CIDRC by OEM65

Randomized Trial of Three Intravenous Immunoglobulin Doses for Treating Chronic

Inflammatory Demyelinating Polyneuropathy

Cornblath DR, van Doorn PA, Hartung H-P, et al, and the ProCID Investigators. Brain. 2022 Jan 17:awab422. doi: 10.1093/brain/awab422. Epub ahead of print. PMID: 35038723.

INTRODUCTION

• Treatments for chronic inflammatory demyelinating polyneuropathy (CIDP) include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange. Where available, IVIg is most frequently used as first-line treatment, usually starting with an induction dose of 2.0 g/kg over 2 to 5 days followed by maintenance dosing of 1.0 g/kg every 3 weeks. No dose-ranging studies with IVIg maintenance therapy have been published

• Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) was the largest randomized trial to assess the safety and efficacy of IVIg maintenance therapy in adults with CIDP—and was the first and only IVIg trial to evaluate different (lower and higher) maintenance dosing options for CIPD

METHODS

• Prospective, double-blind, randomized, multicenter, phase 3 study conducted in 142 adults with CIDP

• Treatment: Panzyga (2.0 g/kg induction dose) followed by standard maintenance dose of 1.0 g/kg given every 3 weeks, and two other doses, 0.5 g/kg and 2.0 g/kg over 6 months (24 weeks)

• Primary endpoint: Response rate in the 1.0 g/kg group at week 24, defined as ≥1 point improvement in adjusted INCAT (Inflammatory Neuropathy Cause and Treatment) score at Week 6 vs baseline and maintained at Week 24

• Secondary endpoints: INCAT responses in 0.5 g/kg and 2.0 g/kg arms vs the 1.0 g/kg arm; time to INCAT response; Inflammatory Rasch-built Overall Disability Scale (I-RODS) score; grip strength; Medical Research Council (MRC) score; Pain Intensity Numeric Rating Scale; sum of distal evoked amplitude of 8 motor nerves; safety/tolerability

The ProCID study was the first to examine systematically a higher (2.0 g/kg) maintenance dose of IVIg in CIDP and compare efficacy and safety with standard dosing of 1.0 g/kg.1

• All 142 patients were assessed for safety and 139 for efficacy; 121 patients were previously on corticosteroids

INDICATION AND USAGE

Panzyga (Immune Globulin Intravenous [Human] - ifas) is indicated for the treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older; this includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies; chronic immune thrombocytopenia (cITP) in adults to raise platelet counts to control or prevent bleeding; and chronic inflammatory demyelinating polyneuropathy (CIDP) in adults to improve neuromuscular disability and impairment.

WARNING: THROMBOSIS, RENAL DYSFUNCTION, AND ACUTE RENAL FAILURE

• Thrombosis may occur with immune globulin intravenous (IGIV) products, including Panzyga. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive IGIV products, including Panzyga. Patients predisposed to renal dysfunction include those with a degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. Panzyga does not contain sucrose.

• For patients at risk of thrombosis, renal dysfunction, or acute renal failure, administer Panzyga at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. [see Full Prescribing Information, Warnings and Precautions (5.2, 5.4)]

Please see accompanying full Prescribing Information, including Boxed Warning.

Immune Globulin

Intravenous (Human) - ifas 10% Liquid Preparation

The First and Only IVIg Therapy With 2 FDA-approved Maintenance Dosing Options for CIDP in Adults

Panzyga Dosing and Rate of Administration for Patients With CIDP2

LOADING DOSE

2 g/kg (20 mL/kg)

divided into 2 daily doses (1 g/kg [10 mL/kg] on 2 consecutive days)

INITIAL INFUSION RATE (first 30 minutes)

1 mg/kg/min (0.01 mL/kg/min)

MAINTENANCE DOSE

1 g/kg or 2 g/kg (10-20 mL/kg) every 3 weeks divided in 2 doses given over 2 consecutive days

MAXIMUM INFUSION RATE (as tolerated)

12 mg/kg/min (0.12 mL/kg/min)

• In the ProCID study, a loading dose of 2 g/kg of Panzyga was given followed by 7 maintenance infusions every 3 weeks over a period of 6 months

• The initial infusion rate should be maintained for 30 minutes, and if tolerated, the infusion rate may be gradually increased every 15-30 minutes to a maximum of 12 mg/kg/min (0.12 mL/kg/min) as tolerated2

All patients enrolled in the ProCID study received IVIg induction and maintenance therapy with Panzyga® (Immune Globulin Intravenous [Human] – ifas)

For additional Important Safety Information, please see full Prescribing Information and Boxed Warning for Panzyga.

Immune Globulin Intravenous (Human) - ifas 10% Liquid Preparation

ProCID STUDY RESULTS

PRIMARY ENDPOINT: 80%

of Patients Receiving a Standard 1 g/kg Maintenance Panzyga Dose Achieved an INCAT Response at 6 Months

INCAT Responder Rates

• Median time to INCAT improvement: 1 g/kg arm, 26 days; 2 g/kg arm, 23 days

• In patients previously on corticosteroids or Ig therapy, overall response rate was 82% and 61%, respectively

• INCAT responder rates increased as the maintenance dose increased, although the effect was driven by a significant difference between the 0.5 and 2.0 g/kg groups (P=0.04)

• Odds ratio analysis of the effect of treatement group on response showed overlapping confidence intervals

Contraindications

Panzyga is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin and in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

Warnings and Precautions

Monitor renal function, including blood urea nitrogen and serum creatinine, and urine output in patients at risk of developing acute renal failure.

Hyperproteinemia, increased serum osmolarity, and hyponatremia may occur in patients receiving Panzyga. Aseptic meningitis syndrome may occur in patients receiving Panzyga, especially with high doses or rapid infusion.

Please see accompanying full Prescribing Information, including Boxed Warning.

Similar Incremental Improvements in Response Rates Were Observed for Secondary Efficacy Variables

Responder Rates By Panzyga Maintenance Dosing*

NOTE: These were secondary study endpoints only and not included in final approved labeling.

*Responders defined as: I-RODS=Scores using minimum clinically important difference related to the varying standard errors (MCID-SE).

Grip Strength=Minimum clinically important difference (MCID) cut-off of 8 kPa. MRC Sum Scores=Increase of at least 4 points compared with baseline.

• Pain Intensity Numeric Rating Scale score increased during the wash-out phase, then tended to decrease through Week 24. Mean changes from baseline were -2.2 and -2.2 in the 1.0 and 2.0 g/kg groups, respectively

• There were no clear trends over time in the nerve conduction studies

• Of the 29 non-responders in the study:

– 22 were on prior corticosteroids

– 11 remained on corticosteroids during the study

– 13 received rescue treatment – 16 withdrew from the study

– 7 were in the 1.0 g/kg group

– Only 3 were in the 2.0 g/kg group

• Of the 16 non-responders who withdrew, 7 were in the 1.0 g/kg group, and 3 in the 2.0 g/kg group. At the time of early termination, a 51-point improvement in adjusted INCAT scores had been achieved by 5/7 patients in the 1.0 g/kg group, and none of the 3 patients in the 2.0 g/kg group

Warnings and Precautions

Carefully consider the relative risks and benefits before prescribing the high dose regimen (for cITP) in patients at increased risk of volume overload.

