Background:
Migraine is the first cause of disability in the most active ages of life. Unlike other
diseases, there are effective treatments that can lessen the burden of the disease.
Currently, there are different treatments that act at different levels, many of them being
non-migraine-specific and associated to poor tolerability. The monoclonal antibodies
targeting calcitonin gene-related peptide (mAb-CGRP), or its receptor have shown efficacy in
the treatment of episodic and chronic migraine, with a significantly lower rate of side
effects. In Spain, the National Health System subsidizes them in patients with high-frequency
episodic migraine or chronic migraine with prior failure to at least three preventive drugs.
There is preliminary evidence that suggest that approximately one-third of patients who have
not responded to one mAb-CGRP may respond to a different mAb-CGRP, not necessarily with a
different mechanism of action. The aim of this study is to provide Class II evidence about
the effectiveness and tolerability of the mAb-CGRP switching in patients with migraine,
treated in a real-world setting.
Study design:
Observational analytic study with a retrospective cohort design.
Endpoints:
The study endpoints will be based on the International Headache Society guidelines for
controlled trials of chronic migraine, and will include effectiveness endpoints and safety
endpoints.
Sample Size:
According to real-world data in our setting, the effectiveness rate of monoclonal antibodies
in clinical practice conditions ranges between 40-60%. We aim to collect at least 300
patients treated with a secondary mAb-CGRP.
Methodology:
Observational analytic study with a retrospective cohort design. Spanish Hospitals with
Headache Units or monographic headache consultations participate in the study. In all
participant centers, patients carried out a headache diary that assesses the frequency of
headache, migraine and acute treatment use.
Study intervention:
A structured questionnaire will be administered to patients, including demographic variables,
such as sex, age at migraine onset, age at first mAb-CGRP use, age at second mAb-CGRP use.
The following clinical variables were collected type of migraine (episodic / chronic),
duration (in months) of high-frequency episodic migraine or chronic migraine; presence and
type of aura; number and type of prior prophylactic drugs; mAb-CGRP used in first and second
place; reason for discontinuation (lack of efficacy, lack of tolerability); frequency of
headache, migraine, acute medication and triptan use per month; presence and type of adverse
effects.
All the information was introduced in a standardize data collection form that will be hosted
in RedCap.
Recruitment and sampling:
All consecutive patients treated with mAb-CGRP in the participating sites were screened for
eligibility, including the administrative databases of all patients treated during the study
period.
Data sources:
Paper or electronic health records was used, and structured headache diaries were provided to
patients.
Ethics:
The study has been approved by the Ethics Review Board of East Valladolid (PI-22-2658). The
study is conducted in accordance with the principles of the Declaration of Helsinki
Statistical Analysis:
First, a descriptive analysis will be carried out. The proportion of patients treated with a
monoclonal antibody who receive treatment with a second will be described. A sub-group
analysis will be done, depending on whether the reason for the mAb-CGRP switch an
effectiveness failure or a tolerability failure was. The 50%, 30%, and 75% response rates
will be calculated in the pre-specified study periods, as well as the frequency and type of
adverse effects. To evaluate the reduction in days of headache per month, days of migraine,
days of use of analgesics, and days of triptans, in the study periods, in relation to the
baseline period, the Student's T-test for paired samples will be used. or the Mann-Whitney U,
depending on the type of distribution of the sample. Normality of the sample will be assessed
with the Kolmogorov-Smirnov test. To evaluate the predictors of response, a logistic
regression analysis will be performed in which the independent variable will be the presence
of a 50% response between weeks 8-12, and the rest of the study variables will be evaluated
first by univariate regression, and after that, analysis multivariate in those with a P value
less than 0.1.
Statistical analysis will be performed both by intention to treat (including all patients
receiving treatment with a second monoclonal) and per-protocol analysis (those in which the
information is complete). In case of missing data, for variables related to treatment, a
conservative imputation will be performed using baseline-carried forward, for variables from
8-12 weeks and last-observation carried forward for variables from weeks 8-12.
A stratified analysis will be performed according to whether the reason for discontinuation
of the first monoclonal antibody was the failure of effectiveness or lack of tolerance. A
stratified analysis will also be performed in treatments between drugs directed against CGRP
and their receptor A statistical significance level of 5% will be considered. The correction
will be made for multiple comparisons by False Discovery Rate, using the Benjamini-Hochberg
method.