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

Inclusion Criteria:

The participants must meet all of the inclusion criteria to participate in this study:

1. Informed and written consent.

2. Male or female, between 18 and 70 years of age

3. Masters a Scandinavian language at level sufficient to fully understand the writtenand verbal study information

4. Migraine, with or without aura, fulfilling the International Classification ofHeadache Disorders (ICHD) III criteria 1.3. for chronic migraine at time ofinclusion

5. Chronic migraine at least for a period of 1 year prior to inclusion

6. Debut of episodic migraine before the age of 50, and chronic migraine before the ageof 65.

7. The condition is pharmacologically refractory as defined in this study asinsufficient treatment effect, contraindication(s) or intolerable side effect(s) ofat least 3 medications from at least 2 of the following medication (drug) classes

8. Beta-blockers

9. RA(A)S-inhibitors

10. Calcium-antagonists

11. Antiepileptic drugs

12. Tricyclic antidepressants

13. Botulinum toxin A

14. CGRP antagonists

15. Subject has had no change in type, dosage or dose frequency of preventive headachemedications < 3 months prior to baseline/screening, or a minimum of 5 half-lives,whichever is longer.

16. Subject agrees to maintain current preventive headache medication regimens (nochange in type, frequency, or dose) during the whole study period.

17. In the case of women of childbearing potential (WOCBP) they have to commit to highlyeffective contraception in a period of 4 weeks after injection (for details, confersection 4.3)

18. Ability to understand study procedures and to comply with them for the entire lengthof the study

Exclusion Criteria:

All candidates meeting any of the exclusion criteria at baseline or visit 2 will be excluded from study participation:

1. Allergy or hypersensitivity reactions to marcaine, lidocaine, xylocaine, adrenaline,any botulinum toxin or similar substances.

2. Subject is unable to differentiate migraine from other concomitant headaches.

3. Subject with secondary headache conditions, with the exception of medication overuseheadache.

4. Non-responder in regular clinical practice to preventive medications from ≥6 of thefollowing 7 drug classes:

5. Beta-blockers

6. RA(A)S-inhibitors

7. Calcium-antagonists

8. Antiepileptic drugs

9. Tricyclic antidepressants

10. Botulinum toxin A

11. CGRP antagonists

12. Subject has had a change in type, dosage or dose frequency of preventive headachemedications < 3 months prior to baseline/screening, or a minimum of 5 half-lives,whichever is longer.

13. Subject has had a change in type, dosage or dose frequency of preventive headachemedications during the baseline period, eg. prior to IMP administration

14. Botulinum toxin injections in the head and neck region, as part of migrainetreatment or otherwise indicated on medical or cosmetic grounds, in the last 4months before inclusion.

15. The discontinuation of CGRP-antagonists within 3 months before study inclusion or 5half-lives, whichever is longer,

16. Participation in a clinical study of a new chemical entity or a prescriptionmedicine within 2 months before study inclusion or 5 half-lives, whichever islonger.

17. Subject is currently participating or has participated in the last 3 months inanother clinical study in which the subject has, is, or will be exposed to aninvestigational or non-investigational drug or device.

18. Subject has had previous radiofrequency ablation, balloon compression, gamma knife,or chemical denervation (e.g. glycerol treatments) of the trigeminal ganglion or anybranch of the trigeminal nerve.

19. Subject has had previous radiofrequency ablation (including non-lesional pulsedradiofrequency), balloon compression, gamma knife, or chemical denervation (e.g.glycerol treatments) of the SPG.

20. Subject has had blocks of short-acting anaesthetics of the SPG in the last 3 months.

21. Subject is or has been treated with occipital nerve stimulation or deep brainstimulation.

22. Ongoing abuse of drugs (including narcotics) or alcohol.

23. More than 4 days of opioid use per month (including codeine and tramadol), and anyuse of barbiturates

24. Treatment with pharmacological substances prior to SPG-injection that may interactwith BTA (aminoglycosides, spectinomycin, neuromuscular blockers, both depolarizingagents (such as succinylcholine) or non-depolarizing (tubocurarine derivates), andanticholinesterases).

25. Inadequate contraceptive use. Women of childbearing potential (WOCBP) who do not usehighly effective contraception (HEC) or use other medication that may interactand/or otherwise reduce the efficacy of the contraceptive agents in use.

26. Subject has undergone facial surgery in the area of the pterygopalatine fossa orzygomaticomaxillary at the planned injection site that, in the opinion of theInvestigator, may lead to an inability to properly conduct the procedure.

27. Facial anomaly or trauma which renders the procedure difficult.

28. Subject currently has an active oral or dental abscess or a local infection at thesite of injection based on present symptoms.

29. Subject has been diagnosed with any major infectious processes such asosteomyelitis, or primary or secondary malignancies involving the face that havebeen active or required treatment in the past 6 months.

30. Patients with comorbid psychiatric disorders with psychotic or other symptoms makingcompliance with the study protocol difficult, at the discretion of the investigator

31. Patients exhibiting a high degree of comorbidity and/or frailty associated withreduced life expectancy or high likelihood of hospitalization, at the discretion ofthe investigator

32. Patients with disorders that severely inhibits lacrimation, at the discretion of theinvestigator

33. Patients with previous ischemic cardiovascular and cerebrovascular disorder with, inthe opinion of the investigator, a moderate to high risk of new ischemic episodes.

34. Known infection or history of human immunodeficiency virus, tuberculosis, or chronichepatitis B or C infection.

35. Subject has a history of bleeding disorders or coagulopathy, that, in the opinion ofthe Investigator, may lead to an inability to properly conduct the procedure.

36. Unable to stop antithrombotic medication e.g. platelet aggregation inhibitors and/oranticoagulation therapy, prior to procedure.

37. The patient cannot participate or successfully complete the study, in the opinion oftheir 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, orbeing admitted to a sanatorium or social institution

• has any other condition, which, in the opinion of the investigator, makes thepatient inappropriate for inclusion in the study

31. The patient is a study centre employee who is directly involved in the study or therelative of such an employee.