David W. Wright, MD

Director, Emergency Neurosciences 

Department of Emergency Medicine

March 28th, 2013

Therapeutic Interventional Trials in 

Traumatic Brain Injury
COI 

Inventor 

DETECTTM Technology – a novel tool for detecting 

concussions 

BHR Pharma – Inventor of 

technology licensed from Emory to create 

path for progesterone technology to 

consumer. Eligible for Royalties through 

Emory University.
Faul, M et al. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, 2010

Public Health Burden of TBI in 

the United States

52,000 

Deaths

275,000

Hospitalizations

1,365,000

Emergency Departments 

Visits

3 
747 Passenger Airline

286 passengers

175 Airliners
5 Primary Injury
Secondary Injury

Neurotoxic 

Cascade  Excitatory Amino Acids

 Glutamate, Glycine, others

 Critical Ions

 Calcium, Sodium, Magnesium

 Receptor Activation

 NMDA, AMPA, etc.
R 

CPG

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

DAG

cGMP

AC

NFAT p300

CBP

MEF2

Gs,Golf,

Gt

Ca++

P 

t xeT

I 

P 

3 

R 

Ca++

Ca++

Ca++

Ca++

NAADP

Sph

IP3

DAG

DAG

DAG

PIP2

PIP2

PIP2

PIP2

PKC

Calm

Caln CamK-IV

cAMP

Ca++

Hormones,

Neurotransmitters

Hormones,

Neurotransmitters,

Growth Factors,

Osmolarity

Light, 

Odorants,

Test 

Molecules

ADP-Ribose,

Arachidonic

Acid,

Sphingosine

Gene Expression

Hypertrophy

Depolarization/Voltage Intracellular Calcium Signaling

Ca++

Acetylcholine,

Glutamate,

Serotonin, ATP

GTP

ATP

Na+ 

CNG

GC

 2009

ProteinLounge.com

C 
Secondary Cascade after TBI

TBI

Demyelination

Mitochondrial

Uncoupling

Excitotoxic 

cascade

Receptor activation

Reduced 

GABA

Inflammatory

Cytokines 

Apoptosis Cerebral

Edema

Cytotoxic 

Edema

Vasogenic 

Edema

Pro Apoptotic 

cascade

Free radicals & lipid 

peroxidation

Completed 

“Neuroprotection” 

Clinical Trials in Severe 

Traumatic Brain Injury, 

February 1999 a 

USA, United States of 

America; EU, European 

Union; UK, United 

Kingdom; DBPCRT, 

double-blind, placebocontrolled, randomized 

trial; HIT, Head Injury 

Trial; ICP, intracranial 

pressure; SAH, 

subarachnoid hemorrhage; 

PEG-SOD, polyethylene 

glycol-conjugated 

superoxide dismutase; 

NMDA, N-methyl-Daspartate; THAM, 

tromethamine.














At Present There Are No Effective 

Drug Treatments For Traumatic 

Brain Injury

Failure of past TBI clinical Trials 
Brain Injury Trials and the 

hope for a treatment
HUGE GAPS in 

RESEARH still 

EXIST! 
Benchtop to 

Bedside – are 

our models 

correct?

? 

= 

? 

= 

90% 98.5% 

Is the Animal model relevant?
TBI classification

 Mild (GCS 14-15)

 Moderate (GCS 9-13)

 Severe (GCS 3-8)
Glasgow Coma Score 

Finding Pediatric Specific Score

15

 EYE OPENING

 Spontaneously 4 

 To speech 3 

 To pain 2 

 No response 1 

 VERBAL RESPONSE

 Alert & oriented Smiles/Coos 5 

 Converses but disoriented Inappropriate cries 4 

 Speaking nonsensical Persistent scream 3 

 Moans, unintelligible sounds Grunts 2 

 No response 1 

 MOTOR

 Follows commands Spontaneous move 6 

 Localizes to pain 5 

 Movement or withdrawal to pain 4 

 Abnormal flexion (decorticate) 3 

 Abnormal extension (decerebrate) 2 

 No response 1

E 

V 

M 
6 Different Examples of Severe TBI

Epidural hematoma Contusion/Hematoma

Subdural hematoma Subarachnoid hemorrhage

Diffuse axonal injury

Diffuse swelling


 Mechanistic 

Approach

 Single Target

Is our approach wrong?

