Multiple Sclerosis
Conditions
Keywords
cognitive behavioral therapy, modafinil, Provigil, fatigue, MS
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.
Interventions
BEHAVIORALTelephone-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.
DRUGModafinil
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).
Sponsors
University of Washington
Patient-Centered Outcomes Research Institute
National Multiple Sclerosis Society
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Rater blinded
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with clinically definite Multiple Sclerosis (MS, all MS subtypes); 2. Age 18 years or older; 3. Presence of chronic, problematic fatigue that, in the opinion of the patient, has interfered with their daily activities for ≥ 3 months; 4. Average Fatigue Severity Scale (FSS) score greater or equal to 4 at screening.
Exclusion criteria
1. Current shift work sleep disorder, or narcolepsy diagnosed with polysomnography and multiple sleep latency test 2. History of MS relapse within the last 30 days prior to screening (participants will be considered eligible after the 30-day window); 3. Current stimulant or wake-promoting agent use (such as amantadine, modafinil, methylphenidate, or amphetamine) within 30 days of screening; 4. Pregnancy or breastfeeding; 5. 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; 6. Current suicidal ideation (SI) with intent or plan; 7. Known hypersensitivity to modafinil or armodafinil or its inactive ingredients; 8. 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; 9. History of prescription or illicit stimulant abuse (such as cocaine, amphetamine, methamphetamine); 10. Any other medical, neurological, or psychiatric condition that, in the opinion of the investigators, could affect participant safety or eligibility.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Modified Fatigue Impact Scale (MFIS) Score | Baseline-12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fatigue Intensity as Assessed by Self-reported Numerical Rating Scale (NRS) Score. | Baseline-12 weeks | 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. |
| Change in Fatigue Interference as Assessed by Self-reported Numerical Rating Scale (NRS) Score | Baseline-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. |
| Change in 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 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
Of 343 enrolled participants, 336 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 114 |
| 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). | 114 |
| 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). | 108 |
| Total | 336 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Became Ineligible | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Cognitive Behavioral Therapy + Modafinil | Modafinil | Cognitive Behavioral Therapy |
|---|---|---|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 11.6 | 49.1 years STANDARD_DEVIATION 11.3 | 47.4 years STANDARD_DEVIATION 11.7 | 48.8 years STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 18 Participants | 8 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 305 Participants | 97 Participants | 106 Participants | 102 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 13 Participants | 3 Participants | 4 Participants | 6 Participants |
| Fatigability as Assessed by the Self-reported Fatigue Intensity Numerical Rating | 0.07 units on a scale STANDARD_DEVIATION 0.05 | 0.07 units on a scale STANDARD_DEVIATION 0.07 | 0.07 units on a scale STANDARD_DEVIATION 0.04 | 0.07 units on a scale STANDARD_DEVIATION 0.04 |
| Fatigue Intensity as Assessed by Self-reported Numerical Rating Scale (NRS) Score. | 9.0 units on a scale STANDARD_DEVIATION 3 | 8.8 units on a scale STANDARD_DEVIATION 3 | 9.0 units on a scale STANDARD_DEVIATION 3.2 | 9.2 units on a scale STANDARD_DEVIATION 2.9 |
| Fatigue Interference as Assessed by Self-reported Numerical Rating Scale (NRS) Score | 7.5 units on a scale STANDARD_DEVIATION 3.3 | 7.30 units on a scale STANDARD_DEVIATION 3.32 | 7.33 units on a scale STANDARD_DEVIATION 3.52 | 7.75 units on a scale STANDARD_DEVIATION 3.15 |
| Modified Fatigue Impact Scale (MFIS) Score | 52.7 units on a scale STANDARD_DEVIATION 14.1 | 52.3 units on a scale STANDARD_DEVIATION 14.1 | 53.2 units on a scale STANDARD_DEVIATION 14.4 | 52.6 units on a scale STANDARD_DEVIATION 13.7 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Bi/Multi-Racial | 19 Participants | 7 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 21 Participants | 6 Participants | 8 Participants | 7 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 1 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 286 Participants | 92 Participants | 98 Participants | 96 Participants |
| Region of Enrollment United States | 336 Participants | 108 Participants | 114 Participants | 114 Participants |
| Sex: Female, Male Female | 256 Participants | 78 Participants | 93 Participants | 85 Participants |
| Sex: Female, Male Male | 80 Participants | 30 Participants | 21 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 114 | 1 / 114 | 0 / 108 |
| other Total, other adverse events | 1 / 114 | 12 / 114 | 19 / 108 |
| serious Total, serious adverse events | 1 / 114 | 4 / 114 | 1 / 108 |
Outcome results
Primary
Change in the Modified Fatigue Impact Scale (MFIS) Score
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.
Time frame: Baseline-12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cognitive Behavioral Therapy | Change in the Modified Fatigue Impact Scale (MFIS) Score | -15.2 score on a scale | Standard Deviation 11.9 |
| Modafinil | Change in the Modified Fatigue Impact Scale (MFIS) Score | -16.0 score on a scale | Standard Deviation 15.9 |
| Cognitive Behavioral Therapy + Modafinil | Change in the Modified Fatigue Impact Scale (MFIS) Score | -17.3 score on a scale | Standard Deviation 16.2 |
Comparison: Comparison of treatment effect of CBT monotherapy vs. combination therapy (reference) on total MFIS score, in linear regression models adjusted for age, sex, anxiety, pain, activity level, study site, and baseline MFIS score. Output reflects models that were imputed for missing data.p-value: 0.3451Regression, Linear
Comparison: Comparison of treatment effect of modafinil monotherapy vs. combination therapy (reference) on total MFIS score, in linear regression models adjusted for age, sex, anxiety, pain, activity level, study site, and baseline MFIS score. Output reflects models that were imputed for missing data.p-value: 0.4834Regression, Linear
Secondary
Change in Fatigability as Assessed by the Self-reported Fatigue Intensity Numerical Rating Scale (NRS) Score and Physical Activity Level
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.
Time frame: Baseline-12 weeks
Population: Some participants in the study did not complete their 12-week Pro-Diary entries.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cognitive Behavioral Therapy | 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 |
| Modafinil | Change in Fatigability as Assessed by the Self-reported Fatigue Intensity Numerical Rating Scale (NRS) Score and Physical Activity Level | -0.0175 score | Standard Deviation 0.032 |
| Cognitive Behavioral Therapy + Modafinil | Change in Fatigability as Assessed by the Self-reported Fatigue Intensity Numerical Rating Scale (NRS) Score and Physical Activity Level | -0.0075 score | Standard Deviation 0.0404 |
Comparison: Comparison of treatment effect of CBT monotherapy vs. combination therapy (reference) on change in fatigability score, in complete case linear regression models adjusted for age, sex, anxiety, pain, activity level, study site, and baseline fatigability score.p-value: 0.4955Regression, Linear
Comparison: Comparison of treatment effect of modafinil monotherapy vs. combination therapy (reference) on change in fatigability score, in complete case linear regression models adjusted for age, sex, anxiety, pain, activity level, study site, and baseline fatigability score.p-value: 0.1333Regression, Linear
Secondary
Change in Fatigue Intensity as Assessed by Self-reported Numerical Rating Scale (NRS) Score.
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.
Time frame: Baseline-12 weeks
Population: Some participants who completed the study did not complete their 12-week Pro-Diary entries.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cognitive Behavioral Therapy | Change in Fatigue Intensity as Assessed by Self-reported Numerical Rating Scale (NRS) Score. | -1.41 units on a scale | Standard Deviation 2.43 |
| Modafinil | Change in Fatigue Intensity as Assessed by Self-reported Numerical Rating Scale (NRS) Score. | -1.69 units on a scale | Standard Deviation 2.33 |
| Cognitive Behavioral Therapy + Modafinil | Change in Fatigue Intensity as Assessed by Self-reported Numerical Rating Scale (NRS) Score. | -2.03 units on a scale | Standard Deviation 2.82 |
Comparison: Comparison of treatment effect of CBT monotherapy vs. combination therapy (reference) on change in EMA fatigue intensity NRS score, in complete case linear regression models adjusted for age, sex, anxiety, pain, activity level, study site, and baseline EMA fatigue intensity score.p-value: 0.257Regression, Linear
Comparison: Comparison of treatment effect of modafinil monotherapy vs. combination therapy (reference) on change in EMA fatigue intensity NRS score, in complete case linear regression models adjusted for age, sex, anxiety, pain, activity level, study site, and baseline EMA fatigue intensity score.p-value: 0.5017Regression, Linear
Secondary
Change in Fatigue Interference as Assessed by Self-reported Numerical Rating Scale (NRS) Score
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.
Time frame: Baseline-12 weeks
Population: A few participants in each arm who stayed in the study, did not complete the NRS Survey at 12 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cognitive Behavioral Therapy | Change in Fatigue Interference as Assessed by Self-reported Numerical Rating Scale (NRS) Score | -1.41 score on a scale | Standard Deviation 2.6 |
| Modafinil | Change in Fatigue Interference as Assessed by Self-reported Numerical Rating Scale (NRS) Score | -1.73 score on a scale | Standard Deviation 2.52 |
| Cognitive Behavioral Therapy + Modafinil | Change in Fatigue Interference as Assessed by Self-reported Numerical Rating Scale (NRS) Score | -1.78 score on a scale | Standard Deviation 2.98 |
Comparison: Comparison of treatment effect of CBT monotherapy vs. combination therapy (reference) on change in EMA fatigue interference NRS score, in complete case linear regression models adjusted for age, sex, anxiety, pain, activity level, study site, and baseline EMA fatigue interference score.p-value: 0.154Regression, Linear
Comparison: Comparison of treatment effect of modafinil monotherapy vs. combination therapy (reference) on change in EMA fatigue interference NRS score, in complete case linear regression models adjusted for age, sex, anxiety, pain, activity level, study site, and baseline EMA fatigue interference score.p-value: 0.61Regression, Linear