UCSD Human Research Protections Program New Biomedical Application RESEARCH PLAN instructions for completing the Research Plan are available on the website The headings on this set of instructions correspond to the headings of the Research Plan. General Instructions: Enter a response for all topic headings. Enter ?Not Applicable" rather than leaving an item blank if the item does not apply to this project. Version date: 9/30/2013 1. PROJECT TITLE A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL TO EVALUATE THE TREATMENT EFFICACY OF PERSONALIZED REPETITIVE TRANS-CRANIAL MAGNETIC STIMULATION FOR PATIENTS WITH POST-TRAUMATIC STRESS DISORDER (PTSD) 2. PRINCIPAL Scott Matthews, MD (co-principal investigator) Murray Stein, MD (co-principal investigator) Sonia Jain, (co-investigator) Kevin T. Murphy, MD (consultant) 3. FACILITIES VASDHS Aspire Center 4. ESTIMATED DURATION OF THE STUDY 24 months 5. LAY LANGUAGE SUMMARY OR SYNOPSIS no more than one are re The goal of this study is to test the hypothesis that personalized magnetic stimulation of the brain will decrease of posttraumatic stress disorder (PTSD). To test this hypothesis, we will randomly assign patients who have PTSD to either or placebo, then measure PTSD over time. A?er a period of study, all atient will have a chance to receive so that no patient enrolled in the study remains untreated. 6. SPECIFIC AIMS Speci?c Aim 1: To quantify the severity of clinical as PTSD sleep, depression, anxiety and quality of life) well as impairments in performance attention, executive function and memo and brain ?rnctioning among individuals with Speci?c Aim 2: To perform a randomized, double-blinded, placebo-controlled study to evaluate ,the ef?cacy 'pf a course of personal ized repetitive trans-cranial magnetic stimulation administered once per week for 8 weeks compared to a standardized (non-personalized) course of in subjects suffering from PTSD using the change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) as the primary endpoint. Speci?c Aim 3: To perform a subsequent open-label active treatment trial for the subjects who received initial standardized treatment (as described in Aim ?2 above) and assess their response to following lacebo treatment using the same primary lendpointf. 7. BACKGROUND AND SIGNIFICANCE Post Traumatic Stress Disorder (PTSD): PTSD is a disabling, prevalent, and dif?cult to treat disorder characterized by reSponse to a traumatic event that involves ?intense fear, helplessness, or horror?.? Despite phannacologic and therapies, 74 percent of patients have lasting over 6 months, and up to 30 percent of patients with PTSD will not recover from this illness at 10 years following diagnosis? In order to be diagnosed with PTSD, patients, a?er experiencing a traumatic event, have (1) intrusive recollections of the event, (2) avoidance of stimuli associated with trauma or generalized emotional numbing, (3) of hyperarousal, and (4) ?inctional distress or impairment in social, occupational, or other important areas'. Furthermore, as suggested in the PTSD affects a wide spectrum of not just emotional, but also cognitive and physiologic processes. As such, patients often have deficits in cognitive function, including deficits in attention, memory, and leaming?. Commented Consider to have the as an exploratory aim (cg. relationship of to clinical and assessments) Commented And safety? Although is established to be safe, still will need to collect safety data in this speci?c population Commented A "pm-post" design implies reasonable stability in PTSD elsewhere in the protocol further elaboration of the nature of these analyses is required Lifetime prevalence of PTSD is estimated at 5 to 8 percent of men and 10 to 14 percent of women, making it the fourth most common disorderi 6' 7. It affects 15-24 percent of people exposed to a traumatic events. Traumatic ev proved device ents precipitating PTSD include interpersonal violence (55 percent of rape victims develop PTSD), exposure to life threatening accidents, natural disasters, and others7. In addition, large numbers of service members develop PTSD following combat exposure. In a recent survey of members of the National Guard following combat in Iraq, 23.4% developed PTSD with some functional impairment, and 8.9 percent develop PTSD with serious functional impairment?. Among disorders, PTSD is particularly disabling and has a high association with other comorbiditics. In another study of members of the National Guard deployed to Iraq, PTSD was associated with higher impairment in social adjustment and lower quality of life than all other diagnoses in the survey, including depression, other forms of anxiety and alcohol abuse?. Civilians with PTSD also have a high risk of developing comorbid disorders, including a 5.7 times higher risk of having a major depressrve Current Treatment for Post Traumatic Stress Disorder (PTSD) Given the scope and disabling nature of PTSD, much work has been done to identify effective treatment options. Converging evidence supports the ef?cacy of such as cognitive processing therapy and prolonged exposure, in the management of PTSD. Pharmacologic options for treating PTSD include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, other antidepressants, alpha-adrenergic receptor blockers, beta-adrenergic receptor blockers, benzodiazepines, mood commented mm: ?in. this amnion. elsewhere in in local protocol, a description of permitted or excluded preexisting or concurrent therapy is required see comments later in the pro Quantitative Electroencephalography Quanitative electroencephalography applies digital signal analysis, including wavelet analysis, Fourier analysis and other tools, to electroencephalography (EEG). This quantitate analysis of EEG data also allows . . . . . . . . for correlation between EEG and human behavror, mcludmg pathologic conditions, . Commented reference to asystemic rcviewwould useful at [his Poll? as you are attempting to provide El context for including this measure Commented yes. also unfortunately in clinical trials? is most frequently used to assist in the diagnosis of epilepsy, cerebro-vascular disorders, and other brain states such as coma. provides a gross measure ofneural electric activities in the brain cortex. To our roi predictive analyses these have not been useful . . . . . . . knowledge few SlUdleS have formally examined ?1 the Commented trim]; the indication is PTSD, not chemotherapy activrty re?ects the degree of neuronal activation and beneath the recordmg lead. The relative understand thisto be a typograp ic enor magnitude and distribution among different frequency bands re?ects the brain status whether in sleep, relaxation or vigilance. In addition to the epileptic spikes found in seizure patients, individuals with different neuroeognitive disorders often have a ldi??erent and unique patterns in their pro?leL? Commented reference would be helpful. Unfortunately speci?c patterns for conditions are not as well de?ned Unpublished analysis at the Del Mar Neuro Center (DMNC), and at the Medical Center MSC) have shown pathological brainwave activity in patients suffering from chemobrain. DMNC and MSC Biomedical IRB Application Instructions Page 2 have also observed differences in in a range of patients with cognitive impairment such as autism Spectrum, post-traumatic stress and generalized anxiety disorders. pro?les of patients treated at DMNC and MSC show that the dominant alpha (range 8-12 Hz) is disturbed and I acks in patients with ichemobrairi--_tt1 between the degree of reduced brainwave activity or ?coherence?, and expressed neurocognitive disruption Repetitive Transcranial Magnetic Stimulation Repetitive Transcranial Magnetic Stimulation is a non-invasive therapy that