Clinical trial NCT04628429: CGRP Inhibition, Autonomic Function, and Migraine
Official title: Autonomic Functions in Migraine Patients as a Function of Migraine Status and CGRP Inhibition
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Episodic Migraine
Chronic Migraine
Keywords: Calcitonin gene-related peptide inhibition
Monoclonal antibodies
Autonomic function
Composite Autonomic Symptom Scale 31
Migraine Disability Assessment Scale
Depression Anxiety Stress Scales
Cardiovascular Autonomic Dysfunction
Headache Impact Questionnaire
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2020-11-13
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients diagnosed to be suffering from migraine without aura, migraine with aura or chronic migraine according to the diagnostic criteria of the International Classification of Headache Disorders, third edition (ICHD-3). Patients will be ages 18 to 64. It is mandatory they have valid health insurance provided by one of the insurance institutions of Austria.

Controls must be healthy (free of any diagnosed chronic disease or acute infection requiring medication), chosen to be as similar as possible to migraine patients, in terms of age and sex

Brief summary: The purpose of this clinical study is to better understand the function of the autonomic nervous system in patients with migraine. We aim to understand whether the autonomic functions change depending on the migraine status (i.e. whether they are between or during attacks) and whether the CGRP monoclonal antibody (mAb) class of drugs affects the autonomic functions. The aim is not to investigate the effect of CGRP-mAb on migraine frequency. Calcitonin gene-related peptide (CGRP) is a neurotransmitter in the nervous system that plays an essential role in the development of migraine headache. Monoclonal antibodies can block the function of this messenger substance. Several studies have shown that this blockade leads to a reduction in the frequency of migraine.

In addition to its role in migraine, CGRP also acts on the blood vessels and the autonomic nervous system. The autonomic nervous system is responsible for everything we have no control over in our body. This includes everything from heart rate and blood pressure to our digestion.

Detailed description: Background:

Headache disorders are among the leading illnesses contributing to the Global Burden of Disease. They are so common, that they rank second in prevalence and years lived with disability. Additionally, headache disorders are the second-ranked cause of years lived with disability in females, worldwide. Migraines are so prevalent in human history that there exist records from the ancient Egyptians documenting symptoms of attacks.

Migraines are classified by the International Headache Society in their International Classification of Headache Disorders 3 (ICHD-3) guidelines as: migraine without aura, migraine with aura, chronic migraine, and probable migraine. They are considered episodic if headache is present on fewer than 15 days per month; or chronic if headache occurs "on 15 or more days/month for more than 3 months, which, on at least 8 days/month, has the features of migraine headache". Until now, researchers have made numerous connections between migraines and the autonomic symptoms that manifest both ictally and interictally. Research, using standardized autonomic tests, has improved our ability to evaluate these symptoms. Furthermore, strides have been made to map migraine attacks and visualize them. Finally, research directed towards the molecular mechanism of these attacks has also yielded results.

Current recommendations for pharmacological migraine treatment comprise abortive drugs (i.e. non-opioid analgesics and triptans) and prophylactic medication (e.g. beta-blockers, calcium-channel blockers, antidepressants, anti-seizure medications and onabotulinumtoxin A). None of these prophylactic drugs were specifically developed against migraine. Their dosages must be slowly increased, since these medications can lead to fatigue, depression, nausea, insomnia, decreased libido, along with many other side effects specific to the individual modalities. Therefore, a more favorable treatment is required.

Molecular evidence is accumulating that calcitonin gene-related peptide (CGRP) contributes greatly to this pathophysiology. In tandem, evidence of CGRP's role in other physiological mechanisms has also been elucidated. These include roles in: vasodilation, cardioprotection, blood pressure regulation, sepsis, wound healing, bone re-growth, among others. The majority of CGRP is sequestered at the trigeminal level; however, it is released from both peripheral and central nerve terminals. As such, investigation of parasympathetic - and reciprocally, the sympathetic - autonomic nervous system (ANS) pathways are of particular interest. It is, however, CGRP's connection to migraines which has, consequently, led to the development of several CGRP receptor antagonists, an anti-CGRP-receptor monoclonal anti-body (mAb) and several anti-CGRP-ligand mAbs.

