Efficacy and Safety of Lisdexamfetamine Dimesylate in Adults With Chronic Fatigue Syndrome

Use of Lisdexamfetamine Dimesylate in Treatment of Cognitive Impairment (Chronic Fatigue Syndrome): A Double Blind, Placebo Controlled Study

Over the past decade, the Rochester Center for Behavioral Medicine (RCBM) has evaluated many patients with attention deficit hyperactivity disorder (ADHD). A recurrent finding in these patients is a history of unexplained fatigue and musculoskeletal pain. Treatment of these patients in our clinic has revealed that when their underlying ADHD is treated with psychostimulant medication, many patients report significant improvements with regard to their fatigue and musculoskeletal pain. Patients report less subjective fatigue and pain and note overall functional improvement, although the initial and primary objective was the treatment of their attention or hyperactivity problems. We speculate that stimulants are efficacious by offering two distinct clinical properties. 1) anti-fatigue properties and 2) properties that allow patients to filter out extraneous stimuli (i.e. chronic muscle pain).

As a result of these findings RCBM developed a chronic fatigue/fibromyalgia clinic in the early 2000's. This clinic was staffed by a board-certified rheumatologist and the psychiatric staff at RCBM. Through the major referral hospital in the area, patients with self-identified fibromyalgia and chronic fatigue were referred to our clinic. Over eighteen months, we evaluated 75 patients, and found that in patients who had comprehensive evaluations, nearly 70 percent also had a history of ADHD, inattentive or combined types. Diagnosis was made using clinical history and standardized symptom checklists. Oftentimes, the ADHD had been previously undiagnosed. This finding supports the link between ADHD and FMS/CFS. Results from these evaluations reinforced our initial findings: patients who are treated for their ADHD symptoms also show a reduction in their chronic pain and fatigue symptoms. This is true regardless of previous (unsuccessful) therapies to treat their fibromyalgia. As a result of these findings, we are conducting a controlled study to further demonstrate the efficacy of lisdexamfetamine dimesylate (LDX) in controlling fatigue symptoms in patients presenting with chronic fatigue syndrome. This is a double-blind, placebo-controlled study over a period of 8 weeks, where subjects are randomized to either LDX or placebo. We will evaluate subjects through standardized pain, fatigue and ADHD assessment scales.

Subjects will be started with a single pill containing 30mg of LDX or comparable placebo, depending on the treatment assignment. At the week 2 visit, the dose will be increased to 50 mg (or comparable placebo) if the patient exhibits no significant adverse effects as judged by the Investigator. At the week 4 visit, the dose will be increased to 70 mg (or comparable placebo) if the patient exhibits no significant adverse effects as judged by the investigator.

Will be randomly assigned to one of two treatment arms in a 1:1 ratio of either LDX or placebo for 6 weeks. Subjects will be started with a single pill containing 30mg of LDX or comparable placebo, depending on the treatment assignment. At the week 2 visit, the dose will be increased to 50 mg (or comparable placebo) if the patient exhibits no significant adverse effects as judged by the Investigator. At the week 4 visit, the dose will be increased to 70 mg (or comparable placebo) if the patient exhibits no significant adverse effects as judged by the investigator.

Will be randomly assigned to one of two treatment arms in a 1:1 ratio of either LDX or placebo for 6 weeks. Subjects will be started with a single pill containing 30mg of LDX or comparable placebo, depending on the treatment assignment. At the week 2 visit, the dose will be increased to 50 mg (or comparable placebo) if the patient exhibits no significant adverse effects as judged by the Investigator. At the week 4 visit, the dose will be increased to 70 mg (or comparable placebo) if the patient exhibits no significant adverse effects as judged by the investigator.

The BRIEF-A (Behavior Rating Inventory of Executive Function-- Adult Form) is comprised of the following sub-scales: Metacognition Index, Behavioral Regulation Index, Inhibit, Shift, Emotional Control, Self-Monitor, Initiate, Working Memory, Plan/Organize, Task Monitor, and Organziation of Material. These subscales are summed to provide the GEC or Global Executive Composite. Listed below are the mean improvement scores on the GEC index from baseline to endpoint. The Global Executive Composite raw score range is 70-182, with higher scores indicating more compromised executive functioning. The scores listed in the table depict mean improvement on the GEC from the beginning to the end of the study.

The Fatigue Severity Scale is designed to measure the impact of fatigue on the life of the subject. It is a nine-question likert scale survey with a raw score range of 0-63. Scores of 36 and above indicate significant fatigue. In this study, we compared the mean change in the Fatigue Severity Scale (FSS) from baseline to endpoint between LDX and placebo treated patients.

The Hamilton Anxiety Scale is a 14-items clinician-rated scale designed to measure anxiety severity. Each of the 14 items is scored from 0 (symptom not persent) to 4 (severe symptom). The total range is 0-56. A total score of less than 17 indicates mild severity, 18-24 indicates mild to moderate severity, and a score of 25-30 indicates moderate to severe symptoms. In this study, we compared the mean change in the Hamilton Anxiety scale from baseline to week 6 between LDX and placebo-treated patients.

The McGill Pain Questionniare (Short Form) consists of 15 pain descriptors (11 sensory; 4 affective) which are rated on an intensity scale. 0 = none, 1 = mild, 2 = moderate or 3 = severe. The sum of the intensity scores of the words chosen for sensory, affective and total descriptors are added for a total score. The score range is 0-45. In this study, we compared the change in the Short Form McGill Pain Questionnaire (SF-MPQ) from baseline to week 6 between LDX and placebo treated patients.

The Fibromyalgia Impact Questionnaire (FIQ) is an assessment that quantifies the impact of fibromyalgia on an individual, including questions on pain level, fatigue, sleep disturbance, and psychological distress, among others. The score range is 0 to 100, with higher number indicating higher Fibromyalgia severity/impact. Below, we compare the mean change in the Fibromyalgia Impact Questionnaire (FIQ) from baseline to week 6 between LDX and placebo treated patients.

The Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) is an 18-item scale based on DSM-IV criteria for ADHD. Each item is rated using a likert scale from 0 (none) to 3 (severe), with a total score range of 0-54, with higher scores indicating more symptoms/severity. In this study, we compared mean change in ADHD-RS total score from baseline to endpoint of the study.

The Clinical Global Impression (Severity) is a one-item clinician-rated measure. The item is a likert scale on which the clinician rates the subject based on perceived severity of psychopathology, with higher numbers indicating higher severity. In this study, we compared the mean change in severity from baseline to endpoint.

Inclusion Criteria: BRIEF-A Global Executive Composite score (GEC) ≥ 65, or Behavioral Regulation Index score (BRI) ≥ 65, or Metacognition Index score (MI) ≥ 65. Subjects must meet consensus criteria for chronic fatigue syndrome. Provide written informed consent for participation in the trial before completing any study-related procedures. 18-60 years at time of consent Male or non-pregnant females who are not breastfeeding. Females of reproductive potential must agree to use a medically accepted means of contraception when engaging in sexual intercourse at any time during the study. Are able to swallow study medication. Exclusion Criteria: CFS and executive functioning impairment are not present or not diagnosable Serious comorbid psychiatric condition Subjects who were pregnant, nursing, or intended to become pregnant Subjects who had been on a psychostimulant regimen in the last six months Subjects who had a medical condition that would have been affected by psychostimulant medication Subjects who were of low intelligence, or who were unable to communicate effectively with the study team