new renal replacement therapy. Venous of arterial thrombotic fevents were diagnosed based on treating clinicians’ suspicion and subsequent confirmation by appropriate ‘maging tests. The supplementary appendix provides details about the confirmatory tests required for ascertainment of thrombotic events. For example, deep vein thrombosis was diagnosed in the presence of confirmatory findings on vascular ultrasonography, contrast enhanced computed tomography, magnetic resonance imaging, or invasive venography, or at autopsy. Routine screening for thrombotic events ‘was not dictated in the study protocol. The treating clinicians performed the diagnostic tests according to ‘thelr clinical judgment. Prespecified safety outcomes included an increase {in liver enzyme levels (defined as mote than three times the upper limit of normal) and new clinically diagnosed myopathy, as identified by treating Clinicians. Another safety outcome, major bleeding, was assessed according to the Bleeding Academic Research Consortium criteria (BARC type 3 or 5). A clinical events committee blinded to treatment assignment adjudicated all clinical efficacy and safety ‘outcomes. The supplementary appendix provides additional details about the definitions of the outcomes, {also see table 2). Patients who were discharged alive {rom the hospital received regular weekly telephone follow-up. Statistical analysis To avoid typeI eror inflation, it was prespecified tonot conduct interim analyses to test the superior efcacy of atorvastatin versus placebo.””® The data and safety monitoring board had independent access to the study data and conducted prespecified interim safety analysesat 25%, 50%, and 7596 of recruitment Patients enrolled between 29 July 2020 and 19 November 2020 were considered for eligibility to bbe randomized to anticoagulation, followed by randomization to statin teatment.”” At tral design phase, considering a two sided ‘ype I ertor rate of 0.05 and a 25% relative risk reduction for the primary outcome with statin treatment compared with placebo, the investigators estimated a priori tht the study would be underpowered to detect a significant dliference between the groups (supplementary ig S1). Therefore, the study protocol prespecified that if resources allowed and the study investigators agreed to collaborate, enrollment forthe statin randomization could be continued after completion of enrollment for the anticoagulation hypothesis (e, randomization to intermediate dose prophylactic anticoagulation versus standard dose prophylactic anticoagulation). To maintain harmony with eligibility criteria, the steering committee used the same eligibility criteria (ndluding the anticoagulation hypothesis eligibility citer) for patients who would be considered onl for the statin randomization, By the time randomization ‘elms 1472022376 0068407 | dol 101126/bu) 2021 068407 EEEerws ‘of 600 patients was completed for the anticoagulation study, 364 were assigned to atorvastatin orto placebo. Based on an estimated event rate of 5596 from the pre-tandomization period at enrolling sites, this sample size would have provided a 63% power to detect a significant difference forthe primary outcome between the two groups forthe statin randomization. Considering an actual pooled event ate of 44.8%6for the primary outcome in the INSPIRATION (anticoagulation) study, a sample of 596 patients was estimated to provide 8036 power to detect a significant difference for the primary outcome between statin treatment and. placebo. The target sample size for INSPIRATIONS was increased to 626 patients (313 in each group) to account for an exclusion rate of 5% owing to duplicate fr incortect entries. Therefore, enrollment for only the statin randomization was planned to continue from 20, Novembet 2021. n4 April 2021 thesteering committee terminated enrollment owing to the lack of additional funding and the excessive burden of new enrollment to site investigators. By that time, 605 patients were randomized to receive atorvastatin or placebo, The primary analysis population consisted of randomized patients who received at least one dose of the study drug (atorvastatin or placebo), were not excluded, and did not withdraw consent. Additional analyses wete performed among all randomized patients and in the per protocol efficacy cohort that included only those patients who completed the treatment as originally allocated until reaching the primary endpoint or the end of 30 day follow-up, Whichever occurred first. Assessment ofthe primary outcome was performed through generalized linear mixed models accounting {or the enrolling site as a random effec, the assigned treatment as the exposure variable, and adds ratio as the main effect measure. The conditional distribution of the primary endpoint given the random effects was assumed to be Bernoulli, with success probability determined by the logistic cumulative distribution function. Risk difference was also reported for descriptive purposes, by subtracting the cumulative Incidence in the placebo group from the cumulative incidence in the statin group, with the respective 95% confidence interval through the Clopper- Pearson interval. In @ supplementary