Anti-CGRP Monoclonal Antibody Response After Switching (AMARAS)

NCT ID: NCT05785988

Last Updated: 2024-02-14

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 600 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-11-01
• Study Completion Date: 2024-11-10

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.

Conditions

Migraine; Head Pain

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Study Groups

Patients with migraine treated with a second anti-CGRP

Patients with migraine treated with a second anti-CGRP monoclonal antibody as per responsible physician criteria in routine clinical practice.

No interventions assigned to this group

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León

OTHER

Sponsor Role: collaborator

Hospital Clínico Universitario de Valladolid

OTHER

Sponsor Role: lead

Responsible Party

David García Azorín

Headache Unit, Department of Neurology, Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David García Azorín, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Research coordinator

Locations

Hospital Clínico Universitario de Valladolid

Valladolid, , Spain

Site Status: RECRUITING

Countries

Spain

Central Contacts

David García-Azorín, MD, MSci

Role: CONTACT

davilink@hotmail.com

+034 665 872228

Yesica Gonzalez Osorio

Role: CONTACT

ygoinvestigacion@outlook.com

+34 634330426

Facility Contacts

David Garcia Azorin, MD, PhD

Role: primary

References

Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z; Lifting The Burden: the Global Campaign against Headache. Migraine remains second among the world's causes of disability, and first among young women: findings from GBD2019. J Headache Pain. 2020 Dec 2;21(1):137. doi: 10.1186/s10194-020-01208-0. No abstract available.

Reference Type: BACKGROUND

PMID: 33267788 (View on PubMed)

Deuschl G, Beghi E, Fazekas F, Varga T, Christoforidi KA, Sipido E, Bassetti CL, Vos T, Feigin VL. The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017. Lancet Public Health. 2020 Oct;5(10):e551-e567. doi: 10.1016/S2468-2667(20)30190-0.

Reference Type: BACKGROUND

PMID: 33007212 (View on PubMed)

GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):459-480. doi: 10.1016/S1474-4422(18)30499-X. Epub 2019 Mar 14.

Reference Type: BACKGROUND

PMID: 30879893 (View on PubMed)

Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018 Feb;17(2):174-182. doi: 10.1016/S1474-4422(17)30435-0. Epub 2017 Dec 8.

Reference Type: BACKGROUND

PMID: 29229375 (View on PubMed)

Ashina M, Terwindt GM, Al-Karagholi MA, de Boer I, Lee MJ, Hay DL, Schulte LH, Hadjikhani N, Sinclair AJ, Ashina H, Schwedt TJ, Goadsby PJ. Migraine: disease characterisation, biomarkers, and precision medicine. Lancet. 2021 Apr 17;397(10283):1496-1504. doi: 10.1016/S0140-6736(20)32162-0. Epub 2021 Mar 25.

Reference Type: BACKGROUND

PMID: 33773610 (View on PubMed)

Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019 Nov 9;394(10210):1765-1774. doi: 10.1016/S0140-6736(19)32504-8. Epub 2019 Oct 23.

Reference Type: BACKGROUND

PMID: 31668411 (View on PubMed)

Drellia K, Kokoti L, Deligianni CI, Papadopoulos D, Mitsikostas DD. Anti-CGRP monoclonal antibodies for migraine prevention: A systematic review and likelihood to help or harm analysis. Cephalalgia. 2021 Jun;41(7):851-864. doi: 10.1177/0333102421989601. Epub 2021 Feb 10.

Reference Type: BACKGROUND

PMID: 33567891 (View on PubMed)

Gantenbein AR, Agosti R, Gobbi C, Flugel D, Schankin CJ, Viceic D, Zecca C, Pohl H. Impact on monthly migraine days of discontinuing anti-CGRP antibodies after one year of treatment - a real-life cohort study. Cephalalgia. 2021 Oct;41(11-12):1181-1186. doi: 10.1177/03331024211014616. Epub 2021 May 17.

Reference Type: BACKGROUND

PMID: 34000847 (View on PubMed)

Vernieri F, Altamura C, Brunelli N, Costa CM, Aurilia C, Egeo G, Fofi L, Favoni V, Pierangeli G, Lovati C, Aguggia M, d'Onofrio F, Doretti A, Di Fiore P, Finocchi C, Rao R, Bono F, Ranieri A, Albanese M, Cevoli S, Barbanti P; GARLIT Study Group. Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study). J Headache Pain. 2021 May 3;22(1):35. doi: 10.1186/s10194-021-01247-1.

Reference Type: BACKGROUND

PMID: 33941080 (View on PubMed)

Overeem LH, Peikert A, Hofacker MD, Kamm K, Ruscheweyh R, Gendolla A, Raffaelli B, Reuter U, Neeb L. Effect of antibody switch in non-responders to a CGRP receptor antibody treatment in migraine: A multi-center retrospective cohort study. Cephalalgia. 2022 Apr;42(4-5):291-301. doi: 10.1177/03331024211048765. Epub 2021 Oct 13.

Reference Type: BACKGROUND

PMID: 34644203 (View on PubMed)

Porta-Etessam J, Gonzalez-Garcia N, Guerrero AL, Garcia-Azorin D. Failure to monoclonal antibodies against CGRP or its receptor does not preclude lack of efficacy to other drugs from the same therapeutic class. Neurologia (Engl Ed). 2020 Nov 8:S0213-4853(20)30312-1. doi: 10.1016/j.nrl.2020.10.009. Online ahead of print. No abstract available. English, Spanish.

Reference Type: BACKGROUND

PMID: 33176918 (View on PubMed)

Ferreira JA. The Benjamini-Hochberg method in the case of discrete test statistics. Int J Biostat. 2007;3(1):Article 11. doi: 10.2202/1557-4679.1065.

Reference Type: BACKGROUND

PMID: 22550651 (View on PubMed)

Other Identifiers

PI-22-2658

Identifier Type: -

Identifier Source: org_study_id