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

• ClinicalTrials.gov Identifier: NCT03621761
• Recruitment Status: Completed
• First Posted: August 8, 2018
• Last Update Posted: March 3, 2022
• Sponsor: University of Michigan
• Collaborators: University of Washington; Patient-Centered Outcomes Research Institute; National Multiple Sclerosis Society
• Information provided by (Responsible Party): Tiffany J. Braley, MD, MS, University of Michigan

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 (Clinical Trial)
• 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: November 15, 2018
• Actual Primary Completion Date: October 26, 2021
• Actual Study Completion Date: October 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 Name: 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 Name: Provigil

Outcome Measures

Primary Outcome Measures :

1. Change in the Modified Fatigue Impact Scale (MFIS) Score [ Time Frame: 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 :

1. Change in fatigue intensity as assessed by self-reported Numerical Rating Scale (NRS) score. [ Time Frame: 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.

2. Change in fatigue impact as assessed by self-reported Numerical Rating Scale (NRS) score [ Time Frame: 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.

3. Change in Physical Fatigability as assessed by the self-reported fatigue intensity Numerical Rating Scale (NRS) score and physical activity level [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Michigan

The University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Washington

The University of Washington

Seattle, Washington, United States, 98195

Sponsors and Collaborators

University of Michigan

University of Washington

Patient-Centered Outcomes Research Institute

National Multiple Sclerosis Society

Investigators

• Principal Investigator: Tiffany J Braley, MD, MS; University of Michigan

More Information

Publications:

Krupp L. Fatigue is intrinsic to multiple sclerosis (MS) and is the most commonly reported symptom of the disease. Mult Scler. 2006 Aug;12(4):367-8.

Lerdal A, Celius EG, Krupp L, Dahl AA. A prospective study of patterns of fatigue in multiple sclerosis. Eur J Neurol. 2007 Dec;14(12):1338-43. Epub 2007 Sep 26.

Janardhan V, Bakshi R. Quality of life in patients with multiple sclerosis: the impact of fatigue and depression. J Neurol Sci. 2002 Dec 15;205(1):51-8.

Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988 Apr;45(4):435-7.

Smith MM, Arnett PA. Factors related to employment status changes in individuals with multiple sclerosis. Mult Scler. 2005 Oct;11(5):602-9.

Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994 Feb;21(1):9-14.

Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.

Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989 Oct;46(10):1121-3.

Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003 Nov;41(11):1284-92.

Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13.

• Responsible Party: Tiffany J. Braley, MD, MS, Assistant Professor of Neurology, University of Michigan
• ClinicalTrials.gov Identifier: NCT03621761
• Other Study ID Numbers: HUM00143319
• First Posted: August 8, 2018
• Last Update Posted: March 3, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Tiffany J. Braley, MD, MS, University of Michigan:

cognitive behavioral therapy; modafinil; Provigil; fatigue; MS

Additional relevant MeSH terms:

Multiple Sclerosis; Sclerosis; Fatigue; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Modafinil; Central Nervous System Stimulants; Physiological Effects of Drugs; Wakefulness-Promoting Agents; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 Enzyme Inducers; Molecular Mechanisms of Pharmacological Action