Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 2 3 BAMCIWHMC PROTOCOL FOR CLINICAL INVESTIGATION - EXPEDITED 1.0 Title: A Comparative Study: ImPACT MIL versus ANAM4TM TBI MIL for Acute Concussion 2.0 Principal Investigator (PI): r(b)(6) f(b)(6) 4 5 6 iPh.D., (Clini cal Neuropswhol agist 7 1 8 9 10 II 12 13 14 15 2.1 Associate Investigators (AI): ~~~;_ _ _ _--"!PLhl!..A.1D~AB~PuPLll{C..L!lcUinil.Cic"",au...I.....,N,-"e""uro""o"'-'svu.cCl.!h""'oJ"""o:-.Q;i""st""-,) ..... I 16 17 18 19 20 21 22 23 ~)m ~ Ph.D. (Clinical Neurop.~ychologistlMedical Psychologist) 24 25 26 27 28 29 30 31 [--------' l(b)(6) I Ph.D., MAl (Clinical Neuropsychologist)Chief, Neuropsychology Service I l(b)(6) I 32 33 34 35 36 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 2 37 38 39 (b)(6f~~~ (b)(6) - - - - 40 41 42 43 44 45 (b)(6) 46 47 48 49 50 51 52 53 54 (b)(6) [u>x6) IPh.D. (Clinical Neuropsychologist) 55 56 57 58 59 ,-~._ _ _ ~ . .~_--,MD, MSM, FACEP Colonel, Medical Corps, US Arm---'y'--_ _ _ _ _ _-. 60 61 62 63 I ~~(6)_???_ _ 64 65 66 67 68 69 !(Clinical Psychologist) 70 71 72 MS 73 74 75 76 77 (b)(6) l - - - - - - - - ' (Rehabilitation Psychologist) ' Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 78 79 3 80 81 82 83 84 85 3.0 Locations: Brooke Army Medical Center 3851 Roger Brooke Drive Fort Sam Houston, TX 78234 Carl R. Darnall Army Medical Center 36000 Darnall Loop Fort Hood, TX 76544-4752 LandstuhI Army Medical Center Bldg 3703 LandstuhllKirchberg 66849 TripIer Army Medical Center 1 Jarrett White Road Honolulu, HI 96859 Martin Army Community Hospital 7950 Martin Loop Fort Benning, GA 31905-5637 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 4.0 Research :Plan 4.1 Purpose: The study's purpose is to evaluate the differences in clinical utility and effectiveness between the Automated Neuropsychological Assessment Metrics 4th edition Military Version (ANAM 4 TBI MIL) and the Immediate Post-Concussion Assessment and Cognitive Testing Military Version (ImP ACT MIL), which are both designed to determine the effect of mild traumatic brain injury (mTBI) on neurocognitive functioning. Since a decreased ability to maintain balance is also a characteristic ofmTBl, the Unipedal Stance Test (UPST) will be given as a measure of potential neurological impairment, and compared to the traditional neurocognitive tests. Another proposed indicator of the presence of brain injury after mild head 108 109 110 III 112 113 114 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version # 10, 6 March 2012 4 ll5 116 trauma is a quantitative electroencephalogy (QEEG), which will be also given as an additional measure using a portable EEG monitoring device, the AHEAD M-I00. 117 118 4.2 Hypotheses/Research Questions: 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 A. To what extent do individuals diagnosed with mTBI differ from otherwise healthy, non- injured individuals on the ANAM4 TBI MIL and ImPACT MIL? B. Does either neurocognitive assessment battery demonstrate significantly greater sensitivity and specificity for an acute concussion in a military sample? C. To what extent do individuals diagnosed with mTBI differ from otherwise healthy, non- injured individuals on the Ahead M-lOO device using the manufacturer's proprietary interpretive algorithms? D. Does the use of the Ahead M-IOO demonstrate significantly greater sensitivity and specificity for an acute concussion in a military sample when compared to traditional neurocognitive measures? 4.3 Significance: Mild TBI can be found in both the civilian and military environments. Common causes of TBI, both civilian and military, include falls, motor vehicle accidents, striking or being thrown against an object, and assault. According to existing data, more than l.5 million people experience a traumatic brain injury (TBI) each year in the United States. These injuries have been identified as possibly causing long-term or permanent impairments. In addition to the growing population of the injured, mTBI costs the nation nearly $17 billion each year in funding (Binder, 2003). Accurate neurocognitive assessment calculated by a valid, sensitive, specific, computerized instrument would greatly assist in the medical care of concussed patients. A rapid test that shows strong validity and utility will provide the capacity for assessment in remote locations that lack neuropsychological services. 4.4 Military Relevance: 145 146 147 148 The army is currently using two different computerized neurocognitive batteries for measuring concussion: ANAM4 and INIPACT. Both tests have their advocates and detractors, but there is no data as to which is superior for this purpose. This study will allow the Army to best serve its service members by selecting the superior instrument for wider fielding and use. Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 149 150 151 152 153 154 155 156 5 157 158 Management of acute concussion is a significant problem for the military today. As an alternative to traditional neuropsychological testing, which can only be conducted by a licensed clinical neuropsychologist, automated (computerized) neurocognitive testing has been proposed for the assessment of cognitive impairment in individuals who are suspected to have mTBI/concussion. It is known that mTBI often does not present with apparent visible symptoms, and the symptoms may also overlap with other diagnoses; therefore, the most effective test needs to be chosen to aid in the detection and treatment of mTBI. Additional benefits would include the means to monitor the injured soldier's status, treatment progress, and return-to-duty potential. The study seeks to establish which of the tests currently in use by the military has the strongest validity and utility for soldiers suffering from mild traumatic brain injury (TBI) is considered the Table 1. Common Symptoms of Traumatic Brain Injury Gcner:ll Sym toms of TBI Head.u:hes DiHintiry organizing daily tasks fvletltal ,~onfusion (easilv confused, e;lSily feeling ovenvh':lmed) iJgluheldnt"ss or dizzy fI.?lore sensicivt:' to auditon? srjm\lll, lighr5 1 or other diHr;Ktions Beh.ayior or mood change5 {feeling sad. anxious, Of listless) Sym toms of l\1oderare ( 0 Severe TB[ L;.ss of o:msciousne...;;s 00 minutes or more) Lo.~s of Cl.1<..'l\.1iuarion Weakness or lHU11bness in rhe e:(tl-enliries Slurred speech Dilation of one or both pupil> bLun'od vision. or Inability to awaken Rid. !::.lSre in The mouth Enigue or krharb"Y (fedillg tired all or nausea A sevet"C, pC'l'?isrenc, 01' worsening headache ofthe time) A change in slee , patterns Trouble WITh men1.011~, c.oncenrrarion, 01' I..:"kulations Ea.sily in:iH1.r("1..1 or .illlge red -;-_ _ _-/-_ _ _ _ _ _ _ _ _ _ _ _ _ _ __ ImpllhillhT (bek of lnhibidoll,l Slowed movement, mJkillg, l'e.ldIng. or rhinking Sexual dyshll1<;:tion 159 160 161 162 163 164 165 signature wound of the current conflicts (Okie, 2005; Keltner, 2007). As of September 30,2007 the Pentagon listed 4471 TBI diagnoses from OEF and OIF. However, the founder of the Congressional Brain Injury Task Force, estimates more than 150,000 instances ofTBI have occurred among approximately 1.5 million OEF/OIF participants (Zoroya, 2007). The discrepancy may be due to the idea that an estimated 80% ofTBls are mild (mTBI); a condition that is not readily apparent (Heegaard, 2007). Most mTBI patients make a rapid recovery, suffer few post-injury complications, and, for these reasons, often bypass acute medical attention or Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version # 10,6 March 2012 6 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 hospitalization. Nevertheless, between three to five percent of mTBI patients develop chronic symptoms, and delayed symptom onset is not uncommon (McCrea, 2008). In OEF and OIF, the most common sources ofTBI are explosives and blasts (Keltner 2007; DePalma, 2005; Finkel, 2006; and Warden 2006). Traumatic brain injury accounts for approximately 60% of war injuries caused by blasts (Keltner, 2005). The severity of the TBI depends on the magnitude of symptoms that result from the injury, and outcomes can range from a complete recovery to permanent disability or death (Rao, 2000; Heegaard, 2007; Moppett, 2007). When blasts and other mechanisms of injury that result in loss of consciousness produce a TBI, the injury may be defined as mild (:s 30 minutes) (American Congress of Rehabilitation Medicine definition). Also accompanying TBI may be anterograde memory loss or post- traumatic amnesia, as well as difficulty encoding new information following the injury. Not all TBI victims suffer from loss of consciousness or amnesia. Those with more mild exposure to trauma may become dazed and confused, characterized by difficulties with orientation, perception, concentration, memory encoding and retrieval, and judgment. Further complicating recovery from mTBI is an assemblage of cognitive, physical, and emotional symptoms that can occur following mTBI, termed post-concussive syndrome (Bazarian, 2001; Lishmann, 1988; Vanderploeg 2007). Patients with post-concussive syndrome may complain of headaches, postural imbalance, insomnia, memory problems, fatigue, irritable or depressed mood, or interpersonal conflict (Lew, 2006; Vanderploeg, 2005). This syndrome is challenging to diagnose using a detailed physical exam or neuroimaging alone. It is often the case, unfortunately, that misattributions of underlying psychopathology prevent post-concussive syndrome patients from receiving appropriate care. To date, studies which have attempted to detect the effects of mTBI in a population have produced only modest results. The natural course of concussion is to heal with few if any residual symptoms, (Wyman, 2008). Further, as also pointed out by Wyman, the current classification system for concussion is based upon the criteria of Kay and Associates (1993) which allows the diagnosis of mTBI with only a transient alteration of consciousness-easily non-neurologic in etiology-and thus the vast maj ority of mTBI subjects have suffered no unconsciousness nor loss of memory. Ifthere is a common group neuropsychological correlate in such a popUlation, it is likely transient and needs to be acutely measured in recent concussion. Despite the prevalence of wartime mTBI, the chronological stages in improvement of related sequelae are poorly understood. Due to the complexity of injury, there has been a recent surge of research to improve techniques for early detection and assessment. Clinicians and researchers have begun to recognize the utility of computerized testing for assessing neurological insult (i.e., mTBI; Register-Mihalik, Guskiewicz, Mann & Shields, 2007). There remains a paucity of evidence that computerized testing immediately following possible brain injury from blast exposure or alternative sources is beneficial. A study conducted by McCrea et al. 2005, reported increased sensitivity to acute concussion when comparing Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 7 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 neuropsychological testing to a brief battery consisting ofa graded symptoms checklist (GSC), standardized assessment of concussion (SAC), and Balance Error Scoring System (BESS). The BESS has been studied for over 10 years (Broglio 2009) and has become a standard test for assessing concussion in high school and college athletes. They demonstrated the relative sensitivity of neurocognitive testing increased by five percent two days following concussion and by fourteen to thirty percent seven days following a concussion. They noted, however, that the increased sensitivity at seven days post-mTBI rate must be balanced against the false-positive rate of nine percent identified in the normal control group. A small but clinically significant percentage of injured athletes who reported being symptom free by day two continued to be classified as impaired on the basis of objective balance (the Balance Error Scoring System (BESS>> and computerized neurocognitive testing. These data suggest that neuropsychological testing may be of incremental utility to subjective symptom checklists in identifying the residual effects of sport-related concussion. The implementation of neuropsychological testing to detect subtle cognitive impairment is most useful once post concussive symptoms have resolved. This