Selective Activation of the Adrenomedullin Receptors in Migraine

Official title

Selective Activation of the Adrenomedullin Receptors in Migraine: A Randomized, Double-Blind, Placebo-Controlled Crossover Study

Overview

Adrenomedullin is a neuropeptide implicated in the pathogenesis of migraine. This study investigates whether its administration, after pre-treatment with erenumab (a CGRP-receptor blocking monoclonal antibody), can trigger migraine attacks in individuals with migraine without aura.

Detailed description

Adrenomedullin is an endogenous neuropeptide structurally related to CGRP that can activate both the adrenomedullin receptor and, to a lesser extent, the CGRP receptor. Prior human provocation studies have shown that administration of adrenomedullin can elicit migraine attacks in people with migraine. Because adrenomedullin lacks receptor selectivity, physiological responses observed after its administration might represent a composite of adrenomedullin-receptor activation and potential off-target activation of the CGRP receptor. The extent to which selective activation of the adrenomedullin receptor alone can provoke migraine-relevant responses remains unknown.

To isolate adrenomedullin receptor-mediated effects, participants will receive the monoclonal antibody erenumab prior to adrenomedullin administration in order to block CGRP receptor activation.

This study therefore aims to determine whether selective activation of adrenomedullin receptors - isolated from confounding CGRP receptor activation - can induce migraine-relevant physiological responses.

Interventions

• Drug Adrenomedullin
  Continous intravenous infusion of 20 mL (19.9 pmol/kg/min) adrenomedulin over 20 minutes
• Other Placebo
  Continous intravenous infusion of 20 mL isotonic saline over 20 minutes

Primary outcome measures

• Incidence of migraine attacks [Time frame: Assessed from baseline to 12 hours post-infusion of adrenomedullin or placebo]

Secondary outcome measures (1)

• Headache intensity [Time frame: Assessed from baseline to 12 hours post-infusion of adrenomedullin or placebo]

Eligibility criteria

Inclusion criteria

• Written informed consent has been obtained prior to the initiation of any study-specific procedures.
• Age ≥18 years at the time of screening.
• History of migraine without aura for at least 12 months prior to screening, with a frequency of 1-5 migraine attacks per month, based on medical records and/or patient self-report, and diagnosed in accordance with the ICHD-3 criteria.

Exclusion criteria

• History of any other primary headache disorder, except for tension-type headache with <5 headache days per month, based on ICHD-3 classification.
• History of any secondary headache disorder, per ICHD-3 criteria, prior to screening.
• Use of prophylactic migraine medication within 30 days or within 5 plasma half-lives (whichever is longer) prior to screening.
• Previous use of any therapies targeting the CGRP signaling pathway, including anti-CGRP ligand monoclonal antibodies, anti-CGRP receptor monoclonal antibodies, or small molecule CGRP receptor antagonists.
• Known risk of self-harm or harm to others, including a history of suicidal behavior.
• Any clinically significant disorder, condition, or disease (other than those permitted in the protocol) that, in the opinion of the investigator, could compromise participant safety or interfere with study procedures or data integrity.
• Positive urine pregnancy test at screening or on Day 1 in female participants of childbearing potential.
• Pregnancy or breastfeeding, or plans to become pregnant or breastfeed during the study period.
• Evidence of current pregnancy or breastfeeding based on self-report or medical records.
• Inability or unwillingness to complete all protocol-required visits and procedures, or concerns regarding protocol adherence, as judged by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Basic science

Study locations

Denmark · 1 center

• Danish Headache Center — Glostrup Municipality

Publications

• Do TP, Younis S, Ashina M. Erenumab [Internet]. 2021. p. 121-9.Available from: https://link.springer.com/10.1007/978-3-030-69032-8_9
• Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017 Nov 30;377(22):2123-2132. doi: 10.1056/NEJMoa1705848. PMID 29171821
• de Hoon J, Van Hecken A, Vandermeulen C, Yan L, Smith B, Chen JS, Bautista E, Hamilton L, Waksman J, Vu T, Vargas G. Phase I, Randomized, Double-blind, Placebo-controlled, Single-dose, and Multiple-dose Studies of Erenumab in Healthy Subjects and Patients With Migraine. Clin Pharmacol Ther. 2018 May;103(5):815-825. doi: 10.1002/cpt.799. Epub 2017 Oct 24. PMID 28736918
• Giamberardino MA, Affaitati G, Costantini R, Cipollone F, Martelletti P. Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab. J Pain Res. 2017 Dec 8;10:2751-2760. doi: 10.2147/JPR.S128143. eCollection 2017. PMID 29263689
• Meeran K, O'Shea D, Upton PD, Small CJ, Ghatei MA, Byfield PH, Bloom SR. Circulating adrenomedullin does not regulate systemic blood pressure but increases plasma prolactin after intravenous infusion in humans: a pharmacokinetic study. J Clin Endocrinol Metab. 1997 Jan;82(1):95-100. doi: 10.1210/jcem.82.1.3656. PMID 8989240
• Ashina M, Hansen JM, A Dunga BO, Olesen J. Human models of migraine - short-term pain for long-term gain. Nat Rev Neurol. 2017 Dec;13(12):713-724. doi: 10.1038/nrneurol.2017.137. Epub 2017 Oct 6. PMID 28984313
• Hay DL, Garelja ML, Poyner DR, Walker CS. Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol. 2018 Jan;175(1):3-17. doi: 10.1111/bph.14075. Epub 2017 Nov 28. PMID 29059473
• Ghanizada H, Al-Karagholi MA, Arngrim N, Morch-Rasmussen M, Walker CS, Hay DL, Ashina M. Effect of Adrenomedullin on Migraine-Like Attacks in Patients With Migraine: A Randomized Crossover Study. Neurology. 2021 May 18;96(20):e2488-e2499. doi: 10.1212/WNL.0000000000011930. Epub 2021 Apr 7. PMID 33827963

Identifiers

NCT: NCT07451769 · 118122

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