Clinical trial NCT05313503: KETOMIGRAINE: Ketogenic Diet in Drug-resistant Chronic Migraineurs
Official title: KETOMIGRAINE: "Ketogenic Diet in Patients With Drug-resistant Chronic Migraine, "Non-responder" to Treatment With Monoclonal Antibody Targetting CGRP Pathway: a Pilot Study, Open Label"
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Chronic Migraine, Headache
Keywords: Ketogenic Diet
reistant migraine
CGRP
headache
pain
Lead sponsor: IRCCS National Neurological Institute "C. Mondino" Foundation
Sponsor class: OTHER
First posted: 2022-04-06
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: interventional, monocentric, open label
Primary purpose: TREATMENT

Brief summary: Our protocol, named "KETOMIGRAINE", is based on the prescription of a Ketogenic Diet (KD) to twenty subjects with diagnosis of Chronic Migraine (CM), resistant to oral preventive treatments and non-responders to monoclonal antibodies targeting the CGRP pathway. The trial starts with one month of baseline during which are verified inclusion/exclusion criteria. After that, participants will assume KD for three months, a transitional diet (TD) for other three months. Follows a period of three months of free diet (FD). Neurological and dietician visits are scheduled during the course of the trial.

Detailed description: The duration of the trial for individual participants is approximately 10 months, divided as follows: 1 month of baseline + 3 months of KD + 3 months of TD+ 3 months of follow-up.

The protocol includes 6 neurological evaluations (T0-T5); 11 dietary evaluations, some of which can be remote visits, and will be defined below with the acronym "V" (V1-V11).

The planned activities are listed below:

* T0 screening: neurological and general physical examination, extended anamnestic evaluation, evaluation of the inclusion / exclusion criteria. Signature of the informed consent for participation in the research study, assignment of an identification code (increasing number starting from 01); headache diary delivery for prospective baseline data collection.
* T1 baseline (30 days +/- 3 after T0): assessment of compliance in filling in the headache diary and confirming the diagnosis of chronic migraine; execution of electrocardiogram, pregnancy test (if female patient with childbearing potential) and blood tests (renal, hepatic, lipidic, endocrinological profile); first dietary visit (V1 - anthropometric measurements-BMI, interview on eating habits), nutritional instrumental evaluations (calorimetry and body composition).
* T2 Day 1 (Enrollment -7 days +/- 3 after T1): verification of inclusion and exclusion criteria with the results of blood tests; blood sample for collection of PACAP, CGRP and metabolites of kynurenines; compilation of the disability and impact questionnaires - MIDAS and HIT-6; compilation of Migraine Specific Quality of Life Questionnaire (MSQ); dietary assessment (V2): prescription of the KD that the patient will follow for the next 3 months. Subjects overweight will follow a KD with a low-calorie content (low-calorie ketogenic diet); patients with a lower BMI will follow a normo-caloric diet: those represent the two subgroups of the study. Both subtypes of diet (normo and low-calorie) will induce at the same way ketosis; the only difference between the two subgroups is the fact that one will be associated with weight loss and the other not. During the three months of KD, dietician evaluations will be carried out every two weeks, alternating those remotely with those onsite (V3-V7). The dietary visits at the end of the 1st, 2nd and 3rd month of KD will be carried out onsite and the ketone dosage will be carried out using blood sticks.
* T3 (3 months from T2 - end of KD and start of transitional diet - TD): evaluation of the headache diary and compilation of the disability and impact scales - MIDAS and HIT-6); repetition of blood tests in order to check dietary tolerance; blood sample for CGRP, PACAP, metabolites of kynurenines (II point); repetition of instrumental measurements (calorimetry and body composition); dietary visit (V8) for the last check of ketonemia and prescription of TD. This type of diet is not ketogenic and is characterized by the gradual introduction of carbohydrates starting from breakfast, it will last for 3 months. Onsite dietary visits (V9-V10) follow on a monthly basis
* T4 (3 months after T3 - end of TD and start of free diet - FD): neurological and dietary visit (V 11) at the end of 3 months of TD. The patient will start a free diet, during which he/she can eat what is preferred.
* T5 (3 months after T4 - end of study): The last visit is a follow-up, 9 months after T2, its purpose is to evaluate the trend of headache parameters, BMI and biochemical markers studied (III point). During this visit will be filled the following questionnaires: disability and impact questionnaires - MIDAS and HIT-6, Migraine Specific Quality of Life Questionnaire (MSQ), Patient's Global Impression of Change (PGIC).

Eligibility criteria: Inclusion Criteria:

* Age: 18-65 years old
* Chronic migraine, diagnosed according to ICHD-3 criteria.
* Patients with resistant form of migraine defined as: persistence of 8 days of headache per month; therapeutic failure (after therapeutic treatment of adequate dose and duration) or contraindication of 3 classes of drugs with validated evidence of efficacy in the prevention of migraine.
* Non-responder (absence of reduction of MIDAS score of at least 50% after at least 3 months of treatment) to at least one anti-CGRP monoclonal antibody
* Absence of prophylactic therapies for migraine or prophylaxis therapy with a single drug taken at a stable dose for at least two months
* BMI \> 16.5 kg/m2 and \< 35 kg/m2
* Hypothesized compliance in filling the headache diary and following the prescribed diet

Exclusion Criteria:

* Kidney failure
* Liver failure
* Heart failure
* Recent heart attack
* Pancreatitis
* Alcoholism
* Severe osteoporosis
* Other neurological disorders, including other forms of primary headache, except sporadic episodic tension-type headache
* Diabetes Mellitus
* Severe lipid metabolism disorders
* Women of childbearing age without active contraception
* Pregnancy or breastfeeding
* Psychiatric disorders that the clinician thinks may interfere with patient compliance / eating disorders
* Other anomalies considered significant in preliminary examinations (blood tests and EKG)

Primary outcomes:
measure: Change of mean monthly migraine days
timeFrame: During the 3 months of Ketogenic diet period
Secondary outcomes:
measure: Change of number of headache day per month
timeFrame: Through study completion, an average of 10 months
measure: Change of doses of symptomatic drug intake per month
timeFrame: Through study completion, an average of 10 months
measure: Change of number of days of moderate to severe headache
timeFrame: Through study completion, an average of 10 months
measure: Change of days of symptomatic drug intake per month
timeFrame: Through study completion, an average of 10 months
measure: Change of average pain intensity
timeFrame: Through study completion, an average of 10 months
measure: change in disability of headache
timeFrame: Through study completion, an average of 10 months
measure: change in impact of headache
timeFrame: Through study completion, an average of 10 months
measure: change in total pain burden
timeFrame: Through study completion, an average of 10 months
measure: change in quality of life
timeFrame: Through study completion, an average of 10 months
measure: Patient's Global Impression of Change
timeFrame: Through study completion, an average of 10 months
measure: Evaluation of persistence of KD benefits
timeFrame: Through study completion, an average of 10 months
measure: Mechanism of action of KD
timeFrame: During the 3 months of Ketogenic diet period
Other outcomes:
measure: Effect of KD in the subgroups identified by the type of diet (normal-calorie and low-calorie diet)
timeFrame: Through study completion, an average of 10 months
Locations:
city: Pavia
country: Italy
facility: Headache Science Center
Study officials:
affiliation: IRCCS Mondino Foundation, Pavia
name: Cristina Tassorelli, Prof
role: STUDY_DIRECTOR
References:
citation: de Almeida Rabello Oliveira M, da Rocha Ataide T, de Oliveira SL, de Melo Lucena AL, de Lira CE, Soares AA, de Almeida CB, Ximenes-da-Silva A. Effects of short-term and long-term treatment with medium- and long-chain triglycerides ketogenic diet on cortical spreading depression in young rats. Neurosci Lett. 2008 Mar 21;434(1):66-70. doi: 10.1016/j.neulet.2008.01.032. Epub 2008 Jan 19.
citation: Di Lorenzo C, Coppola G, Sirianni G, Di Lorenzo G, Bracaglia M, Di Lenola D, Siracusano A, Rossi P, Pierelli F. Migraine improvement during short lasting ketogenesis: a proof-of-concept study. Eur J Neurol. 2015 Jan;22(1):170-7. doi: 10.1111/ene.12550. Epub 2014 Aug 25.
citation: Bongiovanni D, Benedetto C, Corvisieri S, Del Favero C, Orlandi F, Allais G, Sinigaglia S, Fadda M. Effectiveness of ketogenic diet in treatment of patients with refractory chronic migraine. Neurol Sci. 2021 Sep;42(9):3865-3870. doi: 10.1007/s10072-021-05078-5. Epub 2021 Feb 1.