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

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ClinicalTrials.gov Identifier: NCT03185065
Recruitment Status : Active, not recruiting
First Posted : June 14, 2017
Last Update Posted : March 19, 2019
Sponsor:
Collaborator:
Patient-Centered Outcomes Research Institute
Information provided by (Responsible Party):
Johns Hopkins University

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.

Condition or disease Intervention/treatment Phase
Fatigue in Multiple Sclerosis Drug: Amantadine Drug: Modafinil Drug: Methylphenidate Drug: Placebos Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis
Actual Study Start Date : October 4, 2017
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2019


Arm Intervention/treatment
Experimental: 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: 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: 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: 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




Primary Outcome Measures :
  1. modified fatigue impact scale (MFIS) score [ Time Frame: Week 5 of each treatment period ]
    MFIS score at the end o each treatment period


Secondary Outcome Measures :
  1. Neuro-QoL Item Bank - Fatigue score [ Time Frame: Week 5 of each treatment period ]
    Neuro-QoL Item Bank - Fatigue score at the end o each treatment period

  2. Epworth Sleepiness Scale (ESS) score [ Time Frame: Week 5 of each treatment period ]
    ESS score at the end o each treatment period

  3. "Taken into consideration the possible benefits and/or disadvantages of this medication, would you choose it, going forward to treat your MS fatigue?" [ Time Frame: Week 5 of each treatment period ]
    Participants will answer to this question yes or no.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03185065


Locations
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United States, California
University of California San Francisco
San Francisco, California, United States, 94158
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Johns Hopkins University
Patient-Centered Outcomes Research Institute
Investigators
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Principal Investigator: Bardia Nourbakhsh, MD Johns Hopkins University

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT03185065     History of Changes
Other Study ID Numbers: IRB00119702
First Posted: June 14, 2017    Key Record Dates
Last Update Posted: March 19, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Additional relevant MeSH terms:
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Sclerosis
Multiple Sclerosis
Amantadine
Fatigue
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Signs and Symptoms
Methylphenidate
Modafinil
Central Nervous System Stimulants
Physiological Effects of Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents
Wakefulness-Promoting Agents
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers
Antiparkinson Agents
Anti-Dyskinesia Agents
Antiviral Agents
Anti-Infective Agents
Analgesics, Non-Narcotic