Project Information. a) Protocol. Rationale and aims of research:

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1 Project Information a) Protocol Rationale and aims of research: Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system that afflicts roughly 1 in 1000 people in Northern regions of Europe and North America (Pryse- Phillips & Costello, 2001). MS patients frequently experience physical disability, severe fatigue, and depression. Cognitive deficits are also common. In fact, over 50% of MS patients experience problems with aspects of attention, processing speed, executive functioning, and learning (Rao et al., 1991). These cognitive symptoms are associated with problems managing independent activities of daily living, poorer vocational status, difficulty driving, and lower social functioning (Benedict et al., 2005; Higginson, Arnett, & Voss, 2000; Rao et al., 1991). As such, the identification of pharmacologic agents that improve cognition in MS may have wide ranging implications for patients overall quality of life. Aims: 1. Determine whether armodafinil ameliorates cognitive difficulties in MS as measured by objective neuropsychological tests. It is hypothesized that armodafinil will be associated with improved performance on tests of cognitive functioning. 2. Determine whether armodafinil ameliorates self-reported cognitive difficulties as measured by questionnaires. It is hypothesized that armodafinil will be associated with fewer selfreports of memory and other thinking problems. Results of similar or related studies: Armodafinil is a novel psychostimulant that has shown promise as a cognitive enhancer in normal adults and patient populations, including schizophrenia and attention deficit hyperactivity disorder (Baranski et al., 2004; Randall et al., 2005; Turner et al., 2004a; Turner et al., 2004b). Commonly prescribed to treat MS-related fatigue (Zifko, 2004), armodafinil is also an alertness-promoting agent that reduces lapses of attention and vigilance that are caused by sleep deprivation and fatiguing disorders (Baranski et al., 1998; Gill et al., 2005; Hirshkowitz et al., 2007). Indeed, it has been suggested that the nootropic effects of armodafinil may be magnified among people with pronounced fatigue and pre-existing cognitive difficulties (Muller et al., 2004; Randall et al., 2005). As MS patients frequently suffer from significant fatigue and neuropsychological deficits, armodafinil has strong potential as a highly efficacious cognitive enhancer in this population. Despite this, no published studies have examined the use of armodafinil to treat cognitive impairment in MS. The proposed study will examine how armodafinil impacts objective neuropsychological performance and self-reported cognitive difficulties in MS. Benefits and Risks: 1

2 Participants will receive a $150 economic benefit for participation. Aside from the monetary compensation, they will not receive any other direct benefits. The results of this study may help clinicians improve the treatment of cognitive dysfunction in MS. Armodafinil is used as the standard of care for MS-related fatigue. However, no studies have examined how armodafinil might impact cognition in MS. The most commonly observed adverse side effects of armodafinil include headache, stomach upset, dizziness, anxiety and insomnia. Armodafinil can also reduce the efficacy of steroidal contraceptives and has rarely been associated with heart palpitations and chest pain among people with a history of mitral valve prolapse (patients with a history of heart problems will be excluded). Very rarely, a serious rash has been observed among people taking armodafinil. Studies demonstrating these side effects required regular use of armodafinil; participation in our study only requires taking a single 250mg dose. Participants will be advised of these possible adverse reactions. Participants will remain at the clinic for testing for 4 hours following the drug administration and the principal investigator, Dr. Lynch, will be available to address any adverse event. The study will also require participants to complete tests of thinking and fill out questionnaires. Though there are typically no risks associated with these tasks, occasionally participants become frustrated when they feel they are doing poorly on a behavioral task or may feel uncomfortable when asked questions about their MS symptoms. Participants will be advised that they can discontinue the study at any time and that they can decline to answer any question. Inclusion/exclusion criteria: 40 participants with secondary progressive or relapsing-remitting MS will be included in the study. Interested participants will be administered a structured screening interview to determine their eligibility for the project by evaluating the following inclusion criteria: (a) no history of alcohol/drug abuse or nervous system disorder other than MS; (b) no sensory impairments that might interfere significantly with cognitive testing; (c) no developmental history of learning disability or attention-deficit/hyperactivity disorder; (d) no medical condition other than MS that could substantially affect cognition; (e) no relapse and/or corticosteroid use within four weeks of assessment; (f) absence of severe physical/neurological impairment that would make testing insurmountable; (g) and no current use of armodafinil or other psychostimulants; (h) not currently pregnant or breastfeeding; (i) no history of severe renal or hepatic impairment; (j) no history of heart disease. Because high doses of caffeine have been shown to have similar cognitive enhancing effects as armodafinil, only patients who report consuming fewer than 300mg caffeine daily will be included in the study. Each patient will be diagnosed as having MS based on established criteria by a board-certified neurologist who will determine disease duration, assess disease course based on Lublin & Reingold criteria, and rate patients on Kurtzke s EDSS. Additionally, interested participants will complete a brief cognitive screen at the time of the screening interview; the oral version of the Symbol Digit Modalities Test (SDMT) is a measure of speed of information processing that is commonly used in multiple sclerosis. Having shown 2

