Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis (TRIUMPHANT-MS)

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.

Study Overview

• Status: Completed
• Conditions: Fatigue in Multiple Sclerosis
• Intervention / Treatment: Drug: Amantadine; Drug: Modafinil; Drug: Methylphenidate; Drug: Placebos

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.

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California San Francisco
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; amantadine, placebo, modafinil, methylphenidate	Drug: Amantadine; 100 mg of amantadine increased to 200 mg of amantadine, if tolerated; Drug: Modafinil; 100 mg of modafinil increased to 200 mg of modafinil, if tolerated; Drug: Methylphenidate; 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated; Drug: Placebos; 1 placebo capsule increased to max of 2 capsules twice daily
Experimental: Arm B; placebo, methylphenidate, amantadine, modafinil	Drug: Amantadine; 100 mg of amantadine increased to 200 mg of amantadine, if tolerated; Drug: Modafinil; 100 mg of modafinil increased to 200 mg of modafinil, if tolerated; Drug: Methylphenidate; 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated; Drug: Placebos; 1 placebo capsule increased to max of 2 capsules twice daily
Experimental: Arm C; modafinil, amantadine, methylphenidate, placebo	Drug: Amantadine; 100 mg of amantadine increased to 200 mg of amantadine, if tolerated; Drug: Modafinil; 100 mg of modafinil increased to 200 mg of modafinil, if tolerated; Drug: Methylphenidate; 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated; Drug: Placebos; 1 placebo capsule increased to max of 2 capsules twice daily
Experimental: Arm D; methylphenidate, modafinil, placebo and amantadine	Drug: Amantadine; 100 mg of amantadine increased to 200 mg of amantadine, if tolerated; Drug: Modafinil; 100 mg of modafinil increased to 200 mg of modafinil, if tolerated; Drug: Methylphenidate; 5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated; Drug: Placebos; 1 placebo capsule increased to max of 2 capsules twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: Patient-Centered Outcomes Research Institute
• Investigators: Principal Investigator: Bardia Nourbakhsh, MD, Johns Hopkins University

Publications and helpful links

General Publications

• Nourbakhsh B, Revirajan N, Morris B, Cordano C, Creasman J, Manguinao M, Krysko K, Rutatangwa A, Auvray C, Aljarallah S, Jin C, Mowry E, McCulloch C, Waubant E. Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial. Lancet Neurol. 2021 Jan;20(1):38-48. doi: 10.1016/S1474-4422(20)30354-9. Epub 2020 Nov 23.
• Nourbakhsh B, Revirajan N, Waubant E. Treatment of fatigue with methylphenidate, modafinil and amantadine in multiple sclerosis (TRIUMPHANT-MS): Study design for a pragmatic, randomized, double-blind, crossover clinical trial. Contemp Clin Trials. 2018 Jan;64:67-76. doi: 10.1016/j.cct.2017.11.005. Epub 2017 Nov 4.

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2017
• Primary Completion (Actual): November 21, 2019
• Study Completion (Actual): November 21, 2019

Study Registration Dates

• First Submitted: June 9, 2017
• First Submitted That Met QC Criteria: June 9, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): October 20, 2020
• Last Update Submitted That Met QC Criteria: October 16, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Fatigue; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Antiparkinson Agents; Anti-Dyskinesia Agents; Wakefulness-Promoting Agents; Methylphenidate; Amantadine; Modafinil
• Other Study ID Numbers: IRB00119702

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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