Ketamine for Multiple Sclerosis Fatigue
(INKLING-MS Trial)
Recruiting in Palo Alto (17 mi)
Overseen byBardia Nourbakhsh, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Johns Hopkins University
Must be taking: Fatigue medications
Disqualifiers: Severe depression, Untreated sleep apnea, Coronary artery disease, others
No Placebo Group
Prior Safety Data
Approved in 5 Jurisdictions
Trial Summary
What is the purpose of this trial?The proposed study is a single-center, phase II, randomized, double-blind, parallel-group, active-placebo-controlled trial of intravenous low-dose ketamine in patients with MS fatigue.
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 that the drug ketamine can help with fatigue in multiple sclerosis?
While there is no direct evidence from the provided research about ketamine's effectiveness for multiple sclerosis fatigue, ketamine has been studied for its effects on depression, which is often linked to fatigue in MS. Additionally, other treatments like vitamin B12 have shown some promise in reducing fatigue in conditions similar to MS, suggesting that exploring different treatments for fatigue could be beneficial.
12345Is ketamine safe for human use?
The provided research articles do not contain relevant safety information about ketamine or its various names for human use.
678910How does the drug ketamine differ from other treatments for multiple sclerosis fatigue?
Ketamine is unique because it is primarily known for its rapid-acting antidepressant effects and its use as an anesthetic, which may offer a novel approach to managing fatigue in multiple sclerosis by potentially affecting brain chemistry differently than traditional treatments.
1112131415Eligibility Criteria
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.
+4 more
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
+12 more
Trial Timeline
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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Group I: Midazolam-KetamineExperimental Treatment2 Interventions
Participants in this arm will receive one infusion of midazolam followed four weeks later by an infusion of ketamine.
Group II: Ketamine-MidazolamExperimental Treatment2 Interventions
Participants in this arm will receive one infusion of ketamine followed four weeks later by an infusion of midazolam.
Group III: Ketamine-KetamineExperimental Treatment1 Intervention
Participants in this arm will receive two infusions of ketamine four weeks apart.
Ketamine is already approved in United States, European Union, United States, European Union, Canada for the following indications:
๐บ๐ธ Approved in United States as Ketalar for:
- Anesthesia
- Treatment-resistant depression
๐ช๐บ Approved in European Union as Ketalar for:
- Anesthesia
- Treatment-resistant depression
๐บ๐ธ Approved in United States as Spravato for:
- Treatment-resistant depression
๐ช๐บ Approved in European Union as Spravato for:
- Treatment-resistant depression
๐จ๐ฆ Approved in Canada as Spravato for:
- Treatment-resistant depression
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Johns Hopkins UniversityBaltimore, MD
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Who Is Running the Clinical Trial?
Johns Hopkins UniversityLead Sponsor
United States Department of DefenseCollaborator
References
Depressive state and chronic fatigue in multiple sclerosis and neuromyelitis optica. [2015]Depression and chronic fatigue are frequently present in multiple sclerosis (MS); however, the prevalence rates have not been investigated in neuromyelitis optica (NMO). Thirty-nine consecutive NMO and 75 MS patients were compared using self-rating questionnaires for depressive states, daily activity, and fatigue, as well as serum carnitine levels. A subgroup of patients with low carnitine levels were re-evaluated regarding depression and fatigue after levocarnitine treatment. Depression and fatigue were equally prevalent in MS and NMO and were strongly correlated with one another. Measurement of the serum carnitine levels and the administration of levocarnitine did not appear to be beneficial.
A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine. [2022]To assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo.
Open Trial of Vitamin B12 Nasal Drops in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison of Responders and Non-Responders. [2020]Introduction: A recent study reported a favorable effect of vitamin B12 injections/oral folic acid support in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Recently, vitamin B12 nasal drops were developed as an alternative to the vitamin B12 injections. As no data are available on efficacy of this formulation, we studied vitamin B12 serum levels, the physical activity scale of the RAND-36, the number of steps on an activity meter, and the fatigue and concentration scales of the CIS20r questionnaires, before and after 3 months of treatment in ME/CFS patients. Methods and Results: Fifty-one patients completed all measurements. Forty-four were female. Mean age was 42 years, and mean disease duration was 16 years. Median vitamin B12 levels before treatment were 328 (244-429) pmol/l, and 973 (476-1,476) pmol/l after treatment. Thirty-four patients reported a favorable response to treatment. In the non-responders, only a small but significant increase in vitamin B12 levels was observed. In contrast, in responders, the number of steps, the physical activity scale of the RAND-36, and the vitamin B12 serum levels increased significantly. The CIS20r fatigue scale decreased significantly, and the CIS20r concentration scale was unchanged. Conclusions: Nasal drop vitamin B12 administration resulted in a significant increase in vitamin B12 serum levels and therefore may be effective. This pilot study suggest that the nasal drops may be used as an alternative to injections because two thirds of ME/CFS patients reported a positive effect, accompanied by an increased number of steps, improvement of the RAND-36 physical functioning scale and the CIS20r fatigue scale, and a significant increase in serum vitamin B12 levels.
Fatigue associated with multiple sclerosis: diagnosis, impact and management. [2022]In patients with multiple sclerosis (MS) fatigue is the most common symptom and one of the most disabling features. As many as 40% have described it as the single most disabling symptom--a higher percentage than weakness, spasticity, motor problems, or bowel or bladder problems. The etiology and pathophysiology of MS-related fatigue remain unknown. Studies have failed to demonstrate an association between MS-related fatigue and the level of disability, clinical disease subtype, or gender, although recent data show an association between MS-related fatigue and depression and quality of life. Imaging studies using positron emission tomography suggest that fatigue in MS is related to hypometabolism of specific brain areas, including the frontal and subcortical circuits. The impact of fatigue on patient functioning and quality of life clearly warrants intervention. In addition to nonpharmacologic measures, such as exercise and energy conservation strategies, several pharmacologic agents have been evaluated for their ability to reduce MS-related fatigue, including amantadine, central nervous system stimulants (pemoline), and the novel wake-promoting agent modafinil.
Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. [2018]Patients with myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) may respond most favorably to frequent vitamin B12 injections, in vital combination with oral folic acid. However, there is no established algorithm for individualized optimal dosages, and rate of improvement may differ considerably between responders.
Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of ฮฒ-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for ฮฒ-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for ฮฒ-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.
The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study. [2020]This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults.
K.Vita: a feasibility study of a blend of medium chain triglycerides to manage drug-resistant epilepsy. [2022]This prospective open-label feasibility study aimed to evaluate acceptability, tolerability and compliance with dietary intervention with K.Vita, a medical food containing a unique ratio of decanoic acid to octanoic acid, in individuals with drug-resistant epilepsy. Adults and children aged 3-18 years with drug-resistant epilepsy took K.Vita daily whilst limiting high-refined sugar food and beverages. K.Vita was introduced incrementally with the aim of achieving โค35% energy requirements for children or 240 ml for adults. Primary outcome measures were assessed by study completion, participant diary, acceptability questionnaire and K.Vita intake. Reduction in seizures or paroxysmal events was a secondary outcome. 23/35 (66%) children and 18/26 (69%) adults completed the study; completion rates were higher when K.Vita was introduced more gradually. Gastrointestinal disturbances were the primary reason for discontinuation, but symptoms were similar to those reported from ketogenic diets and incidence decreased over time. At least three-quarters of participants/caregivers reported favourably on sensory attributes of K.Vita, such as taste, texture and appearance, and ease of use. Adults achieved a median intake of 240 ml K.Vita, and children 120 ml (19% daily energy). Three children and one adult had ร-hydroxybutyrate >1 mmol/l. There was 50% (95% CI 39-61%) reduction in mean frequency of seizures/events. Reduction in seizures or paroxysmal events correlated significantly with blood concentrations of medium chain fatty acids (C10 and C8) but not ร-hydroxybutyrate. K.Vita was well accepted and tolerated. Side effects were mild and resolved with dietetic support. Individuals who completed the study complied with K.Vita and additional dietary modifications. Dietary intervention had a beneficial effect on frequency of seizures or paroxysmal events, despite absent or very low levels of ketosis. We suggest that K.Vita may be valuable to those with drug-resistant epilepsy, particularly those who cannot tolerate or do not have access to ketogenic diets, and may allow for more liberal dietary intake compared to ketogenic diets, with mechanisms of action perhaps unrelated to ketosis. Further studies of effectiveness of K.Vita are warranted.