analysis, results were assessed in generalized linear mixed models accounting for the enrolling site as a random effec, the assigned treatment as the exposure variable, and. hazard ratio as the effect measure. The proportionality assumption was tested by the Schoenfeld residuals, which did not indicate violation of the assumption. Time to event was showin with Kaplan-Meler curves. ‘Subgroupanalyses were performed based onage, sex, history of smoking (curtent or former v non-smoker), history of hypertension, diabetes mellitus, obstructive airway disease, history of _renin-angiotensin- aldosterone system inhibitor use, symptom onset (<7 days v>7 days}, cotteatment with corticosteroids, body ‘mass index (BMI 230 or <30), aspirin use at baseline, type of assigned anticoagulation regimen during the warget'01 se paysiand isiy sre, quBuxdoo hq payoa}0%d 1S9N6 Aq ZzOZ YOHEHY GI Uo /usoo fwug'mMM/-cy WOH papeojUMo “Zzoz AUENUEr J UO Lo¥Ee90-1Z0%statin treatment (standard dose, intermediate dose, and therapeutic dose prophylactic anticoagulation), and duration of assigned regimen (280% of study. period v <80%). Sensitivity analyses were performed ‘with inclusion of all randomized patients meeting the eligibility criteria, and also in the per protocol cohort, consisting of patients who received the assigned treatment until completion of 30 day follow-up or who. ‘met the primary efficacy outcome. All clinical outcomes were available for assessment inall patients and no outcome values were missing, For baseline characteristics, the study protocol allowed for ‘multiple imputations if missing values occurred for 596 but <2096 of values. Since none of the baseline characteristics met these criteria, multiple imputations. ‘were not used for the study variables. No adjustment \was planned for the P value thresholds for multiplicity of comparisons. Therefore, owing to the potential for type 1 ertor, results from analyses other than the primary efficacy outcome should be considered exploratory Statistical analyses were performed using Rstatistical package, version 4.0.3 (R Core Team). Patient and public involvement In the context of the pandemic and the need to design. the study ina short period, no patients were involved. in setting the research questions or the outcome ‘measures, nor were they Involved in developing plans forrecruitient, design, orimplementation of the study. No patients were asked to advise on interpretation or writing up of results. The study results and the ‘manuscript were shown (0 few members ofthe public after submission of the manuscript. Results A total of 2868 patients were screened for eligibility between 29 July 2020 and 4 April 2021, of whom 6605 were enrolled and randomized: 303 assigned (0 atorvastatin and 302 assigned to placebo. After the exclusion of 14 patients who did not meet the eligibility criteria and four who did not ecelve at least one dose of the study drugs, 587 entered the prespecified primary analysis population: 290 assigned to atorvastatin and. 297 assigned to placebo (fig 1). No losses to follow. up occurred and no values were missing for clinical outcomes. ‘Table 1 summarizes the baseline characteristics of the two groups. Median age of the study participants was 57 years (interquartile range 45-68 years) and 256 (4496) were women. The two groups were balanced for baseline characteristics, except for history of smoking, ‘which was more common in patients assigned to atorvastatin than to placebo (31 (11%) v 10 (396) patients), and median white blood cell count, which ‘was lower in patients assigned to atorvastatin than to placebo (8.6=10°/L (interquartile range 6.1-11.710"/ Lv 9,.5x10"/L (7.0-12.510"/L)). Among patients in the prespecified primary analysis population, the median duration of use of the assigned treatment was 21 days (interquartile range 7-30 days) for atorvastatin and 19 (7-30) days for placebo sere (P-0.79). Supplementary table $3 summarizes the reasons for postrandomization changes 10 the assigned treatments. Efficacy Because no interactions occurred hetween the two interventions (le, anticoagulation intensity and use of atorvastatin) for the primary efficacy outcome based on Mantel Haenszel y° test (P-0.97 for interaction), the results for statin randomization are reported independently By 30 day follow-up, the primary efficacy outcome occurred in 95 (33%) patients assigned to atorvastatin and 108 (369%) assigned to placebo (ods ratio0.84,95%confidenceinterva0.58101.21,P=0.35, fig 2). This translated t0 a risk difference of -3.6%6 (6596 confidence interval -11.2¥0 to 4,086). Results for the primary outcome were largely driven by all cause ‘mortality: 90 (319) deaths occured inthe atorvastatin sroup and 103 (359%) in te placebo group (odds ratio 0.84, 9536 confidence interval 0.58 to 1.22), No patient ‘was treated with extracorporeal membrane oxygenation. The use of imaging tests for the diagnosis of ‘venous thromboembolism was similar between the study groups. 57 (209%) in the atorvastatin group ‘and 58 (20%) in the placebo group; P=0.64). These tests included 17 computed tomography pulmonary angiograms in each group, and 40 venous doppler studies in the atorvastatin group and 41 in the placebo group (supplementary table S4). Venous thromboembolism was diagnosed in six (2%) patients, assigned t0 atorvastatin and nine (396) assigned to placebo (odds ratio 0.71, 95% confidence interval 0.24 to 2.06). The rate of arterial thrombosis did not differ significantly between the two groups (0% v 0.3% risk difference ~0.3%, 954% confidence interval -0.9% to 0.3%; P-0.32). Adjudicated type 1 myocardial infarction was not clinically diagnosed in either group. The median length of ICU stay was 5 days Gaterquartle range 3-9 days) inthe atorvastatin group ‘and 5 (2-10) days inthe placebo group. The median duration of ventilator free days was 30 (interquartile range 10:30) days inthe atorvastatin group and 30 (¢- 30) days inthe placebo group (P-0.08). No significant differences were found between patients assigned to atorvastatin or to placebo for 30 day incident atial fibrillation (two (19) v four (196) patients; odds ratio 0.51, 9596 confidence interval 0.09 to 2.87) or new renal replacement therapy (10 v6) v8 (3%) patients; 1.30, 0.50 to 3.38). Table 2 ‘surnmarizes the results of efficacy and safety outcomes in te two groups, Safety An Increase in liver enzyme lovels more than three times the upper limit of normal occurred in five (286) patients assigned to atorvastatin and six (296) assigned. {a placebo (odds ratio 0.85, 95% confidence interval 0.25 to 2.81; P-0.79). Myopathy was not clinically diagnosed in ether group. Major bleeding was adjudicated in 11 (496) patients assigned to atorvastatin and five (296) assigned to do 101136 /bmy) 2001 068407 | 472022375.068407 | heb warget'01 se paysiand isiy sre, quBuxdoo hq payoa}0%d 1S9N6 Aq ZzOZ YOHEHY GI Uo /usoo fwug'mMM/-cy WOH papeojUMo “Zzoz AUENUEr J UO Lo¥Ee90-1Z0%Peer eo Patents sreenedfor ely (5) Excluded 165 Dic not meet agolty cetera ‘317 Decinedto parteipate 81 Treating cleans clined to partepate 5 Randomized a 5 Randomized to recive atorvastatin 20 mgonce daly © Excluded (© Withirew consent and decined to ‘contbute data © Duplcateenty (1303) Randomized and planned to receive atorvastatin 20 mgonce daly ap Excluded 11 Incorrect randomization (id not meet elgblty criteria 11 Strong ndieation for statin strategy 6 Strongindietion for anticoagulation therapy 4 Treatngphysiciandecined to participate (0 withdrew informed consent 2 Dic notreceWve atleast one dose of ‘assigned treatment © Losttofalowup (1250) {Included in prespecified primary analysis a Excluded 75 Thalreginen interrupted without eetingmain safety reffcacy ‘outcome (0 withdrew consent and decined to ‘contnbute data © Duplcateenty 5) Completed tia eaimen and Included n per protocol analysis Fig 1 | Study low diagram. Of 605 randomized patients, 587 met the criteria tobe considered inthe primary analysis placebo (odds ratio 2.30, 9596 confidence interval 0.78 to 6.73; P=0.12). The rate of fatal bleeding was ‘not significantly different between the atorvastatin ‘group and placebo group (two (196) v two (196); 1.02, (0.14 07.32; P=0.98). Table 2 reports additional safety outcomes, ‘elms 1472022376 0068407 | dol 101126/bu) 2021 068407 Randomized to receive placebo once daily o Excluded (0 withdrew consent and decid to ‘contbute data © Duplcateenty = Randomized and planned receive ‘matching daly placebo © Excluded 2 Incomectrandomization (dd not meet lgity crea 1 Stongindicaton for statin strategy 1 Svongindicaton for anticoagulation therapy 1 Treating physician decined to participate © wathrew informed consent 2 Didnt recawve at lear one dose of ‘ssgned treatment © Loettefolow-un Included in prespecified primary analysis © Excluded (68 Tal cogmen interrupted without meeting main safety oeficacy (0 withdrew consent and decined to Ncontrbute daa © Duplcateenty (i229) Complete ial egimen and Included per protocol analysis ‘Subgroup and sensitivity analysis Findings were consistent in most of the prespecified subgroups, including in women and men, those with ‘or without obesity, and those with or without diabetes (Gg 3). In a prespecified subgroup analysis, use of atorvastatin compared with placebo was associated. Jwarge 1-01 se pausuand yuu ewe quBuxdoo hq payoa}0%d 1S9N6 Aq ZzOZ YOHEHY GI Uo /usoo fwug'mMM/-cy WOH papeojUMo “Zzoz AUENUEr J UO Lo¥Ee90-1Z0%Table 1] Bassline characteristics of patcipatsasigned a storvastatn orto placebo in prespecified primary analysis population * Values are means interquartile anges) ules stated otherwise Characteristics ‘Norasatn group (+290) Placebo grup (0=297) Agee 57.05.67) 574568) No C0) ef women 17563). 