Assessment of Pexelizumabin in Acute Myocardial Infarction.ppt

Assessment of Pexelizumabin in Acute Myocardial Infarction

1. AAssessment of ssessment of PexPexelizumab elizumab
in in AAcute cute MMyocardial yocardial IInfarctionnfarction

2. OverviewOverview
▲Trial OverviewTrial Overview
▲Investigator ObligationsInvestigator Obligations
▲Protocol, Study Flow and Patient Protocol, Study Flow and Patient
Care OverviewCare Overview
▲Safety ReportingSafety Reporting
▲Pharmacy, IVRS and HotlinePharmacy, IVRS and Hotline
▲MonitoringMonitoring
▲Data and eCRFData and eCRF

3. EuropeEurope
AustraliaAustralia
New ZealandNew Zealand
HFCCHFCCMCTSMCTS ParexelParexelLeuvenLeuven
GreenGreen
LaneLane
FlindersFlinders
GLOBALGLOBAL
PARTNERSPARTNERS
IVRS — ICTIIVRS — ICTI
Drug Distribution — CTS/FlindersDrug Distribution — CTS/Flinders
CDM — Phase ForwardCDM — Phase Forward
REGIONAL OPERATION TEAMSREGIONAL OPERATION TEAMS
GLOBAL OPERATIONS TRIADGLOBAL OPERATIONS TRIAD
ALEXION – DCRI – P&GPALEXION – DCRI – P&GP
DCRIDCRICVCCVC
North AmericaNorth America

4. AUZ/NZ Study OrganizationAUZ/NZ Study Organization
Alexion
Sponsor
Procter & Gamble
Sponsor
Executive Steering Committee
Scientific & Clinical Leadership
DCRI/CVC
Scientific & Clinical Leadership
Site Management
Monitoring
Coordinating Center
Data Management
FCC & GLCC
Scientific & Clinical Leadership
Site Management
Monitoring
ExecutiveExecutive
Steering Steering
CommitteeCommittee
ProcterProcter
& Gamble& Gamble
AlexionAlexion
CVC, DCRICVC, DCRI
ICTI / IVRSICTI / IVRS
SitesSites
PatientsPatients
FCCFCC
PharmacyPharmacy
FCCFCC
& GLCC& GLCC
Partnerships

5. FCC Site Management ContactsFCC Site Management Contacts
▲Clinical Leadership Clinical Leadership
Phil Aylward, MDPhil Aylward, MD 618-82045725618-82045725
▲Project ManagerProject Manager
Caroline ThomasCaroline Thomas 618-82045986618-82045986
▲MonitorsMonitors
Jan GarrettJan Garrett618-94575364618-94575364
Cindy HallCindy Hall 617-32405145617-32405145
Melissa SchofieldMelissa Schofield 618-82045637618-82045637
▲Administrative AssistantAdministrative Assistant
Michelle ShawMichelle Shaw618-82044440618-82044440

6. AUZ/NZ Pharmacy & IVRS ContactsAUZ/NZ Pharmacy & IVRS Contacts
▲Flinders Clinical Trials Pharmacy Flinders Clinical Trials Pharmacy
Sandra DolanSandra Dolan 61 8 8404 61 8 8404
20102010
▲IVRS Project Manager IVRS Project Manager
Cheryl HudsonCheryl Hudson 267-685-4284267-685-4284
▲IVRS Project Specialist IVRS Project Specialist
Kate McClintock Kate McClintock 267-685-4284267-685-4284

7. AUZ Additional Important AUZ Additional Important
Numbers to KnowNumbers to Know
▲24/7 Clinical Questions and Assistance24/7 Clinical Questions and Assistance
1 800 007524 (IVRS) and press “0”1 800 007524 (IVRS) and press “0”
▲IVRS IVRS
1 800 0075241 800 007524
4-digit study code: 2739 (APEX)4-digit study code: 2739 (APEX)
▲ Phase Forward Helpdesk (InForm technical questions)Phase Forward Helpdesk (InForm technical questions)
1 800-143-695 1 800-143-695

8. Trial TimelineTrial Timeline
Apr May Jun Sept Dec Mar June Sep Nov Feb May Jun DecApr May Jun Sept Dec Mar June Sep Nov Feb May Jun Dec
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20042004
8,500 8,500 PatientsPatients
300–400 300–400 Sites Sites
WorldwideWorldwide
1–2 1–2 pt/site/monthpt/site/month
D
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9. Data Flow and TimelinesData Flow and Timelines
▲Baseline eCRF completion within 5 days of Baseline eCRF completion within 5 days of
patient’s hospital dischargepatient’s hospital discharge
▲30 Day, 90 Day, 180 Day, 365 Day eCRF 30 Day, 90 Day, 180 Day, 365 Day eCRF
completion within 1 business day of contactcompletion within 1 business day of contact
▲Query resolution is continuousQuery resolution is continuous
▲CEC within eCRF – submit source CEC within eCRF – submit source
documentation of date of death, otherwise no documentation of date of death, otherwise no
source document submission unless requestedsource document submission unless requested
▲SAEs reported within eCRF SAEs reported within eCRF

10. OverviewOverview
▲Trial OverviewTrial Overview
▲Investigator ObligationsInvestigator Obligations
▲Protocol, Study Flow and Patient Protocol, Study Flow and Patient
Care OverviewCare Overview
▲Safety ReportingSafety Reporting
▲Pharmacy, IVRS and HotlinePharmacy, IVRS and Hotline
▲MonitoringMonitoring
▲Data and eCRFData and eCRF

11. Investigator Obligations Investigator Obligations
▲Investigator’s Qualifications & AgreementsInvestigator’s Qualifications & Agreements
▲Ensuring Adequate Resources throughout StudyEnsuring Adequate Resources throughout Study
▲Medical Care of Trial SubjectsMedical Care of Trial Subjects
▲Prompt Communications with IRB/IECPrompt Communications with IRB/IEC
▲Compliance with ProtocolCompliance with Protocol
▲Obtaining Informed Consent of Trial SubjectsObtaining Informed Consent of Trial Subjects

12. Investigator Obligations Cont.Investigator Obligations Cont.
▲Careful Management of Investigational DrugCareful Management of Investigational Drug
▲Adherence to Randomization ProceduresAdherence to Randomization Procedures
▲Maintaining Adequate & Accessible Records and Maintaining Adequate & Accessible Records and
ReportsReports
▲Providing Periodic Progress Reports to IRB/IECProviding Periodic Progress Reports to IRB/IEC
▲Safety Reporting per ProtocolSafety Reporting per Protocol
▲Submitting Final Report by Investigator to IRB/IEC Submitting Final Report by Investigator to IRB/IEC

13. The Informed Consent The Informed Consent ProcessProcess
▲Person explaining the IEC approved informed Person explaining the IEC approved informed
consent must sign and consent must sign and personally datepersonally date their their
signature.signature.
▲The subject must sign and The subject must sign and personally datepersonally date their their
signature.signature.
▲The informed consent process should be The informed consent process should be
documented including the date, documented including the date, timetime and summary and summary
of the consent process.of the consent process.

14. Study Staff & Delegation of TasksStudy Staff & Delegation of Tasks
▲Medically qualified Principal Investigator and Medically qualified Principal Investigator and
qualified site staff are requiredqualified site staff are required
▲Investigator Exercises OversightInvestigator Exercises Oversight

Supervise qualified study personnelSupervise qualified study personnel

Declare which tasks have been assigned/delegated Declare which tasks have been assigned/delegated
and document including start/stop dates (use log)and document including start/stop dates (use log)

Demonstrate training of team membersDemonstrate training of team members

Exhibit communication with study staff, patients, Exhibit communication with study staff, patients,
monitors, etc.monitors, etc.
▲Responsibility for conduct of the clinical trial cannot Responsibility for conduct of the clinical trial cannot
be delegatedbe delegated

15. OverviewOverview
▲Trial OverviewTrial Overview
▲Investigator ObligationsInvestigator Obligations
▲Protocol, Study Flow and Patient Protocol, Study Flow and Patient
Care OverviewCare Overview
▲Safety ReportingSafety Reporting
▲Pharmacy, IVRS and HotlinePharmacy, IVRS and Hotline
▲MonitoringMonitoring
▲Data and eCRFData and eCRF

16. Acute MI, < 6 hr sx onsetAcute MI, < 6 hr sx onset
20% isolated inferior ST 20% isolated inferior ST 
Pexelizumab
bolus +
0.05 mg/kg/hr
X 20 hrs
Placebo
Primary endpoint: infarct size by
CK-MB area under curve through 72 hours
Secondary endpoints:
Death, CHF, shock, disabling stroke to day 90; death to 6 months
Pexelizumab
bolus
(2.0 mg/kg/10min)
80% power to detect 20% reduction in CK-MB AUC
ThrombolyticThrombolytic
N = 943N = 943
Primary PCIPrimary PCI
N = 960N = 960
RandomizeRandomize
Double blindDouble blind

17. Mortality (6 Month) COMMAMortality (6 Month) COMMA
Primary PCIPrimary PCI
0%
2%
4%
6%
8%
10%
0 30 60 90 120 150 180
M
o
r
t
a
l
i
t
y
Days Post-Randomization
Placebo
Bolus
Bolus + Inf
7.4%
4.2%
3.2%
P = 0.018
Bolus + inf v placebo

18. PRIMO-CABG: Primary Endpoint at PRIMO-CABG: Primary Endpoint at
30 Days (CABG-Only)30 Days (CABG-Only)
Relative Risk (vs Placebo)
0.25 0.5 1 2 4
Death or MI
MI
Death
Event Rates (%)
Placebo
n = 1368
Pex
n = 1378
Risk
Reductionp-value
11.8
10.3
2.9
9.8
8.1
2.3
18%
22%
19%
0.069
0.036
0.359

