The VCU Plasma Trial

Pre-Hospital Use of Plasma in Traumatic Hemorrhage (PUPTH)

Dr. Bruce Spiess, PI

Anticipated launch October 2014

• Delays primarily because of in-house regulatory bottlenecks

• Loss of key personnel

IRB approval timeline

Initial IRB submissionMay 15 2012

VCU IRB approval for community consultation

April 2013

Contract awarded June 2012

Community surveysMay-Nov 2013

Survey data analyzed; IND re-submitted;MJ Michaels, P Reynolds added

Jan 2014

FDA review amendments required

Feb 2014

VCU-IRB RevisionsOct-Nov 2013

New team structure implementedJan-Feb 2014

REGULATORY APPROVAL PROCESS

REGULATORY APPROVAL PROCESS

Functional Operations MappingPI

Dr B SPIESS

PROJECT COORDINATORM J MICHAEL

SAFETY OVERSIGHTDR J CLORE

OPERATIONS PLANS SUPPORT SERVICES FINANCE DSMB

LIAISONS

EMS

EMERGENCY MEDICINE

TRAUMA SURGERY

IRB

DATA

DOCUMENTATION

BLOOD BANK

COAG LAB

PIDr B SPIESS

PROJECT COORDINATORM J MICHAEL

SAFETY OVERSIGHTDR J CLORE

OPERATIONS PLANS SUPPORT SERVICES FINANCE DSMB

LIAISONS

EMS

EMERGENCY MEDICINE

TRAUMA SURGERY

IRB

DATA

DOCUMENTATION

BLOOD BANK

COAG LAB

PLANS

IRB

DATA

DOCUMENTATION

J KATZEN*J HAN

STATISTICIANSDATA ANALYSES

DATA MANAGEMENT, IT

J WEGELIN*E GLASSZ MARTIN

BRIAN BUSH

J. KATZEN

FORMSDATA COLLECTION

DATA ENTRY

PIDr B SPIESS

PROJECT COORDINATORM J MICHAELS

SAFETY OVERSIGHTDR J CLORE

OPERATIONS PLANS SUPPORT SERVICES FINANCEC JETER

DSMB

LIAISONS

EMS

EMERGENCY MEDICINE

TRAUMA SURGERY

IRB

DATA

DOCUMENTATION

BLOOD BANK

COAG LAB

STEVE ARMSTRONG*A STALLEY*

[DR S ROSEFF]DR M DOK SANDFORD

DR D BROPHYDR G BROPHYE MARTIN*

LIAISONS

LIAISON: E MARTIN

FINANCE SAFETY OVERSIGHT[EXTERNAL

REVIEW]Analogous to Incident Command structure• Hierarchy of organizational modules Allowed identification of • Major functions• Leadership and liaisons accountability• Only necessary functions/positions filled.• Bottlenecks identified

Functional Operations Mapping

Assess and map functional abilities to provide• Identification of technical

resources, expertise;• Management of

equipment/resources;• Supervision of participants; • Assessment of ability to respond;• Chain of accountability

IRB approval timeline

IND resubmitted to VCU-IRB Mar 2014

Changes approved for community

consultation June 2014

IND provisional approval Approved for public disclosure

Acknowledged receipt of IND from FDAJune 2014

Finalized IRB authorization agreements with EMS agenciesSubmission and review of disclosure summary reports, consent documentation etc

June 2014

VCU-IRB convened Aug 28 2014

VCU-IRB lost quorum; deferred IND review to

May 2014

REGULATORY APPROVAL PROCESS

EMS training begins -

pedagogical

REGULATORY APPROVAL PROCESS

REGULATORY APPROVAL PROCESS

IRB approval timeline

Final protocol approvals pending

Sept 2014

EMS/ED personnel in-service rehearsals

in progressSept 2014

Projected Trial launch

October 2014

REGULATORY APPROVAL PROCESS

Coagulation lab

Patient blood sampling20 mL per sampling time point• Coagulation (ROTEM, TEG)15 ml• 5mL for lipidomics

Barcoded and manually labelled

4 time points post-injury:• On scene• ED• 8 hr• 24 hr

Lipidomic profiles will provide a unique patient-specific fingerprint

• Eicosanoid profiles give an index of pro-inflammatory marker status

• Will be related to patient-specific trauma profile

time 5-iPF2alpha-VI TXB2 Cys LTD4 Cys LTE4 Cys LTC4 LTB4 15-HETE 5-HETE EicPent DHA AA

1 0.58 0.63 0.02 0.01 0.05 1.93 3.13 2.86 117.99 64.17 6056.062 0.22 0.03 0.01 0.01 0.10 27.17 70.79 17.42 309.35 196.41 12364.343 1.25 6.59 0.02 0.26 0.15 110.35 91.73 2.28 121.21 582.52 8398.44

1 0.58 0.58 0.01 0.00 2.36 1.06 3.45 2.95 40.85 41.42 3264.842 0.14 0.89 0.02 0.01 1.18 3.53 3.85 7.75 90.80 40.17 5289.863 0.85 0.13 0.05 0.00 2.50 0.34 4.26 6.17 43.72 30.53 2195.65

1 0.13 1.24 0.02 0.03 0.07 64.08 10.68 0.00 26.70 147.51 50.682 0.46 2.94 0.02 0.03 0.00 18.36 20.05 10.00 32.09 119.50 45.923 0.18 2.43 0.01 0.05 0.14 10.00 180.45 0.00 28.30 101.06 53.83

1 0.20 0.07 0.02 0.01 100.00 3.94 21.58 5.93 110.03 54.93 5319.872 0.81 0.47 0.04 0.01 0.00 1.45 11.14 7.28 149.24 54.67 3993.293 0.49 0.02 0.04 0.02 0.00 16.08 19.86 6.48 124.02 80.30 5625.004 0.52 0.07 0.02 0.03 33.26 7.96 140.02 5.79 126.52 97.15 8846.15

1 0.51 0.60 0.03 0.03 2.65 1.70 1.70 4.27 35.28 27.13 2025.572 0.75 0.96 0.03 0.02 12.27 35.45 9.79 1.29 62.70 50.00 5116.883 0.13 0.45 0.08 0.15 100.34 13.63 5.13 2.21 60.39 38.59 2761.754 0.21 0.09 1.17 0.04 0.00 19.71 2.22 4.45 76.18 26.68 2202.70

1 0.34 0.32 0.02 0.00 50.00 3.90 3.28 11.60 40.90 30.75 2660.942 0.05 2.05 0.02 0.03 7.16 17.14 16.93 12.63 131.00 44.49 5324.323 0.42 0.02 0.07 0.03 5.00 2.59 12.52 5.79 81.75 48.77 4479.77

1 0.10 1.92 0.00 0.01 0.00 11.14 33.33 0.00 8.01 37.53 21.342 0.73 10.20 0.01 0.05 0.06 11.14 189.14 5.56 48.18 118.63 44.963 0.47 24.08 0.01 0.02 0.00 35.00 150.23 10.02 16.95 46.26 26.44

1 0.29 0.70 0.01 0.02 0.06 26.25 7.89 0.00 35.56 358.73 202.382 0.17 1.09 0.02 0.01 0.12 11.56 38.46 0.00 103.13 332.39 119.893 0.19 0.38 0.01 0.01 0.00 8.33 0.00 0.00 43.91 1113.64 133.18

1 0.72 0.67 0.01 0.01 0.55 5.46 361.61 8.71 168.82 91.48 8178.842 0.06 3.43 0.02 0.01 0.00 3.93 38.43 3.42 64.66 45.24 4845.363 1.40 9.76 0.02 0.02 49.83 2.67 11.61 3.49 131.15 905.49 12098.214 0.82 3.95 0.02 0.01 2.38 4.97 19.48 2.10 94.21 419.64 14325.07

1 0.62 0.10 0.01 0.01 17.17 30.69 204.93 33.30 341.38 170.10 10191.082 0.17 2.29 0.02 0.03 0.33 21.67 98.57 35.29 223.67 101.28 8131.313 0.11 4.45 0.02 0.03 16.63 3.13 59.61 9.61 187.27 883.12 11341.464 0.22 0.07 0.07 0.05 15.77 3.83 9.35 4.67 135.64 540.44 10812.58

1 0.83 0.21 0.05 0.01 1.70 2.16 5.85 3.45 96.90 73.53 6217.392 2.07 0.21 0.01 0.04 0.07 9.82 115.76 18.10 357.76 126.95 28571.433 1.07 1.13 0.22 0.14 21.41 20.38 83.95 5.18 205.99 487.01 7410.074 0.87 0.08 0.12 0.03 50.00 8.56 72.52 11.34 97.85 206.59 5486.73

1 0.70 1.27 0.00 0.03 0.03 6.91 32.26 16.63 168.37 84.82 7887.932 6.65 3.32 0.02 0.05 0.14 55.44 155.78 17.20 433.78 106.93 33191.493 1.73 21.60 0.06 0.03 4.06 102.59 131.50 48.55 393.28 596.35 19157.304 0.74 0.46 0.03 0.03 0.77 11.28 154.39 25.93 253.50 188.50 13636.36

1 0.40 1.78 0.02 0.01 24.91 1.14 21.41 9.21 163.53 76.01 6686.752 0.09 0.29 0.01 0.02 0.00 9.55 94.19 25.48 327.47 151.62 13294.573 1.58 3.50 0.01 0.03 1.61 10.12 186.69 88.31 186.52 1567.74 19919.524 0.96 0.40 0.01 0.03 12.48 2.63 4.01 3.70 100.72 1191.41 15245.90

2 0.39 0.50 0.00 0.02 0.00 1.05 372.67 20.42 189.87 120.68 9233.933 3.17 37.84 0.01 0.02 1.92 9.85 140.18 33.33 194.20 1126.58 13805.974 0.61 0.42 0.02 0.01 0.83 7.05 61.91 20.69 98.97 909.63 20916.91

1 0.06 3.22 0.02 0.04 0.00 21.43 3.57 0.00 19.23 161.97 38.732 0.11 1.51 0.01 0.03 0.05 75.00 58.33 0.00 37.87 94.40 29.073 0.11 0.89 0.01 0.23 0.07 7.14 35.71 28.64 27.80 285.31 71.19

1 0.11 0.67 0.01 0.02 0.06 0.00 0.00 0.00 5.41 31.00 12.392 0.59 1.95 0.01 0.01 0.07 6.25 25.06 0.00 26.54 45.45 21.553 0.19 0.93 0.01 0.84 0.08 21.46 28.64 0.00 14.76 21.53 11.94

1 0.17 2.61 0.00 0.01 0.00 12.49 50.06 0.00 8.38 45.50 25.722 0.33 1.78 0.01 0.05 0.06 13.66 9.11 0.00 8.57 35.24 17.253 0.44 0.89 0.01 0.72 0.08 14.30 68.02 0.00 13.46 45.95 36.64

1 0.06 1.63 0.01 0.01 0.06 50.00 8.35 4.17 15.76 143.50 49.442 0.12 1.50 0.01 0.02 0.00 68.75 0.00 6.25 25.48 127.81 48.883 0.13 5.82 0.01 0.25 0.16 70.00 100.00 0.00 18.52 237.04 73.33

1 0.06 2.34 0.01 0.01 0.05 21.43 3.57 0.00 5.43 17.20 23.792 0.17 0.35 0.02 0.04 0.00 65.91 0.00 5.00 19.62 41.45 26.073 0.16 0.26 0.01 0.91 0.06 5.56 5.56 0.00 9.33 136.11 52.38

ID

Swine FFP, Glycine pretreatmentSwine FFP untreatedSwine FFP, Glycine pretreatmentSwine FFP, Asc. Acid pretreatmentSwine FFP, Glycine pretreatmentSwine FFP, Asc. Acid pretreatmentSwine FFP untreatedSwine FFP pre-spray dry, no Treatmenthuman normal plasma spiked 2.5ng/ml PGE2Human normal plasma spiked 25ng/ml PGE2Human normal plasma no pretreatmentPlasmaSafe, Glycine pretreatmentPlasmaSafe, untreatedKedrion plasma Glycine pretreatmentPlasmaSafe, Asc. Acid pretreatmentKendrion Plasma, Asc. Acid pretreatmentKendrion Plasma Glycine pretreatmentKEDY003 pre-spray dryPlasmaSafe pre-spray dry, no treatmentKendrion Plasma, untreatedKEDY003 reconstituted in Cit pot pH 3.5

Swine FFP, Glycine pretreatmentSwine FFP untreatedSwine FFP, Glycine pretreatmentSwine FFP, Asc. Acid pretreatmentSwine FFP, Glycine pretreatmentSwine FFP, Asc. Acid pretreatmentSwine FFP untreatedSwine FFP pre-spray dry, no Treatmenthuman normal plasma spiked 2.5ng/ml PGE2Human normal plasma spiked 25ng/ml PGE2Human normal plasma no pretreatmentPlasmaSafe, Glycine pretreatmentPlasmaSafe, untreatedKedrion plasma Glycine pretreatmentPlasmaSafe, Asc. Acid pretreatmentKendrion Plasma, Asc. Acid pretreatmentKendrion Plasma Glycine pretreatmentKEDY003 pre-spray dryPlasmaSafe pre-spray dry, no treatmentKendrion Plasma, untreatedKEDY003 reconstituted in Cit pot pH 3.5

ID

AA

5H

ET

E11

HE

TE

12H

ET

E1

5HE

TE

PG

E2

PG

F2

alp

ha6

kPG

F1

alp

haE

icP

entAA

5H

ET

E11

HE

TE

12H

ET

E1

5HE

TE

PG

E2

PG

F2

alp

ha6

kPG

F1

alp

haE

icP

ent AA 5HETE 11HETE

12HETE 15HETE PGE2

PGF2alpha 6kPGF1alpha EicPent

Lipidomic profiles for major resuscitation fluid types

AA

5HE

TE

11H

ET

E12

HE

TE

15H

ET

EP

GE

2P

GF

2al

pha

6kP

GF

1alp

haE

icP

ent

AA

5HE

TE

11H

ET

E12

HE

TE

15H

ET

EP

GE

2P

GF

2al

pha

6kP

GF

1alp

haE

icP

ent

AA048

1216202428323640

5HETE0

9000180002700036000450005400063000720008100090000

11HETE0

700140021002800350042004900560063007000

12HETE0

175350525700875

10501225140015751750

15HETE0

90180270360450540630720810900

PGE20

2.755.5

8.2511

13.7516.5

19.2522

24.7527.5

PGF2alpha0.9

0.971.041.111.181.251.321.391.461.53

1.6

6kPGF1alpha0.550.610.670.730.790.850.910.971.031.091.15

EicPent255075

100125150175200225250275

FFP glycine pretreFFP untreated

FFP pretreFFP AA pretre

FFF glycine pretreFFP untreatedDried plasma

FFP PGE2FFP PGE2

FFP untreatedDried plasma glycine pretre

Dried plasma untreatedDried plasma AA pretreDried plasma AA pretre

Dried plasma glycine pretreDried plasma untre

Dried plasma untreatedDried plasma untreated

Dried plasma + citrate