Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients

75 Pages·2017·1.71 MB·English

Research
JAMA | OriginalInvestigation | CARINGFORTHECRITICALLYILLPATIENT
Effect of Human Recombinant Alkaline Phosphatase
on 7-Day Creatinine Clearance in Patients
With Sepsis-Associated Acute Kidney Injury
A Randomized Clinical Trial
PeterPickkers,MD,PhD;RavindraL.Mehta,MD;PatrickT.Murray,MD;MichaelJoannidis,MD;BruceA.Molitoris,MD;JohnA.Kellum,MD;
MirjamBachler,PhD;EricA.J.Hoste,MD,PhD;OscarHoiting,MD;KennethKrell,MD;MarliesOstermann,MD,PhD;WimRozendaal,MD;
MiiaValkonen,MD,PhD;DavidBrealey,MD,PhD;AlbertusBeishuizen,MD,PhD;FerhatMeziani,MD,PhD;RaghavanMurugan,MD,MS,FRCP;
HildedeGeus,MD,PhD;DidierPayen,MD,PhD;ErikvandenBerg,MSc;JacquesArend,MD;fortheSTOP-AKIInvestigators
Supplementalcontent
IMPORTANCESepsis-associatedacutekidneyinjury(AKI)adverselyaffectslong-termkidney
outcomesandsurvival.Administrationofthedetoxifyingenzymealkalinephosphatasemay
improvekidneyfunctionandsurvival.
OBJECTIVE Todeterminetheoptimaltherapeuticdose,effectonkidneyfunction,and
adverseeffectsofahumanrecombinantalkalinephosphataseinpatientswhoarecriticallyill
withsepsis-associatedAKI.
DESIGN,SETTING,ANDPARTICIPANTS TheSTOP-AKItrialwasaninternational(53recruiting
sites),randomized,double-blind,placebo-controlled,dose-finding,adaptivephase2a/2b
studyin301adultpatientsadmittedtotheintensivecareunitwithadiagnosisofsepsisand
AKI.PatientswereenrolledbetweenDecember2014andMay2017,andfollow-upwas
conductedfor90days.Thefinaldateoffollow-upwasAugust14,2017.
INTERVENTIONS Intheintention-to-treatanalysis,inpart1ofthetrial,patientswere
randomizedtoreceiverecombinantalkalinephosphataseinadosageof0.4mg/kg(n=31),
0.8mg/kg(n=32),or1.6mg/kg(n=29)orplacebo(n=30),oncedailyfor3days,toestablish
theoptimaldose.Theoptimaldosewasidentifiedas1.6mg/kgbasedonmodelingapproaches
andadverseevents.Inpart2,1.6mg/kg(n=82)wascomparedwithplacebo(n=86).
MAINOUTCOMESANDMEASURES Theprimaryendpointwasthetime-correctedareaunder
thecurveoftheendogenouscreatinineclearancefordays1through7,dividedby7toprovide
ameandailycreatinineclearance(AUC ECC).Incidenceoffatalandnonfatal(serious)
1-7
adverseevents([S]AEs)wasalsodetermined.
RESULTS Overall,301patientswereenrolled(men,70.7%;medianage,67years
[interquartilerange{IQR},59-73]).Fromday1today7,medianECCincreasedfrom26.0
mL/min(IQR,8.8to59.5)to65.4mL/min(IQR,26.7to115.4)intherecombinantalkaline
phosphatase1.6-mg/kggroupvsfrom35.9mL/min(IQR,12.2to82.9)to61.9mL/min(IQR,
22.7to115.2)intheplacebogroup(absolutedifference,9.5mL/min[95%CI,−23.9to25.5];
P=.47).Fataladverseeventsoccurredin26.3%ofpatientsinthe0.4-mg/kgrecombinant
alkalinephosphatasegroup;17.1%inthe0.8-mg/kggroup,17.4%inthe1.6-mg/kggroup,and
29.5%intheplacebogroup.RatesofnonfatalSAEswere21.0%forthe0.4-mg/kg
recombinantalkalinephosphatasegroup,14.3%forthe0.8-mg/kggroup,25.7%forthe AuthorAffiliations:Author
1.6-mg/kggroup,and20.5%fortheplacebogroup. affiliationsarelistedattheendofthis
article.
CONCLUSIONSANDRELEVANCE Amongpatientswhowerecriticallyillwithsepsis-associated GroupInformation:TheSTOP-AKI
Investigatorsarelistedattheendof
acutekidneyinjury,humanrecombinantalkalinephosphatasecomparedwithplacebodidnot
thisarticle.
significantlyimproveshort-termkidneyfunction.Furtherresearchisnecessarytoassess
CorrespondingAuthor:Peter
otherclinicaloutcomes.
Pickkers,MD,PhD,Departmentof
IntensiveCareMedicine,Radboud
TRIALREGISTRATION ClinicalTrials.govIdentifier:NCT02182440 UniversityNijmegenMedicalCenter,
POBox9101,InternalPost710.0,
JAMA.2018;320(19):1998-2009.doi:10.1001/jama.2018.14283 6500HBNijmegen,theNetherlands
PublishedonlineOctober24,2018. ([email protected]).
1998 (Reprinted) jama.com
©2018AmericanMedicalAssociation.Allrightsreserved.
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EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI OriginalInvestigation Research
A
cutekidneyinjury(AKI)occursinupto60%ofpa-
tientsinintensivecareunits(ICUs),anditsincidence KeyPoints
isincreasing.1,2DevelopmentofAKIinpatientswith
Question Doestheuseofhumanrecombinantalkaline
sepsisisassociatedwithincreasedmortality,3andsurvivors phosphataseimprovekidneyfunctioninpatientswhoarecritically
areatriskofdevelopingchronickidneydisease,4resultingin illwithsepsis-associatedacutekidneyinjury?
aburdenforbothpatientandsociety.Sepsis-associatedAKI
Findings Inthisrandomized,double-blind,placebo-controlled,
isamultifactorialsyndromewithinflammatory,nephro-
dose-findingadaptivephase2a/2btrialenrolling301adults,
toxic,andischemicinsultsoccurringsimultaneouslywithother theoptimaltherapeuticdoseofrecombinantalkalinephosphatase
pathophysiologicalresponsesrapidlyleadingtokidney was1.6mg/kg.Treatmentwiththisdosefor3dayswhen
impairment.5Currently,nopharmacologicinterventionsare addedtostandardcareresultedinamedianincreasein
availabletopreventortreatAKI.6 endogenouscreatinineclearanceof27.6mL/minvs14.7mL/min
forplacebointhefirst7days,adifferencethatwasnot
Alkalinephosphataseisanendogenousenzymethat
statisticallysignificant.
exertsdetoxifyingeffectsthroughdephosphorylationof
variouscompounds,includingbacterialendotoxins7and Meaning Amongpatientswhowerecriticallyillwith
proinflammatorymediatorssuchasextracellularadenosine sepsis-associatedacutekidneyinjury,treatmentwithhuman
triphosphate.8Inanimalsepsismodels,treatmentwith recombinantalkalinephosphatasedidnotimprovekidney
functioninthefirstweekoftreatment.
alkalinephosphataseattenuatedsystemicinflammation
andorgandysfunctionandimprovedsurvivalrates.9In2
smallclinicaltrials,administrationofbovinealkalinephos- inpatienttrialwithrecombinantalkalinephosphataseand
phatasesignificantlyimprovedkidneyfunctioninpatients thereforedifferencesin,forexample,pharmacokinetics
withsepsis.10,11 couldbepossible.