has been FDA approved for treating adults with major depression?. Furthermore, investigational use is reported in the literature for other neurobehavioral conditions such as schizophrenia,20 'l?ourrette?s,2 conversion disorder22 and autismi?i is considered safe and well-tolerated, as demonstrated by a number of clinical trials including a large clinical trial of over 300 patients treated for major depression wherein discontinuation rates due to adverse effects where similar between active and sham participants (5 and 3 percent, respectively .: through Friday. All therapy will be provided by LVNs who have undergone training at one of the treatment will be personalized to their pretreatment Repeat will be conducted and analyzed on a once per week basis during the treatment course, allowing for (stimulation) frequency adjustments, or As different patients present with different patterns of dysregulation, we believe that a personalized treatment that delivers customized magnetic stimulation to different areas of aberrant neural activity will be more ef?cacious than standard Only recently have so?ware and analysis algorithms, and delivery schemes, advanced enough to allow this level of personalization. Our breliminary data show that QEEG restinealph? wavsftesriisnsxis. able to create a much more robust and lasting effect compared to traditional In order to perform an initial baseline is ?rst obtained to determine the patient?s degree of neuronal dysregulation or lack of coherence. A resting posterior cortex and/or predominant alpha frequency speci?c to the patient is chosen as the ?resonant frequency.?A similar frequency is then used as the stimulus frequency applied to selected areas of the neocortex based upon Biomedical Application instructions Page 3 Commented will need to expand on this statement .4 Commented PTSD is the indication Commented Agree, focus only on relevance to PTSD or other similar disorders (if no info on also consider as exploratory, not primary. this point I Commented [MMll]: Reference for the correlation useful at Commented also reported for PTSD e.g. Watts BV, Landon 8, Craft A, Young-Xu Y. A sham controlled study of repetitive lranscranial magnetic stimulation for posttraumatie stress disorder. Brain Stimul. 20l2 Jan;5( 0:38-41, Karsen EF, Watts BV, Holtzheimcr PE. Review of the effectiveness of magnetic stimulation for post-traumatic stress disorder. Brain Slimul. 2014 15 1-7. Commented nice addition ?historical data informing tolerance and safety useful to reference Commented local sensory effects have been reported not persistently this is highlighted elsewhere in this protocol as are potential risk of seizure, and exacerbations presumptively in patients atrisk H?s. .. Commented yes, and some local discomfort, pain and tapping sensation, depending on the machine used Commented criteria for stimulation parameters are needed given the variability implied. Sec elsewhere in the protocol regarding details Commented customarily. details of procedures are included in an appendix including the number of patients previously treated with in any condition, the number previously treated with PTSD, and whether or not data are available describing either ef?cacy or safetv? altematively the article by Taghva in in November 2015 would be excellent reference at this point Formatted: Highlight Commented an appendix is prudent given the many questions likely to arise regarding the technique [Preliminary positive results in for chemobrain, as well as various other neurocognitive disorders, lead us to hypothesize a theoretical bene?t and warrant testing in a randomized placebo-controlled setting. Please see the materials and methods section for more details:i Signi?cance: This study will be the ?rst to evaluate as a measure and discriminator of PTSD. It will also be ?rst to test the ef?cacy of as a novel, low-risk therapy for PTSD, where few other robust therapy options currently exist. 8. PROGRESS REPORT drop in PCL-M score was achieved in 4M'eekslr compared to placebo. Preliminary Data Summary: A 65% be durable and statistically signi?cant Prelimina Study Details: lThirty-six included analysiadlts @1119. p16. and withdrew from the trial. The study was designed with two treatment phases: 1) double-blind and 2) open- [cvsanf the Commented [MM21]:additionaldc treatment code label. All patients were randomly assigned into one of the two study groups: 0 weeks hgiagnlesslfollowed.by were evaluated by the at baseline, ends of week 1, week 2, and week 4. i Figure below displays the PCL-M mean score change ?om baseline following phase 1 and phase 2 treatments 'n both study groups. Analysis of covariance of PCL-M score shows signi?cant difference between Sham and treatment group a?er week 1 and week 2 double-blind ftrialitFpi 4l.__62_p no difference a?erweek? open?label [treatmentth 191 phase treatment is 65%. ths: some xisting medical treatment the Shararespszase, maxrs?est the 0f. Two of 15 patients in the Sham group Since most patients remained on their other treatment. tesponded bigni?cantl Biomedical IRB Application Instructions Page 4 ham ht . .. p: the tiycz; Commented this is written in an NIH grant format (including the section on the progress report below and the way the speci?c aims are written). Will need to modify the fonnaL scriptions regarding the sample, such as demography, disease severity baseline, describing the basis for the contrast pre-versus post, or concurrent active versus placebo control etc. commenting on total score as well as any sub score, and providing details of the intervention would be requested. Additionally, the concept of ?durability". and the method by which a statistically signi?cant result was detected compared to placebo need to be de?ned. Commenmd This section is key as it provides a justi?cation for the design subsequently proposed. Therefore, providing as much detail as is available is prudent. There are a number of missing elements (see below). Please clarify the number of subjects treated. The ?gures below reference 100 patients rather than 36 Commented Study dates ?aft Commented details of procedure Commented details on the regimen required the frequency of treatment within two weeks and any spacing Commented magnitude of difference required in addition to statistical results Commented magnitude of the effect, and clari?cation on the basis for the contrast the comparison is unclear Commented responder de?nition required in the absence of a published report, the section could benefit from a description of patient demography, as well as presenting PTSD and any other eomorbidities. Etc. Over 100 combat veterans with were treated at the De] Mar Neuro prior to treat was 55, and a score reduction of treatment groups. to determine the magnetic stim revealed by quantitative EEG mapping, and the individual?s motor threshold. Patient was treated 705 65 60 255Ms.? 45 5 2" 4? "name?sin 35 Maintainer-cup 30 SlumGlonp 25 Baseline Week 1 Week 2 Week 3 Week 4 Center. Their [average 61% was evident at 4 weeks in both the sham/open label andm Change in POL-M Seams 157.53, p<0.m1 ?5 - - Mean 15. Omaha Pea-rt: ulus rate. Stimulus location was set at the most apparent [abnormal 33;; site agnetic output intensity was set between 60-80% of the Commented size actually evaluated deviation, range, etc. A Requires a statement regarding sample and variability average - standard 5 illustrated within the graph (standard apparentand ?nishing attribute ol'the in compari becoineadistin other'l'MS 50010 there arenot 100 subjects in this graphic. ootnote above However, given the relatively itisause?il depiction ofthedata lsthe this graph all active, or a combination ofactivo sham? it appears to be only patients treated with active. Commuter! Clari?cation and de?nition 6 sec /min, 30 min day for 5 days llweeld Biomedical IRB Application Instructions Page 5 Commented for a total of two weeks? Was this any ?ve days within a seven day period, or ?ve sequential days etc. 9. RESEARCH DESIGN AND METHODS The primary objective of this study is to establish the safety and ef?cacy of treatment in conjunction with current standard of treatment medicationsbamong combakeqused veterans \vith_ Commented Potential strati?cation factor based upon PTSD. The primary outcome measure will be the CAPS. Secondary outcomes will include: clinical ?mm? measures of sleep, depression anxiety and quality of life ?inction and memory and to measure brain ?tnctioning. A total of 100 subjects will be treated for an eight-week interval. A?er signing informed consent, enrolled subjects will be randomly assigned to either active or traditional groups at [1:1 ratio clinical evaluation for the severity of baseline Commented here are elsewhere. are randomization Treatment will be initiated after the completion of an bvidenced based 32"}333222: 3:55;: 33?30? total oft? treatment weeks weekly: antistatic?! who - emanates, 1?.me blocks ?inn. micr- intentions participate in the clinical evaluation will be blind to the treatment type or control by ?mm? Assessment instruments will include the CAPS-5 (primary outcome), administered by trained assessors; Post- Traumatic Checklist Military (PCL-M), GAD-7, Patient Health Questionnaire 9 (PHQ-9), Wechsler Adult interventions PS5 PC Intelligence Scale Fourth Edition (WAIS IV), Sheehan Disability Index Trail Making Test A (TMT Comm {Mnemofmummeds and Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A) Additlonal follow-up evaluation C'a??mi?m 4-9: 3 dni'i occurring at using the BTACT will be conducted I month, 3 months, 6 months, and 12 months after the completion of "i umc'mumng camcnd Commented an unblinded clinician is implied at some i . point in the engagement: an individual responsible for assuring either sham or active has been delivered, but not implicated in the a, . ?r evaluators are blinded, . but the individual delivering therapy may not be. qEEG-guided Commented ""39 _Wm. I . . will be customized to each patient as follows. Following a and ?equencb{__se_lec_t_ior_i_, wi_ll__b_e_ ofthc measures is requireld, a ?emu,? delivered by a trained technician using the MagPro R30 transcranial stimulator and 8?65 transducer (magnetic paddle). The patient will be treated in the seated position in a quiet room with the eyes closed. No sedation is required. Commented speci?city likely requested by the agency please see other comments in this regard Parameters: Available Frequency Range: 8-13 Hz Amplitude of Magnetic Field: customized per patient as above for comfort, with typical amplitudes 50- 60% ofthe patient?s inotor Motor threshold detenn ination: elicited by operator stimulus of the motor strip Session: 30 minutes per day,l5 days per Commented a seven-day week was previously implied. Similar to previous comment, more speci?city regarding the days in which the procedure is to be applied the exact procedure can be arranged by selection of numerous coil con?gurations, varied in stimulation area to rate Commented and this is an approved device (single pulse to <30/sec), and output intensity (up to 3.9 tesla) depending on the triggering program and type of ?mm? Mum?) Commented magma. needs to um the peripheral nervous system in clinical neurological practice, and research in Transcranial Magnetic Stimulation FDA guidance - see additional notation from Sujata Shah, repeated here for convenience: ?If the protocol that is described is utilizing a (TMS) and repetitive Transcranial Magnetic Stimulation cleared device and labeling would be sufficient. However. if the is utilizing the device outside of its cleared intended use/indication for use, then certainly additional supporting information would be required". Both the and will be delivered by the same TMS machine (MagVenture MagProTM). The only difference between the two procedures is the type of coils. A sham coil provided by the manufacture will be identical in appearance to the treatment coil except that it will not generate a magnetic ?eld. The placebo coil will make the same click noise during stimulation and a separate surface (forehead) attached TENS unit will be used to simulate the sensation and slight muscular contraction experienced by patients using the treatment coil. HUMAN SUBJECTS I Biomedical IRB Application Instructions Page 6 Approximately 100 male and female subjects of any ethnic background who are diagnosed with PTSD will be randomized to receive or sham treatment, with randomization in a ratio with 50 subjects per group. 50 combat control subjects will also complete the study. All subjects will receive treatment as usual medication). Subjects who have provided informed consent and are likely to comply with the visit schedule will be entered into the study provided they conform to the following criteria. Inclusion Criteria for PTSD subjects: Subjects must meet all of the following inclusion criteria to qualify for enrollment into the study: 1. Primary diagnosis of Post Traumatic Stress Disorder rendered by Clinician Administered PTSD Scale for DSM-S dCAPsb 2 3. English language pro?ciency 1.2 Inclusion Criteria for combat control subjects: 1. Deployed to a combat zone as evidenced by the DD-214. 2. No current or prior diagnosis of rendered by the CAPS. 3. <10] 4. English language pro?ciency 1.3 Exclusion Criteria for all subjects: 1. Individuals with the following conditions (current unless otherwise stated): History of open skull traumatic brain injury. History of [clinically signi?cant seizure History of clinically signi?cant manic episodes. 2. Individuals with a clinically de?ned neurological disorder including, but not limited to: Any condition likely to be associated with increased intracranial pressure. Space occupying brain lesion. History of cerebrovascular accident. Cerebral aneurysm. 3. EEG abnormalities that indicate risk of seizure, abnormal focal or general slowing or spikes during the EEG recording. 4. Any type of treatment within 3 months prior to the screening visit. 5. Currently receiving or anticonvulsant medication ltreatmenti. 6. Intracranial implant aneurysm clips, shunts, stimulators, cochlear implants, stents, oriiele-Ctrodes) bi'any' other metal object within or near the head, excluding the mouth, which cannot be safely removed. 7. Clinically signi?cant abnormality or clinically signi?cant unstable medical condition (including active suicidality) that in the Investigator?s judgment might pose a potential safety risk to the subject or limit 8. Clinically signi?cant medical illness, including any uncontrolled thyroid disorders, hepatic, cardiac, pulmonary and renal malfunctioning. 9. Any condition which in the judgment of the investigator would prevent the subject from completion of the study. 10. Recently started pharmacological or therapy lspeci?cally intended to remediate the subjects on ?stable? doses no change in Rx in past 4 weeks; completed active phase of evidence-based for PTSD) are permitted to participate. 1.4 Additional Safety Considerations Biomedical Application Instructions Page 7 Commented structured diagnostic interview - SCIDI, It as in the prior publication provided to Medical or MINI as has been discussed in teleconference Additionally. a number of other assessments have been requested, and should be listed here if any threshold level of is desired as an eligibility criterion traditionally associated with eligibility criteria 3, consistent and in-line with scoring conventions t. Please see the reference provided on PTSD for the granularity Watts BV, Landon B, Groft A, Young-Xu Y. A sham controlled study of repetitive transcranial magnetic stimulation for 1? posltraumatic stress disorder. Brain Stimul. 2012 Commented Can glean PTSD severity from the CAPS screening version; perhaps this is something to consider, as it is clinician rated and approach to severity scoring is more likely to be Commented Minimum inclusion score for a. depression and/or anxiety? If so, use clinic-rated HAM-D A scores for inclusion. Scores of 18 for either scalc= moderate severity 'Emmented Please see above electoral genie focus Commented clari?cation in an adult patient is there any seizure disorder that we would not assume to be clinically important? This particular exclusion might be key given presumptive concerns regarding creation or acecntuation of inept Commented a list of excluded and permitted concomitant treatment (including and medicati req uired this would occur in a different section on) is Commented formal assessment is required using the Columbia Commented all medication or forms of therapy either prohibited or permitted needs to be referenced within the protocol, regardless of its intended treatment For example one could prescribe an antidepressant for reasons unrelated to core of PTSD, although it may be targeting ancillary used as an hypnotic). Clarification of "evidence-based' required Clinical providers will evaluate the patients on a weekly basis for adverse events under occur at less than I per 100,000 sessions] Subject Screening and Enrollment Prior to recruitment of any subjects into the study, be obtained from the Institutional Review Board (1 Subjects interested in participating in this clinical tri is found to be eligible for enrollment, the study cons bene?ts, and requirements will be explained. Writte will be maintained for all subjects who are screened written approval of the RB). al will be screened for [eligibilityi ent form will be reviewed and th informed consent will then be ob for enrollment but either do not qualify or decide not to participate in the study. A copy of the signed consent form will be provided to the study participant and the original signed consent form will be maintained in the subject?s medical record. 2.2 Assignment of Subject Identi?cation Once a subject has been enrolled in the study, a sequential Subject Identi?cation (Sule) Number will be on any study document other than the infomred consentiformitm? 2.3 Randomization and Blinding This study is randomized, double-blind, and placebo- at baseline following the post-washout screening analysis to one of the two treatment groups vs. lacebo treatment), at a 1:1 ratio. The group assignm iaysstigatsirs 91213959359 treatment condition. To further ensure the blindness, eat is predetermined by a computer generated random willy? the investigator performing the treatments will not be allowed to perform the assessments at any time point. The investigator will also be blinded to the exact frequency of stimulation em loyed, although the frequency algorithm purveyor (Medical Center) ifr be delayed. will have a record of chosen treatment coil. 2.4 Unblinding Procedures The randomization table will be kept in a separate ?le. It completed unless unblinding is needed. Unblinding the treatment necessary to ensure a subject?s safety. In most cases, the unblindi equenciesi TMS machine (MagVenture MagProTM). The only difference between the two procedures is the type of corls A sham coil provided by the manufacture will be identical in appearanc not generate a magnetic ?eld. The placebo coil will make click noise be reported with the SAE to the IRB. The unblindcd case will be withdrawn from the study. 2.5 Prior and Concomitant Medications Prior medications are de?ned as all medications taken within 30 days (whether continuing or not) prior to Baseline (Day 1). All prior and concomitant medications must be listed in the subject?s medical record and Eventsl adverse protocol and informed consent must thCmiamarticipam study methods, risks and tained. A screening log controlled to minimize bias. Subjects will be randomized to the treatment coil except that it will and mechanical tapping to simulate the ill not be accessible before the study is will be allowed during the study only if ng will be part ofmanaging a SAE, and will Commented suggested: patient treating physician sponsor. Biomedical IRB Application Instructions Page 8 Commented spontaneously reported, nondirectcd intcn?iew Commented reference describing the nature of adverse events Commented an informed consent is usually obtained when the screening process begins the method of randomization requires further explanation (cg. use of permuted blocks within center). additionally as this likely is a multicentcr trial. the number of centers, and the potential minimum and maximum number of patients/center should be described Commented more detail as previously described Commented assurance of trial integrity, by completely isolating the treatment clinician from the assessing clinicians is useful. This sentence implies that the sponsor will have access to treatment codes in an ongoing fashion, and therefore cannot be implicated in data review prior to analyses. Triple blinded trial is Commented Agreed, ?e have successfully done this with other studies The treating physician ?as not permitted to administer efficacy measures. as, however, allowed to administer diagnostic measures at screening. At least two different rater mlcs- efficacy rater and treating physician will need to be speci?ed For each medication taken, the following information will be collected: Medication trade name Indication for which the medication was given Dose, route, and frequency of administration Date started Date stopped. 3 STUDY MATERIALS MagPro R30 manufactured by MagVenture is a versatile ma hbovel 4 VISITS AND PARAMETERS Examination lScheduld gnetic stimulator has been previously described Treatment Sham Baseline EEG EEG - HX, RBANS, TMT, PCL-M, Hx, RBANS, TMT, PCL-M, PSQI-A, HAM-D, HAM-A, PSQI-A, HAM-D, HAM-A, FACT-G, TFI, and THI. FACT-G, TF1, and THI. Week I EEG EEG PCL-M, HAM-D, HAM-A, PSQI-A, PCL-M, HAM-D, HAM-A, PSQI-A, PHQ-9, and FACT-G PHQ-9, and FACT-G Sham/Placebo treatment Week 2 EEG EEG - RBANS, TMT, PCL-M, HAM- RBANS, TMT, PCL-M, HAM- D, HAM-A, PHQ-9, FACT-G, TFI, and D, HAM-A, PHQ-9, FACT-G, TF I, and - Sham/Placebo treatment Week 3 EEG EEG PCL-M, HAM-D, HAM-A, PCL-M, HAM-D, HAM-A, PSQI-A, PHQ-9, and FACT-G PHQ-9, and FACT-G 0 Week 4 EEG EEG - RBANS, TMT, PCL-M, PSQI-A, HAM- RBANS, TMT, PCL-M, PSQI-A, HAM- D, HAM-A, PHQ-9, FACT TFI, and D, HAM-A, PHQ-9, ACT-G, TFI, and THI. Week 5 EEG EEG - PCL-M, HAM-D, HAM-A, PSQI-A, PCL-M, HAM-D, HAM-A, PSQI-A, PHQ-9, and FACT-G and FACT-G Week 6 EEG EEG - PCL-M, HAM-D, HAM-A, PSQI-A, RBANS, TMT, PSQI-A, HAM- PHQ-9, and FACT-G D, HAM-A, PHQ-9, FACT-G, TF1, and THI. Week 7 EEG EEG - PCL-M, HAM-D, HAM-A, PSQI-A, PCL-M, HAM-D, HAM-A, PSQI-A, PHQ-9, and FACT-G PHQ-9, and FACT-G Week 8 EEG EEG - Hx, RBANS, TMT, PCL-M, PCL-M, HAM-D, HAM-A, PSQI-A, HAM-D, HAM-A, PHQ-9, PHQ-9, and FACT-G FACT-G, TFI, and THI. Biomedical IRB Application instructions Page 9 . Commented As previously mentioned, clari?cation that this is an FDA approved device for TMS, and that the stimulation parameters are within the framework and consistent with parameters have already been approved (Commoner! as a general suggestion, the sequence of the assessments should be specified within each visit, thereby obviating orcontrolling for sequence effects within session. Also, con?rmation that the ?cquency of these assessments - generally on a weekly basis are consistent with guidance for use of the measure to examine) Commented Recommendation is: Diagnostic measures: MINI v.7 CAPS RBANS and TMT to be done first, to ensure patients are as alert and focused as necesary ~Consider clinician rated. structured interview guides for the depression and anxiety measrues. for more standardired approaches to scoring, potential for reduced variability, as well as reducing the possibility of placebo response. Done in this order: -Considcr the MADRS as the depressive measure (Montgomery Asberg Depression Scale) has proven to be a more sensitive efficacy measure in clinical trials over the HAM-D. The SIGMA (structured interview guide) is shorter than the one for (note: is widely used for inclusion, with MADRS as efficacy) (Structured Interview Guide for HAM-A) -"lhough there are correlating items, fewer similar items bw MADRS HAM-A than between HAM-D HAM-A clinician rated. and can be utilized to assess PTSD severity. would utilize the past week version (Columbia Suicide Severity Rating Scale)- necessary as a safety measure. done at each visit should be the last scale rated. Answers to these questions can potentially be gleaned from earlier assessments; however, if done first and a hx of suicidality, this may in?uence answers to MADRS and items -May want to consider: Global Impression Scale- Severity (at screen) and Change (to rate level of improvement. clinician rated). This scale is rated after all clinic-rated assessments are completed. This is not an interview "Weekly administration of above scales is appropriate PROS (Patient Reported Outcomes) to be done afler clinic rated scales. ??Nolc PHQ-9 has a 2 week timcframc PCL, is a Quality of Life measure but associated with Cancer Treatment (validated with cancer patients). Consider other measures, arch as the SF-36, QLS. or EQ-SD-SL Week 9 0 None 0 EEG PCL-M, HAM-D, HAM-A, PHQ-9, and FACT-G Week 10 0 None 0 EEG 0 Hx, RBANS, TMT, PCL-M, HAM-D, HAM-A, PHQ-9, FACT-G, TF1, and 4.2 Clinical Parameters The clinical parameters to be evaluated are: l. EEG: per above 2. Physical Examination (including medical and history): Screening, Baseline and weeks 10, for treatment group and sham group, at completion of study. 3. Vital Signs (blood pressure, heart rate, respiration rate): Screening, Baseline and weeks 8 10, for treatment group and sham group, at completion of study. 4. Weight and height: Baseline, and weeks 8 10, for treatment group and sham group, at completion of study. 5. Neurobehavioral/cognitive battery evaluation: per above 6. Adverse Events: At each and every visit and at each evaluation point 4.3 Withdrawal from Study Subjects have the right to withdraw from the study at any time, for any reason, without jeopardizing his/her medical care. The Investigator and the IRB have the right to withdraw subjects or terminate the trial for the following reasons: 9. Occurrence of unacceptable risk to the subjects enrolled in the study. 10. A decision on the part of the investigative team to suspend or discontinue testing, evaluation, or development of the product. The Investigator may use the weekly clinical evaluation to determine if the subject?s or quality of life have signi?cantly heterioratect?ubiectinho withdraw from ?119.5I1t4xf0r aaxrcason will._n_9t harmless: Subjects who voluntarily withdraw from the study will be asked to complete the Early Termination assessments. Subjects who are withdrawn due to adverse events will be followed until resolution or stabilization of the adverse event. 5 STUDY OUTCOMES 5.1 Primary Efficacy Outcome The primary efficacy outcome measure will consist of the percentage change in CAPS-5 total score at the end of week 8 of treatment. Treatment ef?cacy will be de?ned as a statistically signi?cant reduction in CAPS-5 total score of the active treatment group compared to the control treatment group at the end of week 2. 5.2 Secondary Outcomes The secondary efficacy outcomes will include the comparison of subjects between and sham treatment groups at the end of 2 weeks of treatment. Percentage changes over the course of the 8 weeks of treatment will These additional outcomes are the score changes and comparison of the Functional Assessment of Cancer Therapy General (F ACT-G), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Commented a diagnostic interview for axis and Axis ll disorders is prudent within teleconference. the MINI was recommended Commented further clari?cation as to the algorithm permitting a physician to discontinue a subject otherwise. only patients doing "well" complete the protocol, and all patients potentially having any transient deterioration for whatever reason are discontinued the protocol selects out only good responders regardless of treatment group assigned Commented within group comparison? Biomedical IRB Application Instructions Page 10 Anxiety (HAM-A), Patient Health Questionnaire 9 (PHQ-9), Repeatable Battery for Neurophysiological Status (RBANS), Tinnitus Functional Index (TF1), Tinnitus Handicap Inventory (THI), and Pittsburgh Sleep Quality Index 5.3 Safety Data Safety will be assessed by the adverse event log and weekly evaluation of the patient in regards to headache, possible seizure activity or any other unanticipated neurologic or physiological change. 6 STATISTICAL METHODS This is a prospective, randomized, double-blind, controlled trial to evaluate the safety and ef?cacy of compared to standard in subjects with posttraumatic stress disorder. The objective of this study is to establish the ef?cacy of the treatment in comparison to standard treatment in the similar affected population. The primary ef?cacy endpoint is the [reduction in measured by CAPS-5 total baseline to treatment week 8. Secondary ef?cacy endpoint is the number of clinical tesponders as measured by the additional outcomes of Trail Making Test A (TMT Repeatable Battery for the Assessment of Status (RBANS), Patient Health Questionnaire-9 (PHQ-9), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), Functional Assessment of Cancer Therapy General (F Tinnitus Functional Index (TF1), Tinnitus Handicap Inventory (THI), and Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A) between and standard treatment 6.1 Primary Ef?cacy The primary ef?cacy outcome measure will consist of the change in PCL-M total score at the end of week 8 of treatment. Treatment ef?cacy will be defmed as a statistically signi?cantly greater reduction in mean PCL-M total score of the active treatment group compared to the sham treatment group. Linear model of analysis of variance (ANOVA) with repeated measure of time will be used to test the statistical signi?cance of overall grouping variance and treatment by time effect interaction. Clinical improvement will be calculated as percentage change in the following formula Baseline PCLM WeekZ PCLM Baseline PCLM Phasel Change Score Post-hoe Student t?test will be used to delineate the e?ect of treatment and ltimeJL 6.2 Secondary Ef?cacy Outcomes The secondary ef?cacy outcome will include the comparison of number of subjects with iclinically signi?cant response ibetneen steedere treatmentaeupe-et the endeftt weeks ef baseline and end of week 2 compared to week 10 as measured by, Trail Making Test A (TMT Repeatable Battery for the Assessment of Status (RBANS), Patient Health Questionnaire-9 (PHQ-9), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), Functional Assessment of Cancer Therapy General Tinnitus Functional Index (TF1), Tinnitus Handicap Inventory and Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A) between and standard treatment groups. Nonparametric data will be tested with Chi Square. measure will consist of the change in PCL-M total score at the end of week 10 of treatment. Linear model of analysis of variance (ANOVA) with repeated measure of time will be used to test the statistical si i?cance of overall grouping variance and treatment by time effect interaction. The end of Phase I Biomedical Application Instructions Page 11 - Commented Additional detail required. including listing these in a hierarchical fashion of importance To be discussed is the use of the term "key secondary outcome". Within drug divisions ofthe FDA, and in particular the division of products (assuming they are implicated in review) all of the above dictates product labeling Commented absolute change versus percentage change "i Commented respondct de?nitions required Commented sample size justi?cation is missing from this section. and should be provided as a stand-alone paragraph Commented additional contributions by WCT biostatistics requested for this section de?nitions regarding response criteria evaluation will be used as second baseline for Phase 2 assessment to calculate the percentage change in in the following formula Baseline PCLM Week8 PCLM 0 Total Change Score Baseline PCLM 100 Ph 2 Ch 3 (y WeekZ PCLM WeeklO PCLM 100 ase ange core( 0) WeekZ PCLM Student t-test will be used post?hoc to compare the mean Change Score difference between and standard treatment groups to delineate signi?cant time-point steps. In addition, parameters associated with PTSD will be established and examined at baseline, and will be expected to improve with statistical signi?cance in the group as compared to Sham treatment, the Sham group are expected to normalize along the same pattern as seen in the treatment group. Comparison to neurocognitive batteries and quality of life assessments will act as a means to standardize the use of as an assessment _g The fdurabilityiof thehclirtical effect will__be_us_ed as another outcome. Evaluations at 3,6, and 12-monthpost- treatment will be used-has comparisons. Optimal length oftreatiilent (2-8 weeks) will alsioub?emassessed by analyzing magnitude and durability of clinical effect from treatment time points. 6.3 Safety Outcomes Safety will be assessed by counting the incidence of adverse events, if any. Most notably special attention will be paid to headache, seizure or any other adverse neurological change from baseline. 7 SOURCE DOCUMENTS Source data is all information, original records of clinical ?ndings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents. Examples of these original documents, and data records include: hospital records, clinical and of?ce charts, laboratory notes, memoranda, subjects? diaries or evaluation checklists, device dispensing records, recorded data from automated instruments, copies or transcriptions certi?ed a?er veri?cation as being accurate and complete, micro?ches, photographic negatives, micro?lm or magnetic media, x-rays, subject ?les, and, at the laboratories, and at medico-technical departments involved in the clinical trial. 8 CASE REPORT FORMS il'he study case report form (CRF) is the primary data collection instrument for the study. All data requested on the CRF must be All. missitiagiatamust. be explained-if a .CRF. iaisitpiank basaltss? the procedure was not done or the question was not asked, write If the item is not applicable to the individual case, write All entries should be printed legibly in black ink. If any entry error has been made, to correct such an error, draw a single straight line through the incorrect entry and enter the correct data above it. All such changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clari?cation of illegible or uncertain entries, print the clari?cation above the item, then initial and date it. 9 RECORDS RETENTION It is the investigator?s responsibility to retain study essential documents for at least 2 years a?er the study is completed. Biomedical IRB Application Instructions Page 12 Commented parameters are not speci?ed. as are de?nitions ofnormalization or improvement based upon these parameters Commented sentence is not clear? nature of comparison to being employed. and the decision made based upon that comparison As a general point, this may all be deferred into a companion statistical analysis plan and not fully specify within protocol Commented please see comment within the graphic provided Commented data capture methods TBD 10 ETHICAL CONSIDERATIONS This study is to be conducted according to US and international standards of Good Clinical Practice, applicable government regulations and institutional research policies and procedures. This protocol and any amendments will be submitted to a properly constituted independent Institutional Review Board for formal approval of the study conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this decision will be provided to the sponsor before commencement of this study. The investigator should provide a list of members and his/her af?liate to the sponsor. All subjects for this study will be provided a consent form describing this study and providing suf?cient information for subjects to make an informed decision about his/her participation in this study. See Attachment for a copy of the Subject Informed Consent Form. This consent form will be submitted with the protocol for review and approval by the IRB for the study. The formal consent of a subject, using the IRE-approved consent form, must be obtained before that subject undergoes any study procedure. The informed consent form must be signed by the parents or legally acceptable surrogate, and the investigator-designated research professional obtaining the consent. 11. RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH Patients will be recruited from the principal investigators practice at Naval Medical Center San Diego, and/or from other centers as lappropriatelm 12. INFORMED CONSENT Subjects interested in participating in this clinical trial will be screened for eligibility. If a potential participant is found to be eligible for enrollment, the study consent form will be reviewed with the subject?s legal custodian and the study methods, risks and bene?ts, and requirements will be consent will then be obtained. A screening log will be maintained for all subjects who are screened for enrollment but either do not qualify or decide not to participate in the study. A copy of the signed consent form will be provided to the study participant and the original signed consent form will be maintained in the subject?s medical record. 13. ALTERNATIVES TO STUDY PARTICIPATION The alternative is to not participate in the current study. 14. POTENTIAL RISKS is a noninvasive method to cause depolarization or hyperpolarization in the neurons of the brain. It uses electromagnetic induction to induce weak electric currents using a rapidly changing magnetic ?eld. These weak electrical currents may cause activity in speci?c or general parts of the brain. There is typically no or very little discomfort with A variety of protocols have been tested as a treatment tool for various neurological and disorders including migraines, strokes, Parkinson?s disease, dystonia, tinnitus, depression and auditory lhallucinationsLm Most treatment protocols are carried out with uni?ed stimulation parameters, such as le? dorsolateral prefrontal cortex (DLPF C) stimulation for patients with major depressive disorder using 10 Hz repetitive pulses at 120% motor threshold. Our highly individualized EEG-guided protocol of personalized is tailored speci?cally to each patient?s intrinsic alpha ?equency as determined by the predominant alpha presence in the occipital and parietal leads. For extra safety parameters, sub-threshold stimulation intensity is set at 50-60% of motor threshold, and the location is determined by the EEG mapping that shows the area with the most apparent alpha wave de?cit. Biomedical IRB Application Instructions Page 13 trial, list the maximum number ofcenters to be inclu and within the text indicate the number of patients/center protocol must specify this is a dcd. Commented clari?cation of timing of informed consent Commented this paragraph appears to be written for the patient, the subsequent paragraph for the clinician. In general, there is a mixture of content in this section appropriate for either a patient, or a clinician. but not both. What is the intention ol'scction l4? Is this the informed consent for the patient? The FDA has approved for the treatment of adult major depressive disorder. While we anticipate no increased risk between personalized and standard there remains a lack of clinical trials to prove this. Our clinical trial will help provide this evidence. Transient headache is the most common adverse effect of in adults. This most commonly resolves spontaneously or may require mild analgesics. High-frequency has been reported to induce seizures, and induce manic switch and delusions in patients with depression25'2". lHowever, severe adverse events associated with have rarely been reported and most were found to be mild and rare; Seizure was the most serious adverse event, and occurred in a 0. l6% crude per-subject risk?. Other studies suggest that treatment of resistant depression in adolescents do not have long-term cognitive deterioration?. It seems that some subjects may derive long-term benefit from the course. Another review article on the safety ef?cacy in children showed that most subjects responded favorably to the treatment and no adverse events were reportedzs??. In conclusion, the Medical Center (MSC) believes that especially with reduced intensity and individualized frequency coupled with EEG monitoring, is a very safe procedure when applied to patients with PTSD and associated neurocognitive disorders. 15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES EVALUATION OF . . .. An adverse event (AB) is de?ned as any untoward medical occurrence in a subject treated with an investigational product, and does not necessarily have to have a causal relationship with the treatment under investigation. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory ?nding), or disease temporally associated with the use of an investigational product whether or not considered related to the investigational product. A Serious Adverse Event (SAE) is de?ned as an adverse event that results in any of the following outcomes: Results in death Is life-threatening Requires hospitalization or prolongation of existing hospitalization Results in persistent or signi?cant disability/incapacity Is a congenital anomaly or birth defect An unanticipated adverse device event (UADE) is defmed as any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identi?ed in nature, severity, or degree of incidence in the protocol and/or Instruction For Use or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of the subject. All adverse events that do not meet any of the criteria for SAEs or UADEs should be regarded as non-serious adverse events. Progression ofdisease re?ects lack of therapeutic efficacy and should not be treated as serious adverse events. However, other events or complications meeting the criteria for serious adverse events should be considered as a serious adverse event and should be reported to regardless of presumed relationship to the investigational treatment. 1. Adverse Event Assessment All adverse events, including the following, will be assessed by the investigator, and recorded in the subjects study chart and on the appropriate case report form pages. Biomedical IRB Application Instructions Page 14 Commented Further clari?cation. The sentence appears to be at odds against the one previous description othem'ise. Vhat have been the serious adverse events, frequency, reversibility appears to be consistent TBD by WCT please see protocol template provided by Sriqu Shah in medical writing jar-[Commented Standard FDA nomenclature required 1 Observed or volunteered problems Complaints Physical signs and Medical condition which occurs during the study, having been absent at baseline Medical condition present at baseline, which appears to worsen during the study The need to capture AEs is not dependent upon whether or not the clinical event is associated with the use of the investigational treatment. Severity will be assessed using the following de?nitions: Mild Aware of Sign or but easily tolerated Moderate Discomfort enough to cause interference with usual activity Severe lncapacitating with inability to work or do usual activity The relationship to investigational treatment will be assessed by the investigator using the following de?nitions: Not Related. Evidence exists that the adverse event de?nitely has a cause other than the investigational treatment preexisting condition or underlying disease, intercurrent illness, or concomitant medication) and does not meet any other criteria listed. Possibly Related. A temporal relationship exists between the event onset and administration of investigational treatment. Although the adverse event may appear unlikely to be related to the investigational treatment, it cannot be ruled out with certainty; and or the event cannot be readily explained by the subject?s clinical state or concomitant therapies. Probably Related. A temporal relationship exists between the event onset and administration of investigational treatment, and appears with some degree of certainty to be related based on known therapeutic and phannacologic actions of the investigational treatment. It cannot be readily explained by the subject?s clinical state or concomitant therapies. De?nitely Related. Strong evidence exists that the investigational treatment caused the adverse event. There is a temporal relationship between the event onset and administration of the investigational treatment. There is strong therapeutic and phannacologic evidence that the event was caused by the investigational treatment. The subject?s clinical state and concomitant therapies have been ruled out as a cause. 2. Adverse Event Reporting All subjects who have been exposed to investigational treatment will be evaluated for adverse events. All adverse events will be evaluated beginning with onset, and evaluation will continue until the last day of the study, until resolution or recovery is observed or until the investigator determines that the subject?s condition is stable, whichever is earlier. The investigator will take all appropriate and necessary therapeutic measures required for resolution of the adverse event. Any medication necessary for the treatment of an adverse event must be recorded on the concomitant medication case report form. If more than one distinct adverse event occurs, each event should be recorded separately. The study period during which adverse events must be reported is normally de?ned as the period from the initiation of any study procedures to the end of the study treatment follow-up. For this study, the study treatment follow-up is de?ned as 14 days following the last administration ofstudy treatment. 3. Reporting of Serious Adverse Events and Unanticipated Adverse Device Effects Biomedical IRB Application Instructions Page 15 All Serious Adverse Events (SAE) and Unanticipated Adverse Device Effects that occur during the study, including death, must be reported within one working day by telephone to Study?s Medical Monitor, and followed up in writing within 24 hours. The urgency for reporting SAE is four-fold: to facilitate discussion (and implementation, if necessary) by the sponsor and the Investigator of appropriate follow-up measures; (2) to facilitate Investigator reporting of unanticipated problems involving risk to human subjects to the (3) to facilitate the sponsor?s rapid dissemination of infonnation regarding ABS to other Investigators/sites in a multi- center study; and (4) to enable the sponsor to fulfill the reporting requirements to the appropriate regulatory authority. Within the following 48 hours, the investigator must provide further infomiation on the serious adverse event or the unanticipated problem in the form of a written narrative. This should include a copy of the completed Serious Adverse Event form, and any other diagnostic infomration that will assist the understanding of the event. Signi?cant new information on ongoing serious adverse events should be provided to the study sponsor. 16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT CONFIDENTIALITY Information about study subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and Accountability Act of 1984 (HIPAA). Those regulations require a signed subject authorization informing the subject of the following: What protected health information (PHI) will be collected from subjects in this study Who will have access to that information and why Who will use or disclose that information The rights of a research subject to revoke his/her authorization for use of his/her PHI. In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all information collected prior to the revocation of subject authorization. For subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status that the subject is alive) at the end of his/her scheduled study period. 17. POTENTIAL BENEFITS As noted above. 18. RATIO As noted above. 19. EXPENSE TO PARTICIPANT - There will be no expense to the participant. 20. COMPENSATION FOR PARTICIPATION There will be no compensation for participation. Biomedical IRB Application Instructions Page 15 21. AND RESEARCH TEAM RESPONSIBILITIES Not applicable. 22. BIBLIOGRAPHY 20. American Association, American Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders 4th ed. Washington, DC: American Association; 2000. Breslau N. Outcomes ol?posttraumatic stress disorder. [in 2001 :62 Suppl 17:55-59. Vasterling JJ, Brailey K, Constans .iI, Sutker PB. Attention and memory dysfunction in posttraumatic stress disorder. Neuropsi-?chology. Jan 1998;12( Vasterling Duke LM. Brailey K. Constans Jl. Allain AN, Sutker PB. Attention. leaming, and memory performances and intellectual resources in Vietnam veterans: PTSD and no disorder comparisons. Jan 20021160 Breslau N, Davis GC, Andreski P, Peterson E. Traumatic events and posttraumatic stress disorder in an urban population of young adults. Arch Gen Mar Kessler RC, Sonnega A. Bromct E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Dec 1995;52( Yehuda R. Post-traumatic stress disorder. Eng] Med. Jan 10 2002:3468): 108-1 14. Breslau N. The epidemiology ofposttraumatic stress disorder: what is the extent of the problem? [in 2001 :62 Suppl 17:16-22. Thomas JL. Wilk JE, Riviere LA, McGurk D. Castro CA, Hoge CW. Prevalence ofmental health problems and functional impairment among active component and National Guard soldiers 3 and 12 months following combat in Iraq. Arch Gen Pg?chiatljv. Kehle SM. Reddy MK. Ferrier-Auerbach AG. Erbcs R, Arbisi PA, Polusny MA. diagnoses. comorbidity, and functioning in National Guard troops deployed to Iraq. P.9?chiatr Res. Jun 9 . Davidson .IR, Hughes D, Blazer DG. George LK. Post-traumatic stress disorder in the community: an epidemiological study. Med. Aug 199] . Kessler RC. Posttraumatic stress disorder: the burden to the individual and to society. ]in 2000;61 Suppl 5:4-12; discussion 13-14. . Hien DA, .liang H. Campbell AN, Hu MC, Miele GM. Cohen LR. Brigham GS. Capstick C, Kulaga A. Robinson .1, Suarez-Morales L, Nunes EV. D0 treatment improvements in PTSD severity affect substance use outcomes? A secondary analysis from a randomized clinical trial in NIDA's Clinical Trials Network. Am Jan; 167( 1 ):95-101. Stein DJ, lpser .IC, Seedat S. Phamiacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Rev. . Van Etten ML, Taylor S. Comparative Ef?cacy of Treatments for Post-traumatic Stress Disorder: A Meta-Analysis. Clin. 199815: 126-144. Bisson .1, Andrew M. treatment of post-traumatic stress disorder (PTSD). ochrane Database Rev. . Breslau N. Outcomes ofposttraumatic stress disorder. [in 2001 :62 Suppl 17:55-59. . Maschio, Marta, Francesco Marchesi, Sabrina Dispenza, Loredana Dinapoli, Francesca Sperati, Gianluca Petreri, Svitlana Gumenyuk, Maria Laura Dessanti, Alessia Zarabla, Tonino Cantelmi, and Andrea Mengarelli. "Effect of High Dose Cytosine Arabinoside on Quantitative EEG in Patients with Acute Myeloid Leukemia." Cogn Neurodyn Cognitive Nearoafvnamics 10.2 (2016): 185?88. . George MS, Lisanby SI-I, Avery D, et a1. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen 2010; 67:507. Dlabac-de Lange JJ, Knegtering R, Aleman A. Repetitive transcranial magnetic stimulation for negative of schizophrenia: review and meta-analysis. Clin 2010; 71:411. Biomedical IRB Application Instructions Page 17 21. Mtinchau A, Bloem BR, Thilo KV, et al. Repetitive transcranial magnetic stimulation for Tourette Neurology 2002; 59: 1789. 22. Pollak TA, Nicholson TR, Edwards David AS. A systematic review of transcranial magnetic stimulation in the treatment of functional (conversion) neurological Neurol Neurosurg 2014; 85:191. 23. Sokhadze EM, El-Baz A, Baruth J, et al. Effects of low frequency repetitive transcranial magnetic stimulation on gamma frequency oscillations and event-related potentials during processing of illusory ?gures in autism. Autism Dev Disord 2009; 39:619. 24. O'Reardon JP, Solvason HB, Janicak PG, et al. Ef?cacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol 2007; 62: 1208. 25. Bae EH, Schrader LM, Machii K, et al. Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature. Epilepsy Behav. 26. Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis V, Politis A, et al. Induction of mania by Report of two cases. Eur 2003; I 8: 196?8. 27. Dunner DL, Aaronson ST, Sackeim HA, et al. A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a I-year follow-up period. Clin 2014 Dec;75( 12): 1394?401. 28. Walter l, Torrnos JM, Israel JA, Pascual-Leone A, et al. Transcranial magnetic stimulation in young persons: a review of known cases. Child Adolesc 2001 Spring;1 29. Rossi et al. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol (2009), 23. FUNDING SUPPORT FOR THIS STUDY This study is fully funded through the research account of Dr. Kevin T. Murphy, with monies escrowed in a UC San Diego Health System research account. 24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT There is no required Biological Materials Transfer Agreement. 25. INVESTIGATIONAL DRUG FACT SHEET AND HOLDER Not applicable. 26. IMPACT ON STAFF The current study will have no impact on existing staff. 27. CONFLICT OF INTEREST The primary investigators have no con?ict of interest in the performance of the study. 28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES None 29. OTHER APPROVALSIREGULATED MATERIALS Not applicable. 30. PROCEDURES FOR SURROGATE CONSENT DECISIONAL CAPACITY ASSESSMENT Subjects interested in participating in this clinical trial will be screened for eligibility. If a potential participant is found to be eligible for enrollment, the study consent form will be reviewed with the subject?s egall Biomedical IRB Application Instructions Page 18 consenting process bcgi fl commented as has been previously suggested ns with screening process. 3 custodian and the study methods, risks and bene?ts, and requirements will be explained. Written informed consent will then be obtained. A screening log will be maintained for all subjects who are screened for enrollment but either do not qualify or decide not to participate in the study. A copy of the signed consent form will be provided to the study participant and the original signed consent form will be maintained in the subject?s medical record. Biomedical IRE Page 19