19. Pexelizumab (24h) vsPexelizumab (24h) vs.. Placebo Placebo
Overview for Death at 30 days (ITT)Overview for Death at 30 days (ITT)
—Van de Werf ACC 2004
CABG
AMI
All trials
Phase II
COMPLY
Thrombolytic
Phase III
P-value
0.340
0.167
0.055
0.560
0.017
RR
(95% CI)
0.44 (0.11, 1.67)
0.75 (0.49, 1.12)
0.42 (0.18, 1.01)
0.82 (0.49, 1.40)
0.69 (0.52, 0.93)
COMMA
PCI
Placebo
(n/N)
7/306
52/1539
16/315
28/316
103/2476
Pexelizumab
(n/N)
3/300
39/1549
7/328
23/315
72/2492
0.5 1.01.5
Pex betterPlacebo better
0.0
CABG
AMI

20. Complement System—Complement System—
Cascade of Inflammatory MediatorsCascade of Inflammatory Mediators
Downstream: good and bad Downstream: good and bad
(inflammatory actions)(inflammatory actions)
C5aC5a
C5b-9 C5b-9
membrane membrane
attack complexattack complex
Vesiculation of platelets & Vesiculation of platelets &
endothelial cellsendothelial cells
Formation of pro-thrombic Formation of pro-thrombic
microparticlesmicroparticles
Activation of leukocytes & Activation of leukocytes &
endothelial cellsendothelial cells
Potent inflammatory Potent inflammatory
propertiesproperties
Induces changes in smooth Induces changes in smooth
muscle & vascular tonemuscle & vascular tone
Increases vascular Increases vascular
permeabilitypermeability
Activates both neutrophils & Activates both neutrophils &
endothelial cellsendothelial cells
C5C5C1, C3C1, C3
Immobilizes and Immobilizes and
destroys bacteriadestroys bacteria
Upstream benefit: C1-C3Upstream benefit: C1-C3
(Bacterial opsonin)(Bacterial opsonin)

21. V
H
C
L
C
H
V
L
V
H V
L
26 kD
Pexelizumab Pexelizumab
Humanized anti-C5 complementHumanized anti-C5 complement
monoclonal antibody fragment monoclonal antibody fragment
▲Binds to and prevents Binds to and prevents
cleavage of C5cleavage of C5
▲Highly specific for C5Highly specific for C5
▲Drug ActionDrug Action

Bolus completely Bolus completely
inhibits complement inhibits complement
hemolytic activity for 4 hemolytic activity for 4
hourshours

Bolus plus infusion Bolus plus infusion
inhibits C5 cleavage for inhibits C5 cleavage for
24 hours24 hours

22. Study ObjectiveStudy Objective
To determine whether pexelizumab To determine whether pexelizumab
treatment reduces all cause treatment reduces all cause
mortality at Day 90 in patients with mortality at Day 90 in patients with
acute STEMI who were expected to acute STEMI who were expected to
undergo primary PCIundergo primary PCI

23. Acute MI, < 6 hr sx onsetAcute MI, < 6 hr sx onset
Anterior or large inferior*Anterior or large inferior*
Plan to perform primary PCIPlan to perform primary PCI
PexelizumabPexelizumab
2 mg/kg bolus + 2 mg/kg bolus +
0.05 mg/kg/hr X 24 hrs0.05 mg/kg/hr X 24 hrs
PlaceboPlacebo
Bolus plus infusionBolus plus infusion
Over 24 hrsOver 24 hrs
Primary endpoint: all-cause mortality through day 90Primary endpoint: all-cause mortality through day 90
Secondary endpoints: Secondary endpoints:
Death, CHF, shock to day 90; Death to day 180Death, CHF, shock to day 90; Death to day 180
80% power to detect 24% RRR in mortality80% power to detect 24% RRR in mortality
RandomizeRandomize
Double blindDouble blind
(n = 8500)(n = 8500)
** 2 mm ST 2 mm ST  in in
2 inf leads 2 inf leads
& 2 mm ST & 2 mm ST  in in
2 ant leads with 2 ant leads with
total ST dev of total ST dev of
 8 mm 8 mm

24. Inclusion CriteriaInclusion Criteria
1.1.≥ ≥ 18 Years of age18 Years of age
2.2.Ischemic (cardiac) Ischemic (cardiac)
symptoms symptoms ≥≥ 20 minutes 20 minutes
3.3.Symptom onset within Symptom onset within
past 6 hours, and expected past 6 hours, and expected
to undergo primary PCIto undergo primary PCI
4.4.Has an ECG indicative of an Has an ECG indicative of an
acute STEMI showing:acute STEMI showing:

≥≥ 2 mm ST elevation in 2 2 mm ST elevation in 2
anterior or lateral leads; anterior or lateral leads; oror

new left bundle branch block new left bundle branch block
with at least 1 mm with at least 1 mm
concordant ST elevation; concordant ST elevation; oror

High-risk inferior:High-risk inferior: ≥≥ 2 mm 2 mm
ST ST  in 2 inferior leads in 2 inferior leads
coupled with ST coupled with ST  in 2 in 2
contiguous anterior leads for contiguous anterior leads for
a total ST deviation of a total ST deviation of ≥≥ 8 8
mmmm

25. Exclusion Criteria Exclusion Criteria
1.1.Isolated inferior wall MI without anterior ST Isolated inferior wall MI without anterior ST
depression (e.g., ST elevation only in II, III, AVF)depression (e.g., ST elevation only in II, III, AVF)
2.2.Received thrombolytic therapy for treatment of Received thrombolytic therapy for treatment of
the qualifying event.the qualifying event.
3.3.Known or suspected hereditary complement Known or suspected hereditary complement
deficiency.deficiency.
4.4.Presence of or suspected active neisserial Presence of or suspected active neisserial
infection.infection.
5.5.Evidence of a serious, active infection in the Evidence of a serious, active infection in the
opinion of the Investigatoropinion of the Investigator

26. Exclusion Criteria Exclusion Criteria (continued)(continued)
6.6.Currently receiving or is planning to receive Currently receiving or is planning to receive
any other investigational drug/device during any other investigational drug/device during
this study or has been exposed to an this study or has been exposed to an
unapproved investigational agent within the unapproved investigational agent within the
past 30 days.past 30 days.
7.7.Is pregnant or breast-feeding.Is pregnant or breast-feeding.
8.8.Serious medical condition.Serious medical condition.
9.9.Previously been enrolled in this trial.Previously been enrolled in this trial.

27. Screening ScenariosScreening Scenarios
Can Be EnrolledCan Be Enrolled
▲Patients already in shockPatients already in shock
▲Post Cardiac ArrestPost Cardiac Arrest
▲GP IIb/IIIa already begunGP IIb/IIIa already begun
▲LBBB not known to be oldLBBB not known to be old
▲Intubated Intubated
((Consider consent proceduresConsider consent procedures))
Cannot Be EnrolledCannot Be Enrolled
▲Prior or planned lytic RxPrior or planned lytic Rx
▲Not a candidate for cathNot a candidate for cath
▲Active serious infectionActive serious infection
▲Post Primary PCIPost Primary PCI
▲Not available for (phone) Not available for (phone)
follow upfollow up

28. Enrollment WorksheetEnrollment Worksheet

29. Endpoint DefinitionsEndpoint Definitions
CHFCHF
▲Symptoms begin or persist 24-hrs after enrollment +Symptoms begin or persist 24-hrs after enrollment +
▲MD’s decision to treat CHF with IV medication +MD’s decision to treat CHF with IV medication +
▲At least 1 of the following:At least 1 of the following:

Pulmonary Edema on CXRPulmonary Edema on CXR

Rales > 1/3 up the lung fieldsRales > 1/3 up the lung fields

Wedge Pressure (PCWP) or (LVEDP) greater than 18 Wedge Pressure (PCWP) or (LVEDP) greater than 18
mmHgmmHg
Dyspnea, with pODyspnea, with pO
22 less than 80 mmHg or O less than 80 mmHg or O
22 saturation saturation
less than 90% on room air, without significant lung less than 90% on room air, without significant lung
diseasedisease

30. Endpoint DefinitionsEndpoint Definitions
Cardiogenic ShockCardiogenic Shock
▲SBP < 90 mmHg secondary to cardiac SBP < 90 mmHg secondary to cardiac
dysfunction lasting for dysfunction lasting for ≥ ≥ 1
 hour
1
 hour
▲Not responsive to fluid resuscitation Not responsive to fluid resuscitation
and/or heart rate correctionand/or heart rate correction
▲Associated with at least one sign of hypo-Associated with at least one sign of hypo-
perfusionperfusion

31. Patient TimelinePatient Timeline
All other care—standard AMI care at the discretion of investigator All other care—standard AMI care at the discretion of investigator
Bolus given Bolus given
prior to PCIprior to PCI
Infusion for 24 hrsInfusion for 24 hrs
ECG—ECG—baseline, 30 min baseline, 30 min
post PCI, DC or Day 14post PCI, DC or Day 14
Screened and Screened and
randomized to randomized to
APEX AMIAPEX AMI
BloodBlood—baseline (all US + selected angio centers) —baseline (all US + selected angio centers)
P
re s e n ta tio n
P
C
I
Enroll Labs Bolus Infusion
I C
U
/ C
C
U
D
C
/D
a
y 1
4
9
0
D
a
y
Phone Follow-Up
3
0
D
a
y
1
8
0
&

3
6
5 D
a
y

32. Patient Follow UpPatient Follow Up
▲90-day mortality is primary endpoint 90-day mortality is primary endpoint
▲Telephone Follow up after Discharge / Day 14Telephone Follow up after Discharge / Day 14
▲Vital status on all patients randomizedVital status on all patients randomized
P
re s e n ta tio n
P
C
I
D
is c h a rg e /
1 4 D
a y s
1 8 0 -D
a y
Clinical Follow Up
(Telephone)
9 0 -D
a
y
3 6 5 -D
a y
3 0 -D
a
y

33. Preferred Treatment in PCI PatientsPreferred Treatment in PCI Patients
▲GP IIb/IIIa inhibitor use is encouraged: starting prior to GP IIb/IIIa inhibitor use is encouraged: starting prior to
or at time of PCIor at time of PCI
▲Any use of fibrinolytic therapy is a contraindication to Any use of fibrinolytic therapy is a contraindication to
enrollmentenrollment
▲Coronary stentsCoronary stents
▲Please reference the July 2004 AHA/ACC Guidelines for Please reference the July 2004 AHA/ACC Guidelines for
Management of Patients with STEMIManagement of Patients with STEMI

Pocket Version:Pocket Version:
http://www.acc.org/clinical/guidelines/stemi/index_pkt.pdfhttp://www.acc.org/clinical/guidelines/stemi/index_pkt.pdf

Full Text Version:Full Text Version:
http://www.acc.org/clinical/guidelines/stemi/index.pdfhttp://www.acc.org/clinical/guidelines/stemi/index.pdf

34. Concomitant TherapyConcomitant Therapy
Patients will receive concomitant therapy Patients will receive concomitant therapy
at the discretion of the Investigator.at the discretion of the Investigator.
▲Aspirin 75–325 mg qdAspirin 75–325 mg qd
▲Heparin or enoxaparinHeparin or enoxaparin
▲Glycoprotein IIb/IIIa inhibitor use prior Glycoprotein IIb/IIIa inhibitor use prior
to and at time of PCIto and at time of PCI
▲Beta-blockersBeta-blockers
▲StatinsStatins

35. Patient ScenariosPatient Scenarios
▲No PCINo PCI

Continue study drug for 24 hours Continue study drug for 24 hours
unless determined that patient is not unless determined that patient is not
having acute MIhaving acute MI
▲CABGCABG

Continue study drug for entire 24 hour Continue study drug for entire 24 hour
infusion post randomizationinfusion post randomization

No need to unblindNo need to unblind

36. Important FeaturesImportant Features
SafeSafe
▲Patients will receive a bolus Patients will receive a bolus
and infusion for 24 hours—and infusion for 24 hours—
no effect in prior studies on no effect in prior studies on
hemodynamics, infection, hemodynamics, infection,
bleedingbleeding
EasyEasy
▲Electronic case report form—Electronic case report form—
no mailing, streamlined no mailing, streamlined
queries for the enrolling queries for the enrolling
sites; post-discharge sites; post-discharge
telephone follow-uptelephone follow-up
NovelNovel
▲ST-elevation MI trial using ST-elevation MI trial using
a novel anti-inflammatory a novel anti-inflammatory
drug at time of PCIdrug at time of PCI
SimpleSimple
▲No change in usual care No change in usual care
pattern of patients, simple pattern of patients, simple
drug administration, data drug administration, data
collection, AE reportingcollection, AE reporting

37. OverviewOverview
▲Trial OverviewTrial Overview
▲Investigator ObligationsInvestigator Obligations
▲Protocol, Study Flow and Patient Protocol, Study Flow and Patient
Care OverviewCare Overview
▲Safety ReportingSafety Reporting
▲Pharmacy, IVRS and HotlinePharmacy, IVRS and Hotline
▲MonitoringMonitoring
▲Data and eCRFData and eCRF

38. AE/SAE ReportingAE/SAE Reporting
▲All AEs/SAEs will be reported via the All AEs/SAEs will be reported via the
eCRF eCRF
▲Two places for reporting:Two places for reporting:

Clinical Events ChecklistClinical Events Checklist

SAE LogSAE Log

39. Clinical Events ChecklistClinical Events Checklist
▲EndpointsEndpoints
▲Other events that may be observed in Other events that may be observed in
the AMI populationthe AMI population
▲Some of these events may meet Some of these events may meet
“serious” criteria – no additional SAE “serious” criteria – no additional SAE
reporting is requiredreporting is required
▲These are the only AEs that will be These are the only AEs that will be
reported (see exception on SAE page)reported (see exception on SAE page)

40. Clinical Events ChecklistClinical Events Checklist
▲DeathDeath
▲CHFCHF
▲Cardiogenic shockCardiogenic shock
▲Recurrent MIRecurrent MI
▲StrokeStroke
▲Recurrent IschemiaRecurrent Ischemia
▲Atrial FibAtrial Fib
▲Sustained V-TachSustained V-Tach
▲Ventricular FibVentricular Fib
▲Complete AV BlockComplete AV Block
▲Electro Mech DissocElectro Mech Dissoc
▲AsystoleAsystole
▲Serious InfectionSerious Infection
▲Cardiac Arrest/ResusCardiac Arrest/Resus
▲PericarditisPericarditis
▲Cardiac TamponadeCardiac Tamponade
▲BleedingBleeding
▲Acute Mitral Valve Acute Mitral Valve
RegurgRegurg
▲Acute Ventricular Acute Ventricular
Septal DefectSeptal Defect
▲Ventricular RuptureVentricular Rupture
▲Symptomatic Symptomatic
HypotensionHypotension
▲PEPE
▲DVTDVT
▲Renal FailureRenal Failure

41. SAE LogSAE Log
▲Any events that meet “serious” criteria Any events that meet “serious” criteria
that are not on the Clinical Events that are not on the Clinical Events
Checklist Checklist
▲Any AE associated with early cessation Any AE associated with early cessation
of study medicationof study medication
▲SAEs are collected from the time of SAEs are collected from the time of
consent until hospital discharge or consent until hospital discharge or
through Day 14 whichever is earliestthrough Day 14 whichever is earliest