management model is also supported by practical and other methodological considerations (McCrea, 2008), In the past, self reported symptom checklists were a significant tool used to evaluate sports- related concussions, but the lack of objective data made it difficult to properly assess those with concussions in the sports arena (Oliaro, 2001). The 2005 study by McCrea et al. indicated that objective balance was clinically significant even when there were no self-reported symptoms in a post-concussion group. The BESS is a modified version of the Romberg test and can be administered in less than 10 minutes. It is conducted under six stance conditions: a double-leg stance, single-leg stance, and heel-to-toe tandem stance - each on a firm surface, then on a flexible foam surface (Broglio, 2009). The subject is tested with their eyes open as well as eyes closed. During the trial, the number of errors an athlete makes is counted, with the higher number of errors representing suppressed balance, If there is an increase of three or more errors above the baseline this may represent a significant change indicative of a balance impairment (Valovish-McLeod, 2006) with a sensitivity to concussion reported at 34% and specificity at 91% (McCrea, 2005). The BESS has been demonstrated to be both reliable and valid for sports-related concussions (Guskiewicz et aI., 200]; Riemann et at, 1999; Riemann & Guskiewicz, 2000). The BESS is recommended for use with military personnel (Iverson, 2008). However, the BESS has often been noted as having poor inter-rater reliability. While the stances of the BESS are simple, often there is an issue with administrators' subjective evaluation of the test. One rater will count a fault while another rater watching the same subject would not. Thus this difference can result in a decrease in test reliability. Per Springer, Marin, Cyhan, Roberts, and Norman (2007), being able to remove the subjective portions of the test and reduce the number of stances conducted should result in a test with great reliability and validity, If the necessary clinical information can be gathered in a shorter period of time using two stances completed twice rather than three stances completed twice (on two different surfaces), that test may have greater clinical Template Revised 13 April 09 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion 8 Version if 10,6 March 2012 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 application than the BESS when assessing for mTBI. The Unipedal Stance Test (UPST) is described as a method of quantifying static balance ability (Newton, 1989). In this test the subj ect stands barefoot, both on a hard surface and again of a foam surface, on the leg of their choice, with the other leg raised near, but not touching, the ankle of their supporting limb. The subject is asked to focus on a spot on the wall at eye level in front of them and to cross their arms over their chest. They are to hold this stance as long as possible or up to 45 seconds (Springer et al., 2007). The measure is then repeated with the patient's eyes closed. Each session is completed three times and is timed. The timing of the session is stopped if any of the following occur: the non-stance foot touches the floor, the arms are uncrossed, the stance foot shifts, participants open their eyes during the eyes closed test, or they reach the maximum time of 4S seconds. Two computerized, neuropsychological tests, the Immediate Post-concussion Assessment and Cognitive Testing (ImP ACT) and the Automated Neuropsychiatric Assessment Metric (ANAM) are currently being administered to active duty military personnel to assess for mTBI. However, there has been little research supporting the efficacy or accuracy of either test. Therefore, the best method for assessing mTBI has yet to be established. The most efficacious approach to addressing uncertainty surrounding the validity and clinical utility of the ImP ACT and the ANAM is to systematically conduct research comparing the two tests, which will indicate the assessment that can offer the most accurate measurements of mTBI. Currently there is a dearth of data in the scientific literature on the computer-based neurocognitive/neuropsychological test batteries and their use with active duty military personnel. According to Lovell (2001), the ImPACT 2.0 was designed to objectively measure visual and verbal memory, working memory, processing speed, visual motor skills, and reaction time to assist in the diagnosis and tracking recovery of the concussed individual. The test was developed at the University of Pittsburgh Medical School and has been widely used with high school and college athletes following sports related concussions. Lovell (2001) noted that the short administration time of20 minutes as it relates to sports injuries relies on two administrations; one pre-season (baseline) and one post-injury, in order to measure cognitive deficits post-concussion. Research indicated one of the key attributes of the ImPACT was its ability to accurately identify cognitive data and post- concussive symptoms following an injury, as well as playa key role in determining whether the concussed individual is fit for play return to work, or requires additional evaluation or services. The military is currently using ImP ACT MIL, which consists often cognitive tasks (subjective profile and health history questionnaire, current symptoms, injury description and conditions, and six neuropsychological tests (word discrimination, design memory, Xs and Os, symbol matching, color match, and three letters). The ImP ACT MIL is currently being used to aid in the detection, diagnosis, and treatment of Special Forces soldiers with mTBI. It can be administered individual1y or in a group setting, thus making its administration to large groups easier than traditional paper and pencil neuropsychological tests. In terms of sensitivity of specificity, Schatz et al. (2005) found that among high school athletes suffering from a concussion; the ImP ACT was successful at identifying 85.5 % of the Template Revised 13 April 09 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version # 10, 6 March 2012 9 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 cases as either concussed or non-concussed. Visual memory, reaction time, and processing speed subtest composite scores were found to be very sensitive to detecting mild concussion in high- school athletes. Sensitivity was reported at 81.9% and specificity at 89.4 %. A study by Van Kampen et al. (2006) supported the idea that objective neuropsychological tests may be more consistent than that of a measure of self-reported symptoms. According to Aubry et aL (2001), the risk of false negatives is higher when only paper and pencil neurocognitive measures are used due to the test's susceptibility to practice and learning effects. ANAM is the culmination of a long line of computer-based test systems developed by the Department of Defense and evolved principally from the Unified Tri-Service Cognitive Performance Assessment Battery (UTC-PAB; Englund, Reeves, et aI., 1987). According to Reeves et al. (2007), the AN AM was specifically designed to meet the needs of researchers and clinicians assessing neuropsychological function in long-term (6-12 months), short-term (daily to weekly), and within session repeated measures assessment. After the Center for the Study of Human Operator Performance (C-SHOP) based at the University of Oklahoma received the exclusive license for ANAM, researchers and staff at the center surveyed ANAM users, initiated a quality assurance assessment of the existing ANAM software, and then set about making improvements and innovations in order to produce an enhanced suite of ANAM software products that would provide greater uniformity, capability, and usability, C-SHOP released an improved version of the ANAM test modules (version 4.0 or ANAM4TM) in the Fall of2006. The ANAM4TM TBI MIL Battery is the current version being used by the military today. C-SHOP says the ANAM4TM TBI MIL Battery provides "precise, objective, automated measures of fundamental neurocognitive functions including response speed, attention/concentration, immediate and delayed memory, spatial processing, and decision processing speed and efficiency" (Helmick, et a1., 2006). These qualities of the ANAM4TM TBI MIL Battery are consistent with past applications of computer-based testing of TBI, with normative work conducted by DVBIC, and with the Clinical Practice Guidelines and Recommendations published by the Defense and Veterans Brain Injury Center Working Group on the Acute Management of Mild Traumatic Brain Injury in Military Operational Settings (Helmick, et aI, 2006). Levinson and Reeves (1997) conducted a study in which a battery of ANAM tests was able to correctly classify brain-injured patients with 91 % accuracy, a better level of accuracy than alternative neuropsychological tests or staff ratings. A review of recent studies involving ANAM by Cernich, et al. (2007) focused on the sensitivity and specificity of the ANAM. Bleiberg and Warden (2002) showed that none of the control subjects they tested showed a reliable decline on more than one ANAM test in comparison to all the injured subjects. Additionally, the Mathematical Processing test showed the greatest specificity for concussive injury. It was also noted by Bleiberg and Warden (2002) that the percentage of concussed subjects who failed to demonstrate practice effects was much greater in comparison to that of the control subjects. 311 312 313 J 14 315 316 317 318 319 320 321 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version 10,6 March 2012 10 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 Recently, portable, user-friendly EEG devices have been used in the detection and tracking ofmTBI following sports-related concussions. The McCrea et al. 2010 study-using QEEG to track mTBI recovery in a cohort of28 athletes-found QEEG results showed a typical course of recovery following concussion. However, the study also said QEEG findings "suggest that the duration of physiological recovery after concussion may take longer than observed clinical recovery." Naunheim et al. 2010 found the use ofQEEG in a TBI-positive population to have 92.45% sensitivity and 90% specificity when compared to a CT for TBI, thus adding to the validity ofQEEG as a sensitive index of brain function. 4.4.1 BrainScope QEEG Background Information The BrainScope Ahead M-l 00 is a QEEG device indicated for use to aid in the triage of patients who are suspected of a traumatically induced structural brain injury and/or clinical maniffestions of functional brain injury, as a result of an insult to the head from an external force. BrainScope has spent many years and millions of dollars developing a medical device to address the unmet need for detecting the level of structural injury and functional impairment from TBI in an acute setting. The Ahead M-I 00 uses a sophisticated mathematical algorithms to collect and obtain an output that has clinical utility for the Military, Emergency Medicine and Sports Medicine. It has been specifically designed to accommodate current military environmental needs including digital signal processing and immunity to external noise interference. The Ahead M-I 00 device is a single-use, proprietary headset containing pre-gelled electrodes will be placed on the subject's forehead and earlobes according to the standard locations of the modified International 10/20 system, including: FPI, FP2, AFZ, F7, F8, left and right earlobes and a ground at FPZ. The forehead will be cleaned with a mild abrasive sponge used as standard practice to improve contact of the headset with the skin. All electrode impedances will be below lOll prior to the start of the recording. Subjects will undergo approximately 5 minutes of eyes closed EEG recording. At the end of 5 minutes, if the device has acquired 48 epochs (each 2.5 seconds) of artifact-free data, the embedded algorithms will process the stored data to obtain the classification result. If 48 epochs were not recorded in 5 minutes, the device will continue recording for an additional 5 minutes. In no instance will the algorithm use fewer than 24 epochs of artifact-free data to calculate the BrainScope Classification Output. The Ahead M-lOO utilizes