Induction of Migraine Attacks With Aura Using Pituitary Adenylate Cyclase Activating Polypeptide-38

Induction of Migraine Attacks With Aura Using Pituitary Adenylate Cyclase Activating Polypeptide-38: A Randomized Clinical Trial

Pituitary Adenylate Cyclase Activating Polypeptide-38 (PACAP-38) is a key neuropeptide in migraine pathophysiology and treatment. This study investigates whether PACAP-38 administration can trigger aura in individuals with a diagnosis of migraine with aura.

Study Overview

• Status: Not yet recruiting
• Conditions: Migraine With Aura; Migraine Aura
• Intervention / Treatment: Drug: Placebo; Drug: Pituitary Adenylate Cyclase Activating Polypeptide-38 (PACAP-38)

Detailed Description

In a series of studies, pharmacological triggers of migraine headache were able to induce aura as well migraine headache. Recent open-label findings show that calcitonin gene-related peptide (CGRP) can trigger aura attacks-despite its limited ability to cross the blood-brain barrier. This suggests CGRP might induce migraine aura via trigeminovascular activation, the same pathway involved in migraine headache. To further explore this concept, it is fundamental to examine whether other migraine-inducing signaling molecules that pass the BBB to a minimal degree, such as PACAP-38, are able to induce aura as well. If PACAP-38 is able to induce aura, the anti-PACAP monoclonal antibody may provide a promising therapeutic option for preventing migraine with aura.

To validate this effect, a randomized, double-blind, placebo-controlled trial is essential. Its outcomes could inform future therapies targeting the migraine-aura connection.

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hakan Ashina, MD, PhD; Phone Number: +4528102495; Email: haakan.ashina@regionh.dk
• Study Contact Backup: Name: Haidar Al-Khazali, MD, PhD; Phone Number: +4541598494; Email: halk0007@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 to 65 years of age upon entry into screening
• History of migraine with aura for ≥ 12 months according to the International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria
• ≥ 1 monthly day with aura that meets criteria as aura on average across the three months before screening
• Provision of informed consent prior to initiation of any study-specific activities/procedures.

Exclusion Criteria:

• Any history of a primary or secondary headache disorder other than migraine without aura, migraine with aura, chronic migraine, and episodic tension-type headache
• History or evidence of any other clinically significant disorder, condition, or disease (except for those outlined above) that, in the opinion of the site investigator, would pose a risk to subject safety or interfere with study evaluation, procedures or completion
• The subject is at risk of self-harm or harm to others as evidenced by past suicidal behavior
• Female subjects of childbearing potential with a positive pregnancy test during any study visit
• Cardiovascular disease of any kind, including cerebrovascular diseases Hypertension (systolic blood pressure of ≥150 mmHg and/or diastolic blood pressure of ≥100 mmHg) prior to the start of infusion on the experimental day Hypotension (systolic blood pressure of ≤90 mmHg and/or diastolic blood pressure of ≤50 mmHg)
• Initiation, discontinuation, or change of dosing of prophylactic medications within 2 months prior to study inclusion
• Intake of acute medications (e.g. analgesics, triptans) within 48 hours of infusion start
• Headache of any intensity within 48 hours of infusion start
• Aura within 48 hours of infusion start

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo (isotonic saline) will be administered by intravenous infusion.	Drug: Placebo; The participants will receive a continuous intravenous infusion of 20 mL of placebo (isotonic saline) over 20 minutes.
Experimental: Pituitary Adenylate Cyclase Activating Polypeptide-38 (PACAP-38); PACAP-38 will be administered by intravenous infusion.	Drug: Pituitary Adenylate Cyclase Activating Polypeptide-38 (PACAP-38); The participants will receive a continuous intravenous infusion of 10 pmol/kg/min PACAP-38 over 20 min

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of migraine attacks with aura	Difference in incidence of migraine attack with aura between PACAP-38 and placebo during the 12-hour observational period after infusion start. Experimentally induced migraine aura is defined as aura that meet Criteria B and C of 1.2 Migraine with Aura in ICHD-3.	12 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of migraine attacks without aura	Difference in incidence of migraine pain (headache) between PACAP-38 and placebo during the 12-hour observational period after infusion start. Experimentally induced migraine pain is defined as headache that meet Criteria C and D of 1.1. Migraine without Aura in ICHD-3 as well as resembles the subject's usual migraine attack or is treated with an acute headache medication.	12 hours
Headache intensity scores	Difference in area under the curve (AUC) for headache intensity scores between PACAP-38 and placebo during the 12-hour observational period after infusion start. The intensity of headache is rated by the subject on the 11-point numerical rating scale (0 being no headache, 10 being the worst imaginable headache).	12 hours

Collaborators and Investigators

• Sponsor: Danish Headache Center

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: January 8, 2026
• First Submitted That Met QC Criteria: January 8, 2026
• First Posted (Actual): January 15, 2026

Study Record Updates

• Last Update Posted (Actual): January 15, 2026
• Last Update Submitted That Met QC Criteria: January 8, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: migraine; aura; Pituitary Adenylate Cyclase Activating Polypeptide-38
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Migraine with Aura; Epilepsy; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Nerve Tissue Proteins; Proteins; Biological Factors; Intercellular Signaling Peptides and Proteins; Nerve Growth Factors; Pituitary Adenylate Cyclase-Activating Polypeptide
• Other Study ID Numbers: H-23042432

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized data not published within this article will be made available on reasonable request from any qualified investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No