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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.