a combination of three classification algorithms that enable discrimination among 4 patient groups. These classification algorithms are combined in a sequential fashion that maximizes accuracy (sensitivity and specificity) of classification. The sequence of the classifiers to determine the Ahead M-I 00 Classification in which a patient belongs is as follows: [1] The first classifier discriminates between patients in Group 4 and all other Groups combined (all "non-4"). For a patient identified as a "4", the classification process is over and the results are displayed; if not classified as a 4, then [2] a second classifier is used to discriminate patients in Group 1 from the balance of the patients (2, 3, or 4). For a patient Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 11 361 362 363 364 365 identified as a "1", the classification process is complete; ifnot classified as a "1", then [3] a third classifier is used to discriminate patients in Groups "2" and "3". This sequence separates the patients into the 4 classifications uniquely. Potential Physician Interpretation ofDevice Output Device Output Potential Output Interpretation o Structural brain injury (positive CT finding) Potential Physician Interpretation o Obtain a head CT rapidly o Transfer to higher level of care if CT is unavailable. o Do not release the patient o Non-structural brain ' injury and more severe clinical manifestations of functional injury o May require further evaluation o Hold for close, medical observation o Clinician may decide to obtain CT based on other assessment factors (History of event, LOC, PTA, symptoms, etc.) Patient may be released if consistent with other assessments (neurological exam, symptoms, etc). Re-evaluation should be scheduled. o 1 o Normal or patients without head InJunes o Normal patient, may be released if other assessments are normal. 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Mild traumatic Brain Injury and Postconcussion Syndrome. New York, NY: Oxford University Press. McCrea, M., Prichep, L. et al. (2010). Acute Effects and Recovery After Sport-Related Concussion: A Neurocognitive and Quantitative Brain Electrical Activity Study. Journal ofHead Trauma Rehbilitation,25(4), 283-292 Moppett, LK., (2007), Traumatic Brain Injury: Assessment, Resuscitation and Early Management. British Journal ofAnesthesia, 99 (1), 18-31. Naunheim, R. et al. (2010). Use ofBrain Electrical Activity to Quantify Traumatic Brain Injury in the Emergency Department. Brain Injury (Early Online), Online publication date, July 5,2010. Newton R. (1989). Review of Tests of Standing Balance Abilities. Brain Injury, 3,335 - 343. Okie S. (2005). Traumatic Brain Injury in the War Zone. The New England Journal ofMedicine, 6, 633- 634. Oliaro, S., Anderson S., & Hooker D. (2001). Management of Cerebral Concussion in Sports: the Athletic Trainer's Perspective. Journal qfAthletic Training, 36(3), 257 - 262. 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 14 Randolph e., McCrea M., & Barr WE. (2005). Is Neuropsychological Testing Useful in the Management of Sport-Related Concussion? Journal ofAthletic Training, 41(2), 13 7 152. Riemann B.L., & Guskiewicz KM. (2000). Effects of Mild Head Injury on Postural Stability as Measured Through Clinical Balance Testing. Journal ofAthletic Training, 35(1), 19 -25. Schatz P., Pardini lE., Lovell M.R, Collins M.W., & Podell K (2006) Sensitivity and Specificity of the ImPACT Test Battery for Concussion in Athletes. Archives Clinical Neuropsychology, 21(1), 91 - 99. Springer B.A., Marin E., Cyhan T., Roberts R,& Grill N. W., (2007) Normative Values for the Unipedal Stance Test with Eyes Open and Closed. Journal ofGeriatric Physical Therapy, 30(1), 8 15. Valovich-McLeod T.e., Barr W.B., McCrea M., & Guskiewicz KM.(2006) Psychometric and Measurement Properties of Concussion Assessment Tools in Youth Sports. Journal of Athletic Trainers, 41(4),399 408. Vanderplorg RD., Belanger H.G., Duchnick lD., & Curtiss G. (2007). Awareness Problems Following Moderate to Sever Traumatic Brain Injury: Prevalence, Assessment Methods and Injury Correlates. Journal ofRehabilitation Research and Development, 44, 937 - 950. Vanderplorg RD., Curtiss G., & Belanger H.G. (2005). Long-Term Neuropsychological Outcomes Following Mild Traumatic Brain Injury. Journal ofthe International Neuropsychological SOCiety, 11(3),228 - 236. Van Kampen D.A, Lovell M.R, Pardini lE., Collins M.W., & Fu F.R (2006) The "Value Added" ofNeurocognitive Testing After Sports-Related Concussion. The American Journal of5/Jorts Medicine, 34 (10), 1630 - 1635. Warden D. (2006). Military TBI During the Iraq and Afghanistan Wars. Journal ofHead Trauma Rehabilitation, 21, 398 - 402. Wilken J.A, Sullivan C.L., LeSwandowski A, & Kane R.L., (2007). The Use of Automated Neuropsychological Assessment Metrics to Assess the Side-Effect Profiles and Efficacy of Medication. Archives ofNeuropsychology 22, 127 - 133. Wymer, lH., (2008). Psychological and Neuropsychological Correlates of Post-ConcussionaI Disorder. Neuropsychological Trends, 3,45- 84. Zoroya G. Thousands ofTBI Cases Off the Record. USA Today. Publication date: Nov. 29, 2007. 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 4.6 Research Design and Methods: SUMMARY: The study consists oftwo arms. Each arm will be given the same set of automated neurocognitive test batteries. The participants will be as follows: 100 cases of acute concussion, which will be tested using the ANAl\14(TM) TBI MIL, ImPACT MIL, AHEAD M-IOO and the Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version # 10, 6 March 2012 15 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 UPST. A sample of200 normal healthy soldiers will be given the ANAM4TM TBI MIL, ImPACT MIL, AHEAD M - 100 and UPST. Controls are necessary to establish the use of the ANAM4TM TBI MIL and the ImPACT MIL on normal healthy active duty military controls. The order in which the tests are administered will be changed so that half of the concussed and control group participants take the ANAM4TM TBI MIL first and then the ImP ACT MIL while the other half will take the ImPACT MIL first and then the ANAM4TM TBI MIL, thus allowing for a counterbalance of any possible order effect, carryover, or fatigue. The effects of carryover or fatigue is unknown at this time. The test manufactures believe it would be minimal, however, this is an important variable to determine. Between the two test administrations participants will be given a brief break before beginning their second test battery. At some point during test administration a short known as AHEAD M - 100, will be given. The AHEAD M-I 00 device is a handheld portable EEG (brain electrical signals) monitor. The monitor involves the use of a non-invasive adhesive headset to collect the data in a very similar way to the ECG monitor for the heart. The device performs some initial processing of the EEG signal giving each patient a score from one to four which reflects their clinical risk. Study personnel will be blinded to the clinical data. The results of testing will not be shared with the clinicians involved in treatment decisions to be assured that treatment plans are not influenced. For purposes of the study, the BrainScope Classification result will not display at the conclusion of the test. The result will be stored on the device and electronically transferred to the study monitor for data analysis. This data will be used for study analysis, but not for clinical decision-making. During the break period the UPST will be administered and scored. All tests will be administered by staff trained in the administration of the ANAM4 TBI MIL, ImP ACT MIL, UPST, and AHEAD M - 100. SAMPLE SIZE: This study will use a target sample size of 100 acutely concussed cases and 200 active duty military controls, for a total study size of 300 participants with full data sets. The large sample size will provide sufficient power of .90 to detect between and with in-group effects. RECRUITMENTIELIGIBILITY: Participants in the concussion group will be recruited from the Emergency Department (ED) at each of the research locations: (SAMMC), (CRDAMC), (LRMC), , (MACH) and (TAMC), each site will define testing locations as necessary. All participants will be age 18 - 55. All research investigators will work at the hospitals in question and will have appropriate staff identification and access. Participants with a diagnosis ofmTBI will be contacted and tested within 72 hours of the concussion event. Participants may be recruited from the ED and tested on site or may have an appointment scheduled for testing within 72 hours post-concussion. Recruitment from the ED will include participation from the ED staff to aid in identifying those with possible concussion. The ED staffwill be informed about the study and referral information will be given to the staff Also a member of the study team will be placed in the ED Template Revised 13 April 09 510 51 I 512 513 514 515 516 517 518 519 520 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion 16 Version #10, 6 March 2012 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 and will recruit from there when appropriate for them to do so without interrupting the ongoing functions of the ED. If a member of the study team is not at the ED at time of discharge the concussed person will be given the research assistances contact information and asked to contact them as soon as possible pertaining to the study. No patient HIP AA information will provided to the research staff by the ED staff. The ED staffwill act to identify possible participants and initial study contact will be made either using a study recruitment flyer or by study staff located in the ED at the time. Study recruitment for controls will be conducted at the SRP site in a group setting prior to the administration of the ANAM. Service members are tested in groups of25 - 50 depending on the size of the testing location. Prior to testing, testing instructions are given to group members in a class like setting. Recruitment of potential control group members will be conducted at that time. Recruitment efforts will be brief consisting of a non-military civilian research assistant giving a brief (less than 5 minutes) speech to the group asking for participants (see appendix). Participants who choose to participate in the study will be asked to move into a separate designated testing area to continue with the consent, screening questionnaire and testing. INCLUSION CRITERIA: 1) TBI-positive group [mTBI). Individuals age 18 - 55 who have access to care at the medical treatment facilities used in the gathering of research, who report to a level II point of care for suspected concussionlmTBI, and who subsequently meet the DoD criteria for acute concussion as determined by gathered information set forth on page 1 of the MACE which has been incorporated into the screening questionnaire used for this study. Participants must be fluent in English. 2) Healthy military control group [HMC; no-TBI]. Military controls will consist of otherwise healthy soldiers, 18 55 years of age, and recruited from the Soldier Readiness Processing (SRP) site at Ft. Hood, Texas, and Schofield Barracks, Hawaii. These soldiers will be asked to participate in the study since they are already scheduled to take the ANAM4 TBI MIL as part of the SRP requirements. Participants must be fluent in English. EXCLUSION CRITERIA: 1) TBI-positive group [mTBI]. Individuals taking any mind-altering medication or reporting a level of pain >7 (10 point scale). 1fthe Principal Investigator determines that individuals with lower pain levels are unable to focus attention adequately on the neurocognitive assessment task, the exclusion criteria will be expanded with approval of the IRB. Individuals with disorders requiring any of the following medications will be excluded from the study, any anti-psychotic medications or Phenothiazane (e.g. Seroquel, Thorazine, Haldol, or Olanzapine). Anyone taking any kind of Benzodiazepines (e.g. Valium or Klonopin) will be excluded. Other exclusionary medication will include Benadryl or similar sedating antihistamines, stimulants such as Ritalin or other Template Revised 13 April 09 Protocol Title: A Comparative Study; ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 17 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 Amphetamines and mood stabilizers (e.g. Tegretol, Lithium, Topamax, Depakote, or Lamictal). Individuals who report the use of any mind altering substances within eight hours prior to testing will be excluded from participating. Female participants who are pregnant will also be excluded from the study. 