Basedontheseresults,ahumanrecombinantformof TheSTOP-AKItrialwasaninternationalrandomized,
alkalinephosphatasewasdevelopedthatcombinedthe double-blind,placebo-controlled,4parallel-group,dose-
propertiesof2humanisoenzymes,intestinalandplacental finding,adaptivephase2a/2btrialconductedincriticallyill
alkalinephosphatase.12Replacingthecrowndomainof adultswithsepsis-associatedAKI.Theprotocol,including
intestinalalkalinephosphatase(themostbiologicallyactive slightchangesineligibilitycriteria(upperagelimitfrom80
isoenzyme)withthecrowndomainofplacentalalkaline yearsto85years,weightlimitfrom≤100kgto≤115kg,sepsis
phosphatase (which has the longest half-life) created a timewindowfrom<72hoursto<96hours,andthetime
highlystable,biologicallyactiveenzyme.12Thetherapeutic windowinwhichtheserumcreatinineincreaseshouldbe
effectsofhumanrecombinantalkalinephosphatasewere observedfrom<24hoursto<48hours)implementedafter
confirmedinvariousAKImodels.Inhumanproximaltubu- inclusion of 120 patients, was published previously15
larepithelialcells,recombinantalkalinephosphatasewas (Supplement1andSupplement2).Patientsadmittedtothe
abletodephosphorylateendotoxinandadenosinetriphos- ICU who were aged 18 to 85 years with a diagnosis of
phate,resultinginanattenuatedinflammatoryresponse.13 sepsis,16adiagnosisofAKI,17andwerenotexpectedtohave
Inrats,renalischemia–inducedandinflammation-induced arapidlyfataloutcomewereeligibleforstudyparticipation
AKIwasattenuatedbyrecombinantalkalinephosphatase.14 (foranoverviewofallinclusionandexclusioncriteria,see
Theintentofthecurrentclinicaltrialwastodeterminethe eMethods1inSupplement3).Priortotheadministrationof
optimaltherapeuticdose,effectonkidneyfunction,and thestudydrug,toensurethatpatientswithprerenalAKI
adverseeffectsofrecombinantalkalinephosphatasein werenotenrolled,theAKIdiagnosisneededtoberecon-
patientswithsepsis-associatedAKI. firmed.Inpractice,patientswerevolumeresuscitatedand
onlywhenAKIdemonstratedtobenonresolving(asdefined
by a sustained increase in serum creatinine corrected
for fluid resuscitation or ongoing oliguria), the patient
Methods
remainedeligible.
TrialDesignandParticipants Patientsenrolledduringthefirstpartofthestudywereran-
The study protocol and informed consent form were domlyassignedtoreceiveeitherplaceboor1of3recombi-
reviewedandapprovedbytheinstitutionalreviewboardor nantalkalinephosphatasedoses(0.4,0.8,or1.6mg/kg)once
independentethicscommitteeateachparticipatingsite. dailyfor3daysusinga1:1:1:1allocationratio.
Thetrialwasconductedinaccordancewithethicalprin- Thedataandsafetymonitoringboard(DSMB)performed
ciplesofGoodClinicalPractice.Priortoinitiationofany regular,unblindedsafetyevaluations.Aftertheinclusionof
study-relatedprocedures,writteninformedconsentwas 120patients,futilityorsuperiorityoftheinterventiononthe
obtainedfromthepatientorthepatient’slegalrepresenta- primaryendpointdataandthefittoanassumedmaximum
tive.Raceandethnicityinformationwasself-reportedor effectattributabletothedrug(E )modeldose-response
max
fromafirst-degreerelativeinaccordancewiththeUSFood curvewasassessed(eMethods2inSupplement3).Theadap-
andDrugAdministrationguidance.Datawereobtained tivedesigndirectedthecessationof2treatmentgroupsat
fromallsites,exceptthosefromFrance,whereitisprohib- theinterimanalysis,asdescribedinthestatisticalanalysis
itedtocollectdataonrace/ethnicity.Thereasonforinclu- plan. The DSMB was provided with the time-corrected
sionofrace/ethnicityinthisstudywasthatthiswasthefirst (ie,measuredperday)AUCoftheendogenouscreatinine
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Research OriginalInvestigation EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI
clearancefordays1through7,dividedby7toprovideamean beginningandattheendoftheurinecollectionperiodwas
dailycreatinineclearance(AUC ECC)(primaryendpoint) usedforECCcalculations.15
1-7
andsafetydataofthepatientsinpart1ofthestudy.The
DSMBwasinstructedtoselectthehighestdose,provided KeySecondaryEndPoint
thattheE modelappliedandthatnosafetyconcernspro- Requirementforrenalreplacementtherapy(RRT)wasthe
max
hibitedtheselectionofthisdose.Thisdoseselectionmethod mainrelatedclinicalparameter.Siteswereadvisedtofollow
wasbasedontheobservationthatbiologicsexhibitalinearor criteriafortheinitiationandterminationofRRT.23Only
E doseresponsecorrelation.18Patientswererandomized continuousformsofRRTwereallowedduringthefirst7days
max
toeitherplaceboortheselecteddoseofrecombinantalkaline followingenrollmenttopreventareboundeffectonECCby
phosphataseinpart2. intermittenthemodialysis.
TrialOversight SecondaryEndPoints
AllstudymedicationwasmanufacturedbyNovaLaborato- KidneysecondaryendpointsincludedECCandbloodureani-
ries(Leicester,UK)accordingtoGoodManufacturingPrac- trogenclearanceupthroughday28,urinevolume,serumcre-
ticeregulations.Thedesignofthestudywasdiscussedwith atinine,bloodureanitrogen,proteinuria,andestimatedglo-
EuropeanandUSregulatoryagencies.Followingtheinterim merularfiltrationrate.Nonkidneysecondaryendpointswere
analysis,anadjudicationcommitteewasinstalledasadvised liverfunction,pulmonaryfunction,shock-freedays,Sequen-
bytheDSMBandsteeringcommitteetoadjudicatetheday1 tialOrganFailureAssessment(SOFA)scores,biomarkeras-
to7ECCdataofallpatients(eMethods3inSupplement3). sessment,andmortality.Aprioriexploratorysubgroupanaly-
seswereplannedtodeterminewhetherrecombinantalkaline
RandomizationandStudyMedication phosphatasetreatmentdemonstratesdifferentlevelsofeffi-
Therandomizationschedulewasstratifiedbysite.Aninde- cacyinspecificpatientgroups.
pendentstatisticiangeneratedapermutedblockrandomiza-
tionschedule(per8inpart1andper4inpart2)foraninter- OtherEndPoints
activevoice/webresponsesystem,whichlinkedsequential Otherexploratoryendpointsincludedcompositemajor
patientrandomizationnumberstotreatmentcodes.Study adversekidneyevents(MAKE)scoresatdays28,60,and90;
drugdoserationale15isexplainedineMethods4inSupple- serology;ICUandhospitallengthofstay;andqualityoflife.
ment3.Thelowestdosewaschosenwithpredictedtrough AllendpointsarespecifiedineMethods6inSupplement3.
plasmaconcentrationsbelowtheassumedeffectiveconcen-
tration.Themiddleandhighdoseswerechosenbasedon AdverseEvents
troughconcentrationsreachingorexceeding,respectively, Incidenceoffatalandnonfatal(serious)AEs([S]AEs),toler-
the estimated effective concentration. Study drug was ability,pharmacokinetics(inthefirst120patients),immuno-
administeredasa1-hourintravenousinfusionwithin24 genicity,laboratoryassessments,vitalsigns,andelectrocar-
hoursaftersepsis-associatedAKIwasfirstdiagnosed,and diographydatawereincludedinthesafetyanalysis.
