Trial Outcomes & Findings for Cognitive Behavioral Therapy, Modafinil, or Both for Multiple Sclerosis Fatigue (NCT NCT03621761)

Last Updated: 2022-12-27

Results Overview

The Modified Fatigue Impact Scale is a 21-item self-report survey. Each item is rated 0-4, Total scores range from 0-84. . Higher scores indicate a greater impact of fatigue on a person's activities. The primary outcome measure will be the mean within-subject difference between baseline and 12-week Modified Fatigue Impact Scale values (delta-MFIS), compared between the 3 treatment groups.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

343 participants

Primary outcome timeframe

Baseline-12 weeks

Results posted on

2022-12-27

Participant Flow

Participants were recruited based on physician or clinic referral at two university medical centers, social media advertising, web site postings, email, letter, and phone calls to participants on our health registries. The first participant was enrolled on November 15, 2018 and the last participant was enrolled on June 2, 2021.

Of 343 enrolled participants, 336 met inclusion criteria and were randomized to treatment.

Participant milestones

Participant milestones
Measure	Cognitive Behavioral Therapy 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).
Overall Study STARTED	114	114	108
Overall Study Week 8 Follow-up Timepoint	111	111	105
Overall Study Week 12 Follow-up Timepoint	111	110	105
Overall Study Week 24 Survey Timepoint	111	110	105
Overall Study COMPLETED	111	110	105
Overall Study NOT COMPLETED	3	4	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Cognitive Behavioral Therapy 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).
Overall Study Lost to Follow-up	1	1	2
Overall Study Withdrawal by Subject	2	1	1
Overall Study Became Ineligible	0	2	0