131) No Co efmen 165.67) 165,66) Body mass nde 77 2629) 27 2636) No Co) of caren sma sna) 106) Comrise) Diablos Bum Bue Apres 39.81) 96.) Hiperisdema 11) 53) ‘battery dase 2 @) 2 Hs are ° 2 econ eebroarear ert 7 2 Henerragiesoke © o Vetous tvomboem balan ° ° ‘Dusan of sypons blo Rasp aislon ays). TES) as ‘Dustion of hospital admission pr andomzation ay) 305) 425) Bastin indica. af ies Sever ‘No wih st led pressure 100 mm Higa ime orandomzaton 78) 760) No) equingvasopessor agent support hous of esi 351020), a9 (164) Acie Shysisiogy and Chon Hea Evaluation Wat tne of andombation (10) 7-10) No 69 wih faction of nsiredongen 60% at tine of rdomization 1254) FETC eaeresiatory suport ime of envlinent No Cs asl annua 7600) 3000) facemask 7500) S10) Resanor mask 105655), a6 igh How nasa cannula 106) 96) onavasive postive pressure vation 3760. GD, Ins posive presur venation endbachel abo) 3602) 25.05) Tnvasie peste pressure vetistin within aBhou's of eranene 57 20) 76255) ‘rug histor do) Bac dy sp Tey Bw Pv iors a n@, Goivetent ‘Any anil aby Te 270) Render 195.60) 194,65) Feiiavir S007) 708) onion 1103) 30) _Atraraistona 146) 76. Coneaseris 26800) 250 (9) ‘okhicine 72) 90) Chorquie or ydronehoroquine 275) 220) Fenin-angtesin- lotro ye Dore 51075) 806) Toca 3.05) 42 4) brary yas at basno Plasma cet Gl) 84 707-106.) ‘55 796-106.) wate bead cls cout («77 6 (61-117) 950.0125) Heron evel /D 135 418-147), 134 20-147) Alatlet cout «1070 227 70-289) 240 (180-308) Dismer (nb 50016011865), 1000 520-1943) Asgaat rnsamirase U7) 23 65257) 66 360) ‘Anite tarssmiase UL 012658) 39258) otal birin Como 68034102) 63G4119) Direct rube ro 5164-68) 516468) Creatine phosphokinase UU 105 (65-204) 115 67-215), Eryhroc seelmeraton at Gani 555278) 509.570) reac rte (8/0 6250109431 560 640-800) Fen Gait 525 677-335) 459 2103505) “Inbalonce betwen te vo gvps wa sini RO Toco moles rd wit lod cals count rds pearly mporantmbaane (R15 oD deel These ype tests wee not austes or mati of amostcos. tier sere fsa ange 71), composed of tree cargoes ase Sober ge and chi heath ths, Mahe snes pore outcomes. ‘Mo patie reeves conser sem Shoral nee of sere ory ee dred 5 525-1227 yma ena cethin. 85-1330 freed ll cun. 136-175 Lorman 2 120.56 IL ‘ome for meal eve 15050-207/ fps coun 500 a foD dev 10 0 UL ome and 932 Lr women fe zxparate Varearana eo 436 ULI ane earns, 51-17 nlf ftir ead 4120 polo det vine 200395 UN sper Unt roma cea ashok vel 0 pu Creactne Deneve and 24336 al ere 21307 yl for women rin. Noel ae lr voce scene aes Wh ead se {Daimerieve at bent war ae for 199 pets (00 surnam, 9 peso =m) eR a ee eee Semianisive ssn he ad seve patents epee which ave Ben nied ine eset nas {Sthecetn 00 tet 19 nsomasn m7 nto ams wh gare oy led researc pens engine ay Getincidein pean . do 101136 /bmy) 2001 068407 | 472022375.068407 | heb quBuxdoo hq paya}o%g 1S9N6 Aq ZzOZ YOHEH GI UO juloo Twig’ WH/-cY| WK papeojUmod “Zzoz AUENUEF J UO LovE9O-IZOZ-lwIAIgEL OF SB PaUSHANG ys PvEPeer Probab of inary outcome pee Hazard ratio 0.841063 1011.19) % a ee) Days. Intermediate dose Patients at rik 290262239223 08198185, Primary outcome Osi ‘Alleause mortality Oi ‘Venous thrammboembollsm 0 3 " 1 1 ° ° lechemic stroke 0 ° o ° ° ° ° Standard dose Patients atrisk 297 264 = 236217196193 189, Primary outcome ee 3 4 ‘ilcouse mortality OR oe og ioe 3 4 ‘Venous thramboembalism cas 1 we v lechemic stroke Oe 0 ° ° ° ° Fig2| Time to event for the primary outcome, a composite of venous or arterial thrombosi censored by a precedent ischemic stroke event {treatment with extracorporeal membrane oxygenation, or all cause ‘mortality during 30 days from randomization, in the prespecified primary cohort, consisting of patents who received at leat one dose ofthe study drug, were not ‘excluded, and dig not withdraw consent. “All cause mortality events were censored by precedent venous thromboembolism events. Venus thromboembolism event was with lower odds of the primary efficacy outcome ‘among patients with symptom onset within seven days of hospital admission (0,60, 959% confidence interval 0.37 to 0.99) but not among patients with symptom ‘onset more than seven days before hospital admission (2.27, 0.73 to 2.21) (P-0.05 for interaction). Results from sensitivity analyses including all randomized patients and all randomized patients who ‘met the eligibility criteria yielded similar results to those of the primary analysis (supplementary tables $88 and $9), Findings were similar when hazard ratio ‘was used as the effect measure, Discussion In this study of adults with covid-19 admitted to the ICU, use of atorvastatin 20 mg once daily compared with placebo was not associated with a significantly reduced odds of the primary outcome, @ composite ‘elms 1472022376 0068407 | dol 101126/bu) 2021 068407 of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause ‘mortality. Findings were consistent for several additional outcomes, including mortality and venous thromboembolism, and in study subgroups and sensitivity analyses. The current trial does not support a large 30 day benefit from statin treatment in patients with covid-19 admitted to the ICU. Despite adjustments for sample size estimates midway during the trial, the event rates were ultimately lower than expected and we cannot exclude a smaller treatment effect. Potential explanations for the observed findings ‘These findings can be explained in several ways. First, it is possible that statin eatment in this study had a small protective role, which was not detected. Despite our re-estimation of the sample size, the primary efficacy outcome event rate was lower than expected. This issue might have been multifactorial, including more frequent use of corticosteroids,” better general care in the ICU, and lower acuity of illness in some patients. Second, its possible that statin treatment is. beneficial in early covid-19 before the inflammatory response leads 10 irreversible damage.” This is in line with the prespecified subgroup analysis that suggested a potential treatment effect in patients who ‘wore enrolled within the first seven days of hospital ‘admission. However, as this finding was not adjusted for multiplicity, the results should be considered exploratory. Thitd, it is possible that the effect of statins on venous or arterial thrombosis or mortality, become apparent beyond the 30 days of follow-up. Assessment of outcomes at 90 days is still ongoing and will be reported in the future, The rate of thrombotic events in the current study was lower than in several other studies.’ 