A multicenter randomized controlled trial of the effectiveness of amantadine

Protocol

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

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

Procedures Manual for:

A multicenter randomized controlled trial of the effectiveness of amantadine

hydrochloride in promoting recovery of function following severe TBI

8 ^th Revision

5/20/09

PI: Joseph T. Giacino, Ph.D.*

JFK Johnson Rehabilitation Institute 2048 Oak Tree Rd.

Edison, NJ 08820

Co-PI: John Whyte, MD, Ph.D.

Moss Rehabilitation Research Institute 60 E. Township Line Rd.

Elkins Park, PA 19027

Funded by the National Institute on Disability and Rehabilitation Research Award # H133A031713

*Current address:

Spaulding Rehabilitation Hospital Joseph T. Giacino, PhD

125 Nashua St.

Boston, MA 02114

TABLE OF CONTENTS

Section Page

Study Overview………....…………. 3

Protocol Synopsis………....…….……. 5

Protocol Outline………. 14

Plan for Data Analysis………..……… 10

Protocol Instructions………...………..………... 19

DRS Screening Exam………..…. 19

Patient Recruitment Tracking………..………... 21

Monitoring and Submitting Recruitment Statistics………...…… 24

Consent Procedures………..…. 26

Prohibited Drug Taper Guidelines……… 28

Guidelines for Treatment of Specific Clinical Problems………..…… 32

CT/MRI Studies……….………..…. 35

Creatinine Clearance Screening……… 36

Final Review of Inclusion/Exclusion Criteria ………..… 37

DRS/CRS-R Enrollment Exams………..……….. 38

Participant Enrollment and Randomization……….….………. 40

Concomitant Medication Inventory………..……….… 42

Transfer of CT/MRI Data……….……….…… 43

Completing Enrollment Checklist to Identify Treatment Precautions…………... 44

Establishing Pre-Treatment Symptom Baseline……….………... 46

Extraction of Demographic and Acute Course Data………. 47

Administration of Study Drug………..…..….. 49

Drug Accountability Log………. 49

Procedure for Managing Unanticipated Drug Shortage………... 50

Follow-Up Assessments (Weeks 1-4)……….….. 53

Weekly DRS Exam……….. 53

Recording Patient Location……….. 53

Concomitant Medication Monitoring………... 54

Adverse Event Monitoring………..…. 55

Week 4 CRS-R Exam………... 59

Study Drug Taper……….. 60

Protocol Violations……… 61

Guidelines for Breaking the Blind……….…… 62

Reporting Deaths………. ……. 64

Interim DRS and CRS-R Exams………... 65

Data Collection on Patients Discharged before Study Completion…………..… 66

Study Completion Procedures……….…….. 67

Data Quality Monitoring Procedures………. 68

Summary of Amendments to Procedures Manual………. 69

Study Overview

This is a manual of operations for the conduct of the clinical trial entitled, “A multicenter randomized controlled trial of the effectiveness of amantadine hydrochloride in promoting recovery of function following severe TBI.” This study is a multicenter prospective randomized double blind placebo controlled trial designed to determine whether participants treated with amantadine hydrochloride (AH) during acute inpatient rehabilitation achieve more significant functional recovery than those who receive placebo. The purpose of the manual is to provide guidance to ensure the standardized collection of all data and maximize the safety of research participants. While all encounters in clinical practice cannot be anticipated, we have attempted to provide a description of procedures for the most common situations as well as for the less frequent ones. Despite this, situations may arise in which the appropriate procedure is not evident. Please contact the study PI or Co-PI for additional assistance.

From time to time, we will prepare additions and amendments to this manual. Please store these documents with the manual and list them on the place provided in the Table of Contents.

The manual consists of detailed descriptions of the procedures for this study. In addition, the required start up documentation is reviewed and guidelines for record-keeping, data transfer, storage of source documents, compliance with local Institutional Review Board regulations, obtaining consent and other regulatory documentation is described.

This manual is organized by study phase. The study protocol involves five phases: Pre- Enrollment, Enrollment, Treatment, Treatment Follow-up and Termination. The Pre-Enrollment phase encompasses activities between the time a potential subject is identified and the time of final enrollment. Following re-confirmation that the subject meets the eligibility criteria, the Enrollment phase begins with submission of randomization data to the DCC and ends when the DCC advises the clinical site which coded medication bottle to use for the subject. At this point, the participant is considered enrolled and will be included in the cohort that is entered into the intention-to-treat analysis. The treatment phase commences with the initial medication dose and concludes after completing the fourth weekly DRS examination. The Treatment Follow-up phase begins at the end of week 4 after the medication has been stopped. This phase ends two weeks after the subject has been off the medication. The Termination phase is initiated with submission

of the Study Completion form and concludes after the subject is offered an open-label trial of AH.

An outline of the procedures required during each phase of the protocol is provided on page 14.

The manual also includes detailed instructions for completing the Case Report Forms (CRF) that are required at each study phase.

Protocol Synopsis

Study Title: A multicenter randomized controlled trial of the effectiveness of amantadine hydrochloride in promoting recovery of function following severe TBI.

Sample: Rehabilitation inpatients between ages 16 and 65 unable to follow commands or communicate reliably between 4 and 16 weeks post-traumatic brain injury.

Objective: To determine the safety and effectiveness of AH in promoting recovery of

consciousness and function in patients diagnosed with the vegetative state (VS) or the minimally conscious state (MCS).

Primary Aims:

1. To determine whether AH, given in a dose of 200 - 400 mg/day improves functional recovery from VS and MCS.

2. To determine whether any AH-related gains in function persist following drug discontinuation.

Secondary Aims:

1. To determine whether the response to AH differs by time post-injury, or according to whether the patient is in VS or MCS at the time of treatment initiation.

2. To determine whether degree of recovery and/or degree of AH response is affected by injury history or nature of the neuropathology.

3. To determine whether any improvement in recovery related to AH treatment corresponds to clinically meaningful change in the eyes of caregivers.

4. To evaluate the safety of AH given in this dose to this patient population.

Study Design:

Prospective randomized double blind placebo controlled trial with stratification by diagnosis and length of time post-injury.

Sample Size:

184 participants will be enrolled over 6.5 years (amantadine group n = 87; placebo group n = 97).

Inclusion Criteria:

Individuals between ages 16 and 65 with traumatic brain injury as defined by the TBI Model System syllabus (i.e., damage to brain tissue caused by an external mechanical force as

evidenced by loss of consciousness or post-traumatic amnesia due to brain trauma, skull fracture, or objective neurological findings that can be reasonably attributed to TBI on physical or mental status examination) who are at least 4 weeks but less than 16 weeks post-injury and have a Disability Rating Scale (DRS) score at enrollment of 12 or greater, and no consistent command following or functional communication (as defined by the JFK Coma Recovery Scale-Revised (CRS-R)).

Exclusion Criteria:

Women who are pregnant, individuals with missile-type penetrating brain injury, premorbid major CNS/developmental abnormality (e.g., mental retardation, prior significant brain damage, etc.), history of more than 1 seizure (clinical or electrographic, but not including epileptiform or other irritative discharges) in the 4 weeks prior to enrollment (individuals with premorbid idiopathic epilepsy are eligible to enroll under two conditions: a) if their pre-injury seizure frequency was less than once/month and they have had no more than 1 seizure/month since injury and b) if a clear provocation was present that would otherwise disqualify a subject, the subject can be enrolled, since these events would not be considered idiopathic), prior exposure to AH post-TBI, unwillingness to discontinue or change confounding psychotropic drugs prior to enrollment, allergy or medical contraindication to AH and significant impairment of renal function (as evidenced by a calculated creatinine clearance of < 60 ml/min)

Formulation:

For seven of the 8 participating clinical sites in the U.S., the study medication will be prepared and distributed by a central pharmacy located in New York. The eighth U.S. site will receive study medication from an in-state supplier as state laws in North Carolina prohibit medication delivery from an out-of-state provider. AH will be prepared as a 100mg/ml dose in a 90ml pink, raspberry flavored solution and packaged in a 90ml amber prescription bottle meeting USP requirements labeled with the medication name, strength, quantity, lot number, beyond use date, trial name or code and randomization number. Placebo will be prepared in an identical fashion.

Both medications will be blinded to appearance, smell and taste. The European sites will receive study medication from a research pharmacy located in Germany. The formulas used to produce AH and placebo will be indistinguishable from those used by the U.S. centers.

Outcome Measures:

Primary:

Disability Rating Scale score (at enrollment and weekly from week 1 through week 6 post- enrollment).

Secondary:

JFK Coma Recovery Scale- Revised score (at enrollment and after weeks 4 and 6 post- enrollment).

Adverse Events (weekly from enrollment through termination).

Safety Parameters:

CT or MRI of the brain will be obtained within two weeks of enrollment to rule out

hydrocephalus and other undetected complications. Adverse events and medical complications

will be monitored weekly. The pattern of adverse events in relation to drug dose will be

examined to provide the option to stop dose escalation rather than discontinuing the medication.

Dosing Schedule:

All participants will be randomized by the DCC to receive either 100mg (2x/day at 6:00am and 2:00pm) of AH or placebo. All medications will be administered through a feeding tube. After 2 weeks of treatment, those participants whose DRS scores do not improve by at least 2 points from their score at randomization will receive a dosage increase to 150 mg (2x/day at 6:00am and 2:00pm) of AH (or an adjustment of their placebo dose). After 3 weeks of treatment, those participants who still have not improved by at least 2 points from their score at randomization will be increased to 200 mg (2x/day at 6:00am and 2:00pm). This approach was chosen to

minimize exposure to high doses of AH among those participants who are recovering briskly, but to ensure that those who are not showing rapid recovery receive the maximal tolerated dose prior to abandoning the intervention. After 4 weeks of treatment, the study medication will be tapered by 100 mg/dayover 1 - 3 days depending on the final dose achieved.

Data Analyses:

“Intention-to-treat” Analysis All analyses will be conducted blindly, according to the intention- to-treat principle . All subjects randomized to the study and followed up will be included in the statistical analysis, regardless of protocol violations or treatment compliance.

The most common protocol violation anticipated is the concurrent administration of

psychoactive medications with potential to interfere with AH or, alternatively, potentiate its effects. Other potentially confounding violations include neurosurgical interventions, serious adverse events, functional deterioration and increase in seizure frequency. Subjects who violate

the protocol will remain in the study, even if they discontinued the study drug before the full four week course.

The following contingencies have been put in place to guide decision-making relative to continuation of the study medications:

• Exposure to “prohibited” psychoactive drugs: In order to reduce the likelihood of study participants receiving confounding “prohibited” drugs, a list of the clinical problems most likely to require treatment in this patient population was developed, and an order of treatment choices for each condition prepared. This list will be available to all investigators. Alternative treatments have been “prescribed” in a prioritized order to minimize confounding drug interactions. For some problems, all available treatments would constitute a protocol violation, if given. Study participants that are already on medications at the time of consent, will need to be withdrawn from those medications that are “prohibited,” but not from other prioritized treatment options.

Once in the study, if a clinical problem requires treatment, the treating physician will be asked to prescribe drugs for these conditions in the order listed unless the patient has a specific

contraindication to the recommended treatment, or until the patient fails treatment with a previous treatment choice. This constraint on routine clinical practice has been IRB-approved and discussed in the informed consent document.

• Neurosurgical/Medical Procedures: Participants should continue to receive the assigned study drug unless, in the view of the treating physician, AH administration is deemed unsafe. If the treating physician believes that AH should not be given peri-operatively, but could be

resumed at a later time, the study participant should receive as much of the scheduled study drug as possible within the 4-week treatment window.

• Adverse events: AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal lab finding), syndrome or disease which either occurs during the

study (having been absent at baseline), or, if present at baseline, appears to worsen. Adverse events that are serious and assessed as possibly, probably, or definitely associated with the study drug, will result in discontinuation of the drug. Adverse events that are mild, moderate, or severe and possibly, probably, or definitely associated with the study drug may also result in

discontinuation, depending on the physician’s judgment. However, if the study drug is stopped temporarily or permanently, the patient should remain in the assigned treatment group for the remainder of data collection.

• Functional deterioration: Unexplained functional deterioration, defined as a decrease in DRS score over two consecutive weeks, will result in discontinuation of the study drug. If a clear cause of functional deterioration is identified that bears no plausible relationship to the study drug (e.g., an expansion of a subdural hematoma), the study drug should be continued or resumed with the approval of the attending physician.

• Increase in seizures: An increase in the frequency or severity of clinical or electrographic seizures that meets predefined study criteria will result in discontinuation of the study drug.

Plan for Data Analysis:

Primary Analyses:

The DRS is an ordinal variable with unequal item spacing by Rasch analysis criteria (wider spacing at the “better” end). However, the wider spacing biases in favor of seeing less recovery.

Despite the ordinal nature, we have found DRS to be analyzable with parametric methods, sometimes requiring log or square root transformation. The DCC’s process for communicating with the PIs and the individual sites should ensure a minimum of missing data. The highest priority will be placed on obtaining week 4 (treatment completion) scores and post-washout scores. Missing weekly DRS scores, to the extent that they occur, will be addressed through imputation methods, after verification that the scores are missing at random.

Primary analysis, Aim 1:

DRS scores recorded in weeks 1 through 4 will be used as the dependent variables in the primary analysis. We will use mixed effect regression models (Laird & Ware, 1982) to estimate the rate of change in DRS score in the first 4 week of treatment and to determine if there is a difference in the rate of change between the two treatment groups. DRS at enrollment and the time between injury and enrollment will be considered in the regression models as covariates. Since this study is stratified by center, this variable will also be added as covariate.

Primary analysis, Aim 2:

This hypothesis will be tested again using random effects models with DRS at post-washout (6 weeks) as the dependent variable, DRS at 4 weeks, and time post-enrollment as covariates and drug group as the independent variable. If the benefits of AH are transient, we would expect an interaction between drug group and DRS at 4 weeks, meaning either than the AH group

deteriorates while the placebo group continues to improve, or that the AH group improves less than the placebo group over those next 2 weeks (because their drug-withdrawal “deterioration” is being “subtracted” from the remaining spontaneous recovery seen in the placebo group).

A total of 3 analyses (2 interim analyses and 1 final analysis) will be conducted for primary efficacy comparison during the course of the study. These formal interim analyses will be conducted at approximately 60 and 120 patients recruited. The analyses report will present all aspects of the trial. An error spending function with an O’Brien-Fleming boundary will be used in order to be flexible with respect to the timing of the analyses (O’Brien & Fleming, 1984). The p-values used for the first interim analysis will be 0.0005. The p-value for the second interim analysis will be 0.014. The final analysis will be conducted on the total of 184 participants, using a significance level of 0.045. If the interim analysis shows statistically significant results, the

independent DSMB will advise the study investigators to consider early termination of the study and disclosure of the study results.

Secondary analysis, Aim 3:

This analysis will be conducted similarly to that for Aim 1, but with interaction of time post injury and drug group entered; or with interaction of VS vs. MCS at enrollment (defined by CRS-R diagnosis) with drug group.

Secondary analysis, Aim 4:

We will conduct exploratory analyses where presence or absence of various neuroimaging

findings and/or various complications by history are included as additional predictors of recovery and/or drug response. Because of the exploratory nature of these analyses, we will not correct for multiple comparisons. However, to reduce the likelihood of spurious findings, we will use a strategy that we used in the previous longitudinal observational study. We will test the influence of each potential variable individually, while controlling for DRS at enrollment and time until enrollment. Those that appear promising, based on a relaxed p value of .20, will be entered into a multivariate model.

Secondary analysis, Aim 5:

The specific analysis cannot be specified in advance of identifying the variable(s) of interest.

However, the basic approach to analysis will be analogous to those described above.

Secondary analysis, Aim 6:

Adverse events will be fully described and presented in frequency tables by treatment. The two treatments will be compared by Fisher’s exact test. Adverse events will be summarized for both the number of patients and the number of events by treatment group and body system. They will also be summarized by severity and causality.

Study Power:

Sample size was estimated based on information from the observational study. Using these data we estimated the total variance of the DRS scores, the correlation between repeated measures and the rate of DRS change in the first 4 weeks. Sample size calculations were based on the following assumptions:

1. An approximately normal distribution of the outcome (after appropriate transformation, if necessary)

2. A type I error of 0.045 on a two-tailed test

3. An intraclass correlation (i.e. the correlation between repeated DRS scores) of 0.70 in the first 4 weeks

4. An estimated total variance of the DRS score measurements of 17.56 5. Measurements are made at equally spaced intervals

6. A difference between the treatment and the control group in the rate of DRS score change of 0.305 per week (1.22 DRS point mean difference at completion of treatment).

Given the above assumptions, a study of 184 patients (92 per group) will have 80% power to detect the above stated difference between the groups, if it exists (Diggle, et al, 2002). With this sample size we will be able to detect any unforeseen adverse events that have a prevalence of at least 2.5% in each group with 90% probability. With 92 patients per group we will be able to estimate the rate of adverse events to within ±10%.

Across the 8 clinical sites, we estimate admitting approximately 150 eligible patients/year. If we assume that active enrollment will occur for 4.25 years (leaving 3 months for startup and 6 months for data analysis and dissemination activities), this means that approximately 637 eligible patients will be admitted during the course of the trial. In order to enroll the required 184

participants specified by the power analysis above, this would require only a rather conservative consent rate of 29% of those eligible.

Protocol Outline:

The following Protocol Outline is designed to give the investigator a glimpse of all the procedures that must be completed during each phase of the study. These procedures are

explicated more fully in the next section on Protocol Instructions. In this section, we present the study protocol as a step-by-step sequence of activities that must occur with all patients enrolled in the study. In reality, some of these steps will have to occur simultaneously while others may occur in a different order depending on the particular circumstances of a specific patient. This situation is particularly true during the pre-enrollment phase of the study as many different issues must be assessed and monitored. Several activities are likely to need to take place concurrently in order to reduce the length of time between patient identification and patient enrollment, and, therefore, maximize the number of patients enrolled. Among patients screened, those admitted to rehabilitation beyond 16 weeks post-injury, with non-traumatic brain injury, or with the wrong diagnosis (i.e., non-VS/MCS), for example, will be permanently excluded upon initial chart review. Patients who are not excluded for these reasons, however, may have multiple concurrent reasons for temporary exclusion (e.g., current treatment with prohibited medications, active workup for possible hydrocephalus, etc.). Unless these reasons are dealt with promptly and efficiently, such individuals will eventually be excluded (if working out these issues takes them beyond 16 weeks post-injury) or may be enrolled so late in their rehabilitation stay that it will be difficult to complete the 6 weeks of data collection. Because of this, those factors that currently prevent randomization to treatment should be checked and rechecked on a frequent basis, and their relative priority for “solving” may shift as time passes.

To illustrate the procedural guidelines described above, two contrasting case examples are provided: Patient A is admitted 2 weeks post-injury with only an acute CT scan, is currently receiving methylphenidate, has a long estimated length of stay, and a very anxious family.

Patient B is admitted 14 weeks post-injury, has had several CT scans along the way, including one 3 weeks ago, is currently receiving bromocriptine, and has a short estimated length of stay.

Patient A can’t be enrolled yet anyway because of the recent injury. There is little information available to gauge the odds of hydrocephalus. Methylphenidate takes no time to discontinue.

Therefore, one might decide to simply monitor this patient up until nearly 4 weeks post-injury before addressing consent, and defer the scan and discontinuation of methylphenidate until that point, keeping in mind that the patient will not be able to be randomized to treatment until the scan results have been obtained and the drug has been stopped. But in this case, the “risk” that the patient may improve substantially over the next 2 weeks may justify waiting before

approaching the family about consent, scanning, and drug changes. In contrast, patient B is rather unlikely to have hydrocephalus now, since it hasn’t shown up in a sequence of previous scans, but may pass the 16 week window if we wait to get the scan till after the bromocriptine is discontinued. Thus, in this patient, one may choose to get family consent right away, taper the bromocriptine ASAP, and schedule the scan during the drug taper, knowing that there is a slight risk that the scan could show hydrocephalus, and the patient will ultimately be excluded because she will be more than 16 weeks post-injury by the time the shunt is placed.

The examples cited above demonstrate the need for dynamic reassessment of all potential participants who are not clearly excluded on a permanent basis, and the need for local site PIs to regularly supervise the prioritization of the procedural steps with their recruitment coordinators.

Although we encourage some flexibility in the process to minimize the time between patient identification and patient enrollment, it is critical to remember that certain steps can ONLY be

taken after consent has been obtained. Some key steps are time consuming and consent should be obtained early. These include obtaining CT scans specifically for purposes of the research, drug tapers and changes related to research eligibility and administering CRS-R examinations (except where they are part of routinely scheduled clinical practice).

Procedural steps are separated by study phase. The five phases of the study are Pre-Enrollment, Enrollment, Treatment, Treatment Follow-up and Termination. The steps for each of these phases are summarized briefly below in their usual form. They are discussed subsequently in greater detail, including a variety of modifications and approaches to problems that are likely to arise.

Pre-Enrollment:

1. DRS admission screening exam administered to determine eligibility.

2. Patient Recruitment Tracking Form initially reviewed to rule out permanent exclusion criteria. This form should be completed for every TBI patient admitted who has a DRS score

>11.

