Supplementary Appendix

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Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 2012;366:819-26.

(PDF updated March 8, 2012.)

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Supplementary Material for:

Placebo Controlled Trial of Amantadine for Traumatic Brain Injury

Joseph T. Giacino, PhD,John Whyte, MD, PhD,Emilia Bagiella, PhD, Kathleen Kalmar, PhD, Nancy Childs, MD, Allan Khademi, MD, Bernd Eifert, MD, PhD,David Long, MD,Douglas I. Katz, MD,Sooja Cho, MD,Stuart A. Yablon, MD, Marianne Luther, MD, Flora M. Hammond, MD, Annette Nordenbo, MD, Paul Novak, AOTA, Walt Mercer, PhD,Petra Maurer-Karattup, PhD, Mark Sherer, PhD

Table of Contents Page*

Supplementary Table S1. Breakdown of treatment arm by dose of study drug 2

Supplementary Figure S2. Consort Diagram 3

Supplementary Table S3. Comparison of centrally-active medications 4 Supplementary Figure S4. Comparison of DRS change between early and late subgroups 5 Supplementary Figure S5. Comparison of DRS change by diagnostic subgroups 5 Supplementary Table S6.Comprehensive listing of serious adverse events 6-8 Supplementary Figure S7.Disability Rating Scale Scoring Syllabus 9-12 Supplementary Figure S8. Coma Recovery Scale- Revised Record Form 13

Acknowledgements 14

*Supplementary figures and tables are numbered according to the order of appearance in the manuscript.

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Supplementary Table S1.Breakdown of percentage of subjects from each treatment arm by daily dose of study drug received.

Group 200 300 400

Amantadine 47 (54%) 11 (13%) 22 (25%) Placebo 40 (41%) 20 (21%) 35 (36%)

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Screened for eligibility n = 1170

Excluded: n = 986 Did not meet inclusion criteria: n = 820

Refused consent: n = 85 Other reasons: n = 81 Randomized: n = 184

(U.S. = 134)

Allocated to AH: n = 87 Compliance:

≥ 75% of doses taken: n = 75

< 75% of doses taken: n = 12

Status Completed Study: n = 86 Lost to follow-up:

Death: n = 1

Analyzed in Primary Analysis:

n = 87

Allocated to Placebo: n = 97 Compliance:

≥ 75% of doses taken: n = 88

< 75% of doses taken: n = 9

Status Completed Study: n = 95 Lost to follow-up:

Transferred to acute care facility: n = 2

Analyzed in Primary Analysis:

n = 97 Supplementary Figure S2. Consort Diagram.

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Supplementary Table S3. Comparison of frequency of use of potentially confounding centrally-active medications during the six-week treatment phase.

DRUG CLASS AH PLACEBO pVALUE

(FISHER’S - uncorrected)

Stimulant/Arousing drugs 5 2 0.2580

AH (open label) 8 3 0.1188

Atypical Antipsychotics 3 8 0.2201

Anticonvulsants 42 32 0.0367

Antihistamines 7 12 0.4676

Beta blockers 50 54 0.8818

Benzodiazepines 17 23 0.5919

Anticholinergics 6 2 0.1518

Metaclopramide 21 18 0.3722

Narcotics 36 53 0.0782

Non-benzodiazepine hypnotics 6 5 0.7585

Choral hydrate 2 2 1.0000

Antispasticity agents 34 29 0.2149

Anidepressants (SSRI and

Serotonergic/Noradrenergic) 41 42 0.6572

Corticosteroids 4 4 1.0000

Other 18 22 0.8582

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Supplementary Figure S4. Comparison of DRS change between early and late enrolled subgroups.

Supplementary Figure S5.Comparison of DRS change by diagnostic subgroups.

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Supplementary Table S6.Comprehensive listing of serious adverse events.

Patient ID

Date of Onset

Is this AE

unexpected? Adverse Event Severity

of AE

Relation to study drug

Is this a Serious AE?

Was treatment required?

AE Outcome

1009 06JUL2005 Yes Fever. Severe Unrelated Yes Yes

Recovered without sequelae

1016 31JUL2005 Yes

Pt admitted to acute care hospital with pneumonia and is on ventilator support.