Panzyga is made from human plasma and may contain infectious agents, e.g. viruses and theoretically, the Creutzfeldt-Jakob disease agent.

Please see accompanying full Prescribing Information, including Boxed Warning.

Incidence of Related Treatment Emergent Adverse Events (TEAEs) Was Similar Across Treatment Arms (Except for Headaches, Which Was Dose Related)

On Average, Headache Was Reported in 15% of Patients Across All Panzyga Dosing Arms

Most commonly reported related TEAEs across all treatment arms

• Headache was most prevalent in the 1.0 and 2.0 g/kg arms (15% and 24%)

• The only TEAE where a dose effect was apparent was headache: 3% in the 0.5 g/kg arm, 14.5% in the 1.0 g/kg arm, and 24% in the 2.0 g/kg group

• There were no treatment-related deaths. Two serious adverse reactions (headache and vomiting) were reported in 1 patient but did not lead to discontinuation

“Treatment was well tolerated even in IgG-naïve patients and in those regularly treated with high dose IVIg.”1

Adverse Reactions

PI—most common adverse reactions (≥5% study subjects): headache, nausea, fever, fatigue, abdominal pain. cITP in adults—most common adverse reactions (≥5% study subjects): headache, fever, nausea, vomiting, dizziness, anemia. CIDP in adults—The most common adverse reactions reported in greater than 5% of subjects were: headache, fever, dermatitis, and blood pressure increased.

Please see accompanying full Prescribing Information, including Boxed Warning.

“In summary, the ProCID study demonstrated that 1.0 g/kg IVIg is efficacious and well tolerated as maintenance treatment following a 2.0 g/kg induction dose in patients with active CIDP...”1

Contact Octapharma:

Octapharma USA, Inc. 117 W. Century Road Paramus, NJ 07652 Tel: 201-604-1130

Reimbursement Assistance usreimbursement@octapharma.com Tel: 800-554-4440 www.octapharmausa.com

Medical Affairs usmedicalaffairs@octapharma.com

For all inquiries relating to drug safety, or to report adverse events, please contact our local Drug Safety Officer: Tel: 201-604-1137 | Cell: 201-772-4546 | Fax: 201-604-1141 or contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References: 1. Cornblath DR, van Doorn PA, Hartung H-P, et al, and the ProCID Investigators. Brain. 2022 Jan 17:awab422. doi: 10.1093/ brain/awab422. Epub ahead of print. PMID: 35038723 2. Panzyga full Prescribing Information. Paramus, NJ: Octapharma USA Inc.; 2021.

RandomizedtrialofthreeIVIgdosesfor treatingchronicinflammatory demyelinatingpolyneuropathy

DavidR.Cornblath,1 PieterA.vanDoorn,2 Hans-PeterHartung,3,4,5,6 IngemarS.J.Merkies,7,8 HansD.Katzberg,9 DorisHinterberger,10 ElisabethClodi10 andtheProCIDInvestigators

Intravenousimmunoglobulintreatmentforchronicinﬂammatorydemyelinatingpolyneuropathyusuallystarts witha2.0g/kginductiondosefollowedby1.0g/kgmaintenancedosesevery3weeks.Nodose-rangingstudieswith intravenousimmunoglobulinmaintenancetherapyhavebeenpublished.

TheProgressinChronicInflammatoryDemyelinatingpolyneuropathy(ProCID)studywasaprospective,doubleblind,randomized,parallel-group,multicentre,phaseIIIstudyinvestigatingtheefficacyandsafetyof10%liquid intravenousimmunoglobulin(PanzygaV R )inpatientswithactivechronicinflammatorydemyelinatingpolyneuropathy.Patientswererandomized1:2:1toreceivethestandardintravenousimmunoglobulininductiondoseand theneither0.5,1.0or2.0g/kgmaintenancedosesevery3weeks.Theprimaryendpointwastheresponseratein the1.0g/kggroup,definedasanimprovement 51pointinadjustedInflammatoryNeuropathyCauseand TreatmentscoreatWeek6versusbaselineandmaintainedatWeek24.Secondaryendpointsincludeddoseresponseandsafety.ThistrialwasregisteredwithEudraCT(Number2015–005443-14)andclinicaltrials.gov (NCT02638207).

BetweenAugust2017andSeptember2019,thestudyenrolled142patients.All142wereincludedinthesafety analyses.Asnopost-infusiondatawereavailableforthreepatients,139wereincludedintheefficacyanalyses,of whom121werepreviouslyoncorticosteroids.Theresponseratewas80%(55/69patients)[95%confidenceinterval (CI):69–88%]inthe1.0g/kggroup,65%(22/34;CI:48–79%)inthe0.5g/kggroup,and92%(33/36;CI:78–97%)inthe 2.0g/kggroup.Whiletheproportionofresponderswashigherwithhighermaintenancedoses,logisticregression analysisshowedthattheeffectonresponseratewasdrivenbyasignificantdifferencebetweenthe0.5and2.0g/ kggroups,whereastheresponseratesinthe0.5and2.0g/kggroupsdidnotdiffersignificantlyfromthe1.0g/kg group.Fifty-sixpercentofallpatientshadanadjustedInflammatoryNeuropathyCauseandTreatmentscoreimprovement3weeksaftertheinductiondosealone.Treatment-relatedadverseeventswerereportedin16(45.7%), 32(46.4%)and20(52.6%)patientsinthe0.5,1.0and2.0g/kgdosegroups,respectively.Themostcommonadverse reactionwasheadache.Therewerenotreatment-relateddeaths.

Intravenousimmunoglobulin(1.0g/kg)wasefficaciousandwelltoleratedasmaintenancetreatmentforpatients withchronicinflammatorydemyelinatingpolyneuropathy.Furtherstudiesofdifferentmaintenancedosesof intravenousimmunoglobulininchronicinflammatorydemyelinatingpolyneuropathyarewarranted.

1DepartmentofNeurology,JohnsHopkinsUniversity,Baltimore,MD21287,USA 2DepartmentofNeurology,ErasmusUniversityMedicalCenter,Rotterdam3015CE,TheNetherlands 3DepartmentofNeurology,HeinrichHeineUniversity,Du¨sseldorf40225,Germany 4BrainandMindCenter,UniversityofSydney,Sydney,NSW2050,Australia 5DepartmentofNeurology,MedicalUniversityofVienna,Vienna1090,Austria

ReceivedAugust16,2021.RevisedOctober15,2021.AcceptedNovember09,2021.AdvanceaccesspublicationJanuary17,2022 V C TheAuthor(s)(2022).PublishedbyOxfordUniversityPressonbehalfoftheGuarantorsofBrain. ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttribution-NonCommercialLicense(https://creativecommons.org/licenses/ by-nc/4.0/),whichpermitsnon-commercialre-use,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.For commercial re-use,pleasecontactjournals.permissions@oup.com https://doi.org/10.1093/brain/awab422BRAIN2022:Page1of10

