Ketamine for Multiple Sclerosis Fatigue

(INKLING-MS Trial)

Overseen By Lauren Vega, BSN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Johns Hopkins University

Must be taking: Fatigue medications

Disqualifiers: Severe depression, Untreated sleep apnea, Coronary artery disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 8 weeks

110 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how low-dose ketamine, administered through an IV, might reduce fatigue in people with multiple sclerosis (MS). Researchers compare different combinations of ketamine and midazolam to determine the most effective option. Participants should have MS with fatigue as a main symptom, be able to walk at least 20 feet with assistance, and have stable use of current fatigue medications. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for the trial?

You can continue taking your current medication for fatigue if it's not one of the disallowed therapies. You must have been on a stable dose for at least four weeks before the trial and be willing to keep the same dose during the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ketamine, tested for fatigue in people with multiple sclerosis (MS), has promising safety results. The FDA has already approved ketamine as an anesthetic, indicating its safety for certain uses. In this trial, researchers use low doses, which generally have a good safety record.

Studies have found that ketamine can cause side effects like dizziness or changes in mood or perception. These side effects are usually mild and resolve quickly. As this trial is in Phase 2, it aims to determine the right dose and assess its safety for people with MS fatigue.

Overall, while ketamine can cause some side effects, it is generally well-tolerated in low doses. Researchers will closely monitor participants to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for multiple sclerosis (MS) fatigue, like amantadine and modafinil, focus on stimulating the brain to reduce tiredness. However, ketamine offers a fresh perspective by potentially acting on the brain's glutamate system, which might help recalibrate how the brain processes energy and fatigue signals. Researchers are excited about ketamine because it might provide rapid relief from fatigue, unlike many current options that take longer to show effects. Additionally, ketamine's ability to modulate mood and cognitive function could offer added benefits for MS patients who often experience these related symptoms.

What evidence suggests that this trial's treatments could be effective for MS fatigue?

Research shows that ketamine might help reduce tiredness in people with Multiple Sclerosis (MS). Studies have found that ketamine treatments are usually safe and well-tolerated. In this trial, participants will receive different combinations of ketamine and midazolam to evaluate their effects on MS-related tiredness. Some research suggests that ketamine could help manage this tiredness by affecting certain brain signals. Although the reduction in tiredness isn't immediate, ketamine may improve symptoms over time. ^{2 6 7 8 9}

Who Is on the Research Team?

Bardia Nourbakhsh, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for ambulatory adults aged 18-65 with Multiple Sclerosis (MS) who suffer from fatigue as a main symptom. They must meet specific MS diagnostic criteria, have stable health, and be on a consistent dose of any current fatigue medication. Exclusions include severe depression, active cancer treatment, certain heart or liver conditions, substance abuse within the last year, and allergies to ketamine or midazolam.

Inclusion Criteria

Subject must have internet and email access and ability to use a computer or tablet or smartphone

Subject must meet McDonald 2017 diagnostic criteria for multiple sclerosis based on the PI review of the medical records

I can walk at least 20 feet with some help.

Exclusion Criteria

I am currently receiving treatment for cancer.

Breastfeeding or pregnant

Clinically unstable medical or psychiatric disorders that require acute treatment as determined by the PI

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive infusions of ketamine or midazolam according to their assigned group, with infusions four weeks apart

8 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine

Trial Overview The study tests low-dose intravenous ketamine against an active placebo (midazolam) for treating MS-related fatigue. It's phase II, randomized (participants are randomly assigned to one of the two treatments), double-blind (neither participants nor researchers know who gets which treatment), and involves parallel groups where each group receives different treatments.

How Is the Trial Designed?

Group I: Midazolam-Ketamine Experimental Treatment 2 Interventions

Participants in this arm will receive one infusion of midazolam followed four weeks later by an infusion of ketamine.

Group II: Ketamine-Midazolam Experimental Treatment 2 Interventions

Participants in this arm will receive one infusion of ketamine followed four weeks later by an infusion of midazolam.

Group III: Ketamine-Ketamine Experimental Treatment 1 Intervention

Participants in this arm will receive two infusions of ketamine four weeks apart.

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

In a study involving nine recreationally active men, ketone monoester (KME) supplementation was found to reduce cognitive fatigue during a simulated soccer match, leading to a smaller decrease in cognitive performance compared to a placebo.

KME also lowered blood glucose and lactate levels during exercise, suggesting it may help spare carbohydrates, which could be beneficial for athletes during high-intensity activities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone Ester Supplementation Improves Some Aspects of Cognitive Function during a Simulated Soccer Match after Induced Mental Fatigue. Quinones, MD., Lemon, PWR.[2023]

The study demonstrated that hyperpolarized 2-keto[1-(13)C]isocaproate (KIC) can be effectively used to visualize and measure brain metabolism, particularly showing significant conversion to leucine within 20 seconds of administration in normal rats.

Higher metabolic activity of KIC was observed in the hippocampus compared to muscle tissue, suggesting that hyperpolarized KIC could serve as a valuable tool for assessing BCAT activity in the brain, especially in the context of neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging cerebral 2-ketoisocaproate metabolism with hyperpolarized (13)C magnetic resonance spectroscopic imaging. Butt, SA., Søgaard, LV., Magnusson, PO., et al.[2021]

Diets high in branched-chain alpha-keto acids (BCKAs) significantly activate liver BCKA dehydrogenase (BCKD) in rats, with complete activation observed when consuming specific BCKAs like alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or alpha-ketoisovalerate.

The combination of BCKAs in the diet not only doubled the basal activity of liver BCKD but also led to substantial activation in muscle BCKD, indicating that these dietary components can effectively enhance enzyme activity related to amino acid metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High branched-chain alpha-keto acid intake, branched-chain alpha-keto acid dehydrogenase activity, and plasma and brain amino acid and plasma keto acid concentrations in rats. Crowell, PL., Block, KP., Repa, JJ., et al.[2018]

Depression and chronic fatigue are equally common in patients with neuromyelitis optica (NMO) and multiple sclerosis (MS), and these two conditions are strongly correlated.

Treatment with levocarnitine did not show any beneficial effects on depression or fatigue in patients with low serum carnitine levels, suggesting that this intervention may not be effective for these symptoms in NMO.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depressive state and chronic fatigue in multiple sclerosis and neuromyelitis optica. Akaishi, T., Nakashima, I., Misu, T., et al.[2015]

N-acetyl cysteine (NAC) was found to be well-tolerated in individuals with progressive multiple sclerosis (MS), with a high adherence rate of 94%, and a similar incidence of adverse events compared to placebo (60% vs. 80%).

While NAC did not significantly reduce fatigue compared to placebo (mean improvement of 11 points on NAC vs. 18 points on placebo), it did not show a meaningful impact on oxidative biomarkers, suggesting that the dosing or administration method may need to be reconsidered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine. Krysko, KM., Bischof, A., Nourbakhsh, B., et al.[2022]

Acute administration of α-ketoisocaproic acid (KIC) in young male rats led to decreased levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), suggesting that these neurotrophic factors may be negatively impacted in conditions like maple syrup urine disease (MSUD).

The reduction in BDNF and NGF levels could contribute to the neurodegenerative processes associated with MSUD, indicating a potential link between the accumulation of α-ketoacids and brain dysfunction in this disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracerebroventricular administration of α-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats. Wisniewski, MS., Carvalho-Silva, M., Gomes, LM., et al.[2018]

Fatigue is the most common and disabling symptom in multiple sclerosis (MS), affecting up to 40% of patients more than other symptoms like weakness or spasticity.

Imaging studies suggest that MS-related fatigue may be linked to reduced brain metabolism in specific areas, and while various treatments, including pharmacologic agents like modafinil, have been explored, the exact causes and effective interventions for this fatigue remain unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatigue associated with multiple sclerosis: diagnosis, impact and management. Bakshi, R.[2022]

In a study of 38 patients with myalgic encephalomyelitis (ME), those who responded well to vitamin B12 injections had significantly higher frequencies and doses of injections, along with longer treatment durations and higher daily folic acid intake compared to those with mild responses.

Good responders reported substantial improvements in their condition, while mild responders often relied on analgesics, suggesting that the effectiveness of B12 and folic acid may be influenced by individual factors such as MTHFR genotype and co-existing conditions like thyroid dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. Regland, B., Forsmark, S., Halaouate, L., et al.[2018]

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate effectively elevates blood ketone levels in healthy volunteers, reaching maximum plasma concentrations of 3.30 mM for β-hydroxybutyrate within 1-2 hours after ingestion.

This ketone monoester was generally well-tolerated over a 5-day period, although some gastrointestinal side effects were noted at higher doses, indicating it is a safe alternative to traditional ketogenic diets for enhancing physical and cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

K.Vita, a medical food with a specific ratio of fatty acids, was well accepted and tolerated by individuals with drug-resistant epilepsy, with 66% of children and 69% of adults completing the study despite some gastrointestinal disturbances that decreased over time.

The dietary intervention with K.Vita led to a significant 50% reduction in seizure frequency, suggesting it may be an effective alternative for those who cannot tolerate ketogenic diets, with potential mechanisms of action that do not rely on achieving ketosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

K.Vita: a feasibility study of a blend of medium chain triglycerides to manage drug-resistant epilepsy. Schoeler, NE., Orford, M., Vivekananda, U., et al.[2022]

Branched chain keto-acids (BCKAs) like alpha-ketoisocaproate (KIC) significantly inhibit oxygen consumption in liver and brain tissues, particularly affecting key enzymes involved in energy metabolism, which could contribute to conditions like maple syrup urine disease.

