Botulinum Toxin Type A Blockade of the Sphenopalatine Ganglion in Treatment-refractory Chronic Cluster Headache
Botulinum Toxin Type A Blockade of the Sphenopalatine Ganglion in Treatment-refractory Chronic Cluster Headache
Cluster headache is a primary headache condition characterized by clusters of one-sided,
 high-intensity pain attacks. The headache may be episodic or chronic. Treatment options are
 limited and their effects unsatisfactory. An important nerve pathway involved in the pain
 attacks has a switching station at the sphenopalatine ganglion (SPG) located in the depth of
 the facial bones. SPG is a known therapy target for cluster headache. The area can be
 identified on CT images, but is difficult to access due to its location. Thus, the Multiguide
 navigation system has been developed to enable precise delivery of the drugs that target SPG
 activity. In Trondheim, two phase 1 / Phase 2 study have been carried out using botulinum
 toxin A (Botox®) against SPG in patient with chronic cluster headache and chronic migraine.
 The results indicate that such a treatment strategy is safe and beneficial. The current study
 is a randomized, placebo-controlled, triple-blinded study to investigate whether precise
 single-injection of botulinum toxin A reduces the frequency of attacks in 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 ≥ 8 cluster attacks/week on the side of their dominant headache
 laterality in the 3 months prior to inclusion and in the baseline period.

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

 7. Subject agrees to maintain current preventive headache medication regimens (no change
 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 highly
 effective contraception in a period of 4 weeks after injection.

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

 Exclusion Criteria:

 1. Subject has had a change in type, dosage or dose frequency of preventive headache
 medications < 1 months prior to baseline/screening or 5 half-lives, whichever is
 longer.1

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

 3. Non-responder to both oxygen and triptan.

 4. Non-responder in regular clinical practice at the discretion of the investigator to ≥4
 of the listed preventive medications

 1. Verapamil

 2. Lithium

 3. Topiramate

 4. Valproate

 5. Greater occipital nerve (GON) block

 6. CGRP-antagonist

 5. Participation in a clinical study of a new chemical entity or a prescription medicine
 within 2 months before study drug administration or 5 half-lives, whichever is longer.

 6. 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.

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

 8. Abuse of drugs or alcohol.

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

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

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

 12. Pregnancy or breastfeeding in the study period

 13. Subject has undergone facial surgery in the area of the pterygopalatine fossa or
 zygomaticomaxillary buttress ipsilateral to the planned injection site that, in the
 opinion of the Investigator, may lead to an inability to properly conduct the
 procedure.

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

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

 16. 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.

 17. 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.

 18. Patients with comorbid psychiatric disorders with psychotic or other symptoms making
 compliance with the study protocol difficult, at the discretion of the investigator.

 19. Patient with active infectious disease or infections that warrants special infection
 control measures, such as human immunodeficiency virus, tuberculosis, or chronic
 hepatitis B or C infection.

 20. Patient with disorders that are known contraindication for Botox® treatment,
 especially neuromuscular disorders such as motorneuron disorders and myasthenic
 syndromes

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

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

 23. Subject is currently or has been previously treated with occipital nerve stimulation
 or deep brain stimulation.

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

 25. Subject has undergone onabotulinumtoxinA injections of the head and/or neck or has had
 an occipital nerve block in the last 3 months.

 26. Subject is anticipated to require any excluded medication, device, or procedure during
 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/or
 antiplatelet therapy, before procedure.

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

 31. 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.

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