6DepartmentofNeurology,PalackyUniversity,Olomouc77147,CzechRepublic 7DepartmentofNeurology,MaastrichtUniversityMedicalCenter,Maastricht6229HX,TheNetherlands 8Curac¸aoMedicalCenter,Willemstad,Curac¸ao 9DepartmentofNeurology,UniversityofToronto,TorontoM5G2C4,Canada 10ClinicalR&D,OctapharmaPPG,Vienna1100,Austria

Correspondenceto:DavidR.Cornblath,MD DepartmentofNeurology,JohnsHopkinsUniversity,Meyer6-181a 600NorthWolfeSt.,Baltimore,MD21287,USA E-mail:dcornbl@jhmi.edu

Keywords: chronicinﬂammatorydemyelinatingpolyneuropathy;intravenousimmunoglobulin;ProCIDstudy; panzygaV R ;randomizedcontrolledtrial

Abbreviations: CIDP=chronicinflammatorydemyelinatingpolyneuropathy;I-RODS=InflammatoryRasch-built OverallDisabilityScale;INCAT=InflammatoryNeuropathyCauseandTreatment;IVIg=intravenousimmunoglobulin;MRC=MedicalResearchCouncil;ProCID=progressinchronicinflammatorydemyelinatingpolyneuropathy; TEAE=treatment-emergentadverseevents

Introduction

Chronicinflammatorydemyelinatingpolyneuropathy(CIDP)isa rare,auto-immunemediatedpolyneuropathyandcanbediagnosedusingguidelinesfromtheEuropeanFederationof NeurologicalSocieties/PeripheralNerveSociety(EFNS/PNS).1 2 However,thediagnosisofCIDPisnotstraightforward,3 andanumberofdisorderscanbemistakenforCIDP.4

ThreetreatmentshavebeenproveneffectiveforCIDP:intravenousimmunoglobulin(IVIg),corticosteroids,andplasmaexchange.5 Whereavailable,IVIgisthemostfrequentlyused first-linetreatmentduetoitssafetyandefficacy.Basedonseveral clinicalstudies,treatmentwithIVIginCIDPusuallystartswithan inductiondoseof2.0g/kgover2to5daysfollowedbymaintenance dosingof1.0g/kgevery3weeks.6–8

Theoptimalmaintenancedosemayvarybetweenpatients, andtheEFNS/PNSguidelinesrecommendthatthemaintenance dosemayneedtobeadjustedtosuitanindividualpatient’s needs.2 Whilsttailoreddosinghasbeenlongadvocatedandissupportedbyretrospectiveandreal-lifedata,9–12 therehavebeenno randomized,prospectivetrialsevaluatingdifferentIVIgmaintenancedoseregimensinpatientswithCIDP.Onlyonesmallopen, randomizedstudyhasevaluateddifferentinductiondosesofIVIg forCIDPandmultifocalmotorneuropathy,andtheresultsshowed apotentialdose-relatedeffect5weeksafterinductiontreatment.13

ThePATHstudyevaluatedtwodosesofsubcutaneousimmunoglobulin(SCIg),0.2and0.4g/kgeveryweek,inpatientswithCIDP andshowednosignificantdifferencesinoutcomesbetweenthose twoSCIgdosesduringastudyperiodof24weeks.14

TheProgressinChronicInflammatoryDemyelinatingpolyneuropathy(ProCID)studyinvestigatedtheefficacyandsafetyof IVIgaftera2.0g/kginductiondosefollowedbyastandardmaintenancedoseof1.0g/kggivenevery3weeks,andtwootherdoses, 0.5g/kgand2.0g/kg,onoutcomesinpatientswithCIDPduringa studyperiodof24weeks.

Materialsandmethods

Studydrug

IVIg(PanzygaV R ,Octapharma)isaglycine-stabilized10%liquid humanIVIg15,16 withprovenefficacyandsafetyasreplacement

therapyinprimaryimmunodeficiency17 andforimmunomodulationinpatientswithimmunethrombocytopenicpurpura.18 This IVIgproductislicensedfordifferentindications(includingCIDP)in theUSA,19 Canada20 andtheEU.21

Studydesignandparticipants

TheProCIDstudy(EudraCTNumber2015–005443-14andclinical trials.gov identifierNCT02638207)wasdesignedin2016/2017and initiatedin2017.22 Thetrialprotocolandstatisticalanalysisplan werepublishedpreviously.22

Patientswereeligibleiftheywereatleast18yearsoldandhad beendiagnosedwithdefiniteorprobableCIDPaccordingtopublishedcriteria1 andiftheyweredependentontreatmentwith immunoglobulinsorcorticosteroids.Themainexclusioncriteria includedpreviousfailureofimmunoglobulintreatment,treatment withotherimmunomodulatory/suppressiveagentsintheprior 6months,treatmentwithimmuno-chemotherapeuticregimens, andclinicalevidenceofperipheralneuropathyfromanother cause.Fullinclusionandexclusioncriteriawerepublishedpreviously.22 Allpatientsgavewritteninformedconsentpriortoany study-relatedprocedures.Theethicscommitteesofallparticipatingcentresapprovedthestudyprotocol.

Procedures

Thestudyconsistedofscreening,wash-out,anddose-evaluation phases(Fig.1).Patientswerescreened,and,ifeligible,enteredthe wash-outphase,duringwhichtheircurrentmedicationwas reducedinapredefinedstandardmanner,todeterminewhether theyhadactiveCIDP.ForthosepreviouslyonIVIg,thedosewas reducedby25%ateachsequentialinfusionuntildeterioration.For thosepreviouslyoncorticosteroids,thedosewasreducedatthe discretionoftheinvestigatorataratetoexpectstudyentrywithin 6–12weeksandtoadoseofprednisolone 420mg/dayorequivalentwhendeteriorationoccurred.Lowdosesofcorticosteroidsat deteriorationcouldbecontinuedduringthestudy.Thewash-out phasehadamaximumof12weeks,andonlypatientswhodeterioratedinthistimeframewereenrolledandrandomizedintothe dose-evaluationphase.Patientswhodidnotdeteriorateinthe wash-outphasewereconsiderednottohaveactiveCIDPandwere excludedfromthestudy.Deteriorationwasdeterminedby

worseningoftheiroverallstatusaccordingtothePatients’Global ImpressionofChangeScaleandeitheranincreaseinadjusted InflammatoryNeuropathyCauseandTreatment(INCAT)scoreby 51point,oradecreaseof 58kPaongripstrengthinonehand, orreachedtheInflammatoryRasch-builtOverallDisabilityScale (I-RODS)minimumclinicallyimportantdifferencerelatedtothe varyingstandarderrorscut-offof–1.96orless.23

Allpatientswhodeterioratedwererandomlyassigned1:2:1to maintenancedosesof0.5,1.0or2.0g/kgIVIginthe24-weekdoseevaluationphase.TheythenreceivedaninductiondoseofIVIg 2.0g/kg,followedbysevenmaintenanceIVIgdosesof0.5,1.0or 2.0g/kgevery3weeks(± 4days).Themaskedassignmentofthe correctdoseandtreatmentforeachstudyvisitwasmanagedusing aninteractivewebresponsesystem.Thetreatmentgroupassignmentwasonlyreportedtothehospitalpharmacistordesigneeby adedicatedemailtowhichnootherstudypersonnelhadaccess. Thepatientwasmaskedtothemedicationbytheuseofanopaque (non-transparent)infusionlineandoverpouches.Theevaluating investigatorwasnotinvolvedwithadministeringmedicationto thepatient.Dosingwasbasedonactualbodyweightandadministeredovertwoconsecutivedayswithoutpre-medication. Corticosteroids(prednisoloneorequivalent) 420mg/dayasconcomitantCIDPmedicationwerepermittedduringthedose-evaluationphaseforpatientswithpriorcorticosteroidtherapy.Forall patientsinthe0.5and1.0g/kgdosegroupswhowerestable(unimproved)atWeek6ordeterioratedbetweenWeeks3and18,there wastheoptiontoadministerrescuetreatmentwithtwoconsecutiveinfusionsofIVIg2.0g/kgat3-weekintervals(± 4days). FollowingthetwoIVIgrescuetreatments,patientsattendedan endofstudyvisit.PatientsdeterioratingafterWeek18or21 droppedoutandhadtheirendofstudyvisitatWeek21or24,respectively.Patientsinthe2.0g/kgarmwerediscontinuedfromthe studyiftheywerestable(unimproved)atWeek6ordeteriorated afterWeek3andbeforeWeek21.

Outcomes

Theprimaryoutcomewastheproportionofrespondersinthe 1.0g/kgarmatWeek24.8,24 Aresponderwasdefinedasasubject

whoshowedanimprovement(decrease) 5 1pointinadjusted INCATscoreatWeek6comparedwithbaseline(firstvisitofthe dose-evaluationphase),completedthe24-weekstudy,andmaintainedtheresponseatWeek24.Anon-responderwasdefinedasa subjectwhodidnotachieveanimprovementof 51pointin adjustedINCATscorebyWeek6,orwhodeterioratedbetween Week3andWeek21,orwhodiscontinuedbeforeWeek24,irrespectiveofadjustedINCATscoreattermination.

Themainsecondaryoutcomesweretheproportionofrespondersinthe0.5g/kgand2.0g/kgarmsatWeek24relativetobaseline comparedwiththe1.0g/kgarmbasedontheadjustedINCAT score,gripstrength,I-RODSscore,andMedicalResearchCouncil (MRC)score,andtimetofirstconfirmedworseningontheadjusted INCATscoreby 51pointfromthevalueatbaseline.OthersecondaryoutcomeswerethePainIntensityNumericRatingScaleand thesumofthedistalevokedamplitudeofeightmotornerves.To assesssafetyandtolerability,treatment-emergentadverseevents (TEAEs)perinfusionandthenumberofpatientswithTEAEswere recorded.AnadverseeventwasdefinedasaTEAEiffirstonsetor worseningoccurredafterthestartofthefirstIVIgadministration inthestudy.Thefulllistofoutcomesvariableshaspreviously beenpublished.22

Statisticalanalysis

Thesamplesizecalculationwasbasedontheexpectedproportion ofrespondersbasedontheadjustedINCATscoreinthe1.0g/kg dosegroup.Atthetimethisstudywasdesigned,experienceswith thisdosingregimenwereavailablefromtheICE6 andPRIMA7 studies.InthePRIMAstudy,7 thelowerlimitofthe95%Wilson-Score confidenceinterval(CI)fortheproportionofresponders(R)was 42%,andthus42%wasselectedasthethresholdforevaluationof theprimaryendpoint:nullhypothesis(H0)R 5 0.42;alternative hypothesis(H1)R 5 0.42.Thiswastestedbycomparingthelower limitofthe95%Wilson-ScoreCIfortheobservedproportionofresponderswithapre-definedthresholdof0.42.Weestimatedthe truepercentageofrespondersinCIDPpatientstreatedwithIVIgas 60%.Incomparison,60.7%ofpatientswererespondersinthe PRIMAstudyand54.2%intheICEstudy.6,7 Weappliedthese

Figure1Trialdesign.

parameterstoacomputersimulationusingSASV R statisticalanalysissoftwareandcalculatedthataminimumof62evaluable patientsinthe1.0g/kgdosegroupwasneededtoachievea powerofatleast80%.Toaccountforpossibledropouts,itwas plannedtoenrol70patientsintothisgroup.Toallowforthe comparisonbetweendosegroups,itwasplannedtoenrolhalf thenumberofevaluablepatientsintothe0.5and2.0g/kg groups,resultinginatotalof124evaluablepatientsandanenrolmenttargetof140patients.Theprimaryevaluationofefficacyendpointswasbasedonthefullanalysissetinan intention-to-treatanalysis.

Theresponseratesinthealternativedosegroupswerecompareddescriptivelyandbyanoddsratioanalysis.Allotherend pointswereanalysedbymeansofdescriptivestatistics.Safetywas analysedinallpatientswhoreceivedanyamountofIVIginthe study.

Inaddition,anexploratorylogisticregressionanalysiswasperformedthatincludedthepretreatmentaswellasthedosegroup aspredictorvariablesforresponsebasedonadjustedINCATscore. Thesamemodelwasappliedtotreatmentresponsesbasedongrip strength,I-RODSscoresandMRCsumscore.

Dataavailability

Individualparticipantdatacollectedduringthetrialwillnotbe shared.Thestudyprotocolandmainresultsareavailableat https://clinicaltrials.gov/ct2/show/study/NCT02638207 (Accessed 24February2022).

Results

Patientdisposition

Patientswereenrolledfrom25centresworldwidebetween9 August2017and5September2019.Atotalof171patientswere screened,and150enteredthewash-outphase.Eightpatients werenoteligibleforinclusionintothedose-evaluationphase duetotheirdiseasenotbeingtreatmentdependent(n =4)or withdrawalofconsent(n =4).Atotalof142patientsexperienced deteriorationduringthewash-outphaseandwererandomized:

35(24.6%)toIVIg0.5g/kg,69(48.6%)toIVIg1.0g/kg,and38 (26.8%)toIVIg2.0g/kg.All142randomizedpatientsreceivedat leastoneinfusionofIVIgandwereincludedinthesafetyanalysisset.Theintention-to-treatpopulationconsistedof139 patientsbecausenopost-infusiondatawerecollectedinthree patients.Theper-protocolsetcomprised129patients:five patientswereexcludedduetodosingerrors,fourpatientswithdrewfromstudy,andonepatientwaslosttofollow-up.Intotal, 123patients(86.6%)completedthestudy(Fig.2).Ofthe19 patients(13.4%)whoterminatedearlyandwerethuscountedas non-responders,themostcommonreasonswerepatient’sdecision(n =7,4.9%)andTEAEs(n =6,4.2%).Thehighestincidence ofearlyterminationswasseeninthe0.5g/kggroup(20.0%),comparedwith11.6%inthe1.0g/kggroupand10.5%inthe2.0g/kg group.