Severe Unrelated Yes Yes

1017 03AUG2005 Yes gastrointestinal bleeding. Severe Unknown Yes Yes

1018 04AUG2005 Yes Osteomyelitis. Moderate Unrelated Yes Yes

Recovered with sequelae

1021 17AUG2005 Yes

Patient developed spontaneous bleed into chronic subdural hematoma

Severe Unlikely Yes Yes

1022 25AUG2005 Yes Gastritis Severe Unrelated Yes Yes

1023 05SEP2005 Yes

Patient became febrile, developed lung congestion, O2 sats fell, sent to acute hospital, found to have pneumonia

1030 11OCT2005 No Decreased arousal/alertness. Severe Unrelated Yes Yes

1036 05DEC2005 Yes

Right hand and finger, swelling, infection with the apearance of cellulitis, Positive blood cultures, Zosynperscribed for 4 weeks, Resolution Per MD 1/4/06

Moderate Unrelated Yes Yes

1044 13FEB2006 Yes pneumonia/acute respiratory

failure Severe Unlikely Yes Yes

Recovered with sequelae 1054 19JUN2006 Yes Worsening of corneal infiltrate Severe Unrelated Yes Yes Unresolved

1056 03JUL2006 Yes Patient pulled out J-tube. Moderate Unrelated Yes Yes

1056 20JUL2006 Yes Bowel Obstuction Severe Unlikely Yes Yes

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1059 27JUL2006 Yes Sepsis. Severe Unrelated Yes Yes

1071 01DEC2006 Yes aspiration pneumonia with acute

respiratory failure Severe Unlikely Yes Yes

1073 15JAN2007 Yes

Colon Carcinoma with bowel obstruction and perferation, vomiting and aspiration

Severe Unrelated Yes Yes Unresolved

1078 03FEB2007 Yes new right LL Pneumonia,

desaturation to 65% Severe Unlikely Yes Yes Unknown

1083 18MAR2007 Yes autonomic storm Severe Possible Yes Yes

1084 10APR2007 Yes Hydrocephalus Severe Unrelated Yes Yes

1110 19JAN2008 Yes Left arm tremor and head tremor Moderate Unrelated Yes Yes

1113 03FEB2008 Yes cardiac arrest (consecutive

reanimation) Severe Possible Yes Yes Patient died

1116 25FEB2008 Yes pneumonia Severe Unrelated Yes Yes Unresolved

1119 16MAR2008 Yes craniectomy site changed from

concave to convex overnight Severe Unrelated Yes Yes

1119 28MAR2008 Yes pneumonia Severe Unrelated Yes Yes

1133 09SEP2008 Yes

strong suspicion of an infection of the amputation stump of the right foot

1134 25AUG2008 Yes

sudden onset high fever with tachycardia, hypotension and respiratory insufficiency, urinary tract infection and sepsis

1136 23AUG2008 Yes Weight loss Mild Unlikely Yes No

1138 27OCT2008 Yes Pneumonia Severe Unrelated Yes Yes

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1139 12NOV2008 Yes Anemia Severe Unrelated Yes No

Recovered without sequelae 1139 11NOV2008 Yes Lower Extremity (LE) swelling Severe Unrelated Yes Yes Unresolved

1142 06NOV2008 No Patient vomited and possible

aspiration Severe Unrelated Yes Yes

1146 26NOV2008 No seizures X2 Severe Possible Yes Yes

1146 26NOV2008 Yes Hydrocephalus Severe Unrelated Yes Yes

1150 19DEC2008 Yes Seizures Moderate Possible Yes Yes Unknown

1150 19DEC2008 No increased WBC Mild Unlikely Yes No Unknown

1151 03JAN2009 Yes Other Infection Severe Unlikely Yes Yes Unresolved

1151 03JAN2009 Yes Hydrocephalus Severe Unrelated Yes Yes Unresolved

1163 08APR2009 Yes Peritonitis Severe Unrelated Yes Yes Patient died

1163 19APR2009 Yes Hydrocephalus Severe Unrelated Yes Yes Patient died

1179 30NOV2009 Yes

Peritonitis after PEG. Transferred to surgery for undiagnosed diaframatic rupture

Severe Unrelated Yes Yes Unresolved

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Supplementary Figure S7.Disability Rating Scale Scoring Syllabus

Eye opening

0 SPONTANEOUS: eyes open with sleep/wake rhythms indicating active and arousal mechanisms; does not assume awareness.

1 TO SPEECH AND/OR SENSORY STIMULATION: a response to any verbal approach, whether spoken or shouted, not necessarily the command to open the eyes. Also, response to touch, mild pressure.

2 TO PAIN: tested by a painful stimulus.( Standard painful stimulus is the application of pressure across index fingernail of best side with wood or a pencil; for quadriplegics pinch nose tip and rate as 0, 1, 2 or 5.)

3 NONE: no eye opening even to painful stimulation.

Best communication ability (if patient cannot use voice because of tracheostomy or is aphasic or dysarthric or has vocal cord paralysis or voice dysfunction then estimate patient's best response and enter note under comments.)

0 ORIENTED: implies awareness of self and the environment. Patient able to tell you a) who he is; b) where he is; c) why he is there; d) year; e) season; f) month; g) day; h) time of day.

