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HeadacheILIMNCT04853797

Effect of Ivabradine on Levcromakalim-Induced Symptoms in Individuals With Migraine Without Aura (ILIM)

A study testing Levcromakalim and Ivabradine in people with Headache and Migraine Without Aura, run by Danish Headache Center at 2 sites in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study aims to explore the effect of Ivabradine on Levcromakalim-induced migraine in individuals with migraine without aura. Read more about this study

Who is it for?
Ages 18 to 60 years
Conditions the study is for
Headache, Migraine Without Aura
What is being tested?
Levcromakalim and Ivabradine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
37 participants
Where
2 sitesDenmark
Study dates
11 May 2021to 6 Jul 2025
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 9Show fewer
  • 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.

Trial locations and contacts

2 sites in 1 country.

Denmark2 sites

  • Danish Headache Centre, Rigshospitalet-Glostrup

    Glostrup, Region Sjælland, 2600

  • Danish Headache Center

    Glostrup Municipality, 2600

Other trials in Denmark

About this study

Official title: Effect of Ivabradine on Levcromakalim-Induced Symptoms in Individuals With Migraine Without Aura: A Randomized Double-Blind Two-Way Crossover Study

This study aims to explore the effect of Ivabradine on Levcromakalim-induced migraine in individuals with migraine without aura.

Read the detailed description

Hyperpolarization-activated cation (HCN) channels have recently been implicated in neuropathic and inflammatory pain processes through their hyperfunction and/or overexpression.

HCN channels may play a significant role in migraine pathophysiology, as 1) both an inflammatory and a neuropathic component has been hypothesized to contribute to migraine, and 2) 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.

Opening of adenosine 5'-triphosphate-sensitive potassium channels (KATP channels) using Levcromakalim causes migraine attacks with and without aura in a high proportion of patients. KATP channel activation leads to hyperpolarization, which in turn could increase the open probability of HCN channels.

This study aims to explore the effects of Ivabradine on Levcromakalim-induced migraine in individuals with migraine without aura.

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.

Being tested
Levcromakalim, Ivabradine, Placebo
Medical subject headings
Headache, Migraine without Aura

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LevcromakalimDrug

    20 min infusion of 1 mg Levcromakalim followed by either oral Ivabradine or Placebo.

  • IvabradineDrug

    15 mg oral Ivabradine.

  • PlaceboDrug

    Oral placebo (calcium supplements).

Study groups in NCT04853797
Study groupRoleWhat they receive
Levcromakalim - IvabradineActive comparatorInfusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of ivabradine (15 mg orally).
Receives: Drug: Levcromakalim; Drug: Ivabradine
Levcromakalim - PlaceboPlacebo comparatorInfusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of placebo.
Receives: Drug: Levcromakalim; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of migraine attacks

    A migraine attack is defined as an attack fulfilling either (i) or (ii):

    (i) Headache fulfilling criteria C and D for migraine without aura according to the International Headache Society criteria:

    1. Headache has at least two of the following characteristics:
    • unilateral location
    • pulsating quality
    • moderate or severe pain intensity (moderate to severe pain intensity is considered ≥4 on verbal rating scale)
    • aggravation by cough (in-hospital phase) or causing avoidance of routine physical activity (out-hospital phase)
    1. 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).

    Measured: Assessed from baseline to 12 hours after infusion of levcromakalim

Secondary outcomes (6)

  1. Incidence of headache

    Incidence of headache is defined as headache intensity ≥1 as measured by a numerical rating scale (NRS) from 0 to 10. It is a verbally declared scale from 0 to 10, where 0 is no pain; 10 is the worst pain imaginable

    Measured: Assessed from baseline to 12 hours after infusion of levcromakalim

  2. Intensity of headache

    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 pain; 10 is the worst pain imaginable.

    Measured: Assessed from baseline to 12 hours after infusion of levcromakalim

  3. Changes in cerebral hemodynamics (velocity of blood flow in middle cerebral artery and diameter of superficial temporal artery) 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.

    Measured: Assessed from baseline until 150 minutes after levcromakalim infusion.

  4. Changes in blood pressure

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

    Measured: Assessed from baseline until 150 minutes after levcromakalim infusion.

  5. Heart rate

    Changes in heart rate over time.

    Measured: Assessed from baseline until 150 minutes after levcromakalim infusion.

  6. Incidence of adverse events

    Participants are instructed to inform the investigators in the case of adverse events.

    Measured: Assessed from baseline to 12 hours after infusion of Levcromakalim.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Apr 2021
  2. Study start11 May 2021
  3. Primary completion6 Jul 2025
  4. Study completion6 Jul 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Other
Allocation
Randomised
Intervention model
Crossover
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
37 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04853797
Sponsor's protocol ID
Ivabradine H-20061329
Acronym
ILIM
Status last verified
Jan 2026
First submitted
16 Mar 2021
Last updated
8 Jan 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Zhuang ZA, Thuraiaiyah J, Kokoti L, Moreno RD, Gozalov E, Hakimzadeh Z, Al-Karagholi MA, Clement A, Kristensen DM, Abdulla J, Christensen SL, Ashina M. Migraine induced by vascular KATP channel activation is independent of HCN channel activity: A randomised controlled trial with translational validation. Cephalalgia. 2026 Apr;46(4):3331024261431770. doi: 10.1177/03331024261431770. Epub 2026 Apr 3.

    PubMed 41930571

Questions about this trial

What is this clinical trial studying?

A study testing Levcromakalim and Ivabradine in people with Headache and Migraine Without Aura, run by Danish Headache Center at 2 sites in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of migraine attacks (time frame: Assessed from baseline to 12 hours after infusion of levcromakalim). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04853797, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jan 2026.

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