7” In INSPIRATIONS, routine Imaging screening for thrombotic disease was not part ofthe study protocol. Imaging tests were performed only in cases of clinical suspicion. Although underdiagnosis is possible, many more patients were tested with imaging than those with an ultimate diagnosis of thrombosis, Among patients who had diagnostic imaging tests for venous thromboembolism, the proportion with confirmed venous thromboembolism was 13% (supplementary table $2). Some studies suggest that ‘most thrombotic events in patients admitted to the ICU with covid-19 include subsegmental pulmonary embolism, distal deep vein thrombosis, and catheter associated thrombosis, which are less severe forms of venous thromboembolism, Furthermore, recent large multicenter observational studies” ®* suggest lower event rates for venous thromboembolism in covid-19 than initially estimated in smaller studies; a finding that was confirmed in a recent systematic review and. ‘meta-analysis."” This finding could be partly related t0 more frequent use of prophylactic anticoagulation and ant-inflammatory treatments in more recent studies, compared with those that were conducted early during the covid-19 pandemic Jwarge 1-01 se pausuand yuu ewe quBuxdoo hq payoa}0%d 1S9N6 Aq ZzOZ YOHEHY GI Uo /usoo fwug'mMM/-cy WOH papeojUMo “Zzoz AUENUEr J UO Lo¥Ee90-1Z0%Table 2 | Thity day outcomes in prespecified primary analysis population. Values are numbers (percentages) unless stated otherwise NeW) ‘Norastatn group Placebo group Risk diference tomes (=290) (0297) GENCE) Odds etlo OSC). Pralue Primary outcome. Compost facts venous Hronods, aver vonboss, reammenewit 95 G2) TaGe __3ECILIwEH ORM OSEWIA O35 ECMO, oral cause moray” ‘Secondary outcomes ‘Als morality soa, TIGHT COSwAD ORM OSEw IA OF ‘enous thiomioenbolsm 6a 30) =09(351015) _071(0.2410206 053 ‘ein (QR ventiats fe dst 30 (1030) 30 (630) 08 Exploratory outcomes Cincaly lagnosed ype acute yocai Wareoon 2 a Cieay lagosed soe o 103 a3 caste os) om ‘incall lagnosed acute peripheral ata Tronboss 0 0 Medan 0QR)ICU eng fy 55) 5210) oa Pan's discharged fom CU her nome War) 201 (65) 199167) 20CS4w96 IAL @TEw16)_058 Incident tial beilaton 20) a, =06 (221009) 051100910287) 0.45 ‘Undeong new in hosp eral sicementtheapy 100) 3B) 07 (200035) 130105010338) 057 Safety outcomes Fata bleeding @ARCIype 3) 70 70) OCigwig___ Lov O1aw7 37) 098 ‘ajar leding BARC ype 30578 11) 52) 21051047) 230(07810679) 0.12 nical relevant nonmajor blecing™ GARCIyp@ 2 6a) 30) =06 (301018) 07(0.26102.27) 064 Severetrombocrtopenatt a0) 30) 03(-13t021) 130(0.2810598) 073 Cancaly lagnosed moosthiae 0 0 Increase in iver enzyme vl 3D 6a Oa C2ate Te) Oss 0751078) O78 EO acrporea mean eget Rieu ange ]CU-heave ce unis BARC er esac Conrur Patcpasb NSP RATION ard NSPRATONS wee ot complete el Fem 2] 2020 19 November 2020p wee bei sceees he at coapstionandonzaton, ‘ane salam int ahr te an agnor many ong sn exsist forest eatmen) onc te ancanaiton demnten compton -pessriedn th sypoos pire fre sn ransotin cme, ee splemeno ae 1 ets “venous tromboembalem vers neve adudented yh one inl event corms, Exch ven aso eorbmed by preset» ase reconmended aging st ‘sopkmerty append. Act steal tronbase wae sed arp | oct nocd en, eceic vo an acu perdhra aeal trode No patents rece CMO, {tierce bese tal mumbo as ave poser anal umber ae ene mechani ven, {yet myocardial nrcton wa deed ancestor eee eb cardactporn aves tat ons va bowie 9th cere pp me rormalwih test one of tclowng™ symptom: of ecient a resumed nen whem eerocegnphe i) ehege, 3 evelpre page oer on hearing ee eo ‘te enim rea wat aten sary a ype onset mtn nsereme econ by coma arsogmpy. etme agnor ry Moca. Inurywtn ots in spate ombnatianfeesce ears ome’ and Es mgr Ceonyangsphy war ony pred one pent ath mma eranon ns) ‘ests mgs ise sent ented ype ste ‘or everwhere ence none oun o abst sh aes was repr ‘rdteo BAR pe 3 5, whch ted ws ype 3a for ove looting Hus hmealobir dees of 301 0 oa asin wth overt Hee oe 3 br ae sda ls emogiabn deeso f 50 / caaclmporade Heong moun aril menerion fare pe Jclorabacanalbmrge np 5 atl ecg” Hritecttnnt 20s le eee eee Sennen in er nye levels re upper bet rm Other ongoing and completed studies biomarker study. Results from other randomized is conceivable that lipid modulating agents might controlled. trials, assessing the results based on affect the risk of thrombosis or inflammation in background and interval changes in biomarkers patients with covid-19.” Several ongoing randomized and use of other antvinflammatory drugs (such as conttolled tials are assessing the effects