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

Study Overview
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Brief Summary
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To investigate whether administration of calcitonin gene-related peptide (CGRP) binding monoclonal antibodies eptinezumab prevents pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) induced migraine attacks in migraine without aura patients.

Detailed Description
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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.

Official Title
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Molecular Stratification of Signaling Pathways Underlying Migraine Pathophysiology.

Conditions
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Migraine

Intervention / Treatment
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* Drug: Eptinezumab
* Drug: PACAP-38


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled design in migraine without aura patients.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Eptinezumab and PACAP-38<br>The participants will receive an intravenous infusion of eptinezumab (300 mg) over 30 minutes followed (2 hours later) by an intravenous infusion of PACAP-38 (10 pmol/kg/min) over 20 minutes. | Drug: Eptinezumab<br>* 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.<br>Drug: PACAP-38<br>* 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.<br>|
| Placebo Comparator: Placebo and PACAP-38<br>The participants will receive an intravenous infusion of placebo (saline) over 30 minutes followed (2 hours later) by an intravenous infusion of PACAP-38 (10 pmol/kg/min) over 20 minutes. | Drug: PACAP-38<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A subjective report of a migraine attack | The participants report whether they feel a migraine attack (Yes or no). | Time of reporting migraine attack is from the baseline to 24 hours after eptinezumab/placebo administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache | 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). | Time of headache measurements is from from the baseline to 24 hours eptinezumab/placebo administration. | 
| Changes in the superficial temporal artery (STA). | 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). | Time of headache measurements is from from the baseline to 24 hours eptinezumab/placebo administration. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Headache, Vascular effect