Comparison of Early-onset Efficacy of Anti-calcitonin Gene-related Peptide Monoclonal Antibodies for Patients with Migraine in Real-world Clinical Practice: Study Protocol for an Exploratory Clinical Trial

Abstract

Three anti-calcitonin gene-related peptide monoclonal antibodies (CGRP-mAbs) are available in Japan: galcanezumab, fremanezumab, and erenumab. Early-onset efficacy has been demonstrated for each CGRP-mAb in comparison with placebo, but differences among the drugs are unclear. Only galcanezumab requires 2 doses at the initial injection. This study is a multicenter, open-label, randomized, two-group comparison trial, consisting of the random selection of a CGRP-mAb and 6 consecutive injections, and then discontinuation of the CGRP-mAb after 6 injections. The primary outcome is a comparison of early-onset efficacy between galcanezumab and both fremanezumab and erenumab after the initial injection. The secondary outcomes are comparisons between galcanezumab and both fremanezumab and erenumab, and between fremanezumab and erenumab as follows: weekly number of headache days, migraine days, and acute medication use are compared to baseline during one month after initial injection; time of subjectively perceiving onset of effect after initial injection; monthly changes in headache status from baseline to after third (3rd) injections; effective rates after initial and 3rd injections; improvement rates of depression scores between baseline and after 3rd injections; changes in number of absenteeism and presenteeism days in each month from baseline to after 3rd injections; proportion of ineffective cases after 3rd injections; recurrence rates and time to recurrence after CGRP-mAb discontinuation; effective rates of CGRP-mAb re-injections; detection of clinical factors associated with effectiveness after the initial and 3rd injections. The aim of this study is to investigate differences in early-onset efficacy among the CGRP-mAbs, and when and to what extent headache symptoms recur after discontinuation.

Introduction {6, 7}

Migraine is a disease that affects approximately 8.4 million people in Japan and significantly reduces quality of life. The economic loss caused by migraine attacks in Japanese society amounts to 2 trillion yen per year.¹⁾ The current situation with migraine treatment in Japan is that patients with long-term headaches rarely visit hospitals, and appropriate drug treatments such as triptans and oral prophylactic medications are not sufficiently implemented. A recent comprehensive population-based survey showed that approximately 50% of migraine patients do not seek medical attention despite having headache symptoms, 46% of migraines are accurately diagnosed, and appropriate medication is prescribed in only 15% of cases.²⁾ Furthermore, it has been reported that one in 5 migraine patients of childbearing age in Japan abandon pregnancy due to migraines.³⁾

Calcitonin gene-related peptide (CGRP) is a neuropeptide present in the trigeminal ganglion and trigeminal nerve terminals on the dura mater. Overexpression of CGRP induces migraine through vasodilatory effects and neurogenic inflammation.⁴⁾ Anti-CGPR monoclonal antibody (CGRP-mAb) treatment has been developed to suppress migraines by inhibiting the activity of CGRP and has been available in Japan since 2021.^5,6) CGRP-mAbs have dramatically changed preventive treatment for migraine patients who do not respond to conventional oral prophylactic medicines such as anticonvulsants, antidepressants, calcium channel blockers, and beta-blockers. Three CGRP-mAbs, galcanezumab, fremanezumab, and erenumab, are available in Japan. Each CGRP-mAb has been shown to be effective each month and reduce migraine attacks by approximately 4 times per month after injection.^7-11)

Migraine patients expect medications to be effective, have early effects, and have few side effects.¹²⁾ For migraine patients seeking rapid headache relief, information on which CGRP-mAb provides the earliest onset efficacy is important. Early-onset efficacy of each CGRP-mAb has been demonstrated in comparison with placebo,^13-18) but differences among the drugs are unclear. Of the CGRP-mAbs, only galcanezumab requires 2 doses at the first (1st) injection, whereas fremanezumab and erenumab require one dose. Even in clinical practice with drug selection bias, galcanezumab has been shown to have earlier onset efficacy than fremanezumab and erenumab. Therefore, we hypothesized that galcanezumab has earlier onset efficacy after the 1st injection than fremanezumab and erenumab. The aim of this exploratory study is to investigate this hypothesis in real-world clinical practice. In addition, when and to what extent headache symptoms recur after discontinuation of CGRP-mAb treatment, and whether symptoms improve if the drug is restarted have not been fully elucidated; these clinical questions will also be investigated.

Materials and Methods

Study design {8}

This is a prospective, multi-center, open-label, randomized, two-group comparison, exploratory trial.

Patient population {9, 10, 15}

Patients are selected based on the inclusion and exclusion criteria described below. The main criterion for enrollment is migraine patients who meet the indications of CGRP-mAb treatment. Patients will be recruited from new patients from standard clinical practice at Nagoya University Hospital or Nagoya Garden Clinic.

Inclusion criteria

・High frequent episodic migraine (HFEM), chronic migraine (CM), or medication-overuse headache (MOH), all with ≥ 8 monthly headache days (MHDs)

・Magnetic resonance imaging/angiography reveals no intracranial diseases

・Age ≥18 years

・Meets the criteria for the use of CGRP-mAb treatment

・Written, informed consent

Exclusion criteria

・Intracranial disease

・Serious concomitant diseases (liver disease, kidney disease, heart disease, lung disease, blood disease, brain disease, etc.)

・Pregnant or potentially pregnant

・Breastfeeding

・Considered inappropriate by the head of research or researcher to allocate patients

Who will take informed consent? {26a}

Potential participants will be identified from patients who visit Nagoya University Hospital or Nagoya Garden Clinic. After clinical research physicians assess potential participants for the inclusion and exclusion criteria, they will be given the study information in detail of the purpose, procedure, and potential risks. Written and verbal informed consent will be obtained. The right of a participant to refuse to participate in this trial without giving reasons for the decision will be respected.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

The consent form received from the patients includes their agreement to use the data in related future studies. Of course, patients can only agree to the current study and not accept future studies. This study does not involve collecting biological specimens.

Study procedures {11a}

This study is conducted in the following 6 steps and consists of 2 major parts (Fig. 1): the first part consists of 6 months of consecutive CGRP-mAb injections (steps 1-3), and the second part consists of discontinuing CGRP-mAb after 6 injections (steps 4-6).

Fig. 1.

Schematic diagram of the study procedure.

This study consists of 2 major parts: 6 months of consecutive CGRP-mAb injections (first part) and discontinuing CGRP-mAb after six injections (second part). AMU: acute medication use, CGRP-mAb: anti-calcitonin gene-related peptide monoclonal antibody, HIT-6: headache impact test-6, MHD: monthly headache day, MMD: monthly migraine days, MSQ: migraine-specific quality of life questionnaire, QIDS-J: quick inventory of depressive symptomatology, 1st: first, 3rd: third, 6th: sixth, w: week

1) A CGRP-mAb is randomly selected for patients who meet the eligibility criteria for its use. During the study, oral prophylactic medicines and acute medications used for headaches continued to be used as before enrollment.

2) For 4 weeks after the 1st CGRP-mAb injection, the number of headache days, migraine days, and acute medication use (AMU) are calculated for each week. Four weeks after the 1st CGRP-mAb injection, a simple questionnaire is administered to assess the time that patients subjectively felt the effects of the CGRP-mAb.

3) The randomly selected CGRP-mAb is injected 3 consecutive times at 4-week intervals. Clinical symptoms are assessed using a headache diary and several questionnaires at baseline and 4 weeks after each CGRP-mAb injection. Baseline is defined as 4 weeks before the 1st CGRP-mAb injection. Efficacy of the CGRP-mAbs is assessed based on the percentage reduction in migraine headache days (MHD) compared with baseline as follows: a reduction in MHD of ≥50% is “effective,” a reduction of <25% is “ineffective,” and a reduction of ≥25% but <50% is “alleviation.” After the 3rd CGRP-mAb injection, if the efficacy is judged to be effective or alleviated, the same CGRP-mAb is continued until the sixth injection. However, if the efficacy is judged to be ineffective at that time point, CGRP-mAb injection is stopped, and participation in the study is terminated.

4) All patients who receive 6 consecutive CGRP-mAb injections will have the injections temporarily stopped after the sixth injection (discontinuation). During discontinuation, patients will continue to take the same oral prophylactic medicines and acute headache medications as before discontinuation.

5) During the discontinuation period, clinical symptoms are also assessed every 4 weeks using a headache diary and several questionnaires. After discontinuation, patients are followed for 12 weeks, at which point the study is terminated.

6) Recurrence is defined as MHD ≥8 after discontinuation. If recurrence occurs during the discontinuation period, injection of the same CGRP-mAb is resumed (re-injection). In patients undergoing re-injection, clinical symptoms are assessed using a headache diary and several questionnaires 4 weeks after re-injection, at which point the study is terminated.

7) The following is an exploratory analysis. The various collected clinical data are comprehensively analyzed using artificial intelligence (AI) techniques.

Criteria for discontinuing or modifying allocated interventions {11b}

Any patients requesting to end their participation in the study can be withdrawn from the study regardless of the stage they have reached in the study process. Patients do not have to provide the reason for withdrawal. Patients found to be pregnant or those judged ineligible to continue participating in the study by the investigators will also be withdrawn from the study.

Strategies to improve adherence to interventions {11c}

All treatments will be administered to participants by their physicians on an outpatient basis. Participants will visit the outpatient clinic every month, receive detailed explanations of their condition from the physicians, and proceed with treatment with full understanding.

Relevant concomitant care permitted or prohibited during the trial {11d}

All other treatments will be allowed.

Provisions for post-trial care {30}

All patients who will suffer harm from the study participation will be covered by the Japanese public healthcare system.

Assessment items {18a}

The following headache data will be extracted from patients' self-maintained headache diaries: MHD, monthly migraine days (MMD), AMU, and monthly days of absenteeism and presenteeism. Assessments of headache condition are performed by the following questionnaires: Headache Impact Test-6 (HIT-6), Migraine-Specific Quality of Life Questionnaire (MSQ), and Daily Living Disability Questionnaire. Assessments of mental health are performed by the Quick Inventory of Depressive Symptomatology (QIDS-J). Determination of subjectively perceived time to onset of effect after the 1st CGRP-mAb injection is performed by a simple questionnaire called the Effectiveness Evaluation Sheet.

HIT-6

The HIT-6 consists of 6 items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress.¹⁹⁾ The patient answers each of the 6 related questions using one of the following 5 responses: “never,” “rarely,” “sometimes,” “very often,” or “always.” The total score ranges from 36 to 78 points, and a higher score indicates a greater impact of headaches on the daily life of the respondent.

MSQ

The 14-item MSQ is designed to measure how migraines affect and/or limit daily functioning over the past 4 weeks across 3 domains: role function-restrictive (7 items), role function-preventive (4 items), and emotional function (3 items).²⁰⁾ Patients answer each item using a 6-point scale: “none of the time,” “a little bit of the time,” “some of the time,” “a good bit of the time,” “most of the time,” and “all of the time,” which are assigned scores of 1 to 6, respectively. The total score ranges from 14 to 84 points, and a higher score indicates greater impairment in quality of life.

Daily living disability questionnaire

This is a questionnaire designed for the study to assess the specific impact of headaches on daily life. This questionnaire asks patients to answer by marking whether or not they have experienced the following 12 items due to headaches in the past 4 weeks: have to take time off; unable to concentrate; unable to work or study as planned; worry about how others see you; worry about headaches when making an appointment; worry about headaches when attending events or meetings; unable to spend time with family or loved ones; unable to do housework as usual; worry about headache attacks; unable to spend time with a smile; unable to engage in hobbies or sports; and feel unwell both physically and mentally.

QIDS-J

The QIDS-J consists of 16 questions and plays a role in the diagnostic criteria for major depressive disorder.²¹⁾ These questions are divided into 9 categories. Four concern sleeping disorders, 4 appetite and body weight, 2 psychological disorders, and the remaining 9 other topics. The total score ranges from 0 to 48 points, and a higher score indicates a higher level of depressive disorder.