then24hours(±1hour)and48hours(±1hour)following
administrationofthefirstdose.Administrationofnephro- StatisticalAnalyses
toxicdrugswasavoidedwherepossible,asrecommendedby Custom-programmedsimulationswereperformedusing
Kidney Disease: Improving Global Outcomes (KDIGO) SASsoftware(SASInstitute),version9.2,todeterminepower
guidelines.19Personnelinvolvedinthisstudywereblindedto andtypeIerrorrateofthechosensamplesizeanddesign
treatmentassignment.Tomaintaintheblinding,clinicians inanumberofdifferentdose-responsescenarios.Eachsce-
werenotallowedtomeasurecirculatingalkalinephospha- narioassumedastandarddeviationof49mL/minforthepri-
tase concentrations until day 14 (details on blinding in maryendpointwithanassumedresponseof60mL/minfor
eMethods5inSupplement3). theplacebogroup,andfrom60mL/min(notreatmenteffect)
to79mL/min(strongtreatmenteffect)fortherecombinant
OutcomeMeasures alkalinephosphatasedosegroups.Theseestimationsand
PrimaryEndPoint standarddeviationweretakenfromtheprevioustrialusing
Theprimaryobjectiveofthisstudywastodeterminethe bovinealkalinephosphatase.11Asamplesizewasplanned
optimaltherapeuticdoseandadverseeffects(AEs)ofrecom- of30patientspertreatmentgroupinpart1withanaddi-
binantalkalinephosphatase,andtoevaluateitseffecton tional85patientsrecruitedtotheoptimalrecombinant
kidneyfunction(AUC ECC).Inviewofthelimitationsof alkalinephosphatasedoseandplacebotreatmentgroupsin
1–7
serumcreatininevaluesinpatientswhoarenotinasteady part2,(eMethods7inSupplement3).Missingvalueswere
stateandthelimitedfeasibilitytouseothermeasuresof imputedbyinterpolationbetweenmeasuredvaluesand
kidneyfunction,ECCwaschosenastheprimaryefficacyend extrapolationbasedonlastobservationcarriedforward,
point.20Allpatientshadanindwellingcathetertoensure accordingtopredefinedrulesdescribedinthestatistical
accuratemeasurementsofurinevolume,withaurinecollec- analysisplan.Thesafetydatasetconsistedofallpatients
tionperiodof6hours(±1hour)daily.21,22Inpatientswho whowereassignedtoatreatmentgroupandreceivedatleast
wereanuric,anECCof0mL/minwasimputed.Themean 1doseofstudydrug.Efficacyandexploratoryendpoints
valueoftheserumcreatinineconcentrationmeasuredatthe wereanalyzedaccordingtotheintention-to-treat(ITT)
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EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI OriginalInvestigation Research
Figure1.FlowofPatientsThroughtheSTOP-AKITrialofRecombinantAlkalinePhosphataseinAcuteKidneyInjury(AKI)
326Patients assessed for eligibility
25Excluded
11Did not meet AKI criteria
3Did not meet time window
1Required RRT in <24 h
1Required immunosuppressant therapy
9Other exclusion criteria (not specified)
301Randomized
39Randomized to receive 35Randomized to receive 111Randomized to receive 116Randomized to receive placebo
0.4 mg/kg of recombinant 0.8 mg/kg of recombinant 1.6 mg/kg of recombinant
alkaline phosphatase alkaline phosphatase alkaline phosphatase
31Included in the ITT analysis 32Included in the ITT analysis 29Included in the ITT analysis 30Included in the ITT analysis
8Excluded due to randomization 3Excluded due to randomization (part 1)b (part 1)b
during interim analysisa during interim analysisa 82Included in the ITT analysis 86Included in the ITT analysis
(part 2) (part 2)
38Included in the safety analysis 35Included in the safety analysis
1Died prior to study drug 109Included in the safety analysis 112Included in the safety analysis
administration 1Withdrew consent prior to 2Did not receive placebo within
study drug administration the set time frame
1Kidney function improved 1Died prior to placebo
considerably prior to study administration
drug administration 1Withdrew consent prior to
placebo administration
111Continued in the ITT analysis 116Continued in the ITT analysis
(part 2) (part 2)
Day 60 Day 60
109Completed follow-up 116Completed follow-up
2Lost to follow-up
Day 90 Day 90
107Completed follow-up 115Completed follow-up
2Lost to follow-up 1Lost to follow-up
AKIindicatesacutekidneyinjury;ITT,intention-to-treat;RRT,renalreplacement whowereassignedtothehumanrecombinantalkalinephosphatase
therapy;andSTOP-AKI,Safety,Tolerability,Efficacy,andQualityofLifeStudyof 0.4mg/kgor0.8mg/kgtreatmentgroupbecausethese2treatmentgroups
HumanRecombinantAlkalinePhosphataseintheTreatmentofPatientsWith weredroppedfollowinginterimanalysis.
Sepsis-AssociatedAcuteKidneyInfection.Part1ofthetrialidentifiedthe bAnunblindedinterimanalysiswasconductedonthepart1datatodetermine
optimaldoseofrecombinantalkalinephosphatase.Part2comparedthe theoptimalrecombinantalkalinephosphatasedoseforpart2.Thisanalysis
optimaldose(1.6mg/kg)withplacebo. comparedtheprimaryefficacyendpointandaselectionofthesafety
aTheITTpopulationincludedpatientsfromwhominformedconsentwas dataforthe4treatmentgroupsfrompart1.Theinterimanalysiswas
obtainedandwhowererandomizedtoatreatmentgroup.TheITTpopulation conductedwhenthefirst7daysoflaboratorydatahadbeencollected
didnotincludepatientswhowererandomizedduringinterimanalysisand for120patientsfrompart1.
principleforpatientsfromwhominformedconsentwas centagesandanalyzedusingχ2tests.Survivalanalyseswith
obtainedandwhowererandomizedtoatreatmentgroup. Kaplan-Meiercurveswereusedforgraphicalpresentation.
Patientswhowererandomizedduringinterimanalysisand Coxproportionalhazardregressionanalyseswereusedto
whowereassignedto1ofthe2treatmentgroupsthatwere estimatethehazardratioforsurvivalandforthenumber
droppedfollowinginterimanalysiswerenotpartoftheITT ofRRT-free,shock-free,andmechanicalventilation–free
population.Theper-protocolanalysissupplementedtheITT daysduringstudydays1through28withtheuseofrecom-
analysisandcomparedtheinterventiongroupswiththepla- binantalkalinephosphatasevsplacebo.Theassumptionof
cebogroupforpatientswhoreceivedstudymedicationac- proportionalhazardswasconfirmedbyvisualinspection
cordingtothestudyprotocolandhadnomorethan2missing ofthosecurves.
ECCvaluesondays1through7,asdetailedinthestatistical Ahierarchicalmethodwasemployedtoaddressany
analysisplan. multiplicityarisingfromtheanalysisofthekeysecondary
Forthedescriptivestatistics,continuousvariablesare endpoint.Incaseofanonsignificanteffectontheprimary
presentedasleast-squaremeanswithstandarderrorof outcomemeasure,RRTrequirementisviewedasanexplor-
mean,ormedianwithinterquartilerange,dependingon atoryendpoint.Allanalysesperformedontheothersec-
their distribution. Normally distributed variables were ondary end points were for exploratory purposes only;
comparedusingthettest;Mann-WhitneyUtestswereused therefore,nofurthermultiplicityadjustmentwasused.The
tocomparenonnormallydistributedvariables.Categorical analysisoftheprimaryefficacyendpointwasperformed
(andbinary)variablesarepresentedasnumberswithper- byanalysisofvariancewithsiteasafixedeffect.
