Fatigue in Multiple Sclerosis
Conditions
Brief summary
Randomized, placebo-controlled, crossover, 4-sequence, 4-period, double-blind (participants and investigators), multicenter trial of 3 commonly used medications for treatment of MS-related fatigue (amantadine, modafinil, methylphenidate) versus placebo in fatigued subjects with MS defined by McDonald Criteria.
Detailed description
This is a randomized, placebo-controlled, crossover, 4-sequence, 4-period, double-blind (participants and investigators), multicenter trial of 3 commonly used medications for treatment of MS-related fatigue (amantadine, modafinil, methylphenidate) versus placebo in fatigued subjects with MS defined by McDonald Criteria. Using a balanced Latin-square crossover design, subjects will be allocated, in a double-blind, randomized fashion, to one of the four treatment sequences (Figure 1): 1) amantadine, placebo, modafinil, methylphenidate; 2) placebo, methylphenidate, amantadine, modafinil; 3) modafinil, amantadine, methylphenidate, placebo; and 4) methylphenidate, modafinil, placebo and amantadine. Each medication will be titrated over four weeks to the participants' highest tolerated dose or the pre-defined highest dose. The dosing and titration schedule of the study medications are depicted in Figure 2. Each treatment period will be 6 weeks and there will be a 2-week washout period between each treatment period. At the beginning of the trial, a biostatistician at University of California, San Francisco (UCSF) will prepare a concealed allocation schedule, randomly assigning the four sequences, in blocks of 4, to a consecutive series of numbers and at the time of enrollment, each participant will be assigned the next consecutive number (and hence the sequence of study medications). The primary endpoint of the study will be fatigue severity as measured by the MFIS score, between 26th and 35th day of each treatment period (while the patient is taking the maximal tolerated or target dose). The MFIS is a validated patient-reported outcome. The questionnaire will be administered remotely (through internet, phone or mailed forms) and the participants can answer the questions in few minutes while at home or at their work place. The questionnaire has been validated in English and Spanish.
Interventions
DRUGAmantadine
100 mg of amantadine increased to 200 mg of amantadine, if tolerated
DRUGModafinil
100 mg of modafinil increased to 200 mg of modafinil, if tolerated
DRUGMethylphenidate
5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated
DRUGPlacebos
1 placebo capsule increased to max of 2 capsules twice daily
Sponsors
Patient-Centered Outcomes Research Institute
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
Intervention model description
randomized, placebo-controlled, crossover, 4-sequence, 4-period, double-blind, multicenter trial of 3 commonly used medications for treatment of Multiple Sclerosis related fatigue versus placebo in fatigued subjects with MS.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years and older. * Females of childbearing age must have a negative urine pregnancy test at baseline and use an effective method of contraception during the study. * Diagnosis of MS (according to the 2010 McDonald criteria). * Expanded Disability Status Scale (EDSS) score at the time of screening 0.0-7.0. * Fatigue reportedly present and screening Modified Fatigue Impact Scale (MFIS) score more than 33. * At least a two-week washout for any fatigue-related drug, including study medications.
Exclusion criteria
* Neurodegenerative disorders other than relapsing or progressive MS. * Breastfeeding or pregnant. * History of coronary artery disease or congestive heart failure. * Uncontrolled hypertension at screening (history of high blood pressure and screening systolic blood pressure \>160 or diastolic blood pressure\>100). * Glomerular Filtration Rate (GFR) (glomerular filtration rate) \< 50. * Abnormal liver function at screening (AST or Alanine Aminotransferase (ALT) more than twice the upper limit of normal). * Terminal medical conditions. * Currently treated for active malignancy. * Planned surgery or move within 8 months of screening. * Alcohol or substance abuse in the past year (except marijuana or other cannabinoids). * A history of intolerance or allergic or anaphylactic reaction to amantadine, modafinil, methylphenidate or any component of the preparation. * Clinically unstable medical or psychiatric disorders that require acute treatment as determined by the PI. * Concurrent use of monoamine oxidase inhibitors-B. * Hypersensitivity/idiosyncrasy to sympathomimetic amines * Inability to communicate or answer the questionnaires in English or Spanish. * Severe untreated anemia (blood hemoglobin \<9gr/dl) * History of untreated hypothyroidism * History of untreated sleep apnea * History of long QT syndrome, atrial fibrillation or tachyarrhythmias (other than sinus tachycardia) * History of ischemic or hemorrhagic stroke * History of glaucoma * History of Tourette syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Fatigue Impact Scale (MFIS) Score | Week 5 of each treatment period | MFIS score during the fifth week of treatment period. The total score of the MFIS ranges from 0 to 84. Higher scores denote more severe fatigue. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score | Week 5 of each treatment period | Neuro-QoL Item Bank - Fatigue T score during the fifth week of treatment period. T-score distributions rescale raw scores into standardized scores with a mean of 50 and a standard deviation (SD) of 10. Higher T-scores denote more severe fatigue. |
