IfOxygensaturation≤93%onroomair*Forpregnantwomen,O2sat<95%

YNHHSInitialTreatmentAlgorithmforHospitalizedADULTSwithNon–Severe*COVID-19Disclaimer:TherearenoFDA-approvedtreatmentsforCOVID-19,supportivecareisstandardofcare.Limitedtreatmentdataareavailable&clinicaljudgmentiswarranted– Algorithmlastupdated4/27/20

PatientwithconfirmedPOSITIVESARS-CoV-2byPCR�Assessallpatientsroutinelyforclinicaltrialeligibility(seeAppendix6)

*(IfmechanicallyventilatedoronECMO,proceedtoSeverealgorithm)

A-Presenceof:Oxygensaturation≤93%onroomairORonchronicO2supplementation(ifO2>93%seeboxB)

SUPPORTIVECARE&EVERY4HOUR

OXYGENMONITORING

Doespatienthave:Age>60ORBMI>30OR

Diabetes(HgbA1c>8.0)ORChronicheartdisease/HTNOR

ChroniclungdiseaseORImmunosuppressed*

YES

NO

NO

COVID-SPECIFICTESTS1)  Baseline&every12hours(for5days,thendaily

thereafter):CRP,D-dimer

2)  Baseline&every12hoursx3:Troponin(continuelongeriffurthertestingclinicallyindicated)

3)  Baseline&every24hours(for5days*):CBCwithdifferential,CMP,Ferritin,Procalcitonin,BNP,fibrinogen,PT/PTT,Mg

4)  Baseline&ICUtransfer:Cytokinepanel5)  Baselineandwithacutekidneyinjury(AKI):

urinalysisandurineprotein/albuminratio

6)  BaselineEKG,andifnotontelemetry,dailyEKGx3.(seeAppendix3forQTcrecommendations)

7)  RepeatChestX-Ray:ifclinicaldeterioration.(CXRnotindicatedfordischargeortodocumentclinicalimprovement)

*Mayextendlongerifclinicallyindicated

AlgorithmreviewedbyYNHHSSASandYNHH/YSMAd-HocCOVID-19TreatmentTeam

B-Presenceof:1)Feverand/orsigns&symptomsofrespiratorydisease(e.g.cough,dyspnea)

OR2)ChestX-Rayshowinglungopacities

STARTTREATMENT(seetreatmentbelow)

STARTTREATMENT

YES

YNHH:IDconsultisnotmandatory;considerIDinputifimmunosuppressed*orclinicallydecompensatingBH,GH,LMH,orWH:consultID

If≥3LiterO2requirementOR≥2LiterO2requirement&hs-CRP>70

Considertocilizumab(seeAppendix1forexclusioncriteria)

TREATMENTStarthydroxychloroquinex5days

SeePage3ofalgorithmformulti-disciplinarymanagementbysub-specialtyrecommendations

YES

ConsiderMICUevaluationif>4LiterO2requirementorhemodynamicinstability

(atYNHHseeAppendix2forsuggestedtriageguidelines)

ReportsuspectedadverseeventsrelatedtotherapeuticsthroughRLsolutions

YNHHSInitialTreatmentAlgorithmforHospitalizedADULTSwithSevereCOVID-19

PatientwithconfirmedPOSITIVESARS-CoV-2byPCR�Assessallpatientsroutinelyforclinicaltrialeligibility(seeAppendix6)

*(IfmechanicallyventilatedoronECMO,proceedtoSeverealgorithm)

TREATMENTStartHydroxychloroquinex5days

Considertocilizumabx1dose(seeAppendix1forexclusioncriteria)

incombinationwithhydroxychloroquine

Disclaimer:TherearenoFDA-approvedtreatmentsforCOVID-19,supportivecareisstandardofcare.Limitedtreatmentdataareavailable&clinicaljudgmentiswarranted-Algorithmlastupdated4/27/20

AlgorithmreviewedbyYNHHSSASandYNHH/YSMAd-HocCOVID-19TreatmentTeam

Ifprogressionin48hours(worseningrespiratory/clinicalstatusorworsening

inflammatorymarkers):

