Amylin-Induced Migraine Attacks Without Aura

Amylin-Induced Migraine Attacks Without Aura: A Randomized Clinical Trial

Pramlintide is a peptide analogue of human amylin which is a vasoactive signaling molecule involved in the pathogenesis of migraine. This study investigates whether pramlintide induces migraine attacks without aura in people with migraine without aura.

Study Overview

• Status: Not yet recruiting
• Conditions: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Migraine Disorders; Headache; Headache Disorders, Primary; Headache Disorders; Signs and Symptoms; Hormones; Pathological Conditions, Signs and Symptoms; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Amylin; Pramlintide
• Intervention / Treatment: Drug: Amylin; Drug: Placebo

Detailed Description

Amylin is a vasoactive substance that acts on vascular smooth muscle and can cause vasodilation. It is naturally present in the trigeminovascular system, an important structure involved in headache development. Recent studies indicate that intravenous infusion of pramlintide, an amylin analogue, can trigger migraine attacks in people with migraine. This study aims to determine whether intravenous pramlintide can induce migraine attacks without aura in individuals who experience migraine without aura. To test this, the investigators will conduct a randomized, double-blind, placebo-controlled, two-way crossover trial.

• 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: haidardk@hotmail.com

Study Locations

• Denmark
  • Glostrup Municipality, Denmark, 2600
    • Rigshospitalet Glostrup
    • Contact: Hakan Ashina, MD, PhD; Phone Number: +4528102495; Email: haakan.ashina@regionh.dk
    • Contact: Haidar Al-Khazali, MD, PhD; Phone Number: +4541598494; Email: haidardk@hotmail.com

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
• A body weight of 50 to 100 kg
• History of migraine without aura for ≥12 months and in accordance with ICHD-3
• Between 1-5 monthly migraine days without aura on average across the 3 months prior to 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 and infrequent episodic tension-type headache
• Any history of moderate to severe traumatic brain injury
• Any history of cardiovascular disease, including cerebrovascular diseases
• Any history of pulmonary disease
• Any other clinically significant disorders, conditions, or diseases that might impact the safety of the subject or interfere with the study's evaluation, procedures, or completion, aside from those mentioned above. This includes any relevant medical history or evidence that, in the opinion of the site investigator, might pose a risk to the subject or impact the validity of the study results
• 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)
• Abnormalities on the electrocardiogram that, in the opinion of the site investigator, might pose a risk to the subject or impact the validity of the study results
• Daily use of any medication other than contraceptives
• Intake of any medication other than contraceptives within 48 hours of infusion start
• Intake of caffeine, nicotine, and alcohol within 12 hours of infusion start
• Headache of any intensity within 48 hours of infusion start
• Migraine attack 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 continuous intravenous infusion of 20 mL of placebo (isotonic saline) over 20 minutes.
Experimental: Amylin; Pramlintide (Amylin) will be administered by intravenous infusion.	Drug: Amylin; The participants will receive continuous intravenous infusion of 20 mL (6 μg/min) of pramlintide (amylin) over 20 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of migraine attacks without aura	The difference in the incidence of migraine attacks without aura between pramlintide and placebo during the 12-hour observational period after infusion start.	12 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Headache intensity scores	The secondary outcome is the difference in the area under the curve (AUC) for median headache intensity scores between pramlintide and placebo during the 12-hour observational period after infusion start.	12 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Superficial temporal artery dilation	The difference in AUC for relative superficial temporal artery (STA) dilation between pramlintide and placebo from the start of infusion to 2 hours after the infusion.	2 hours
Middle cerebral artery blood flow velocity	The difference in AUC for change in middle cerebral artery (MCA) mean blood flow velocity between pramlintide and placebo from the start of infusion to 2 hours after the infusion.	2 hours

Collaborators and Investigators

• Sponsor: Danish Headache Center

Publications and helpful links

General Publications

• Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018 Jan;38(1):1-211. doi: 10.1177/0333102417738202. No abstract available.
• Ashina M, Terwindt GM, Al-Karagholi MA, de Boer I, Lee MJ, Hay DL, Schulte LH, Hadjikhani N, Sinclair AJ, Ashina H, Schwedt TJ, Goadsby PJ. Migraine: disease characterisation, biomarkers, and precision medicine. Lancet. 2021 Apr 17;397(10283):1496-1504. doi: 10.1016/S0140-6736(20)32162-0. Epub 2021 Mar 25.
• Ashina M. Migraine. N Engl J Med. 2020 Nov 5;383(19):1866-1876. doi: 10.1056/NEJMra1915327. No abstract available.
• Asmar M, Bache M, Knop FK, Madsbad S, Holst JJ. Do the actions of glucagon-like peptide-1 on gastric emptying, appetite, and food intake involve release of amylin in humans? J Clin Endocrinol Metab. 2010 May;95(5):2367-75. doi: 10.1210/jc.2009-2133. Epub 2010 Mar 1.
• Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacol Rev. 2015 Jul;67(3):564-600. doi: 10.1124/pr.115.010629.
• Ghanizada H, Al-Karagholi MA, Walker CS, Arngrim N, Rees T, Petersen J, Siow A, Morch-Rasmussen M, Tan S, O'Carroll SJ, Harris P, Skovgaard LT, Jorgensen NR, Brimble M, Waite JS, Rea BJ, Sowers LP, Russo AF, Hay DL, Ashina M. Amylin Analog Pramlintide Induces Migraine-like Attacks in Patients. Ann Neurol. 2021 Jun;89(6):1157-1171. doi: 10.1002/ana.26072. Epub 2021 Apr 8.
• Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010 Oct;30(10):1179-86. doi: 10.1177/0333102410368444. Epub 2010 May 12.
• Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA. Migraine and the trigeminovascular system-40 years and counting. Lancet Neurol. 2019 Aug;18(8):795-804. doi: 10.1016/S1474-4422(19)30185-1. Epub 2019 May 31.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): October 30, 2028
• Study Completion (Estimated): October 30, 2028

Study Registration Dates

• First Submitted: January 5, 2026
• First Submitted That Met QC Criteria: January 5, 2026
• First Posted (Actual): January 14, 2026

Study Record Updates

• Last Update Posted (Actual): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Pain; Migraine; Headache; Amylin
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Migraine Disorders; Headache Disorders; Headache; Brain Diseases; Nervous System Diseases; Central Nervous System Diseases; Headache Disorders, Primary; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Pancreatic Hormones; Amyloidogenic Proteins; Amyloid; Islet Amyloid Polypeptide
• Other Study ID Numbers: H-24025082

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Access Criteria: 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