3. Consent obtained if patient meets all eligibility criteria that can be determined without informed consent.

4. Medical record requested from the referring trauma center (may be deferred until actual enrollment if there appears to be a high probability the patient will be excluded prior to enrollment).

5. If the patient requires withdrawal of prohibited medications, “Guidelines for Minimizing Confounding Psychoactive Drugs and Treating Specific Clinical Problems” reviewed with the attending physician and prohibited drug taper and/or substitution initiated.

6. Patient Recruitment Tracking Form reviewed and completed weekly (or more frequently as circumstances dictate) until patient is off drug taper.

7. CT/MRI results obtained if patient does not require drug taper. If patient requires drug taper, CT/MRI scan deferred until after taper is completed or nearing completion (depending on other time pressures). Scan must be obtained no more than 14 days prior to enrollment so the timing of the scan should be carefully considered.

8. If the patient is on drug taper, or is medically unstable (i.e., has hydrocephalus, requires a major surgical procedure or has significant agitation requiring use of prohibited medication), inclusion/exclusion criteria should continue to be monitored until patient is medically stable or off drug taper.

9. Creatinine clearance testing re-administered within 60 hours of randomization if participant has a clinical condition or event affecting renal function?

10. After drug taper is complete, all inclusion/exclusion criteria have been met and the patient is medically cleared (i.e., no hydrocephalus, pending major surgical procedure or significant

agitation), DRS is re-administered and the CRS-R is completed to confirm that the patient meets all criteria for enrollment.

11. Patient excluded post-consent if the DRS or CRS-R criteria are failed.

12. Qualifying DRS and CRS-R scores entered on the Randomization Form on page A0 in the Appendix for submission to the DCC.

At Enrollment:

1. Remainder of Randomization Form completed and submitted to DCC by web entry within 24 hours of completion of the DRS and CRS-R exams. Randomization Forms should be

submitted to the DCC as soon as possible after the scores are obtained during Monday through Friday office hours. If it is not possible to submit the Randomization Form within this time frame, the DRS and CRS-R exams must be repeated to assure that the patient continues to meet the clinical eligibility criteria.

2. Patient randomized to treatment group by DCC. Participant ID furnished to local PI and Randomization code provided to designated pharmacy staff. Participant’s identifying information recorded on “Standard Confidential List of Patients” stored in locked cabinet.

3. DCC simultaneously advises central pharmacy to send a new bottle to the clinical site in preparation for the next patient enrolled.

4. Local pharmacy provided with designated bottle number.

5. Medication inventory of all relevant drugs on-board at the time of randomization completed and recorded on Concomitant Medication form.

6. CT/MRI films sent to JFK within 7 days of enrollment. If a previously-obtained scan is not available within 2 weeks of enrollment, a new scan must be obtained before treatment is initiated.

7. Enrollment Checklist completed to a) identify medical conditions or concurrent medications that may increase the risk of adverse events following introduction of AH and b) establish a symptom baseline as reference for monitoring subsequent adverse events.

8. Demographic, Acute Course and Acute Complications forms completed and submitted to DCC as soon as possible after obtaining consent.

Treatment:

1. Day 0 (day of randomization)

2. Day 1: Administer starting dose of AH/placebo (100mg, 2x/day at 6:00am and 2:00pm) 3. Day 7: DRS re-administered (between days 6 and 8) at starting dose of med (100mg, 2x/day

at 6:00am and 2:00pm). Submitted to DCC via web entry system by the end of the day obtained:

a. Week 1 F/U,

b. Concomitant Medications (if there are changes) c. AE forms (if any AEs have resolved)

4. Day 14: DRS re-administered (between days 13 and 15), med dose increased to 150mg (2x/day at 6:00am and 2:00pm) if DRS has not increased by at least 2 points since enrollment. Submitted to DCC via web entry system by the end of the day obtained:

a. Week 2 F/U,

b. Concomitant Medications (if there are changes) c. AE forms (if any AEs have resolved).

5. Day 21: DRS re-administered (between days 20 and 22), med dose increased to 200mg (2x/day at 6:00am and 2:00pm) if DRS still has not increased by at least 2 points since enrollment. Submitted to DCC via web entry system by the end of the day obtained

a. Week 3 F/U.

b. Concomitant Medications (if there are changes) c. AE forms (if any AEs have resolved)

6. Day 28: DRS and CRS-R re-administered (between days 27 and 29), med taper initiated (decrease dose by 100mg/day until completely withdrawn). Submitted to DCC via web entry system by the end of the day obtained:

a. Week 4 F/U

b. Concomitant Medications (if there are changes) c. AE forms (if any AEs have resolved).

Treatment Follow-up:

1. Day 35: DRS re-administered (between days 34 and 36). Submitted to DCC via web entry system by the end of the day obtained:

a. Week 5 F/U,

b. Concomitant Medications (if there are changes) c. AE forms (if any AEs have resolved)

2. Day 42: DRS and CRS-R re-administered (between days 41 and 43). Submitted to DCC via web entry system by the end of the day obtained:

a. Week 6 F/U,

b. Concomitant Medications c. AE forms

3. With a few exceptions, the 6 week follow up date will serve as the date at which remaining concomitant medications were “stopped” or AEs resolution being reported.

If subject has been prematurely discharged, ongoing data collection is conducted at discharge site. If direct examination is not possible on-site, DRS (but not CRS-R) scores obtained by phone interview.

Termination:

1. Study Completion form submitted.

2. Open-label trial offered.

Note: All deaths and serious adverse events must be communicated within 24 hours to the 1) local IRBs, 2) the DCC and 3) the Project Directors. The DCC will forward all pertinent documentation about SAEs to the Data Safety and Monitoring Board (DSMB) chair. Adverse Event forms should be submitted to the DCC at the end of each follow-up week. The Death form should be submitted as soon as possible following the subject’s death.

Protocol Instructions Procedure: DRS Screening Exam

When: On admission

Form: DRS Screening Form (Paper form only) Staff Responsible: Data collector.

Instructions: The Disability Rating Scale (DRS) will be used as an initial screen to determine whether potentially eligible participants meet diagnostic criteria for the vegetative and minimally conscious states. Patients must meet the diagnostic criteria for one of these two conditions to qualify for inclusion in the study. Additional criteria must also be met but the diagnostic criteria must be met first. The DRS will also serve as the primary outcome measure and scores on this scale will be obtained during all six weeks of the study.

To qualify for inclusion in the study, participants must receive a total DRS score of 12 or higher.

DRS Administration and Scoring Procedures

• The Data Collector is responsible for obtaining a DRS score as soon as possible following the patient’s admission to the rehabilitation program.

• All Data Collectors must be certified in DRS administration and scoring procedures as outlined on the COMBI website http://www.tbims.org/combi/.

• During the pre-enrollment phase only, DRS scores may be estimated through chart review in order not to over-burden clinical team members with repeated requests to score. However, if there is any question whether the potential participant is near the upper cutoff, a formal score based on direct examination should be obtained. In every case, a formal score obtained in this manner is required for the final enrollment score and throughout subsequent data collection.

