Clinical trial NCT03132233: Energy for the Brain
Official title: Safety, Tolerability and Efficacy of Exogenous Ketone Bodies for Preventive Treatment of Migraine: A Randomised, Placebo-controlled, Double-blind Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Migraine
Episodic Migraine
Keywords: Migraine
Prevention
Prophylaxis
Ketone bodies
Beta-hydroxybutyrate
Double-blind
Randomised
Placebo controlled
Mitochondrial functioning
Energy metabolism
Intervention
Dietary Supplement
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2017-04-27
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

Brief summary: Approx. one billion people are suffering from migraine worldwide and yet, therapeutic options are still very limited. Research suggests that changes in energy metabolism could be part of migraine pathophysiology. Ketone bodies (KB) are endogenous alternative energy substrates. Our clinical trial assesses the efficacy and safety of KB supplements in 60-90 adult migraineurs (5-14 migraine days / months) at the University Hospital Basel. The total duration of the trial is approx. 6 months, consisting of 4 weeks baseline, 12 weeks intervention with KB powder or matched placebo and 8 weeks follow-up. The primary endpoint is the change in migraine days at the end of intervention compared to baseline. Additionally, changes in gene expression, fat-, and glucose metabolism, inflammatory markers and quality of life will be examined.

Detailed description: Migraine is a complex, common and debilitating neurological disorder. It affects approximately 17% of women and 8% of men in Europe and yet, its primary pathogenic mechanisms are still largely unknown. Various lines of research suggest that brain energy metabolism abnormalities are likely to be part of migraine pathophysiology. Specifically, there is some evidence for reversible abnormalities in mitochondrial functioning in migraine. For example, treatment with riboflavin and coenzyme Q10 has been shown to have migraine protective effects, probably via a positive effect on energy metabolism. Lactic and pyruvic acid, markers of mitochondrial (mt) disease, have been found to be increased in migraineurs; 31P-magnetic resonance spectroscopy (MRS) patterns seen in migraine are consistent with what is seen in mitochondrial disorders; cytochrome oxidase (COX)-negative fibres typical of mt diseases have also been seen in some patients with migraine. A break-down of the resting membrane potential due to lack of adenosine triphosphate (ATP) could explain cortical abnormalities in excitability, which have been reported in migraine. Despite causing a huge amount of suffering and a substantial amount of costs for society current migraine treatment options are limited. None of the prophylactic agents licensed to date are migraine-specific and most are associated with significant- sometimes intolerable- side-effects. Furthermore, their migraine-preventive properties are moderate at most. Hence, there is a need for developing alternative anti-migraine therapies. Several case studies and a first proof of concept study have demonstrated a reduction in migraine attack frequency, severity and use of acute anti-migraine medication during ketosis - with effects sizes ranging from total absence of attacks to a reduction to 1/5th of the run-in period. In addition, preliminary evidence suggests that the migraine-protective effect may outlast the duration of ketosis. This might be a result of longer-lasting gene-expression changes. However, a strict ketogenic diet (KD) is unlikely to provide a feasible long-term solution for episodic migraine patients, because it is difficult to implement in an ambulatory setting and patient adherence may be limited. An alternative means to induce a state of mild to medium nutritional ketosis (0.4-1 mmol/l), irrespective of blood glucose levels, is the dietary supplementation with ketogenic substances, such as beta-hydroxybutyrate (bHB) salts (and unpublished observations). This approach could be easily implemented with intake of a ketogenic powder dissolved in water (consisting of a calcium-magnesium-bHB salt) three times a day (with or after a meal). This nutritional intervention seems much more feasible than a KD in larger patient populations and avoids the complications of a very restricted high-fat diet.

Eligibility criteria: Inclusion Criteria:

* Has been previously diagnosed with migraine (with or without aura) in accordance with the ICHD-3 Beta Classification criteria.
* Experience between 5 and 14 migraine days per month (over the last 4 months).
* Has age of onset of migraine less than 50 years old.
* Agrees to refrain from initiating or changing the type, dosage or frequency of any prophylactic medications (exclusive of medications taken for acute relief of migraine symptoms) as well as dietary supplements (such as Q10, riboflavin etc) against migraine and for indications other than migraine that in the opinion of the clinician may interfere with the study objectives (e.g. antidepressant, anticonvulsants, beta blockers, etc.) for the duration of the study.
* Has not changed type, dosage or frequency of any prophylactic medications (exclusive of medications taken for acute relief of migraine symptoms) as well as dietary supplements (such as Q10, riboflavin etc) against migraine and for indications other than migraine that in the opinion of the clinician may interfere with the study objectives (e.g. antidepressant, anticonvulsants, beta blockers, etc.) for at least 3 months prior to study onset.
* Refrains to make any drastic changes to the diet for the duration of the study, including periods of fasting.
* Agrees to use the study intervention as intended, follow all of the requirements of the study including follow-up visit requirements, record required study data in the subject dairy and other self-assessment questionnaires and is okay with drawing blood samples.
* Is able to provide written Informed Consent.

