Ketamine for Treatment of MS Fatigue

August 5, 2020 updated by: Johns Hopkins University

Ketamine for Treatment of Multiple Sclerosis-related Fatigue

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ketamine
Drug: Ketamine
One intravenous infusion of ketamine 0.5 mg/kg over 40 minutes
Placebo Comparator: Midazolam
Drug: Midazolam
One intravenous infusion of midazolam 0.05 mg/kg over 40 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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].
Baseline (infusion visit) through day 7

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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].
Baseline (infusion visit) through day 28 post-infusion
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].
Baseline (infusion visit) through Day 28 post-infusion
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].
Baseline (infusion visit) through day 28 post-infusion
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].
Baseline (infusion visit) through day 28 post-infusion
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].
Baseline (infusion visit) through day 28 post-infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Johns Hopkins University

Collaborators

National Multiple Sclerosis Society

Investigators

  • Principal Investigator: Bardia Nourbakhsh, MD, MAS, Johns Hopkins University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 10, 2018

Primary Completion (Actual)

August 30, 2019

Study Completion (Actual)

August 30, 2019

Study Registration Dates

First Submitted

April 4, 2018

First Submitted That Met QC Criteria

April 11, 2018

First Posted (Actual)

April 18, 2018

Study Record Updates

Last Update Posted (Actual)

August 18, 2020

Last Update Submitted That Met QC Criteria

August 5, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB00164017

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe