CGRP Inhibition, Autonomic Function, and Migraine
CGRP Inhibition, Autonomic Function, and Migraine
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.
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.
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