Considermethylprednisolone40mgQ8Hfor72hours.Reassessforextendedcourseor

taper(upto5-7daystotal).Steroidsgivenatdiscretionofprimaryteam

YNHH:considerIDinputasneededBH,GH,LMH,orWH:consultID

COVID-SPECIFICTESTS1)  Baseline&every12hours(for5days,thendaily

thereafter):CRP,D-dimer

2)  Baseline&every12hoursx3:Troponin(continuelongeriffurthertestingclinicallyindicated)

3)  Baseline&every24hours*:CBCwithdifferential,CMP,Ferritin,Procalcitonin,BNP,fibrinogen,PT/PTT,Mg

4)  Baselineandwithacutekidneyinjury(AKI):urinalysisandurineprotein/albuminratio

5)  OnICUadmission:Cytokinepanel

6)  BaselineEKG,andtelemetryQTcmonitoring.EKGforclinicalchange(seeAppendix3forQTcrecommendations)

7)  RepeatChestX-Ray:ifclinicaldeterioration.(CXRnotindicatedfordischargeortodocumentclinicalimprovement)

*Mayextendlongerifclinicallyindicated

ReportsuspectedadverseeventsrelatedtotherapeuticsthroughRLsolutions

IfpatientonECMOorplannedforECMO,alsoseeECMOalgorithm

SeePage3ofalgorithmformulti-disciplinarymanagementbysub-specialty

recommendations

Hematologic:-IfD-dimer<5mg/L:Allpatientsshouldreceivestandardprophylacticanticoagulationunlesscontraindicated★

-IfD-dimer≥5mg/L:useweight-basedintermediateprophylacticanticoagulationunlesscontraindicated★

-IfconfirmedVTEorhighclinicalsuspicion,starttherapeuticdoseanticoagulationunlesscontraindicated★

-IfsuddenandunexplainedchangeinO2ORnewasymmetricalupperorlowerextremityedema,considervenousU/Sofaffectedextremity

-Ifferritin>100,000orD-dimer>10mg/L,considerHematologyconsultatdiscretionofprimaryteam

(★seeAppendix4fordosingrecommendations)

Cardiac:-Monitorelectrolytes:RepleteMg>2,K>4

-BaselineEKGandmonitortelemetrycloselyforQTcProlongation(Appendix3forrecommendations)

-CautioncombiningQTcprolongingmedications

-IfsignificantlyelevatedtroponinorEKGabnormalitiesand/orhemodynamicinstability,considerPOCUSforLVfunctionassessmentandcardiologyconsult

Nephrology:-Ifacutekidneyinjury,checkurinalysisandbaselineurineprotein/albumin.-If≥1gramofprotein,considerrenalinput

*Immunosuppressionincludesfollowing:Cancertreatmentwithin1year,theuseofimmunosuppressivedrugs(biologics,chronicprednisone≥20mgdaily),solidorgantransplant,bonemarrowtransplantation,HIV/AIDS(regardlessofCD4count),leukemia,lymphoma,SLE,vasculitis,andpregnancy

Obstetrics:TreatmentProtocolissimilar.Alternativecut-offsfor:-Treatmentadministrationwithoxygensaturationof<95%.-D-dimercutoffforanticoagulation(seeAppendix4b)

YNHHSInitialTreatmentAlgorithmforHospitalizedADULTSwithCOVID-19Disclaimer:TherearenoFDA-approvedtreatmentsforCOVID-19,supportivecareisstandardofcare.Limitedtreatmentdataareavailable&clinicaljudgmentiswarranted-Algorithmlastupdated4/27/20

YNHHSAlgorithmforHospitalizedADULTSwithSEVERECOVID-19requiringECMODisclaimer:TherearenoFDA-approvedtreatmentsforCOVID-19,supportivecareisstandardofcare.Limitedtreatmentdataareavailable&clinicaljudgmentiswarranted– Algorithmlastupdated4/27/20

AlgorithmreviewedbyYNHHSSASandYNHH/YSMAd-HocCOVID-19TreatmentTeam

GuidanceforPatientswithConfirmedCOVID-19andRefractoryRespiratoryFailureRequiringECMO

Evaluation/ManagementofSecondaryCausesofRespiratoryFailure

•  Vigorouspulmonarytoilette•  Infection–bloodandsputumcultures•  Pulmonaryembolism•  Heartfailure–limitedTTE

