Recall Enhancement Through Treatment With Atomoxetine in MS (RETAIN-MS)

Approximately half of persons with multiple sclerosis (MS) develop memory decline, which
makes it difficult to maintain gainful employment, manage a household, and lead a
fully-engaged social life. There are currently no validated symptomatic treatments for memory
deficits in persons with MS. The study team will perform a fourteen week double-blind
phase-two crossover randomized controlled trial (RCT) of atomoxetine (80mg qd, six weeks)
versus placebo (six weeks) to improve memory in MS patients with documented memory impairment
(two-week washout between phases). Atomoxetine is a non-stimulant selective norepinephrine
reuptake inhibitor FDA-approved to treat cognitive-behavioral symptoms of attention deficit /
hyperactivity disorder (ADHD; Strattera, Eli Lilly). Pre-clinical evidence suggests that
atomoxetine may also improve memory by targeting brain mechanisms responsible for memory
function (norepinephrine in the hippocampus). Twenty-four MS patients demonstrating objective
memory impairment on neuropsychological screening tests will be randomly assigned to
once-daily orally-administered atomoxetine or identically-encapsulated placebo. After a
two-week washout period, patients will be switched to the opposite condition. The RCT will be
performed at the Corinne Goldsmith Dickinson Center for MS at the Icahn School of Medicine at
Mount Sinai. Baseline and follow-up evaluations will assess change in objective memory
function (Primary Outcome), as well as Secondary Outcomes of patient-reported memory change,
additional objective measures of memory function, and a measure of speeded symbol-digit
coding (the most widely-used test of cognition in persons with MS). Tertiary / Other Outcomes
examine sustained attention, processing speed, working memory, fatigue, mood, manual
dexterity, and walking speed. The researchers predict that atomoxetine will lead to
significantly greater improvements in Primary and Secondary memory outcomes relative to
placebo. Consistent with the ADHD literature, there may be additional benefits of atomoxetine
versus placebo on measures of attention, processing speed, and working memory. Results of
this phase 2 trial will inform decisions / planning for a possible phase 3 trial, which may
ultimately support the use of non-stimulant, once-daily atomoxetine as a memory treatment
option for MS patients.

Inclusion Criteria:

- Diagnosis of Multiple Sclerosis based on the Revised McDonald criteria

- Age 21 - 60 years.

- Patient self-report of memory decline from previously higher level of functioning.

- Memory Impairment on validated neuropsychological memory screening tests, as follows:

1. performance ≤16th percentile on both (i) Rey Auditory Verbal Learning Test
(RAVLT) Total Learning (TL) and (ii) WMS-IV Visual Reproduction I (VR-I); and b)
mean normative memory performance (RAVLT TL and WMS-IV VR-I) is at least 1.0
standard deviation below expectations based on the Wechsler Test of Adult Reading
(WTAR)

Exclusion Criteria:

- Current stimulant medication usage.

- Previous diagnosis or treatment for ADHD or any neurologic condition other than
multiple sclerosis (e.g., traumatic brain injury, epilepsy)

- Clinical relapse of MS within 60 days of screening,

- Change in disease-modifying therapy within 90 days of screening,

- Below average estimated premorbid intelligence (WTAR, < 16th percentile),

- Severe cognitive impairment indicated by a Mini-Mental Status Examination (MMSE) <
24/30.

- Contraindications for atomoxetine use: (a) self-reported history of suicidal ideation
within the last twelve months (Columbia Suicide Severity Rating Scale), (b) diagnosis
of bipolar illness, (c) moderate or severe current depressive symptomatology (Beck
Depression Inventory Fast Screen ≥ 9), (d) diagnosis of hepatic disease, (e) narrow
angle glaucoma, (f) pheochromocytoma, (g) monoamine oxidase inhibitor within 14 days
of study drug start, (h) taking strong CYP2D6 inhibitors (e.g., paroxetine,
fluoxetine, quinidine), (i) diagnosis of heart disease, (j) pregnant or planning
pregnancy during the study period, (k) breastfeeding, (l) hypersensitivity to
atomoxetine or component of formulation.