The Effects of a Long-lasting Infusion of Vasoactive Intestinal Peptide (VIP) in Episodic Migraine Patients

• ClinicalTrials.gov Identifier: NCT04260035
• Recruitment Status: Completed
• First Posted: February 7, 2020
• Last Update Posted: October 20, 2020
• Sponsor: Danish Headache Center
• Information provided by (Responsible Party): Lanfranco Pellesi, Danish Headache Center

Tracking Information

• First Submitted Date: February 5, 2020
• First Posted Date: February 7, 2020
• Last Update Posted Date: October 20, 2020
• Actual Study Start Date: May 19, 2020
• Actual Primary Completion Date: September 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2020)

Occurrence of migraine-like attacks [ Time Frame: Before (-10 minutes) and after the drug administration (+12 hours) ]

Migraine-like attack fulfilling either (i) or (ii): (i) Headache fulfilling criteria C and D for migraine without aura according to the International Classification od Headache Disorders: C. Headache has at least two of the following four characteristics: unilateral location; pulsating quality; moderate or severe pain intensity (moderate pain intensity is considered 5 or 4 on verbal rating scale); aggravation by cough (hospitalization phase) or causing avoidance of routine physical activity (out-hospital phase); D. During headache at least one of the following: nausea and/or vomiting; photophobia and phonophobia; (ii) Headache described as mimicking the patient's usual migraine attack and treated with acute migraine medication (rescue medication).

Original Primary Outcome Measures (submitted: February 5, 2020)

• Change in cranial hemodynamic [ Time Frame: Before (-10 minutes) and after the drug administration (+2 hours) ]
  Change on diameter (mm) of superficial temporal artery (STA)
• Occurrence of headache and change of headache intensity scores [ Time Frame: Before (-10 minutes) and after the drug administration (+2 hours) ]
  Headache intensity scores are measured by numerical rating scale (NRS)

Current Secondary Outcome Measures (submitted: October 19, 2020)

• Change in cranial hemodynamic [ Time Frame: Before (-10 minutes) and after the drug administration (+3 hours) ]
  Change on diameter (mm) of superficial temporal artery (STA)
• Occurrence of headache and change of headache intensity scores [ Time Frame: Before (-10 minutes) and after the drug administration (+12 hours) ]
  Headache intensity scores are measured by a numerical rating scale (NRS). It is a verbally declared scale from 0 to 10, where 0 is no headache; 1 is a very mild headache, including a feeling of pressing or throbbing; 5 is a moderate headache; 10 is the worst imaginable headache.
• Change in Mean Arterial Pressure [ Time Frame: Before (-10 minutes) and after the drug administration (+3 hours and 20 minutes) ]
  Blood pressure was measured using an auto-inflatable cuff (Protocol, Oregon, USA). Blood pressure was registered as mean arterial pressure (MAP), equal to diastolic blood pressure + 1/3 (systolic blood pressure - diastolic blood pressure).
• Change in Heart Rate [ Time Frame: Before (-10 minutes) and after the drug administration (+3 hours and 20 minutes) ]
  Heart rate was measured using an auto-inflatable cuff (Protocol, Oregon, USA).

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Other

Condition

• Migraine
• Pain
• Neurologic Manifestations
• Signs and Symptoms
• Brain Diseases
• Central Nervous System Diseases

Intervention

• Drug: Vasoactive Intestinal Polypeptide (VIP)
  20 episodic migraine patients without aura of both genders are randomized to receive a 2-hour infusion of VIP and/or sterile saline on two days, with at least one week in between.
  Other Name: Vasoactive Intestinal Peptide (VIP)
• Drug: Sterile saline
  20 episodic migraine patients without aura of both genders are randomized to receive a 2-hour infusion of VIP and/or sterile saline on two days, with at least one week in between.
  Other Names:

  • Isotonic saline
  • 0.9% saline

Study Arms

• Active Comparator: Vasoactive Intestinal Polypeptide (VIP)

  Intravenous infusion of 8 pmol/Kg/min of Vasoactive Intestinal Polypeptide (VIP).

  The infusion is administered at constant speed by an automatic pump, lasting 120 minutes.

  Intervention: Drug: Vasoactive Intestinal Polypeptide (VIP)
• Placebo Comparator: Sterile, isotonic, non-active saline (Placebo)
  Intravenous infusion of sterile, isotonic, non-active saline 9 mg/ml (placebo). The infusion is administered at constant speed by an automatic pump, lasting 120 minutes.
  Intervention: Drug: Sterile saline

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 28, 2020): 21
• Original Estimated Enrollment (submitted: February 5, 2020): 20
• Actual Study Completion Date: September 15, 2020
• Actual Primary Completion Date: September 15, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 40 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT04260035
• Other Study ID Numbers: H-19075630
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Lanfranco Pellesi, Danish Headache Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Danish Headache Center
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Messoud Ashina, MD, PhD; Danish Headache Center

• PRS Account: Danish Headache Center
• Verification Date: October 2020