Priortocannulation•  Goalsofcarediscussion•  FollowYNHHCOVID-19Severe

Algorithmfortreatmentandtesting•  Evaluateforsecondarycausesof

respiratoryfailure•  Orderpre-ECMOcytokinepanel

ECMO(24-48hours)•  RepeatSARS-CoV-2PCRtestingon

endotrachealaspirateimmediatelyaftercannulation

•  Orderpost-ECMOcytokinepanel(after~48hours)

•  Assesseligibilityforclinicaltrials/expandedaccessprotocols

ECMO(2-3weeks)•  Revisitgoalsofcarediscussionsif

noclinicalimprovementafteraddressingpotentiallyreversibleprocesses

PotentialAdjunctiveTherapeuticResources

TargetvirusifendotrachealSARS-CoV-2PCRispositive

•  Remdesivircompassionateuseifeligible(CurrentRemdesivirtrialexcludespatientsonECMO)

•  Convalescentserumadministrationifeligible

-and/or-

Targetcytokinesifimmunedysregulationispresent

•  ConsultAllergy/Immunology•  PossiblerepeatTocilizumabdosing•  Sarilumabtrialifeligible(Currenttrial

excludespatientswhoreceivedanIL-6antagonistintheprior30days)

•  CytokineadsorptionviaECMOcircuit

*Availableoptionsaresubjecttorapidchange*

ECMO(48hours–2weeks)•  ConsiderAllergy/Immunologyand

InfectiousDiseasesconsultation•  Consideradjunctivetherapeutic

resources

Appendix1:TocilizumabExclusionCriteriaa.Anticipatedimmediatedeath(≤24hours)regardlessofcriticalcaresupportb.Cardiac:NYHAClassIVheartfailure;Severe,inoperablemulti-vesselcoronaryarterydisease;Cardiacarrest;Recurrentarrestsinthecurrentpresentation,orunresponsivetodefibrillationorpacing,orunwitnessedout-of-hospitalcardiacarrestwithpoorprognosisc.Hepatic:CirrhosiswithMELD-Nascore≥25(inpatientswhoarenottransplantcandidates),alcoholichepatitiswithMELD-Na>30,advancedlivercancerd.Neurologic:SeveredementialeadingtodependenceinmultipleADLs;Rapidlyprogressiveorend-stageneuromusculardiseasee.Oncologic:Advancedmalignancyorhigh-gradeprimarybraintumorsreceivingonlypalliativetreatmentwithestimated3orfewermonthprognosis.f.Pulmonary:Severe,chroniclungdiseasewithbaselineoxygenrequirementof>60%FiO2;PrimarypulmonaryhypertensionwithNYHAClassIII-IVheartfailure(andpatientrefractoryto/notacandidateforpulmonaryvasodilators)g.Trauma:Severetrauma;Severeburns:age>60and50%oftotalbodysurfaceareaaffectedh.FunctionalStatus:DependentinallADLsduetoaprogressivechroniccomorbidcondition

Appendix2:YNHHAcuteRespiratoryFailurewithCOVID-19MICU/SDUTriageGuidelines

ObtainABG

>4LNCwithO2sat<93%

RR<25

HypercapniawithpH<7.32

ConsultMICU

pH>7.32

ConsiderSDUevaluation,reassessin2-4hours

RR>25+/-AMS+/-inabilitytomanage

secretions

ObtainABGandconsultMICU

Appendix3:CarePathwaysforMitigationofDrug-InducedMalignantArrhythmiasinCOVID-19PatientsRecommendations:AllCOVID-19patientsshouldhavethefollowing:• WhenorderinganEKGforaCOVID19patienttomonitortheirQTc,selectthediagnosis“COVID19”toalertcardiologytoexpeditetheformalreadingoftheEKG.

• Dailymonitoringofelectrolytes;maintainK>4andMg>2• AllunnecessaryQTprolongingdrugsshouldbeavoidedorswitchedtoalternativeswheneverpossible.

Recommendations:Aflowchartforthemonitoringofpotentialmalignantarrhythmiasinthesepatientsisshownbelow.