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Research OriginalInvestigation EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI
Table1.DemographicandBaselineDiseaseCharacteristicsofPatientsWhoWereCriticallyIllWithSepsis-AssociatedAcuteKidneyInjury
TreatedWithRecombinantAlkalinePhosphatasevsPlacebo,Intention-to-TreatPopulation
RecombinantAlkalinePhosphataseGroups,No.(%)
PlaceboGroup(n=116),
Characteristics 0.4mg/kg(n=31) 0.8mg/kg(n=32) 1.6mg/kg(n=111) No.(%)
Age,median(IQR),y 67.0(61.0-72.0) 66.5(62.5-72.0) 65.0(57.0-73.0) 68.0(61.0-75.0)
Men 23(74.2) 16(50.0) 82(73.9) 84(72.4)
Women 8(25.8) 16(50.0) 29(26.1) 32(27.6)
Race/ethnicity
White 25(80.6) 27(84.4) 95(85.6) 95(81.9)
Black 0 0 1(0.9) 4(3.4)
Asian 2(6.5) 0 1(0.9) 1(0.9)
Other(specificsnotobtained) 0 1(3.1) 0 0
Notcollected 4(12.9) 4(12.5) 14(12.6) 16(13.8)
Weight,median(IQR),kg 78.0(70.0-86.0) 79.0(72.0-90.0) 80.0(71.8-90.0) 79.2(70.0-86.5)
Height,median(IQR),cm 172.5(165.0-184.0)[n=30] 167.0(160.0-174.0)[n=29] 173.0(168.0-179.0)[n=110] 174.0(165.0-178.0)[n=115]
BMI,median(IQR) 25.8(22.4-28.4)[n=30] 27.4(25.2-30.7)[n=29] 26.8(23.9-30.2)[n=110] 26.3(23.9-29.4)[n=115]
Diseaseseverity,median(IQR)
APACHEIIscorea 30.0(25.0-35.0) 26.0(20.0-34.5) 25.0(19.0-31.0) [n=110] 26.0(20.0-33.5)
SAPSIIb 52.0(42.0-70.0)[n=30] 50.5(38.0-60.5) 50.0(42.0-61.0)[n=97] 47.0(39.0-60.0)[n=97]
SOFAscorec 10.0(8.0-13.0)[n=29] 9.0(8.0-11.0) 10.0(8.0-12.0)[n=108] 10.0(8.0-12.0)[n=113]
Mechanicalventilation 23(74.2) 20(62.5) 70(63.1) 68(58.6)
Vasopressor/inotropic 28(90.3) 30(93.8) 102(91.9) 103(88.8)
therapyuse
Vitalsigns
Heartrate,median(IQR), 93.0(77.0-115.0)[n=31] 90.0(75.5-107.5) 95.0(83.0-110.0) 98.0(85.0-111.0)
beats/min
SystolicBP,median(IQR), 108.0(100.0-119.0) 118.5(96.0-131.0) 107.0(95.0-119.0) 112.0(101.5-131.5)
mmHg
DiastolicBP,median(IQR), 54.0(49.0-62.0) 58.0(54.0-62.0) 55.0(49.0-62.0)[n=110] 56.5(51.0-63.5)
mmHg
Bodytemperature 31(100) 32(100) 108(100) 114(100)
<36°C 4(12.9) 5(15.6) 11(9.9) 11(9.5)
≥36°C-≤38°C 20(64.5) 22(68.8) 79(71.2) 76(65.5)
>38°C 7(22.6) 5(15.6) 18(16.2) 27(23.3)
Kidneyfunction
eGFR,median(IQR),mL/mind 27.2(20.0-42.4)[n=27] 25.6(20.4-40.7)[n=28] 29.7(20.5-46.5)[n=98] 37.5(23.9-50.8)[n=102]
ECC,median(IQR),mL/mine
Day0 14.4(8.8-58.0)[n=10] 26.0(5.4-30.6)[n=12] 24.1(10.5-54.9)[n=46] 31.8(14.7-62.5)[n=49]
Day1 28.3(4.3-64.4)[n=30] 25.2(9.4-61.0)[n=31] 26.0(8.8-59.5)[n=102] 35.9(12.2-82.9)[n=103]
AKIstagef 31(100) 32(100) 109(100) 112(100)
1(Leastaffected) 22(71.0) 23(71.9) 81(73.0) 91(78.4)
2 5(16.1) 5(15.6) 17(15.3) 16(13.8)
3(Mostaffected) 4(12.9) 4(12.5) 11(9.9) 5(4.3)
Urineoutput,median(IQR), 50.0(21.7-101.7)[n=13] 27.4(16.4-50.0)[n=14] 39.1(10.9-85.7)[n=50] 60.0(21.8-99.3)[n=53]
mL/h
Serumcreatinine, 2.3(1.5-2.8)[n=29] 1.9(1.5-2.8) 2.0(1.4-2.8)[n=110] 1.8(1.3-2.4)[n=113]
median(IQR),mg/dL
Abbreviations:AKI,acutekidneyinjury;APACHEII,AcutePhysiologyand serumNa+152mEq/L(1point),creatinine140mg/dL(2points),hematocrit
ChronicHealthEvaluationII;BMI,bodymassindex—weightinkilogramsdivided 47%(1point),andwhitebloodcellcount29×109/L(2points).
byheightinmeterssquared;BP,bloodpressure;ECC,endogenouscreatinine bSAPSIIrangesfrom0-163,withhigherscoresindicatinggreaterseverity.
clearance;eGFR,estimatedglomerularfiltrationrate;SAPSII,SimplifiedAcute
cSOFAscoresrangefrom0-24,withhigherscoresindicatingmoresevere
PhysiologyScoreII;SOFA,SequentialOrganFailureAssessment.
dysfunction.Themaximaldeviationfromnormalin24hatbaselinewasused
SIconversionfactors:ToconvertECCtomL/s,multiplyby0.0167. forheartrate,bloodpressure,bodytemperature,andAKIstage.
aAPACHEIIscoresrangefrom0-71,withhigherscoresindicatinggreater dTheeGFRwascalculatedaccordingtotheChronicKidneyDisease
severity.Forexample,apatientwithAPACHEIIscoreof26atadmission, EpidemiologyCollaborationequation.24
onmechanicalventilationandvasopressorsupport,couldbeelderly
eStudydruginfusionwasadministratedassoonaspossible,andinvestigators
(eg,76y[6points]),withatemperatureof39.5°C(3points),meanarterial
didnotwaituntildataofday0werecompleted.Therefore,dataaregivenas
pressure62mmHg(2points),heartrate145/min(3points),respiratoryrate
changefromday1,thedayofstudydruginfusion.
37/min(3points),PaO265mmHg(1point),arterialpH7.25(2points),
fAKIstagewasstratifiedaccordingtotheAKI-Networkdefinition.25
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EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI OriginalInvestigation Research
Figure2.EndogenousCreatinineClearance(ECC)AmongPatientsWhoWereCriticallyIllWithSepsis-AssociatedAcuteKidneyInfection
A Change in median ECC B AUC ECC
1-7
Exploratory efficacy end points
60 300
n
Endogenous Creatinine ClearanceChange from Day 1, Median mL/ min 5432100000 Primary efficacy end point Rpheocospmhbaitnaasnet 1 a.l6k amlign/ekg Placebo eatinine Clearance AUC Median, mL/mi 22115050500000
Cr
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Recombinant Placebo
Time, d Alkaline
Phosphatase
No. of patients 1.6 mg/kg
Recombinant alkaline phosphatase
1.6 mg/kg11110295 92 92 86 82 82 64 47 38
Placebo 11610292 95 90 86 83 81 63 46 30
AUC ECCindicatestheareaunderthetime-corrected(ie,measuredperday) toavoidsuperimposition.B,MedianAUC ECCforpart1andpart2(combined
1-7 1-7
curve(AUC)forECCfromday1through7,dividedby7toprovideameandaily data)ofthetrial.ThetopandbottomoftheboxesindicatetheIQR,whiskers
creatinineclearance.A,MedianincreaseinECCfrombaselinetoday28from indicate95%CI,andthecirclesindicatetheindividualswhosevalueswere
part1andpart2(combineddata)ofthetrial.Errorbarsindicatedistribution outsidethe5thand95thpercentilesoftheAUC ECC.
1–7
freeintervals.Thedatapointsofthe2treatmentgroupswereslightlystaggered
Fourposthocanalyseswereperformed:First,onthepri- fittedtothedataandthesecondmostinfluentialfactorwas
maryendpoint,asensitivityanalysisusingamixed-effects chosenbasedonthelowestPvalue.Thisprocesswascontin-
modelwithrandomtermsforsitewasperformed.Second,sen- ueduntiltheintroductionofanynewfactordidnotaffectover-
sitivityanalyseswereundertakenusingamixedmodelofre- allsurvivalsignificantly(P>.10).
peatedmeasures(MMRM)withtimeofmeasurementasafixed AllstatisticaltestsperformedontheITTpopulationwere
effectandsiteandpatient(nestedwithinsite)asrandomef- conductedwithSAS(SASInstitute),version9.4,andwitha
fects.Thisanalysiswasinitiallyundertakenondatawithim- 2-sidedPvaluelessthan.05forsignificance.
putationtoalignwiththeprespecifiedanalysisofthepri-
maryendpointandadditionallywithoutimputationforthe
datafromday1throughday28.Third,todeterminetowhat
Results
extentkidneyfunctioninfluencesitsrecovery,baselinecre-
atinineclearancewascorrelatedwiththeprimaryendpoint Participants
AUC ECC.Fourth,aposthoc,forwardstepwise,multivari- FromDecember2014throughMay2017,of326patientswho
1-7
ableanalysiswasundertakentoassesswhethertheobserved passedaninitialscreen,301patients(men,70.7%;medianage,
differencesinoverallsurvivalwererelatedtobaselineimbal- 67years[interquartilerange{IQR},59to73])wereenrolledacross
ancesinprognosticfactors.Thefollowingfactorswerecon- 53sitesin11countriesintheEuropeanUnionandUnitedStates
sidered;timetotreatment,C-reactiveprotein,sex,weight,age, (eTable1inSupplement3).Siteswereactivefor17months(±8
AcuteKidneyInjuryNetworkstage,PaO2/FiO2ratio,mechani- months).Follow-upwasconductedfor90daysandthefinalvisit
calventilationstatus,vasopressorandinotropictherapy, tookplaceonAugust14,2017.Thesafetyanalysisincluded
KidneyInjuryMolecule-1,ECC,SimplifiedAcutePhysiology 294patientsandITTincluded290patients.IntheITTdataset,
ScoreII(SAPSII),SOFAscore,andAcutePhysiologicAssess- patientsreceivedrecombinantalkalinephosphatasedosesof
mentandChronicHealthEvaluationII(APACHEII)score. 0.4mg/kg(n=31),0.8mg/kg(n=32),1.6mg/kg(n=29inpart
Proportionalhazardswereassumed. 1andn=82inpart2),orplacebo(n=30inpart1andn=86in
Becausethesewereexploratoryanalyses,modelassump- part2)(Figure1).Randomizationresultedinwell-balanceddemo-
tionswerenotassessedinanyformalwayexceptbyconfirm- graphicandpatientcharacteristics(Table1;forexploratorysub-
ingaconsistenteffectinsubgroupsasindicatedbyForestplots. groupanalyses,seeeFigures1-23inSupplement3.
ACoxproportionalhazardsmodelincludingtreatmentwas
fittedtothedatatogetherwitheachoftheprognosticfactors. PrimaryEndPoint
TheprognosticfactorhavingthelowestPvalueonoverallsur- Inpart1,thedose-findingpartofthetrial,themedianAUC
1–7
vivalwaschosentobeinthemodel.Amodelcontainingthis ECCwas47.0mL/min(IQR,6.6to88.4)inthe0.4-mg/kgre-
factor,treatment,andeachoftheremainingfactorswasthen combinantalkalinephosphatasegroup,63.5mL/min(IQR,8.1
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Research OriginalInvestigation EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI
Table2.AdverseEventsandSeriousAdverseEventsintheFirst28DaysAmongPatientsWhoWereCriticallyIllWithSepsis-Associated
AcuteKidneyInjuryTreatedWithRecombinantAlkalinePhosphatasevsPlacebo,intheSafetyDataPopulationa
AdverseEventsFromDay1-28,No.(%) SeriousAdverseEventsFromDay1-28,No.(%)
RecombinantAlkalinePhosphataseGroups RecombinantAlkalinePhosphataseGroups
Placebo Placebo
0.4mg/kg 0.8mg/kg 1.6mg/kg Group 0.4mg/kg 0.8mg/kg 1.6mg/kg Group
AdverseEvent (n=38) (n=35) (n=109) (n=112) (n=38) (n=35) (n=109) (n=112)
Totalevents 277 252 898 806 34 19 76 89
Nonfatalevents 24 13 57 56
Patientswithafatalevent 10(26.3) 6(17.1) 19(17.4) 33(29.5)
Patientswithanonfatalserious 8(21.0) 5(14.3) 28(25.7) 23(20.5)
adverseevent
Patientswithatleast1event 35(92.1) 31(88.6) 103(94.5) 111(99.1) 18(47.4) 11(31.4) 47(43.1) 56(50.0)
Gastrointestinaldisorders 17(44.7) 16(45.7) 63(57.8) 49(43.8) 3(7.9) 2(5.7) 11(10.1) 6(5.4)
Infectionsandinfestations 16(42.1) 16(45.7) 60(55.0) 47(42.0) 5(13.2) 5(14.3) 18(16.5) 18(16.1)
Metabolismandnutrition 13(34.2) 13(37.1) 49(45.0) 41(36.6) 0 0 0 1(0.9)
disorders
Generaldisordersand 10(26.3) 13(37.1) 44(40.4) 43(38.4) 2(5.3) 0 5(4.6) 9(8.0)
administrationsiteconditions
Cardiacdisorders 11(28.9) 12(34.3) 43(39.4) 44(39.3) 0 3(8.6) 9(8.3) 11(9.8)
Psychiatricdisorders 12(31.6) 13(37.1) 42(38.5) 39(34.8) 0 0 1(0.9) 0
Respiratory,thoracic, 14(36.8) 14(40.0) 40(36.7) 52(46.4) 6(15.8) 3(8.6) 9(8.3) 14(12.5)
andmediastinaldisorders
Vasculardisorders 12(31.6) 9(25.7) 36(33.0) 40(35.7) 1(2.6) 0 5(4.6) 7(6.3)
Investigations 8(21.1) 10(28.6) 30(27.5) 30(26.8) 0 0 1(0.9) 1(0.9)
Bloodandlymphaticsystem 10(26.3) 8(22.9) 24(22.0) 22(19.6) 2(5.3) 0 2(1.8) 2(1.8)
disorders
Skinandsubcutaneoustissue 7(18.4) 5(14.3) 22(20.2) 17(15.2) 0 0 1(0.9) 0
disorders
Nervoussystemdisorders 6(15.8) 10(28.6) 19(17.4) 15(13.4) 4(10.5) 1(2.9) 4(3.7) 1(0.9)
Kidneyandurinarydisorders 6(15.8) 2(5.7) 16(14.7) 12(10.7) 1(2.6) 0 1(0.9) 2(1.8)
Injury,poisoning, 13(34.2) 7(20.0) 14(12.8) 15(13.4) 3(7.9) 2(5.7) 0 3(2.7)
andproceduralcomplications
Musculoskeletalandconnective 3(7.9) 1(2.9) 13(11.9) 14(12.5) 0 0 0 1(0.9)
tissuedisorders
Hepatobiliarydisorders 1(2.6) 1(2.9) 9(8.3) 9(8.0) 1(2.6) 0 0 4(3.6)
Endocrinedisorders 1(2.6) 1(2.9) 3(2.8) 4(3.6) 0 0 0 0
Eyedisorders 3(7.9) 1(2.9) 3(2.8) 2(1.8) 0 0 0 0
Earandlabyrinthdisorders 0 0 2(1.8) 1(0.9) 0 0 1(0.9) 0
Neoplasmbenign,malignant, 0 0 1(0.9) 1(0.9) 0 0 0 0
andunspecified
(includingcystandpolyps)
Congenital,familial, 0 0 1(0.9) 0 0 0 0 0
andgeneticdisorders
Reproductivesystem 0 0 1(0.9) 0 0 0 0 0
andbreastdisorder
aAdverseeventsandseriousadverseeventswerecodedaccordingtothe werecountedonceforeacheventcategory,eveniftheyhadmultipleevents
MedicalDictionaryforRegulatoryActivities,version19.0.Allpatientswho inthatcategory.Onlypatientswhoreceivedatleast1doseofstudydrugwere
diedwereanalyzedandclassifiedasafatalseriousadverseevent.Patients includedinthesafetyanalysisdataset.
to96.8)inthe0.8-mg/kgrecombinantalkalinephosphatase 22.7to115.2)intheplacebogroup,resultinginanAUC ECC
1–7
group,and60.7mL/min(IQR,3.7to92.4)inthe1.6-mg/kg of55.1mL/min(IQR,15.0to93.9)inthe1.6-mg/kgrecombi-
recombinantalkalinephosphatasegroupcomparedwith nantalkalinephosphatasegroupvs45.6mL/min(IQR,17.7to
46.2mL/min(IQR,21.5to114.6)intheplacebogroup. 112.4)intheplacebogroup(absolutedifference,9.5mL/min
Followingtheinterimanalysis,theDSMBadvisedcon- [bootstrap95%CI,−23.9to25.5];P=.47)(Figure2).Forthe
tinuingthestudywith1.6mg/kgofrecombinantalkalinephos- primaryendpoint,10.2%ofdataweremissingandfollowing
phatase.Asperthestatisticalanalysisplan,onlytheeffects thejudgmentoftheadjudicationcommittee,3.1%ofdatawere
ofthe1.6-mg/kgrecombinantalkalinephosphatasegroupwere discarded.Missingordiscardeddatawereimputedaccord-
comparedwiththoseoftheplacebogroupintheprimaryend ingtotheprespecifiedmethod.
pointanalysis.Fromday1today7,medianECCincreasedfrom
26.0mL/min(IQR,8.8to59.5)to65.4mL/min(IQR,26.7to SecondaryEndPoints
115.4)inthe1.6-mg/kgrecombinantalkalinephosphatasegroup TherequirementofRRT(days1-28)was36.0%inthe1.6-mg/kg
vsfrom35.9mL/min(IQR,12.2to82.9)to61.9mL/min(IQR, recombinantalkalinephosphatasegroupvs29.3%inthe
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EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI OriginalInvestigation Research
placebogroup(oddsratio,1.4[95%CI,0.8to2.4];P=.28).
Figure3.CumulativeIncidenceofFatalEventsFromBaselineto90Days
However,duetothenullprimaryendpointandtherequire-
forAllTreatmentGroupsintheSafetyDataPopulationofPatients
mentforhierarchicaltesting,thisfindingdoesnotrepresent WhoWereCriticallyIllWithSepsis-AssociatedAcuteKidneyInfection
aformalanalysis.
