Hypersensitivity to Amylin in Post-Traumatic Headache

Hypersensitivity to Amylin in Post-Traumatic Headache: A Randomized Clinical Trial

Pramlintide is a peptide analogue of human amylin which is a vasoactive substance involved in the pathogenesis of headache. This study investigates whether pramlintide induces migraine-like headache in people with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI).

Study Overview

• Status: Not yet recruiting
• Conditions: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders; Headache Disorders, Secondary; Signs and Symptoms; Post-Traumatic Headache; 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: Placebo; Drug: Amylin

Detailed Description

Amylin is a vasodilator released from nerve fibers within the trigeminovascular system, which is considered a key anatomical and physiological substrate in the pathogenesis of migraine and persistent post-traumatic headache (PTH). Persistent PTH attributed to mild traumatic brain injury frequently presents with migraine attacks, suggesting shared underlying mechanisms with migraine. This study aims to determine whether intravenous infusion of pramlintide, an analogue of amylin, can induce migraine-like headache in individuals with persistent post-traumatic headache. To test this hypothesis, we will conduct a randomized, double-blind, placebo-controlled, two-way crossover study.

• 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
• History of persistent headache attributed to mild traumatic injury to the head for ≥ 12 months and in accordance with the International Classification of Headache Disorders, 3rd Edition (ICHD-3)
• ≥ 4 monthly headache days on average across the 3 months prior to screening
• Provision of informed consent prior to initiation of any study-specific activities/procedures

Exclusion Criteria:

• > 1 mild traumatic injury to the head
• History of any primary or secondary headache disorder prior to mild traumatic injury to the head (except for infrequent episodic tension-type headache)
• History of moderate or severe injury to the head
• History of whiplash injury
• History of craniotomy
• History or evidence of any other clinically significant disorder, condition or disease (except for those outlined above) than, 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
• Baseline headache intensity of >3 on an 11-point numeric rating scale (0 being no headache, 10 being the worst imaginable headache)
• Baseline migraine-like headache or self-reported baseline headache that mimics the subjects' usual migraine-like headache

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 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-like headache	Difference in incidence of migraine-like headache (0 to 12 hours) between pramlintide and placebo.	12 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Headache Intensity Scores	Difference in area under the curve (AUC) for headache intensity scores (0 to 12 hours) between pramlintide and placebo.	12 hours

Collaborators and Investigators

• Sponsor: Danish Headache Center

Publications and helpful links

General Publications

• Ashina H, Porreca F, Anderson T, Amin FM, Ashina M, Schytz HW, Dodick DW. Post-traumatic headache: epidemiology and pathophysiological insights. Nat Rev Neurol. 2019 Oct;15(10):607-617. doi: 10.1038/s41582-019-0243-8. Epub 2019 Sep 16.
• 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.
• Ashina H, Iljazi A, Al-Khazali HM, Ashina S, Jensen RH, Amin FM, Ashina M, Schytz HW. Persistent post-traumatic headache attributed to mild traumatic brain injury: Deep phenotyping and treatment patterns. Cephalalgia. 2020 May;40(6):554-564. doi: 10.1177/0333102420909865. Epub 2020 Feb 26.
• Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic headaches in a general population. Neurology. 1992 Jun;42(6):1225-31. doi: 10.1212/wnl.42.6.1225.
• Ashina H, Eigenbrodt AK, Seifert T, Sinclair AJ, Scher AI, Schytz HW, Lee MJ, De Icco R, Finkel AG, Ashina M. Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment. Lancet Neurol. 2021 Jun;20(6):460-469. doi: 10.1016/S1474-4422(21)00094-6.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 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; Amylin; Post-traumatic headache
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Headache Disorders; Brain Diseases; Nervous System Diseases; Central Nervous System Diseases; Post-Traumatic Headache; Headache Disorders, Secondary; 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-21067689

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