抗疟疾药国外临床实验方案.docx

抗疟疾药国外临床实验方案.docx

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抗疟疾药国外临床实验方案

CLINICALTRIALPROTOCOL

EfficacyandtoleranceofCOTRIFAZID（rifampicin,co-trimoxazole,isoniazid）againstresistantmalariainsemi-immunesubjects :

amulticentric,open,block-randomised,comparativetrial

PapuaNewGuineaInstituteofMedicalResearch,Maprik,PapuaNewGuinea

SwissTropicalInstitute,Basle,Switzerland

24April1999

Dateofprotocol:

April24,1999

Protocoltitle:

EfficacyandtoleranceofCOTRIFAZID（rifampicin,co-trimoxazole,isoniazid）againstresistantmalariainsemi-immunesubjects :

amulticentric,open,block-randomised,comparativetrial

Version:

fourthdraft

Numberofcentres:

2

INVESTIGATORS

PrincipalInvestigator:

BlaiseGentonMDPhDMScDTM&H

Clinicalepidemiologist,DepartmentofMedicalParasitologyandInfectionBiology

SwissTropicalInstitute

Socinstrasse57

Postfach

4002BaselSwitzerland

Telephonenumber:

+41612848130

Faxnumber:

+41612718654

Email :

Blaise.genton@chuv.hospvd.ch

Co-principalinvestigator :

InoniBetuelaMD

PapuaNewGuineaInstituteofMedicalResearch

PoBox400

MaprikPapuaNewGuinea

Telephonenumber:

+6758581414

Faxnumber:

+6758581257

Email :

imrmap@.pg

PROTOCOLTITLEEfficacyandtoleranceofCOTRIFAZID（rifampicin,co-trimoxazole,isoniazid）againstresistantmalariainsemi-immunesubjects :

amulticentric,open,block-randomised,comparativetrial

PROJECTPHASEIII

SPONSORFatolArzneimittelGmbH

INDICATIONUNDERSTUDYResistantmalaria

OBJECTIVES1）TocomparetheefficacyofCotrifazidversusLariam（mefloquine）orstandardtreatmentinsemi-immunesubjectswithresistantmalaria

2）TocomparethetoleranceofCotrifazidversusLariamorstandardtreatmentinsemi-immunesubjectswithresistantmalaria

EXPERIMENTALDESIGN

OFTHETRIALOpen,block-randomised,comparative

PLANNEDSAMPLESIZE330（110Cotrifazid,110Lariam,110 standard

treatment）

NUMBEROFCENTRES2

SUBJECTSELECTIONCRITERIASubjectswithresistantmalaria（anyspecies）withaweight>5kg

SUBJECTEXCLUSIONCRITERIAPregnantwomen,infantslessthan6monthsofage,severemalaria

TREATMENTCotrifazid（rifampicin,co-trimoxazole,isoniazid）

DOSAGESubjects >40kg :

2x2tabletsperdayfor7days

Subjects<40kgand>20kg :

2x1tablet perdayfor7d

Subjects<20kg :

2x½tablet perdayfor7d

SCHEDULEEvery12hours

ROUTEOFADMINISTRATIONOral

COMPARATORILariam（mefloquine）

DOSAGESubjects>60kg :

6tabs（3,2,1）

Subjects>40kg and<60kg :

5tabs（2,2,1）

Subjects<40kgand>30kg :

3½tabs（1½,1,1）

Subjects<30and>20kg :

3tabs（1,1,1）

Subjects<20kgand>10kg :

1½tabs（½,½,½）

Subjects<10kg :

¾tablet（¼,¼,¼）

SCHEDULEHour0,8,24

ROUTEOFADMINISTRATIONOral

COMPARATORIIStandardtreatment（presentlyquinine+Fansidar）

DOSAGEQuinine

Subjects>60kg :

3x600mg/dayfor5daysSubjects<60kg :

3x10mg/kg/dayfor5days

+

Fansidarasasingledose

Subjects>40kg :