1 CONFUSED: attention can be held and patient responds to questions but responses are delayed and/or indicate varying degrees of disorientation and confusion.

2 INAPPROPRIATE: intelligible articulation but speech is used only in an exclamatory or random way (such as shouting and swearing); no sustained communication exchange is possible.

3 INCOMPREHENSIBLE: moaning, groaning or sounds without recognizable words; no consistent communication signs.

4 NONE: no sounds or communication signs from patient.

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Best motor response

0 OBEYING: obeying command to move finger on best side. If no response or not suitable try another command such as "move lips," "blink eyes," etc. Do not include grasp or other reflex responses.

1 LOCALIZING: a painful stimulus at more than one site causes a limb to move (even slightly) in an attempt to remove it. It is a deliberate motor act to move away from or remove the source of noxious stimulation. If there is doubt as to whether withdrawal or localization has occurred after 3 or 4 painful stimulations, rate as localization.

2 WITHDRAWING: any generalized movement away from a noxious stimulus that is more than a simple reflex response.

3 FLEXING: painful stimulation results in either flexion at the elbow, rapid withdrawal with abduction of the shoulder or a slow withdrawal with adduction of the shoulder. If there is confusion between flexing and withdrawing, then use pin prick on hands, then face.

4 EXTENDING: painful stimulation results in extension of the limb.

5 NONE: no response can be elicited. Usually associated with hypotonia. Exclude spinal transection as an explanation of lack of response; be satisfied that an adequate stimulus has been applied.

Cognitive ability for feeding, toileting and grooming.

Rate each of the three functions separately. For each function answer the question, does the patient show awareness of how and when to perform each specified activity. Ignore motor disabilities that interfere with carrying out a function, this is rated under Level of Functioning described below.Rate best response for toileting based on bowel and bladder behavior. Grooming refers to bathing, washing, brushing of teeth, shaving, combing or brushing of hair and dressing.

0 COMPLETE: continuously shows awareness that he knows how to feed, toilet or groom self and can convey unambiguous information that he knows when this activity should occur.

1 PARTIAL: intermittently shows awareness that he knows how to feed, toilet or groom self and/or can intermittently convey reasonably clearly information he knows when the activity should occur.

2 MINIMAL: shows questionable or infrequent awareness that he knows in a primitive way how to feed, toilet or groom self and/or shows infrequently by certain signs, sounds or activities that he is vaguely aware when the activity should occur.

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3 NONE: shows virtually no awareness at any time that he knows how to feed, toilet or groom self and cannot convey information by signs, sounds, or activity that he knows when the activity should occur.

Level of functioning

0 COMPLETELY INDEPENDENT: able to live as he wishes, requiring no restriction due to physical, mental, emotional or social problems.

1 INDEPENDENT IN SPECIAL ENVIRONMENT: capable of functioning independently when needed requirements are met (mechanical aids).

2 MILDLY DEPENDENT: able to care for most of own needs but requires limited assistance due to physical, cognitive and/or emotional problems (e.g. needs non-resident helper).

3 MODERATELY DEPENDENT: able to care for self partially but needs another person at all times.

4 MARKEDLY DEPENDENT: needs help with all major activities and the assistance of another person at all times.

5 TOTALLY DEPENDENT: not able to assist in own care and requires 24-hour nursing care.

"Employability"

The psychosocial adaptability or "employability" item takes into account overall cognitive and physical ability to be an employee, homemaker or student. This determination should take into account considerations such as the following: 1. Able to understand, remember and follow instructions; 2. Can plan and carry out tasks at least at the level of an office clerk or in simple routine, repetitive industrial situations or can do school assignments; 3. Ability to remain oriented, relevant and appropriate in work and other psychosocial situations; 4.Ability to get to and from work or shopping centers using private or public transportation effectively; 5.Ability to deal with number concepts; 6.Ability to make purchases and handle simple money exchange problems; 7.Ability to keep track of time schedules and

appointments.

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0 NOT RESTRICTED: can compete in the open market for a relatively wide range of jobs commensurate with existing skills; or can initiate, plan, execute and assume responsibilities associated with homemaking; or can understand and carry out most age relevant school assignments.

1 SELECTED JOBS, COMPETITIVE: can compete in a limited job market for a relatively narrow range of jobs because of limitations of the type described above and/or because of some physical limitations; or can initiate, plan, execute and assume many but not all

responsibilities associated with homemaking; or can understand and carry out many but not all school assignments.

2 SHELTERED WORKSHOP, NON-COMPETITIVE: cannot compete successfully in job market because of limitations described above and/or because of moderate or severe physical limitations; or cannot without major assistance initiate, plan, execute and assume

responsibilities for homemaking; or cannot understand and carry out even relatively simple school assignments without assistance.

