Migraine Induction Properties of PACAP-38 After Eptinezumab in Migraine Without Aura Patients.

The aim of the present study is to investigate whether

\- CGRP binding monoclonal antibodies eptinezumab prevents PACAP-38 induced migraine attacks in migraine without aura patients.

Clinical and basic research have established calcitonin gene-related peptide (CGRP) as central molecule in migraine pathophysiology, yet existing CGRP antagonizing therapies such as the CGRP and CGRP receptor binding monoclonal antibodies are only effective in 50-60% of migraine patients. PACAP-38 and CGRP colocalize in the trigeminovascular system, and both activate adenylate cyclase upon receptor binding which causes increased formation of cyclic AMP (cAMP). It is unknown if CGRP and PACAP-38 signaling pathways differ sufficiently for PACAP-38 to be an alternative treatment target to CGRP. Whether administration of CGRP binding monoclonal antibodies eptinezumab prevents PACAP-38 induced migraine attacks in migraine without aura patients is yet to be investigated.

• Eptinezumab (Drug): Eptinezumab or ALD403 is a humanized anti-calcitonin gene-related peptide IgG1 monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). It selectively binds human CGRP ligand to prevent activation of the CGRP receptor and blocks its binding to the receptor for the prevention of migraine.
• PACAP-38 (Drug): PACAP-38 is a naturally occurring peptide diffusely expressed throughout the body. The Danish Headache Center has used infusion of PACAP-38 for several years and the first time in 2007 where infusion of PACAP-38 triggered headaches and migraines in migraine patients.

Primary outcomes

• A subjective report of a migraine attack [Time of reporting migraine attack is from the baseline to 24 hours after eptinezumab/placebo administration.]: The participants report whether they feel a migraine attack (Yes or no).

Secondary outcomes

• Headache [Time of headache measurements is from from the baseline to 24 hours eptinezumab/placebo administration.]: Headache intensity will be recorded by numerical rating scale (NRS) from 0 to 10 (0, no headache; 1, a feeling of pressure; 10, worst imaginable headache).
• Changes in the superficial temporal artery (STA). [Time of headache measurements is from from the baseline to 24 hours eptinezumab/placebo administration.]: Diameter of the frontal branch of the superficial temporal artery (STA). Repeated measurements covering the diameter of STA before and after eptinezumab/placebo administration and PACAP-38 infusion measured by millimeters (mm).

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* Healthy volunteers of both sexes.
* 18-60 years.
* 50-100 kg.
* Women of childbearing potential must use adequate contraception
* History of migraine without aura for ≥ 12 months according to the International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria.
* No migraine preventive treatment.

Exclusion Criteria:

* A history of serious somatic disease
* > 50 years of age at migraine onset.
* History of any other primary headaches disorder (except ≤ 5 monthly days with tension- type headache).
* Daily intake of any medication except contraceptives

• Results publication: Al-Karagholi MA, Zhuang ZA, Beich S, Ashina H, Ashina M. PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial. J Headache Pain. 2025 Apr 14;26(1):79. doi: 10.1186/s10194-025-02022-2. PMID 40229719