Only recently have anti-CGRP antibodies been approved by the European Medicines Agency. There are three prophylactic pharmaceutical options targeting CGRP currently available and reimbursed in Austria. Erenumab (Aimovig® - anti-receptor) is available since September 2018, Galcanezumab (Emgality® - anti-ligand) since March 2019 and Fremanezumab (Ajovy® - anti-ligand) since May 2019. Randomized controlled trials are also ongoing for Eptinezumab (anti-ligand). The largest benefit provided by anti-CGRP monoclonal antibodies is that they are relatively well-tolerated - shown to reduce the frequency of attacks experienced by the patient each month. As such, CGRP-related monoclonal antibodies are being increasingly utilized; however, there is a very limited amount of exogenous medication that does not have unwanted interactions once administered into the body.

In randomized, placebo-controlled studies on the efficacy and tolerability of anti-CGRP monoclonal antibodies (ant-CGRP-mAbs), no serious side effects were found. Those that were found and are provided in official documentation, include: injection site reactions, constipation, muscle cramps, vertigo, pruritus, and urticaria. Meanwhile other recipients of the therapy reported: nasopharyngitis, infection, sinusitis, fatigue, hypertension, nausea, arthralgia, back pain, and migraine. Due to potent vasodilative functions of CGRP, a list of contraindications was created. This list includes: manifestation of vascular diseases (myocardial infarction, unstable angina pectoris, stroke, transient ischemic attacks, coronary bypass surgery or other revascularization procedures within the last 12 months) and poorly controlled hypertension. It is still unknown what the potential course and prognosis of de novo myocardial infarction, cerebral ischemia and subarachnoid hemorrhage could be for patients receiving anti-CGRP medication. Calcitonin gene related peptide has been shown to promote angio- and lymphangiogenesis. Post-ischemic angiogenesis has been observed with the release of CGRP. Meanwhile, CGRP has been shown to improve lymphangiogenesis in secondary lymphedema. Further warnings concerning pregnancy and the desire to have children, potential damage to the blood-brain barrier (e.g. meningitis, stroke, after neurosurgery) and recent peripheral nerve lesions have arisen; and, appropriate longitudinal observations are only now being reported.

While autonomic symptoms of migraine are well known - such as: nausea/vomiting, hyperhidrosis, pallor, palpitations, and lightheadedness - the methods with which earlier investigations evaluated them are not as well-standardized. A review by Miglis, from 2018, summarizes that most studies of autonomic function in migraine showed reduced sympathetic function in migraineurs; while others, reported increased sympathetic function; and others still, showed normal sympathetic function. Likewise, the majority of studies reported normal parasympathetic cardiovagal function; while others, reported decreased parasympathetic function. Miglis goes on to describe in his review, a variety of investigations used to arrive at these conclusions - heart rate variability (HRV) studies, autonomic cardiovascular reflex testing and imagining studies. These paradoxical results can be interpreted as being caused by methodological inconsistency between investigations. For example, some HRV investigations elect to use 24h continuous electrocardiogram (ECG) monitoring, while others use ECG measurements during the head-up tilt test to gather HRV data. This results in the uncoordinated use of different methods, which ultimately illustrates the need for consistent, standardized testing of the ANS in migraine studies.

Considering the concerns expressed by Tringali and Navarra - to observe the long-term effects of CGRP-inhibition, as it pertains to autonomic function - there currently exists great potential to address this gap in knowledge. Therefore, this non-therapeutic biomedical study aims to address this lack of literature, by obtaining and comparing standardized healthy CAD values with those of migraineurs, observing CAD values in migraine patients off prophylactic therapy - in both the ictal and peri-ictal phases of the migraine cycle - and then comparing baseline CAD values with CAD values during anti-CGRP therapy.

Primary explorative questions:

This study will aim to address the autonomic aspects of migraine, through a newly published objective autonomic function scoring. It aims to explore whether differences exist in the autonomic function values (CAD) between healthy people and migraine patients. Furthermore, it will aim to explore the CAD differences between migraine attack-phases (peri-ictal and interictal). Lastly, over the course of 5 months, this study will explore whether inhibition of CGRP - as an anti-CGRP-mAb class-effect - affects these autonomic function scores. The following questions will be answered:

Q1: Is there a difference in CAD values between healthy controls and migraine patients off prophylactic medication?

Q2: Is there a difference in the CAD values of migraine patients during a migraine attack (peri-ictal phase) and their respective CAD values between attacks (interictal phase)?

Q3: Is there a difference in CAD values of migraine patients before anti-CGRP treatment and during treatment with anti-CGRP-mAbs (class effect on autonomic functions)?

Secondary Question:

To support the examination of these three questions, validated questionnaires will be used to assess the subjective effect of anti-CGRP-mAbs on: monthly migraine and headache days, autonomic function, quality of life and psychiatric symptoms.

Study Proceudres:

For the patients the study will comprise of: 1) a patient screening phase (following recruitment); 2) two clinical baseline visits (day 0 and one day between days 1 and 30); 3) an evaluation visit (month 5), which will also serve as the End of Study (EOS); and 4) a telephone follow-up. For the healthy controls the study will comprise: 1) a patient screening phase; 2) one testing visit (day 0); and 3) a telephone follow-up.

Eligibility criteria: Inclusion Criteria:

* Chronic migraine according to ICHD-3
* Episodic migraine without aura or with aura according to ICHD-3
* Unsuccessful treatment with 3 or more established prophylactic drugs
* Medicine costs are covered by health insurance
* Healthy controls must be free from any diagnosed chronic disease or acute infection requiring medication

Exclusion Criteria:

* Pregnancy and lactation
* Neurosurgical interventions performed within the last 12 months
* Coronary bypass surgery or revascularization procedures performed within the last 12 months
* History of transient ischemic attacks (TIA), stroke, stable or unstable angina pectoris, myocardial infarction or uncontrolled hypertension
* Known hypersensitivity to therapy with an anti-CGRP Antibodies
* History of a disorder (other than migraine) that may affect the results of autonomic tests
* Healthy controls must have no personal or family history of migraine

Primary outcomes:
measure: Change from Day 0 Cardiovagal Autonomic Dysfunction (CAD) at 5 months
timeFrame: Day 0, Month 5 (EOS)
measure: Change from Days 1-31 Cardiovagal Autonomic Dysfunction (CAD) at 5 months
timeFrame: Days 1-31, Month 5 (EOS)
measure: Change from Days 0 Cardiovagal Autonomic Dysfunction (CAD) at Days 1-31
timeFrame: Day 0, Days 1-31
Secondary outcomes:
measure: Change from Days 0 Composite Autonomic Symptom Scale 31 (COMPASS-31) at 5 months
timeFrame: Day 0, Month 5 (EOS)
measure: Change from Days 0 Day Impact Questionnaire (HIQ) at 5 months
timeFrame: Day 0, Month 5 (EOS)
measure: Change from Days 0 Non-Headache Day Impact Questionnaire (Non-HIQ) at 5 months
timeFrame: Day 0, Month 5 (EOS)
measure: Change from Days 0 Migraine Disability Assessment Scale (MIDAS) at 5 months
timeFrame: Day 0, Month 5 (EOS)
measure: Change from Days 0 Depression Anxiety Stress Scale (DASS) at 5 months
timeFrame: Day 0, Month 5 (EOS)
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
affiliation: Medical University of Vienna
name: Christian Wöber, Prof. MD
role: PRINCIPAL_INVESTIGATOR
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