3 promise as a screening tool for cognitive impairment in MS, only patients who perform below established screening cutoffs on the SDMT will be accepted into the study. Study procedures: Participants will be approached during regularly scheduled meetings at the Landon Center MS clinic. If they express interest in learning more about the study and report a history of cognitive difficulties, they will be given informed consent. If they agree to participate following informed consent, an eligibility interview will be conducted. Additionally, female patients will be asked to provide a urine sample in order to test for potential pregnancy prior to both testing sessions. Moreover, patients will be told not to consume caffeine the day of testing or eat any food for three hours prior to the administration of the pill, in order to ensure a more standardized peak plasma concentration among all participants. Patients who report MS-related cognitive difficulties and perform at least one standard deviation below the mean on a brief cognitive screen will be given a thorough neuropsychological evaluation at two time points. The investigation will involve a double-blind, placebo controlled, cross-over study examining the efficacy of armodafinil in reducing cognitive problems in MS. Half of the patients will be randomized to receive a single oral dose of lactose placebo prior to the first testing session. After a weeklong washout period, they will then receive 250mg of armodafinil prior to a second testing session (P/M group). The other half of patients will be randomized to receive the active drug first, followed by the placebo (M/P group). As plasma levels of armodafinil peak between 2-4 hours after administration, participants will be asked to take a single 250mg capsule 2 hours prior to the scheduled testing sessions. Dr. Lynch will be prescribing and dispensing the armodafinil and placebo for this study. Cephalon will ship both the armodafinil and lactose placebo tablets to Dr. Bruce, who will securely transport them to Dr. Lynch upon their arrival. Dr. Lynch will place both the armodafinil and lactose placebo tablets in a locked cabinet upon her receipt of the tablets; the tablets will remain locked until dispensed by Dr. Lynch. Primary outcome measures for the study are computer and paper/pencil tests of attention, concentration, memory, and other types of thinking. In addition, we will be giving questionnaires that assess self-reported thinking skills, depression, fatigue, anxiety, and other common MS symptoms. Cognitive Measures Cognition will be examined with well-validated neuropsychological measures of intelligence, speed of information processing, attention, executive functioning, and learning. The most common cognitive problems in MS are speed of information processing and attention. As armodafinil has shown special promise in augmenting attention and speed of information processing, emphasis will be placed on neuropsychological tasks that measure these domains. In addition, we will administer a test of effort that has been shown to be highly correlated with self-reported cognitive fatigue in MS. When possible, counterbalanced alternate test forms will be given to minimize potential practice effects (please see Appendix A for a more detailed description of the proposed neuropsychological measures). 3

4 Self-Report Measures Patients will complete commonly used self-report questionnaires assessing current cognitive difficulties and medication-related side-effects. Cognitive fatigue will be measured using a standard measure of MS fatigue and a modified measure that asks participants to rate their fatigue at the moment of the evaluation. The modified measure will coincide with estimated peak plasma concentrations of armodafinil. As emotional problems have sometimes been linked to cognitive difficulties and fatigue in MS, questionnaires assessing mood and anxiety will also be administered. Safety Procedures Plan to monitor and report unanticipated problems: Unanticipated problems will be reported by research team members to Dr. Lynch who is responsible for project oversight. Dr. Lynch will notify other team members of the unanticipated problem and will convene a meeting with all team members to resolve the problem when necessary. Any adverse events will be reported to the Human Subjects Committee at The University of Kansas Hospital, as well as the Institutional Review Board at the University of Missouri-Kansas City, Cephalon and the FDA. A study timeline will be created which will include scheduling of quarterly meetings to monitor study procedures and data collection and entering. Plan to follow-up with participants: The research assistant will contact each participant by phone 24 hours following each testing session and inquire about how they are feeling, whether they have concerns about any part of the study in which they have participated. The research assistant will then coordinate with Dr. Lynch to address any follow-up issues if they arise. Plan to provide contact information to participants: Information regarding how to contact the investigators on the study will be provided to participants in the consent form, which they will have a signed copy of, in the event they should need to or desire to contact investigators for any reason. Study withdrawal/discontinuation procedures: The research assistant will inform the subject that he/she may terminate participation in the study at any time. The research assistant will observe the subject through the course of this testing. If the subject is unable to perform the tasks presented, becomes emotionally upset over his/her performance, becomes fatigued or confused by the testing, or in any other way, gives evidence of problems that would lead to sub-optimum performance, the research assistant will discontinue the testing and indicate the reason for this discontinuation in the record form. 4