of lipid corticosteroids) should elucidate this issue ‘modulating agents, including statins, omega 3 fatty The daily dose of statin used in the curtent study acids, fibrates, and niacin across the spectrum of (atorvastatin 20 mgonce daily) was relatively similar Co illness severity in covid-19." Specifically, for patients that used in HARP-2 (simvastatin 80 mg once daily)” admitted to the ICU, three additional tials are ongoing This dose was chosen in INSPIRATIONS to minimize (NcTO4813471, NCTO4359095, and NCT04631536) the risk of statin associated adverse effects, especially and the results will be informative about whether by coadministration of antiviral agents. The rates statins do have a benefit in the treatment of acute of statin associated adverse events (increased liver severe covid-19. In the adaptive Randomized enzyme levels and myopathy) were, however, low in Embedded Multfactorial Adaptive Platform for the current study. This observation isin part explained Community-acquired Pneumonia (REMAP.CAP) tial by the brief perlod of study intervention, compared (cT02735707), simvastatin (80 mg orally once with cardiovascular trials in which patients receive daily for up to 28 days) is being compared with no statin treatment for months or years.” In this regard, treatment. The main study outcomes include daysalive atorvastatin 40 mg once daily or rosuvastatin 20 mg, not receiving organ support in the ICU by day 21, and once daily might have been more effective without 90 day all cause death. ‘compromising safety. ‘A distinct treatment effect for statins based on the Since INSPIRATIONS focused on patients with underlying inflammatory biomarkers is possible.””” covid-19 admitted to the ICU, the findings are not INSPIRATIONS, however, did not have a prespecified generalizable to other patient subgroups, including 8 do 101136 /bmy) 2001 068407 | 472022375.068407 | heb Jwarge 1-01 se pausuand yuu ewe quBuxdoo hq payoa}0%d 1S9N6 Aq ZzOZ YOHEHY GI Uo /usoo fwug'mMM/-cy WOH papeojUMo “Zzoz AUENUEr J UO Lo¥Ee90-1Z0%Peer Subgroup ‘Atorvastatin No/ Placebo No/ (ds ratio Oddsratio Pvalue ‘TotalNeCo” Total NoCD ‘sxe ‘osxe Age (years) 034 -265(186) 46/89152 56/9758) —— 026,046 10167) <650401) 49712 52/2008) oe 077004810120 Sex 070 Women (256) aai2sao 44/1019 —_ 0760043t01.39) Men a3) SING — 64/1669) os 087005410142) Current smoker oa7 Yest#1) sai — 6/1060) +» 0270004t0180) No(S46) 82/2590 102/287035) ae 084005710120) Diabetes ost Yes(08) 2a/a9ia 24/4949) 091 0.29%0214) No(s) Trac — 84/2480 085.0.56101.28) Hypertension on. Yes (185) 40/89149 38/9640) — 134 @61t0219 No(o2) S821) 70/2010) ee 071 0.45t01.12) Obstructive irway disease on Yess) ancy wns) —— 06000.15t0220) No(S40) 87/2660) 97/2749) oe (095.0.5810125) ‘Symptom onset (days) 0s, 57640) SANG 6/7140 — 0800370099) 270245) an90s) 39/1260 —- 12707310220 Corticosteroid use at baseline ost Yes 548) 90/2684) 102/280135) os 087006010128) Nowa 8/20) = 6/17Q3) | + ______ 0470.08 02.78) AAS blocker use a baseline 060 Yes199) 2a/S1a 21/4843) ee 09900.42t0239) Noe) T9090 97/2495) et 078(052t01.17) Body mass index 080 20413) ssn — 69/20200 ee 0.88,0.5610138) 2200174) 30/7938) 39/95c41) — (082004310155) Prophylactic anticoagulation regimen ost 260% Standard dose(175) 31/7939) 41/9643) ee 077003910159) 280% Intermediate dose(148) 25/6897) —_-37/76049) ——— 108200300136) ‘280% Therapeuticdose(16) — 7/@(875) —-7/8@75)_ | + |_______J) se @otto2862) Others 252) 3213504 23/1170) ee 126106110258) Aspirin use at baseline 030 Yest157) 267206 40/8547) — 061 031 01.20) No.0) 69/2180 68/2120 oe 096008210148) or 1 10 Statin better Placebo better represent 95% confidence intervals 3 | Effect of atorvastatin in prespecified subgroups. RAASsrenin-angiotensin-aldosterone system. The x axis is on a log scale, Whiskers those admitted to medical wards or outpatients with covid-19. Other randomized controlled trials are Investigating the effects of statinsin these subgroups.”” ‘Most recently, results from a randomized controlled ‘tial of 40 patients admitted to hospital with reverse transcription polymerase chain reaction confirmed covid-19 who were randomized to atorvastatin 40 ‘mg once daily (in addition to combined lopinavir and ritonavir) compared with lopinavir-itonavir alone, was published, suggesting reductions in C reactive protein levels (P=0.01) and hospital length of stay (8.0 v9.8 days, P-0.01). The study was small, however, and ‘elms 1472022376 0068407 | dol 101126/bu) 2021 068407 ‘open label and did not identify a significant difference between the two groups forthe clinical outcomes.” ‘Strengths and limitations of this study The strengths of this study include the multicenter enrollment of mote than 500 patients from the ICU. Also, the double blind design reduced the risk of performance bias. A committee blinded to teatment assignment adjudicated all clinical outcomes, which enhances the reliability of reported outcomes. This study has several limitations. First, type I error remains possible, Enrollment was stopped before the quBuxdoo hq paya}o%g 1S9N6 Aq ZzOZ YOHEH GI UO juloo Twig’ WH/-cY| WK papeojUmod “Zzoz AUENUEF J UO LovE9O-IZOZ-lwIAIgEL OF SB PaUSHANG ys PvEtarget sample size was reached, Although the study included 98% ofthe planned sample size based on re- estimations in 2020, the final primary outcome event rate was lower than expected. This situation might hhave been because of improved care for patients with, covid-19 in the later months of enrollment compared ‘with the early months of the pandemic. Therefore, the trial was underpowered for the original hypothesis. Findings from the other ongoing statin trials in patients admitted to the ICU are awaited.” Second, the acuity of illness in this study was lower than in ICU cohorts in some other studies, which might impact generalizability to extremely sick patients in the ICU. This challenge fs likely multifactorial. The enrollment criteria required a minimum estimated survival of 24 hours and excluded patients already treated with extracorporeal membrane oxygenation to be able to discern a treatment effect if one were to exist. Such factors could have led to the exclusion of the sickest patients, such as those with unstable respiratory satus on invasive mechanical ventilation or those receiving ‘multiple vasopressors from enrollment. Nevertheless, the study population was very ill as evidenced by the need for cardiopulmonary support and high mortality rates at 30 day follow-up. Several of the baseline treatments and presenting features are similar to those of other randomized controlled tials of patients in the ICU with covid-19."” Finally, the weatments and care for patients with covid-19 have improved over time and could have affected the results. However, we did not identify a significant interaction between the assigned treatment and season of enrollment for the primary outcome (supplementary table $11), Conclusions In patients with covid-19 admitted to the ICU, atorvastatin 20 mg daily compazed with placebo was not associated with a significant reduction in the composite of venous or arterial thrombosis, treatment ‘with extracorporeal membrane oxygenation, or all cause mortality. The effects of a more potent statin, regimen or the impact on a more targeted population of patients with covid-19 require additional Investigation, ‘Authors of study: Behncod Bie, Ata Teas, aba Sha shan Fai ashi Mohammad TghiSeigmotarmad ean Gohat oghadan, SomayeRezaan, al Dabbagh, syed Hestem ‘Sezova, Monsen Faeknpou Hoon Bxhstandeh ate aden soul lane Toph Ra, Mahl Ydoakzaden, Soman Lozada Rese, Sama Mae, Ou Tahaan Keyan Moarraa Ene Zen, Hamid Rahman, Sayed Hoss Hse Saye Mazo Mossi, oma Aon, Padi Soden, Eahe Baghzadeh,Famar fae. Seen janalitan, md Ami, tram Motebb Sey Ehsan Paizgar Mahi olsimarzade, Maryam ‘Apkouctatzadeh, Yahi ai, Poa Pajandeely, Hossein al, Hamed Tite, Tran Tot tad stale Samrand Fata tan, Sane Tabi essam Kakavand, ez Kashatzade, Shaghayea Shohmiaae, bak Najaf, Mahsmitad Fah, Dodd ‘mene, Aaa Gupta, Mahesh V Mocnvan, Sanam § Sth, Sa 2 Parkh Marue Nene Naser advan Alera Hajar all Ansan Moi ale, Sead Sadeshion, Gregor aa, iy Kinane, Briar Van Tssl rege W Store, Gregory ¥ HU, Haran ouou Sarwel 2 Godabe, Paha Sadeehipou ‘See Appeal corms nd subcommitees. ‘We han tne members ofthe dat and slaty noitrna boat Sacldeh Maioonzader, Shvo Wlegpare, Bestia Ghoeeoost Noss Mowenrease, an Mohan es Oy (0 (Graves, Meal an Research Cente, Fein Hoo (ase Craiova Meal and Reseach Cente fis suppor in pefoming ths study, Harkeza Sharia and Arezzo Ama Sina Hospi Tetran Unies of Medial Sclnces, Teena Sasan Tovana an Nasser MlekpouAamdat (Shania Madore Hosta, Saha Bates Urs of Media Sciences, Tein an), Mosaba Horan am Komen Hsp Compe, Tena Unwersty fecal scenes, Tera, fa), Navid Dav000)RasoureAMaM esnraan Unies of Neda Slences, Tran an fr helt "Bnd super for tent erutmens, ane Maryam Zarisaca Sra Te Fame Faroktzadeh Fae Nezamabadl, and Esme Soma jal Cardiac Meal and Resch Cente) fe ‘hat spp and conturon ote NSPRATION Su, Te study coordinating centres were th Rai Cadinasculat scala Reseach Corer andthe evan Heat Centr. The al protocol ee supplementary append 1) was approved bythe Rae avast Moca and Resaarn Cater this commie and coped byl alg ses. Contbutors: 5 nd H ak responsi othe negy othe daca and te accrcy ofthe aralysesin is manuscript. They athe Busan 88, 5, nd AT Jesianed the ial FR PP, HB, A, HW SAP MM GP ARB, GS, GL, Sz, and HK canted ‘tha al dsign PS, AMT, BS, F, MTD i, SB AD, SHS, MF, A,B, Te, My, SL PR, ST, ZH SHS, SMS, A, MS, AVE, HITS Se S,HK AK and 5 ete esponible or oiecion and Acquis fe dt. 8, PS, ANT, a 8 crated the manus, ‘aie wees ised ty al NSPRATION vests. 88 and F3 console he analysis plan and th desiono submit. HB onducted the anaes with ep om PS 2 BB PS an HB ad $cess oa the stay data an vou or he acUray othe anaes ‘Alar take me resperty fr he desson to submit or pletion. The corespanaing autor atest at al sted authors eet author eta anda notte mesg th cari ave been omits Funding: The stay was funded by thease Crdovascuar Medal and Research Cnt Some study authors clung the senior aur, ‘eft wt the aie Cainasular Medal and Research Cee. Acasa and mactng pao were roves ty Sabhan Darou, wich sot among the ty sponsors, Nether tender ro thecompary who dete he sty rus Rac any oe nthe estan ond condctof re study colecton, management, ana nd imerpretaton of he data; peparaion ese apes the manure ore deelson ta sume the manuseto puns, Competing inoress: lt autor have complete he CME tunarm dle fom aw ie ong/decosue of eres na dele epee tot hea conse expe.on aera ot tha plant for ston ret toto spec brand mae’ of WC Fes has served sean aso or consular or Bayer HealthCare Pramaceutas, Boahinger nga, ss Myes Squib, Dale Sakyo, eo Praia, Piz, ROM and San seed as speaker 03 member ofa speokers bara for Byer encore Pama’ Booting ington Bristol-Myers Squib, Dac Sniyo, Leo Parma, 8M ad Sots and rea arts rn esearch from Daich Sanyo, Sano, ane ROU Arcee ames he ‘rnd & Porter Fm for york sted one sano condo! Igation and fom the en Carin Law Fm fo work ltd 0 the Cookin vena cava fie gation. AG holds equity in a etc eearlogy startup, Heartbeat Heath and feceied Consulting res tom EavardsUecencs. NVA Was supported by Sent Fom the Navorl Insts of Heth Natonl Mee, Lin, nd Bod tae to Columbia Univers lv Medial Cente (722 ito07854) 555 eps rece pecan ees fo Janssen ar (hues and rae fom the Amrean Her ASscition Ouse the submits nor SD prt ecen sans rom AD Vase, Boston Scene, Sumodies apd Teme Macias nor fanaa Support fo Cotas, Medi lips and Caravans: nd posal foe mn Terao, biomed and Pera fusde he submited yore. nae receiad earch gt pp to Engh ana Womens Hospital rom x05, 2 6 InteraonalGroup company, ye the Bristol jets Squbb/Pizer lance, Pola, nd ansen He nas recoied consti es rom Agen. ze, Boston Scie, nd Trombols. Ai eporreceing tuto Tuncirg Cotania Unversty andor te Craovscu Resch Foundation rom Medvonic Boston Scena, Abbot asa, Ablomed,Catclorsulr Syste, Candas, Sens, Pps, 2d FeCor Mecca incudngfes pai o Columbia Unversity andor do 101136 /bmy) 2001 068407 | 472022375.068407 | heb quBuxdoo hq paya}o%g 1S9N6 Aq ZzOZ YOHEH GI UO juloo Twig’ WH/-cY| WK papeojUmod “Zzoz AUENUEF J UO LovE9O-IZOZ-lwIAIgEL OF SB PaUSHANG ys PvEthe Cardiasclr Reseach Foundation for specing engagements anafor const; consti ees tom Neuron; na exe ‘xpenses/mets om Medel, ston Sei, Abbett ascuar, Aojoned, Cros Stems, Cathet, Siemens, Pips, Ror Metal Cis. Sens. Zo, at Regeneron. SUVT has caved ‘esearch suport tom Novartis, Swedsh Orhan Bioirun, Otec “aapeuic, an erin Para and as een a consti Pharm and Seria Parma, GH eps rece personal es from Terumo. Cook, TerOx Reva, scar Dyemics, Robot, Hea Fow Gore, Abate Slutons, Mate, Mears News ‘Var, biomed, MAK Pramaceate, Shack, Vectors, CGlomacn sated Bo equ cy options rm pla: “haapeuics, MecFocis, Ses, Ava, Cage and Card Success personal ees and equi ecuy aon fom Specrawave, Val and ‘Ancora: and personal fees, eutyeqlty opts, an hora ‘rom Orenests Bred and outcethe submited work GPL ‘epors being const and speaker BS/Pwr, Boehner Ingetei and DaiciSanyo. No fes are ecived posonay, HK ‘epors teeing personal es fom Ueda AM Wasa Heath, lemer Scene, Aes, aceck, Sieg ensen am Fm, Amoi Pore aw in arinBaghman Law Fr, Prine, She atonal Center for Carhvascusr isazen, sing being {he cofounder of Hugeeath a personal heh infomation pat, and Reto Heath an enterprise ean areata inetignce— ugented data anagem company eet contacts fom {he Centers for Medicare a Media Sees, though Yale New Hoven Hostal to del and mariah measures hosp ‘berfomance; ang reeling rams om Neeonk, he US Food and ‘rug Admunstator, hrs Jonson, andthe Sherer Center ‘ore nomen eutade te submited work SZ has ced ‘esearch suppor rom Bye, Bodnar Ingelheim Bristol Mrs Saul, Boston scent, Dalen, Jansen he Nona ean, {ng and locate andthe Tomes Reseach nite, and asreeedconsuting es fam aye Age, Boston Scent, nd Sostringer ingen tical approval: Te tal protocol was approved bythe Rane (arvana ana Research Cnmeeisconmtee and ‘accepted bl evong sts (RRM AEC 1399.045). ates ‘rth neatncare ros pewided writen informed consent or parpation. ‘ata staring Data wl become avaiable rested investigators upon subting reasonable esearch request yell ond Spproved by esteenngcommitee heal 0B ace ‘Goidetiabuh harvard) oP Sadephipcur (sadeshipoure atmaicom, ‘0 ans afr ht the manus san honest, accuse 3ne ‘ransparert account ofthe study being repre tat 1 mparant _aspets othe tty have bee ome and that any dscepanes ftom me study as ognaty punned (and retvane, ested) have een enplne, Dissemination to participants and related patent and public ‘communities: Mesudy was designed dung Me second wave of ‘he avide19 pandemic aca apd pac, and cansequety no specie ‘ans made for dssaminaon oe a's testo pats and buble cormunites. 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Barbu Raghu Faghunth' Stary: Rel ot Safety and Pte Se ects. Aca Coda Sn 2016.2.6319 39. Dawood orp Oa. rasta reap (COM: 19adut patents: daub, ardor cone (Yan Cot ert se 202136100875, 010 1016. iehag023 100875 40 The RENAD-CA0, ACT a, and ATACvestigaos Terapete Ariccaguatonn Cialy Patents ath Cov15 Pray epee Med 2021;385:777 89, 95103056) eos2103417 Appendix 1: trial protocol Appendix 2: statistical analysis plan Appendix 3: additional figures, tables, and other information ‘Supplementary information: Full list of author affiliations do 101136 /bmy) 2001 068407 | 472022375.068407 | heb quBuxdoo hq paya}o%g 1S9N6 Aq ZzOZ YOHEH GI UO juloo Twig’ WH/-cY| WK papeojUmod “Zzoz AUENUEF J UO LovE9O-IZOZ-lwIAIgEL OF SB PaUSHANG ys PvE