Appendix4a:AnticoagulationDosingGuidelines(Non-PregnantPatients)¥

DOACDosing

*Targetanti-Xalevelsbetween0.3–0.7units/mL¥Enoxaparinisthepreferredformofanticoagulation

€Patientsreceivingtreatmentshouldcontinuefulldoseanticoagulationfor3monthsConsultpharmacyforassistancewithdosingrecommendations,ifneeded

Seekhematologyinputforfurtherrecommendationsontreatmentasneeded,includingdurationandextendedprophylaxisfordischarge

D-dimer BMI<40kg/m2 BMI≥40kg/m2

<5mg/LProphylaxis

CrCl≥30mL/min

• Enoxaparin40mgsqdailyCrCl<30mL/min

• Enoxaparin30mgsqdaily• Heparin5000unitssqQ8-12H

CrCl≥30mL/min

• Enoxaparin40mgsqQ12HCrCl<30mL/min

• Enoxaparin40mgsqQ24H• Heparin7500unitssqQ8-12H

≥5mg/LIntermediateDoseProphylaxis

CrCl≥30mL/min

• Enoxaparin0.5mg/kgsqQ12H*• DOAC

CrCl<30mL/min• Enoxaparin0.5mg/kgsqQ12H*• DOAC• Heparin7500unitssqQ8-12H

CrCl≥30mL/min

• Enoxaparin0.5mg/kgsqQ12H*• DOAC

CrCl<30mL/min• Enoxaparin0.5mg/kgsqQ12H*• DOAC• Heparin7500unitssqQ8H

ConfirmedVTE,highclinicalsuspicion,orclottingofdialysislines/tubing

TREATMENT€

CrCl≥30mL/min

• Enoxaparin1mg/kgsqQ12H• DOAC

CrCl<30mL/min• Enoxaparin1mg/kgsqQ24H• DOAC• Therapeuticheparin

CrCl≥30mL/min

• Enoxaparin1mg/kgsqQ12H• DOAC

CrCl<30mL/min• Enoxaparin1mg/kgsqQ24H• DOAC• Therapeuticheparin

DOACD-dimer≥5mg/L

IntermediateDoseProphylaxisConfirmedVTEtreatment,highclinicalsuspicionor

clottingofdialysislines/tubing

Apixaban5mgPOQ12Hregardlessofrenal

function10mgPOQ12Hx7daysfollowedby5mgPOQ12H(limiteddatafor10mginCrCl<25orCr>2.5)

Rivaroxaban(mayfavorinBMI≥40kg/m2)

20mgQ24HAvoidusewithCrCl<30mL/min

15mgPOQ12Hx21daysfollowedby20mgPOQ24H

AvoidusewithCrCl<30mL/min

Appendix4b:AnticoagulationDosingGuidelines(PregnantPatients)

DosingweightforPREGNANTpatientsshouldbeactualbodyweightandPOST-PATRUMdosingshouldbePRE-PREGNANCYweight

*Targetanti-Xalevelsbetween0.3–0.7units/mLConsultpharmacyforassistancewithdosingrecommendations,ifneeded

Seekhematologyinputforfurtherrecommendationsontreatmentasneeded,includingduration

D-dimer BMI<40kg/m2 BMI≥40kg/m2

<3.5mg/LProphylaxis

CrCl≥30mL/min

• Enoxaparin40mgsqdailyCrCl<30mL/min

• Enoxaparin30mgsqdaily

CrCl≥30mL/min

• Enoxaparin40mgsqQ12HCrCl<30mL/min

• Enoxaparin40mgsqQ24H

≥3.5mg/LIntermediateDoseProphylaxis

CrCl≥30mL/min

• Enoxaparin0.5mg/kgsqQ12H*CrCl<30mL/min

• Enoxaparin0.5mg/kgsqQ12H*

CrCl≥30mL/min

• Enoxaparin0.5mg/kgsqQ12H*CrCl<30mL/min

• Enoxaparin0.5mg/kgsqQ12H*

≥7mg/LConfirmedVTEorhighclinical

suspicionTREATMENT

CrCl≥30mL/min

• Enoxaparin1mg/kgsqQ12HCrCl<30mL/min

• Enoxaparin1mg/kgsqQ24H

CrCl≥30mL/min

• Enoxaparin1mg/kgsqQ12HCrCl<30mL/min

• Enoxaparin1mg/kgsqQ24H

Appendix5

CurrentlyrecommendedmedicationsforCOVID-19(Subjecttochangeasmoredatabecomesavailableandbasedonmedicationavailability)

Drug Dose Mechanism Rationaleforuse NotableAdverseReactions Otherconsiderations

Hydroxy-chloroquine(HCQ)1-9,48-52

400mgPOq12hx24hfollowedby200mgq12hx4daysfora5daytotalduration

• Preventsacidificationofendosomesinterruptingcellularfunctionsandreplication

• PreventsviralentryviaACE2binding

• Reductionofviralinfectivity

• Immunomodulator

• In-vitrodatashowspotentSARS-COV-2inhibitionandearlyclinicaldatashowspossiblebenefit

• HCQwasfoundmorepotentthanchloroquineininhibitingSARS-CoV-2invitro

• QTcprolongation• Rash• Retinopathyisrare

(BaselineeyeexamisnotrequiredforuseforCOVID-19)

• ThereisatheoreticalpotentialforanincreaseinhydroxychloroquinelevelswhenusedwithatazanavirthereforemonitorforpossibleQTcprolongation

• ForpatientswithNG/OG/NThydroxychloroquinecanbecrushedforenteraladministration

IMMUNOMODULATINGAGENTS

Tocilizumab10-

13

8mg/kgIVx1dose(actualbodyweight);dosemax800mg)

• MonoclonalantibodytoIL6receptor

• IL-6receptorantagonistmayattenuatecytokinereleaseinpatientswithseveredisease

• Retrospectivedatasuggestpossiblebenefit(clinicaltrialsongoing)

• Headache• Elevatedliver

enzymes• Infusionreactions

(e.g.flushing,chills)

• TheuseofIL-6levelsshouldNOTguidedecisiontoadministertocilizumabatthistime

• Additionaldosesnotindicatedatthistime

MedicationswhichmaybeavailablethroughClinicalTrials(Subjecttochangeasmoredatabecomesavailableandbasedonmedicationavailability)

Remdesivir14-17

ClinicalTrialdosing

• ViralRNAdependentRNApolymeraseinhibitor

• In-vitrodatarevealspotentSARS-COV-2inhibitionandearlyclinicaldatashowspossiblebenefit

• Nausea,vomiting,• Elevatedliver

enzymes• Rectalbleeding

• Asof3/22/20,remdesivirisavailablethroughclinicaltrials

• Compassionateuseprogramisavailabletopregnantpatientsandthose<18yearsofage

• Gileadwillopenanexpandedaccessprogram

IMMUNOMODULATINGAGENTS

Sarilumab18-20

ClinicalTrialdosing

• MonoclonalantibodytoIL6receptor

• IL-6receptorantagonistmayattenuatecytokinereleaseinpatientswithseveredisease

• Elevatedliverenzymes

• Leukopenia• Infusionreactions

(e.g.flushing,chills)

• Availablethroughclinicaltrialonlyatthistime

MedicationsNOTcurrentlyrecommendedasfirstlineforCOVID-19(CanbeconsideredincertaincasesafterdiscussionwithInfectiousDiseasesandPharmacy)

Drug Dose Mechanism Rationaleforpossibleefficacy RationaleforNOTincludingasfirstlineagent

Lopinavir/Ritonavir8,21 N/A • Viralprotease

inhibitor • In-vitrodatarevealspotentSARS-COV-2inhibition• Limitedavailability,poortolerability(suchasGI

sideeffects)andrecentdatademonstratedquestionableclinicalefficacy

Atazanavir22

NOLONGERRECOMMENDEDASFIRST

LINEduetoupdatedLopinavir/ritonavirdata19

N/A • Viralproteaseinhibitor

• Morepotentbindingtotheviruscomparedtootherproteaseinhibitorsinvitro(lowerthanlopinavir)

• DrugmorewidelyavailablethanotherPI’sincludinglopinavir/ritonavirandbettertolerated

• Mildindirecthyperbilirubinemiaiscommonandnotindicativeofhepaticdysfunction

• CYPenzymeinhibitor(3A4,2C8)monitor/discusswithpharmacypotentialfordrug-druginteractions

• ForpatientswithNG/OG/NJopencapsulesforenteraladministration

• Atazanavirneedsanacidicenvironmentforabsorptionandthereforeantacids,H2blockers,protonpumpinhibitors(PPIs)shouldbeavoided.Iftheseagentsmustbegiventheadministrationshouldbeseparatedasbelow:

o Atazanavirshouldbegiven2hoursbeforeor1hourafterantacids

o AtazanavirshouldbegivenatthesametimeastheH2blockerortheatazanavirshouldbegiven10hoursafteror2hoursbeforetheH2blocker

• ForPPIsavoidconcomitantuse

Azithromycin

23

500mgx1,followedby250mgq24hx4days

• Notwelldefined;possibleimmunomodulator

• Inasmallstudy,combinationofHCQandazithromycinwasassociatedwithsignificantareductioninSARS-CoV-2viralload

• Verylimiteddataonuseofazithromycinaloneorincombinationwithotheragentso Gautret,etal.studyislimitedbysmallsample

size(only6patientsreceivedHCQ&azithromycincombination)andthosepatientshadlowerviralloadsthanotherincludedpatients

• CombinationofHCQandazithromycinand

atazanavircanincreasetheriskforQTcprolongation

Darunavir/Cobicistat24 N/A • Viralprotease

inhibitor • In-vitrodatashowsSARS-COV-2inhibition • Decreasedbindingtoviralproteasecomparedtoatazanavir.Noclinicaldataatthistime

Ribavirin25-27 N/A

• ViralRNApolymeraseinhibitorandinhibitionofelongationofRNAfragments

• InvitrodataforuseinSARS-CoVandMERS-CoVindicatespossibleactivity

• LimitedevidenceforSARS-CoV-2andtoxicityriskoutweighsbenefitofuse

• Typicallyusedwithinterferon• Studiedinpatientswithothercoronaviruseswith

mixedresults

Oseltamivir28 N/A

• Inhibitsinfluenzavirusneuraminidaseblockingviralrelease

• Activityagainstinfluenzavirus

• Nocurrentdatatosupportuseofthisdrug.• Additionally,SARS-CoV-2doesnotuse

neuraminidaseinthereplicationcyclesomechanisticallytherewouldbenobenefit

Nitazoxanide29 N/A • Augmentshost

antiviralresponse • In-vitrodatarevealsSARS-COV-2inhibition • Noclinicaldataavailable

IMMUNOMODULATINGAGENTS

Interferon-beta30-32 N/A • Immunomodulat

or

• PossibleactivityagainstSARS-CoVandMERS-CoV• Typicallyusedincombinationwithribavirin

• LimiteddatawithSARS-CoV-2,toxicityriskoutweighsbenefitofuse

• Havebeenstudiedforpatientswithothercoronaviruseswithmixedresults

• Notinterferon-alphaorinterferon-gamma

Corticosteroids33-37

Ifindicated

perprotocol:

Methyl-prednisol

one

40mgq8hrIVforthreedays,thenre-assess

• InhibitproductionofinflammatorycytokinesthatregulateneutrophilandT-cellresponsesleadingtoimmunesuppression

• Maybehelpfulinattenuatingcytokinereleaseinpatientswithseveredisease

• LackofeffectivenessandpotentialharmshowninliteraturespecificallyinhibitionofviralclearanceinsevereinfluenzaandSARS31-34,thoughpossiblebenefitwithcriticallyillCOVID19patients35

• Maybeconsideredforusebycriticalcareteamforsalvagetherapy

• Corticosteroidsshouldbeusedifclinicallyindicated

aspartofstandardofcaresuchasforanasthmaorCOPDexacerbation,orshockwithhistoryofchronicsteroiduse

Intravenousimmunoglobulin(IVIG)38-39

N/A• Neutralizing

antibodiesagainstthevirus

• Mayhavebothantiviralandimmunomodulatoryeffects

• Arecentobservationalstudyreportedclinicaland

radiographicimprovementin3patientswhoreceivedhighdoseIVIGattimeofrespiratorydistress

• DrugisoncriticalnationalshortageandhasanunclearroleascurrentpreparationswillnotcontainantibodiesagainstSARS-CoV-2atthistime

Baricitinib40-41 N/A

• JanusKinase

(JAK)inhibitorbindingcyclinG-associatedkinase,mayinhibitviralentryviaendocytosis

• Mayhavetargetedantiviralandimmunomodulatoryeffectwithlessside-effectsataneffectivedosethanotherJAKinhibitors

• Notavailableforofflabeluse

• Noclinicaldataavailable• Riskofsevereinfectionswithuse

Zinc42,43 N/A

• DirectlyimpairsRNAsynthesisinSARS-CoVbyinhibitingthereplicationandtranscriptioncomplex,aswellas

• IncreasingintracellularzincconcentrationsmayinhibitRNAsynthesis

• Noclinicaldataisavailabletodemonstrateefficacyinvivo.

• Noinvitrostudieshaveevaluatedtheeffectofzinc

onSARS-CoV-2replication,orhydroxychloroquineasazincionophore

RNA-dependentRNApolymerase.Chloroquinehasbeendemonstratedtobeazincionophore.Alldataisbasedoninvitrostudiesonly.

Ascorbicacid&Thiamine44-47

N/A• Unclear;?rolein

septicshock/ARDs

• ?benefitinsepticshock/ARDs

• NopublishedpeerreviewedstudiesinthemedicalliteraturewerefoundtosupporttheusageofthesevitaminsforCOVID-19.Thereareongoingclinicaltrialsassessingpossiblebenefit.

• Tworecentlypublishedopen-labelstudiesevaluatingtheuseofvitaminCaloneandincombinationinothertypesofinfections,associatedwithsepticshockandacuterespiratorydistresssyndrome(ARDS)showednoclearevidenceofbenefit.ItcannotbeconcludedthatintravenousvitaminCorthiamineisaneffectivetreatmentofARDS(resultingfromCOVID-19,orotherwise).

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Appendix6:ActiveCoronavirus(SARS-CoV)-2infectionClinicalTrialsforHospitalizedPatients

Drug,studydescriptionandrationaleforuse InclusionandExclusionCriteria

Notableadverseeffects

PrimaryInvestigator(s)/ContactInformation

Drug:RemdesivirViralRNAdependentRNApolymeraseinhibitorRationale:In-vitrodatarevealspotentSARS-COV-2inhibitionandearlyclinicaldatashowspossiblebenefitDescription:APhase3RandomizedStudytoEvaluatetheSafetyandAntiviralActivityofRemdesivir(GS-5734™)inParticipantswithSevereCOVID-19

Mild/ModerateDisease

Inclusion

• Aged≥18yearsorAdolescents12–18yearsweighing>40kg• Lunginvolvementconfirmedwithchestimaging• Coronavirus(SARS-CoV)-2infectionconfirmedbypolymerasechainreaction(PCR)test≤4daysbeforerandomization(mayrepeattestif>4days)

• Willingnessofstudyparticipanttoacceptrandomizationtoanyassignedtreatmentarm

• MustagreenottoenrollinanotherstudyofaninvestigationalagentpriortocompletionofDay28ofstudy

NauseaVomitingElevatedliverenzymes

PI:OnyemaOgbuaguContact:Onyema.Ogbuagu@yale.eduLaurie.Andrews@yale.eduContact(GHexpandedaccesstrial):Gavin.McLeod@greenwichhospital.org

KeyExclusion

• Severeliverdisease• SaO2/SPO2≤94%inroomaircondition,orthePa02/Fi02ratio<300mgHg• Severerenalimpairmentorreceivingrenalreplacementtherapy• Pregnantorbreastfeeding,orpositivepregnancytestinapredoseexamination• ReceiptofanyexperimentaltreatmentforCOVID-19withinthe30dayspriortothetimeofthescreeningevaluation

• Creatinineclearance<50mL/min

SevereDisease

Inclusion

• Aged≥18yearsorAdolescents12–18yearsweighing>40kg• SevereAcuteRespiratorySyndromeCoronavirus(SARS-CoV)-2infectionconfirmed

bypolymerasechainreaction(PCR)test≤4daysbeforerandomization(mayrepeattestif>4days)

• Peripheralcapillaryoxygensaturation(SpO2)≤94%orrequiringsupplementaloxygenatscreening