Exclusion Criteria:

* Has a concomitant medical condition that will require oral or injectable steroids during the study.
* Has a history of any significant neurological, psychiatric or other medical condition that in the opinion of the investigator may confound the study assessments, liver and kidney diseases in particular.
* Is currently treated for a thyroid disease or has a history thereof.
* Has a cardiovascular disease (hypertension in particular) or a history thereof.
* Has a known history of suspected secondary headache.
* Currently takes simple analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) greater then 14 days per month or triptans greater than 10 days per month for headaches or other body pain.
* Currently takes prescription opioids.
* Has previous diagnosis of medication overuse headache (MoH) , which has reverted to episodic migraine within the last 6 months.
* Meets the ICHD-3 Beta Classification criteria for chronic migraine (\> 15 headache days per month).
* Has failed an adequate trial (two months or greater) of at least 3 classes of a drug therapy for the prophylaxis of migraine .
* Has had surgery for migraine prevention.
* Has received Botox injections within the last 6 months.
* Is pregnant or thinking of becoming pregnant during the study period, or of childbearing years and is unwilling to use and accepted form of birth control.
* Is participating in any other therapeutic clinical investigation or has participated in a clinical trial in the preceding 30 days.
* Belongs to a vulnerable population or has any condition such that his or her ability to provide informed consent, comply with the follow-up requirements, or provide self- assessments is compromised (e.g. homeless, developmentally disabled and prisoner).
* Is thinking to start, change or stop a hormone-based contraception.

Primary outcomes:
measure: Number of migraine days
timeFrame: Last 4 weeks of intervention compared to baseline 4 weeks.
Secondary outcomes:
measure: Number of headache days
timeFrame: Last 4 weeks of intervention compared to baseline 4 weeks.
measure: Acute migraine medication
timeFrame: Last 4 weeks of intervention compared to baseline 4 weeks.
measure: Migraine intensity
timeFrame: Last 4 weeks of intervention compared to baseline 4 weeks.
measure: Migraine Disability Assessment (MIDAS)
timeFrame: Last 4 weeks of intervention compared to baseline 4 weeks.
measure: Headache Impact Test (HIT)
timeFrame: Last 4 weeks of intervention compared to baseline 4 weeks.
Other outcomes:
measure: Exploratory biomarker assessments
timeFrame: Last 4 weeks of intervention compared to baseline 4 weeks.
Locations:
city: Basel
country: Switzerland
facility: University Children's Hospital (UKBB)
state: Basel-Stadt
Study officials:
affiliation: Professor and head doctor
name: Dirk Fischer, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Putananickal N, Gross EC, Orsini AL, Schmidt S, Hafner P, Gocheva V, Nagy S, Henzi BC, Rubino D, Vogt DR, Cichon S, Sandor P, Fischer D. Efficacy and safety of exogenous beta-hydroxybutyrate for preventive treatment in episodic migraine: A single-centred, randomised, placebo-controlled, double-blind crossover trial. Cephalalgia. 2022 Apr;42(4-5):302-311. doi: 10.1177/03331024211043792. Epub 2021 Sep 20.
citation: Gross EC, Putananickal N, Orsini AL, Vogt DR, Sandor PS, Schoenen J, Fischer D. Mitochondrial function and oxidative stress markers in higher-frequency episodic migraine. Sci Rep. 2021 Feb 25;11(1):4543. doi: 10.1038/s41598-021-84102-2.
citation: Gross E, Putananickal N, Orsini AL, Schmidt S, Vogt DR, Cichon S, Sandor P, Fischer D. Efficacy and safety of exogenous ketone bodies for preventive treatment of migraine: A study protocol for a single-centred, randomised, placebo-controlled, double-blind crossover trial. Trials. 2019 Jan 17;20(1):61. doi: 10.1186/s13063-018-3120-7.