LC-MS/MS method for quantification of raspberry ketone in rat plasma: application to preclinical pharmacokinetic studies. [2023]Background: Raspberry ketone (RK), derived from red raspberry fruit (Rubus idaeus, family Rosaceae), is a reported potent antiobesity agent. This study aims to investigate method development, validation, and in vitro and in vivo pharmacokinetics in rats. Materials & methods: LC-MS/MS was used to conduct method development, validation, stability, and oral PK samples of RK in plasma analyses. Results: RK was highly soluble in Tris buffer and stable in gastrointestinal fluids as well as plasma. Rat liver microsomal stability of RK in phase I and II studies was 84.96 ± 2.39 and 69.98 ± 8.69%, respectively, after 60 min. Intestinal permeability was 4.39 ± 1.37 × 10-5 cm/s. Maximal concentration was 1591.02 ± 64.76 ng/ml, which was achieved after 1 h (time to maximal concentration), and absolute oral bioavailability was 86.28%. Conclusion: Pharmacokinetic data serve as a keystone for preclinical and clinical adjuvant therapy.
Effect of Raspberry Ketone on Normal, Obese and Health-Compromised Obese Mice: A Preliminary Study. [2021]Raspberry ketone (RK)-an aromatic compound found mostly in red raspberries (Rubus idaeus) is widely used as an over the counter product for weight loss. The present study was conducted to determine adverse effects associated with RK in obese and health-compromised obese mice. Two sets of experiments were conducted on normal obese and health-compromised obese mice treated with RK for a duration of 10 days. Obese conditions were induced by feeding mice a high fat diet for 10 weeks, while the health compromised obese mouse model was developed by a single intraperitoneal injection of a nontoxic dose of lipopolysaccharide (LPS) (6 mg/kg) to obese mice. Results showed that RK (165, 330, and 500 mg/kg) under obese as well as health-compromised condition retarded the gain in body weights as compared to the control groups. RK at doses 330 and 500 mg/kg resulted in 67.6 and 50% mortality, respectively in normal obese mice and 70% mortality was observed in health-compromised obese mice treated with RK at 500 mg/kg. At higher doses deaths were observed earlier than those given lower doses of RK. Significant elevations in blood alanine transaminase (ALT) were also observed with RK treatment in obese mice. Blood glucose levels were significantly elevated in all groups of mice treated with RK. This study suggests that higher doses of RK may cause adverse effects in health compromised conditions. Under these conditions, prolonged use of RK, especially in high doses, may pose a health hazard.
Ketone Ester Supplementation Improves Some Aspects of Cognitive Function during a Simulated Soccer Match after Induced Mental Fatigue. [2023]Ketone supplementation has been proposed to enhance cognition during exercise. To assess whether any benefits are due to reduced cognitive fatigue during the latter portions of typical sport game action, we induced cognitive fatigue, provided a ketone monoester supplement (KME) vs. a non-caloric placebo (PLAC), and assessed cognitive performance during a simulated soccer match (SSM). In a double-blind, balanced, crossover design, nine recreationally active men (174.3 ยฑ 4.2 cm, 76.6 ยฑ 7.4 kg, 30 ยฑ 3 y, 14.2 ยฑ 5.5 % body fat, VหO2 max = 55 ยฑ 5 mLยทkg BMโ1ยทminโ1; mean ยฑ SD) completed a 45-min SSM (3 blocks of intermittent, variable intensity exercise) consuming either KME (25 g) or PLAC, after a 40-min mental fatiguing task. Cognitive function (Stroop and Choice Reaction Task [CRT]) and blood metabolites were measured throughout the match. KME reduced concentrations of both blood glucose (block 2: 4.6 vs. 5.2 mM, p = 0.02; block 3: 4.7 vs. 5.3 mM, p = 0.01) and blood lactate (block 1: 4.7 vs. 5.4 mM, p = 0.05; block 2: 4.9 vs. 5.9 mM, p = 0.01) during the SSM vs. PLAC, perhaps indicating a CHO sparing effect. Both treatments resulted in impaired CRT performance during the SSM relative to baseline, but KME displayed a reduced (p
Intracerebroventricular administration of ฮฑ-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats. [2018]Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine as well as their corresponding transaminated branched-chain ฮฑ-ketoacids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. However, the effect of accumulating ฮฑ-ketoacids in MSUD on neurotrophic factors has not been investigated. Thus, the objective of the present study was to evaluate the effects of acute intracerebroventricular administration of ฮฑ-ketoisocaproic acid (KIC) on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the brains of young male rats. Ours results showed that intracerebroventricular administration of KIC decreased BDNF levels in hippocampus, striatum and cerebral cortex, without induce a detectable change in pro-BDNF levels. Moreover, NGF levels in the hippocampus were reduced after intracerebroventricular administration of KIC. In conclusion, these data suggest that the effects of KIC on demyelination and memory processes may be mediated by reduced trophic support of BDNF and NGF. Moreover, lower levels of BDNF and NGF are consistent with the hypothesis that a deficit in this neurotrophic factor may contribute to the structural and functional alterations of brain underlying the psychopathology of MSUD, supporting the hypothesis of a neurodegenerative process in MSUD.