3tablets

Subjects<40kgand>30kg :

2tablets

Subjects<30and>20kg1½tablet

Subjects<20kgand>10kg1tablet

Subjects<10kg½tablet

SCHEDULEEvery8hoursforquinine,hour0forFansidar

ROUTEOFADMINISTRATIONOralforquinineandFansidar,orI.M.forquinine

ParametersOFEFFICACY1.Feverclearancetime

2.Parasiteclearancetime

3.Rateofearlyandlatetreatmentfailure（ETF,LTF）

4.Occurrenceofcomplications

PARAMETERSOFTOLERANCE:

1.ReportedAdverseEvents（AEs）

2.Clinicalandlaboratoryvalues

SecondaryParametersofEfficaCY1.Symptomclearancetime

2.Haemoglobinconcentration

PROCEDURES

Allsubjectswhoarediagnosedwithmalaria（historyoffeverandnoothermajorsymptom,OptiMALtestpositive）andhavebeenalreadytreatedformalariainthelast28dayscanbeincludediftheygivetheirinformedconsentandiftheclinicianinchargewouldhavegiventhestandardtreatmentforresistantmalariaintheabsenceofthestudy.Apatientshouldnotbeincludediftheclinicianpreferstousequinineforwhateverreason,ifthepatienthasoneofthesymptomsorsignsofcomplicatedorseveremalaria（i.e.historyofrecentconvulsion,anyneurologicalsignorimpairmentofconsciousness,temperature>40C0,heavyvomiting,haemoglobinuria,respiratorydistress,bleeding,circulatorycollapse,shock,jaundice,haemoglobin<5g/dl）,islessthan6monthsofageorispregnant.ThepatientswillberandomisedonthespottohaveeitherCotrifazid,Lariamorstandardtreatment（atpresentquinine+Fansidar）.ThetreatmentdosageandscheduleforCotrifazidwillbethefollowing :

subjects >40kg :

2x2tablets,subjects<40kgand>20kg :

2x1tablet,subjects<20kg :

2x½tablet,ever12hoursfor7days.ThetreatmentdosageandscheduleforLariamwillbethefollowing :

subjects>60kg :

6tabs（3athour0,2athour8,1athour24）,subjects>40kg and<60kg :

5tabs（2,2,1）,subjects<40kgand>30kg :

3½tabs（1½,1,1）,subjects<30and>20kg :

3tabs（1,1,1）,subjects<20kgand>10kg :

1½tabs（½,½,½）,subjects<10kg :

¾tablet（¼,¼,¼）.Follow-upassessmentswillbedoneathours24,48and72（clinical,parasitological,pharmacological）anddays7（clinical,parasitological,biochemicalandpharmacological）and14（clinical,parasitological,haematological,pharmacological）,ormoreintensivelyincaseofpersistingsymptomsorpathologicalsigns.Treatmentwillbechangedtothestandardtreatment（atpresentquinine+Fansidar）ifnecessary（problemsoftolerance,aggravationofclinicalstatus,increaseinparasitaemiaetcwithCotrifazidorLariam）.

STATISTICALANALYSIS

EFFICACY :

1.ComparisonofthefeverclearancetimeintheCotrifazidandcomparatorgroups

2.ComparisonoftheparasiteclearancetimeintheCotrifazidandcomparatorgroups

3.ComparisonoftherateofETFandLTFintheCotrifazidandcomparatorgroups

4.ComparisonoftherateofcomplicationsintheCotrifazidandcomparatorgroups

5.ComparisonofthehaematologicalconcentrationintheCotrifazidandcomparatorgroups

TOLERANCE:

1.ComparisonoftherateofadverseeventsintheCotrifazidandcomparatorgroups

2.ComparisonofthetypeofadverseeventsintheCotrifazidandcomparatorgroups

3.ComparisonoftherateofpatientsrequiringanadditionaldrugbecauseoftoleranceproblemsintheCotrifazidandcomparatorgroups（e.g.antivomiting）

