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Energy for the Brain (MigraKet)

Primary Purpose

Migraine, Episodic Migraine

Status

Completed

Phase

Not Applicable

Locations

Switzerland

Study Type

Interventional

Intervention

Beta-hydroxybutyrate calcium and magnesium salt

placebo powder

About this trial

This is an interventional prevention trial for Migraine focused on measuring Migraine, Prevention, Prophylaxis, Ketone bodies, Beta-hydroxybutyrate, Double-blind, Randomised, Placebo controlled, Mitochondrial functioning, Energy metabolism, Intervention, Dietary Supplement

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University Children's Hospital (UKBB)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Verum

Placebo

Arm Description

Receives the investigational medicine product (IMP; Beta-hydroxybutyrate calcium and magnesium salt).

Receives a matched placebo powder to the IMP.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

Migraine Disability Assessment (MIDAS)

Score in Migraine Disability Assessment (MIDAS; end of baseline versus end of intervention).

Headache Impact Test (HIT)

Score in Headache Impact Test (HIT-6; end of baseline versus end of intervention).

Full Information

NCT ID

NCT03132233

First Posted

April 11, 2017

Last Updated

March 26, 2020

Sponsor

University Hospital, Basel, Switzerland

1. Study Identification

Unique Protocol Identification Number

NCT03132233

Brief Title

Energy for the Brain

Acronym

MigraKet

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

2. Study Status

Record Verification Date

March 2020

Overall Recruitment Status

Completed

Study Start Date

May 8, 2017 (Actual)

Primary Completion Date

January 16, 2020 (Actual)

Study Completion Date

January 31, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Basel, Switzerland

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Migraine, Episodic Migraine

Keywords

Migraine, Prevention, Prophylaxis, Ketone bodies, Beta-hydroxybutyrate, Double-blind, Randomised, Placebo controlled, Mitochondrial functioning, Energy metabolism, Intervention, Dietary Supplement

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Masking Description

Double-blind

Allocation

Randomized

Enrollment

42 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Verum

Arm Type

Active Comparator

Arm Description

Receives the investigational medicine product (IMP; Beta-hydroxybutyrate calcium and magnesium salt).

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Receives a matched placebo powder to the IMP.

Intervention Type

Dietary Supplement

Intervention Name(s)

Beta-hydroxybutyrate calcium and magnesium salt

Intervention Description

Exogenous ketone body in mineral salt form.

Intervention Type

Other

Intervention Name(s)

placebo powder

Intervention Description

matched placebo powder to the IMP.

Primary Outcome Measure Information:

Title

Number of migraine days

Description

Time Frame

Last 4 weeks of intervention compared to baseline 4 weeks.

Secondary Outcome Measure Information:

Title

Number of headache days

Description

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.

Time Frame

Last 4 weeks of intervention compared to baseline 4 weeks.

Title

Acute migraine medication

Description

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.

Time Frame

Last 4 weeks of intervention compared to baseline 4 weeks.

Title

Migraine intensity

Description

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.

Time Frame

Last 4 weeks of intervention compared to baseline 4 weeks.

Title

Migraine Disability Assessment (MIDAS)

Description

Score in Migraine Disability Assessment (MIDAS; end of baseline versus end of intervention).

Time Frame

Last 4 weeks of intervention compared to baseline 4 weeks.

Title

Headache Impact Test (HIT)

Description

Score in Headache Impact Test (HIT-6; end of baseline versus end of intervention).

Time Frame

Last 4 weeks of intervention compared to baseline 4 weeks.

Other Pre-specified Outcome Measures:

Title

Exploratory biomarker assessments

Description

Serum concentration changes from baseline of oxidative and nitrosative stress markers (malondialdehyde (MDA), carbonylated proteins, nitrate, nitrite, nitrotyrosine), levels in cytokines, levels in lactate, glucose, insulin and markers of thyroid function. Genetic profile (SNPs) of all patients involved in the study and correlation of the genetic markers with 1-5 using a linear regression model. Gene expression changes before and after diet using expression microarrays with a special focus on mitochondrial related genes (Citrate synthesis, Cytochrom C oxidase subunit 1, Succinate dehydrogenase subunit A). Correlation of gene expression changes with the genetic profile of the patients (eQTL analysis in combination with 1-5 as possible covariates.

Time Frame

Last 4 weeks of intervention compared to baseline 4 weeks.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dirk Fischer, MD

Organizational Affiliation

Professor and head doctor

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Children's Hospital (UKBB)

City

Basel

State/Province

Basel-Stadt

ZIP/Postal Code

4031

Country

Switzerland

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

34541914

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.

Results Reference

derived

PubMed Identifier

33633187

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.

Results Reference

derived

PubMed Identifier

30654835

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.

Results Reference

derived

Links:

URL

https://www.youtube.com/watch?v=2YzNjIXk_eY

Description

Study Information Video

Learn more about this trial

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