KeyExclusion

• ParticipationinanyotherclinicaltrialofanexperimentaltreatmentforCOVID-19• ConcurrenttreatmentwithotheragentswithactualorpossibledirectactingantiviralactivityagainstSARS-CoV-2isprohibited<24hourspriortostudydrugdosing

• Evidenceofmultiorganfailure• Mechanicallyventilated(includingV-VECMO)≥5days,oranydurationofV-AECMO• Requiringmechanicalventilationatscreening• Severeliverdisease• Creatinineclearance<50mL/min

Drug:SarilumabMonoclonalantibodytoIL6receptorRationale:IL-6receptorantagonistmayattenuatecytokinereleaseinpatientswithseverediseaseDescription:Phase2/3,Randomized,Double-Blind,PlaceboControlledStudyAssessingEfficacyandSafetyofSarilumabforHospitalizedPatientswithCOVID-19

Inclusion

• Aged≥18years• Evidenceofpneumoniaandhaveoneofthefollowingdiseasecategories:severedisease,multi-systemorgandysfunctionorcriticaldiseaseLaboratory-confirmedSARS-CoV-2infection

ElevatedliverenzymesLeukopeniaInfusionreactions(e.g.flushing,chills)

PI:GeoffreyChuppContact:Geoffrey.Chupp@yale.edu

KeyExclusion

• Lowlikelihoodofsurvivalafter48hoursfromscreening• Presenceofneutropenialessthan2000/mm3• ASTorALTgreaterthan5XULN• Platelets<50,000/mm3priorimmunosuppressivetherapies• Useofchronicoralcorticosteroidsfornon-COVID-19relatedcondition• PatientswhohavereceivedIL-6receptorantagonistwithin30daysofstudyenrollment

• ParticipationinanyotherclinicaltrialofanexperimentaltreatmentforCOVID-19• Knownorsuspectedhistoryoftuberculosis• Suspectedorknownactivesystemicbacterialorfungalinfection

ExpandedaccessprogramforuseofconvalescentplasmainCOVID-19patients

Inclusion

• Aged≥18years• ConfirmedpositiveSARS-CoV-2infectionbyPCR• SevereorLife-threateningdiseasebythefollowingdefinitions• Severedisease

o Requiringsupplementaloxygenwithoneormoreofthefollowing:! Non-rebreather! High-flownasalcannula! Pulmonaryinfiltrateswith≥3LviaNCwithrapidprogression! Mechanicalventilation

• Life-threateningdiseaseo Refractoryrespiratoryfailure,oro Septicshock,oro Multi-organdysfunction

Contacts:YNHH:Mahalia.desruisseaux@yale.eduBH:Tina.McCurry@bpthosp.orgGH:James.Sabetta@greenwichhospital.orgLMH/WH:Christopher.Song@lmhosp.org

RelativeExclusion

• ≥10dayssincefirstpositiveSARS-CoV-2PCR• Confirmedorhighsuspicionforbacterialorfungalinfection• D-dimer≥5mg/Lorevidenceof/suspicionforthrombosis• Recentbleedingorhighriskforbleeding&ontreatmentdoseheparin-basedor

fondaparinuxanticoagulation• KnownsevereIgAdeficiency

ForsinglepatientINDsandemergencyuse,expandedaccessmaybeappropriatewhenallthefollowingapply:

•Patienthasaseriousdiseaseorcondition,orwhoselifeisimmediatelythreatenedbytheirdiseaseorcondition•Thereisnocomparableorsatisfactoryalternativetherapytodiagnose,monitor,totreatthediseaseorcondition•Patientenrollmentinaclinicaltrialisnotpossible•Potentialpatientbenefitjustifiesthepotentialrisksoftreatment•Providingtheinvestigationalmedicalproductwillnotinterferewithinvestigationaltrialsthatcouldsupportamedicalproduct’sdevelopmentormarketingapprovalforthetreatmentindication

Thereareseveralstepsnecessarywhenundertakingemergencyuseofadrugincludingspecificinvestigator,Sponsor,andFDArequirements.IfaproviderassessesemergencyuseofadrugisappropriatetheyshouldcontacttheYaleHumanResearchProtectionProgram(HRPP)andtheInvestigationalDrugService(IDS)(203-688-4872)assoonaspossibletogetassistanceinidentifyingandnavigatingtheapplicablerequirements.