“The magic bullet”

Potential mechanisms in TBI

Progesterone

Remyelination

Mitochondrial

Recoupling

Blocks

Excitotoxicity

Antagonizes 

Sigma Receptor

Enhances

GABA

Reduces

Inflammatory

Cytokines 

Reduce Apoptosis Reduces Cerebral

Edema

Cytotoxic 

Edema

Vasogenic 

Edema

Increases Bcl2

AkT-P 

Decreases free 

radicals & lipid 

peroxidation

Lack of evidence for current 

approach = treatment variability

Death 

“Knell

”
Published Mortality Rate for Severe TBI 

1. Stein, SC., J of Neurotrauma 2010 (Meta-Analysis) 35%

2. Ottochian M, Am J Surgery, 2009 38%

3. O'Phelan K., Journal of Trauma, 2008 51%

4. Stiefel M.F., Journal of Neurosurgery, 2005 (with PO2 monitoring) 25%

5. Lu J., Acta Neurochirurgica, 2005 27%

6. Fakhry, S.M., J. Trauma 2004, 56:492-500 18%

7. Cooper, D.J., JAMA 2004, 291:1350-1357 45%

8. Gan, B.K., Ann Acad Med Singapore 2004, 33:63-67 45%

9. MRC Crash Trial, Curr Opin Crit Care 2003, 9:92-97 39%

10. Palmer S., Journal of Trauma, 2001 16%

11. Stein, SC., J of Neurotrauma 2010 (Meta-Analysis) 35%

Wide range of mortality reported in the literature – treatment variability
...a single episode of hypoxia & 

hypotension increased the 

mortality by 150%...

Chestnut et. al.. 1991

Morbidity

Time and timing have never matter so much
PHASE I-II Studies Acute Interventional

Drug Site/Sponsor Recruit Subjects Type Outcome / Year completion

Esmolol/Propranolol 

(CHAIN) 

JHU N 34 Open HR, Hyperadrenergic Activity 

(2015)

ABELADRUG200 

(AbelaTBI2) 

OSU, UCIrvine

Abela

Pharma

Y 30 Open ICP, Mortality, GOSE Severe TBI 

(2011)

Hypernatremia 

(MGH-HH5)

MGH N 40 Open Prevention of cerebral edema 

(2013)

BM Mononuclear Cells UT-Houston

DOD

Y 20 Open Safety, NeuroEvents, GOSE, DRS 

(2014)

Probenecid & N-Acetyl 

Cysteine (ProNAC) 

U-PITT

NIH-NINDS

Y 20 DB AE, Anti oxidant Reserve - 

Pediatric

Minocycline Wayne State 

U 

Y 14 Open DRS, drug levels, CVLT, SF12 

(2013)

Clinicaltrials.gov – Traumatic Brain Injury-Open Studies-Interventional-Phase II-III
PHASE II Studies Acute Interventional

Drug Site/Sponsor Recruit Subject

s

Type Outcome / Year completion

Propranolol 

(EPAT)

Cedars-Sinai Y 40 Open Safety Sympathetic storm (2015)

Lactate 

(LS_TCC)

Unv. Vaudois

Swiss NSF, ESICM

Y 30 Open Safety BT02, cellular Lactate Pyruvate (2015)

Propranolol/Clonidine 

(DASH) 

Vanderbilt Y 100 DB Vent free days, Catechol levels, LOS, GOSE, NP,QOL (2016)

Atorvastatin Baylor, UT-H 

Mission Connect DOD

Y 200 DB mTBI, less PTS, PTSD, Cog recovery, safety, (2013)

HBO 

(HBO2T)

VCU, HHM VA

US Navy NOMI

Y 60 DB mTBI - Safety, NP, eye track, etc. (2011)

Brain Tiss Mon 

(BOOST II)

PITT, UT-SW, mutli

NINDS-NIH

Y 182 SB SevTBI Reduction of time BTO below 20 RR for GOS (2014)

Mild HypoTherm & Mg 

MHS-TBI

(DOD) Y 105 Open GOS, Vasospasm (2012)

NGF IN 

(NGF-TBI) 

Jinling, China N 118 DB GOS, Neurologic Functions HAMA (2012)

Allopregnanolone UC Davis

DOD

N 136 DB GOSE, Mort, NP, QOL, Sz, Safety (2015)

D-Cycloserine 

(DCS) 

Hadassah N 100 DB ModTBI – NP test, GOSE (2014)

Paracetamol 

(PARITY) 

Sidney, Wales 

The George Instit

Y 80 DB Core Body temp, BP, cerebral hypoperfuse (2013)

Glyburide 

(RPI202) 

U-Maryland, InTRuST

AMRMC - DOD

Y 100 DB Edema/Hemorrhage change, Mort, AE

hCG and Epoetin 

(NTx-265) 

U-Calgary

Stem Cell Therapeutics

Y 10 Open Tier 1 Safety (2012)

Sevoflurane 

(SEPIA)

Assistance Publique Paris

MOH, France

Y 27 Open ICP, sedation, hemodynamics (2013)

NNZ-2566 

(INTREPID2566)

U-Miami multi

Neuren

Pharmaceuticals

Y 260 DB Safety, GOSE, NP, PK Biomarkers, EEG
PHASE III Studies Acute Interventional

Drug Site/Sponsor Recruit Subjects Type Outcome / Year completion

Erythropoietin 

(EPO-TBI) 

Aus, NZ, 

NHMRC -Aus

Y 606 DB GOSE dichot, NO, other, Safety (2014)

Proph Hypotherm 

(POLAR-RCT) 

Aus, NZ, 

NHMRC -Aus

Y 512 SB SevTBI Same Biomarkers (2013)

Progesterone

(ProTECT III)

Emory, NETT

NINDS-NIH

Y 1140 DB GOSE, DRS, M, NP. (2015)

Progesterone 

(SyNAPSe) 

Multi

BHR

Y 1180 DB GOSE, NP test, CPP, (2013)

Tranexamic Acid 

(CRASH 3) 

London School 

of Hygiene

Y 10000 DB Mortality in hospital, SAE, ICU days, etc

(2016)

Tranexamic Acid Khon Kaen U, 

Thailand 

Research Fund

Y 240 DB Progressive Hemorrhage at 24hr, 

mortality, (2009)
0

1

2

3

4

5

6

7

M a le s F e m a le s

( p r o e s tr u s )

F e m a le s

(P P )

C

ere

bral E

d

e

m

a

(% in

cre

a

s

e in tis

s

u

e

water c

o

nte

nt)

Progesterone Reduces Edema

Promising Interventions
Gender, Progesterone, Brain Injury

Are There SEX Differences In The Brain?
Sexual Dimorphism in a Vocal Control Area 

(Robust Nuc. of the Archistriatum) of the Songbird

Male Female

Canary 

Zebra-finch

F. Nottebohm & A. Arnold (1976) Science, 194, 211
Hormonal 

Cycling 
0

1

2

3

4

5

6

7

M a le s F e m a l e s

( p r o e s t ru s )

F e m a le s

( P P )

C

e

re

b

ral E

d

e

m

a

%( in

c

re

a

s

e in tis

s

u

e

w

ate

r

c

o

nte

nt)

Endogenous Progesterone 

Reduces Edema
*

*

No treatm ent

0

1

2

3

4

5

6

7

Males Females

Prog. treatm ent

Cere

bral E

de

ma (%incre

a

se intissue

water conte

nt) Progesterone Administration 

Reduces Edema in Male and Female Rats

REDUCED EDEMA

Potential mechanisms in TBI

Progesterone

Remyelination

Mitochondrial

Recoupling

Blocks

Excitotoxicity

Antagonizes 

Sigma Receptor

Enhances

GABA

Reduces

Inflammatory

Cytokines 

Reduce Apoptosis Reduces Cerebral

Edema

Cytotoxic 

Edema

Vasogenic 

Edema

Increases Bcl2

AkT-P 

Decreases free 

radicals & lipid 

peroxidation
Corroborative Research

 >180 publications showing positive results with 

progesterone in neurological injury

 24 different laboratories 

 4 animal species

 22 different animal models
Will Progesterone work in Humans?
2001-2005 

NINDS # 1RO1 NS39097-01A1 

IRB # 433 – 2001 

GCRC # 9004
Primary Outcome - Safety 
30 day Mortality by Treatment

30.40%

13.60%

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

35.00%

Progesterone Placebo

Treatment Group

Percent dead 100 subjects

p=0.06; RR 0.43 - 95% CI (0.18-0.99)
Disability Rating Scale

Moderate (iGCS 9-12)

5.00

12.70

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

Progesterone Placebo

Treatment Group

Disability 

Severe (iGCS 4-8)

10.70

4.40

0.00

2.00

4.00

6.00

8.00

10.00

12.00

Progesterone Placebo

Treatment Group

Disability Score**

p=0.010, RR 0.33 (0.13 p=0.040, RR 0.33 (0.13-0.83) -0.83) 

Lower DRS = Better outcome

Two Human Pilot Trials

– Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, 

Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, 

Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, 

Stein DG. ProTECT: A Randomized Clinical Trial of Progesterone for 

Acute Traumatic Brain Injury. Ann Emerg Med. Apr 2007;49(4):391-402, 

402 e391-392.

– Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved Outcomes from the 

Administration of Progesterone for Patients with Acute Severe Traumatic 

Brain Injury: A Randomized Controlled Trial. Critical Care. April 2008

2008;12(R61):1-10. 

Two Human Pilot Trials 
ProTECT III

Enrolling
ProTECTTM III 

Progesterone for Traumatic Brain Injury

49 

NINDS # 1U01NS062778 

FDA IND # 108,144

IRB # 000-14409 

ProTECT III PI – David W. Wright

ProTECT Project Manager – Bethany Lane

Statistician – Sharon Yeatts

Blinded Statistician – Vicki Hertzberg, Yuko Palesch

SDMC Statistical Center PI – Yuko Palesch

NETT PI – Bill Barsan, Rob Silbergleit

NETT ProTECT Site Manager – Erin Zaleski

21 Hubs Active

36/39 Sites Active

NINDS # 1U01NS062778 

FDA IND # 108,144

IRB # 000-14409

ProTECTTM III

A Phase III, double-blind, placebo-controlled randomized clinical 

trial 

1. Blunt traumatic brain injury

2. GCS 4-12

3. Can initiate infusion within <4 hours of injury

4. Age >18 yrs
Investigational Drug

•Treatment: Progesterone dissolved in ethanol 

(~50 mg/ml) stock solution – mixed with 

Intralipid 20% just prior to infusion

•Placebo: Same volume of ethanol in Intralipid 

20%

•Treatment and placebo - Not distinguishable

•Weight based formulation – 14 cc for 1 hr, then 

10 cc/hr for remaining then taper)

•Infused over 4 days (72 hrs with 24 hr taper)




Questions?
The Search for Interventions that 

Reversing the Cognitive and Motor 

Deficits the Result from Severe TBI

Robert L. Ruff, MD, PhD

Ronald G. Riechers II, MD

Suzanne S. Ruff, PhD

Cleveland Dept of Veterans Affairs Medical Center

Cleveland OH 44106
Disclosures 

Financial Disclosure 

• Robert L Ruff, Ronald Riechers and Suzanne S 

Ruff have no financial disclosures

Drug/Product Off-Label Use Disclosure

• None 

Grant Support

• This presentation is supported in part by data 

obtained from a Pilot Study supported by VA 

Center of Excellence Grant from VHA Office of 

Rehabilitative Research and Development

• Any opinions or conclusions presented are 

those of the author and do not necessarily 

reflect those of the Department of Veterans 

Affairs.

