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Ketamine for Treatment of MS Fatigue

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ClinicalTrials.gov Identifier: NCT03500289
Recruitment Status : Completed
First Posted : April 18, 2018
Results First Posted : August 4, 2020
Last Update Posted : August 18, 2020
Sponsor:
Collaborator:
National Multiple Sclerosis Society
Information provided by (Responsible Party):
Johns Hopkins University

Tracking Information
First Submitted Date  ICMJE April 4, 2018
First Posted Date  ICMJE April 18, 2018
Results First Submitted Date  ICMJE July 20, 2020
Results First Posted Date  ICMJE August 4, 2020
Last Update Posted Date August 18, 2020
Actual Study Start Date  ICMJE August 10, 2018
Actual Primary Completion Date August 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 20, 2020)
Change in Daily Fatigue Severity Score [ Time Frame: Baseline (infusion visit) through day 7 ]
It is a single item question: 'how much fatigue (tiredness, weariness, problems thinking clearly) have you felt today?' with responses from 0 'None at all' to 10 'Extreme Fatigue'. Reported score changes are the average point/day score change. The mean score is reported based on this calculation: [(last day measure - baseline measure) / the number of days in the study].
Original Primary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • change in Daily Fatigue Severity [ Time Frame: Baseline (infusion visit) through day 7 ]
    It is a single item question: 'how much fatigue (tiredness, weariness, problems thinking clearly) have you felt today?' with responses from 0 'None at all' to 10 'Extreme Fatigue'.
  • change in Daily Fatigue Severity [ Time Frame: Baseline to day 14 postinfusion. ]
    It is a single item question: 'how much fatigue (tiredness, weariness, problems thinking clearly) have you felt today?' with responses from 0 'None at all' to 10 'Extreme Fatigue'.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2020)
  • Change in Quality of Life in Neurological Disorders (NeuroQol) Fatigue Item Bank Score [ Time Frame: Baseline (infusion visit) through day 28 post-infusion ]
    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. Reported score changes are the average point/day score change. The mean score is reported based on this calculation: [(last day measure - baseline measure) / the number of days in the study].
  • Change in Modified Fatigue Impact Scale (MFIS) Score [ Time Frame: Baseline (infusion visit) through Day 28 post-infusion ]
    The total score of the MFIS ranges from 0 to 84. Higher scores denote more severe fatigue. Reported score changes are the average point/day score change. The mean score is reported based on this calculation: [(last day measure - baseline measure) / the number of days in the study].
  • Change in Epworth Sleepiness Scale Score [ Time Frame: Baseline (infusion visit) through day 28 post-infusion ]
    The Epworth Sleepiness Scale score can range from 0 to 24. The higher the score, the higher that person's average sleep propensity in daily life (ASP), or their 'daytime sleepiness'. Reported score changes are the average point/day score change. The mean score is reported based on this calculation: [(last day measure - baseline measure) / the number of days in the study].
  • Change in Beck Depression Inventory (BDI) Score [ Time Frame: Baseline (infusion visit) through day 28 post-infusion ]
    The total score of the BDI ranges from 0 to 63. Higher scores denote more severe depressive symptoms. Reported score changes are the average point/day score change. The mean score is reported based on this calculation: [(last day measure - baseline measure) / the number of days in the study].
  • Change in Fatigue Severity Scale (FSS) Score [ Time Frame: Baseline (infusion visit) through day 28 post-infusion ]
    The total score of the FSS ranges from 9 to 63. Higher scores denote more severe fatigue. Reported score changes are the average point/day score change. The mean score is reported based on this calculation: [(last day measure - baseline measure) / the number of days in the study].
Original Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • change in NeuroQol fatigue item bank [ Time Frame: Baseline (infusion visit) through day 28 postinfusion. ]
  • change in NeuroQol fatigue item bank [ Time Frame: Baseline (infusion visit) through 28 postinfusion. ]
  • change in modified fatigue impact scale [ Time Frame: Baseline (infusion visit) through Day 28 postinfusion. ]
  • change Epworth Sleepiness Scale [ Time Frame: Baseline (infusion visit) through day 28 postinfusion. ]
  • change in Beck Depression Inventory [ Time Frame: Baseline (infusion visit) through day 28 postinfusion. ]
  • change in Fatigue Severity Scale [ Time Frame: Baseline (infusion visit) through day 28 postinfusion. ]
    The Fatigue Severity Scale (FSS) is a method of evaluating the impact of fatigue on you. The FSS is a short questionnaire that requires you to rate your level of fatigue. The FSS questionnaire contains nine statements that rate the severity of your fatigue symptoms. Read each statement and circle a number from 1 to 7, based on how accurately it reflects your condition during the past week and the extent to which you agree or disagree that the statement applies to you. • A low value (e.g., 1) indicates strong disagreement with the statement, whereas a high value (e.g., 7) indicates strong agreement.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine for Treatment of MS Fatigue
Official Title  ICMJE Ketamine for Treatment of Multiple Sclerosis-related Fatigue
Brief Summary

Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disease of the central nervous system and, after trauma, is the most common cause of disability in young adults, affecting more than 400,000 individuals in the US. Of all the symptoms that can occur with MS, chronic fatigue is the most common and disabling, reported by at least 75% of patients at some point. Fatigue limits patients' daily activities, and challenges employment, resulting in substantial socioeconomic consequences. Despite this negative impact, fatigue treatments have been inconsistently studied, in part due to poorly understood underlying pathophysiological mechanisms. Yet to be defined biological processes and lack of clear treatment targets have also hampered the development of drugs for fatigue. As a result, there are no medications approved by the Food and Drug Administration (FDA) for the treatment of MS fatigue.

The investigators recently reported that riluzole, a medication with anti-glutamatergic effects, increased the fatigue severity in patients with relapsing MS who had participated in a clinical trial evaluating potential neuroprotective effects of riluzole versus placebo. Three other clinic trials which examined memantine effects on cognition in patient with MS also reported worsening fatigue as a major side effect. Memantine main mechanism of action is blocking the N-methyl D-aspartate (NMDA) glutamate receptor. These observations prompted the investigators that glutamatergic transmission probably plays an important role in fatigue pathogenesis and modulating these pathways could have potential therapeutic effect on MS-related fatigue. A recent paper reported that ketamine, an NMDA receptor blocker with different kinetics compared to memantine, had a strong and prolonged effect in reducing fatigue in bipolar patients who participated in a clinical trial, evaluating anti-depressive effects of ketamine versus placebo. Interestingly, the effect of ketamine on fatigue was independent of its antidepressant effects.

The primary objective of this study is to determine if modulating glutamatergic transmission with ketamine is safe and efficacious in improving MS-related fatigue. These objectives will be answered in a proof of concept, randomized controlled trial of ketamine versus an active placebo (midazolam) in patients with relapsing or progressive MS who have clinically significant fatigue.

18 patients with MS and reported fatigue, will be randomized 2:1 to one infusion of ketamine 0.5 mg/kg over 40 minutes versus one infusion of midazolam 0.05 mg/kg over 40 minutes. Midazolam is chosen as an active placebo to keep the participants blinded to participants' medication assignment. Primary outcome of the study will be Daily Fatigue Severity measured daily from day one through day seven post-infusion.

Secondary outcomes of the study include other fatigue questionnaires, depression and sleepiness. The length of study will be around 28 days.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Multiple Sclerosis
  • Fatigue
Intervention  ICMJE
  • Drug: Ketamine
    One intravenous infusion of ketamine 0.5 mg/kg over 40 minutes
  • Drug: Midazolam
    One intravenous infusion of midazolam 0.05 mg/kg over 40 minutes
Study Arms  ICMJE
  • Experimental: Ketamine
    Intervention: Drug: Ketamine
  • Placebo Comparator: Midazolam
    Intervention: Drug: Midazolam
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 11, 2018)
18
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 30, 2019
Actual Primary Completion Date August 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age between 18 years 65 years.
  • 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).
  • Ambulatory (at least 20 feet using bilateral assistance).
  • Fatigue reportedly present and screening modified fatigue impact scale (MFIS) score >33.
  • Internet and email access and able to use a computer or tablet

Exclusion Criteria:

  • Beck Depression Inventory (BDI) score of more than 30.
  • 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).
  • History of severe liver disease, including cirrhosis.
  • Terminal medical conditions.
  • Currently treated for active malignancy.
  • Alcohol or substance abuse in the past year (except marijuana or other cannabinoids).
  • A history of intolerance or allergic or anaphylactic reaction to ketamine or midazolam
  • Clinically unstable medical or psychiatric disorders that require acute treatment as determined by the PI.
  • History of severe or untreated coronary artery disease or history of congestive heart failure.
  • History of prior ischemic or hemorrhagic stroke and cerebral vascular aneurysms.
  • History of recurrent seizures or epilepsy.
  • Taking any disallowed therapy(ies) as noted in Appendix 2 of the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03500289
Other Study ID Numbers  ICMJE IRB00164017
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Johns Hopkins University
Study Sponsor  ICMJE Johns Hopkins University
Collaborators  ICMJE National Multiple Sclerosis Society
Investigators  ICMJE
Principal Investigator: Bardia Nourbakhsh, MD, MAS Johns Hopkins University
PRS Account Johns Hopkins University
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP