COMBO-MS: Cognitive Behavioral Therapy, Modafinil, or Both for Multiple Sclerosis Fatigue

Sponsor

University of Michigan (Other)

Overall Status

Completed

CT.gov ID

NCT03621761

Collaborator

University of Washington (Other), Patient-Centered Outcomes Research Institute (Other), National Multiple Sclerosis Society (Other)

336

Enrollment

Locations

Arms

35.4

Actual Duration (Months)

168

Patients Per Site

4.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This clinical trial will compare the effectiveness of 3 treatments for fatigue in Multiple Sclerosis: 1) a commonly used behavioral treatment strategy (telephone-based cognitive behavioral therapy), 2) a commonly used medication (modafinil), and 3) a combination of both therapies. Each participant will receive one of these 3 treatments for a total of 12 weeks. Hypotheses are that, at 12 weeks, treatment with combination therapy will overall lead to greater reductions in fatigue impact, fatigue severity, and fatigability compared to monotherapy, and that comorbid depression, sleep disturbances, and baseline disability level will be important effect modifiers that influence treatment effect and adherence.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Behavioral: Telephone-based Cognitive Behavioral Therapy Drug: Modafinil	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

336 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

Rater blinded

Primary Purpose:

Treatment

Official Title:

A Randomized Controlled Trial of Telephone-delivered Cognitive Behavioral-therapy, Modafinil, and Combination Therapy of Both Interventions for Fatigue in Multiple Sclerosis

Actual Study Start Date :

Nov 15, 2018

Actual Primary Completion Date :

Oct 26, 2021

Actual Study Completion Date :

Oct 26, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Cognitive Behavioral Therapy 8 weekly telephone-based sessions and 2 booster sessions	Behavioral: 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.
Active Comparator: Modafinil 50-400 mg per day (oral)	Drug: 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). Other Names: Provigil
Active Comparator: Cognitive Behavioral Therapy + Modafinil Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral)	Behavioral: 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. Drug: 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). Other Names: Provigil

Arm

Intervention/Treatment

Active Comparator: Cognitive Behavioral Therapy

8 weekly telephone-based sessions and 2 booster sessions

Behavioral: 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.

Active Comparator: Modafinil

50-400 mg per day (oral)

Drug: 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).

Other Names:

Provigil

Active Comparator: Cognitive Behavioral Therapy + Modafinil

Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral)

Behavioral: Telephone-based Cognitive Behavioral Therapy

Drug: Modafinil

Other Names:

Provigil

Outcome Measures

Primary Outcome Measures

Change in the Modified Fatigue Impact Scale (MFIS) Score [Baseline-12 weeks]
The Modified Fatigue Impact Scale is a self-report survey that contains 21 items. Each item is rated 0-4. 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.

Secondary Outcome Measures

Change in fatigue intensity as assessed by self-reported Numerical Rating Scale (NRS) score. [Baseline-12 weeks]
Fatigue intensity 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 will rate their fatigue intensity, and enter the score into the user-interface on the PRO-Diary four times each day, for 7 days, at baseline (pre-intervention) and at 12 weeks post-intervention. All scores over the 7 days will be averaged to produce an aggregate fatigue intensity score. Higher scores indicate greater fatigue intensity. Change in fatigue intensity between baseline and 12 weeks will be compared between the 3 treatment groups.
Change in fatigue impact as assessed by self-reported Numerical Rating Scale (NRS) score [Baseline-12 weeks]
Fatigue impact 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 will rate their fatigue impact, and enter the score into the user-interface on the PRO-Diary four times each day, for 7 days, at baseline (pre-intervention) and at 12 weeks post-intervention. All scores over the 7 days will be averaged to produce an aggregate fatigue impact score. Higher scores indicate greater fatigue impact. Change in fatigue impact between baseline and 12 weeks will be compared between the 3 treatment groups.
Change in Physical Fatigability as assessed by the self-reported fatigue intensity Numerical Rating Scale (NRS) score and physical activity level [Baseline-12 weeks]
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). 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with clinically definite Multiple Sclerosis (MS, all MS subtypes);
Age 18 years or older;
Presence of chronic, problematic fatigue that, in the opinion of the patient, has interfered with their daily activities for ≥ 3 months;
Average Fatigue Severity Scale (FSS) score greater or equal to 4 at screening.

Exclusion Criteria:

Current shift work sleep disorder, or narcolepsy diagnosed with polysomnography and multiple sleep latency test
History of MS relapse within the last 30 days prior to screening (participants will be considered eligible after the 30-day window);
Current stimulant or wake-promoting agent use (such as amantadine, modafinil, methylphenidate, or amphetamine) within 30 days of screening;
Pregnancy or breastfeeding;
Reliance on hormonal contraception AND concomitant unwillingness to use alternative non-hormonal means of birth control (spermicide or condoms) during the course of the study;
Current suicidal ideation (SI) with intent or plan;
Known hypersensitivity to modafinil or armodafinil or its inactive ingredients;
History of the following cardiovascular conditions: recent myocardial infarction (last 6 months prior to screening), unstable angina, left ventricular hypertrophy, mitral valve prolapse, NYHA class III or IV congestive heart failure;
History of prescription or illicit stimulant abuse (such as cocaine, amphetamine, methamphetamine);
Any other medical, neurological, or psychiatric condition that, in the opinion of the investigators, could affect participant safety or eligibility.