Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis

Fatigue in Multiple Sclerosis Clinical Trial

— TRIUMPHANT-MS  

Official title:

Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03185065
• Other study ID #: IRB00119702
• Status: Completed
• Phase: Phase 3
• Start date: October 4, 2017
• Est. completion date: November 21, 2019

Study information

• Verified date: October 2020
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 141
• Est. completion date: November 21, 2019
• Est. primary completion date: November 21, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Fatigue
• Fatigue in Multiple Sclerosis
• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• 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

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of California San Francisco	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Johns Hopkins University	Patient-Centered Outcomes Research Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Week 5 of each treatment period
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.	Week 5 of each treatment period
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'.	Week 5 of each treatment period