Trial Outcomes & Findings for Recall Enhancement Through Treatment With Atomoxetine in MS (RETAIN-MS) (NCT NCT03091400)

NCT ID: NCT03091400

Last Updated: 2020-03-13

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 11 participants
• Primary outcome timeframe: baseline and 14 weeks
• Results posted on: 2020-03-13

Participant Flow

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.

Participant milestones

Measure	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)	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)
Phase 1 - 6 Weeks STARTED	5	6
Phase 1 - 6 Weeks COMPLETED	5	6
Phase 1 - 6 Weeks NOT COMPLETED	0	0
Washout - 2 Weeks STARTED	5	6
Washout - 2 Weeks COMPLETED	4	6
Washout - 2 Weeks NOT COMPLETED	1	0
Phase 2 - 6 Weeks STARTED	4	6
Phase 2 - 6 Weeks COMPLETED	4	6
Phase 2 - 6 Weeks NOT COMPLETED	0	0

Reasons for withdrawal

Measure	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)	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)
Washout - 2 Weeks Withdrawal by Subject	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Atomoxetine, Then Placebo n=4 Participants 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)	Placebo, Then Atomoxetine n=6 Participants 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)	Total n=10 Participants Total of all reporting groups
Age, Continuous	42.0 years STANDARD_DEVIATION 9.1 • n=5 Participants	46.0 years STANDARD_DEVIATION 5.4 • n=7 Participants	44.4 years STANDARD_DEVIATION 6.9 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) White	1 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Atomoxetine n=10 Participants Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	Placebo n=10 Participants 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)
Change in Memory Change	0.32 z-score Standard Deviation 0.60	0.24 z-score Standard Deviation 0.46

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Atomoxetine n=10 Participants Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	Placebo n=10 Participants 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)
Change in Patient-Reported Memory Change	0.70 score on a scale Standard Deviation 1.16	0.90 score on a scale Standard Deviation 1.37

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Atomoxetine n=10 Participants Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	Placebo n=10 Participants 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)
Change in CANTAB Paired Associate Learning	-10.30 score on a scale Standard Deviation 11.98	-8.10 score on a scale Standard Deviation 15.56

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Atomoxetine n=10 Participants Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	Placebo n=10 Participants 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)
Change in NIH Toolbox Picture Sequence Memory Test	4.50 score on a scale Standard Deviation 5.80	3.20 score on a scale Standard Deviation 2.97

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Atomoxetine n=10 Participants Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	Placebo n=10 Participants 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)
Change in Perceived Deficits Questionnaire (PDQ)	-6.60 score on a scale Standard Deviation 9.97	-5.90 score on a scale Standard Deviation 13.14

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Atomoxetine n=10 Participants Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	Placebo n=10 Participants 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)
Change in Symbol Digit Modalities Test	7.20 score on a scale Standard Deviation 7.07	5.50 score on a scale Standard Deviation 5.42

Adverse Events

Atomoxetine

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Atomoxetine n=10 participants at risk Atomoxetine (40 mg qd titration dose for first seven days, followed by 80 mg qd target dose for remaining five weeks)	Placebo n=10 participants at risk 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)
Gastrointestinal disorders Diarrhea	10.0% 1/10 • 14 weeks	0.00% 0/10 • 14 weeks
Nervous system disorders Dizziness	10.0% 1/10 • 14 weeks	0.00% 0/10 • 14 weeks
Psychiatric disorders Abnormal dreams	10.0% 1/10 • 14 weeks	0.00% 0/10 • 14 weeks
General disorders Fatigue	0.00% 0/10 • 14 weeks	10.0% 1/10 • 14 weeks
Renal and urinary disorders Urinary Hesitation	10.0% 1/10 • 14 weeks	0.00% 0/10 • 14 weeks
Reproductive system and breast disorders Pelvic/testicular pain	10.0% 1/10 • 14 weeks	0.00% 0/10 • 14 weeks
Renal and urinary disorders Painful Urination	10.0% 1/10 • 14 weeks	0.00% 0/10 • 14 weeks

Additional Information

James F Sumowski, PhD

Icahn School of Medicine at Mount Sinai

Phone: 212-241-6854

Email: james.sumowski@mssm.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place