2) Healthy military control group [HMC; no-TBI]. Individuals will be excluded from participation if they have a history of mild traumatic brain injury within 90 days, moderate brain injury within the past three years, or any lifetime history of severe brain injury. Individuals who are on any mind altering medication or report a level of pain >7 (10 point scale). If the Principal Investigator determines that individuals with lower pain levels are unable to focus attention adequately on the neurocognitive assessment task, the exclusion criteria will be expanded with approval of the IRB. Individuals who report the use of any mind altering substances within eight hours prior to testing will be excluded as will pregnant females. Use of certain medications will also result in exclusion from the study, including; any anti-psychotic medications or Phenothiazane (e.g. Seroquel, Thorazine, Haldol, or Olanzapine), Benzodiazepines (e.g. Valium or Klonopin), Benadryl or similar sedating antihistamines, stimulants such as Ritalin or other Amphetamines, and mood stabilizers (e.g. Tegretol, Lithium, Topamax, Depakote, or Lamictal). PROCEDURE: 1) TBI-positive group. Participants in the concussed group will be tested individually. They will either be tested at the Emergency Department (ED) or at an office near the ED following their discharge from the ED. Or if admitted for observation or other health issues, testing may be conducted in the participant's room at the hospital. If, for any reason, the participant is either unable to test at that time or does not feel comfortable testing in the ED, an appointment for testing within the 72 hour window after the concussion can be made. If testing cannot be completed within the 72 hour post- concussion window, the participant will be excluded from the study. Because the concussed subjects will be recruited from four different research sites, the order in which the tests are administered will be alternated for each participant at each location. Informed consent will be obtained prior to testing and participants will be given the opportunity to ask questions both before and after testing. Before any testing begins the completion of a screening questionnaire will be required and completed by the research staff in order to ensure the participant meets study criteria. Contact information for follow-up research and delivery of testing results is included within the informed consent. Participants will be contacted by phone one week (7 days) post-concussion and will be asked about their current post-concussion symptoms. This will include questions from page one of the screening questionnaire and should be less than 5 minutes in duration. 2) Both the ANAM4 TBI MIL and ImPACT MIL will be administered in accordance with the current guidelines used for administration by the military. The estimated testing time is approximately 60 minutes. The test battery will include the screening questionnaire (see appendix), which incorporates the same information as the first page of the Military Template Revised 13 April 09 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version # 10, 6 March 2012 18 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 Acute Concussion Evaluation (MACE), currently used to identify mTBI per DoD standards; the ANAM4 TBI MIL instructions and testing (25 minutes); the UPST instructions and testing (5 minutes); the ImPACT MIL instructions and testing (20 minutes) ; and the AHEAD M - 100 (10 minutes) will comprise the test battery for this study. 3) Healthy military control group. Participants in the control group will be active duty soldiers recruited from the Soldier Readiness Process (SRP) sites at Ft. Hood and Schofield Barracks. As part of their SRP soldiers are required to take the ANAM4TM TBI MIL. As per military standards the ANAM4TM TBI MIL will be administered in a group setting. Given that the soldiers are already taking one of the two tests being compared, they will be asked to volunteer to take the ImPACT MIL, AHEAD M 100 and UPST, which will add roughly 40 minutes to their overall testing time. For those who choose to participate they will complete the screening questionnaire in order to ensure those being tested meet the study criteria for inclusion and then the first 100 participants will take the tests in the following order: ANAM4 TBI MIL + ImP ACT MIL and the next 100 vice versa. Between each test administration a short break will be given. Before starting the second test the UPST will be administered and scored. The administration of AHEAD M - 100 will occur either before testing begins or following test completion. The order of test administration will be tracked by the test administrator on the questionnaire form provided in appendix A. Time frame: Data collection is expected to last 330 days from the start of the study once it is approved by the IRB. Test results reporting: Testing results will be reviewed by the PI with disposition to follow. Reports will be mailed out to participants if testing indicates any abnormalities. Participants may choose to include these reports as part of their medical records. The reports may also be used by medical care providers and may help in determining diagnosis and course of treatment for participants. 4.7 Number of Subjects: TOTAL NUMBER OF SUBJECTS (nation-wide/study-wide) 300 Subjects will be recruited until the number of concussed (mTBI) participants reaches 100 and the number of military control subjects reaches 200. The following power analysis was based on Aim #1 for the ANOVA model. Given the desire to maintain a 2: 1 ratio of control to mTBI participants, a power analysis was performed given the following parameters: level of significance of .05, power of .8, a conservative 2-sided test, and a medium effect size: Cohen's d = .5 (standardized effect size). Using the harmonic mean for deriving sample size (based on the desired 2: I ratio) as found in Cohen (1988): n' 2nA nB/(nA + nB) a power of .81 for a medium Template Revised l3 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version if I 0, 6 March 2012 637 638 639 640 641 642 643 644 645 646 19 effect size is achieved when 100 controls and 50 experimental subjects (n' = 66.67) are sampled; thus, a total sample size ofN = 150 will suffice if a medium effect size is attained. Initially it was proposed that 200 controls and 100 experimental subjects would be sampled (N 300); if this was to be the case, a power of .98 (n' = 133.33) would be obtained. Note that an approximate power of.8 for 200 control and 100 experimental subjects will be obtained if the effect size is .35 (which is a more conservative, albeit safer, effect size estimate). 5.0 Human Subject Protection 5.1 Source of Data: No additional data sources will be used at this time for this protocol. 5.2 Benefits: This is an important study. The study will help to ensure the clinical instruments that are currently being used to detect mTBI in the active duty army population are actually measuring what needs to be measured. This will make it possible to diagnose mTBI faster and more accurately, increasing the Army's ability to monitor the Soldier's status, recovery, and return-to- duty potential. Benefits to concussed subjects participating in the study will include optional documentation of their neurocognitive functioning within 72 hours of their concussion. Subjects can retain the documentation for their medical records. There is no direct benefit to those in the control group for their participation. 647 648 649 650 651 652 653 654 655 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 20 5.3 Risks: The PI of this protocol will use a continuous monitoring process to insure the data at participating sites is of high quality and the study is properly conducted. o Pre-Training: Each site will be visited by a training team comprised of PI verified experts on the tools and techniques of the study and train study personnel to criteria on proper data collection for the study prior to any data being collected. The local PI will, in all cases, be a licensed and credentialed independent health care provider known to be of good character and in good standing with their health care facility. The PI will visit each site early in the data collection process to insure proper procedures are being followed. All subject data will be returned to the primary coordinating center as collected, where they will be audited to insure that: o o 0 0 0 o o o Informed consent is properly signed Informed consent is properly witnessed All demographic information is properly completed All study information is properly collected and coded. If any record appears to have any irregularities, the subject will be contacted by the PI to insure they were properly consented, and the data was properly collected. Foreseeable Risks. Neuropsychological testing by its nature is non-invasive and involves no risk of physical harm for any participant. Since these are cognitively taxing exercises, however, individuals may become frustrated or unhappy if they are performing poorly. Examiners are trained in reassurance and encouragement to obtain the patient's best performance. The BrainScope AHEAD M-l 00 is a non-invasive, "non-significant risk" (NSR) device per FDA guidance entitled, "Significant Risk and Non-significant Risk Medical Device studies". A letter from BrainScope Company, Inc. is attached as appendix E to this protocol. In order to fully comply with the abbreviated IDE requirements for the AHEAD M-I00, the following requirements have been met: o The device is labled in accordance with the labeling provisions of the IDE regulation 812.5 - "CAUTION - Investigational Device. Limited by Federal law to investigational use." Template Revised 13 Apri1 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 21 688 689 690 691 692 o o o o o 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 Study PI will obtain and maintain IRB approval throughout the investigation as non- significant risk device study. Informed consent will be obtained from each participant in accordance to 21 CFR 50. Proper monitoring ofthe application and data collection of this device and compliance under the approved protocol will be maintained by AI's and research staff. Records and reports will be maintained as indicated in section 5.4 of this protocol At no time during this study will the AHEAD M-l 00 be commercialized, promoted, test marketed, misrepresented as anything other than an investigational device by the study AI, PIs or research staff It is recognized that the QEEG evaluation is noninvasive and uses passive sensors, so that no electrical current is put into the brain. In order to obtain good sensor connections, it is not unusual for the skin to require cleaning to remove oilss and dead skin cells. A cleansing sponge provided by the manufacturer will be used for this purpose. This may result in the risk of mild skin irritation (temporty reddening of the skin lasting only a few minutes) for some participants in tiny areas under the sensors creating the only foreseeable risk. The most significant foreseeable adverse outcome to the patient would result from triggering the Reporting Criteria mandated by UCMJ. The informed consent process makes clear, and this will be verbally instructed as well, that "there are limits to confidentiality in health care information, and we will be mandated to report serious crimes, such as war crimes, danger to self or others, or domestic abuse." Risk Management and Emergency Response. If the research participant becomes frustrated, they will be allowed to rest until they regain composure and feel they are able to give their best performance. If the research participant is deemed a danger to him or herself or others, appropriate emergency medical systems will be employed. All research will take place in a Health Care Facility of at least level II, and any medical crisis or emergency will engage this health care systems' response. Measurements taken to Minimize Risk. Testing will be paced with a programmed break period each hour. All testing will be done in a climate-controlled area, and participants will be allowed to get water between testing sets. Subjects can terminate testing at any time. Adverse Events Consideration of Adverse Events will hereafter consi st of Adverse Events and Adverse Device Effects, including anticipated adverse device effects and unanticipated adverse device effects. Adverse Event: Any untoward/undesirable clinical occurrence in a clinical investigation of a Subject using a device and/or product and which does not necessarily have a causal relationship with this Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 22 726 727 728 729 treatment. An Adverse Event can therefore be any unfavorable and/or unintended sign, symptom, or disease temporarily associated with the use of a device or product, whether or not it is considered related to the device product. Anticipated Adverse Procedure Effect: Any adverse effect related to the procedure (QEEG), which is identified in the protocol prior to study commencement. Unanticipated Adverse Procedure Effects: Any adverse effects on health or safety or any life threatening problem or death caused by, or associated with, a procedure, if that effect, problem, or death was not previously identified in nature, severity or degree of incidence in the protocol or application (including a supplementary plan or application) or any other unanticipated problem associated with a procedure that relates to the rights, safety or welfare of Subjects (see Appendix F - Reportable Event Submission Form - IRBO). All Adverse Events occurring during the study procedure (venipuncture) and immediately after (within 30 minutes), whether or not attributed to the venipuncture, observed by the PI/AI or reported by the Subject, will be recorded on the Adverse Event CRF. Safety Monitoring The PI/Als will monitor all Adverse Event reports to identify and trend all events that would require temporary discontinuation of study enrollment, to fully characterize device safety, to modify the study protocol, or to terminate the study. Reporting Procedures for All Adverse Events After review with the Subject by the study PI/AIs, all Adverse Events will be documented in the Subject's source document and on the appropriate Reportable Event Submission Form. The following attributes must be assigned: 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 o description of event date of onset date of resolution duration severity relationship to the study procedures actions taken outcomes attending physician treating event determination as to whether event is anticipated or unanticipated o o 757 758 759 o o o o o o o 760 761 762 763 764 765 If the Adverse Event is of such severity in the Investigator's judgment that it warrants withdrawal from the study, the Subject should be withdrawn and a termination assessment Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 766 767 768 769 770 771 772 23 performed (EOS CRFs completed). The Subject should be given appropriate care under medical supervision until symptoms resolve. Adverse Events are described as mild, moderate or severe. The severity of Adverse Events will be assessed on the following severity index scale: 773 774 775 776 777 778 779 780 781 782 783 784 Mild - The Adverse Event is transient, requires no treatment, and does not interfere with the study Subject's daily activity. o Moderate - The Adverse Event introduces a low level of inconvenience or concern to the Subject and may interfere with daily activities, but is usually ameliorated by simple therapeutic measures. o Severe - The Adverse Event interrupts the Subject's usual daily activity and requires systematic therapy or other treatment. Severe is defined as a measure of the intensity of a reaction, effect, or experience. The relationship of an Adverse Event to the study will be graded as follows: o 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 None - The Adverse Event is not associated with the study device use. Remote - The temporal association is such that the study device is not likely to have had an association with the observed Adverse Event. o Possible - This causal relationship is assigned when the Adverse Event: o Follows a reasonable temporal sequence from device use, but o Could have been produced by the study Subject's clinical state or other modes of therapy administered to the study Subject. o Probable - This causal relationship is assigned when the Adverse Event: o Follows a reasonable temporal sequence from device use, o Abates upon discontinuation of the treatment. o Cannot be reasonably explained by known characteristics of the Subject's clinical state. o Highly Probable - This causal relationship is assigned when the Adverse Event: o Follows a reasonable temporal sequence from device use, o Abates upon discontinuation ofthe treatment, and 0 Is confirmed by the reappearance of the Adverse Event on repeat exposure. All unanticipated problems involving risk to subjects or others, serious adverse events related to participating in the study, i and subject deat~s related to artici ation in the study should be promptly reported bv phone ( b ) ( 6 ) b y email (b)(6) or by facsimilei(b){6) to the USAMRMC Office of Research Protections, Human Research Protection Office (HRPO). A complete written report will follow the initial notification. In addition to the methods above, the complete report will be sent to the U.S. Army Medical Research and Materiel Command, ATTN: MCMR-ZB-PH, 504 Scott Street, Fort Detrick, Maryland 21702-5012. ! o o Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version it 10, 6 March 2012 24 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 Reports will be submitted to the BAMC IRB as well as the local IRB if occurring at different study collection point if the Adverse Events are related to the study design or procedures. Serious and Expected Adverse Events. Reportable Event Submission Forms (Appendix G) will be submitted to the HRPO with the Continuing Review. Deaths Deaths which must be reported to the Human Research Protection Office/Institutional Review Boards include: o All deaths while participating in the study. For all deaths, copies of available autopsy reports and relevant medical reports should be sent to the sponsor or its designee with Subject's name masked (except for the first initials of the first and last name). Withdrawals for Adverse Events All Adverse Events which result in the Subject's withdrawal from the study must be reported immediately by telephone or e-mail to USAMRMC.The Investigator may be asked to provide detailed follow-up information. The PIIAI will report to the appropriate regulatory authorities. The PliAIs must notify their own IRB of all Unanticipated Adverse Device Effects occurring at the site, and Unanticipated Adverse Events reports. Protocol Deviations Protocol deviations or violations that have occurred, have not been pre-approved by the HRPO, and which may adversely affect the rights, safety, or welfare of subjects, or the integrity of the research data will be recorded immediately on discovery by the PI!AIs. Unanticipated protocol problems will also be reported in this way, and include problems that pose a risk to subjects, affect others in the research study, or which significantly impact the integrity of the research data, such as breaches in confidentiality and losses or destruction of research or study samples. Any deviation from the protocol that may have an effect on the safety or rights of the Subject or the integrity of the study must be reported to the USAMRMC ORP HRPS as soon as the deviation is indentified. Reporting Unanticipated Problems Involving Risks To Subjects Or Others, Serious Adverse Events And Deaths To The HQ, USAMRMC IRS. 838 839 840 841 842 843 All unanticipated problems involving risk to Subjects or others. serious adverse events, and all Subject deaths will be promptly reportedbbv ohone!(b)(6) Ibye-mail ~b)(6)J by facsimilel( )(6) I to the HQ, USAMRMC IRB, or sent to the U.S. Army Medical Research and Materiel Command, ATTN: MCMR-RP, 504 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 25 Scott Street, Fort Detrick, Maryland 21702-5012. A complete written report will follow the initial notification. 5.4 Safeguards for Protecting Information: All of the data will be identified with a study participant number rather than the participant's name to maintain confidentiality. The master list will be maintained by the PI during the course of the study. All electronic data will be stored on a secure, password-protected computer. No computer used for storing data will be connected to the server at any time. All paper research records will be kept in a locked file prior to being transferred to a locked file and office at the Warrior Resiliency Program (WRP) BAMC. All electronic research records will be kept in a password-protected computer in the investigator's designated locked office at WRP. As the primary center for this study the staff at BAMC will be the collection point for all participating data collection sites. The electronic information will be sent to the staff located at the WRP, Lincoln Center location weekly for data processing and storage. Each site will save encrypted (Credent To Go) testing data to a CD and then upload that data to a limited access Army Knowledge Online folder for retrieval. After the information has been uploaded from the CD the CD will be destroyed. This information will be retained at WRP during the life of the protocol. Data confidentiality will be strictly protected. Only individuals immediately involved in the study will have access to files that include subject identifying information. The only exceptions to Confidentiality would be for legally mandated disclosures as verified by BAMC's Judge Advocate General, or modification to this protocol approved by the BAMC IRB. Group data will be summarized in final report documents, and aspects of individual volunteer's performance may be reported as well; however, participants' names will never be published as a contributor of specific data points or as a participant in the investigation. The data will be archived and may be used or included in subsequent studies for purposes which cannot be anticipated at the present time. All guarantees of anonymity and confidentiality will still apply. When the results of the study are printed or talked about in conferences, no information will be given out that would tell anyone whom the participants are. Records of participants taking part in this study may only be made public in accordance with federal law, including the Federal Privacy Act, 5 US.C. 552a, and its implementing regulations. DD Form 2005, Privacy Act Statement-Health Care Records, contains the Privacy Act Statement for the records. If participants sign this consent form, they give their permission for information that we get from their participation in this study to be printed in medical literature, discussed for teaching purposes, and used to further medical science. All information about participants will be given without identifying them. Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 26 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 5.5 Informed Consent: Informed consent will be collected prior to collection of data or testing. Each testing site will have either an Associate Investigator or research assistant on the protocol with appropriate CV and CITI training available to answer any questions regarding the study and who will be responsible for ensuring informed consent is appropriately obtained and properly recorded. The Informed Consent forms are different for the Concussion and Control groups they are attached in the appendices. Because this study is limited to individuals with mTBI only, it is not anticipated that the mental capacity of any volunteer will be severely compromised. If, however, an individual does not appear capable of giving informed consent for whatever reason they will not be included in the study. Mind-altering substances such as tranquilizers, conscious sedation, or anesthesia are exclusion criteria, and service members using those will not be allowed to participate. All subjects will be 18 - 55 years of age. Individuals will not be rushed into making the decision to participate and will be allowed to discuss any concerns in private. 6.0 Data Analysis: Study AimslEndpoints: This exploratory study will examine the sensitivity and specificity of three novel devices which are hypothesized to be useful in the diagnosis of concussion (mTBI). Patients with a known concussion (mTBI) meeting the DoD definition of concussion will be compared to matched soldiers with no recent concussion history. Each instrument provides a graded output: Normal/mild/severely abnormaL A multivariate approach will initially be pursued, incorporating all of the instruments simultaneously in the predictive model. This global approach will aid in ascertaining accuracy of classification between groups for each instrument, and as well take into account the extent of collinearity between the instruments. To test the given the dichotomous outcome (i.e., mTBI vs. control) a multiple binary logistic regression will be conducted. A logistic regression and may also incorporate the key predictors (e.g., QEEG) to determine not only the predictive power of each predictor (e.g., logit, odds ratio, etc.) but to also extract classification information on sensitivity (true positives) and specificity (true negative). The results of this analysis can also be used to conduct a receiver operating characteristic (ROC) analysis and a significance test for area under the curve (AUC). There are various ways by which to assess model fit in logistic regression (Hosmer & Lemeshow, 1989), those being as follows: 1) A chi-square test is conducted to see if the model is improved when the predictor are entered. If significance is obtained (a .OS) then the addition of the covariates indicates Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version HIO, 6 March 2012 919 920 921 922 923 924 925 926 27 model improvement over and beyond the origin only model (the difference in -2LL are used for the test statistic). 2) The Hosmer-Lemeshow goodness-of-fit test is used to ascertain how well the model fits the data. For this test, a non-significant result is desired. 3) The individuallogits (log ofthe odds) will be examined and tested for each predictor. Again, a level of significance of .05 will be the nominal level of significance for each covariate. Moreover, the odds ratio (OR) and the accompanying 95% confidence interval (CI) will be furnished for each variable. If the CI around the OR does not include 1.0, then significance is obtained. 4) Additionally, sensitivity (hit rate for true positives) and specificity (hit rate for true negatives) will also be computed for each of the logistic models; hence affording the opportunity to draw comparisons between the instruments (i.e., ANAM, IMP ACT). Any other variables germane to the test ofthe model, such as UPST and/or EEG will also be incorporated if deemed warranted. Moreover, in a reversal of the model, it may be of interest to conduct a multivariate analysis of variance (MANOVA) to see if the two treatment arms differ on the linear combination of the instruments. The role of post hoc analysis: it may be reasonably argued that membership in the category "normal control" does not guarantee lack of pathology in this group. All control members will fill out a TBI history questionnaire and symptom checklist. this data may be reanalyzed to factor in past history ofTBI and whether abnormal controls are truly a 'miss'. Further, it is possible members of the concussed group may have recovered from their concussion prior to testing. Participants will be evaluated based on the number of current symptoms for evidence of recovery. As a further extension for analyzing sensitivity and specificity (I - specificity will be on the x- axis), a Receiver Operating Characteristic (ROC) graphic will be furnished for each of the instruments shedding insight into the relationship of true and false positives. Moreover, another function of the ROC analysis is the possibility oflocating area under the curve (AUC) so as to detect optimal cut points. Additionally, though not a specific aim, so as to assess the extent of convergent validity (i.e., instruments measuring similar constructs should exhibit substantive correlations) a bivariate correlation will be computed for each of the instruments. Though there is no rigid cut-point as to what constitutes convergent validity (AERA, 1999), it is anticipated that correlations will be at least> .3 (i.e., 9% shared variance) which approximates a medium effect size per Cohen (1988) and will then provide preliminary evidence of convergent validity. Another exploratory approach that can be used to shed insight into classification, is finite mixture modeling. Akin to cluster analysis, in this case the group is an unknown quantity, but based on the model covariates (e.g., Template Revised 13 April 09 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version if 10, 6 March 2012 28 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 ANAM, IMPACT, QEEG, certain demographics or ancillary test scores) and their inter- correlation, classification based on maximizing homogeneity within groups and heterogeneity between groups can be exploited (McLachlan & Peel, 2000) and thus engender a closer examination of characteristics unique to these unknown classes. References AERA, APA, NCtvlE (1999). Standards for Educational and Psychological Testing. DC: AERA. (Standards) Cohen (1988). Statistical power analysis/or the behavioral sciences. (2 nd Ed.). Hillsdale, NJ: Lawrence Erlbaum. Hosmer, D. W., & Lemeshow, S. (1989). Applied logistiC regression. NY: John Wiley. McLachlan, G., & Peel, D. (2000). Finite mixture models. NY: John Wiley. 7.0 Duration of Study: Estimated start date and approximate duration of the study: The study is expected to start in May 2011 data collection is expected to take no longer than four months (120 days) and analysis of data to take an additional six months (180 days) after data collection is complete for a total research time of 10 months (300 days). 8.0 Funding: Support for materials and supplies will be provided by Medical Research and Materiel Command through a congressionally mandated research grant. Additional manpower for data collection will be obtained through the Grant Administrator at The Geneva Foundation. 9.0 Signature Section: 9.1 Principal Investigator: I am aware that I am not authorized to accept any funds or other form of compensation for conducting research. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines. Date - - - - - Template Revised 13 April 09 l if Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 29 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 10 10 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 (b)(6) 9.2 Associate Investigator Signature Page I have read the above protocol and agree with its content. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines. Date ---------- ,(b)(6) (b)(6) ~=---------~==~ ... ~~~====~~~~~~~ I have read the above protocol and agree with its content. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines. Date ---------- ~=---------~~~~~~~~~~~~~~~~~~~~~ I Ph.D.{Clinical NeuropsychologistlMedical Psychologist) (b)(6) Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 IBI MIL for an Acute Concussion Version fl10, 6 March 2012 30 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 lO42 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 Template Revised 13 April 09 I-cc---c-c=-_ _ _---'~P-?T'-'D~P-"-'T. I have read the above protocol and agree with its content. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines. Date - - - - - mOCS,(Physical Therapist) I have read the above protocol and agree with its content. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines. Date - - - - - - I have read the above protocol and agree with its content. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines. Date - - - - - - Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 llOO j(b)(6)----l ~~-" .. ---~-------: 31 I have read the above protocol and agree with its content. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines, l(b~)(=6)_ _ _-lI,~ (Clinical NeuroosvchologisO (b){6) Date - - - - - - I have read the above protocol and agree with its content. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines, w ID , MSM FACEP Date - - - - - - , Colonel, Medical Corps, lIS Army j(b)(6) 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 I have read the above protocol and agree with its content. All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines. Date - - - - - ,_"_.. _ . _ __~- (Clinical Psychologist) MS Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 1113 1114 1115 1116 1117 1118 1119 ll20 ll21 1122 ll23 ll24 1125 1126 1127 1128 1129 32 I have read the above protocol and agree with its content All subjects will be treated in compliance with all applicable organizational, service, DoD and Federal regulations, and all applicable FDA and HHS guidelines. Date - - - - - - 9.3 PI Service Chief (BAMC) I have considered this protocol and am able to approve personnel and resource support. I understand that I will be the point of contact for correction of deficiencies should the principal investigator fail to meet the requirements agreed to in the Letter of Compliance. Date _ _ _ _ . . . -'Psy.D. Il30 1131 1132 1133 1134 1135 ll36 1137 1138 1139 1140 ll41 1142 1143 1144 ll45 1146 ------ 9.4 Statistical Review I have reviewed the data analysis plan for this protocol and approve of the plan as written. I understand that I will be the point of contact for this project's data analysis. Date- - - - - - Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 33 9.5 Scientific Merit Review: This protocol has been reviewed and found to have sufficient scientific merit for consideration by the Institutional Review Board. Date_ _ _ _ __ Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version it 10, 6 March 201 2 34 Appendix A - Questionnaire Demographic Information Gender: Male Ethnicity: Marital Status: D Single Education: D Married D Separated D Divorced D HS Diploma D Graduate Degree Civilian: Occupation Prior Military Service Military Dependent DYes DNo DYes DNo Widowed D College Courses D Professional Degree D No HS Diploma D College Degree Total Education in Years: Military: Branch of Service Rank/Grade Time in Service MOS Deployed OEF/OIF Number of Deployments Rate your current level of pain TODAY-From 1 (nothing) to 10 (The worst pain you can imagine): None Poor Poor 1 2 D Female Age: Date of Birth: _ _ _ _ _ _(month/day/year) 3 3 4 5 6 7 8 9 10 Severe How would you rate your OVERALL physical health? 1 2 4 4 5 Excellent Excellent How would you rate your OVERALL mentaVemotional health? 2 3 5 History of Health Problems and Treatment: Are you on any current prescribed medication? DYes DNo Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version lO,6March2012 TypelDosage: a. 35 b. c. d. List any non-prescription medication, supplemental vitamins or alternative medications (ex. St John's Wort, Kava, Melatonin, Glucosamine) a. b. c. d. Have you been diagnosed with a concussion in the past? If yes, when? _ _ _ _ _ _ _ _ _ __ How many concussions have you had? Height: Have you OYes ONo 0 I 02 o 3 4 0 5 0 6 or more Weight: _ _ _ _ _ _ _.lbs. 0 lost 0 gained weight in the past 3 months? _ _ __ lbs. How many hours of sleep do you get per night? _ _ _ _ _ _ _ __ Any 0 increased 0 decreased sleep in the past 3 months? _ _ _ _.hours Yes hours ONo Do you have problems falling asleep, restless sleep, early awakening? How much sleep did you get in the last 24 hours? Do you drink alcohol? Have you had any alcohol in the last 8 hours? Have you taken any mind altering substances in the last 8 hours? If yes, what did you take? Have you ever been diagnosed with a learning disorder? Have you ever had brain surgery of any kind? Do you have a seizure disorder? o Yes o Yes o Yes o Yes o Yes Yes ONo ONo DNo ONo ONo ONo Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 36 The following is to be completed by study staff: Post Concussion Group ONLY Description of Incident: What happened? Tell me what you remember? Were you dazed, confused, "saw stars" Did you hit your head? Cause of Injury? (Circle all that apply): o Yes o Yes ONo ONo 0 0 0 0 Motor vehicle accident Fall Sports related Other Was a helmet worn? o Yes If yes, how long _ _ __ ONo Amnesia before: Are there any events just BEFORE the injury that are not remembered? (Assess for continuous memory prior to injury) o Yes 0 No Amnesia after: Are there any events just AFTER the injuries that are not remembered? (Assess time until continuous memory after the injury) Yes 0 No If yes, how long _ _ __ Does the individual report "blacking out" or loss of consciousness? o o o Yes o No If yes, how long _ _ __ Did anyone observe a period of loss of consciousness or unresponsiveness? Yes No If yes, how long _ _ __ Have you had any concussions in the last 12 months? Yes 0 No If yes, howlong _ _ _ __ Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 Symptoms: (check all that apply) 37 o Headaches o Dizziness Memory problems o o Difficulty concentrating Irritability o Balance problems o Nausea/vomiting Symptom Score 0 Visual disturbances 0 Ringing in the ears Other _ _ _ _ _ _ __ B (one or more current symptoms) A (no current symptoms) Curent DATE/TI'NIE: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ Concussive Event DATE/TIME: Time eJapsed since this injury? -------------------------------------- hours hours Time elapsed since this injury and beginning of testing? Questions for seven day follow up interview (con cussed group ONLY) Rate your current level of pain TODAY -From 1 (nothing) to 10 (The worst pain you can imagine): None 2 Headaches 3 4 5 6 7 8 9 10 Severe Symptoms: (check all that apply) D 0 Dizziness Memory problems Balance problems Nausea/vomiting 0 D D 0 D 0 Difficulty concentrating Irritability Visual disturbances Ringing in the ears Other Note the order the tests were administered in 1 - 4: D AHEAD D Template Revised 13 April 09 ANAM ImPACT D UPST I ~ Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 Appendix B - Unipedal Test Instructions U nipedal Leg Stance 38 Subject ID: 0 0 o o Date: Read the following to the subject 1) During this test you will stand on your non-dominant foot. This is the opposite foot that you would kick a ball with. 2) The test will begin on a hard surface and then we will have you stand on a piece offoam. 3) Stand barefoot on your non-dominant foot, with the other leg raised so that the raised foot is near but not touching the ankle of your stance leg. 4) Prior to raising the limb, cross your arms over your chest, like this (demonstrate) 5) Focus on a spot on the wall at eye level in front ofyou, for the duration of the eyes open test. 6) I will use a stopwatch to measure the amount oftime you are able to stand on one foot. 7) The time starts when you raise your foot off the floor. 8) The time ends when you either: (1) use your arms (i.e., uncrossed arms), (2) use your raised foot to touch the floor, (3) move your weight-bearing foot to maintain your balance (i.e., rotate foot on the ground) 4) open your eyes during the eyes closed test or (5) a maximum of 45 seconds had elapsed. 9) I will conduct this test 3 times in each position. Dominate foot: (circle one) Time 1 Time 2 Time 3 Average Time / Right o Hard surface eyes open Left I i i I : Hard surface eyes closed . Foam surface eyes open i Foam surface eyes closed I Template Revised 13 April 09 I: Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version # 10, 6 March 2012 39 Appendix C - Recruitment Script Concussed Group Recruitment Script for concussed group for ImPACT MIL v. ANAM4 To be read prior to persons who meet the prerequisites of having sustained a mTBIIconcussion within the last 72 hours. This will be read to those who have had sustained a concussion and were referred from the ED prior to collecting informed consent. It will be read in private to the concussed by a member of the research staff. Recruitment efforts will be brief consisting of a non-military civilian research assistant giving a brief (less than 5 minutes) speech asking forthe concussed participation. The script for the speech will be read as follows: Hello my name is . I am here on behalf of the U.S. Army Medical Research and Material Command (USAMRMC) and I am recruiting volunteers to participate in a study on mTBIIconcussion. There are currently two different neurocognitive tests used by the US Army today. One of them is the ANAM (automated neuropsychological assessment metric) and the other test is the ImPACT MIL (Immediate Post-Concussion Assessment and Cognitive Testing Military Version) currently being used to evaluate Special Forces troops. The study you are being asked to volunteer to participate in is designed to compare these two tests to see which of the tests is better suited for detecting the effects of acute concussion. For the purpose of this study we have asked the emergency department staff to aid in identifying those who have recently (within the last 72 hours) received a concussion. Everyone who has sustained a concussion is being asked to participate as part of the study group. If you choose to participate in the study it would take approximately one hour and will include the following: review of the Informed Consent sheet; a short screening questionnaire; two computerized neurocognitive tests, the ANAM and ImPACT; a short balancing test (UPST); and AHEAD M - 100, which involves the administration of a noninvasive, short EEG to monitor brain electrical signals.. There will be a break between each test and the balancing test will be conducted prior to the start of the second test. You will receive no financial benefit for your participation in this study but your time is greatly appreciated. Testing results will be reviewed by a neuropsychologist and if there are any abnormal results a write-up of the testing results will be sent to you for your medical records. At this time would you be interested in learning more about this study? Those who elect to learn more about the study will be given the protocol ICD to review and ask questions about prior to testing if they agree to participate. Each member will be asked to complete the short screening questionnaire consisting of demographic information and the first page of the MACE (post-concussion symptom checklist). After each participant has completed the ICD and the questionnaire the first computerized test will be administered. Participants will complete the first test and be given a short break (10 mins.). During this time they may get Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 40 something to drink, use the restroom, smoke, stretch, etc. prior to starting the next test session each participant will be given a short balance test and then testing instruction will be given. Template Revised 13 April 09 I l: Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 41 Appendix D - Recruitment Script Control Group Recruitment Script for control group for ImPACT MIL v. ANAM4 To be read prior to service members already registered to take the ANAM as part of the SRP process. Service members are tested in groups of25 - 50 depending on the size of the testing location. Prior to testing, testing instruction are given to group members in a class like setting. Recruitment of potential control group members will be conducted at that time. Recruitment efforts will be brief consisting of a non-military civilian research assistant giving a brief (less than 5 minutes) speech to the group asking for participants. The script for the speech will be read as follows: Hello my name is . I am here on behalf of the US. Army Medical Research and Material Command (USAMRMC) and I am recruiting volunteers to participate in a study. There are currently two different neurocognitive tests used by the US Army today. One of them is the ANAM (automated neuropsychological assessment metric) which you will be taking today as part of the SRP process. The other test is the ImPACT MIL (Immediate Post-Concussion Assessment and Cognitive Testing Military Version) currently being used to evaluate Special Forces troops. The study you are being asked to volunteer to participate in is designed to compare these two tests to see which of the tests is better suited for detecting the effects of acute concussions in an active duty population. Everyone here is being asked to participate as part ofthe control group. Since everyone here is taking the ANAM the additional time I am asking for participation is an additional 40 minutes and will include the following: review of the Informed Consent sheet, a short screening questionnaire; two computerized neurocognitive tests, the ANAM and ImPACT; a short balancing test (UPST and AHEAD M - 100, which involves the administration of a noninvasive, short EEG to monitor brain electrical signals .. There will be a break between each test and the balancing test will be conducted prior to the start of the second test. You will receive no financial benefit for your participation in this study but your time is greatly appreciated. At this time who would be interested in learning more about this study? Those who elect to learn more about the study will be asked to step across the hall into another testing room and will be given the protocol ICD to review and ask questions about prior to testing if they agree to participate. Each member will be asked to complete the short screening questionnaire consisting of demographic information and the first page of the MACE (post- concussion symptom checklist). After each participant has completed the ICD and the questionnaire the first computerized test will be administered. Participants will complete the first test and be given a short break (10 mins.) during this time they may get something to drink, use the restroom, smoke, stretch, etc. prior to starting the next test session each participant will be Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version 10,6 March 2012 42 given a short balance test and then testing instruction will be given. Participants will be free to continue with the SRP process once they have completed their second test. Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version # 10, 6 March 2012 43 Appendix - E BrainScope CEO IDE Letter .::1 ....o. o?!Id~e_" ..o.. ift ??o??o??o?? o .o. . "'~"","", "-10 o.? II November 19, 2010 c._ _ _ _---' I$Wgj Ph.D. NeurocooniliveAssessmenl Br~ L ..... _ _ __ Dear Dr. The BrainScope Ahead M-100 device is a non-invasive, 'non-significant risk? (NSR) device [see 21 CFR 812.2(b) arid FDA Guidance entitled, "Significant Risk and Non-significant Risk Medical Device Studies"]. This generic type of device, designed and marketed for EEG signal acquisition and processing, falls under ?Class I\" per 21 CFR 882.1400. FDA policy allows that EEG devices are specifically exempt from the need for an Investigational Device Exemption ODE) [see 21CFR812.2(c) and FDA Guidance for IRBs and Cis - 1998 Update at http://www.fda.goviociohrthrbsidevices.html]. The BrainScope system consists of a handheld, battery operated device and a disposable non-invasive adhesive headset which contains electrodes that are similar to standard, off-the-shelf silver-silver chloride EEG electrodes. The data acquisition time for the BrainScope is 5 to 10 minutes total, depending mostly upon patient compliance. The device is intended as an assessment tool, not for continuous monitoring, thus the amount of time the electrodes reside on the patient's skin is minimal. The purpose of the clinical investigation is to collect brain electrical activity from human subjects. During clinical investigational use, the device will not provide any diagnostic or classification information and therefore will not impact upon patient care. In summary, the BrainScope Ahead M-100 device used in this study does not pose a significant risk to the study subjects. Therefore, the study of the BrainScope device may be considered a non-significant risk study. Sincerely, j'- '" ! . if Michael E. Singer, Ph.D. Chief Executive Officer BrainScope Company, Inc. Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 44 8120 Woodmont Ave. Suite 250 Bethesda, MD 20814 (240) 752-7680 (800) 230-7573 www.BrainScop Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 45 Appendix F - Site Impact Statements IMPACT STATEMENT 3 ~ ;) 6 ProjC2: Title: A Comparative Stul),: ImPACT MIL V~l'StlS A:t'\A.v14 TBI '\-llL:o:: Acute c."Hcl:.ssion 7 8 PrindpuJ Invcslig I(} C! .2 H 14 15 E ~ 11 A"",";starl'Ce Req uested: Requesting ED staff waid in identifying wid referring I.htt:lle patie!llts with mlTSI. too ANAM researllhslaff'tm panici"alj~n in tlxcum::nt-study. Study inform!;1 ion '.1.'il! be given to t~ ED ~12ff pertaining; to i 1\(:1 ust.oftJe;xcltlsia!l c:rile:ria and a mt:m bet oflht: tt'.,r;carchtCflm will be av~il~hle to rf"iew thelen, an!i14Jt1tRy q~iom: prntuning \<;,1 ttl; ~I udy lind !C'h<>Judy requires tbepanicipatJofl oralie hundred COncU:5IS.:G {mTill} p:.tlenlS from (our Army Mcd1C4J Cmtcr!l. PW11clpants: will Jl 1~ be l'el.'ru~l"d tlfitillhe toIalllutnb.el' of oonc ussooim1'01 pllti;:I'l!!> has readwd ~ne tnmdred.. There is 110 set numbt,-r ~)r patientS n:quircd pcrlocation. i);ll'lt 2) 24 23 11 Number of fla.ttent:! per Month: lhere .~ nl) ~t nulJtbi:r nfpaticnl.'i fI.:quircd per month. will be collected for a lotal OCrt1ur mon!hs (120 days). Length Of:S1U~.b; The study is expected to start ill Se'p(~bet 26] 0 daia col~lion i$ expect~d (0 take nu longl!T Ihanfour mOl'llh~ (120days)nnd III1l1lysis cf dnl.lllo mite :m adwtiQlLalsix Illonth$ (l SO (l,f1Y$) Ilflcr?data .:oUc:;t.:ligfl j~l:Qrnplel; for IIlmal f?s,wc;h time !8 ~9 ;1.0 )1 l:! )3 )4 35 ;J(, fm:~; __.. --.lrllIJ.... D'--'-Lw.T~C...;!J"-'1...... S..Ll{C-"i""'it)w.j{""'iduN.1I.'e..LIU.l.l.lj"rYdK>I.gi~J )1 III 19 4(} I 41 ill 4:/ .14 v" 'J;;' Di~l!ppN,wed. CMIlO! sUPJ!On. OCli?il)'. Apprcw(!(l, 1!1(1 (XI1ll~l1t Approved will! eom.m~nL 45 46 'r;/ Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 Dalt;!' .hlt?ltl tJ6. lO!f} .17 48 48 49 jU jl ~~__ ~________~~.. ~ _____~ jJ :54 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 49 Dale' June 06, 2{) 1() I IMPACT STATEMENT 2 4 5 6 Project Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for Acute Concussion 7 g Principal Investigator: ~-----~--------~ 9 Service/Depa.rtment: Fe Hood Soldier Readiness Process Site Assistance Requested: Allow study staff ANAM test administrators to brief SRP soldiers prior to ANAM testing about the current study and recruit study participants. This may add an additional 40 minutes to the length of the participants testing time. Total Number of Service Members to be Studied: This study requires the participation of two hundred control (non-ooncussed) active duty service members from two active duty SRP sites. Participants will be recruited until the total number of controllnon-concussed service members has reached two lllUldred. There is no set number of service members required per location. Number of Patients per Month: There is no set number ofpamcipants required per month. Data will be collected for a total of four months (120 days). Length of Study: The study is expected to start in September 201 0 data collection is expected to take no longer than four months (120 days) and analysis of data to take an additional six months (180 days) after data collection is complete for a total research time to II 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 3! Date J() Jllf'I~ /0 32 33 34 35 ~ I L. :(b)(6)=--_~h,D., LTC, MS (Clinical Neuropsychologist) I ! 36 37 38 39 40 41 42 43 Disapproved, cannot support activity. 44 45 46 ~~roved, no comment. C Approved with comment. Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 50 l(b)(6) JUt - 12010 ~l (b)(6) (b)(6)~- 54 ~5 5/, Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 S1 Template Revised 13 April 09 I I t Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 52 I Pr.~:':"l 11th:: A C'nmpllT,lUv,;' (I)l'\\;U$~il1!! Shu]:', lmrAC1MIL\'el~U,~ANAM4 'IU' Mlllbt tktlt? f'rindp;jJ bLY~');llf::lwr: ~b)(6) ., Ii) ?\!!h'SI),,:';lh.~ 1fn~~~liuak.r:'~~~~~_ _ _~ s.:nkeiLkpm lHient. Maltitl Army (\II,l\n\tll1l:y HospiJ:u ~.i!1 l\ umi-tl,,'I' IIf P;l!h:nt~ lore Sl\~jj?l.l: Thi:;smdy rcquite:ithep:n1icJ[lI1\lQll ot' Ql'le' hundred ':()ll>:U$!\l.!:i (luml ~ i}:llkm~ irum iiw Arm~ Mc,lic~Jt:et\I~l1i.ll""1j~i""'lUla ,,,ill 111: (LX'HII!1.....1Ulllillhcl"UllIlIU111"Cf ,,) c"I~~I.. im'IIH(l~lict1f1! hlls R:1~clgdunl:ill1l11dred. ~ 11~:c i~ lkl ~\~~ u-!:unhcr vfp;uj..~nl$,t\~,tuil\?\lperloc~Tifln. Nljml~r<)f Vi'llit'l'l!li [1..(M~ntl}l: TikI\' is IIIl ""JnlH~r uf')~tticnt:i n:qulw.:lpcr UitlJllh, Dal,!!, wil! b<~, c()I1I,,">.:b..':wd III t,"tkcnu J~~r 11l!1Ilftilir n;onw j 12(1d.'1)';'J)und ... :;tb;si~ ~If ,!;jI;1 \\1 (.lke an nddiduO'Ji ~ix momh:,; (ISOdil!,'S) anerdatacolieClioll is ' 1(.[ II JOlaJ IC,Cilrch Jim&: of II! mjml~ c:mo d.~'$)_ 2~ 1/, :1 =S f(ibXlelr" )?1 :N' "'J ''! Di:,appn,\vI,,"l1 C'llit)()t ;;'tl))l)(II'1 aclh"it)'; II I~ AVPI~I\'~'d, IWi.!lI1lllWl1l, .1.\ ,~-4 ~I:; 'i Al)rtu~?~ witht.ltnlllCl1l. 1(, Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 53 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 54 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 55 Appendix G Reportable Event Submission Form U S Army Medical Research and Materiel Command Office of Research Protections HO, USAMRMC InstiMional Revfew Board Reportable Event Submi$slon Form Purpose,' Use this (ann for the initial reporting of any study-related event that requires prompt reporting e$ per the "Re$pOnsibiJiIies of the Pr'inQpallnvestigatOf in Humlitll Subjects Res8erch Investigator Agreement." Directions: Place the cursor where )'00 wish to type. and tab through the form. ThtJcompieted form and any supporting documentallonshould be sent by emai/to Date of this report: Person Reporting Event Name: TltlelPosition/Association ~1h Study: Phone numb&r. Email address: -~. ~~--------.------,,-.-,~---------- -------------------~-----~ .. Protocol Information Protocol Number: Study Title: Name of Prindpallllv$stiaator: Event Information SubjedlO#; Data of Event Time of Ev&rlt: f---- - Location of Ewnt ---~. , _~~_. _ _ _ _ _ _ _ _ _ w _ _ _ _--I .~ Event type(s) Check a/l that apply D Unanticipated problem Invol\ilng risks to subjects or others D Sedous adverse event D Oealh D Protocol deviatkm hat may affect the safety or rights of subjects and/or th& integrity of the study D Ch ange to the prollX:Ol taken without pria' IRB riWiew to eDmlnate an apparoot imm$dlaIB hazll'd to research $lJbject D Incarceration of a subject Significant mdings that might aff$Cl h wW.,gness of subjects to enroll or to continue to take pa-t Co!ll)lalnt by subject or other D NOl'lOOmpliancEl'Mth lhe regulations or reqUlr&rn&nts D Pending compliance InspectlonMslt by the FDA, OHRP. or other governmentaf agency D Other event o o Template Revised 13 April 09 Protocol Title: A Comparative Study: ImP ACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10,6 March 2012 56 rief Description of Event (who, what, why) Initial Actions Taken Follow-up Actions to be Taken I FOR INTERNAL USE ONL'f. Reportfec.eiYid by Date and Urne reporl received Repod HI01:Jived vra o Email o Fax o Phcnecal ROIJliog Name ___________ Dele. Reromrnerlded Action lI1!tisls Recommended ActiOn: _ _ _ _ _ _ _ rete, Name Reoommended. Acbl. CcnoHlencs of HQ tJ.RMC lRBApp/owal Authority 0 YesD NoD NA (signaluffI) Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 57 Appendix H Individual Investigator Agreement Department of Defense Human Research Protection Program DoD INDIVIDUAL INVESTIGATOR AGREEMENT Part 1 AGREEMENT INFORMATION This Department of the Defense (000) Individual Investigator Agreement describes th8 responsibilities of the Individual who is engaged In human subject research and is not an employee of the assured insti1ution, but is essocia1ed with the assured institution for the purpose of conducting research, This Agreement also describes the responsibilities of the (:Issured institution. This Agreement, when signed, becomes part of the institution's Federal A~urance for the Protection of Human Research Subjects (e.g" 000 Assurance or Department of Health and Human Services (DHHS) Federalwide Assurence (FWA>>. A, Nama of Investigator: ~~_ _ _ _ _ PhD B. Institution with the Assurance: Name: US Army Institute of Surgical Research 000 Assurance Number: DOD A20104 OHHS PNA Number [if applicable]: FWA00009672 C. Scope: This Agreement applies to all research performed by this Investigator and supported by the Ins1itution with the Assurance, unless sr:ecified below. Limitation of Scope (if applicable): This individualln~.c!lli;lU!.llg~ment will apply to approved protocols conducted by Or~ until this agreement is rescinded. D. Effective Date: This Agreement is effective as of the date signed by the DoD Component DeSignated Official and expires on the date listed in Part 4, paragraph D. Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 58 Part 2 INVESTIGATOR RESPONSIBILITIES As the Investigator named above, I: A. Havs reviewed: a) The Belmont Report: EftlicaJ Principles and Guidelines for the Proiectiofi cf Human Subjects of Researcli; b) the U.S. Department of Defense (000) regulations for the protccticn of human subjects at 32 Coda of Federal Reguiafions, Part 219 (32 CFR 219) and DoD Directive 3216.02; c) the Assurance of the institution refe'enced above; d) the DoD Component policies ide!''!l!fied in Part 3 of the 000 Assurance (if applicable); and e) the relevant insti1utional policies and procedures for the protection of human subjects, 8, Understand and accept the responsibihty to comply with the standards ;ma requirements stipulated in the above doclIments and to protect the rights and welfare of human subjects Involved in research conducted under this Agreement. C. Will comply with all other applicable federal. 000, international, state, and loeallaVls, regulations, and poiicies that provide protections for human subjects participating in research conducted under this Agreement D. Will complete any education and training required by the InstitutiDn and the IRB prior to initiating research covered under this Agreement (attach documentaiion). E. 'NlII abide by all determinations of the Institutional RevIew Board(s) (iRB) designated under the Institution's Assurance and will acoept the final authority and deoisions of the IR8, including but not limited 10 directives to terminate my participation in designated research activities. F, Will not enroll subjects or start research activities under this Agreement prior to its review and aPP"oval by the IRB and the Institution. G, Will comply with requirernenis from the IRS when responsible for enrolling subjects, to illclude ootaining, documenting, and maintaining reoords of informed consent for each such subjeLi. or each subject's legally authorized representative as required under DoD regulations at 32 CFR 219. H. Ackilowledge and agree to cooperate with t!i& IRD for initial and continuing review. report for the research referenced above, and provide all information requested by the IRS or institution in a timely fashion, I. Will seek prior IRS revrew and approval for all proposed Ghanges in the research except where necessary to eliminate apparent immediate hazards to subjects or others. J, Will report immediately to the IRS a) unanticipated problems involving risks to subjects or others and b) serious or continuing non-compliance 2 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 59 K. Will comply with recordkeeping requirements for research protocols referenced above. . L. Will make all other notifications as specified by the IRS and the Institution. M. Acknowledge my primary responsibility for safeguarding the rights and vJelfare of each research subject, and that the subject's rights and welfare wlll take precedence over the goals alld requirements of the research. Part 3 ASSURED INSTITUTION'S R!:SPONSI8IUTIES This Institution will apply the tt3rms of its assurance 10 Ule as specified in tile scope of tllis Agreement, Part 1. Part 4 lJ1v~tigator aM the researCh AGREEMENT BETWeEN AN INVESTIGATOR AND AN ASSURED INSTITUTION The Investigator or an official of lhe assured Institution may unilaterally terminate this agreement upon written noUfication to other signatories. A. Investigator: Il,Inders1and my responsibilities as described in 1his Agreement and the policies referenced in Part 'd.A above, I acknowledge and accept my responsibility for protecting the rights and welfare of human research subjects and for complying with all appiicable provi?ions ~~~~'-"-"-"'=~~=.!..:~~_~ Signature: 'Clinical Neuropsychologist) 3 Template Revised 13 April 09 Protocol Title: A Comparative Study: ImPACT MIL versus ANAM4 TBI MIL for an Acute Concussion Version #10, 6 March 2012 60 B. Acknowledgement by Investigator's Employer (or 000 Supervisor if 000 Employee): I am aware that my employee is entering into this agreement. Name:l(b)(6) i OPT. OCS Fl?