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
Authors: Sven Cichon
Peter Sandor
Simone Schmidt
Dirk Fischer
Niveditha Putananickal
Anna-Lena Orsini
Elena Gross
Deborah R Vogt
Journal: Trials (2019)
Discipline: CLINICAL MEDICINE
Keywords: 3-Hydroxybutyrate; Beta-hydroxybutyrate; Clinical trial; Crossover; Exogenous ketone bodies
Affiliations: Division of Neuropaediatrics, University of Basel Children's Hospital, University of Basel, Spitalstrasse 33, Postfach, 4056, Basel, Switzerland., Division of Neuropaediatrics, University of Basel Children's Hospital, University of Basel, Spitalstrasse 33, Postfach, 4056, Basel, Switzerland. ., Department of Clinical Research, Clinical Trial Unit, University of Basel Hospital, University of Basel, Basel, Switzerland., Department of Medical Genetics, University of Basel Hospital, University of Basel, Basel, Switzerland., RehaClinic, Bad Zurzach, Switzerland.

Abstract:  Background: Currently available prophylactic migraine treatment options are limited and are associated with many, often intolerable, side-effects. Various lines of research suggest that abnormalities in energy metabolism are likely to be part of migraine pathophysiology. Previously, a ketogenic diet (KD) has been reported to lead to a drastic reduction in migraine frequency. An alternative method to a strict KD is inducing a mild nutritional ketosis (0.4-2 mmol/l) with exogenous ketogenic substances. The aim of this randomised, placebo-controlled, double-blind, crossover, single-centre trial is to demonstrate safety and superiority of beta-hydroxybutyrate (βHB) in mineral salt form over placebo in migraine prevention. Methods/design: Forty-five episodic migraineurs (5-14 migraine days/months), with or without aura, aged between 18 and 65 years, will be recruited at headache clinics in Switzerland, Germany and Austria and via Internet announcements. After a 4-week baseline period, patients will be randomly allocated to one of the two trial arms and receive either the βHB mineral salt or placebo for 12 weeks. This will be followed by a 4-week wash-out period, a subsequent second baseline period and, finally, another 12-week intervention with the alternative treatment. Co-medication with triptans (10 days per months) or analgesics (14 days per months) is permitted. The primary outcome is the mean change from baseline in the number of migraine days (meeting International Classification of Headache Disorders version 3 criteria) during the last 4 weeks of intervention compared to placebo. Secondary endpoints include mean changes in headache days of any severity, acute migraine medication use, migraine intensity and migraine and headache-related disability. Exploratory outcomes are (in addition to routine laboratory analysis) genetic profiling and expression analysis, oxidative and nitrosative stress, as well as serum cytokine analysis, and blood βHB and glucose analysis (pharmacokinetics). Discussion: A crossover design was chosen as it greatly improves statistical power and participation rates, without increasing costs. To our knowledge this is the first RCT using βHB salts worldwide. If proven effective and safe, βHB might not only offer a new prophylactic treatment option for migraine patients, but might additionally pave the way for clinical trials assessing its use in related diseases. Trial registration: ClinicalTrials.gov, NCT03132233 . Registered on 27 April 2017. 

Retracted: No

PubPeer comments:
 Both this article and related preprint manuscript https: www.researchsquare.com article rs-11532 v1 ( Mitochondrial function and oxidative stress markers in higher-frequency episodic migraine ) , posted 15 Jan, 2020 appear to have **undisclosed** potential conflicts of interest. ** Competing interests: The authors declare that they have no competing interests. ** ** Conflicts of Interest Competing interests: The authors declare no conflict of interest. ** Elena Gross is CEO, CSO and Founder of KetoSwiss AG, developer of the MigraKet product used in this study. Elena Gross and Dirk Fischer are inventors of the patent WO 2018 115158 Al held by the UKBB and University of Basel ![file] ,