Effectiveness evaluation sheet

This is a simple questionnaire designed for the study to assess when patients subjectively feel the onset of efficacy after the 1st CGRP-mAb injection by circling only one item on a scale of 1 to 5: 1, within 1 week after injection; 2, 1-2 weeks after injection; 3, 2-3 weeks after injection; 4, 3-4 weeks after injection; and 5, no effect perceived.

Clinical assessments {13}

At entry, clinical research physicians obtain information from patients regarding age, sex, past history (mental disturbance, epilepsy, others), migraine classification (HFEM, CM, MOH), family history of headache, laterality of headache, migraine with aura, smoking, aggravating factors (weather, temperature, alcohol, menstruation), monthly AMU (triptans, non-steroidal anti-inflammatory drugs, acetaminophen, over-the-counter medications, others), oral prophylactic medicines currently being used (antiepileptic drugs, antidepressants, β-blockers, calcium antagonists, others), duration of the disease, monthly days of absenteeism and presenteeism, headache status (MHD and MMD), and several questionnaires (HIT-6, MSQ, Daily Living Disability Questionnaire, QIDS-J). During the study, the above assessment items are evaluated according to the plan (Table 1).

Table 1.

Summary of assessment items and schedule

Primary outcome {12}

Comparison of early-onset efficacy between galcanezumab and the other drugs, fremanezumab and erenumab, 1 week after the 1st CGRP-mAb injection.

Secondary outcomes

1) Comparison of early-onset efficacy between fremanezumab and erenumab 1 week after the 1st CGRP-mAb injection.

The following secondary outcomes are comparisons between galcanezumab and both fremanezumab and erenumab and between fremanezumab and erenumab.

2) During the month after the 1st CGRP-mAb injection, the weekly number of headache days, migraine days, and AMU are compared to the baseline weekly averages.

3) Comparison of the time when the patient subjectively perceived the onset of effect after the 1st CGRP-mAb injection.

4) Comparison of monthly changes from baseline in MHD, MMD, AMU, and other assessment items after the 1st, second (2nd), and third (3rd) CGRP-mAb injections.

5) Comparison of effective rates after 1st and 3rd CGRP-mAb injections.

6) Comparison of improvement rates of depression scores between baseline and after the 3rd CGRP-mAb injection.

7) Comparison of changes in the number of absenteeism and presenteeism days in each month from baseline to after the 1st, 2nd, and 3rd CGRP-mAb injections.

8) Comparison of the proportion of cases judged to be ineffective after the 3rd CGRP-mAb injection.

9) Comparison of recurrence rates and time to recurrence in the period up to 12 weeks after CGRP-mAb discontinuation.

10) Comparison of effective rates of CGRP-mAb re-injection in patients with recurrence, and of changes in MHD, MMD, AMU, and other assessment items before and after CGRP-mAb re-injection.

11) Detection and comparison of baseline clinical factors associated with effectiveness after the 1st and 3rd CGRP-mAb injections.

12) Extraction of diseases related to this trial.

The following are exploratory analyses.

- Comparison of monthly changes in MHD, MMD, AMU, and other assessment item scores after the fourth to sixth CGRP-mAb injections and during the discontinuation period.

- Comprehensive AI analysis of headache diaries, pre-examination questionnaires, several questionnaires, and clinical data.

Sample size {14}

Early-onset efficacy of each CGRP-mAb including galcanezumab,^13,14) fremanezumab,^15,16) and erenumab^17,18) has been demonstrated by comparison with placebo. However, the results of these placebo-controlled trials cannot be simply compared because the patient background characteristics and other factors varied. Therefore, the sample size is not set based on statistical assumptions but is set as the collectible sample size as follows. Assume that there are approximately 30 cases that meet the inclusion criteria of the study in a year. Assuming a 70% consent rate for study enrollment, approximately 20 cases will be enrolled per year. The sample size is set to 60 (galcanezumab: 20, fremanezumab: 20, erenumab: 20) as the number that can be achieved in 3 years.

Data management {16a,c, 19}

After consent to participate in the study has been obtained, enrollment of participants and randomization will be performed centrally through the web-based system with a minimization procedure by TT and YF. Enrollment must be completed before CGRP-mAb injection, and no subsequent enrollment will be permitted. The allocation sequence using the web-based system will be generated at the data center (Department of Advanced Medicine, Nagoya University Hospital). Allocation adjustment factors are institution, age (≤40 vs ≥41 years), sex (male vs female), and headache classification (HFEM vs CM vs MOH). Registration, randomization, and data collection will be performed using an electronic data capture (EDC) system. Statistical analyses will be performed at the data center. Data are entered into the electronic data capture system (REDCap) independently by one researcher and checked by another researcher. Access to REDCap is strictly regulated and only with personal credentials. All data are monitored and verified via a tracking system.

Concealment mechanism {16b}

The results of the allocation will be shown via the interactive web response system.

Assignment of interventions: blinding

Who will be blinded? {17a}

Not applicable.

Procedure for unblinding if needed {17b}

Not applicable.

Plans to promote participant retention and complete follow-up {18b}

Medical interviews and medication adjustments will be booked for all patients.

Confidentiality {27}

The form used to code patients will be stored in a locked cabinet with logged access only available to the researchers and administrators responsible for the study.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Not applicable. No biological specimens will be involved in this study.

Statistical analysis {20a}

The primary outcome analysis assesses early-onset efficacy by calculating the number of headache days during the 7 days following the 1st CGRP-mAb injection (from the day after injection to 1 week later). Early-onset efficacy is defined as ≥50% reduction in the number of headache days in the week following the 1st CGRP-mAb injection compared to the weekly average number of headache days at baseline. The proportion of cases with early-onset efficacy between galcanezumab and both fremanezumab and erenumab is compared using logistic regression analysis with age (≤40 vs ≥41 years), sex (male vs female), and headache classification (HFEM vs CM vs MOH) as covariates. Binomial distributions and 95% confidence intervals (CIs) are calculated for galcanezumab and both fremanezumab and erenumab.

*For the secondary outcomes 1) to 8), in order to avoid multiplicity, a comparison is made between galcanezumab and both fremanezumab and erenumab using a linear mixed model fixed effects type 3 test. If significant results are found, a further comparison is made between fremanezumab and erenumab.

1) If a significant difference is found in the primary analysis, the proportion of cases with early-onset efficacy between fremanezumab and erenumab is compared using logistic regression with the same factors as in the primary analysis as covariates.

2) Weekly number of headache days, migraine days, and AMU are compared between groups over a 4-week period following the 1st CGRP-mAb injection. Outcome variables are the changes in weekly headache days and migraine days assessed at each measurement time point: baseline (weekly average over 4 weeks before the 1st CGRP-mAb injection), 1 week (from the day after the 1st CGRP-mAb injection to day 7 later), 2 weeks (days 8-14 after injection), 3 weeks (days 15-21 after injection), and 4 weeks (days 22-28 after injection). Adjusted means and 95% CIs at each assessment point are calculated using linear mixed models with the pre-injection value of each indicator, assessment point, drugs (galcanezumab and both fremanezumab and erenumab), and an interaction term between assessment point and drug as fixed effects. Changes in each index at each assessment time point are compared between groups after correcting for multiplicity using the Tukey-Kramer method. For the amount of acute medication used, the change in the number of times the medication is taken as needed is evaluated in a similar manner.

3) The proportion of cases marking 1 on the Effectiveness Evaluation Sheet is compared between groups using logistic regression with the same factors as in the primary analysis as covariates. In each group, the proportion of each of the questionnaires 1 to 5 is calculated.

4) The changes in each of the following indicators (MHD, MMD, AMU, HIT-6, MSQ, and Daily Life Impairment Score [total score]) from baseline to after each of the 1st to 3rd CGRP-mAb injections are compared among the groups. Outcome variables are the change in each index at each measurement point: baseline (monthly average over the 4 weeks before the 1st CGRP-mAb injection), after the 1st injection (from the day after injection to 4 weeks later), after the 2nd injection (same as above), and after the 3rd injection (same as above). Adjusted means and 95% CIs at each assessment point are calculated using linear mixed models with the pre-injection value of each indicator, assessment point, group, and an interaction term between the assessment point and drug as fixed effects. Changes in each index at each assessment time point are compared between groups after correcting for multiplicity using the Tukey-Kramer method. For the amount of AMU, the change in the number of times the medication is taken as needed is evaluated in a similar manner. Changes in each index at each assessment time point are compared between groups after correcting for multiplicity using the Tukey-Kramer method.

5) Compare effective rates after the 1st and 3rd CGRP-mAb injections between groups using logistic regression with the same factors as in the primary analysis and the treatment group as covariates. For each group analyzed, the binomial distribution effective rates and 95% CIs are calculated.

6) Improvement rates of depression scores from baseline after the 3rd CGRP-mAb injection are compared between groups, based on analysis of covariance with the same factors as in the primary analysis as covariates.

7) Using the same linear mixed model as in secondary outcome 4), the changes from baseline in the number of days of absenteeism and presenteeism each month after the 1st, 2nd, and 3rd CGRP-mAb injections are compared between groups.

8) The proportion of patients who are judged ineffective after the 3rd CGRP-mAb injection or who request discontinuation by the time of evaluation is compared between groups using logistic regression with the same factors as in the primary analysis as covariates. For each group analyzed, the binomial distribution effective rates and 95% CIs are calculated.

9) Regarding recurrence rates and time to recurrence in the period 12 weeks after CGRP-mAb discontinuation, the cumulative recurrence rates for groups are calculated using the Kaplan-Meier method, with patients who discontinue the study and patients with no recurrence within 12 weeks of discontinuation censored. The groups are compared using the Cox proportional hazards model with the same factors as in the primary analysis as covariates.

10) CGRP-mAb re-injection is defined as effective if there is ≥50% reduction in the number of MHDs in the 4 weeks after re-injection compared with the previous 4 weeks. Effective rates after CGRP-mAb re-injection and proportions of effective cases are compared between groups using logistic regression with the same factors as in the primary analysis as covariates. For each group analyzed, the binomial distribution effective rates and 95% CIs are calculated.

Changes in each index (MHD, MMD, AMU, HIT-6, MSQ, and Daily Living Problems Score) from 4 weeks before to 4 weeks after CGRP-mAb re-injection are compared between groups using analysis of covariance with the same factors as in the primary analysis as covariates. If there are significant differences, groups are compared using the Bonferroni method.

11) Regarding factors affecting effective rates after the 1st and 3rd injections of each CGRP-mAb, prognostic factors are compared using univariate and multivariate logistic regression for each group (galcanezumab vs fremanezumab vs erenumab) and clinical factors at enrollment (migraine type: HFEM, CM, MOH; headache location: unilateral, bilateral, generalized, fluctuating; age at onset: teens, 20s, 30s, 40s or older; family history, aura; medical history, motion hypersensitivity, photosensitivity, nausea; triggering factors: weather, temperature, alcohol, menstruation, stiff shoulders, lack of sleep, stress, smoking).

12) The occurrences of side effects related to the study such as injection site symptoms, allergic reactions to CGRP-mAb, dizziness, constipation, and others are recorded in the EDC. The above side effects are extracted during the following 4 periods: from the 1st to after the 3rd CGRP-mAb injections, from the fourth to after the sixth CGRP-mAb injections, the discontinuation period, and up to 4 weeks after CGRP-mAb re-injection, and summary statistics for safety evaluation indicators are calculated.

Interim analyses {21b}

Interim analyses are not planned.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

No statistical methods will be used to compensate for missing data.

Plans to give access to the full protocol, participant-level data, and statistical code {31c}

The study is registered at the Japan Registry of Clinical Trials (jRCTs). At the end of the study, the full protocol, data and analysis results will be available from the corresponding author upon reasonable request.

Oversight and monitoring

Composition of the coordinating center and trial screening committee {5d}

Nagoya University will serve as the coordinating center. Only the investigators and members of the data center will have access to the anonymized data in REDCap.

Composition of the data monitoring committee, its role and reporting structure {21a}

Two participating researchers at Nagoya University Hospital or Nagoya Medical Center will monitor the data. They have the responsibility of verifying patients' eligibility, written informed consent, compliance with the protocol, and accuracy of the data in REDCap.

Adverse event reporting and harms {22}

Researchers will immediately report serious adverse events associated with CGRP-mAb treatment to the chief investigator. Then, the chief investigator will report serious adverse events to the director of the hospital and the principal investigator. Data about all serious adverse events will also be collected in REDCap.

Frequency and plans for auditing trial conduct {23}

No audits are to be conducted in this study. During the study period, monitoring will be carried out by the monitoring staff to ensure that the study is conducted properly. Monitoring staff are SM and YN, and they are a member of the study team. The monitoring will be conducted by visits, email, etc. at an appropriate frequency. Check the following items; 1) consent acquisition, 2) conducted eligibility, 3) observance of the study protocol, 4) presence or absence of diseases, 5) consistency between source documents and case reports, 6) confirmation of serious illness, 7) clinical study procedures, and 8) storage status of documents.

Plans for communicating important protocol amendments to relevant parties {25}

Any protocol modifications will be reviewed by the Certified Review Board of Nagoya University Graduate School of Medicine and then registered at jRCT. All relevant information will be shared among the researchers.

Dissemination plans {31a}

The results of this study will be published in a peer-reviewed journal and presented at national and international medical congresses.

Results/Discussion

The strengths of this study include the random allocation of 3 CGRP-mAbs, the uniform timing of drug discontinuation, and the direct comparison of galcanezumab with fremanezumab and erenumab. Although this is an exploratory study, and the results will not be conclusive, the analysis should provide clinicians with useful information about the differences among the CGRP-mAbs. Galcanezumab requires 2 initial injections and is therefore more invasive and economically burdensome than either fremanezumab or erenumab. Prior to participating in the study, patients will be fully informed in writing and verbally that if they are assigned to the galcanezumab group, the financial burden for the initial injection will be twice that of other drugs, and consent to participate in the study will be obtained. If this study suggests that galcanezumab has earlier onset efficacy than fremanezumab and erenumab, either in objective items or subjective impressions, it could provide useful information for selecting galcanezumab as an initial treatment. The latest review reported consistent findings of worsened headache frequency and quality of life after discontinuation of CGRP-mAb therapy.²²⁾ Most studies included in the review had treatment durations of 12 months because many guidelines and consensus statements recommend 6-12 months before treatment discontinuation or tapering.²³⁾ Therefore, in this study, we will investigate recurrences occurring after a relatively short treatment period of 6 months.

Sources of Funding {4}

This research is supported by Nagoya University Hospital Funding for Clinical Development.

Author Contributions {5a, 31b}

All authors contributed to the study protocol design. TT, MH, and SY: investigators, conceptualization, methodology, and draft writing, YN, SM, YN, TI and TW: conceptualization and methodology, AH, MA and YK: conceptualization, methodology, statistical analysis, and draft writing, RS: supervision and project administration. All authors have read and approved the final manuscript.

Ethics Approval and Consent to Participate {24}

This study protocol was approved by the Certified Review Board of Nagoya University Graduate School of Medicine and was registered at jRCT on February 14 2024 (jRCT 1041230151), and last modified on 13 June 2024. Written, informed consent to participate will be obtained from all participants.

Trial Status {2a, 3}

This manuscript is based on the protocol (version 1, last updated on January 10, 2024). The first patient was recruited on April 27, 2024. Recruitment will be completed by December 2026.

Consent for Publication {32}

The informed consent documents are not included as supplementary files due to their length. The informed consent documents can be obtained at request from the senior supervisor.

Availability of Data and Materials {29}

Any data required to support the protocol can be supplied on request.

Conflicts of Interest Disclosure {28}

All authors have no conflict of interest.