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

Phase Two Randomized Controlled Crossover Trial of Atomoxetine to Treat Memory Impairment Due to Multiple Sclerosis

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03091400

Enrollment

Registered

2017-03-27

Start date

2017-03-16

Completion date

2018-06-11

Last updated

2020-03-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Memory Disorders, Multiple Sclerosis

Keywords

Memory Disorders, Multiple Sclerosis, Atomoxetine Hydrochloride

Brief summary

The purpose of this crossover trial is to investigate whether atomoxetine (versus placebo) improves memory function in persons with memory deficits due to multiple sclerosis.

Detailed description

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.

Interventions

DRUGAtomoxetine

Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)

DRUGPlacebo

Identically encapsulated placebo, with dose matched to experimental agent (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

21 Years to 60 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Memory Change	baseline and 14 weeks	Composite memory function (mean normative z-score) across verbal memory and visuospatial memory tasks: (1) Selective Reminding Test (SRT) assesses verbal learning of a 12-item word list over six trials (a. Total Learning; possible raw score range of 0-72), and recall after a delay (b: Delayed Recall; possible raw score range of 0-36); (2) Brief Visuospatial Memory Test, Revised (BVMT-R; possible raw score range of 0-36) assesses learning of six geometric shapes in six locations over three trials (c. Total Learning), and recall after a delay (d. Delayed Recall; possible raw score range of 0-12). Results reported as composite memory at follow-up minus baseline. Higher scores indicate better outcomes.

Secondary

Measure	Time frame	Description
Change in Patient-Reported Memory Change	baseline and 14 weeks	Patients will endorse memory change over the past six weeks as: much improved (3), improved (2), slightly improved (1), unchanged (0), slightly worse (-1), worse (-2), much worse (-3).
Change in CANTAB Paired Associate Learning	baseline and 14 weeks	CANTAB Paired Associate Learning (Total Errors Adjusted; possible raw score range of 0-70): a tablet-based memory task requiring subjects to study and recall the location of complex visual images not easily verbalized. Errors are tallied. Results reported as follow-up minus baseline. Higher scores indicate worse outcomes.
Change in NIH Toolbox Picture Sequence Memory Test	baseline and 14 weeks	NIH Toolbox Picture Sequence Memory Test (possible raw score range of 0-31): a tablet-based task requiring subjects to study the sequence of many activity scenes (e.g., flying a kite) presented visually and audibly. Correct sequences tallied. Results reported as follow-up minus baseline. Higher scores indicate better outcomes.
Change in Perceived Deficits Questionnaire (PDQ)	baseline and 14 weeks	Perceived Deficits Questionnaire (PDQ): the PDQ asks subjects to rate twenty cognitive difficulties on a scale from never (0) to almost always (4). Total ranges from 0-80. Results reported as follow-up minus baseline. Higher scores indicate worse outcomes. If a change is detected, will proceed to identify which of the four subscales were affected: retrospective memory, prospective memory, attention, planning / organization.
Change in Symbol Digit Modalities Test	baseline and 14 weeks	Symbol Digit Modalities Test (Oral Version, total raw; possible range of 0-110): A test of processing speed requiring subjects to rapidly complete symbol-digit pairings based on a key. Incidental learning may contribute to performance. Total correct in 90 seconds is tallied. Results reported as follow-up minus baseline. Higher scores indicate better outcomes.

Countries

United States

Participant flow

Recruitment details

Enrollment Period: 03/16/2017 - 02/20/2018. There was a two-phase screening. Of the 35 participants who met initial screening criteria (e.g., age, MS diagnosis), 24 did not meet secondary screening requirements (e.g., objective memory impairment on assessment). Eleven (11) participants met secondary screening requirements and were randomized.

Participants by arm

Arm	Count
Atomoxetine, Then Placebo Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks) then a two-week washout period, then Identically encapsulated placebo, with dose matched to experimental agent (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	4
Placebo, Then Atomoxetine Identically encapsulated placebo, with dose matched to experimental agent (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks) then a two-week washout period, then Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	6
Total	10

Withdrawals & dropouts

Period	Reason	FG000	FG001
Washout - 2 Weeks	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Placebo, Then Atomoxetine	Total	Atomoxetine, Then Placebo
Age, Continuous	46.0 years STANDARD_DEVIATION 5.4	44.4 years STANDARD_DEVIATION 6.9	42.0 years STANDARD_DEVIATION 9.1
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	3 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants	7 Participants	3 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	4 Participants	3 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	5 Participants	6 Participants	1 Participants
Sex: Female, Male Female	2 Participants	3 Participants	1 Participants
Sex: Female, Male Male	4 Participants	7 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 10	0 / 10
other Total, other adverse events	4 / 10	1 / 10
serious Total, serious adverse events	0 / 10	0 / 10

Outcome results

Primary

Change in Memory Change

Composite memory function (mean normative z-score) across verbal memory and visuospatial memory tasks: (1) Selective Reminding Test (SRT) assesses verbal learning of a 12-item word list over six trials (a. Total Learning; possible raw score range of 0-72), and recall after a delay (b: Delayed Recall; possible raw score range of 0-36); (2) Brief Visuospatial Memory Test, Revised (BVMT-R; possible raw score range of 0-36) assesses learning of six geometric shapes in six locations over three trials (c. Total Learning), and recall after a delay (d. Delayed Recall; possible raw score range of 0-12). Results reported as composite memory at follow-up minus baseline. Higher scores indicate better outcomes.