2 
US Military – 

about 

300,000 

recognized 

cases of TBI 

from Iraq and 

Afghanistan, 

>90% mild 

TBI (aka 

concussion)
TBI Classification

LOC - loss of consciousness, AOC - alteration of consciousness, PTA - post-traumatic

amnesia, GCS – Glasgow Coma Scale ; Imaging excludes – DTI, fMRI, SPECT, PET


Kraus, M. F. et al. Brain 2007 130:2508-2519

Example region of interest masks for a single representative subject: (A) forceps minor (green), 

cortico-spinal tract (purple), inferior frontal-occipital fasciculus (red), external capsule (yellow), 

sagittal stratum (blue); (B) anterior corona radiata (green), superior longitudinal fasciculus (red), 

posterior corona radiata (blue); (C) cingulum (red), corpus callosum body (blue), splenium 

(yellow), and genu (green) and forceps major (purple)

Mild 

TBI is 

not 

always 

benign
Kraus, M. F. et al. Brain 2007 130:2508-2519

Diffusion-Tensor MRI Reveals White Matter Pathway Damage

Mild TBI (M), Moderate to 

Severe TBI (MS) – Note 

more extensive damage in 

MS TBI.

Preliminary results from 

veterans with high energy 

blast injury suggest that mild 

TBI from blast produces 

changes that resemble 

moderate non-blast TBI
Kraus, M. F. et al. Brain 2007 130:2508-2519

Neuropsychological Deficits Correlate with Severity of 

White Matter Damage

Civilian Data 

Mean domain scores 

(normalized zscores) 

for the MTBI (white) 

and M/STBI (dark 

gray) 
Treatments for Severe TBI 

 Medication Trials – Recent trial using 

amantidine showed that attention 

improved to permit rehab. Amphetamine 

stimulants and not very useful

 Deep Brain Stimulation – Bilateral 

Stimulation of Intralaminar Nuclei for 

individuals with preserved language cortex 

and reduced cortical activation due to 

damage to RAS
Pontine and Midbrain RAS Activate 

Cortex via Intralaminar Nuclei 
Intralaminar Nuclei 
In the latest case study, 

neuroscientists describe how they 

implanted electrodes in the brain 

of a 38-year-old man who had been 

in a minimally conscious state for 

more than six years following a 

serious assault. By electrically 

stimulating a brain region called 

the central thalamus, they were 

able to help him name objects on 

request, make precise hand 

gestures, and chew food without 

the aid of a feeding tube
• Intermediate in the generation of 

phosphatidylcholine 

• Brain uses choline to synthesize acetylcholine

• Animal studies and preliminary clinical pilot 

studies citocoline reduced cerebral injury from 

TBI & ischemia

• However, in randomized clinical trials, Citicoline

was ineffective in TBI (Zafonte et al. 2012) or 

stroke (Dávalos et al. Lancet 2012) 

Citicoline – Unrealized Promise
Why Did Citicoline Fail?

1.Animals may have more resilient brains – perhaps 

rodents are not the best model

2.Citicoline might improve only some aspects of 

functional clinical recovery

3.Motor and cognitive rehabilitation are critical for 

optimal recovery could not control

4.One of the major mechanisms of clinical brain 

damage in TBI is diffuse axonal injury – the injuries 

in the patients have been far more extensive then 

just DAI
Thank You

Robert L. Ruff, MD, PhD

Suzanne S. Ruff, PhD

Cleveland Dept of Veterans Affairs Medical Ctr.

Cleveland OH 44106

robert.ruff1@va.gov

suzanne.ruff2@va.gov

ronald.riechers@va.gov

216-791-3800 ext 5230 (Robert) 1165 (Suzanne)