42. SAE LogSAE Log
▲PI will need to assess relationship to PI will need to assess relationship to
study drug:study drug:

All unlikely study drug related SAEs or All unlikely study drug related SAEs or
AEs leading to early discontinuation of AEs leading to early discontinuation of
study drug must be reported within study drug must be reported within
one week or lessone week or less

All likely study drug related SAEs All likely study drug related SAEs
must be reported within 24 hours of must be reported within 24 hours of
discovery (these are Immediately discovery (these are Immediately
Reportable AEs – IRAEs)Reportable AEs – IRAEs)

43. Study Drug Relationship AssessmentStudy Drug Relationship Assessment
▲Unlikely study drug relatedUnlikely study drug related

There is no medical evidence to There is no medical evidence to
suggest the SAE is related to study suggest the SAE is related to study
drug usage, ordrug usage, or

There is another more probable There is another more probable
medical explanationmedical explanation
▲Likely study drug relatedLikely study drug related

There is medical evidence to suggest There is medical evidence to suggest
the SAE may be related to the study the SAE may be related to the study
drug usagedrug usage

44. SAE Follow-upSAE Follow-up
▲Requests for additional follow-up may be required Requests for additional follow-up may be required
and may include:and may include:
●Admission notesAdmission notes
●Lab resultsLab results
●Discharge summaryDischarge summary
●Autopsy reportsAutopsy reports
●Death CertificatesDeath Certificates
▲For IRAEs, follow-up information from site should For IRAEs, follow-up information from site should
be provided as soon as possible after receipt of the be provided as soon as possible after receipt of the
requestrequest
▲All requests will be posted as queries in InFormAll requests will be posted as queries in InForm
▲Please remove any personal identifying information Please remove any personal identifying information
from source documents sent in to support an IRAE from source documents sent in to support an IRAE

45. Regulatory RequirementsRegulatory Requirements
▲SAEs that meet the following criteria will SAEs that meet the following criteria will
be reported expeditiously as investigator be reported expeditiously as investigator
letters:letters:
●Serious
●Likely Drug Related
●Unexpected per Investigator’s
Brochure

46. Special Issue: PregnancySpecial Issue: Pregnancy
▲If a woman is found to be pregnant after If a woman is found to be pregnant after
study drug administration:study drug administration:

AEMG should be notified within 24 AEMG should be notified within 24
hours and they will send the site the hours and they will send the site the
appropriate formappropriate form

Complete Part 1 of the “Exposure Complete Part 1 of the “Exposure
During Pregnancy” questionnaireDuring Pregnancy” questionnaire

Complete Part 2 of the “Exposure Complete Part 2 of the “Exposure
During Pregnancy” questionnaire when During Pregnancy” questionnaire when
the outcome of the pregnancy is knownthe outcome of the pregnancy is known

47. Need a Contact?Need a Contact?
▲P&GP AE Management Group (AEMG)P&GP AE Management Group (AEMG)

Contact for questions regarding Contact for questions regarding
reporting of IRAEs or to provide reporting of IRAEs or to provide
information that cannot be information that cannot be
provided electronically. provided electronically.
•Telephone: [phone]
•Fax: [phone]

48. InForm MalfunctionInForm Malfunction
▲In the rare event InForm is off-line, In the rare event InForm is off-line,
IRAEs must still be reported within 24 IRAEs must still be reported within 24
hours using a paper back-up faxed to hours using a paper back-up faxed to
AEMGAEMG
▲As soon as InForm is back on-line, the As soon as InForm is back on-line, the
SAE page will need to be completed SAE page will need to be completed

49. OverviewOverview
▲Trial OverviewTrial Overview
▲Investigator ObligationsInvestigator Obligations
▲Protocol, Study Flow and Patient Protocol, Study Flow and Patient
Care OverviewCare Overview
▲Safety ReportingSafety Reporting
▲Pharmacy, IVRS and HotlinePharmacy, IVRS and Hotline
▲MonitoringMonitoring
▲Data and eCRFData and eCRF

50. Study Drug KitsStudy Drug Kits
▲Blinded patient kits containing 4 x 50 mL vials of Blinded patient kits containing 4 x 50 mL vials of
pexelizumab OR placebopexelizumab OR placebo
▲Kits must be refrigerated at 2Kits must be refrigerated at 2–8° C and protected –8° C and protected
from light during storagefrom light during storage
▲Study drug does not have to be refrigerated or Study drug does not have to be refrigerated or
protected from light during administrationprotected from light during administration
▲Treatment kits contain enough study drug to Treatment kits contain enough study drug to
treat one patient weighing treat one patient weighing ≤≤ 120 kg 120 kg
▲Patients Patients >> 120 kg will require a second kit 120 kg will require a second kit

51. Drug SuppliesDrug Supplies
▲Multi-lingual label on
outside of box
(Aust #2 on label)
▲Blue overlay = APEX
▲Contents:
●4 – 50mL vials
●4 Filters
●1 Dosing card
●2 Bolus syringe labels
●1 Infusion label
View of Patient Kit & Contents

52. Drug AccountabilityDrug Accountability

P R O C T E R & G A M B L E P H A R M A C E U T I C A L S / A L E X I O N P H A R M A C E U T I C A L S
S t u d y D r u g A c c o u n t a b i l i t y L o g
S t u d y N o . 2 0 0 3 0 5 6 S i t e N o . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ I n v e s t i g a t o r : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
A P E X - A M I S t u d y
A s s i g n e d T o
K i t N u m b e r P a t i e n t N o . D i s p e n s e d B y
I n i t i a l s
D a t e D a t e D e s t r o y e d
D e s t r o y e d B y
I n i t i a l s
S i t e M a n a g e r / C R A
I n i t i a l s a n d D a t e
C o m m e n t s ( i n c l u d e M e t h o d o f D e s t r u c t i o n ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
XXXXX XXXXX
XXX XXX XXXXXX

53. Study Drug AdministrationStudy Drug Administration
▲Bolus Bolus

Administered as soon as possible after randomizationAdministered as soon as possible after randomization

2.0 mg/kg bolus IV over 10 minutes2.0 mg/kg bolus IV over 10 minutes
▲Study drug must be filtered prior to administrationStudy drug must be filtered prior to administration
▲Entire bolus should be given prior to balloon inflation Entire bolus should be given prior to balloon inflation
▲Followed by an infusion Followed by an infusion

Weight adjusted volume of study drug in D5W, Normal Weight adjusted volume of study drug in D5W, Normal
Saline, or ½ N Saline infused at 20 mL/hrSaline, or ½ N Saline infused at 20 mL/hr
▲Infusion should not delay bolus or PCIInfusion should not delay bolus or PCI

54. Drug Receipt and TrackingDrug Receipt and Tracking
▲Study drug will be automatically re-Study drug will be automatically re-
suppliedsupplied
▲Each shipment must be acknowledged as Each shipment must be acknowledged as
received via the IVRSreceived via the IVRS
▲ICTI will monitor the drug levels at your ICTI will monitor the drug levels at your
site and will re-supply based on actual site and will re-supply based on actual
usageusage
▲ Drug will be resupplied based on:Drug will be resupplied based on:

Resupply strategy selected for your siteResupply strategy selected for your site

Number of kits at site/used/damagedNumber of kits at site/used/damaged

55. IVRS Menu OptionsIVRS Menu Options
1.1.Randomize a PatientRandomize a Patient
2.2.Review Patient InformationReview Patient Information
3.3.Acknowledge Receipt of Study Drug KitsAcknowledge Receipt of Study Drug Kits
4.4.Access Hotline Services or Discuss Access Hotline Services or Discuss
Unblinding a PatientUnblinding a Patient
5.5.Obtain a Replacement Drug Kit AssignmentObtain a Replacement Drug Kit Assignment

56. Accessing the IVRS (AUZ)Accessing the IVRS (AUZ)
▲Dial 1 800 007524Dial 1 800 007524
▲Enter the 4-digit study code: 2739 (APEX)Enter the 4-digit study code: 2739 (APEX)
▲Enter your 4-digit site number Enter your 4-digit site number
▲Enter your 4-digit IVRS passwordEnter your 4-digit IVRS password

57. How to Call For Help (AUZ)How to Call For Help (AUZ)
Clinical Hotline:Clinical Hotline:
▲1 800 007524 (IVRS) & 1 800 007524 (IVRS) &
press “0”press “0”
▲1 800 007524 (IVRS) & 1 800 007524 (IVRS) &
enter site #, password, enter site #, password,
press option 4press option 4
▲Pharmacist 24/7Pharmacist 24/7
▲MD 24/7MD 24/7
▲Absolute reasons to call:Absolute reasons to call:

Considering stopping study drug prematurelyConsidering stopping study drug prematurely

UnblindingUnblinding

58. OverviewOverview
▲Trial OverviewTrial Overview
▲Investigator ObligationsInvestigator Obligations
▲Protocol, Study Flow and Patient Protocol, Study Flow and Patient
Care OverviewCare Overview
▲Safety ReportingSafety Reporting
▲Pharmacy, IVRS and HotlinePharmacy, IVRS and Hotline
▲MonitoringMonitoring
▲Data and eCRFData and eCRF

59. MonitoringMonitoring
▲Monitoring will be conducted by:Monitoring will be conducted by:

Australia – Flinders CC Australia – Flinders CC
▲First PMV within 2-3 weeks of patient enrollmentFirst PMV within 2-3 weeks of patient enrollment
▲Average 2-3 visits/year, 1-2 days/visitAverage 2-3 visits/year, 1-2 days/visit
▲100% of one of the first patients enrolled100% of one of the first patients enrolled
▲100% of a sample of 15-20% of patients enrolled100% of a sample of 15-20% of patients enrolled

60. MonitoringMonitoring
▲Monitor will need high speed internet Monitor will need high speed internet
access in proximity to medical recordsaccess in proximity to medical records
▲Monitor will identify records needed prior Monitor will identify records needed prior
to the visitto the visit
▲eCRF will need to be complete prior to eCRF will need to be complete prior to
the monitoring visitthe monitoring visit

61. OverviewOverview
▲Trial OverviewTrial Overview
▲Investigator ObligationsInvestigator Obligations
▲Protocol, Study Flow and Patient Protocol, Study Flow and Patient
Care OverviewCare Overview
▲Pharmacy, IVRS and HotlinePharmacy, IVRS and Hotline
▲MonitoringMonitoring
▲Data and eCRFData and eCRF

62. Data Philosophy & ExpectationsData Philosophy & Expectations
▲Site – stay currentSite – stay current

> 90% of enrolled patients entered at any point> 90% of enrolled patients entered at any point

> 90% of entered data clean at any point> 90% of entered data clean at any point
▲Site Managers/CRAs – help sites stay focusedSite Managers/CRAs – help sites stay focused

> 90% of outstanding Action Variables reviewed > 90% of outstanding Action Variables reviewed
and resolved at any given timeand resolved at any given time

Will call after first patient is enrolledWill call after first patient is enrolled

Will call if entered and/or clean data drops below Will call if entered and/or clean data drops below
90%90%
▲As trial-wide 90 Day lock approaches, percentages As trial-wide 90 Day lock approaches, percentages
will increasewill increase

63. Long-term Follow Up Data CollectionLong-term Follow Up Data Collection
▲DeathDeath

InForm: Enter circumstance of events leading InForm: Enter circumstance of events leading
to deathto death

Submit : Document confirming date of deathSubmit : Document confirming date of death
▲Post discharge rehospitalizationsPost discharge rehospitalizations
Need to obtain medical records to review for Need to obtain medical records to review for
interim events (i.e. CHF/ shock, re-MI, CVA, interim events (i.e. CHF/ shock, re-MI, CVA,
serious infection)serious infection)

InForm: Enter event detailsInForm: Enter event details

Submit: Submit: By special request onlyBy special request only

64. Integrating EDC and CECIntegrating EDC and CEC
▲Source document request for CEC will be done Source document request for CEC will be done
in eCRFin eCRF

The CEC team will place a query in the EDC The CEC team will place a query in the EDC
system on the patient event eCRF requesting system on the patient event eCRF requesting
specific documentationspecific documentation

Dialogue between CEC and the site can occur Dialogue between CEC and the site can occur
easily in this mannereasily in this manner

65. Source DocumentsSource Documents
▲Minimal source documents collectedMinimal source documents collected
▲Narrative included on eCRF for CHF and SHOCK Narrative included on eCRF for CHF and SHOCK
eventsevents
▲Don’t repeat information provided on eCRFDon’t repeat information provided on eCRF
▲Items to include in narrative:Items to include in narrative:

Type of symptomsType of symptoms

Lab test resultsLab test results

Procedure results Procedure results

Response to therapy that support the final diagnosisResponse to therapy that support the final diagnosis
▲Above data is important if there is uncertainty about Above data is important if there is uncertainty about
the initial symptoms; for example, was it a PE? the initial symptoms; for example, was it a PE?
Pneumonia? COPD? Asthma?Pneumonia? COPD? Asthma?

66. Site enters data
InForm System Queries fire
Site resolves queries
ARO/CRO CRA reviews Action
Queries that continue to fire
Site Clean
Monitor Clean
APEX Data FlowAPEX Data Flow

67. Definition of “Late”Definition of “Late”
▲Baseline eCRF - Randomization + 10 daysBaseline eCRF - Randomization + 10 days
▲30 Day Contact - Randomization + 30 days30 Day Contact - Randomization + 30 days
▲90 Day Contact - Randomization + 90 days90 Day Contact - Randomization + 90 days
▲6 Month Contact - Randomization + 6 months6 Month Contact - Randomization + 6 months
▲12 Month Contact - Randomization + 12 months12 Month Contact - Randomization + 12 months
(Randomization = Day 1)(Randomization = Day 1)

68. Definitions of “Clean”Definitions of “Clean”
▲Site CleanSite Clean – All expected pages entered and – All expected pages entered and
site has addressed all queries.site has addressed all queries.
▲Monitor Clean – Site clean, Monitor Clean – Site clean, plusplus CRA has CRA has
reviewed/closed all Action queries that reviewed/closed all Action queries that
continue to fire or are confirmed correct as is.continue to fire or are confirmed correct as is.

69. Action QueriesAction Queries
▲Queries on variables required for Queries on variables required for

endpoint adjudication endpoint adjudication

primary endpoint analysisprimary endpoint analysis

safety analysis safety analysis
▲Cannot be blank, ND/No data, NA/Not Cannot be blank, ND/No data, NA/Not
applicable or Not Availableapplicable or Not Available
▲In-house Site Manager/CRA will call to In-house Site Manager/CRA will call to
assist with resolution if questions assist with resolution if questions
about these variables remainabout these variables remain

70. eCRF RevieweCRF Review

71. AAssessment of ssessment of PexPexelizumab elizumab
in in AAcute cute MMyocardial yocardial IInfarctionnfarction