4.ComparisonofthebiochemicalandhaematologicalresultsintheCotrifazidandcomparatorgroups

TABLEOFCONTENTSPage

1JUSTIFICATIONANDOBJECTIVES

1.1BackgroundandRationale.8

1.2ObjectivesoftheTrial.10

2GENERALDESIGN

2.1OverallDesign.10

2.2NumberofCentres.11

3SUBJECTSELECTIONFORSTUDYENTRY

3.1PopulationBase.11

3.2InclusionCriteria.11

3.3ExclusionCriteria.11

3.4SubjectScreening.11

4DESCRIPTIONOFTRIALDRUG

4.1NamesandFormulations.12

4.2Packaging,StorageandBlinding.12

5STUDYPROCEDURES

5.1Drug12

5.1.1DrugAdministration12

5.1.1.1DosageRegimen&Rationale12

forSelection.

5.1.1.2RouteofAdministration.13

5.1.1.3Duration.13

5.1.1.4Dispensing&AccountabilityofTrial13

DrugSupplies.

5.1.2AssignmenttoDrugorComparatorGroups.13

5.1.3ConcomitantMedication.13

5.2AssessmentofSafety.13

5.2.1SafetyParameters（incl.LaboratoryEvaluations）.13

5.2.2AdverseEvents.14

5.2.3ImmediatelyReportableAdverseEvents.16

5.2.4DrugadministrationandFollow-upofAdverseEvents.17

5.3AssessmentofEfficacy17

5.3.1PrimaryEfficacyParameters17

5.3.2SecondaryEfficacyParameters17

5.4Assessmentofpharmacology17

6WITHDRAWAL

6.1ConditionsforWithdrawal.17

6.2ReplacementPolicy.18

7ETHICS

7.1DeclarationofHelsinkiandGoodClinicalPractice.18

7.2InformedConsent.18

7.3EthicsCommitteeApproval.18

7.4ConfidentialityandDataProtection.18

8ADMINISTRATIVEPRACTICALITIES

8.1DrugSupply19

8.2Monitoring.19

8.3Sponsor’sResponsibilities.19

8.4Investigator'sResponsibilities.20

8.5Publications.21

9SUBJECTANALYSISPOPULATIONS21

10STATISTICALSTATEMENT

10.1StatisticalHypothesis.21

10.2StudyDesign.21

10.3SampleSizeCalculation.21

10.4StrategyforStatisticalAnalysis.21

10.4.1EfficacyParameters21

10.4.1.1.PrimaryEfficacyParameters22

10.4.1.2.SecondaryEfficacyParameters22

10.4.2PrimarySafetyParameters22

10.5DataManagementandAnalysis.22

11REFERENCES22

12SIGNATUREPAGE24

1JUSTIFICATIONANDOBJECTIVES

1.1BackgroundandRationale

Malariaremainsaserioushealthprobleminmostdevelopingcountries,withapprox.2.5milliondeathsperyear.OneofthecontributortomortalityisthespreadingofmalariaresistancefirstinSoutheastAsiaandtheninAfricaandtheSouthPacific.InPapuaNewGuinea（PNG）,chloroquine-resistantfalciparummalariawasfirstdocumentedin1976（YungandBennett,1976;Grimmondetal.,1976）.Sincethen,studiesdoneindifferentprovincesatdifferenttimesshowedtheproblemtobewidespreadandtoincreasegraduallywitharecentshiftfromRItoRIIandRIIItypes（Dulayetal.,1987;Schuurkamp,1992;Trenholmeetal.,1993;Al-Yamanetal.,1996）.IntheWosera,Gentonetal.（unpublisheddata,1998）showedthat16to26%ofthepatientswhoweretreatedwiththestandardregimenforuncomplicatedmalaria（amodiaquineorchloroquine）hadarecrudescenceofsymptomswithparasitaemia.

Sulfadoxine/pyri