CompletedNCT03185065TRIUMPHANT-MSUpdated Oct 20, 2020Results posted

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

A Phase 3 interventional study of Amantadine and Modafinil in Fatigue in Multiple Sclerosis, sponsored by Johns Hopkins University. Completed at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-10-20.

Sponsored by Johns Hopkins University · Phase 3, Interventional, and Treatment

Phase: Phase 3
Study type: Interventional
Enrollment: 141
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study 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.

Read the 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.

Conditions studied

Fatigue in Multiple Sclerosis

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In context

Multiple Sclerosis

3,460 studies on the registry are indexed under Multiple Sclerosis; 661 are open to participants now.

This study's enrollment of 141 is above the median of 50 across 2,342 interventional studies indexed under Multiple Sclerosis.

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Lead sponsor

Johns Hopkins University is the lead sponsor of 1,783 studies on the registry; 313 are open to participants now.

Of its 203 completed or terminated interventional studies of FDA-regulated products, 140 (69%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts 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

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 design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 141 participants (actual)

Study arms

Experimental
Arm A
amantadine, placebo, modafinil, methylphenidate
Drug: Amantadine · Drug: Modafinil · Drug: Methylphenidate · Drug: Placebos
Experimental
Arm B
placebo, methylphenidate, amantadine, modafinil
Drug: Amantadine · Drug: Modafinil · Drug: Methylphenidate · Drug: Placebos
Experimental
Arm C
modafinil, amantadine, methylphenidate, placebo
Drug: Amantadine · Drug: Modafinil · Drug: Methylphenidate · Drug: Placebos
Experimental
Arm D
methylphenidate, modafinil, placebo and amantadine
Drug: Amantadine · Drug: Modafinil · Drug: Methylphenidate · Drug: Placebos

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

What researchers measure

Primary outcomes

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

Secondary outcomes

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
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

Results

Posted Oct 19, 2020

Participant flow

Period 1 (6 Weeks)

Participant flow — Period 1 (6 Weeks)
Milestone	Arm A	Arm B	Arm C	Arm D
Started	35	34	35	37
Completed	32	33	32	36
Not completed	3	1	3	1

Washout (2 Weeks)

Participant flow — Washout (2 Weeks)
Milestone	Arm A	Arm B	Arm C	Arm D
Started	32	33	32	36
Completed	32	31	32	35
Not completed	0	2	0	1

Period 2 (6 Weeks)

Participant flow — Period 2 (6 Weeks)
Milestone	Arm A	Arm B	Arm C	Arm D
Started	32	31	32	35
Completed	32	31	32	34
Not completed	0	0	0	1

Washout (2 Weeks)

Participant flow — Washout (2 Weeks)
Milestone	Arm A	Arm B	Arm C	Arm D
Started	32	31	32	34
Completed	31	29	31	32
Not completed	1	2	1	2

Period 3 (6 Weeks)

Participant flow — Period 3 (6 Weeks)
Milestone	Arm A	Arm B	Arm C	Arm D
Started	31	29	31	32
Completed	31	29	29	32
Not completed	0	0	2	0

Washout (2 Weeks)

Participant flow — Washout (2 Weeks)
Milestone	Arm A	Arm B	Arm C	Arm D
Started	31	29	29	32
Completed	31	28	27	32
Not completed	0	1	2	0

Period 4 (6 Weeks)

Participant flow — Period 4 (6 Weeks)
Milestone	Arm A	Arm B	Arm C	Arm D
Started	31	28	27	32
Completed	31	27	26	31
Not completed	0	1	1	1

Outcome measures

PrimaryModified 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
Reported as:: Least squares mean · score on a scale

Modified Fatigue Impact Scale (MFIS) Score
score on a scale	Placebo	Amantadine	Modafinil	Methylphenidate
Modified Fatigue Impact Scale (MFIS) Score	40.6 (38.2 to 43.1)	41.3 (38.8 to 43.7)	39.0 (36.6 to 41.4)	38.6 (36.2 to 41.0)

SecondaryQuality 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
Reported as:: Least squares mean · score on a scale

Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score
score on a scale	Placebo	Amantadine	Modafinil	Methylphenidate
Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score	53.1 (51.9 to 54.3)	53.0 (51.7 to 54.2)	52.5 (51.3 to 53.8)	52.0 (50.8 to 53.2)

SecondaryEpworth 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
Reported as:: Least squares mean · score on a scale

Epworth Sleepiness Scale (ESS) Score
score on a scale	Placebo	Amantadine	Modafinil	Methylphenidate
Epworth Sleepiness Scale (ESS) Score	9.4 (8.7 to 10.1)	9.3 (8.6 to 10.1)	8.3 (7.6 to 9.1)	8.8 (8.1 to 9.6)

Post-hocAcceptability 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
Reported as:: Count of participants · Participants

Acceptability of Treatment as Assessed by a Single Question Questionnaire
Participants	Placebo	Amantadine	Modafinil	Methylphenidate
Acceptability of Treatment as Assessed by a Single Question Questionnaire	39	41	55	55

Adverse events

Collected over Adverse events were collected during each six-week medication period.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Placebo	0/124 (0%)	0/124 (0%)	38/124 (30.6%)
Amantadine	0/127 (0%)	2/127 (1.6%)	49/127 (38.6%)
Modafinil	0/125 (0%)	1/125 (0.8%)	50/125 (40%)
Methylphenidate	0/129 (0%)	0/129 (0%)	51/129 (39.5%)

Most frequent serious events

Most frequent serious events
Event	Placebo	Amantadine	Modafinil	Methylphenidate
MS exacerbationNervous system disorders	0/124	0/127	1/125	0/129
Pulmonary embolismVascular disorders	0/124	1/127	0/125	0/129
MyocardiitisCardiac disorders	0/124	1/127	0/125	0/129

Most frequent other events

Showing 10 of 17

Most frequent other events
Event	Placebo	Amantadine	Modafinil	Methylphenidate
Nervous system disordersNervous system disorders	13/124	24/127	22/125	20/129
Psychiatric disordersPsychiatric disorders	10/124	20/127	18/125	23/129
Gastrointestinal disordersGastrointestinal disorders	10/124	14/127	19/125	13/129
General disordersGeneral disorders	2/124	4/127	5/125	4/129
Skin and subcutaneous tissue disordersSkin and subcutaneous tissue disorders	2/124	2/127	5/125	0/129
Musculoskeletal and connective tissue disordersMusculoskeletal and connective tissue disorders	4/124	1/127	2/125	1/129
Cardiac disordersCardiac disorders	3/124	3/127	2/125	4/129
Injury, poisoning, and procedural complicationsInjury, poisoning and procedural complications	1/124	0/127	0/125	4/129
Infections and infestationsInfections and infestations	3/124	2/127	2/125	1/129
Metabolism and nutrition disordersMetabolism and nutrition disorders	2/124	1/127	3/125	0/129

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Arm A	Arm B	Arm C	Arm D	Total
Mean	48.3 ± 9.9	46.9 ± 12.4	46.1 ± 10.3	45.8 ± 10.2	46.8 ± 10.7

Sex: Female, Male
Sex: Female, Male(Participants)	Arm A	Arm B	Arm C	Arm D	Total
Female	27	26	27	29	109
Male	8	8	8	8	32

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Arm A	Arm B	Arm C	Arm D	Total
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	4	6	5	4	19
White	27	25	26	29	107
More than one race	0	0	0	0	0
Unknown or Not Reported	4	3	4	4	15

Study locations

2 sites

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

References and documents

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. PubMed 33242419 ↗
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. PubMed 29113955 ↗

Study documents

Protocol and statistical analysis plan · Oct 24, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Oct 20, 2020, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03185065
Lead sponsor: Johns Hopkins University
Collaborators: Patient-Centered Outcomes Research Institute
Responsible party: Sponsor
First posted: Jun 14, 2017
Start date: Oct 4, 2017
Primary completion: Nov 21, 2019
Completion: Nov 21, 2019
Results posted: Oct 19, 2020
Last update: Oct 20, 2020

Study contacts

Bardia Nourbakhsh, MD

principal investigator · Johns Hopkins University

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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

Study summary

Conditions studied

Browse trials for

In context

Multiple Sclerosis

Lead sponsor

Who can participate

✓Inclusion criteria

✕Exclusion criteria

Study design

Study arms

Interventions

What researchers measure

Primary outcomes

Secondary outcomes

Results

Participant flow

Outcome measures

Adverse events

Baseline characteristics

Study locations

References and documents

Publications

Study documents

Individual participant data

Updates

Registry details

Key details

Study contacts

Oversight

Not currently enrolling

Follow this study

Discussion

Other studies in this condition

Other studies from this sponsor

Inclusion criteria

Exclusion criteria