CGRP Inhibition, Autonomic Function, and Migraine

Study Overview
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Brief Summary
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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
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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.

Official Title
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Autonomic Functions in Migraine Patients as a Function of Migraine Status and CGRP Inhibition

Conditions
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Episodic Migraine, Chronic Migraine

Intervention / Treatment
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* Drug: Erenumab
* Drug: Galcanezumab
* Drug: Fremanezumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Episodic Migraine<br>All patients who have been diagnosed with migraine without aura or migraine with aura according to the diagnostic criteria of the International Classification of Headache Disorders, third edition (ICHD-3) and have been unsuccessfully treated with first-line prophylactic medication | Drug: Erenumab<br>* anti-CGRP-receptor monoclonal anti-body<br>* Other names: Aimovig®;Drug: Galcanezumab<br>* anti-CGRP-ligand monoclonal anti-body<br>* Other names: Emgality®;Drug: Fremanezumab<br>* anti-CGRP-ligand monoclonal anti-body<br>* Other names: Ajovy®;|
| Chronic Migraine<br>All patients who have been diagnosed with chronic migraine (≥15 headache days per month 8 of which with migrainous features) according to the diagnostic criteria of the International Classification of Headache Disorders, third edition (ICHD-3) and have been unsuccessfully treated with first-line prophylactic medication | Drug: Erenumab<br>* anti-CGRP-receptor monoclonal anti-body<br>* Other names: Aimovig®;Drug: Galcanezumab<br>* anti-CGRP-ligand monoclonal anti-body<br>* Other names: Emgality®;Drug: Fremanezumab<br>* anti-CGRP-ligand monoclonal anti-body<br>* Other names: Ajovy®;|
| Healthy Control<br>Controls must be healthy (free of any diagnosed chronic disease, acute infection requiring medication, family history or personal history of migraine), chosen to be as similar as possible to migraine patients, in terms of age and sex. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Day 0 Cardiovagal Autonomic Dysfunction (CAD) at 5 months | It is derived from the Composite Autonomic severity scale (CASS), an unbiased and full quantification of the autonomic functions in the cardiovagal, adrenergic and sudomotor domain. The total CASS score has a direct clinical meaning since it ranks the generalized dysautonomia as mild, moderate and severe. By isolating two of the indices of the CASS - adrenergic index (AI) and cardiovagal index (CI) - one can quantify the Cardiovascular Autonomic Dysfunction (CAD). Results are referred to as normal (CAD total score = 0) or abnormal. Abnormal values are considered 1-7, indicating presence of CAD. | Day 0, Month 5 (EOS) | 
| Change from Days 1-31 Cardiovagal Autonomic Dysfunction (CAD) at 5 months | It is derived from the Composite Autonomic severity scale (CASS), an unbiased and full quantification of the autonomic functions in the cardiovagal, adrenergic and sudomotor domain. The total CASS score has a direct clinical meaning since it ranks the generalized dysautonomia as mild, moderate and severe. By isolating two of the indices of the CASS - adrenergic index (AI) and cardiovagal index (CI) - one can quantify the Cardiovascular Autonomic Dysfunction (CAD). Results are referred to as normal (CAD total score = 0) or abnormal. Abnormal values are considered 1-7, indicating presence of CAD. | Days 1-31, Month 5 (EOS) | 
| Change from Days 0 Cardiovagal Autonomic Dysfunction (CAD) at Days 1-31 | It is derived from the Composite Autonomic severity scale (CASS), an unbiased and full quantification of the autonomic functions in the cardiovagal, adrenergic and sudomotor domain. The total CASS score has a direct clinical meaning since it ranks the generalized dysautonomia as mild, moderate and severe. By isolating two of the indices of the CASS - adrenergic index (AI) and cardiovagal index (CI) - one can quantify the Cardiovascular Autonomic Dysfunction (CAD). Results are referred to as normal (CAD total score = 0) or abnormal. Abnormal values are considered 1-7, indicating presence of CAD. | Day 0, Days 1-31 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Days 0 Composite Autonomic Symptom Scale 31 (COMPASS-31) at 5 months | The Composite Autonomic Symptom Scale 31 is a simplified autonomic symptom scoring scheme that follows a homogeneous pattern of scoring throughout the instrument. It quantifies 6 domains: Orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder and pupillomotor functions. The 6 domains sum to a total COMPASS-31 score of 0 to 100. A higher score indicates greater autonomic impairment (worse score). | Day 0, Month 5 (EOS) | 
| Change from Days 0 Day Impact Questionnaire (HIQ) at 5 months | The Headache Impact Questionnaire is a six-item questionnaire which provides group-level comparisons, patient-level screening, and is responsive to changes in impact of days with headache. The HIQ items cover a substantial range of headache impact as defined by a much larger pool of items and include content areas found in most widely used tools for measuring headache impact. The 6 items sum to a total HIQ score of 0 to 24. A higher score indicates a greater burden of headache (worse score). | Day 0, Month 5 (EOS) | 
| Change from Days 0 Non-Headache Day Impact Questionnaire (Non-HIQ) at 5 months | The Non-Headache Day Impact Questionnaire is a six-item questionnaire which provides group-level comparisons, patient-level screening, and is responsive to changes in days without headache. The 6 items sum to a total non-HIQ score of 0 to 24. A higher score indicates a greater burden on headache-free days (worse score). | Day 0, Month 5 (EOS) | 
| Change from Days 0 Migraine Disability Assessment Scale (MIDAS) at 5 months | The Migraine Disability Assessment Scale is a 5-item self-administered questionnaire. It is used to quantify headache-related disability; and, has been shown as highly reliable in population-based samples of migraine headache sufferers. The score is the sum total of days affected by migraine. The 5 items sum to a total MIDAS score of 0 to 155. A higher score indicates greater headache-related disability (worse score). | Day 0, Month 5 (EOS) | 
| Change from Days 0 Depression Anxiety Stress Scale (DASS) at 5 months | The Depression Anxiety Stress Scale is a set of three self-report scales designed to measure the negative emotional states of depression, anxiety and stress. The DASS was constructed to further the process of defining, understanding, and measuring the pervasive and clinically significant emotional states usually described as depression, anxiety and stress. The 21-item sum is multiplied by a factor of 2, to result in a total DASS score of 0 to 126. Scoring is used to discriminate between the three related states of depression, anxiety and stress; with a higher score indicating greater indication of the three emotional states (worse score). | Day 0, Month 5 (EOS) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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