Multiple SclerosisPhase 1/2NCT03500289
Ketamine for Treatment of MS Fatigue
A Phase 1/2 study testing Ketamine and Midazolam in people with Multiple Sclerosis and Fatigue, run by Johns Hopkins University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Multiple Sclerosis, Fatigue
- What is being tested?
- Ketamine and Midazolam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- 10 Aug 2018to 30 Aug 2019
- Phase
- Phase 1/2
- 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 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read more
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.
- Conditions
- Multiple Sclerosis, Fatigue
- Medical subject headings
- Multiple Sclerosis, Fatigue
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KetamineDrug
One intravenous infusion of ketamine 0.5 mg/kg over 40 minutes
MidazolamDrug
One intravenous infusion of midazolam 0.05 mg/kg over 40 minutes
| Study group | Role | What they receive |
|---|---|---|
| Ketamine | Experimental | Not described Receives: Drug: Ketamine |
| Midazolam | Placebo comparator | Not described Receives: Drug: Midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Daily Fatigue Severity Score
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].
Measured: Baseline (infusion visit) through day 7
Secondary outcomes (5)
Change in Quality of Life in Neurological Disorders (NeuroQol) Fatigue Item Bank Score
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].
Measured: Baseline (infusion visit) through day 28 post-infusion
Change in Modified Fatigue Impact Scale (MFIS) Score
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].
Measured: Baseline (infusion visit) through Day 28 post-infusion
Change in Epworth Sleepiness Scale Score
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].
Measured: Baseline (infusion visit) through day 28 post-infusion
Change in Beck Depression Inventory (BDI) Score
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].
Measured: Baseline (infusion visit) through day 28 post-infusion
Change in Fatigue Severity Scale (FSS) Score
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].
Measured: Baseline (infusion visit) through day 28 post-infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2018
- Study start10 Aug 2018
- Primary completion30 Aug 2019
- Study completion30 Aug 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.
- Other trials for 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 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- National Multiple Sclerosis Society
- Responsible party
- Sponsor
- Investigators
- Bardia Nourbakhsh, MD, MAS, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03500289
- Sponsor's protocol ID
- IRB00164017
- Status last verified
- Jul 2020
- First submitted
- 4 Apr 2018
- Last updated
- 18 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ketamine for Treatment of Multiple Sclerosis-related Fatigue
- ClinicalTrials.gov ID
- NCT03500289
- Acronym / sponsor ID
- IRB00164017
- Conditions
- Multiple Sclerosis, Fatigue
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Collaborators
- National Multiple Sclerosis Society
- Study start
- 10 Aug 2018 (actual)
- Primary completion
- 30 Aug 2019 (actual)
- Study completion
- 30 Aug 2019 (actual)
- First posted
- 18 Apr 2018 (actual)
- Results
- Posted 4 Aug 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ketamine | Experimental | Drug: Ketamine |
| Midazolam | Placebo comparator | Drug: Midazolam |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (15 listed)
- 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).
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 |
|---|---|---|
| KetamineOne intravenous infusion of ketamine 0.5 mg/kg over 40 minutes | Drug | Ketamine |
| MidazolamOne intravenous infusion of midazolam 0.05 mg/kg over 40 minutes | Drug | Midazolam |
Primary outcome
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].
5 secondary outcomes
Change in Quality of Life in Neurological Disorders (NeuroQol) Fatigue Item Bank Score
Time frame: 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
Change in Epworth Sleepiness Scale Score
Time frame: 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
Change in Fatigue Severity Scale (FSS) Score
Time frame: Baseline (infusion visit) through day 28 post-infusion
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- 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, MAS principal investigator
Johns Hopkins University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ketamine and Midazolam in people with Multiple Sclerosis and Fatigue, run by Johns Hopkins University at 1 site 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 15 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 18 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 4 Aug 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?
Change in Daily Fatigue Severity Score (time frame: Baseline (infusion visit) through day 7). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 18 Aug 2020.