• DRS scores will be determined based on “consensus” ratings made by the rehabilitation treatment team (e.g., SLP, O.T., P.T., neuropsychologist, attending physician and nursing personnel). Specific team members may be designated to rate particular items (e.g., speech therapist- Verbal subscale; physical therapist- Motor subscale; occupational therapist- Cognitive Ability for Grooming), or the entire team may participate in the ratings for each item. If there is any reported disagreement in ratings, the score assigned should reflect the team’s consensus. This rule applies to both the pre-enrollment and treatment phases of the study.

• “Consensus” is defined as agreement by at least two treatment team members on a particular item. If there is disagreement, the Data Collector assures that the designated raters discuss and resolve the difference of opinion before a final score is assigned.

• Scoring of the “GCS items” (Eye Opening, Motor, Verbal subscales) must be based on direct examination conducted by the appropriate rehabilitation team members. Scores should be based on the consensus method described above.

• Scoring of the Cognitive Ability, Level of Functioning and Employability subscales should be based on behaviors directly observed by team members within 24 hours of the scheduled assessment date. The best score within that interval should be assigned for each subscale.

• The Center For Outcome Measurement in Brain Injury (COMBI) DRS scoring guidelines should be used to determine scores, however, no ½ point scores will be used. The DRS scoring guidelines are included on page Error! Bookmark not defined. of the Appendix.

• DRS total and subscale scores should be recorded on DRS Screening Form.

• Once the participant meets all inclusion/exclusion criteria, the final qualifying DRS scores should be entered on the web-based Randomization Form on page A0 of the Appendix.

• Exclude participant if DRS score is <12.

Procedure: Patient Recruitment Tracking

When: On admission and as often as necessary post-admission until the patient meets all of the required eligibility criteria or is permanently excluded from the study.

Form: Patient Recruitment Tracking Form (Paper form only) Staff Responsible: Data Collector.

Instructions: The Patient Recruitment Tracking Form (see page Error! Bookmark not defined.

of the Appendix) was developed to monitor patients’ enrollment status following admission to the rehabilitation program. This form should be completed on all TBI admissions with a DRS score >11 at admission. It is not necessary to complete this form on non-TBI admissions with a DRS score >11 or on TBI admissions with DRS scores that are clearly < 12. The items

included on the Patient Recruitment Tracking Form should be completed based on review of the transfer chart and discussion with team members and, where necessary, the responsible family member or legal guardian. This form should be completed even if the data collector determines that one or more permanent exclusion criteria have been met. In this case, the reason(s) the patient was excluded should be included on the form so it is possible to track the number of patients eligible for enrollment and the reasons for exclusion, and to allow estimates for how many additional patients might be enrolled if a given exclusion criterion were changed. If the data collector determines that one or more permanent exclusion criteria have been met prior to completing the screening DRS, it is not necessary to obtain an exact DRS score. However, the data collector should determine, based on an estimate from the chart, whether the patient was eligible for the trial in terms of DRS score (e.g., “DRS estimated to be > 11”). Under these circumstances, the data collector should record all of the reasons for exclusion on the Patient Recruitment Tracking Form and the form should be retained in a separate file of de-identified Recruitment Tracking Forms until the DCC requests that they be destroyed. For potentially eligible patients, (i.e., those that are not excluded based on permanent exclusion criteria), the form should be continually updated until the patient meets all of the required inclusion and exclusion criteria or is permanently excluded from the study. In some cases weekly updates will be adequate, while in others, more frequent updates should be conducted. For example, in the case of the patient who meets all of the eligibility criteria, but the family remains undecided about consent, it may be appropriate to update the form on a daily basis until consent is obtained or refused. In other cases, such as the patient who has an abnormal creatinine clearance test, weekly updates may be adequate.

Permanent exclusion criteria are defined as follows:

• Etiology non-traumatic- Primary cause of damage to brain tissue is not due to external mechanical force. Patients diagnosed with anoxic or metabolic encephalopathy, spontaneous cerebral hemorrhage or infarction, CNS infection, intracranial neoplasm, demyelinating disorder or degenerative disease are not eligible for enrollment.

• Non missile-induced penetrating head injury- Damage to skull and brain tissue is directly caused by missile-type injury (e.g., firearm, knife wound).

• Age < 16- Patient must be at least 16 years old at the close of the 112^th day post-injury.

• Age > 65- Patient must be less than 66 years old at the time of randomization (for patients excluded for age > 65, record exact age on admission).

• Admission to rehabilitation program after 16 weeks post-injury- Based on information extracted from the medical record, the time elapsed between the injury and admission to the clinical site is > 112 days. Note that even if the patient is admitted to the rehab unit prior to post-injury day 113, the patient is ineligible for randomization if more than 112 days have elapsed since the date of injury.

• DRS < 12- Total DRS score must not be between 0 and 11.

• Premorbid CNS or developmental abnormality- Prior to sustaining TBI, patient was diagnosed and/or treated for a neurologic condition or pervasive developmental disorder (e.g., MR, autism) that continued to produce functional disability up to the time of injury.

Patients with pre-existing neurologic or developmental disorders that did not cause functional disability up until the time of injury may be enrolled in the study.

• Premorbid seizures > 1 per month- Patients with a history of idiopathic epilepsy may not be enrolled if their pre-injury seizure frequency was > 1 per month. If pre-injury seizure frequency was < 1 per month over the 3 months prior to injury (based on family report) but there is documented evidence that post-injury seizure frequency is > 1 per month or there is documented evidence of an increase in the severity or duration of a single seizure relative to the premorbid history, the patient must be excluded. Irritative features of the EEG alone do not require exclusion. If a clear provocation was present that would otherwise disqualify a subject because of seizure frequency, the subject can be enrolled, since these events would not be considered idiopathic.

• Pregnancy- Female patients with reproductive potential must test negative for pregnancy by blood or urine test within 60 hours prior to enrollment.

• Prior amantadine treatment- Patient must not have received any dose of AH at any time after sustaining TBI.

• Amantadine allergy- Patient must not have any history of allergic reaction to AH as reported by responsible family member/legal guardian or attending physician.

Inclusion and medical screening criteria are defined as follows:

• DRS > 11- Total DRS score must be between 12 and 29 at the time of randomization.

• Diagnosis of vegetative or minimally conscious state- Patient meets diagnostic criteria for VS or MCS (i.e., CRS-R Auditory subscale score < 4 and CRS-R Communication

subscale score < 2) as determined by the results of the CRS-R screening examination (see CRS-R Record Sheet of the CRS-R Administration and Scoring Manual on page B2 of the Appendix) at the time of randomization (if patient emerges from MCS post-

admission, record number of days post-injury at admission).

• < 2 seizures in last 4 weeks- No documented evidence of more than one seizure during the 4 weeks prior to randomization. Evidence of seizure requires either a documented diagnosis of seizure or documented EEG electrographic seizures.

• > 4 weeks post-injury- TBI occurred more than 28 days before the date of randomization.

• < 16 weeks post-injury- TBI occurred no more than 112 days before the date of randomization (if > 16 weeks, record number of days post-injury at admission).

• No renal dysfunction- Creatinine clearance rate ≥60 ml/min. Creatinine clearance will be obtained on all patients following rehabilitation hospital admission and before beginning the study medication. If the patient has a clinical condition that affects renal function, a creatinine clearance value must be obtained again within 60 hours of randomization and before beginning the study medication.

• Free of prohibited medications- Patient is not taking any of the medications listed in italics in the “Guidelines for Minimizing Confounding Psychoactive Drugs and treating Concurrent Medical Problems” at the time of randomization.

• No indication for prohibited drug to manage agitation- Patient does not require use of a prohibited drug for management of aggression, akasthesia, disinhibition or emotional lability.

• No potentially confounding medical issues - Patient does not have any current medical issues or problems that could confound assessment of the effectiveness of AH. This includes CT evidence of hydrocephalus, concurrent medical conditions (e.g., pneumonia) and impending neurosurgical or medical procedures.

• Consent obtained to discontinue prohibited medications (if applicable)- Discontinuation of prohibited medications discussed with family/caretaker and informed consent form signed by patient representative.

Additional Screening Considerations:

The second page of the Patient Recruitment Tracking Form lists concomitant medical conditions and concurrent medications that may increase the risk of adverse events following initiation of the study treatment. It is necessary to screen participants for all of the items included on these lists. Any concomitant medical condition or concurrent medication noted should be recorded on the Patient Recruitment Tracking Form. The purpose of recording these conditions and

medications is to alert the treating physician to potential safety concerns. Such patients may still be enrolled in the study at the discretion of the treating physician, with the understanding that such subjects may require more careful monitoring of the potential complicating factors. While none of these factors represent an absolute contraindication to treatment, additional precautions (e.g., ongoing lab testing, frequent physical examinations) may be required before and after enrollment.

Patient Recruitment Tracking forms should be completed and maintained in a separate file even when patients are excluded so that we can continue to monitor the frequency of exclusions by category. These data will be reported in the final manuscript and will be used to inform decisions concerning potential changes in eligibility criteria. It is not necessary to forward Recruitment Tracking forms to the DCC unless specifically requested, however, exclusion data will continue to be reported by each center in the Recruitment Summary Table that is distributed quarterly by the DCC.

Procedure: Procedure for Monitoring and Submitting Recruitment Statistics When: Every three months

Form: Recruitment Summary Table Staff Responsible: Data Collector

Instruction: On a quarterly basis, centers are responsible for submitting recruitment data to the DCC so that we can continue to monitor the appropriateness of our exisiting inclusion/exclusion criteria. To do so, the number of “potentially eligible” “eligible” “consented” and “randomized”

subjects should be tracked and submitted in tabular form to the DCC (see Recruitment Summary Table on page B1 in the Appendix). These numbers will be reported cumulatively, because subjects who occupied one category at one reporting period may move to another category 2 months later. The DCC will provide the last report as a template for the center providing its update. The following recruitment categories have been defined:

Potentially eligible subjects: This is meant to correspond roughly to the estimates we made during the planning of the grant for how many individuals would be admitted to our institutions who were generally appropriate for the study. This category does not assume that you’ve tracked down the answers to all of the specific inclusion/exclusion criteria. Rather, this is the largest possible pool of subjects who could be appropriate for the study, depending on minor

modifications of the inclusion criteria. Count the number of admissions to your unit who fit the following criteria:

• Traumatic etiology

• DRS > 11 (no need to get an actual DRS score on obviously “high level” patients or VS patients, but an actual score may be needed for patients with DRS scores near the cutoff) Eligible subjects: These are a subset of potentially eligible subjects. Count the number who meet all of the [current] inclusion/exclusion criteria (i.e., including acuity requirements, lack of prior exposure to amantadine, etc.). For any “potentially eligible subject” who does not become an “eligible subject”, we need to know all of the ways in which that individual failed to meet the inclusion/exclusion criteria. In other words, if the patient isn’t admitted until 18 weeks post- injury, we need to know not only that but also, perhaps, that they have chronic renal failure, since this would affect whether that person could have been enrolled if we were to lengthen the enrollment window. The count of “eligible subjects” should be based only on those criteria that can be evaluated prior to informed consent. Therefore, this count should not consider:

• Inability to successfully taper psychoactive medications [unless the treating physician determines that s/he is unwilling to even consider such a taper];

• Hydrocephalus identified on a research-based scan

• Above MCS by CRS-R score [for centers where CRS-R can’t be done prior to consent]

Consented subjects: This is a subset of eligible subjects. It refers to the group of eligible subjects who provide informed consent. Thus, loss of subjects between eligible and enrolled should occur either because the family declines study participation, or because they don’t make up their mind prior to closure of the study enrollment window. For those eligible subjects who do not become consented subjects, we want to know, to the extent that you can determine it, the reason(s) why – i.e., the family’s objections to the study.

Randomized subjects: This is a subset of consented subjects who are actually reported to the DCC and receive a randomization code, regardless of how much study drug they receive or how many data points are collected. Thus, subjects could be lost at this point if:

• They don’t meet post-consent eligibility criteria such as successful medication taper, absence of hydrocephalus on research-based scan [though such patients may still be successfully enrolled post-shunting in some cases], or level above MCS on CRS-R [for centers that can’t make this evaluation until after consent].

• Medical instability develops which, by the time it is resolved, precludes enrollment within the enrollment time window.

• Family withdraws consent prior to randomization or physician drops patient prior to randomization.

Thus, we need to know the specific reason(s) that consented patients are not randomized.

Other “losses”: Of course we may “lose” randomized patients along the way if their families withdraw them prematurely, they are discharged out of range, or they develop a contraindication to study treatment. However, given the intention-to-treat analysis, none of these losses reduce the number of subjects to analyze. They do, however, reduce the power of our analyses, so we need to keep close track of protocol violations, but this is done within the web-based system for reporting data on randomized subjects.

Reason for exclusions: For patients excluded because of 1) age limits only, 2) post injury time window and 3) emergence from MCS during screening, please indicate:

1) Exact age of the patient on admission;

2) Number of days post-injury at admission;

3) Number of days that have elapsed from the date of admission to the date of emergence from MCS.

Procedure: Consent When: On admission

Form: Informed Consent/HIPAA

Staff Responsible: Site PI or senior level researcher

Instructions: Informed consent should be obtained after the patient obtains a qualifying DRS screening score and the investigator determines that none of the permanent exclusion criteria listed on the Patient Recruitment Tracking Form have been met. It is not necessary to obtain consent prior to administering the DRS if this scale is routinely being used for clinical purposes in the rehabilitation program that the patient is participating in. Even then, DRS score can be estimated from the clinical chart until formal scoring is needed, at which point consent might be required. Similarly, it is not necessary to obtain consent to review the patient’s admission or transfer chart as long as the individual conducting the review is a researcher employed by the rehabilitation facility. All of the other pre-enrollment procedures (e.g., request for trauma records, CT/MRI scanning, drug taper) require consent, and the request for records will likely require a separate signed release form acceptable to the referring hospital. A copy of the consent form used by individual sites is included in the Appendix.

When obtaining consent, the subject’s approved decision-making caregiver or legal guardian, and the person obtaining consent must sign the Informed Consent form. The dates of the caregiver/legal guardian and consentor’s signature must match. The consentor’s signature certifies that the caregiver/legal guardian has had the study explained to him or her and has been given the opportunity to ask any questions about participation in this study. The original of the signed and dated Informed Consent remains at the site. The caregiver/legal guardian must always be given a copy and a second copy should be placed in the subject’s medical record. The Health Information Portability and Accountability Act (HIPAA) form must also be signed and dated by the parent/legal guardian (see Appendix) unless it is integrated into the consent form.

If the caregiver/legal guardian is non English-speaking, the investigator is obliged to assure that s/he is able to adequately comprehend the consent form. A translator may be used to assist with the consent process, however, it is recommended that the consent form be translated into the primary language, when feasible. Spanish and German versions of the consent form are included in the Appendix. Investigators should adhere to the local IRB policy with respect to the

procedure for consenting non-English-speaking individuals.

In the event that the subject regains decision-making capacity during participation in the study, consent (or assent if the subject is between the ages of 16 and 18) must be directly obtained from the subject in order to permit continued participation in the study.

As soon as possible after consent is obtained, the patient’s complete medical record should be obtained from the trauma center. These records are necessary to complete the Demographics, Acute Course and Acute Complications Forms, which should be submitted at or shortly after enrollment. Detailed instructions for completion of these forms may be found on page 47.

It is important to be aware that obtaining consent does not guarantee that the patient will begin the treatment trial. There are multiple factors that may influence treatment initiation after consent is obtained. For example, hydrocephalus may be diagnosed post-consent, initially deferring randomization to treatment. In some cases, the hydrocephalus may not be adequately managed before the treatment window closes (i.e., >112 days post-injury),

eventually resulting in exclusion from the study. This possibility should be discussed with the parent/legal guardian during the consent process. For these reasons, the consent process is considered a “Pre-Enrollment” procedure while randomization to treatment is listed under

“Enrollment” procedures.

Procedure: Prohibited Drug Taper

When: After informed consent has been obtained.

Form: None

Staff Responsible: At the discretion of the P.I.

Instructions: Before patients may be enrolled and randomized to treatment, they must be free of psychoactive medications that may either potentiate or interfere with the effects of AH. Thus, once consent is obtained, it is necessary to begin weaning all dopaminergic, cholinesterase inhibitor, NMDA receptor agonist, sympathomimetic, benzodiazepine, anti-psychotic, anti- depressant and selected anticonvulsant (i.e., clonozepam, phenobarbital, primidone) agents that may be on-board. Narcotics are permitted but should be avoided whenever possible, particularly when conducting weekly DRS and CRS-R exams. A list of confounding medications (and their half-lives) is shown below. While this list also includes some of the drugs listed on the Patient Recruitment Tracking Form, the purpose of the list is to prevent protocol violations that would otherwise be inevitable following randomization. After consent has been obtained, the PI should provide a copy of the, “Guidelines for Minimizing Confounding Medications” to the treating physician (see Appendix) and the participant’s current medication regimen should be reviewed to determine which drugs, if any, must be weaned. The drug taper may be considered complete when at least four half-lives have passed since the last dose was administered. The duration of the taper may be as brief as 4 hours (e.g., midazolam) or as long as 280 hours (e.g., flurazepam).

For this reason, the patient’s clinical status should be monitored at least weekly, and the results recorded on the Patient Recruitment Tracking Form. Subsequent to completion of the taper, the DRS must be re-administered to confirm that the total score remains >11. If so, CRS-R

examination is performed to assure that the patient has not emerged from MCS (i.e., regained consistent command-following or reliable communication ability). Those patients who emerge from MCS prior to completion of the taper are excluded from further participation in the study.

Drugs That Must Be Withdrawn Prior to Enrollment (with trade names and half-lives in parentheses)

I. ANTIPSYCHOTICS

a. droperidol (Inapsine,2.3h) b. haloperidol (Haldol, 12h) c. fluphenazine (Prolixin, 33h) d. perphenazine (Trilafon, 9h ) e. pimozide (Orap, 53h) f. thiothixene (Navane, 34h) g. trifluoperazine (Stelazine, 24h) h. molindone (Moban, 24h) i. loxapine (Loxitane, 8h)

j. chlorpromazine (Thorazine, 6h) k. mesoridazine (Serentil, 24h) l. thioridazine (Mellaril, 21h) m. clozapine (Clozaril, 4h)

n. olanzapine (Zyprexa, Zydis, 21h)

o. quetiapine (Seroquel, 6h) p. risperidone (Risperdal, 20h) q. ziprasidone (Geodon, 2h) r. melperon (Eunerpan, 4h) II. BENZODIAZEPINES

a. chlordiazepoxide (Librium, 5h) b. clonazepam (Klonopin, 18h) c. clorazepate (Tranxene, 40h) d. D diazepam (Valium, 20h) e. flurazepam (Dalmane, 70h) f. estazolam (ProSom, 10h) g. lorazepam (Ativan,10h) h. temazepam (Restoril, 8h) i. alprazolam (Xanax, 12h) j. midazolam (Versed, 1h) k. oxazepam (Serax, 8h) l. triazolam (Halcion, 2h) m. tetrazepam (Musaril) III. DOPAMINERGIC AGENTS

a. carbidopa/levodopa (Sinemet, Atamet, 1.5h) b. bromocriptine (Parlodel, 12h)

c. pergolide (Permax, 27h) d. pramipexole (Mirapex, 8h) e. ropinirole (Requip, 6h)

f. selegiline (Eldepryl, Atapryl, Carbex, Selpak, 1.2h) IV. SYMPATHOMIMETICS AND RELATED

a. methylphenidate (Ritalin, Methylin, Metadate, Concerta, 2.7h ) b. dexmethylphenidate (Focalin, 2h)

c. dextroamphetamine (Dexadrine, Dextrostat, 7h)

d. dextroamphetamine and racemic amphetamine (Adderall, 7h) e. modafinil (Provigil, Alertec, 8h)

f. pemoline (Cylert, 12 h)

g. phentermine (Adipex-P, Ionamin, Phentride, 20h) h. sibutramine (Meridia, 1.1h)

i. atomoxetine (Strattera, 6h)

V. ANTIDEPRESSANTS (trazodone, if present, need not be withdrawn) 1. Heterocyclic Compounds

a. amitriptyline (Elavil, Vanatrip, 9h) b. amoxapine (Ascendin, 8h)

c. clomipramine (Anafranil, 19h) d. desipramine (Norpramin, 14h) e. doxepin (Sinequan, Zonalon, 8h) f. imipramine (Tofranil, 6h)

g. maprotiline (Ludiomil, 27h)

h. nortriptyline (Aventyl, Pamelor, 15h)

i. trimipramine (Surmontil, 23h) j. protriptyline (Vivactil, 54h) 2. Monoamine Oxidase Inhibitors (MAOIs)

a. isocarboxazid (Marplan ??) b. phenelzine (Nardil 11h)

c. tranylcypromine (Parnate, 1.5h) 3. Selective Serotonin Reuptake Inhibitors (SSRIs)

a. citalopram (Celexa, 33h) b. escitalopram (Lexapro, 22h) c. fluoxetine (Prozac, 4 days) d. fluvoxamine (Luvox, 15h) e. 5 paroxetine (Paxil, 15h) f. sertraline (Zoloft, 24h)

4. Other antidepressants

a. bupropion (Wellbutrin, 14h) b. mirtazapine (Remeron, 20h) c. nefazodone (Serzone, 2h) d. venlafaxine (Effexor, 5h) e. duloxetine (Cymbalta, 12h) VI. ANTICONVULSANTS (most are allowed)

A. phenobarbital (Luminal, 140h) B. clonazepam (Klonopin,18h ) C. primidone (Mysoline,12h) E. topiramate (Topamax, 22h) VII. ANXIOLYTICS/HYPNOTICS

A. buspirone (BuSpar, Vanspar, 2.4h)

B. chloral hydrate (Aquachloral supprettes,11h) C. zolpidem (Ambien, 2.5h)

D. zopiclon (Lunestra, 5h) VIII. CHOLINESTERASE INHIBITORS

A. donepezil (Aricept, 70h) B. galantamine (Reminyl, 8h) C. rivastigmine (Exelon, 1.5h) IX. NMDA RECEPTOR ANTAGONISTS

A. memantine (Namenda, 80h) X. ANTICHOLINERGICS

A. atropine (AtroPen, Atropine-Care, Isopto Atropine, Sal-Tropine, Donnatal Extentabs, Donnatal, 2-3h)

B. benztropine (Cogentin, 6-48h) C. biperiden (Akineton, 18.4-24.3h)

D. cyclopentolate (AK-Pentolate, Cyclogyl, Cylate, 24h) E. dicyclomine (Bentyl, 9-10h)

F. glycopyrrolate (Robinul Forte, Robinul, 30-75min)

G. hyoscyamine (Anaspaz, Cystopaz-M, Cystopaz, Hyosine, Levbid, Levsin/SL, Levsinex, Levsin, LuLev, Spacol T/S, Spacol, Symax SL, Symax SR, Donnatal Extentabs, Donnatal, 3-5h)

H. mepenzolate (Cantil)

I. methscopolamine (Pamine Forte, Pamine, Librax, AH-Chew, Chlor-Mes-D, Dallergy, Dehistine, Drize-R, Extendryl, Hista-Vent DA, PCM Allergy, 4-6h) J. procyclidine (Kemadrin, 4-6h)

K. scopolamine derivatives (Isopto Hyoscine, Scopace, Transderm Scop, Donnatal Extentabs, Donnatal, Murocoll-2, 4.8h)

L. tolterodine (Detrol LA, Detrol, 2-18h)

M. trihexyphenidyl (Artane, Benzhexol Hydrochloride, 3.3-4.1h) N. trimethobenzamide (Tebamide, Tigan, Trimazide, 7-9h) XI. MISCELLANEOUS

A. lithium (eskalith, lithobid, lithonate, 17h) B. metoclopramide (raglan, 4h)

XII. ANTIHISTAMINES

A. promethazin (phenegran, 9h)

It is possible that some psychoactive drugs may have been inadvertently omitted from the above list, and it is very likely that new psychoactive drugs will come on the market during this study.

If you encounter a drug that is being used to influence cognition or behavior, but which is not on this list- other than the “allowed psychoactive drugs”, this must be communicated to the PI and the Project Director so that a determination may be made as to whether this drug should be added to the list.

Guidelines for the Treatment of Specific Clinical Problems Arising After Enrollment Clinical problems that require treatment may arise after enrollment. The most common problems that are likely to emerge are identified below. For each problem, potential treatments are listed in order of preference. It is recommended that the treating physician prescribe the first choice drug unless there is a specific medical contraindication to its use (e.g., allergy, etc.). If the patient has an inadequate response to the first choice after a reasonable treatment interval, the second choice treatment can be substituted. If this fails, the 3^rd choice may be used, etc. The treatment agents that are considered potentially serious confounders, are listed in italics. Thus, treatments in italics should rarely or never be used. The PI should provide a copy of the, “Guidelines for Treating Specific Clinical Problems” (see Appendix) to the treating physicians to facilitate management of the following clinical problems:

Agitation:

a. Environmental treatments b. Metoprolol or Nadolol c. Carbamazepine or Valproate

d. Trazodone (may use as first line if concurrent sleep disorder)

e. Opiates (may use as first line if concurrent pain syndrome, however, narcotics should be avoided whenever possible, particularly when conducting weekly follow-up exams) f. Antipsychotics

Anxiety

(should be diagnosed only later in the study in a patient who has made substantial recovery; the label of “agitation” should be used for lower level patients).

a. Reassurance b. Buspirone c. Benzodiazepines

Complex regional pain syndrome (requires documentation w/bone scan)

a. Prednisone b. Gabapentin c. Amitriptyline Depression

(should be diagnosed only later in the study in a patient who has made substantial recovery) a. Trazodone

b. SSRI c. Venlafaxine

d. Tricyclic antidepressants

Post-traumatic seizure

Any non-barbiturate, non-benzodiazepine anticonvulsant in no order of preference (review of the literature on newer anticonvulsants and cognitive function may result in future prioritization among non-barbiturate agents). Non-barbiturate anticonvulsants are listed below:

1. Carbamazepine 2. Ethosuximide 3. Ethotoin 4. Felbamate 5. Fosphenytoin 6. Gabapentin 7. Lamotrigine 8. Levetiracetam 9. Oxcarbazepine 10. Phenytoin 11. Tiagabine 12. Trimethadione 13. Divalproex sodium 14. Valproic acid 15. Zonisamide 16. Topiramate

Barbiturate and benzodiazepine anticonvulsants:

1. Clonazepam 2. Phenobarbital 3. Primidone Hypertonia

1. Physical modalities

2. Local neurolytic procedures (phenol, botulinum toxin, etc.) 3. Dantrolene

4. Baclofen 5. Tizanidine 6. Benzodiazepines Insomnia

Keep patient stimulated with activity during the day and provide quiet environment at night 1. Trazodone

2. Zolpidem 3. Zopiclon

4. Chloral hydrate 5. Benzodiazepines 6. Amitriptyline 7. Mirtazapine

Pain due to fractures, surgical procedures, etc.

B. Ensure that there is true pain (e.g., not spontaneous moaning)

C. Opiates (narcotics should be avoided whenever possible, particularly when conducting weekly follow-up exams)

Psychosis/mania (should be diagnosed only later in the study in a patient who has made substantial recovery)

D. Carbamazepine or valproate E. Lamotrigine

F. Quetiapine or olanzapine G. Lithium

H. Typical antipsychotics such as haloperidol Sedation for procedure

I. Hydroxyzine or diphenhydramine

J. Hydroxyzine/opiate (may use as first line if concurrent pain, or uncomfortable procedure) K. Propofol

L. Chloral hydrate Sympathetic storm

M. Metoprolol or Nadolol N. Opiates

O. Bromocriptine Vertigo

P. Antivert Q. Scopolamine

Excessive Pulmonary Secretions R. Atrovent

S. Glycopyrrolate (Robinul) T. Scopolamine

Excessive Sweating or Salivation

(please note that both of these medications are prohibited. When it is necessary to treat excessive sweating or salivation, Glycopyrrolate is preferred).

A. Glycopyrrolate (Robinul) B. Scopolamine

In some cases, the medical chart may list the medication by generic name while in other cases, it may be listed by brand name. Please refer to the Consolidated Medication List for a listing of agents by class, generic name and brand name.