Clinical trial NCT04260035: The Effects of a Long-lasting Infusion of Vasoactive Intestinal Peptide (VIP) in Episodic Migraine Patients
Official title: The Effects of a Long-lasting Infusion of Vasoactive Intestinal Peptide (VIP) on Headache, Cranial Hemodynamic and Autonomic Symptoms in Episodic Migraine Patients Without Aura
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Migraine
Pain
Neurologic Manifestations
Signs and Symptoms
Brain Diseases
Central Nervous System Diseases
Lead sponsor: Danish Headache Center
Sponsor class: OTHER
First posted: 2020-02-07
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: Vasoactive intestinal peptide (VIP) is a peptide of 28 amino acid residues that belongs to the glucagon/secretin superfamily of peptides. Along with other neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP), it is released from the trigeminal afferents and exerts a strong vasodilating activity on the cranial vasculature. Especially, it shares 70% structure with PACAP and acts on the same receptors. But, unlike it, VIP cannot induce a long-lasting vasodilation and has a modest capability to induce migraine attacks. Whether it may induce migraine-like attacks in migraine patients, as a twenty-minute infusion of PACAP, is unknown.

Detailed description: The vasoactive intestinal polypeptide (VIP) is a peptide of 28 amino acid residues that belongs to the glucagon/secretin superfamily of peptides. It is distributed in different regions of the nervous system, including several autonomic ganglia and the brain. Once released from neurons, it acts on the vasoactive intestinal peptide receptor 1 (VPAC1), the vasoactive intestinal peptide receptor 2 (VPAC2) and the pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1). All three belong to a family of G-protein coupled receptors, sharing the activation of adenylate cyclase and the increase in intracellular cyclic adenosine monophosphate (cAMP). The three receptors are involved in many physiological functions, among them the vasodilating and parasympathetic responses. VPAC1 and VPAC2 are expressed in dura mater vessels and are primarily responsible for the relaxation of arteries. PAC1 is located in the trigemino-autonomic system, but not in blood vessels. VIP shares the binding to the three aforementioned receptors with other peptides, including the pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), and the pituitary adenylate cyclase-activating polypeptide-27 (PACAP27).

20-minute infusion of VIP and PACAPs in patients with migraine dilated cranial arteries. However, only PACAP27 and PACAP38 induced a sustained cranial vasodilation, and migraine like-attacks. VIP-induced cranial vasodilation was of short duration, and patients did not report migraine-like attacks. The discrepancy was ascribed to the preferential activation of the PAC1 receptor by PACAPs, but a monoclonal antibody against PAC1 receptor recently failed in migraine prevention. Currently, it is unknown whether the prolonged cranial vasodilation related with the appearance of migraine-like attacks. More recently, a two-hour infusion of VIP promoted a long-lasting cranial vasodilation and delayed headache in healthy volunteers, resembling the effect of PACAP27 and PACAP38, two closely related peptides causing migraine. Whether a long-lasting infusion of VIP may induce a sustained cranial vasodilation and migraine-like attacks in migraine patients, as a twenty-minute infusion of PACAP27 and PACAP38, is unknown.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of migraine without aura as according to the International Classification
* Frequency of migraine attacks between one and six attacks within 8 weeks
* Weight: 50-90 kg
* Fertile women should use contraception. Fertile women do not include hysterectomies women or women who are postmenopausal for at least 2 years. Contraception includes either IUD, birth control pills, surgical sterilization of the woman or depot progesterone

Exclusion Criteria:

* Any other type of headache (including \> 2 days of tension-type headache per month)
* Headache less than 48 hours before the start of the experiment
* Daily intake of any medicine other than oral contraception
* Pregnant or breastfeeding women
* Clinical signs of Hypertension (systolic blood pressure \> 150 mmHg and / or diastolic blood pressure \> 100 mmHg) and/or Hypotension (systolic blood pressure \< 90 mm Hg and / or diastolic blood pressure \< 50 mmHg)
* Cardiovascular disease of all kinds, including cerebrovascular disease
* Anamnestic or clinical signs of mental illness, abuse or smoking

Primary outcomes:
measure: Occurrence of migraine-like attacks
timeFrame: Before (-10 minutes) and after the drug administration (+12 hours)
Secondary outcomes:
measure: Change in cranial hemodynamic
timeFrame: Before (-10 minutes) and after the drug administration (+3 hours)
measure: Occurrence of headache and change of headache intensity scores
timeFrame: Before (-10 minutes) and after the drug administration (+12 hours)
measure: Change in Mean Arterial Pressure
timeFrame: Before (-10 minutes) and after the drug administration (+3 hours and 20 minutes)
measure: Change in Heart Rate
timeFrame: Before (-10 minutes) and after the drug administration (+3 hours and 20 minutes)
Other outcomes:
Locations:
city: Glostrup
country: Denmark
facility: Danish Headache Center
state: Copenhagen
Study officials:
affiliation: Danish Headache Center
name: Messoud Ashina, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Pellesi L, Al-Karagholi MA, De Icco R, Chaudhry BA, Lopez CL, Snellman J, Hannibal J, Amin FM, Ashina M. Plasma Levels of CGRP During a 2-h Infusion of VIP in Healthy Volunteers and Patients With Migraine: An Exploratory Study. Front Neurol. 2022 Apr 1;13:871176. doi: 10.3389/fneur.2022.871176. eCollection 2022.
citation: Pellesi L, Al-Karagholi MA, De Icco R, Coskun H, Elbahi FA, Lopez-Lopez C, Snellman J, Hannibal J, Amin FM, Ashina M. Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial. JAMA Netw Open. 2021 Aug 2;4(8):e2118543. doi: 10.1001/jamanetworkopen.2021.18543.