Energy for the Brain

Study Overview
=================
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.

Official Title
-----------------
Safety, Tolerability and Efficacy of Exogenous Ketone Bodies for Preventive Treatment of Migraine: A Randomised, Placebo-controlled, Double-blind Study

Conditions
-----------------
Migraine, Episodic Migraine

Intervention / Treatment
-----------------
* Dietary Supplement: Beta-hydroxybutyrate calcium and magnesium salt
* Other: placebo powder


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Verum<br>Receives the investigational medicine product (IMP; Beta-hydroxybutyrate calcium and magnesium salt). | Dietary Supplement: Beta-hydroxybutyrate calcium and magnesium salt<br>* Exogenous ketone body in mineral salt form.<br>|
| Placebo Comparator: Placebo<br>Receives a matched placebo powder to the IMP. | Other: placebo powder<br>* matched placebo powder to the IMP.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of migraine days | Mean change from baseline in number of migraine days (meeting International Classification of Headache Disorders (ICHD)-3 criteria) during the last month of intervention in treatment group compared to placebo. | Last 4 weeks of intervention compared to baseline 4 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of headache days | Mean change from baseline in number of headache days of any severity (meeting ICHD-3 criteria) during the last month of intervention in treatment group compared to placebo. | Last 4 weeks of intervention compared to baseline 4 weeks. | 
| Acute migraine medication | Mean change from baseline in consumption of acute migraine medication (analgesics or triptans) measured in days with acute headache medication use during the last month of the intervention. | Last 4 weeks of intervention compared to baseline 4 weeks. | 
| Migraine intensity | Mean change from baseline in migraine intensity (measured with a numerical rating scale from 1-10) during the last of month of the intervention period. | Last 4 weeks of intervention compared to baseline 4 weeks. | 
| Migraine Disability Assessment (MIDAS) | Score in Migraine Disability Assessment (MIDAS; end of baseline versus end of intervention). | Last 4 weeks of intervention compared to baseline 4 weeks. | 
| Headache Impact Test (HIT) | Score in Headache Impact Test (HIT-6; end of baseline versus end of intervention). | Last 4 weeks of intervention compared to baseline 4 weeks. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Migraine, Prevention, Prophylaxis, Ketone bodies, Beta-hydroxybutyrate, Double-blind, Randomised, Placebo controlled, Mitochondrial functioning, Energy metabolism, Intervention, Dietary Supplement