3 NOT EMPLOYABLE: completely unemployable because of extreme psychosocial limitations of the type described above; or completely unable to initiate, plan, execute and assume any responsibilities associated with homemaking; or cannot understand or carry out any school assignments.

Add eight ratings to obtain total DRS score.

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Supplementary Figure S8. Coma Recovery Scale- Revised Record Form.

Record Form

ADM 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

AUDITORY FUNCTION SCALE 4 - Consistent Movement to Command * 3 - Reproducible Movement to Command * 2 - Localization to Sound

1 - Auditory Startle 0 - None

VISUAL FUNCTION SCALE 5 - Object Recognition *

4 - Object Localization: Reaching *

3 - Visual Pursuit *

2 - Fixation *

1 - Visual Startle 0 - None

MOTOR FUNCTION SCALE 6 - Functional Object Use ^t 5 - Automatic Motor Response *

4 - Object Manipulation *

3 - Localization to Noxious Stimulation *

2 - Flexion Withdrawal 1 - Abnormal Posturing 0 - None/Flaccid

OROMOTOR/VERBAL FUNCTION SCALE 3 - Intelligible Verbalization *

2 - Vocalization/Oral Movement 1 - Oral Reflexive Movement 0 - None

COMMUNICATION SCALE 2 - Functional: Accurate ^t

1 - Non-Functional: Intentional *

0 - None

AROUSAL SCALE 3 - Attention

2 - Eye Opening w/o Stimulation 1 - Eye Opening with Stimulation 0 - Unarousable

TOTAL SCORE

Denotes emergence from MCS^t Denotes MCS *

JFK COMA RECOVERY SCALE - REVISED

This form should only be used in association with the "CRS-R Guidelines for Administration and Scoring"

which provide instructions for standardized administration of the scale.

Date

Date of Admission:

Diagnosis: Etiology:

Week Patient:

Date of Onset:

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Acknowledgements Investigators and Other Study Personnel

Site principal investgators were as follows: J. Giacino (JFK Johnson Rehabilitation Institute), S. Cho (MossRehab Hospital), S. Yablon (Methodist Rehabilitation Center), N. Childs (Texas NeuroRehab Center), D. Katz (Braintree Rehabilitation Hospital), D. Long (Bryn Mawr Rehab Hospital), B. Eifert (SRH Fachkrankenhaus Neresheim), P. Novak (Sunnyview Rehabilitation Hospital), F. Hammond (Carolinas Rehabilitation), M. Luther (Schoen Klinik Bad Aibling), A. Nordenbo (Copenhagen University Hospital) and E. Bagiella (Columbia University).

National Institute on Disability and Rehabilitation Project Officers: R. Brannon, L. Caplan; Project Directors: J. Giacino (JFK Johnson Rehabilitation Institute), J. Whyte (MossRehab Hospital), E. Bagiella (Columbia University); Clinical Monitor: K. Kalmar (JFK Johnson Rehabilitation Institute); Dissemination Coordinators: M. Sherer, M. Vaccaro; Statisticians- E. Bagiella, H. Chang; Data Safety Monitoring Board:

W. Lux (Chair, Walter Reed Army Medical Center), A. Sherwood (Secretary, NIDRR), C. Boake (TIRR), D.

Cifu (Veterans Health Administration), E. Elovic (University of Utah), D. Lezotte (University of Colorado- Denver); Co-Investigators, Data Collectors: JFK Johnson Rehabilitation Institute: S. Fynan, H. Platt, B.

Fritz; MossRehab Hospital: S. Cohen, M. Vaccaro, C. Ellis; Bryn Mawr Rehab Hospital: B. Merges, E.

Murphy, R. Plumari; Braintree Rehabilitation Hospital: Meg Polyak, Rebecca Brown, Daniel Coughlan;

Texas NeuroRehab Center: Walt Mercer; Methodist Rehabilitation Center: R. Nakase-Richardson, A.

Sepehri; Sunnyview Rehabilitation Hospital: Laura Wright, Sue Van Wie; Fachkrankenhaus Neresheim:

Petra Maurer-Karratup; Schoen Klinik Bad Aibling: F. Mueller, C. Krewer, C. Sikorski, J. Sageder;

Copenhagen University Hospital: M. Eskildsen; Carolinas Rehabilitation: Marybeth Whitney; Central Neuroradiologist- N. Eshkar (JFK Johnson Rehabilitation Institute); Central Pharmacy Coordinator: R.

Lupo (Wedgewood Pharmacy).

Special thanks to our patients and their families for helping us to develop a greater understanding of the scope and depth of the human spirit.