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

Inclusion Criteria:

1. Informed and written consent.

2. Male or female, 18-85 years of age

3. Headache attacks fulfilling the International Classification of Headache Disorders (ICHD) III criteria for chronic cluster headache (CCH) 3.1.2.

4. Dominant headache laterality with ≥ 80% of cluster headache attacks on one side.

5. Subject reports an average of ≥ 4 cluster attacks/week on the side of their dominantheadache laterality in the 3 months prior to inclusion and in the baseline period.

6. The condition is pharmacologically refractory defined as suboptimal effect orintolerable side effects or contraindication for verapamil or lithium orsuboccipital steroid injection.

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

8. Subject is able to differentiate concomitant headaches from cluster headache.

9. In case of women of childbearing potential (WOCBP) they have to be using highlyeffective contraception in a period of 4 weeks after injection.

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

Exclusion Criteria:

1. Subject has had a change in type, dosage or dose frequency of preventive headachemedications ≥ two weeks prior to baseline/screening or 5 half-lives, whichever islonger.

2. Subject currently treated with occipital nerve stimulation, deep brain stimulationor other implantable device, that have changed parameters in the last month, or areunable to keep parameters stable throughout the study.

3. Current or previous treatment with implanted medical devices targeting the SPG

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

5. Non-responder to both oxygen and triptan.

6. Participation in a clinical study of a new chemical entity or a prescriptionmedicine within 2 months before study drug administration or 5 half-lives, whicheveris longer.

7. 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.

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

9. Abuse of drugs or alcohol.

10. Use of opioids for ≥10 days per month.

11. Treatment with pharmacological substances that may interact with BTA (aminoglycosids, spectinomycin, neuromuscular blockers, both depolarizing agents (such as succinylcholine) or non-depolarizing (tubocurarine derivates),lincosamides, polymyxins, quinidine, magnesium sulfate or anticholinestases.).

12. WOCBP that do not adhere to the requirements for HEC, as noted in inclusion criteria 9 and outlined in section 3.3.

13. Pregnancy or breastfeeding in the study period

14. Subject has undergone facial surgery in the area of the pterygopalatine fossa orzygomaticomaxillary buttress ipsilateral to the planned injection site that, in theopinion of the Investigator, may lead to an inability to properly conduct theprocedure.

15. Facial anomaly or trauma which renders the procedure difficult.2

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

17. 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.

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

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

20. Patient with active infectious disease or infections that warrants special infectioncontrol measures, such as human immunodeficiency virus, tuberculosis, or chronichepatitis B or C infection.

21. Patient with disorders that are known contraindication for Botox® treatment,especially neuromuscular disorders such as motorneuron disorders and myasthenicsyndromes

22. Subject has had previous radiofrequency ablation, balloon compression, gamma knife,or chemical denervation (e.g. glycerol treatments) of the ipsilateral trigeminalganglion or any branch of the trigeminal nerve.

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

24. Subject has had blocks of short-acting anaesthetics of the ipsilateral SPG in thelast 3 months.

25. Subject has undergone onabotulinumtoxinA injections of the head and/or neck in thelast 3 months.

26. Subject is anticipated to require any excluded medication, device, or procedureduring the study.

27. Subject has a history of bleeding disorders and in the opinion of the Investigator,may lead to an inability to properly conduct the procedure.

28. Subject has a history of coagulopathy.

29. Subject is unable to stop antithrombotic medication, eg. anticoagulants and/orantiplatelet therapy, before procedure.

30. The subject has been diagnosed with another trigeminal autonomic cephalalgia ortrigeminal neuralgia.

31. 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.

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