Imaging cerebral 2-ketoisocaproate metabolism with hyperpolarized (13)C magnetic resonance spectroscopic imaging. [2021]The branched chain amino acid transaminase (BCAT) has an important role in nitrogen shuttling and glutamate metabolism in the brain. The purpose of this study was to describe the cerebral distribution and metabolism of hyperpolarized 2-keto[1-(13)C]isocaproate (KIC) in the normal rat using magnetic resonance modalities. Hyperpolarized KIC is metabolized to [1-(13)C]leucine (leucine) by BCAT. The results show that KIC and its metabolic product, leucine, are present at imageable quantities 20 seconds after end of KIC administration throughout the brain. Further, significantly higher metabolism was observed in hippocampal regions compared with the muscle tissue. In conclusion, the cerebral metabolism of hyperpolarized KIC is imaged and hyperpolarized KIC may be a promising substrate for evaluation of cerebral BCAT activity in conjunction with neurodegenerative disease.
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. [2018]Diets containing high quantities of individual branched-chain alpha-keto acids (BCKAs) or a combination of BCKAs as used for treatment of renal disease were fed to rats. When the diet contained a single BCKA, its concentration was high in plasma and the concentration of its corresponding amino acid was high in plasma and brain. Liver BCKA dehydrogenase (BCKD) was 42% active in control rats. Consumption of diets containing 0.38 mol/kg diet of alpha-ketoisocaproate (KIC), alpha-keto-beta-methylvalerate (KMV), or alpha-ketoisovalerate (KIV) resulted in complete activation of liver BCKD. Consumption of the diet containing the combination of BCKAs increased basal BCKD activity of liver twofold. Muscle BCKD was activated after feeding the KIV diet (2-fold), the KIC diet (3-fold), and the KMV diet (15-fold). Total BCKD activity of liver and muscle was unaffected by dietary treatments. Activation of liver and muscle BCKD by dietary BCKA is consistent with their ability to inhibit BCKD kinase in vitro.
Branched chain keto-acids exert biphasic effects on alpha-ketoglutarate-stimulated respiration in intact rat liver mitochondria. [2018]Pathophysiological concentrations of branched chain keto-acids (BCKAs), such as those that occur in maple syrup urine disease, inhibit oxygen consumption in liver homogenates and brain slices and the enzymatic activity of alpha-ketoglutarate- and pyruvate dehydrogenase complexes. Consistent with previous work, studies in isolated rat liver mitochondria indicate that three BCKAs, alpha-ketoisocaproate (KIC), alpha-keto-beta-methylvalerate (KMV) and alpha-ketoisovalerate (KIV), preferentially inhibited State 3 respiration supported by alpha-ketoglutarate relative to succinate or glutamate/malate (KIC, >100-fold; KMV, >10-fold; KIV, >4-fold). KIC was also the most potent inhibitor (K(i,app) 13 +/- 2 muM). Surprisingly, sub-inhibitory concentrations of KIC and KMV can markedly stimulate State 3 respiration of mitochondria utilizing alpha-ketoglutarate and glutamate/malate, but not succinate. The data suggest that physiological concentrations of the BCKAs may modulate mitochondrial respiration.