Theexploratoryendpoint,treatmenteffectofrecombi- Placebo
nantalkalinephosphatasecomparedwithplaceboonECC Recombinant alkaline phosphatase
improvement up to day 28, showed that the 1.6-mg/kg 0.4 0.4 mg/kg
1.6 mg/kg
recombinantalkalinephosphatasegroupexertedadifferen-
0.8 mg/kg
tialtreatmenteffectduringthe28-dayperiod(P=.04for
0.3
interaction),drivenbyday21(meandifference,16.3mL/min
[95%CI,3.07to29.5];P=.02)andday28(meandiffer- y
ence,18.5mL/min[95%CI,5.3to31.7];P=.006)(Figure2). ortalit 0.2
All-causemortalityatday28waslowerinthe1.6-mg/kg M
recombinantalkalinephosphatasegroup(n=16[14.4%])vs 0.1
theplacebogroup(n=31[26.7%];difference,12.3%[95%CI,
1.9%-22.7%];P=.02).Thiseffectpersistedtoday90,17.1%in
0
the1.6-mg/kgrecombinantalkalinephosphatasegroup 0 20 40 60 80
(n=19)vs29.3%intheplacebogroup(n=34)(difference, Time, d
12.2% [95% CI, 1.3% to 23.0%]; P=.03) (eFigure 24 in No. at risk
Recombinant alkaline phosphatase
Supplement3).Kidneyinjurybiomarkers,aswellasother Placebo 112 88 81 79 79
nonkidneysecondaryendpoints,werenotsignificantly 0.4 mg/kg 38 31 28 28 28
0.8 mg/kg 35 31 30 29 29
influencedbyrecombinantalkalinephosphatasetreatment 1.6 mg/kg 109 95 92 90 90
(eTable2inSupplement3).Per-protocolanalysesyielded
comparableresults.Dataofotherexploratorysecondaryend Themedianobservationtime(95%CI)was16.5days(6-28)forthe
0.4-mg/kgrecombinantalkalinephosphatasegroup,9.5days(1-53)for
pointsareprovidedineTable3inSupplement3.
the0.8-mg/kgrecombinantalkalinephosphatasegroup,9days(5-21)
Statisticallysignificantdifferencesintheeffectsonthepri- forthe1.6-mg/kgrecombinantalkalinephosphatasegroup,and8days
maryendpointandkeysecondaryendpointwerenotob- (4-16)fortheplacebogroup.Allpatientswhodiedwereanalyzedandclassified
servedintheaprioridefinedexploratorysubgroups(eFig- asafatalseriousadverseevent.
ures1-8inSupplement3).
1.6-mg/kgrecombinantalkalinephosphatasegroup,and23
OtherEndPoints patients(20.5%)intheplacebogroup.Adverseeventswerere-
Treatmentwithrecombinantalkalinephosphatasedidnotaffect portedforthemajorityofpatientsineachofthegroups
MAKEat28days,butresultedinasignificantlylowerincidence (0.4-mg/kgrecombinantalkalinephosphatasegroup,35
ofMAKEat60days(27.0%inthe1.6-mg/kgrecombinantalka- [92.1%];0.8-mg/kgrecombinantalkalinephosphatasegroup,
linephosphatasegroup[n=30]vs39.7%intheplacebogroup 31[88.6%];1.6-mg/kgrecombinantalkalinephosphatasegroup,
[n=46];hazardratio[HR],1.8[95%CI,1.0to3.1];P=.045) 103[94.5%];placebo,111[99.1%]),withmostAEsineachtreat-
andMAKEat90days(26.1%inthe1.6-mg/kgrecombinant mentgroupbeingeithermildormoderateinseverity.Nore-
alkalinephosphatasegroup:[n=29]vs39.7%intheplacebo combinantalkalinephosphatasedose–dependencyinthein-
group[n=46];HR,1.9[95%CI,1.1to3.3];P=.03),mainlydriven cidenceandnatureof(S)AEswasobserved.Anti-drugantibody
byadifferenceinsurvival(forMAKEdefinitionsateachmea- titerswerejustabovethedetectionlimitin9patientstreated
surement,seeeTable2inSupplement3).Inflammatorybiomark- withrecombinantalkalinephosphatase.
ers,qualityoflife,andotherexploratoryendpointswerenot
significantlyinfluencedbyrecombinantalkalinephosphatase PostHocAnalyses
treatment(eTables2-3andeFigures9-23inSupplement3). Posthoc,MMRMsensitivityanalysis,mixed-effectsregres-
sion,withrandomtermsfortimeofmeasurementandsitewith-
AdverseEvents outimputation,resultedinameandifferenceof27.6mL/min
Inthesafetydatapopulation(Table2),68fatalSAEswerere- (95%CI,8.7to46.6;P=.004)forday21andameandiffer-
portedduringthestudy.FatalSAEswerereportedin26.3%of enceof18.2mL/min(95%CI,−2.5to38.9;P=.08)forday28.
the0.4-mg/kgrecombinantalkalinephosphatasegroup,17.1% Baselineandday1ECCstronglycorrelatedwithAUC ECC
1-7
ofthe0.8-mg/kgrecombinantalkalinephosphatasegroup, (r=0.87;commonslope,1.01[95%CI,0.93–1.09];P<.001).
17.4%ofthe1.6-mg/kgrecombinantalkalinephosphatase Also,alowerbaselineECCcorrelatedwithalog-linearhigher
group,and29.5%intheplacebogroup.eTable4inSupplement relativeHRformortalityaccordingtoaCoxmodel(eFigure25
3providesasummaryofcauseofdeathbyorganclassand inSupplement3).Totesttherobustnessoftherecombinant
Figure3illustratesthecumulativeincidenceoffatalSAEsover alkalinephosphatase–mediatedeffectonsurvival,aforward
timeforalltreatmentgroups.NonfatalSAEswerereportedfor stepwisemultivariableanalysiswasconducted.Ofthevari-
8patients(21.0%)inthe0.4-mg/kgrecombinantalkalinephos- ouscovariatestested,recombinantalkalinephosphatase
phatasegroup,5patients(14.3%)inthe0.8-mg/kgrecombi- treatment,baselineAPACHEIIscore,baselineECC,andtime
nantalkalinephosphatasegroup,28patients(25.7%)inthe torecombinantalkalinephosphatasetreatmentremained
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Research OriginalInvestigation EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI
significantadditiveprognosticfactorsincludedinthemodel ofthisstudy,soeffectsofrecombinantalkalinephosphatase
witharesultingtreatmenteffectformortality(HR,0.47[95% onlonger-termkidneyfunctionandsurvivalshouldbeinter-
CI,0.25to0.88])wasstatisticallysignificantwitha2-sidedP pretedasonlyhypothesis-generating.
valueof.02(eTable5inSupplement3). Inviewofthedetoxifyingpropertiesofalkalinephospha-
tase,therapeuticpropertieswereinvestigatedinanimalmod-
elsofsepsis,demonstratingimprovedoutcomes.33Itre-
mainsuncleartowhatextentkidneyprotectionismediated
Discussion
througheffectsdirectlyontubularcellsorthroughsystemic
Amongpatientswithsepsis-associatedAKI,humanrecombi- effectsindirectlypreventingdamagetothekidneys,orwhether
nantalkalinephosphatasecomparedwithplacebodidnotsig- kidneyfunctionimprovesaspartofageneraleffectofimprov-
nificantlyimproveshort-termkidneyfunction.Therearea ingsepsisoracombinationoftheabove.Alkalinephospha-
numberofexplanationsforthisfinding,thefirstofwhichis taseisdepletedinthekidneyfollowinganischemicinsult,34
thatthismedicationisnotaneffectivetreatmentforsepsis- andrecombinantalkalinephosphataseattenuatestheinflam-
associatedAKI.However,therearealternativepossibleexpla- matoryresponseinisolatedhumanproximaltubulecells.35
nationsincluding,second,thatcreatinineanditsclearanceare However,systemicdetoxifyingpropertiesmayleadtomore
recognizedtobeoflimitedprecisiontoestimatekidney swiftnormalizationofcirculatinginflammatorymarkers11in-
function,26,27especiallyduringnonsteadystateconditions; directlybenefitingthekidneys.Asthislatterobservationcould
however,asuitableclinicalalternativeiscurrentlynotavail- notbeconfirmedinthecurrenttrial,thedirecteffectsonkid-
able.Third,despiterandomization,therewasaslightimbal- neytissuecouldbemoreimportant.
