A Multidisciplinary Approach to the Identification of BIOmarkers of MIGraine: a Proof of Concept Study Based on the Stratification of Responders to CGRP Monoclonal Antibodies
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 243
- 试验地点
- 3
- 主要终点
- Biomarkers and CGRP-targeting mABs
研究概览
简要总结
Migraine is the 2nd most disabling neurological disease. It affects 14.7% of the population (children and adults) of whom 80% are female. In the European Union, the total annual cost of migraine is of 111 billion euros. If not adequately treated, migraine can evolve into the more severe chronic form (CM), defined by >15 headache days/month, where burden and costs increase exponentially.
Until very recently, available preventive treatments for migraine were non-specific, of limited efficacy and scarce tolerability. In 2018, monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) receptor have been approved. Since CGRP is one of the main modulators of the trigeminal system, mABs against CGRP are the first specific preventive treatment for migraine ever developed. They are highly effective in a subgroup of patients, well tolerated, but costly.
In this frame, the main objective of BIOMIGA project is to identify predictive biomarkers of response to CGRP-mABs in patients with severe forms of migraine. To this end, the investigators will use an integrated hypothesis-based and data-driven, multidisciplinary approach that combines' omic testing in a deep-phenotyped migraine population and parallel fundamental research in a validated animal model of migraine. Three partners, Headache Science Centre, IRCCS C. Mondino Foundation, University of Pavia, Italy, Headache Research Group Vall d'Hebron Institute of Research, Barcelona, Spain and Institut für Systemische Neurowissenschaften, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany with an established long-standing and complementary expertise in neuroimaging, biochemical profiling and epigenetics in humans and in animal modeling of migraine will collaborate to achieve the Project's objective.
The investigators expect important spin-offs to the improved management of migraine, both in terms of increased efficacy and cost saving, but also to understand CGRP-based mechanisms underlying migraine pathophysiology and to set the basis for a pathophysiologically driven classification. Healthcare providers and the pharmaceutical industry will be engaged once the biomarker(s) have been identified to optimize access to care and the use of resource, as well as to reduce disability and socio-economic impact of migraine.
详细描述
Almost 15% of European citizens suffer from migraine and its comorbidities. Migraine is the second most disabling chronic neurological disease, with devastating repercussions on the life of those who are affected, their relatives and society. Migraine manifests in recurring attacks lasting 4-72 hours characterized by severe head pain, often throbbing, associated with nausea, photo and phonophobia, vomiting, cognitive deficits, severe emotional distress and complete disability. If not diagnosed and appropriately treated, migraine can transform into a chronic form (15 or more days of headache/ month) often associated with acute medication overuse and severe comorbidities such as depression, anxiety and panic disorders.
The disability associated to migraine is closely related to the frequency of the attacks. Epidemiological studies show that in Europe 34$ of migraineurs suffer from more than 5 headache days per month and 1-3% of the general population has migraine on more than 15 days/month, thus qualifying for the diagnosis of Chronic Migraine (CM).
Migraine is a genetically-driven, chronic "neurosensorial" disorder, where the unpredictable recurrence of the attacks is modulated by the variable efficiency of the fine-tuned interplay of the brain with dynamic sensory stimuli originating from the internal or external environment.
Migraine can be viewed as a cycling functional disorder that affects several areas of the brain, involving multiple pathways ultimately leading to the excessive activation of trigeminovascular afferents in the meninges with the local release of vasoactive substances (calcitonin gene-related peptide - CGRP ) and the activation of the neuroinflammatory cascade.
Unlike several other chronic neurological diseases, migraine can be successfully treated and prevented. Unfortunately, this is true only for subgroups of patients and for a limited period, due to the nonspecific therapeutic armamentarium available: calcium antagonists, beta-blockers, antidepressants, antiepileptics and, only for chronic migraine, onabotulinumtoxin-A. This is the direct consequence of the complex pathophysiology of the disease, but mostly and, more importantly, by the total absence of biomarkers of disease and of responsiveness to available drugs.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 25 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Migraine patients
- •Adults between 25 and 55 years of age of both gender;
- •European background;
- •Patients diagnosed with high-frequency migraine (HFM) 8 or more migraine days days/month) or CM with or without aura (>15 headache days migraine/month, of which 8 have migraine characteristics) according to the International Classification of Headache Disorders, 3rd edition, (ICHD-3);
- •Females have to be postmenopausal for at least one year, surgically sterile or otherwise incapable of pregnancy, or using an acceptable method of birth control.
- •Healthy controls
- •Adults between 25 and 55 years of age of both genders;
- •European background;
- •Absence of any past or first-degree familial history of recurrent primary or secondary headache disorders.
排除标准
- •For the clinical population:
- •Headache on more than 25 days/month in the last 3 months;
- •Medication overuse according to the ICHD-3 criteria.
- •For the entire study population (migraine and healthy controls)
- •Presence of any other significant medical condition (neurological disorders, severe psychiatric illness or cardiovascular disease);
- •Evidence of drug, smoking or alcohol abuse or dependence within 12 months prior to V1, based on medical records or patient self-report. An alcohol consumption >100mg/week will be considered an abuse;
- •Pregnant or breastfeeding women;
- •Women of childbearing potential, defined as all women physiologically capable of becoming pregnant who are not on contraception;
- •Concomitant use of other migraine preventive drugs that may interfere with the endpoints of the study.
研究组 & 干预措施
Migraine patients
- Excellent responder, a patient who experiences a >75% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline;
- Responder, a patient who experiences a >50% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline;
- Non responder, a patient who experiences a decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days ranging from 26 to 49% during the last 4 weeks of treatment as compared to baseline;
- Full non responder, a patient who experiences a <25% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline.
结局指标
主要结局
Biomarkers and CGRP-targeting mABs
时间窗: Day 0 and Week 12
To identify a computational algorithm using a machine learning approach based on different types of biomarkers (demographic, clinical, psychological, cognitive, epigenetic, pharmacogenetic, biochemical and structural \& functional brain imaging) that is predictive of response to the class of the CGRP-targeting mABs.
次要结局
- Methylation levels(Day 0 and Week 12)
- Brain morphometric measures(Day 0 and Week 12)
- Pharmacogenetic, biochemical, clinical and psychological markers(Day 0 and Week 12)
- Methylation levels at the neuroanatomic and neurofunctional levels(Day 0 and Week 12)
- Pharmacogenetic, biochemical, clinical and psychological markers in responder and non responders(Day 0 and Week 12)
- Morphometric measures(Day 0 and Week 12)