Fatigue in Multiple SclerosisPhase 3TRIUMPHANT-MSNCT03185065
Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis
A Phase 3 study testing Amantadine, Modafinil and Methylphenidate in people with Fatigue in Multiple Sclerosis, run by Johns Hopkins University at 2 sites in United States.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Fatigue in Multiple Sclerosis
- What is being tested?
- Amantadine, Modafinil and Methylphenidate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 141 participants
- Where
- 2 sitesUnited States
- Study dates
- 4 Oct 2017to 21 Nov 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
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- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Johns Hopkins University
Baltimore, Maryland, 21287
University of California San Francisco
San Francisco, California, 94158
About this study
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
- Fatigue in Multiple Sclerosis
- Being tested
- Amantadine, Modafinil, Methylphenidate, Placebos
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AmantadineDrug
100 mg of amantadine increased to 200 mg of amantadine, if tolerated
ModafinilDrug
100 mg of modafinil increased to 200 mg of modafinil, if tolerated
MethylphenidateDrug
5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated
PlacebosDrug
1 placebo capsule increased to max of 2 capsules twice daily
| Study group | Role | What they receive |
|---|---|---|
| Arm A | Experimental | amantadine, placebo, modafinil, methylphenidate Receives: Drug: Amantadine; Drug: Modafinil; Drug: Methylphenidate; Drug: Placebos |
| Arm B | Experimental | placebo, methylphenidate, amantadine, modafinil Receives: Drug: Amantadine; Drug: Modafinil; Drug: Methylphenidate; Drug: Placebos |
| Arm C | Experimental | modafinil, amantadine, methylphenidate, placebo Receives: Drug: Amantadine; Drug: Modafinil; Drug: Methylphenidate; Drug: Placebos |
| Arm D | Experimental | methylphenidate, modafinil, placebo and amantadine Receives: Drug: Amantadine; Drug: Modafinil; Drug: Methylphenidate; Drug: Placebos |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Week 5 of each treatment period
Secondary outcomes (2)
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.
Measured: 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'.
Measured: Week 5 of each treatment period
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jun 2017
- Study start4 Oct 2017
- Primary completion21 Nov 2019
- Study completion21 Nov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Fatigue in Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- 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
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 141 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Responsible party
- Sponsor
- Investigators
- Bardia Nourbakhsh, MD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03185065
- Sponsor's protocol ID
- IRB00119702
- Acronym
- TRIUMPHANT-MS
- Status last verified
- Oct 2020
- First submitted
- 9 Jun 2017
- Last updated
- 20 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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 33242419Nourbakhsh 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 at a glance
From the registry record, last updated by the sponsor on 20 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis
- ClinicalTrials.gov ID
- NCT03185065
- Acronym / sponsor ID
- TRIUMPHANT-MS / IRB00119702
- Conditions
- Fatigue in Multiple Sclerosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 141 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Study start
- 4 Oct 2017 (actual)
- Primary completion
- 21 Nov 2019 (actual)
- Study completion
- 21 Nov 2019 (actual)
- First posted
- 14 Jun 2017 (actual)
- Results
- Posted 19 Oct 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
- 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.
| Arm | Type | Receives |
|---|---|---|
| Arm A | Experimental | Drug: Amantadine, Drug: Modafinil, Drug: Methylphenidate, Drug: Placebosamantadine, placebo, modafinil, methylphenidate |
| Arm B | Experimental | Drug: Amantadine, Drug: Modafinil, Drug: Methylphenidate, Drug: Placebosplacebo, methylphenidate, amantadine, modafinil |
| Arm C | Experimental | Drug: Amantadine, Drug: Modafinil, Drug: Methylphenidate, Drug: Placebosmodafinil, amantadine, methylphenidate, placebo |
| Arm D | Experimental | Drug: Amantadine, Drug: Modafinil, Drug: Methylphenidate, Drug: Placebosmethylphenidate, modafinil, placebo and amantadine |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (22 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Amantadine100 mg of amantadine increased to 200 mg of amantadine, if tolerated | Drug | Arm A, Arm B, Arm C, Arm D |
| Modafinil100 mg of modafinil increased to 200 mg of modafinil, if tolerated | Drug | Arm A, Arm B, Arm C, Arm D |
| Methylphenidate5 mg of methylphenidate uptitrated to max of 20 mg of methylphenidate, if tolerated | Drug | Arm A, Arm B, Arm C, Arm D |
| Placebos1 placebo capsule increased to max of 2 capsules twice daily | Drug | Arm A, Arm B, Arm C, Arm D |
Primary outcome
Modified Fatigue Impact Scale (MFIS) Score
Time frame: Week 5 of each treatment period
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.
2 secondary outcomes
Quality of Life in Neurological Disorders (Neuro-QoL) Item Bank - Fatigue Score
Time frame: Week 5 of each treatment period
Epworth Sleepiness Scale (ESS) Score
Time frame: Week 5 of each treatment period
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33242419Nourbakhsh 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.
- Derived from this study: PubMed 29113955Nourbakhsh 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bardia Nourbakhsh, MD principal investigator
Johns Hopkins University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Amantadine, Modafinil and Methylphenidate in people with Fatigue in Multiple Sclerosis, run by Johns Hopkins University at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Modified Fatigue Impact Scale (MFIS) Score (time frame: Week 5 of each treatment period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03185065, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Oct 2020.