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

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ClinicalTrials.gov Identifier: NCT03185065

Recruitment Status : Completed

First Posted : June 14, 2017

Results First Posted : October 19, 2020

Last Update Posted : October 20, 2020

Sponsor:

Collaborator:

Patient-Centered Outcomes Research Institute

Information provided by (Responsible Party):

Johns Hopkins University

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Fatigue in Multiple Sclerosis
Interventions	Drug: Amantadine Drug: Modafinil Drug: Methylphenidate Drug: Placebos
Enrollment	141

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	amantadine, placebo, modafinil, met...	placebo, methylphenidate, amantadin...	modafinil, amantadine, methylphenid...	methylphenidate, modafinil, placebo...
Arm/Group Description	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	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	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	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
Period Title: Period 1 (6 Weeks)
Started	35	34	35	37
Completed	32	33	32	36
Not Completed	3	1	3	1
Period Title: Washout (2 Weeks)
Started	32	33	32	36
Completed	32	31	32	35
Not Completed	0	2	0	1
Period Title: Period 2 (6 Weeks)
Started	32	31	32	35
Completed	32	31	32	34
Not Completed	0	0	0	1
Period Title: Washout (2 Weeks)
Started	32	31	32	34
Completed	31	29	31	32
Not Completed	1	2	1	2
Period Title: Period 3 (6 Weeks)
Started	31	29	31	32
Completed	31	29	29	32
Not Completed	0	0	2	0
Period Title: Washout (2 Weeks)
Started	31	29	29	32
Completed	31	28	27	32
Not Completed	0	1	2	0
Period Title: Period 4 (6 Weeks)
Started	31	28	27	32
Completed	31	27	26	31
Not Completed	0	1	1	1

Baseline Characteristics

Arm/Group Title		Arm A	Arm B	Arm C	Arm D	Total
Arm/Group Description		amantadine, placebo, modafinil, met...	placebo, methylphenidate, amantadin...	modafinil, amantadine, methylphenid...	methylphenidate, modafinil, placebo...	Total of all reporting groups
Arm/Group Description		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	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	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	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	Total of all reporting groups
Overall Number of Baseline Participants		35	34	35	37	141
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	35 participants	34 participants	35 participants	37 participants	141 participants
		48.3 (9.9)	46.9 (12.4)	46.1 (10.3)	45.8 (10.2)	46.8 (10.7)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	35 participants	34 participants	35 participants	37 participants	141 participants
	Female	27 77.1%	26 76.5%	27 77.1%	29 78.4%	109 77.3%
	Male	8 22.9%	8 23.5%	8 22.9%	8 21.6%	32 22.7%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	35 participants	34 participants	35 participants	37 participants	141 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	4 11.4%	6 17.6%	5 14.3%	4 10.8%	19 13.5%
	White	27 77.1%	25 73.5%	26 74.3%	29 78.4%	107 75.9%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	4 11.4%	3 8.8%	4 11.4%	4 10.8%	15 10.6%

Outcome Measures

1.Primary Outcome


Title	Modified Fatigue Impact Scale (MFIS) Score
Description	MFIS score during the fifth week of treatment period. The total 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

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Placebo	Amantadine	Modafinil	Methylphenidate
Arm/Group Description:	1 placebo capsule increased to max ...	100 mg of amantadine increased to 2...	100 mg of modafinil increased to 20...	5 mg of methylphenidate uptitrated ...
Arm/Group Description:	1 placebo capsule increased to max of 2 capsules twice daily	100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Overall Number of Participants Analyzed	123	124	124	127
Least Squares Mean (95% Confidence Interval) Unit of Measure: score on a scale
	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)

2.Secondary Outcome


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 treatme...
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

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Placebo	Amantadine	Modafinil	Methylphenidate
Arm/Group Description:	1 placebo capsule increased to max ...	100 mg of amantadine increased to 2...	100 mg of modafinil increased to 20...	5 mg of methylphenidate uptitrated ...
Arm/Group Description:	1 placebo capsule increased to max of 2 capsules twice daily.	100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Overall Number of Participants Analyzed	123	124	124	127
Least Squares Mean (95% Confidence Interval) Unit of Measure: score on a scale
	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)

3.Secondary Outcome


Title	Epworth Sleepiness Scale (ESS) Score
Description	ESS score during the fifth week of treatment period. The ESS score can...
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

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Placebo	Amantadine	Modafinil	Methylphenidate
Arm/Group Description:	1 placebo capsule increased to max ...	100 mg of amantadine increased to 2...	100 mg of modafinil increased to 20...	5 mg of methylphenidate uptitrated ...
Arm/Group Description:	1 placebo capsule increased to max of 2 capsules twice daily.	100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Overall Number of Participants Analyzed	123	124	124	127
Least Squares Mean (95% Confidence Interval) Unit of Measure: score on a scale
	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)

4.Post-Hoc Outcome


Title	Acceptability of Treatment as Assessed by a Single Question Questionnaire
Description	Participants will answer yes or no to this question: "Taken into ...
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Placebo	Amantadine	Modafinil	Methylphenidate
Arm/Group Description:	1 placebo capsule increased to max ...	100 mg of amantadine increased to 2...	100 mg of modafinil increased to 20...	5 mg of methylphenidate uptitrated ...
Arm/Group Description:	1 placebo capsule increased to max of 2 capsules twice daily.	100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
Overall Number of Participants Analyzed	123	124	124	127
Measure Type: Count of Participants Unit of Measure: Participants
	39 31.7%	41 33.1%	55 44.4%	55 43.3%

Adverse Events

Time Frame	Adverse events were collected during each six-week medication period.
Adverse Event Reporting Description	The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).

Arm/Group Title	Placebo	Amantadine	Modafinil	Methylphenidate
Arm/Group Description	1 placebo capsule increased to max ...	100 mg of amantadine increased to 2...	100 mg of modafinil increased to 20...	5 mg of methylphenidate uptitrated ...
Arm/Group Description	1 placebo capsule increased to max of 2 capsules twice daily.	100 mg of amantadine increased to 200 mg of amantadine, if tolerated.	100 mg of modafinil increased to 200 mg of modafinil, if tolerated.	5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated.
All-Cause Mortality
	Placebo	Amantadine	Modafinil	Methylphenidate
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/124 (0.00%)	0/127 (0.00%)	0/125 (0.00%)	0/129 (0.00%)
Serious Adverse Events Serious Adverse Events
	Placebo	Amantadine	Modafinil	Methylphenidate
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/124 (0.00%)	2/127 (1.57%)	1/125 (0.80%)	0/129 (0.00%)
Cardiac disorders
Myocardiitis ^*	0/124 (0.00%)	1/127 (0.79%)	0/125 (0.00%)	0/129 (0.00%)
Nervous system disorders
MS exacerbation ^*	0/124 (0.00%)	0/127 (0.00%)	1/125 (0.80%)	0/129 (0.00%)
Vascular disorders
Pulmonary embolism ^*	0/124 (0.00%)	1/127 (0.79%)	0/125 (0.00%)	0/129 (0.00%)
* Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Placebo	Amantadine	Modafinil	Methylphenidate
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	38/124 (30.65%)	49/127 (38.58%)	50/125 (40.00%)	51/129 (39.53%)
Cardiac disorders
Cardiac disorders ^*	3/124 (2.42%)	3/127 (2.36%)	2/125 (1.60%)	4/129 (3.10%)
Ear and labyrinth disorders
Ear and labyrinth disorders ^*	0/124 (0.00%)	1/127 (0.79%)	0/125 (0.00%)	0/129 (0.00%)
Eye disorders
Eye disorders ^*	0/124 (0.00%)	1/127 (0.79%)	2/125 (1.60%)	1/129 (0.78%)
Gastrointestinal disorders
Gastrointestinal disorders ^*	10/124 (8.06%)	14/127 (11.02%)	19/125 (15.20%)	13/129 (10.08%)
General disorders
General disorders ^*	2/124 (1.61%)	4/127 (3.15%)	5/125 (4.00%)	4/129 (3.10%)
Immune system disorders
Immune system disorders ^*	0/124 (0.00%)	1/127 (0.79%)	1/125 (0.80%)	0/129 (0.00%)
Infections and infestations
Infections and infestations ^*	3/124 (2.42%)	2/127 (1.57%)	2/125 (1.60%)	1/129 (0.78%)
Injury, poisoning and procedural complications
Injury, poisoning, and procedural complications ^*	1/124 (0.81%)	0/127 (0.00%)	0/125 (0.00%)	4/129 (3.10%)
Metabolism and nutrition disorders
Metabolism and nutrition disorders ^*	2/124 (1.61%)	1/127 (0.79%)	3/125 (2.40%)	0/129 (0.00%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders ^*	4/124 (3.23%)	1/127 (0.79%)	2/125 (1.60%)	1/129 (0.78%)
Nervous system disorders
Nervous system disorders ^*	13/124 (10.48%)	24/127 (18.90%)	22/125 (17.60%)	20/129 (15.50%)
Psychiatric disorders
Psychiatric disorders ^*	10/124 (8.06%)	20/127 (15.75%)	18/125 (14.40%)	23/129 (17.83%)
Renal and urinary disorders
Renal and urinary disorders ^*	0/124 (0.00%)	0/127 (0.00%)	1/125 (0.80%)	0/129 (0.00%)
Reproductive system and breast disorders
Reproductive system ^*	1/124 (0.81%)	1/127 (0.79%)	2/125 (1.60%)	2/129 (1.55%)
Respiratory, thoracic and mediastinal disorders
Respiratory disorders ^*	0/124 (0.00%)	2/127 (1.57%)	2/125 (1.60%)	2/129 (1.55%)
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders ^*	2/124 (1.61%)	2/127 (1.57%)	5/125 (4.00%)	0/129 (0.00%)
Vascular disorders
Vascular disorders ^*	1/124 (0.81%)	3/127 (2.36%)	3/125 (2.40%)	1/129 (0.78%)
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Dr. Bardia Nourbakhsh
Organization:	Johns Hopkins University
Phone:	4106141522
EMail:	bnourba1@jhmi.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Layout table for additonal information

Responsible Party:	Johns Hopkins University
ClinicalTrials.gov Identifier:	NCT03185065
Other Study ID Numbers:	IRB00119702
First Submitted:	June 9, 2017
First Posted:	June 14, 2017
Results First Submitted:	September 24, 2020
Results First Posted:	October 19, 2020
Last Update Posted:	October 20, 2020

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