Baseline Characteristics

Baseline MFIS results (means/SD) are based on the number of participants who completed the entire survey at baseline. 10 participants in the CBT group, 8 participants in the combination group, and 7 in the modafinil group had incomplete survey results.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cognitive Behavioral Therapy n=114 Participants 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil n=114 Participants 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil n=108 Participants Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Total n=336 Participants Total of all reporting groups
Age, Continuous	48.8 years STANDARD_DEVIATION 11.6 • n=114 Participants	47.4 years STANDARD_DEVIATION 11.7 • n=114 Participants	49.1 years STANDARD_DEVIATION 11.3 • n=108 Participants	48.8 years STANDARD_DEVIATION 11.6 • n=336 Participants
Sex: Female, Male Female	85 Participants n=114 Participants	93 Participants n=114 Participants	78 Participants n=108 Participants	256 Participants n=336 Participants
Sex: Female, Male Male	29 Participants n=114 Participants	21 Participants n=114 Participants	30 Participants n=108 Participants	80 Participants n=336 Participants
Ethnicity (NIH/OMB) Ethnicity · Hispanic or Latino	6 Participants n=114 Participants	4 Participants n=114 Participants	8 Participants n=108 Participants	18 Participants n=336 Participants
Ethnicity (NIH/OMB) Ethnicity · Not Hispanic or Latino	102 Participants n=114 Participants	106 Participants n=114 Participants	97 Participants n=108 Participants	305 Participants n=336 Participants
Ethnicity (NIH/OMB) Ethnicity · Unknown or Not Reported	6 Participants n=114 Participants	4 Participants n=114 Participants	3 Participants n=108 Participants	13 Participants n=336 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=114 Participants	0 Participants n=114 Participants	0 Participants n=108 Participants	0 Participants n=336 Participants
Race/Ethnicity, Customized Asian	2 Participants n=114 Participants	1 Participants n=114 Participants	1 Participants n=108 Participants	4 Participants n=336 Participants
Race/Ethnicity, Customized Black or African American	7 Participants n=114 Participants	8 Participants n=114 Participants	6 Participants n=108 Participants	21 Participants n=336 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=114 Participants	0 Participants n=114 Participants	0 Participants n=108 Participants	0 Participants n=336 Participants
Race/Ethnicity, Customized White	96 Participants n=114 Participants	98 Participants n=114 Participants	92 Participants n=108 Participants	286 Participants n=336 Participants
Race/Ethnicity, Customized Other	1 Participants n=114 Participants	3 Participants n=114 Participants	1 Participants n=108 Participants	5 Participants n=336 Participants
Race/Ethnicity, Customized Missing	0 Participants n=114 Participants	0 Participants n=114 Participants	1 Participants n=108 Participants	1 Participants n=336 Participants
Race/Ethnicity, Customized Bi/Multi-Racial	8 Participants n=114 Participants	4 Participants n=114 Participants	7 Participants n=108 Participants	19 Participants n=336 Participants
Region of Enrollment United States	114 Participants n=114 Participants	114 Participants n=114 Participants	108 Participants n=108 Participants	336 Participants n=336 Participants
Modified Fatigue Impact Scale (MFIS) Score	52.6 units on a scale STANDARD_DEVIATION 13.7 • n=104 Participants • Baseline MFIS results (means/SD) are based on the number of participants who completed the entire survey at baseline. 10 participants in the CBT group, 8 participants in the combination group, and 7 in the modafinil group had incomplete survey results.	53.2 units on a scale STANDARD_DEVIATION 14.4 • n=106 Participants • Baseline MFIS results (means/SD) are based on the number of participants who completed the entire survey at baseline. 10 participants in the CBT group, 8 participants in the combination group, and 7 in the modafinil group had incomplete survey results.	52.3 units on a scale STANDARD_DEVIATION 14.1 • n=101 Participants • Baseline MFIS results (means/SD) are based on the number of participants who completed the entire survey at baseline. 10 participants in the CBT group, 8 participants in the combination group, and 7 in the modafinil group had incomplete survey results.	52.7 units on a scale STANDARD_DEVIATION 14.1 • n=311 Participants • Baseline MFIS results (means/SD) are based on the number of participants who completed the entire survey at baseline. 10 participants in the CBT group, 8 participants in the combination group, and 7 in the modafinil group had incomplete survey results.
Fatigue Intensity as Assessed by Self-reported Numerical Rating Scale (NRS) Score.	9.2 units on a scale STANDARD_DEVIATION 2.9 • n=107 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigue intensity data.	9.0 units on a scale STANDARD_DEVIATION 3.2 • n=111 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigue intensity data.	8.8 units on a scale STANDARD_DEVIATION 3.0 • n=105 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigue intensity data.	9.0 units on a scale STANDARD_DEVIATION 3.0 • n=323 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigue intensity data.
Fatigue Interference as Assessed by Self-reported Numerical Rating Scale (NRS) Score	7.75 units on a scale STANDARD_DEVIATION 3.15 • n=107 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigue interference data.	7.33 units on a scale STANDARD_DEVIATION 3.52 • n=111 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigue interference data.	7.30 units on a scale STANDARD_DEVIATION 3.32 • n=105 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigue interference data.	7.5 units on a scale STANDARD_DEVIATION 3.3 • n=323 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigue interference data.
Fatigability as Assessed by the Self-reported Fatigue Intensity Numerical Rating	0.07 units on a scale STANDARD_DEVIATION 0.04 • n=107 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigability data.	0.07 units on a scale STANDARD_DEVIATION 0.04 • n=108 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigability data.	0.07 units on a scale STANDARD_DEVIATION 0.07 • n=100 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigability data.	0.07 units on a scale STANDARD_DEVIATION 0.05 • n=315 Participants • 7 participants in the CBT group, 3 participants in the combination therapy group, and 3 participants in the modafinil group were missing baseline EMA fatigability data.

PRIMARY outcome

Timeframe: Baseline-12 weeks

Outcome measures

Outcome measures
Measure	Cognitive Behavioral Therapy n=114 Participants 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil n=114 Participants 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil n=108 Participants Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).
Change in the Modified Fatigue Impact Scale (MFIS) Score	-15.2 score on a scale Standard Deviation 11.9	-16.0 score on a scale Standard Deviation 15.9	-17.3 score on a scale Standard Deviation 16.2

SECONDARY outcome

Timeframe: Baseline-12 weeks

Population: Some participants who completed the study did not complete their 12-week Pro-Diary entries.

Fatigue intensity was assessed using a wearable monitor, the PRO-Diary (CamNtech) - a wrist-worn accelerometer-based activity monitor which also contains a self-report user interface. Using a 0-10 numerical rating scale, participants entered fatigue intensity ratings into the user-interface on the PRO-Diary 4 times each day, for 7 days, at baseline (pre-intervention) and at 12 weeks post-intervention. All scores over the 7 days were averaged to produce an aggregate fatigue intensity score. Higher scores indicate greater fatigue intensity. Change in fatigue intensity between baseline and 12 weeks was compared between the 3 treatment groups.

Outcome measures

Outcome measures
Measure	Cognitive Behavioral Therapy n=88 Participants 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil n=91 Participants 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil n=93 Participants Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).
Change in Fatigue Intensity as Assessed by Self-reported Numerical Rating Scale (NRS) Score.	-1.41 units on a scale Standard Deviation 2.43	-1.69 units on a scale Standard Deviation 2.33	-2.03 units on a scale Standard Deviation 2.82

SECONDARY outcome

Timeframe: Baseline-12 weeks

Population: A few participants in each arm who stayed in the study, did not complete the NRS Survey at 12 weeks.

Fatigue interference will be assessed using a wearable monitor, the PRO-Diary (CamNtech) - a wrist-worn accelerometer-based activity monitor which also contains a self-report user interface. Using a 0-10 numerical rating scale, participants entered fatigue interference ratings into the user-interface on the PRO-Diary 4 times each day, for 7 days, at baseline (pre-intervention) and at 12 weeks post-intervention. All scores over the 7 days were averaged to produce an aggregate fatigue impact score. Higher scores indicate greater fatigue impact. Change in fatigue interference between baseline and 12 weeks will be compared between the 3 treatment groups.

Outcome measures

Outcome measures
Measure	Cognitive Behavioral Therapy n=88 Participants 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil n=91 Participants 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil n=93 Participants Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).
Change in Fatigue Interference as Assessed by Self-reported Numerical Rating Scale (NRS) Score	-1.41 score on a scale Standard Deviation 2.60	-1.73 score on a scale Standard Deviation 2.52	-1.78 score on a scale Standard Deviation 2.98

SECONDARY outcome

Timeframe: Baseline-12 weeks

Population: Some participants in the study did not complete their 12-week Pro-Diary entries.

Fatigability will be assessed using a wearable monitor, the PRO-Diary (CamNtech) - a wrist-worn accelerometer-based activity monitor which also contains a self-report user interface. The fatigability score will be calculated as the ratio of the self-reported fatigue intensity rating (using a 0-10 numerical rating score) divided by the participant's concurrent physical activity level (measured as the average number of activity counts per minute via actigraphy). All fatigability scores will be averaged over the 7 days to create an aggregate fatigability score. Higher scores indicate greater fatigability. Change in fatigability between baseline and 12 weeks will be compared between the 3 treatment groups.

Outcome measures

Outcome measures
Measure	Cognitive Behavioral Therapy n=83 Participants 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil n=83 Participants 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil n=86 Participants Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).
Change in Fatigability as Assessed by the Self-reported Fatigue Intensity Numerical Rating Scale (NRS) Score and Physical Activity Level	-0.0041 score Standard Deviation 0.0476	-0.0175 score Standard Deviation 0.0320	-0.0075 score Standard Deviation 0.0404

Adverse Events

Cognitive Behavioral Therapy

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Modafinil

Serious events: 4 serious events

Other events: 12 other events

Deaths: 1 deaths

Cognitive Behavioral Therapy + Modafinil

Serious events: 1 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cognitive Behavioral Therapy n=114 participants at risk 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil n=114 participants at risk 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil n=108 participants at risk Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).
Nervous system disorders MS relapse/exacerbation	0.88% 1/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	1.8% 2/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.93% 1/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Nervous system disorders Benign paroxysmal vertigo	0.88% 1/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.00% 0/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Blood and lymphatic system disorders Cerebrospinal fluid leakage	0.88% 1/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.00% 0/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Infections and infestations Sepsis	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.88% 1/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.00% 0/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Immune system disorders Localized edema	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.93% 1/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Nervous system disorders Pneumonia	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.93% 1/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Nervous system disorders Trigeminal neuralgia pain	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.93% 1/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Surgical and medical procedures Surgical/Medical procedure	0.88% 1/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	3.5% 4/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	0.93% 1/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.

Other adverse events

Other adverse events
Measure	Cognitive Behavioral Therapy n=114 participants at risk 8 weekly telephone-based sessions and 2 booster sessions Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.	Modafinil n=114 participants at risk 50-400 mg per day (oral) Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).	Cognitive Behavioral Therapy + Modafinil n=108 participants at risk Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral) Telephone-based Cognitive Behavioral Therapy: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. Modafinil: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).
Nervous system disorders Insomnia	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	7.0% 8/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	7.4% 8/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Nervous system disorders Anxiety	0.00% 0/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	2.6% 3/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	8.3% 9/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.
Nervous system disorders Headache	0.88% 1/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	2.6% 3/114 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.	5.6% 6/108 • 25 weeks, AE data was collected for 25 weeks from consent, in line with 24 week exploratory outcome measures.

Additional Information

Tiffany Braley

University of Michigan

Phone: 734-232-1147

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place