Demographicandbaselinecharacteristics

Demographiccharacteristicsintheintention-to-treatpopulation (Table1)weresimilaracrossrandomizationstrataandinthe safetyanalysisset.Intotal,91.4%ofpatientshadahistoryoftypicalCIDP.Twelve(8.6%)patientshadatypicalCIDP:ninedistal acquireddemyelinatingsymmetricneuropathyandthreemultifocalacquireddemyelinatingsensoryandmotorneuropathy.One hundredandtwenty-onepatients(87.1%)hadbeentreatedpreviouslywithcorticosteroidsfortheirCIDP,and18patients(12.9%) withimmunoglobulins.Thepercentageofpatientspreviously treatedforCIDPwithimmunoglobulinsorwithcorticosteroids wasdistributedequallyacrossthethreedosegroups.Afterdeteriorationandatthestartofthedose-evaluationphase,44/121 patients(36%)previouslyoncorticosteroidsenteringthisphase werestilloncorticosteroids,andthiswasbalancedevenlyacross dosegroups(Table1).Thecorticosteroiddosewasreducedto 420mg/dayinallexcepttwoofthese44patients,oneinthe0.5g/ kggroupandoneinthe1.0g/kggroup,whowereonadoseof 25mg/dayprednisoloneequivalentduetoamiscalculationinthe conversionofmethylprednisolonetoprednisolone.Neitherof thesepatientswereexcludedfromtheanalyses.Twelveofthe18 patients(67%)previouslyonIVIgwerestillonIVIgatthestartof thedose-evaluationphase.

Figure2Trialproﬁle.

Table1Baselinecharacteristics

Characteristic Treatmentgroup(intention-to-treat)

0.5g/kg(n =34)1.0g/kg(n =69)2.0g/kg(n =36)

Female, n (%)

Age,years

13(38)31(45)13(36)

57(40–64)59(51–67)61(49–66)

Bodyweight,kg83(72–97)80(71–93)77(66–89)

Bodymassindex,kg/m2 27(25–31)27(24–30)25(23–29)

EFNS/PNScriteria, n (%)

DeﬁniteCIDP

34(100)68(99)36(100)

ProbableCIDP 01(1)0

TypeofCIDP, n (%)

Typical 33(97)62(90)32(89)

Atypical 1(3)7(10)4(11)

Priortreatment, n (%)

Corticosteroids 29(85)60(87)32(89)

Immunoglobulins5(15)9(13)4(11)

Patientsstilloncorticosteroidsatstartofdose-evaluationphase, n (%)11(38)20(33)13(41)

Prednisoloneequivalent/day(mg)

Median(range)20(2.5–25)18(2.5–25)20(2.5–20)

PatientsstillonIVIgatstartofdose-evaluationphase, n (%)2(40)6(67)4(100)

IVIg(g/kg)

Median(range)0.9(0.3–1.4)0.4(0.3–0.8)0.4(0.2–0.7)

Efﬁcacyscoresatscreening

AdjustedINCATscore(range0–10)4(4–5)4(4–5)4(4–5) I-RODS(range0–48)27(20–32)25(21–31)29(21–32)

Maximumgripstrength(kPa;range0–160)

Dominanthand51(32–68)53(39–78)52(41–64)

Non-dominanthand52(28–70)54(38–76)54(38–67)

MRCsumscore(totalrange0–80)46(42–50)46(42–52)47(43–53)

Allvaluesarethemedian(interquartilerange)unlessotherwisestated(intention-to-treat).

Efficacy

Fortheprimaryendpoint,theresponserateinthe1.0g/kggroup was80%(55/69patients;95%CI:69–88%)(Table2).ThelowerCI limitof69%exceededthepredefinedthresholdof42%,thusthe primaryendpointwasmet.

TheadjustedINCATscoreresponseratesinthe0.5and2.0g/kg maintenancedosegroupswere65%(22/34patients;95%CI: 48–79%)and92%(33/36patients;95%CI:78–97%)atWeek24,respectively.Inpatientspreviouslyoncorticosteroids,theresponse rateacrossallthreedosegroupswas82%(99/121patients;95%CI: 74–88%)and66%,83%and94%inthe0.5,1.0and2.0g/kggroups, respectively.Inpatientspreviouslyonimmunoglobulintherapy, theresponserateacrossallthreedosegroupswas61%(11/18 patients;95%CI:39–80%)and60%,56%and75%inthe0.5,1.0and 2.0g/kggroups,respectively.

Responderratesinthe1.0g/kgdosegroupforgripstrength, I-RODSandMRCsumscorewere65%,55%and72%,respectively (Table2).Responserateswere56%,38%and59%forthe0.5g/kg cohortand83%,72%and86%forthe2.0g/kgcohort,respectively (Table2).

Usinglogisticregressionanalysis,thedosegrouphadaneffect onthetreatmentoutcomesofadjustedINCATscore(P =0.040), gripstrength(P =0.047),andI-RODS(P =0.038),butnotMRCsum score(P =0.066).Oddsratioanalysescomparingthe0.5and2.0g/ kggroupstothe1.0g/kggroupshowedoverlappingCIs(Table3). Furtheranalysesshowedthatthestatisticaldifferenceswerenot driveninastepwisefashionbydose,butduetothedifferencesbetweenthe0.5g/kgand2.0g/kgdosegroups(Table3),withanodds ratioof5.8(95%CI:1.4–23.6)foradjustedINCATscore.

Animprovementinleastsquaremeanschangefrombaseline toendofstudywasachievedinalldosegroupsforadjustedINCAT score,gripstrength,I-RODS,andMRCsumscore(datanotshown).

Ofthe29non-respondersacrossthedosegroups,22wereon corticosteroidspriortostudyenrolmentand11werestilloncorticosteroidsduringthestudy.Ofthe29non-responders,13received rescuetreatment;sixinthe0.5g/kggroupandseveninthe1.0g/kg group(SupplementaryTable1).Thethreeremainingnon-responderswereinthe2.0g/kggroupandthereforenoteligibleforrescue treatment.Threeoutofsix(50%)patientsinthe0.5g/kggroupand 4of7(57%)patientsinthe1.0g/kggrouphadanimproved adjustedINCATscorefollowingrescuetreatment(Supplementary Table1).Inthe0.5g/kggroup,oneofthesepatientsreceivedrescue treatmentdespitetheadjustedINCATscorenotreturningtobaseline.Inthe1.0g/kggroup,anotherpatientreceivedrescuetherapy inerror.Theother16non-respondersdroppedoutofthestudyfor variousreasonsandwereconsideredstudynon-responders,irrespectiveofwhethertheiradjustedINCATscorehadimprovedat thetimetheydroppedout:sixinthe0.5g/kggroup,seveninthe 1.0g/kggroup,andthreeinthe2.0g/kggroup.Atthetimeofearly termination,animprovementof 51pointinadjustedINCATscore hadbeenachievedbyallsixpatientsinthe0.5g/kggroup,fiveof thesevenpatientsinthe1.0g/kggroup,andnoneofthethree patientsinthe2.0g/kggroup.

