Comparing the Effectiveness of Three Treatments for Reducing Fatigue among Patients with Multiple Sclerosis -- The COMBO-MS Trial

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What was the research about?

Multiple sclerosis, or MS, is a condition that affects the central nervous system. Fatigue is a common and disabling symptom of MS.

In this study, the research team wanted to learn how well three treatments helped people with MS feel less fatigued:

• Cognitive behavioral therapy, or CBT. In CBT, patients learn how to change patterns in their thinking and behavior.
• Modafinil, a medicine for fatigue.
• Both CBT and modafinil.

The research team also looked at how much people reported that their MS symptoms and quality of life improved since starting treatment.

What were the results?

After three months, with all three treatments, people felt less fatigued. The level of improvement was about the same for all three treatments.

Compared with modafinil alone, people who received both treatments reported more overall benefits since starting treatment. Compared with CBT alone, people who received modafinil alone or both treatments didn’t differ in their sense of overall improvement.

More people who received modafinil alone or with CBT had side effects than people who received CBT alone. The most common side effects for modafinil were headache, insomnia, and anxiety. Few people stopped treatment.

Who was in the study?

The study included 336 adults with MS and fatigue. Of these, 85 percent were White, 6 percent were Black, 1 percent were Asian, 6 percent were more than one race, and 1 percent were another race. The average age was 49, and 76 percent were women. The study took place at two MS centers in Michigan and Washington.

What did the research team do?

The research team assigned people by chance to one of the three treatments. With CBT, people had eight sessions where they learned skills to lessen the impact of fatigue. They also had two optional sessions where they learned how to keep using those skills. People completed sessions by phone for three months. People took modafinil by mouth twice a day as needed for three months. People who received CBT and modafinil received both treatments together for three months.

At the start of the study and again three months later, people completed an online survey about fatigue, symptoms, function, and quality of life. They also wore a device on the wrist, called PRO-Diary, for one week at the start of the study and three months later. The device measured how active they were and their sleep patterns. The research team gave people instructions on how to use PRO-Diary at home.

People with MS, doctors, MS center staff, a health insurer, and advocacy groups helped plan the study.

What were the limits of the study?

The study took place at two MS centers, and most people in the study were White. Results may differ in other places or for patients from other racial backgrounds.

Future research could look at other health outcomes that matter to patients with MS.

How can people use the results?

People with MS and their doctors can use the results when considering ways to treat fatigue.

Objective

To compare the effectiveness of cognitive behavioral therapy (CBT), modafinil, and a combination of both treatments in reducing fatigue among people with multiple sclerosis (MS)

Study Design

This randomized pragmatic trial compared the effectiveness of three treatments in reducing the impact and intensity of fatigue and fatigability among people with MS. Researchers also evaluated participant reports of change in global function.

Researchers randomly assigned participants to receive telephone-delivered CBT, modafinil, or both. Patients who received CBT had eight primary sessions and two optional maintenance sessions by telephone over 12 weeks. Primary sessions taught participants about fatigue in MS and applying fatigue self-management skills tailored to their strengths and priorities. Maintenance sessions helped patients sustain progress from the primary sessions. Participants who received modafinil took the medication by mouth twice a day as needed for 12 weeks. With combination treatment, patients received both treatments simultaneously for 12 weeks.

The study included 336 adults with MS and fatigue. Of these, 85% were White, 6% were Black, 1% were Asian, 6% were more than one race, and 1% were another race. The average age was 49, and 76% were female. Study activities took place at academic MS centers in Michigan and Washington.

At baseline and 12 weeks later, patients completed an online survey about fatigue, symptoms, function, and quality of life. Participants wore a device on the wrist, called PRO-Diary, that measured their physical activity for seven days at baseline and 12 weeks later. Researchers gave participants instructions on how to use PRO-Diary at home.

People with MS, neuroimmunologists, MS center staff, a health insurer, and patient advocacy groups helped plan and conduct the study.

Results

After 12 weeks, the magnitude of reduction across the three treatments did not differ significantly for fatigue impact, fatigue intensity, or fatigability. Participants in all groups experienced reductions in these outcomes (all, p=<0.01).

Participants who received both treatments perceived more global function improvements compared with modafinil alone (p=<0.01). Participants who received both treatments or modafinil alone did not differ significantly in perceived changes in global function compared with participants who received CBT alone.

Both CBT and modafinil had low frequency of treatment discontinuation, with no significant differences between the two. More patients who received modafinil, alone or with CBT, had side effects than patients who received CBT alone. The most common side effects for modafinil were headache, insomnia, and anxiety.

Limitations

The study took place at two academic MS centers; most study participants were White. Results may differ in other locations or among patients of other racial backgrounds.

Conclusions and Relevance

All three treatments reduced fatigue impact, fatigue intensity, and fatigability among patients with MS. Combination treatment was associated with more global benefits than modafinil alone.

Future Research Needs

Future research could examine treatment effects on other patient-centered outcomes for MS.