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

Primary Purpose

Fatigue in Multiple Sclerosis

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Amantadine
Modafinil
Methylphenidate
Placebos
Sponsored by
Johns Hopkins University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fatigue in Multiple Sclerosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California San Francisco
  • Johns Hopkins University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm A

Arm B

Arm C

Arm D

Arm Description

amantadine, placebo, modafinil, methylphenidate

placebo, methylphenidate, amantadine, modafinil

modafinil, amantadine, methylphenidate, placebo

methylphenidate, modafinil, placebo and amantadine

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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'.

Full Information

First Posted
June 9, 2017
Last Updated
October 16, 2020
Sponsor
Johns Hopkins University
Collaborators
Patient-Centered Outcomes Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03185065
Brief Title
Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis
Acronym
TRIUMPHANT-MS
Official Title
Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
October 4, 2017 (Actual)
Primary Completion Date
November 21, 2019 (Actual)
Study Completion Date
November 21, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins University
Collaborators
Patient-Centered Outcomes Research Institute

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fatigue in Multiple Sclerosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
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.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-blind
Allocation
Randomized
Enrollment
141 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A
Arm Type
Experimental
Arm Description
amantadine, placebo, modafinil, methylphenidate
Arm Title
Arm B
Arm Type
Experimental
Arm Description
placebo, methylphenidate, amantadine, modafinil
Arm Title
Arm C
Arm Type
Experimental
Arm Description
modafinil, amantadine, methylphenidate, placebo
Arm Title
Arm D
Arm Type
Experimental
Arm Description
methylphenidate, modafinil, placebo and amantadine
Intervention Type
Drug
Intervention Name(s)
Amantadine
Intervention Description
100 mg of amantadine increased to 200 mg of amantadine, if tolerated
Intervention Type
Drug
Intervention Name(s)
Modafinil
Intervention Description
100 mg of modafinil increased to 200 mg of modafinil, if tolerated
Intervention Type
Drug
Intervention Name(s)
Methylphenidate
Intervention Description
5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated
Intervention Type
Drug
Intervention Name(s)
Placebos
Intervention Description
1 placebo capsule increased to max of 2 capsules twice daily
Primary Outcome Measure Information:
Title
Modified Fatigue Impact Scale (MFIS) Score
Description
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
Secondary Outcome Measure Information:
Title
Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score
Description
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
Title
Epworth Sleepiness Scale (ESS) Score
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bardia Nourbakhsh, MD
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33242419
Citation
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.
Results Reference
derived
PubMed Identifier
29113955
Citation
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.
Results Reference
derived

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

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