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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Atomoxetine | Experimental | Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks) |
|
| Placebo | Placebo Comparator | 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Atomoxetine | Drug | Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks) |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | baseline and 14 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Patient-Reported Memory Change | 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). | baseline and 14 weeks |
| Change in CANTAB Paired Associate Learning |
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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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| James F Sumowski, PhD | Icahn School of Medicine at Mount Sinai | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Icahn School of Medicine at Mount Sinai | New York | New York | 10029 | United States |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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) |
| FG001 | 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) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 - 6 Weeks |
| |||||||||||||
| Washout - 2 Weeks |
| |||||||||||||
| Phase 2 - 6 Weeks |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | z-score | baseline and 14 weeks |
|
14 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Atomoxetine | Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| James F Sumowski, PhD | Icahn School of Medicine at Mount Sinai | 212-241-6854 | james.sumowski@mssm.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 8, 2017 | Feb 24, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D008569 | Memory Disorders |
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
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| ID | Term |
|---|---|
| D000069445 | Atomoxetine Hydrochloride |
| ID | Term |
|---|---|
| D011437 | Propylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
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| Placebo | Drug | 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) |
|
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. |
| baseline and 14 weeks |
| Change in NIH Toolbox Picture Sequence Memory Test | 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. | baseline and 14 weeks |
| Change in Perceived Deficits Questionnaire (PDQ) | 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. | baseline and 14 weeks |
| Change in Symbol Digit Modalities Test | 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. | baseline and 14 weeks |
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| NOT COMPLETED |
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| BG001 |
| 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) |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | 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) |
|
|
| Secondary | Change in Patient-Reported Memory Change | 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). | Posted | Mean | Standard Deviation | score on a scale | baseline and 14 weeks |
|
|
|
| Secondary | Change in CANTAB Paired Associate Learning | 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. | Posted | Mean | Standard Deviation | score on a scale | baseline and 14 weeks |
|
|
|
| Secondary | Change in NIH Toolbox Picture Sequence Memory Test | 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. | Posted | Mean | Standard Deviation | score on a scale | baseline and 14 weeks |
|
|
|
| Secondary | Change in Perceived Deficits Questionnaire (PDQ) | 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. | Posted | Mean | Standard Deviation | score on a scale | baseline and 14 weeks |
|
|
|
| Secondary | Change in Symbol Digit Modalities Test | 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. | Posted | Mean | Standard Deviation | score on a scale | baseline and 14 weeks |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 4 |
| 10 |
| EG001 | 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) | 0 | 10 | 0 | 10 | 1 | 10 |
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Abnormal dreams | Psychiatric disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Urinary Hesitation | Renal and urinary disorders | Systematic Assessment |
|
| Pelvic/testicular pain | Reproductive system and breast disorders | Systematic Assessment |
|
| Painful Urination | Renal and urinary disorders | Systematic Assessment |
|
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| D013568 | Pathological Conditions, Signs and Symptoms |
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |