Botulinum Toxin Type A Blockade of the Sphenopalatine Ganglion in Treatment-refractory Chronic Migraine

Study Overview
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Brief Summary
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This is a clinical trial to assess the efficacy of botox treatment of the sphenopalatine ganglion as an add-on treatment in drug resistant migraine. An injection targeting the ganglion is made possible by an image-guided device developed specifically for this purpose (MultiGuide) Study participants will be randomized to either placebo or botox after a 4 week run-in period. First, one injection will be given towards both the right and the left ganglion. After that there will be a follow-up of 12 weeks for efficacy and safety evaluation. The main efficacy measure is change in number of moderate to severe headache days before and after injection.

Official Title
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Botulinum Toxin Type A Blockade of the Sphenopalatine Ganglion in Treatment-refractory Chronic Migraine

Conditions
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Migraine Disorders

Intervention / Treatment
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* Drug: Botulinum toxin type A
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participants must meet all of the inclusion criteria to participate in this study: Informed and written consent. Male or female, between 18 and 70 years of age Masters a Scandinavian language at level sufficient to fully understand the written and verbal study information Migraine, with or without aura, fulfilling the International Classification of Headache Disorders (ICHD) III criteria 1.3. for chronic migraine at time of inclusion Chronic migraine at least for a period of 1 year prior to inclusion Debut of episodic migraine before the age of 50, and chronic migraine before the age of 65. The condition is pharmacologically refractory as defined in this study as insufficient treatment effect, contraindication(s) or intolerable side effect(s) of at least 3 medications from at least 2 of the following medication (drug) classes Beta-blockers RA(A)S-inhibitors Calcium-antagonists Antiepileptic drugs Tricyclic antidepressants Botulinum toxin A CGRP antagonists Subject has had no change in type, dosage or dose frequency of preventive headache medications < 3 months prior to baseline/screening, or a minimum of 5 half-lives, whichever is longer. Subject agrees to maintain current preventive headache medication regimens (no change in type, frequency, or dose) during the whole study period. In the case of women of childbearing potential (WOCBP) they have to commit to highly effective contraception in a period of 4 weeks after injection (for details, confer section 4.3) Ability to understand study procedures and to comply with them for the entire length of the study Exclusion Criteria: All candidates meeting any of the exclusion criteria at baseline or visit 2 will be excluded from study participation: Allergy or hypersensitivity reactions to marcaine, lidocaine, xylocaine, adrenaline, any botulinum toxin or similar substances. Subject is unable to differentiate migraine from other concomitant headaches. Subject with secondary headache conditions, with the exception of medication overuse headache. Non-responder in regular clinical practice to preventive medications from ≥6 of the following 7 drug classes: Beta-blockers RA(A)S-inhibitors Calcium-antagonists Antiepileptic drugs Tricyclic antidepressants Botulinum toxin A CGRP antagonists Subject has had a change in type, dosage or dose frequency of preventive headache medications < 3 months prior to baseline/screening, or a minimum of 5 half-lives, whichever is longer. Subject has had a change in type, dosage or dose frequency of preventive headache medications during the baseline period, eg. prior to IMP administration Botulinum toxin injections in the head and neck region, as part of migraine treatment or otherwise indicated on medical or cosmetic grounds, in the last 4 months before inclusion. The discontinuation of CGRP-antagonists within 3 months before study inclusion or 5 half-lives, whichever is longer, Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months before study inclusion or 5 half-lives, whichever is longer. Subject is currently participating or has participated in the last 3 months in another clinical study in which the subject has, is, or will be exposed to an investigational or non-investigational drug or device. Subject has had previous radiofrequency ablation, balloon compression, gamma knife, or chemical denervation (e.g. glycerol treatments) of the trigeminal ganglion or any branch of the trigeminal nerve. Subject has had previous radiofrequency ablation (including non-lesional pulsed radiofrequency), balloon compression, gamma knife, or chemical denervation (e.g. glycerol treatments) of the SPG. Subject has had blocks of short-acting anaesthetics of the SPG in the last 3 months. Subject is or has been treated with occipital nerve stimulation or deep brain stimulation. Ongoing abuse of drugs (including narcotics) or alcohol. More than 4 days of opioid use per month (including codeine and tramadol), and any use of barbiturates Treatment with pharmacological substances prior to SPG-injection that may interact with BTA (aminoglycosides, spectinomycin, neuromuscular blockers, both depolarizing agents (such as succinylcholine) or non-depolarizing (tubocurarine derivates), and anticholinesterases). Inadequate contraceptive use. Women of childbearing potential (WOCBP) who do not use highly effective contraception (HEC) or use other medication that may interact and/or otherwise reduce the efficacy of the contraceptive agents in use. Subject has undergone facial surgery in the area of the pterygopalatine fossa or zygomaticomaxillary at the planned injection site that, in the opinion of the Investigator, may lead to an inability to properly conduct the procedure. Facial anomaly or trauma which renders the procedure difficult. Subject currently has an active oral or dental abscess or a local infection at the site of injection based on present symptoms. Subject has been diagnosed with any major infectious processes such as osteomyelitis, or primary or secondary malignancies involving the face that have been active or required treatment in the past 6 months. Patients with comorbid psychiatric disorders with psychotic or other symptoms making compliance with the study protocol difficult, at the discretion of the investigator Patients exhibiting a high degree of comorbidity and/or frailty associated with reduced life expectancy or high likelihood of hospitalization, at the discretion of the investigator Patients with disorders that severely inhibits lacrimation, at the discretion of the investigator Patients with previous ischemic cardiovascular and cerebrovascular disorder with, in the opinion of the investigator, a moderate to high risk of new ischemic episodes. Known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection. Subject has a history of bleeding disorders or coagulopathy, that, in the opinion of the Investigator, may lead to an inability to properly conduct the procedure. Unable to stop antithrombotic medication e.g. platelet aggregation inhibitors and/or anticoagulation therapy, prior to procedure. The patient cannot participate or successfully complete the study, in the opinion of their healthcare provider or the investigator, for any of the following reasons: mentally or legally incapacitated or unable to give consent for any reason in custody due to an administrative or a legal decision, under tutelage, or being admitted to a sanatorium or social institution has any other condition, which, in the opinion of the investigator, makes the patient inappropriate for inclusion in the study The patient is a study centre employee who is directly involved in the study or the relative of such an employee.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Botox injections towards SPG<br>Botulinum Toxin type A injections | Drug: Botulinum toxin type A<br>* Botulinum toxin 25 Allergan units in 0.5 ml Sodium Chloride (NaCl) 0.9 % Braun. Two injections, one in each side of the face, and targeting the sphenopalatine ganglion.<br>* Other names: Allergan;|
| Placebo Comparator: Controls<br>Placebo injections | Drug: placebo<br>* 0.5 ml Sodium Chloride (NaCl) 0.9% Braun. Two injections, one in each side of the face, and targeting the sphenopalatine ganglion.<br>* Other names: sodium chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the mean monthly headache days at weeks 5 - 8 post intervention | Change from baseline to week 5-8 post-intervention in frequency of moderate to severe headache days. Headache episodes that qualify is in the study defined as headache pain duration of ≥4 hours with a peak severity of moderate or severe intensity, or of any severity or duration if the subject takes and responds to rescue medication. | week 5 through week 8 in the post-injection period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of adverse events and serious adverse events in the treatment | All adverse events and serious adverse events occurring in the 3 months follow up are registered in an electronic CRF. Frequency of AE and SAE are compared between the placebo group and the treatment group | week 1 through week 12 in the post-injection period | 
| Change from baseline in the mean monthly migraine days in the treatment | A migraine day is defined as one day with headache pain fulfilling the ICHD3-criteria for migraine or probable migraine. However, a headache duration of less than 4 hours is allowed if the subject takes and responds to triptans. The frequency of headache days in the baseline period are compared to the frequency in week 5-8 post-intervention | week 5 through week 8 in the post-injection period | 
| number of treatment responders (≥ 30% reduction in mean monthly headache days) | A 30% treatment response is defined as a patient with a ≥ 30% reduction in frequency of headache days during weeks 5 - 8 post-intervention compared to baseline. Headache is defined as in the primary outcome, i.e. moderate to severe headache days. The number of responders is compared between the intervention and the placebo group | week 5 through week 8 in the post-injection period | 
| Change from baseline in the mean monthly headache intensity in the treatment | Attack intensity is reported daily on a 11-point numerical response scale (NRS) in the electronic headache diary. The mean attack intensity in week 5 - 8 post-intervention is compared to baseline in the active group versus the placebo group. | week 1 through week 4, week 5 through week 8 and week 9 through week 12 in the post-injection period | 
| Change from baseline in the mean monthly occurrence of cumulative hours per 28 days of moderate/severe pain in the treatment | The difference in hours with NRS ≥4 in the baseline period and weeks 1-4, 5-8 and 9-12 post injection are compared between the active group and the placebo group | : week 1 through week 4, week 5 through week 8 and week 9 through week 12 in the post-injection period | 
| Change from baseline in the mean monthly number of days with rescue medication in the treatment | Any use of rescue medication is reported in the headache diary every day. The number of days with registered use of any headache related rescue medication in weeks 1-4, 5-8 and 9-12 post-intervention is compared to the baseline period | : week 1 through week 4, week 5 through week 8 and week 9 through week 12 in the post-injection period | 
| Migraine specific quality of life questionnaire | Study participants will fill in the 6-question Headache impact test (HIT-6) at visit 1 (at inclusion) and at week 8 and week 12 postintervention. Scores are compared between the placebo and the treatment group | week 8 and week 12 post-injection | 
| Migraine specific quality of life questionnaire | Study participants will fill in the 14-question Migraine-Specific Quality-of-Life Questionnaire Version 2.1 (MSQ) at visit 1 (at inclusion) and at week 8 and week 12 postintervention. Scores are compared between the placebo and the treatment group | week 8 and week 12 post-injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Botulinum Toxin Type A, Sphenopalatine Ganglion Block, Autonomic Nerve Block, Injections