| Epworth Sleepiness Scale (ESS) Score | Week 5 of each treatment period | ESS score during the fifth week of treatment period. The ESS score can range from 0 to 24. The higher the score, the higher that person's average sleep propensity in daily life, or their 'daytime sleepiness'. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A amantadine, placebo, modafinil, methylphenidate
Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated
Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated
Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated
Placebos: 1 placebo capsule increased to max of 2 capsules twice daily | 35 |
| Arm B placebo, methylphenidate, amantadine, modafinil
Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated
Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated
Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated
Placebos: 1 placebo capsule increased to max of 2 capsules twice daily | 34 |
| Arm C modafinil, amantadine, methylphenidate, placebo
Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated
Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated
Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated
Placebos: 1 placebo capsule increased to max of 2 capsules twice daily | 35 |
| Arm D methylphenidate, modafinil, placebo and amantadine
Amantadine: 100 mg of amantadine increased to 200 mg of amantadine, if tolerated
Modafinil: 100 mg of modafinil increased to 200 mg of modafinil, if tolerated
Methylphenidate: 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated
Placebos: 1 placebo capsule increased to max of 2 capsules twice daily | 37 |
| Total | 141 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Arm C | Arm D | Total |
|---|---|---|---|---|---|
| Age, Continuous | 48.3 years STANDARD_DEVIATION 9.9 | 46.9 years STANDARD_DEVIATION 12.4 | 46.1 years STANDARD_DEVIATION 10.3 | 45.8 years STANDARD_DEVIATION 10.2 | 46.8 years STANDARD_DEVIATION 10.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 5 Participants | 4 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 3 Participants | 4 Participants | 4 Participants | 15 Participants |
| Race (NIH/OMB) White | 27 Participants | 25 Participants | 26 Participants | 29 Participants | 107 Participants |
| Sex: Female, Male Female | 27 Participants | 26 Participants | 27 Participants | 29 Participants | 109 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 124 | 0 / 127 | 0 / 125 | 0 / 129 |
| other Total, other adverse events | 38 / 124 | 49 / 127 | 50 / 125 | 51 / 129 |
| serious Total, serious adverse events | 0 / 124 | 2 / 127 | 1 / 125 | 0 / 129 |
Outcome results
Primary
Modified Fatigue Impact Scale (MFIS) Score
MFIS score during the fifth week of treatment period. The total score of the MFIS ranges from 0 to 84. Higher scores denote more severe fatigue.
Time frame: Week 5 of each treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Modified Fatigue Impact Scale (MFIS) Score | 40.6 score on a scale |
| Amantadine | Modified Fatigue Impact Scale (MFIS) Score | 41.3 score on a scale |
| Modafinil | Modified Fatigue Impact Scale (MFIS) Score | 39.0 score on a scale |
| Methylphenidate | Modified Fatigue Impact Scale (MFIS) Score | 38.6 score on a scale |
Secondary
Epworth Sleepiness Scale (ESS) Score
ESS score during the fifth week of treatment period. The ESS score can range from 0 to 24. The higher the score, the higher that person's average sleep propensity in daily life, or their 'daytime sleepiness'.
Time frame: Week 5 of each treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Epworth Sleepiness Scale (ESS) Score | 9.4 score on a scale |
| Amantadine | Epworth Sleepiness Scale (ESS) Score | 9.3 score on a scale |
| Modafinil | Epworth Sleepiness Scale (ESS) Score | 8.3 score on a scale |
| Methylphenidate | Epworth Sleepiness Scale (ESS) Score | 8.8 score on a scale |
Secondary
Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score
Neuro-QoL Item Bank - Fatigue T score during the fifth week of treatment period. T-score distributions rescale raw scores into standardized scores with a mean of 50 and a standard deviation (SD) of 10. Higher T-scores denote more severe fatigue.
Time frame: Week 5 of each treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score | 53.1 score on a scale |
| Amantadine | Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score | 53.0 score on a scale |
| Modafinil | Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score | 52.5 score on a scale |
| Methylphenidate | Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score | 52.0 score on a scale |
Post Hoc
Acceptability of Treatment as Assessed by a Single Question Questionnaire
Participants will answer yes or no to this question: Taken into consideration the possible benefits and/or disadvantages of this medication, would you choose it, going forward to treat your MS fatigue?. The number of participants who answered Yes to this question is reported here.
Time frame: Week 5 of each treatment period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Acceptability of Treatment as Assessed by a Single Question Questionnaire | 39 Participants |
| Amantadine | Acceptability of Treatment as Assessed by a Single Question Questionnaire | 41 Participants |
| Modafinil | Acceptability of Treatment as Assessed by a Single Question Questionnaire | 55 Participants |
| Methylphenidate | Acceptability of Treatment as Assessed by a Single Question Questionnaire | 55 Participants |