5 Plan for assuring participants privacy and confidentiality: To ensure privacy and confidentiality, the consent process will take place in a private room in the Multiple Sclerosis clinic as part of usual clinic care. The study will be conducted in a private room at the neurology clinic. The name of the subject will be recorded on a single page record form, along with the subject number, age, gender, ethnicity, date of birth, education level, date of diagnosis, and EDSS disability score. Only principal and co-investigators will have access to the record form linking subject numbers with the subjects names. This file will be kept separate from all collected data in a locked file cabinet. The record forms are destroyed when all the data have been collected and the experiment is complete. All raw data will be kept separate from identifying information in a locked cabinet in which only the research team has access. A data spreadsheet will identify subjects by subject number, but not by name and will be stored in a password protected data file. Furthermore, the spreadsheet is shared only by individuals associated with the study and will be retained electronically for five years following publication of any results of this study, as required by sound research practices. However, following the completion of the experiment, there is no way of associating specific individuals with the data recorded in this spreadsheet. 5

6 Appendix Neuropsychological Tests I. Attention and Speed of Information Processing Conner s Continuous Performance Test II (Conners, 2004): The CPT-II is a test of sustained attention, impulsivity, and choice reaction time that has negligible practice effects. The CPT-II has been shown to be sensitive to treatment effects of nootropics in various patient populations. Symbol Digit Modalities Test (Smith, 1982): The oral version of the SDMT is a measure of speed of information processing that is commonly used in multiple sclerosis. Having shown promise as a screening tool for cognitive impairment in MS, only patients who perform below established screening cutoffs on the SDMT will be accepted into the study (Parmenter, et al., 2007). The SDMT will also be used as an outcome measure. Paced Serial Addition Task (Gronwall, 1977): Commonly used a measure of speed of information processing in MS, the PASAT requires participants to quickly add numbers. II. Executive Functioning Stroop Test (Stroop, 1935) A test of executive functioning that requires participants to inhibit a natural response (reading a word) and replace it with another response (saying a color). Word Generation (Stern & White, 2003) A test of a verbal fluency in which a person is asked to generate as many 3 letter words as possible from a random list of letters. Computerized Assessment of Response Bias (Allen et al., 1997): The CARB is a measure of effort and response time variability that has been shown to be highly correlated with selfreported fatigue in MS (Bruce et al., In Press). III. Memory Rey Auditory Verbal Learning Test (Lezak et al., 2004) A test of verbal memory during which a person is asked to learn and recall a list of 15 unrelated words. This test has multiple alternate forms that can be used to reduce practice effects. Brief Visuospatial Memory Test (Benedict et al., 1996) A test of visual memory during which a person is asked to learn and draw a series of abstract designs. This test has multiple alternate forms that can be used to reduce practice effects. IV. General Intellectual Functioning 6

7 Wechsler Test of Adult Reading (Wechsler, 2001): The WTAR will be used as an estimate of intellectual abilities. This test uses a mixture of demographic information and performance on a reading test to accurately estimate general intellectual functioning. Self-Report Measures BDI-Fast Screen (Beck et al., 2000) A self-report questionnaire designed to assess depression in neurologic populations. The Prospective and Retrospective Memory Questionnaire (Smith et al., 2000) A self-report questionnaire designed to assess perceived memory problems. Current Cognition Questionnaire Self-report measure designed to assess the cognitive problems a person is experiencing at the moment they are filling out the questionnaire. Modified Fatigue Impact Scale (Fisk et al., 1994) - A self-report measure designed to assess cognitive, physical, and social fatigue in MS. Current Fatigue Impact Scale Self-report measure designed to assess the fatigue a person is feeling at the moment they are filling out the questionnaire. Epworth Sleepiness Scale (Johns, 1991) A self-report measure designed to assess how tired a person is. State-Trait Anxiety Inventory (Spielberger, 1983) A self-report measure designed to assess situational and stable anxiety. References 7

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