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The Effects of Ivabradine on Levcromakalim-induced Migraine (ILMO)

Primary Purpose

Headache, Migraine

Status

Recruiting

Phase

Not Applicable

Locations

Denmark

Study Type

Interventional

Intervention

Ivabradine

Calcium

About this trial

This is an interventional other trial for Headache, Migraine

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Be able to give voluntary written informed consent to participate.
Have a diagnosis of episodic migraine without aura according to The International Classification of Headache Disorders 3rd Edition.
Be in good general health and without any cardio- or cerebrovascular diseases, psychiatric disorders or other severe comorbidities.
Be 18-60 years of age.
Have a weight between 50-100 kg.
Have a normal standard resting 12-lead ECG at the screening visit with heart rate (HR) ≥ 60 bpm (the inclusion criterium of HR ≥ 60 bpm at screening has previously been used in studies with dosages of ivabradine up to 20 mg as single and multiple doses with no significant adverse events).
Be without any chronic use of medicine.
Have a negative urine-human chorionic gonadotropin (hCG) test at the screening visit if they are female of childbearing potential.

Exclusion Criteria:

Suffer from tension type headache, as defined by the The International Classification of Headache Disorders 3rd Edition, more than five days a month on average in the last year.
Are diagnosed with any primary headache disorder apart from migraine without aura as de-fined in The International Classification of Headache Disorders 3rd Edition (relating to tension type headache, see above).
Suffer from any headache 48 hours prior to the start of the experiment or any migraine 72 hours prior to the start of the experiment.
Are allergic to ivabradine or levcromakalim.
Are lactose intolerant (due to Ivabradine tablets containing lactose).
Have a daily intake of any medicine other than oral contraception or use of drugs or other ed-ibles/beverages with potential serious interactions with ivabradine
Have a history of personal/familial or clinical signs of: cardiovascular and cerebrovascular disease (Long QT Syndrome, Cardiac dysrhythmia, Bradycardia, i.e. a resting heart rate of < 60 bpm at screening, Amnestic information or clinical signs of hyper- or hypotension (Hypertension (systolic blood pressure > 150 mmHg and / or diastolic blood pressure > 100 mmHg)/Hypotension (systolic blood pressure < 90 mm Hg and / or diastolic blood pressure < 50 mmHg)), Heart failure (NYHA II or higher)); Psychiatric conditions; Drug abuse of any kind; Smoking; Other comorbidities or clinical signs of diseases of any kind considered by the investigating physician to make the participant ineligible because of safety concerns).
Are pregnant, breastfeeding or not using appropriate contraception.
Do not want any information on significant pathological findings in the study.

Sites / Locations

Rigshospitalet-GlostrupRecruiting
Danish Headache CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Ivabradine

Placebo

Arm Description

Infusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of ivabradine (15 mg orally).

Infusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of placebo.

Outcomes

Primary Outcome Measures

Headache incidence

Difference in incidence of headache and migraine-like headache in patients with migraine without aura after administrating ivabradine or placebo and the headache-inducing compound levcromakalim.

Secondary Outcome Measures

Change in head-pain intensity rated verbally on a numerical rating scale (NRS) from 0-10

Difference in intensity of headache and migraine-like headache in patients with migraine without aura, rated verbally on a numerical rating scale (NRS) from 0-10 (0 represents no pain, 1 an "altered, pressing or throbbing but not really painful feeling", 5 moderate headache and 10 the worst possible headache), after administrating ivabradine or placebo and the headache-inducing compound levcromakalim.

Changes in cerebral hemodynamics assessed using Transcranial Doppler Ultrasound (TCD) and high-frequency ultrasound (Dermascan C, Cortex Technology, Denmark)

Changes in cerebral hemodynamics will be assessed using Transcranial Doppler Ultrasound (TCD) (2 Mhz, DWL) to measure the velocity of middle cerebral artery (VMCA) blood flow bilaterally, and high-frequency ultrasound (Dermascan C, Cortex Technology, Denmark) to measure the diameter of the superficial temporal artery (STA) bilaterally.

Changes in blood pressure

Changes in blood pressure (systolic and diastolic) over time.

Heart rate

Changes in heart rate over time.

Full Information

NCT ID

NCT04853797

First Posted

March 16, 2021

Last Updated

April 18, 2021

Sponsor

Danish Headache Center

1. Study Identification

Unique Protocol Identification Number

NCT04853797

Brief Title

The Effects of Ivabradine on Levcromakalim-induced Migraine

Acronym

ILMO

Official Title

The Effects of Ivabradine on Levcromakalim-induced Headache in Patients With Migraine Without Aura

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Recruiting

Study Start Date

April 16, 2021 (Actual)

Primary Completion Date

January 1, 2023 (Anticipated)

Study Completion Date

December 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Danish Headache Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Hyperpolarization-activated cation (HCN) channels have recently been implicated in neuropathic and inflammatory pain processes, and HCN channel activity is modulated by signalling molecules, such as cyclic nucleotides (cAMP, cGMP) and extracellular potassium, known to induce migraine. To uncover the role of HCN channels in migraine, the researchers will investigate the anti-migraine effect of ivabradine, the only HCN channel blocker available for clinical use, on levcromakalim-induced migraine.

