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

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.

Keywords: 3-Hydroxybutyrate; Beta-hydroxybutyrate; Clinical trial; Crossover; Exogenous ketone bodies; Ketosis; Migraine; Migraine prevention; Placebo-controlled; Randomised controlled trial.

Fig. 1

Flowchart of study design, including timing of measurements and procedures. V = visit

Fig. 2

Detailed study schedule. ¹Blood pressure, heart rate, weight and height. ²Pen and paper headache dairy. ³Migraine Disability Questionnaire (Migraine Disability Assessment (MIDAS)) and Headache Impact Test (HIT), German versions, standard questionnaires for assessing the extent of migraine-related disability. ⁴Blood beta-hydroxybutyrate and glucose levels, measured with a portable ketone meter (precision xtra by Abbot). ⁵Routine laboratory (renal and liver function tests, electrolytes, full blood count, C-reactive protein, serum cholesterol, triglycerides, serum proteins, albumin, glucose, Hba1c, insulin, cortisol, lactate, TSH, FT4 and FT4). ⁶Blood draw (1 × EDTA, 1 × PAXgene) at each time point for genetic profiling and gene expression analysis using microarrays. ⁷Blood draw at each time point for oxidative and nitrosative stress markers (malondialdehyde (MDA), carbonylated proteins, nitrite, nitrotyrosine) and serum cytokine measurements (including, but not limited to, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, MCP-1, TNF-α, TNF-β, TGF-β1). V = visit

Fig. 3

Sensitivity of sample size with regard to expected difference in reduction in number of migraine days per 4 weeks of IMP compared to placebo. Example given, based on an effect size of 2 and a statistical power of 90%. The curves are smoothed and are for illustrative purposes only