Oneresponderineachdosegroupdidnotreceiverescuemedication(0.5g/kgand1.0g/kggroup)orwasnotdiscontinued(2.0g/ kggroup)accordingtoprotocoldespitebeingstableatWeek6and subsequentlyhadaresponseatWeek9(0.5and1.0g/kgpatients) orWeek12(2.0g/kgpatient)thatwasmaintainedatWeek24.In theperprotocolset,whichexcluded10intention-to-treatpatients

Table2Proportionofrespondersattheendofstudy

ParameterTreatmentgroup(intention-to-treat)Overall P-value

0.5g/kg(n =34)1.0g/kg(n =69)2.0g/kg(n =36)

AdjustedINCATscore65(48–79)

80(69–88)

92(78–97)0.040

Gripstrength56(40–71)65(53–75)83(68–92)0.047

I-RODS38(24–55)55(43–66)72(56–84)0.038

MRCsumscore59(42–74)72(61–82)86(71–94)0.066

Allvaluesare%ofpatients(95%Cl).Theprimaryendpoint(adjustedINCATscoreresponseinpatientstreatedwith1.0g/kgIVIg)isindicatedinitalics.Theoverall P-valueis calculatedusingatype3logisticregressionanalysisofeffectsmodellingresponsefromtreatment,randomizationstratum,CIDPvariant,andbaselinescorewithout interactions.

Table3Oddsratioanalysisoftheeffectoftreatmentgrouponresponse

ParameterOddsratio(95% CI)(intention-to-treat)

0.5g/kgversus1.0g/kg2.0g/kgversus0.5g/kg2.0g/kgversus1.0g/kg

AdjustedINCATscore0.5(0.2–1.2)5.8(1.4–23.6)2.7(0.7–10.2) Gripstrength0.6(0.3–1.4)4.2(1.4–13.3)2.5(0.9–7.0)

I-RODS0.5(0.2–1.3)3.9(1.4–10.8)2.1(0.8–5.0) MRCsumscore0.6(0.2–1.4)4.1(1.2–13.2)2.3(0.8–6.7)

Figure3Timetoimprovementof 51pointinadjustedINCATscore. Databymaintenancedosegroupinpatientswhoachievedsuchanimprovementatanytimeduringthestudy(safetyanalysisset).

includingthosethreeresponders,theresponseratewas72%(21/ 29patients;95%CI:54–85%)inthe0.5g/kggroup,83%(54/65 patients;95%CI:72–90%)in1.0g/kggroup,and91%(32/35patients; 95%CI:78–97%)inthe2.0g/kggroup(SupplementaryTable2).

Morethanhalfofallpatients(n =78;56.1%)showedanimprovementof 51adjustedINCATscorepointaftertheinduction doseof2.0g/kg:23of34(67.6%)inthe0.5g/kggroup,35of69 (50.7%)inthe1.0g/kggroupand20of36(55.6%)inthe2.0g/kg group.ByWeek6,121of139(87.0%)patientshadanimprovement of 51adjustedINCATscorepoint:30of34(88.2%)inthe0.5g/kg group,59of69(85.5%)inthe1.0g/kggroupand32of36(88.9%)in the2.0g/kggroup.

Mediantimetoanimprovementof 51adjustedINCAT scorepointfrombaselinewas22,26and23daysinthe0.5,1.0and

2.0g/kggroups,respectively(Fig.3).Overall,91.2%ofpatientsin the0.5g/kggroup,88.4%ofpatientsinthe1.0g/kggroupand91.7% ofpatientsinthe2.0g/kggrouphadanimprovementof 51 adjustedINCATscorepointatsomepointinthestudy.Thesevaluesarehigherthanintheprimaryanalysisbecausepatientscould showanimprovementinthescoreduringthestudy,butsubsequentlydeclinedordroppedoutandwerethenconsiderednonresponders.MediantimetoresponseinI-RODSwas63,64,and 43.5daysinthe0.5,1.0,and2.0g/kggroups,respectively.

ThetimetofirstconfirmedworseninginadjustedINCATscore byatleast1pointfromthevalueatbaseline(Week0)revealed thatonlyasinglepatientinthe1.0g/kgdosegroupmetthiscriterion,andthereforethisanalysiswasnotpossible.Thiswasalsothe caseforthetimetofirstconfirmedworseninginI-RODSscoresas

Table4SummaryofrelatedTEAEsobservedin 55% ofpatients

TEAE

Treatmentgroup(safetyanalysisset)

0.5g/kg(n =35)1.0g/kg(n =69)2.0g/kg(n =38)

Patients,(% of patients)

Events,(% of infusions)

Patients,(% of patients)

Events,(% of infusions)

Patients,(% of patients)

Events,(% of infusions)

AnyrelatedTEAE16(45.7)37(16.1)32(46.4)80(16.6)20(52.6)56(20.8)

Headache1(2.9)1(0.4)10(14.5)12(2.5)9(23.7)14(5.2)

Somnolence2(5.7)3(1.3)001(2.6)1(0.4)

Allergicdermatitis4(11.4)4(1.7)5(7.2)10(2.1)4(10.5)5(1.9)

Urticaria3(8.6)4(1.7)0000

Pruritus00002(5.3)3(1.1)

Pyrexia3(8.6)4(1.7)6(8.7)6(1.2)2(5.3)3(1.1)

Chills3(8.6)4(1.7)2(2.9)2(0.4)1(2.6)1(0.4)

Bloodpressureincreased2(5.7)3(1.3)5(7.2)6(1.2)00

Bodytemperatureincreased2(5.7)2(0.9)2(2.9)5(1.0)3(7.9)3(1.1)

Bloodlactatedehydrogenaseincreased005(7.2)5(1.0)00

Nausea1(2.9)1(0.4)1(1.4)2(0.4)3(7.9)5(1.9)

thisoccurredinonlythreepatients:oneinthe0.5g/kggroupand twointhe1.0g/kggroup.

Theproportionofpatientsdeterioratingduringthedose-evaluationphaseofthestudywaslow,oneeachinthe0.5g/kgand 1.0g/kggroups,aswasthenumberofpatientswhowerestableat Week6:13(9.4%)patientsintotal,withfiveinthe0.5g/kggroup, sixinthe1.0g/kggroup,andtwointhe2.0g/kggroup (SupplementaryTable1).

MeanpainintensityaccordingtoPainIntensityNumericRating Scalescoreincreasedduringthewash-outphase,thentendedto decreasethroughWeek24.Mean ± standarddeviation(SD) changesfrombaselinewere–2.3 ± 3.0,–2.2 ± 2.9and–2.2 ± 3.3inthe 0.5,1.0and2.0g/kggroups,respectively.

Therewerenocleartrendsovertimeinthenerveconduction studies.

Safety

MediandosesofIVIgadministeredperpatientperinfusion,includingtheinductiondose,were70g(0.7g/kg)inthe0.5g/kggroup, 101g(1.1g/kg)inthe1.0g/kggroup,and155g(2.0g/kg)inthe2.0g/ kggroup.Dosingwasbasedonactualbodyweight,andtherewas nomaximumdailydose.

Inthe0.5g/kggroup,16(45.7%)patientsexperienced37related TEAEsover230infusions(Table4).Inthe1.0g/kggroup,32(46.4%) patientsexperienced80relatedTEAEsover482infusions,andin the2.0g/kggroup20(52.6%)patientsexperienced56relatedTEAEs over270infusions.Overall,themostcommonlyreportedrelated TEAEswereheadachein20patients(14.1%),allergicdermatitisin 13patients(9.2%),pyrexiain11patients(7.7%),increasedblood pressureinsevenpatients(4.9%),andincreasedbodytemperature insevenpatients(4.9%).Headachewasthemostprevalentrelated TEAEinthe1.0and2.0g/kggroups(14.5%and23.7%,respectively), whilethemostcommonrelatedTEAEinthe0.5g/kggroupwasallergicdermatitis(11.4%ofpatients).Generally,theincidenceof relatedTEAEswassimilaracrossthetreatmentgroups.Theonly TEAEwhereadoseeffectwasapparentwasheadache,withanincidenceof2.9%inthe0.5g/kggroup,14.5%inthe1.0g/kggroup, and23.7%inthe2.0g/kggroup.

Fivepatients(3.5%)experiencedTEAEsthatledtodiscontinuationofthestudydrug,oneofwhich,allergicdermatitisinapatientreceiving1.0g/kgIVIg,wasconsideredrelated.

ElevenseriousTEAEswerereportedinsixpatients(4.2%).Two ofthese(headacheandvomiting)werereportedinonepatientin

the1.0g/kggroupandconsideredrelatedtoIVIgtreatment,butdid notleadtostudydiscontinuation.

Twopatients(1.4%)hadTEAEsleadingtodeath,butneither eventwasconsideredrelatedtothestudydrug.Onepatient aspiratedleadingtorespiratoryarrest,andonedeveloped meningoencephalitis.

Duringthestudy,nohaemolysisorthromboembolicevents werereported.Laboratoryanalysesofhaematology,clinicalchemistry,urinalysisandviralmarkersdidnotindicateanysafetyconcerns.Therewerenofindingsofnoteonphysicalexaminationor inthevitalsignsdata.

Discussion

TheProCIDstudyisthelargestrandomizedstudytoshowthat IVIgiseffectiveasmaintenancetherapyinpatientswithCIDPand thefirsttoexaminesystematicallyalowerandhigherIVIgmaintenancedose.Theprimaryobjectivewastoassesstheefficacyof IVIgadministeredasa2.0g/kginductiondosefollowedbyseven maintenancedosesof1.0g/kgevery3weeks.Theresponserateon thisregimenwas80%,andthelower95%CIlimitof69%exceeded thepredefinedthresholdof42%,indicatingthattheprimaryend pointhadbeenmet.Thisthresholdwasalsoexceededinthe0.5 and2.0g/kgmaintenancegroups.Similarresponseswereseenin otheroutcomemeasures.

Publishedguidelinesrecommendthatthemaintenancedoseof IVIgmayneedtobeadjustedindividually.2 TheProCIDstudywas thefirsttoexaminesystematicallyalower(0.5g/kg)andahigher (2.0g/kg)maintenancedoseofIVIginCIDPandcompareefficacy withstandarddosingof1.0g/kg.TheadjustedINCATscore responserateswere65,80and92%inthe0.5,1.0and2.0g/kg maintenancedosegroups,respectively.Similarincremental improvementsinresponserateswereobservedforsecondaryefficacyvariables.Despitethestudynotbeingpoweredtoshowastatisticallysignificantdoseresponse,astatisticallysignificanteffect ofdoseonresponsewasobservedacrossalldosegroupsusinglogisticregressionanalysis.However,statisticallysignificantdifferencesbetweenanytwooftheindividualdosegroupswereonly seenbetweenthe0.5and2.0g/kgmaintenancegroups.Ourdata thereforesuggestthatalowermaintenancedoseof0.5g/kgissufficienttoachieveandmaintainaresponsein65%ofpatientsbut thatahigherdosemaybebeneficialtoimprovethosenotrespondingtoloworstandarddosing.

ThePATHstudyexaminedtwodifferentdosesofSCIgmaintenancetherapy,0.2and0.4g/kgeveryweek,theequivalentof0.6 and1.2g/kgIVIgevery3weeks,inpatientswithCIDP.14 Thestudy evaluateda2-folddosedifferenceandfoundnodifferencesineithersafetyorefficacybetweenthesetwodoseswithastudyperiod of24weeks.14 InthePATHextensionstudy,theoverallrelapse rateswere10%inthe0.4g/kg/weekand48%inthe0.2g/kg/week group.24 Afterdosereductionfrom0.4to0.2g/kg/week,51%(27/53) ofpatientsrelapsed,ofwhom92%(24of26)improvedafterre-initiationofthe0.4g/kg/weekdose.24 Inourstudy,a2-folddosedifference,lowversusstandard,orstandardversushighdosing,also didnotresultinasignificantdifferenceinresponserate.Onlythe 4-folddosedifferencebetweenlow(0.5g/kg)andhigh(2.0g/kg) maintenancedosingdid,withanoddsratioof5.8(95%CI:1.4–23.6) foradjustedINCATscore.Thus,wepostulatethata2-folddosedifferencemightbetoosmalltodetectsignificantdifferencesinresponserate.Therefore,alargerstudy,statisticallypoweredto comparedifferentdoseratios,e.g.2-foldversus3-foldversus 4-fold,wouldbeneededtoconfirmacleardoserelationshipandto identifypotentialpatientcharacteristicsthatmighthelptopredict therequiredmaintenancedoseforanindividualpatient.

TheadjustedINCATscoreoverallresponserateof80%witha 1.0g/kgmaintenancedoseinourstudywashigherthanreported inotherIVIgstudies:ICE54%,PRIMA61%andPRISM76%.6–8 Itisof interesttocomparegroupsofpatientsinthedifferentstudiesthat havebeentreatedpreviouslywithcorticosteroidsorIVIg.Selection ofpatientswhohadpreviouslyrespondedtoIVIgmayimpactthe IVIgresponserateinatrial.14 OurstudyisthefirstIVIgstudytoincludeahighpercentageofpatientswhowerepreviouslytreated withcorticosteroidsandnotwithIVIg.Thehigherproportionof patientshavingbeentreatedwithcorticosteroidsmightbedueto loweravailabilityofIVIginsomeofthecountries.ThePATHstudy preselectedpatientsbasedonIVIgresponse.14 Corticosteroidsare afirst-linetreatmentoptionforCIDP.2 Corticosteroidsarewidely availableandinexpensive,butlong-termusehaspotentiallyserioussideeffects.5,25,26 UnliketheProCIDstudy,patientspreviously oncorticosteroids(410mg/dayprednisoloneorequivalent)were excludedfromtheICEstudy,6 patientspreviouslyon‘high-dose’ corticosteroidswereexcludedfromthePRISMstudy8 and,althoughcorticosteroidusewasnotspecificallyexcluded,noinformationonpriorcorticosteroidusewasprovidedinthePRIMA study.7 Furthermore,thepercentageofpatientsclassifiedasIVIgnaı¨ve,butpotentiallyonpriorcorticosteroids,was23%,6 54%7 and 55%8 intheICE,PRIMAandPRISMstudies,respectively,compared with87%whowereIVIg-naı¨veandonpriorcorticosteroidsinour study.Thesedifferencesinpriortreatment,alongwithotherdifferencesinpatientandstudycharacteristics,mighthaveinfluencedresponseratesacrossstudiesandmakecomparisons betweenthestudiesdifficult.Nevertheless,sincetheProCIDstudy clearlydifferentiatedbetweenpatientspreviouslysuccessfully treatedwithIVIgandthosepreviouslytreatedwithcorticosteroids, withmostsubjectsbeinginthelatterstratum,thestudyprovided auniqueopportunitytoassesstheeffectsofswitchingfromcorticosteroidstoIVIg.Thehighresponseratesinthecorticosteroids stratum,66%,83%and94%inthe0.5g/kg,1.0g/kgand2.0g/kg arms,respectively,clearlyshowthatsubjectspreviouslyoncorticosteroidscansuccessfullyandsafelybetransitionedtoIVIg.

Theincidenceoftreatment-relatedTEAEs,exceptforheadache, wassimilaracrossthedosegroups.Treatmentwaswelltolerated eveninIgG-naı¨vepatientsandinthoseregularlytreatedwithhigh doseIVIg.ThesedatashowthatpatientscanswitchfromcorticosteroidstoIVIgwithconfidencetopotentiallyavoidtheside effectsassociatedwithcorticosteroiduse.

Inthisstudy,56%ofallpatientsand62%ofrespondersshowed animprovementof 51adjustedINCATscorepointafterthe

inductiondosealone,i.e.byWeek3.Incomparison,thepercentageofresponderswhohadanimprovedadjustedINCATscore aftertheinductiondosewas44%intheICEstudy,27 50%inthe PRIMAstudy7 and22%inthePRISMstudy.8 Thishasimportant implicationsforclinicalpractice.OurstudyandtheICEtrial27 showthatnearlyallpatientswhowillrespondtoIVIgdosowithin 6–8weeks,thatis,asingleinductiondoseandtwomaintenance doses.Giventheissuesabovewithactualpatientinclusion,the translationofthistothetreatment-naı¨vepatientislessclear. WhentodecidethatapatientisnotrespondingtoIVIgremainsa clinicaldecision,butthesedatasuggestthattreatinglongerthan 3monthswhilewaitingforasignificantresponseisnotuseful.2

Alimitationofthestudyasdetailedabove,incommonwith otherstudiesevaluatingIVIginpatientswithCIDP,isthatitevaluatesrescuetreatmentmainlyofpreviouslysuccessfullytreated CIDPpatientswhoseconditionhasbeenallowedtodeteriorate priortotreatment,andnotnewlydiagnosedanduntreatedCIDP patients.Giventhatthestudyperiodwas24weeks,thelongertermefficacy,safetyandrelapseratewiththedifferentmaintenancedoseswerenotassessedinthisstudy.However,thestudy demonstratedalowrateofdeterioration(1.4%)afterWeek6across alldosegroups.Otherlimitationsofthestudywerethatitwasnot placebocontrolledandwasnotstatisticallypoweredtodetecta doseresponsebetweenthethreedosingregimens.

Insummary,theProCIDstudydemonstratedthat1.0g/kgIVIg isefficaciousandwelltoleratedasmaintenancetreatmentfollowinga2.0g/kginductiondoseinpatientswithactiveCIDP,evenin thosepatientshavingbeensuccessfullytreatedwithcorticosteroidspreviously.Alowerorhighermaintenancedosemaybe beneficialinsomepatients,althoughfurtherstudiesareneededto confirmthisfinding.

Acknowledgements

ThisstudywassponsoredbyOctapharmaPharmazeutika Produktionsges.m.b.H.(Vienna,Austria)whothankinvestigators, trialpersonnelandpatientsfortheirparticipation.Medicalwriting assistancewasprovidedbynspmltd,Meggen,Switzerland,and fundedbyOctapharma.

Funding

ThisstudywasfundedbyOctapharmaPharmazeutika Produktionsges.m.b.H.(Vienna,Austria).

Competinginterests

D.R.C.reportsconsultingforAmgen,AnnexonBiosciences,argenx SE,BiotestPharmaceuticals,CignaHealthManagement,CSL Behring,Grifols,Johnson&Johnson,MomentaPharma,New EnterpriseAssociates,Octapharma,Pﬁzer,Pharnext,Polyneuron Pharmaceuticals,SeattleGenetics,andUCB.D.R.C.isontheData SafetyMonitoringBoardforthefollowing:Alnylam Pharmaceuticals,Anavex,PledPharma,HansaMedical,and MitsubishiTanabePharmaCorporation.D.R.C.wasinvolvedwith technologylicensingforAstraZenecaPharmaceuticals,LP Pharmaceuticals(Xiamen),Genentech,Levicept,SeattleGenetics, MerrimackPharmaceuticals,andDisarmTherapeutics,outsidethe submittedwork.P.A.v.D.reportsgrantsfromSanquinBlood SupplyandPrinsesBeatrixSpierfonds,duringtheconductofthe study;andgrantsfromGrifols,Takeda,Annexion,Argenx, CommonwealthSerumLaboratories,Octapharma,andHansa,outsidethesubmittedwork.H.P.H.reportsconsultingCSLBehring, SanoﬁGenzyme,andUCB.H.P.H.receivedpaymentsorhonoraria fromCSLBehringandOctapharma.H.D.K.isonSteering

CommitteesforOctapharmaandSanoﬁGenzyme.I.S.J.M.reports grantsfromTalecrisTalentsprogram,GBS/CIDPFoundation InternationalandFP7EUprogram,outsidethesubmittedwork; Furthermore,aresearchfoundationattheUniversityofMaastricht receivedhonorariaonbehalfofhimforparticipationinsteering committeesoftheTalecrisImmuneGlobulinIntravenousFor ChronicInﬂammatoryDemyelinatingPolyneuropathyStudy, CommonwealthSerumLaboratories,Behring,Octapharma,LFB, Novartis,UnionChimiqueBelge,outsidethesubmittedwork. H.D.K.reportstravelsupportandconsultingfeesfrom Octapharmainrelationtoastudydesignadvisoryboard.H.D.K. reportsconsultingforUCB,Terumo,Akcea,Alnylam,andCSL Behring.H.D.K.isonDataSafetyMonitoringBoardsorAdvisory BoardsforUCBandOctapharma.H.D.K.receivedagrantfrom Takedaforinvestigator-initiatedresearch.D.H.andE.C.are employeesofOctapharmaPPG,Vienna,Austria.

Supplementarymaterial

Supplementarymaterial isavailableat Brain online.

AppendixI

ProCIDstudyinvestigators

Fulldetailsareprovidedinthe Supplementarymaterial

S.Kastrev,V.Rizova,R.Massie,R.Talab,M.Bednar,P.Ridzon,J. Schmidt,J.Zschu¨ntzsch,C.Ro´zsa,L.Vecsei,K.Rejdak,M. Koszewicz,S.Budrewicz,A.Dulamea,M.Marian,A.Kadar,L. Zecheru-Lapusneanu,V.Mikhailov,D.Zakharov,N.Suponeva,M. Piradov,N.Smolko,DSmolko.

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