Detailed Description

Hyperpolarization-activated cation (HCN) channels have recently been implicated in neuropathic and inflammatory pain processes through their hyperfunction and/or overexpression, and HCN channels may play a significant role in migraine pathophysiology, as both an inflammatory and a neuropathic component has been hypothesized to contribute to migraine, and HCN channel activity is facilitated by cyclic nucleotides, e.g. cAMP and cGMP (molecules thought to be central in migraine pathophysiology) and increases in extracellular K+ concentration causing Ih current amplification. Indeed, increases in cAMP or directly opening adenosine 5'-triphosphate-sensitive K+ channels (KATP channel) by levcromakalim leads to migraine attacks in a high proportion of patients, suggesting a crucial role for these channels in migraine pathophysiology. KATP channel activation leads to hyperpolarization, which in turn could increase the open probability of HCN channels. To uncover the role of HCN channels in migraine, the researchers will investigate the anti-migraine effect of ivabradine, the only HCN channel blocker available for clinical use, on levcromakalim-induced migraine. The investigators anticipate that this project will contribute greatly to the current understanding of migraine pathophysiology and the hypothesized role of HCN channels in migraine pain mechanisms. This is of great interest in future research, as such knowledge is an important prerequisite for further investigation and understanding of intracellular signalling mechanisms in migraine, which in turn will lead to the development of more effective and mechanism-based drugs.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Headache, Migraine

7. Study Design

Primary Purpose

Other

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Ivabradine

Arm Type

Active Comparator

Arm Description

Infusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of ivabradine (15 mg orally).

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Infusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of placebo.

Intervention Type

Drug

Intervention Name(s)

Ivabradine

Intervention Description

To investigate the role of ivabradine on levcromakalim-induced migraine in patients with migraine without aura.

Intervention Type

Drug

Intervention Name(s)

Calcium

Intervention Description

To investigate the role of calcium on levcromakalim-induced migraine in patients with migraine without aura.

Primary Outcome Measure Information:

Title

Headache incidence

Description

Difference in incidence of headache and migraine-like headache in patients with migraine without aura after administrating ivabradine or placebo and the headache-inducing compound levcromakalim.

Time Frame

10 minutes before levcromakalim infusion until 12 hours after levcromakalim infusion.

Secondary Outcome Measure Information:

Title

Change in head-pain intensity rated verbally on a numerical rating scale (NRS) from 0-10

Description

Time Frame

10 minutes before levcromakalim infusion until 12 hours after levcromakalim infusion.

Title

Changes in cerebral hemodynamics assessed using Transcranial Doppler Ultrasound (TCD) and high-frequency ultrasound (Dermascan C, Cortex Technology, Denmark)

Description

Time Frame

10 minutes before levcromakalim infusion until 150 minutes after levcromakalim infusion.

Title

Changes in blood pressure

Description

Changes in blood pressure (systolic and diastolic) over time.

Time Frame

10 minutes before levcromakalim infusion until 150 minutes after levcromakalim infusion.

Title

Heart rate

Description

Changes in heart rate over time.

Time Frame

10 minutes before levcromakalim infusion until 150 minutes after levcromakalim infusion.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Be able to give voluntary written informed consent to participate. Have a diagnosis of episodic migraine without aura according to The International Classification of Headache Disorders 3rd Edition. Be in good general health and without any cardio- or cerebrovascular diseases, psychiatric disorders or other severe comorbidities. Be 18-60 years of age. Have a weight between 50-100 kg. Have a normal standard resting 12-lead ECG at the screening visit with heart rate (HR) ≥ 60 bpm (the inclusion criterium of HR ≥ 60 bpm at screening has previously been used in studies with dosages of ivabradine up to 20 mg as single and multiple doses with no significant adverse events). Be without any chronic use of medicine. Have a negative urine-human chorionic gonadotropin (hCG) test at the screening visit if they are female of childbearing potential. Exclusion Criteria: Suffer from tension type headache, as defined by the The International Classification of Headache Disorders 3rd Edition, more than five days a month on average in the last year. Are diagnosed with any primary headache disorder apart from migraine without aura as de-fined in The International Classification of Headache Disorders 3rd Edition (relating to tension type headache, see above). Suffer from any headache 48 hours prior to the start of the experiment or any migraine 72 hours prior to the start of the experiment. Are allergic to ivabradine or levcromakalim. Are lactose intolerant (due to Ivabradine tablets containing lactose). Have a daily intake of any medicine other than oral contraception or use of drugs or other ed-ibles/beverages with potential serious interactions with ivabradine Have a history of personal/familial or clinical signs of: cardiovascular and cerebrovascular disease (Long QT Syndrome, Cardiac dysrhythmia, Bradycardia, i.e. a resting heart rate of < 60 bpm at screening, Amnestic information or clinical signs of hyper- or hypotension (Hypertension (systolic blood pressure > 150 mmHg and / or diastolic blood pressure > 100 mmHg)/Hypotension (systolic blood pressure < 90 mm Hg and / or diastolic blood pressure < 50 mmHg)), Heart failure (NYHA II or higher)); Psychiatric conditions; Drug abuse of any kind; Smoking; Other comorbidities or clinical signs of diseases of any kind considered by the investigating physician to make the participant ineligible because of safety concerns). Are pregnant, breastfeeding or not using appropriate contraception. Do not want any information on significant pathological findings in the study.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Mohammad al-Karagholi, MD

Phone

31191647

mahdi.alkaragholi@gmail.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Messoud Ashina, Prof.

Organizational Affiliation

Danish Headache Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Rigshospitalet-Glostrup

City

Glostrup

State/Province

Nordre Ringvej 57

ZIP/Postal Code

2600

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Mohammad A Al-Karagholi, MD

Phone

00 45 31 19 16 47

mahdi.alkaragholi@gmail.com

First Name & Middle Initial & Last Name & Degree

Song Guo, MD, PhD

Facility Name

Danish Headache Center

City

Glostrup

ZIP/Postal Code

2600

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Mohammad Al-Karagholi

Phone

31191647

mahdi.alkaragholi@gmail.com

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

The Effects of Ivabradine on Levcromakalim-induced Migraine

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