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

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ClinicalTrials.gov Identifier: NCT03091400
Recruitment Status : Completed
First Posted : March 27, 2017
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
James F. Sumowski, Icahn School of Medicine at Mount Sinai

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.

Condition or disease Intervention/treatment Phase
Memory Disorders Multiple Sclerosis Drug: Atomoxetine Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Phase Two Randomized Controlled Crossover Trial of Atomoxetine to Treat Memory Impairment Due to Multiple Sclerosis
Actual Study Start Date : March 28, 2017
Actual Primary Completion Date : June 11, 2018
Actual Study Completion Date : June 11, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Atomoxetine
Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)
Drug: Atomoxetine
Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)
Other Name: Strattera (Eli Lilly)

Placebo Comparator: Placebo
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)
Drug: Placebo
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)




Primary Outcome Measures :
  1. Memory Change [ Time Frame: 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), and recall after a delay (b: Delayed Recall); (2) Brief Visuospatial Memory Test, Revised (BVMT-R) assesses learning of six geometric shapes in six locations over three trials (c. Total Learning), and recall after a delay (d. Delayed Recall). This will be reported as one composite score.


Secondary Outcome Measures :
  1. Patient-Reported Memory Change [ Time Frame: 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).

  2. CANTAB Paired Associate Learning [ Time Frame: baseline and 14 weeks ]
    CANTAB Paired Associate Learning (Total Errors Adjusted): a tablet-based memory task requiring subjects to study and recall the location of complex visual images not easily verbalized. Errors are tallied (higher score is worse).

  3. NIH Toolbox Picture Sequence Memory Test [ Time Frame: baseline and 14 weeks ]
    NIH Toolbox Picture Sequence Memory Test (raw): 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 (higher is better).

  4. Perceived Deficits Questionnaire (PDQ) [ Time Frame: 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 (higher is worse). If a change is detected, will proceed to identify which of the four subscales were affected: retrospective memory, prospective memory, attention, planning / organization.

  5. Symbol Digit Modalities Test [ Time Frame: baseline and 14 weeks ]
    Symbol Digit Modalities Test (Oral Version, total raw): 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03091400


Locations
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United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
Sponsors and Collaborators
Icahn School of Medicine at Mount Sinai
Investigators
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Principal Investigator: James F Sumowski, PhD Icahn School of Medicine at Mount Sinai

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Responsible Party: James F. Sumowski, Assoicate Professor, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT03091400    
Other Study ID Numbers: GCO 16-1552
First Posted: March 27, 2017    Key Record Dates
Last Update Posted: June 14, 2018
Last Verified: June 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by James F. Sumowski, Icahn School of Medicine at Mount Sinai:
Memory Disorders
Multiple Sclerosis
Atomoxetine Hydrochloride
Additional relevant MeSH terms:
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Multiple Sclerosis
Memory Disorders
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms
Atomoxetine Hydrochloride
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs