Version 2.0 Introduced new “Other” study endpoints, including evaluation of changes from Baseline in the frequency of monthly migraine attacks during Months 5 and 6, frequency of monthly migraine days across Months 4 through 6, as well as the average daily severity of headaches and all days (including headache-free days) across Months 5 and 6. Additional modifications were made to the protocol: enrollment was capped so that no more than 20% of subjects could meet criteria for acute headache medication overuse; a weekly migraine attack assessment was added; and a new eligibility criterion specified that participants cannot concurrently take part in another clinical trial. The Operations Manual (Appendix F) was updated to provide instructions for procedures affected by regulatory changes related to the COVID-19 pandemic, while Sections 3.1 and 8.2 were amended to include language on Verified Clinical Trials procedures and to define acute headache medication overuse, respectively.

Version 3.0 Updated the language in the Operations Manual's sections on Biomarker Research and Biomarker Research Sampling. Additional changes include revised eligibility criteria in Section 5.1 to incorporate the C-SSRS, clarified requirements for female contraception, and updated language regarding medication overuse headache. Section 5.2 clarified that contraception requirements now extend to 90 days after the last dose of the study drug. Sections 7.4 and 7.5 were revied to include a 'medication overuse subgroup' in the analyses of both primary efficacy and key safety endpoints. In the Operations Manual, references to paper SAE forms were removed from Section 4.2, Section 6.5 specified the number of vials to be reconstituted, and language regarding the relevant time period in Section 8.2 was clarified.

Version 4.0 Provided a summary of BOTOX risks and specifies that participation in biomarker sampling is now optional. Urine biomarker collection was removed in light of recent literature. The Screening/Baseline Phase may be extended for COVID-19 reasons, and visit windows were aligned with Appendix D. Subjects who have failed 2 to 4 preventive treatments will receive continued monitoring, and new language addressed enrollment criteria for those with medication overuse; details were added regarding potential enrollment restrictions and the re-screening process. Reference to legally authorized representatives was removed, and eligibility criteria were updated, correcting an error regarding thyroid status and clarifying the requirement for investigator review. The list of acceptable contraception methods was changed, excluding barrier methods and certain progesterone-only options. Barbiturates were added to the list of permitted migraine medications, and prior exposure to migraine prophylactic treatments was detailed. Adverse event reporting rules were revised to allow for quicker reporting in certain locales to comply with German regulations. Language about suicidal ideation for the C-SSRS was clarified. A blinding assessment was added at Week 24, and urine alcohol screenings were centralized. The PGIC assessment at Week 36 was added to the Operations Manual to match the study protocol.

Version 5.0 The protocol and operations manual were updated to clarify and improve the study processes. Collection time points for EQ-5D-5L and PHQ-9 scores revised to reflect actual collection timing. Enrollment targets were reworded for flexibility. Eligibility was revised to require subjects to be aged 18 to 65 at Visit 1, and applicants must not have allergies to the study drug or its components per UK regulatory feedback. Additional cautions were added for combining aminoglycosides or other agents that affect neuromuscular transmission, also per UK feedback. Ubrogepant is now an allowed migraine-specific treatment during the Open-Label Phase, with restrictions for safety evaluation, and emergency unmasking procedures were clarified. An incorrect pregnancy follow-up statement was removed. The PGI-S score is now used as a baseline covariate for PGIC. At Week 24, weight collection was added for creatinine clearance calculations, and treatment visits should occur every 12 weeks. The PHQ-9 severe depression threshold was updated to include a score of 20; AIM-D was clarified to only one version; and the daily activities domain was corrected to include concentration and clarity assessments. Drug storage requirements were updated; miscellaneous pharmacologic categories are now permitted in all countries; and emergency medical contacts were updated for current personnel.

Version 6.0 Key updates to the protocol and operations manual included the revision of emergency medical and SAE reporting contacts to reflect current personnel. The secondary endpoint regarding change from baseline in frequency of neck pain days was reclassified as an exploratory endpoint. Additional analyses now focus on moderate or severe neck pain in participants with baseline headache-associated neck pain. The analysis of acute headache medication days was simplified due to insufficient baseline data, and a new statement confirmed all primary and secondary endpoints will also be assessed at monthly intervals for efficacy. The protocol was revised to include further subgroup analyses as per regulatory guidelines, and the multiplicity method schematic for controlling Type I error was updated to reflect endpoint changes. The section addressing study conduct in crisis events was updated to now reference any significant disaster rather than just the COVID-19 pandemic, allowing for remote verification under broader circumstances.