anceinkidneyfunctionbetweengroups.Previouswork,28as Adverseeffectswerereportedinthemajorityofpatients,
wellasthecurrenttrial,illustratethatthedegreeofinitialkid- independentoftreatmentwithrecombinantalkalinephos-
neydysfunctionisprognosticfortheextentofkidneyrecov- phataseorplacebo.Inaccordancewiththesafetydatafrom
eryandsurvival,asmoreseverekidneyfailurecorrelateswith thepreviouslyreportedphase1studies,36nocompound-
worseoutcomes.Therefore,thesomewhat-more-impairedkid- specificordose-relatedadverseeffectsemerged.FatalSAEs
neyfunctionintherecombinantalkalinephosphatasegroup occurredinpatientstreatedwithrecombinantalkalinephos-
mayaccountfortheabsenceofasignificantlymorepro- phatase(17.4%)andplacebo(29.5%).
nouncedimprovementofECCinthefirstweek.Fourth,the
7-daytimeframewaspossiblytooshort,asdifferencesinre- Limitations
coveryofECCbetweentreatmentgroupsemergedonday21 Thisstudyhasseverallimitations.First,despiterandomiza-
andday28.Fifth,theexploratoryfindingoflowermortality tion,asmallbutpotentiallyrelevantdifferenceinbaseline
intherecombinantalkalinephosphatase–treatedgroupmay ECCwaspresentthatmayaccountforthelackofaneffecton
havehadaninfluenceontheprimaryoutcomebecausepoor theprimaryoutcomemeasure.Second,thelargenumberof
kidneyfunctioninthemostseverelyill—butsurviving— secondaryendpointsmayhaveintroducedatype1error
patientsinthetreatmentgroupmayhaveattenuatedthein- relatedtothesignificantdifferencesbetweengroups,allof
creaseinECCoftherecombinantalkalinephosphatasegroup. whichneedtobeinterpretedasexploratoryandhypothesis-
Insepsis,injuryisknowntobeheterogeneousthrough- generating.Third,theexploratoryanalysesperformedto
outthekidneywithpatchytubulardamagebeingthemost investigatetherobustnessoftheobservedmortalitydiffer-
commonhistologicalfinding.29Incontrast,ECCisanonspe- ence,werenotpreplannedandshouldbeinterpretedwith
cific,latefunctionalmarker.Consequently,acutemeasuresof caution.Fourth,althoughnosignalswereobservedinthis
organfunctionmaynotreflectunderlyingorgandamagethat trialforAEsrelatedtotreatment,lowincidenceAEsmaybe
onlybecomesevidentlater.Therefore,aninterventional detectedinlargertrialsonly.
therapythatreducesdamageandimprovesorganfunctionby
attenuatingseverityanddurationofAKI,maypreventmal-
adaptiverepairmechanismsandfibrosis,withmanifestation
Conclusions
ofrecoveryonlyafterweeks.30,31Longer-termexploratorykid-
neyendpointsindicatedthatrecombinantalkalinephospha- Amongpatientswhowerecriticallyillwithsepsis-associated
taseresultedinmorecompletelong-termrecoveryofkidney acutekidneyinjury,humanrecombinantalkalinephospha-
functioncomparedwithplacebo.Althoughthesebeneficialef- tasecomparedwithplacebodidnotsignificantlyimprove
fectsaremorepatient-centeredandclinicallyrelevant,32itis short-termkidneyfunction.Furtherresearchiswarrantedto
importanttoemphasizethatthesewereexploratoryendpoints assessotherclinicaloutcomes.
ARTICLEINFORMATION DepartmentofMedicine,UniversityofCalifornia, CenterforCriticalCareNephrology,Universityof
AcceptedforPublication:September18,2018. SanDiego,MedicalCenter(Mehta);Schoolof Pittsburgh,Pittsburgh,Pennsylvania(Kellum);
Medicine,UniversityCollegeDublin,Dublin,Ireland DepartmentofGeneralandSurgicalCriticalCare
PublishedOnline:October24,2018. (Murray);DepartmentofInternalMedicine, Medicine,MedicalUniversityInnsbruck,Innsbruck,
doi:10.1001/jama.2018.14283 DivisionofIntensiveCareandEmergencyMedicine, Austria(Bachler);IntensiveCare,GhentUniversity,
AuthorAffiliations:DepartmentofIntensiveCare MedicalUniversityInnsbruck,Innsbruck,Austria Ghent,Belgium(Hoste);ClinicalResearch
Medicine,RadboudUniversityNijmegenMedical (Joannidis);IndianaUniversity,Indianapolis FoundationFlanders,Brussels,Belgium(Hoste);
Center,Nijmegen,theNetherlands(Pickkers); (Molitoris);DepartmentofCriticalCareMedicine, IntensiveCare,CanisiusWilhelminaHospital,
2006 JAMA November20,2018 Volume320,Number19 (Reprinted) jama.com
©2018AmericanMedicalAssociation.Allrightsreserved.
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EffectofHumanRecombinantAlkalinePhosphataseonKidneyFunctioninSepsis-AssociatedAKI OriginalInvestigation Research
Nijmegen,theNetherlands(Hoiting);Internal AstuteMedical;andaresearchgrantandspeakers’ Bunnik,theNetherlands;DavidBrealey,PhD,
Medicine,EasternIdahoRegionalMedicalCenter, feesfromFresenius.DrMolitorisreported MRCP,FRCA,DivisionofCriticalCare,University
IdahoFalls(Krell);Guy’sandStThomas’Hospital, adjudicatingcreatinineclearancesinthestudy, CollegeLondonHospitalsNIHRBiomedical
King’sCollegeLondon,London,UnitedKingdom whichwaspaidforbyAM-Pharma,andhas ResearchCentreandBloomsburyInstituteof
(Ostermann);IntensiveCare,JeroenBosch conductedpreclinicalstudiesforAM-Pharma. IntensiveCareMedicine,UniversityCollege
Hospital,‘s-Hertogenbosch,theNetherlands DrKellumreportedreceivingconsultingfeesfrom London,UK;HildedeGeus,MD,PhD,Erasmus
(Rozendaal);DivisionofAnesthesiaandIntensive AM-Pharma. MedicalCentre,DepartmentofIntensiveCare,
CareMedicine,HelsinkiUniversityCentralHospital, DrBachlerreportedreceivingtravel Rotterdam,theNetherlands;OscarHoiting,MD,
Helsinki,Finland(Valkonen);DivisionofCritical reimbursementsformeetingsofthistrialfrom CanisiusWilhelminaHospital,IntensiveCare,
Care,UniversityCollegeLondonHospitalsNational AM-Pharma;personalfeesandtravelgrantsfrom Nijmegen,theNetherlands;EricHosteMD,PhD,
InstituteforHealthResearchBiomedicalResearch LFBBiomedicaments;travelgrantsfromBaxter; GhentUniversity,IntensiveCare,Ghent,Belgium,
Centre,London,UnitedKingdom(Brealey); travelgrantsandresearchfundingfromCSL andClinicalResearchFoundationFlanders(FWO),
BloomsburyInstituteofIntensiveCareMedicine, BehringandMitsubishiTanabe;andnonfinancial Brussels,Belgium;MichaelJoannidis,MD,Division
UniversityCollegeHospital,London,United supportfromTEMInternationaloutsidethe ofIntensiveCareandEmergencyMedicine,
Kingdom.(Brealey);IntensiveCare,Medisch submittedwork.DrHostereportedreceivingtravel DepartmentofInternalMedicine,Medical
SpectrumTwente,Enschede,theNetherlands reimbursementsfromAM-Pharma;andspeakers’ UniversityInnsbruck,Innsbruck,Austria;John
(Beishuizen);FacultédeMédecine,Servicede feesfromAlexion.DrKrellreportedreceiving Kellum,MD,CenterforCriticalCareNephrology,
Réanimation,UniversitédeStrasbourg,Hôpitaux supportfromAM-Pharmaforattendancetothe DepartmentofCriticalCareMedicine,Schoolof
UniversitairesdeStrasbourg,NouvelHôpitalCivil, CRRTmeetinginSanDiego2017.DrMurugan Medicine,Pittsburgh,Pennsylvania;KennethKrell,
Strasbourg,France(Meziani);Departmentof reportedreceivingfinancialsupportfrom MD,EasternIdahoRegionalMedicalCenter,Internal
CriticalCareMedicine,CenterforCriticalCare AM-Pharmatoscreenandenrollpatientsinthe Medicine,IdahoFalls,Idaho;RavindraMehta,MD,
Nephrology,UniversityofPittsburghSchoolof trial;financialsupportforothertrialsthroughthe DepartmentofMedicine,UCSDMedicalCenter,
Medicine,Pittsburgh,Pennsylvania(Murugan); UniversityofPittsburghfromLaJolla UniversityofCaliforniaSanDiego;FerhatMeziani,
DepartmentofIntensiveCare,ErasmusMedical Pharmaceuticals;grantsupportfromtheNational MD,PhD,UniversitédeStrasbourg(UNISTRA),
Centre,Rotterdam,theNetherlands(deGeus); InstituteofDiabetesandDigestiveandKidney FacultédeMédecine,HôpitauxUniversitairesde
UnitéMixtedeRechercheINSERM1160,University Diseases;andgrantfundingfromBioportoInc. Strasbourg,servicederéanimation,nouvelhôpital
Paris7DenisDiderot,Paris,France(Payen); DrvandenBergisanemployeeofAM-Pharmaand civil,Strasbourg,France;BruceMolitoris,MD,
DepartmentofAnaesthesiologyandCriticalCare, holdsequityinterestinthecompany;healsohas IndianaUniversity,Indianapolis;PatrickMurray,MD,
HôpitalLariboisière,AssistancePublique—Hôpitaux patentsorlicensesfiledviaAM-Pharmaforwhich SchoolofMedicine,UniversityCollegeDublin,
deParis,Paris,France(Payen);ClinicalDepartment, hereceivesnopersonalcompensation.DrArendis Dublin,Ireland;RaghavenMurugan,MD,MS,FRCP,
AM-PharmaBV,Bunnik,theNetherlands anemployeeofAM-Pharmaandholdsequity FCCM,CenterforCriticalCareNephrology,
(vandenBerg,Arend). interestinthecompany;healsohaspatentsor DepartmentofCriticalCareMedicine,Universityof
licensesfiledviaAM-Pharmaforwhichhereceives PittsburghSchoolofMedicine,Pittsburgh,
AuthorContributions:DrPickkershadfullaccess
nopersonalcompensation. Pennsylvania;MarliesOstermann,MD,PhD,King’s
toallofthedatainthestudyandtakes
responsibilityfortheintegrityofthedataandthe Funding/Support:Thisworkwassupportedby CollegeLondon,Guy’s&StThomas’Hospital,
accuracyofthedataanalysis.DrPickkersisthe AM-Pharma. London,UK;DidierPayen,MD,PhD,UMRINSERM
1160,UniversityParis7DenisDiderotParisCité
principalinvestigatorandchairedthesteering RoleoftheFunder/Sponsor:Theroleofthe Sorbonne&LariboisièreHospital-AP–H,Paris,
committee,whichalsoincludedDrsMehta,Murray, sponsorinthedesignofthestudywasto France;PeterPickkers,MD,PhD,Departmentof
andJoannidis.DrKellumservedasnationalPIfor coordinateandfacilitateprocesses,wherethe IntensiveCareMedicine,RadboudUniversity
theUnitedStates.DrMolitorischairedthe scientificinputwasprovidedbythemembersof NijmegenMedicalCenter,Nijmegen,the
adjudicationcommittee. theprotocolcommittee,steeringcommittee, Netherlands;WimRozendaal,MD,JeroenBosch
Conceptanddesign:Pickkers,Mehta,Murray, andspecificinputbyexternalexpertsindata Hospital,IntensiveCare,Hertogenbosch,the
Joannidis,vandenBerg,Arend. managementandstatistics.Thesponsorcontracted Netherlands;MiiaValkonen,MD,PhD,Divisionof
Acquisition,analysis,orinterpretationofdata:All anexternalcontractresearchorganizationto AnesthesiaandIntensiveCareMedicine,Helsinki
authors. operationallyconductthestudyatthestudysites. UniversityandHelsinkiUniversityCentralHospital,
Draftingofthemanuscript:Pickkers,vandenBerg, Thecontractresearchorganizationwasresponsible Helsinki,Finland;AntonioArtigasRaventos,MD,
Arend. forsettingupthetechnicalsystems,datacollection, PhD,HospitaldeSabadelldeBarcelona,Centrode
Criticalrevisionofthemanuscriptforimportant qualitycontrol,pharmacovigilance,statistics,and Críticos,Sabadell,Spain;FredericBellec,MD,
intellectualcontent:Pickkers,Mehta,Murray, furtheroverallmanagementofthestudy,under CentreHospitalierdeMontauban,Montauban,
Joannidis,Molitoris,Kellum,Bachler,Hoste, coordinationandsupervisionofthesponsor. France;AntoniBetbeseRoig,MD,PhD,Hospitalde
Hoiting,Krell,Ostermann,Rozendaal,Valkonen, Thestatisticalanalysisplanwaspreparedbythe LaSantaCreuiSantPau,MedicinaIntensiva,
Brealey,Beishuizen,Meziani,Murugan,deGeus, contractresearchorganizationwithinputby Barcelona,Spain;AzraBihorac,MD,Universityof
Payen,vandenBerg,Arend. principalinvestigator,sponsor,andexternalexperts Florida,Gainesville;ThierryBoulain,MD,Centre
Statisticalanalysis:Pickkers,Arend. instatistics.Theanalyseswereperformedby HospitalierRégionald'Orléans,Orléans,France;
Obtainedfunding:Arend. externalcontractresearchorganizations.Datawere EdwardCordasco,MD,RemingtonDavisInc,
Administrative,technical,ormaterialsupport: interpretedbythemembersofthesteering Columbus,Ohio;DiannaCruz,MD,Universityof
Pickkers,Joannidis,Molitoris,Bachler,Krell, committee,and,inalaterphase,allcoauthorsand CaliforniaSanDiego;JacquesDevriendt,MD,CHU
Ostermann,Rozendaal,Brealey,Beishuizen, externalexperts,coordinatedbythesponsor,could Brugmann,Soinsintensifs,Bruxelles,Belgium;Alain
Murugan,deGeus,Payen,vandenBerg,Arend. provideinput.Theprincipalinvestigatorwas Dive,MD,PhD,CHUUCLNamurasbl—SiteGodinne,
Supervision:Pickkers,Mehta,Murray,Joannidis, responsibleforpreparationofthemanuscript.All SoinsIntensifs,Yvoir,Belgium;JosephEustace,MD,
vandenBerg,Arend. coauthorsreviewed,madeadjustments,and CorkUniversityHospital,PIN,Cork,Ireland;LuiG.
ConflictofInterestDisclosures:Allauthorshave approvedthemanuscript.Thedecisiontosubmit Forni,MD,PhD,RoyalSurreyCountyHospital,
completedandsubmittedtheICMJEFormfor themanuscriptwasmadebytheprincipal IntensiveCare,Guildford,UK;KevinFinkel,MD,
DisclosureofPotentialConflictsofInterest. investigatorandothercoauthors. UniversityofTexasHoustonMedicalSchool;Bruno
DrPickkersreportedreceivingtravel STOP-AKIInvestigators:JacquesArend,MD, Francois,MD,CentreHospitalierUniversitairede
reimbursementsandfeesformedicalmonitoringof ClinicalDepartment,AMPharmaBV,Bunnik,the Limoges,CHUDupuytren,Réanimation
thistrialfromAM-Pharma.DrMehtareported Netherlands;MirjamBachler,PhD,Medical polyvalente,Limoges,France;RitaGaleiras,MD,
receivingconsultingfeesfromAM-Pharma. UniversityInnsbruck,DepartmentofGeneraland PhD,HospitalUniversitarioACoruña,ACoruña,
DrMurrayreportedreceivingconsultingfeesfrom SurgicalCriticalCareMedicine,Austria;Albertus Spain;HerwigGerlach,MD,PhD,VivantesKlinikum
AM-Pharma.DrJoannidisreportedreceivingtravel Beishuizen,MD,PhD,MedischSpectrumTwente, Neukölln,Berlin,Germany;RichardGerritsen,MD,
reimbursementsandconsultingfeesfrom IntensiveCare,Enschede,theNetherlands;Erik MedischCentrumLeeuwarden,Leeuwarden,the
AM-Pharma;consultingfeesfromBaxter vandenBerg,ClinicalDepartment,AMPharmaBV, Netherlands;MatthiasGründling,MD,PhD,
Healthcare;speakers’feesfromCLSBehringand
jama.com (Reprinted) JAMA November20,2018 Volume320,Number19 2007
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