Anti-CGRP Monoclonal Antibody Response After Switching (AMARAS)

Study Overview
=================
Brief Summary
-----------------
Monoclonal antibodies targeting calcitonin gene-related peptide (mAb-CGRP) have shown efficacy and effectiveness in the treatment of episodic and chronic migraine, however, not all patients respond to them. Preliminary data suggests that some patients who failed to one of them, may respond to a different anti-CGRP monoclonal antibody. Observational analytic study with a retrospective cohort design including patients treated with a second mAb-CGRP due to lack of response to the first one. 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.

Detailed Description
-----------------
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.

Official Title
-----------------
Anti-Calcitonin Gene-Related Peptide (CGRP) Monoclonal Antibody Response After Switching in the Treatment of Migraine

Conditions
-----------------
Migraine, Head Pain

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Age over 18 years old; 2. Confirmed diagnosis of migraine, according to the International Classification of Headche Disorders, 3rd version; 3. Treatment with a mAb-CGRP as per responsible physician criteria in routine clinical practice. Exclusion Criteria: 1. Unavailability of information prior to the treatment use; 2. Other painful disorders that may interfere in the evaluation of the outcomes.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with migraine treated with a second anti-CGRP<br>Patients with migraine treated with a second anti-CGRP monoclonal antibody as per responsible physician criteria in routine clinical practice. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 50% response weeks 8-12 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 50% response | Between weeks 8-12 of treatment, compared to the month prior to the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 50% response weeks 20-24 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 50% response | Between weeks 20-24 of treatment, compared to the month prior to the start of treatment | 
| 50% response weeks 32-36 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 50% response | Between weeks 32-36 of treatment, compared to the month prior to the start of treatment | 
| 50% response weeks 44-48 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 50% response | Between weeks 44-48 of treatment, compared to the month prior to the start of treatment | 
| 30% response weeks 8-12 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 30% response | Between weeks 8-12 of treatment, compared to the month prior to the start of treatment | 
| 30% response weeks 20-24 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 30% response | Between weeks 20-24 of treatment, compared to the month prior to the start of treatment | 
| 30% response weeks 32-36 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 30% response | Between weeks 32-36 of treatment, compared to the month prior to the start of treatment | 
| 30% response weeks 44-48 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 30% response | Between weeks 44-48 of treatment, compared to the month prior to the start of treatment | 
| 75% response weeks 8-12 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 75% response | Between weeks 8-12 of treatment, compared to the month prior to the start of treatment | 
| 75% response weeks 20-24 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 75% response | Between weeks 20-24 of treatment, compared to the month prior to the start of treatment | 
| 75% response weeks 32-36 | Evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 75% response | Between weeks 32-36 of treatment, compared to the month prior to the start of treatment | 
| 75% response weeks 44-48 | To evaluate the proportion of patients with migraine treated with a second anti-CGRP monoclonal antibody that achieve a 75% response | Between weeks 44-48 of treatment, compared to the month prior to the start of treatment | 
| Change in headache days per month weeks 8-12 | To evaluate the change in headache days per month | Between weeks 8-12 compared to the month prior to starting treatment | 
| Change in migraine days per month weeks 8-12 | To evaluate the change in migraine days per month | Between weeks 8-12 compared to the month prior to starting treatment | 
| Change in days of use of symptomatic medication per month weeks 8-12 | To evaluate the change in days of use of symptomatic medication per month | Between weeks 8-12 with respect to the month prior to the start of treatment | 
| Change in days of use of triptan per month weeks 8-12 | To evaluate the change in days of triptan use per month | Between weeks 8-12 with respect to the month prior to the start of treatment | 
| Change in headache days per month weeks 20-24 | To evaluate the change in headache days per month | Between weeks 20-24 compared to the month prior to starting treatment | 
| Change in migraine days per month weeks 20-24 | To evaluate the change in migraine days per month | Between weeks 20-24 compared to the month prior to starting treatment | 
| Change in days of use of symptomatic medication per month weeks 20-24 | To evaluate the change in days of use of symptomatic medication per month | Between weeks 20-24 with respect to the month prior to the start of treatment | 
| Change in days of use of triptan per month weeks 20-24 | To evaluate the change in days of use of triptans per month | Between weeks 20-24 with respect to the month prior to the start of treatment | 
| Change in headache days per month weeks 32-36 | To evaluate the change in headache days per month | Between weeks 32-36 compared to the month prior to starting treatment | 
| Change in migraine days per month weeks 32-36 | To evaluate the change in migraine days per month | Between weeks 32-36 compared to the month prior to starting treatment | 
| Change in days of use of symptomatic medication per month weeks 32-36 | To evaluate the change in days of use of symptomatic medication per month | Between weeks 32-36 with respect to the month prior to the start of treatment | 
| Change in days of use of triptan per month weeks 32-36 | To evaluate the change in days of triptan use per month | Between weeks 32-36 compared to the month prior to the start of treatment | 
| Change in headache days per month weeks 44-48 | To evaluate the change in headache days per month | Between weeks 44-48 compared to the month prior to starting treatment | 
| Change in migraine days per month weeks 44-48 | To evaluate the change in migraine days per month | Between weeks 44-48 compared to the month prior to starting treatment | 
| Change in days of use of symptomatic medication per month weeks 44-48 | To evaluate the change in days of use of symptomatic medication per month | Between weeks 44-48 with respect to the month prior to the start of treatment | 
| Change in days of use of triptan per month weeks 44-48 | To evaluate the change in days of triptan use per month | Between weeks 44-48 compared to the month prior to starting treatment | 
| Frequency and type of adverse events | To assess the frequency and type of treatment-related adverse events | Through study completion, an average of 1 year | 
| Adverse events leading to treatment discontinuation | To evaluate the proportion of patients who discontinue treatment due to an adverse effect | Through study completion, an average of 1 year | 
| Predictors of 50% response | To explore possible predictors of response, using as a response variable the presence of a 50% response | Between weeks 8-12, in relation to the month prior to the start of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Headache disorders, Painful disorders, Calcitonin gene-related peptide (CGRP)