Interestingly, at lower concentrations, KIC and other BCKAs can actually stimulate mitochondrial respiration when using certain substrates, suggesting that these compounds may have complex effects on energy metabolism in cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Branched chain keto-acids exert biphasic effects on alpha-ketoglutarate-stimulated respiration in intact rat liver mitochondria. Shestopalov, AI., Kristal, BS.[2018]

In a study involving 80 healthy older adults, the medium-chain triglyceride GSK2981710 increased plasma β-hydroxybutyrate (BHB) levels but did not lead to significant improvements in cognitive function or memory-related neuronal activity over 14 days.

The most common side effect was diarrhea, affecting 100% of participants in the initial part of the study, indicating that while GSK2981710 is generally well-tolerated, it may cause gastrointestinal discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study. O'Neill, BV., Dodds, CM., Miller, SR., et al.[2020]

In a pilot study of 51 ME/CFS patients, nasal vitamin B12 drops significantly increased serum vitamin B12 levels and improved physical activity, with two-thirds of participants reporting a positive response to treatment.

The treatment led to a notable decrease in fatigue levels as measured by the CIS20r fatigue scale, suggesting that nasal B12 drops could be an effective alternative to injections for managing symptoms in ME/CFS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open Trial of Vitamin B12 Nasal Drops in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison of Responders and Non-Responders. van Campen, CLM., Riepma, K., Visser, FC.[2020]

Raspberry ketone (RK) shows high oral bioavailability of 86.28% and reaches peak concentration in the bloodstream within 1 hour, indicating effective absorption and potential for use as an antiobesity agent.

RK is stable in gastrointestinal fluids and plasma, and demonstrates good intestinal permeability, suggesting it can be effectively utilized in therapeutic applications for weight management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LC-MS/MS method for quantification of raspberry ketone in rat plasma: application to preclinical pharmacokinetic studies. Verma, S., Goand, UK., Garg, R., et al.[2023]

Raspberry ketone (RK) was found to reduce body weight gain in obese mice, but at higher doses (330 and 500 mg/kg), it caused significant mortality rates of 67.6% and 50% respectively in normal obese mice, and 70% in health-compromised obese mice.

The study indicated that RK treatment led to elevated blood levels of alanine transaminase (ALT) and increased blood glucose levels, suggesting that high doses of RK may pose serious health risks, particularly in compromised health conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Raspberry Ketone on Normal, Obese and Health-Compromised Obese Mice: A Preliminary Study. Mir, TM., Ma, G., Ali, Z., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7790846/

Pilot randomized active-placebo controlled trial of low-dose ... Ketamine infusions were safe and well-tolerated. While no change in DFS after seven days was observed, secondary analyses suggest a benefit of ketamine infusion ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06064162

Study Details | NCT06064162 | Ketamine for MS Fatigue The purpose of this study is to see whether using ketamine to increase glutamate in the prefrontal cortex can reduce Multiple Sclerosis (MS) related fatigue ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03500289

NCT03500289 | Ketamine for Treatment of MS Fatigue Secondary outcomes of the study include other fatigue questionnaires, depression and sleepiness. The length of study will be around 28 days. Official Title.

4. neurology.org neurology.org/doi/10.1212/WNL.94.15_supplement.1642

Pilot randomized active-placebo controlled double-blind ... Ketamine infusions were safe and well-tolerated. Results suggest a potential role for modulators of glutamatergic pathways in the treatment of MS-related ...

5. sciencedirect.com sciencedirect.com/science/article/am/pii/S1551714423000290

Low-Dose Ketamine Infusion for the Treatment of Multiple ... infusion last and if two infusions of ketamine are better than one in improving MS fatigue. 37. Conclusion: This study can show whether intervening in the ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4769920/

An Assessment of the Anti-Fatigue Effects of Ketamine from a ... One study showed a reduction in perceived fatigue in individuals with multiple sclerosis after a month of amantadine treatment (Shaygannejad et al, 2012; ...

7. northamerica.covetrus.com northamerica.covetrus.com/Content/SDS/071071.pdf

SAFETY DATA SHEET Ingestion: If a person vomits place them in the recovery position so that vomit will not reenter the mouth and throat. Rinse mouth with water.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36738917/

Low-dose ketamine infusion for the treatment of multiple ... This study can show whether intervening in the glutamatergic pathways would improves MS fatigue.

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2018/016812s040lbl.pdf

ketamine - accessdata.fda.gov WHEN KETALAR IS USED ON AN OUTPATIENT BASIS, THE PATIENT SHOULD NOT BE RELEASED. UNTIL RECOVERY FROM ANESTHESIA IS COMPLETE AND THEN SHOULD BE ACCOMPANIED BY. A ...