• Difference in occurrence of adverse events (AEs) and serious adverse events (SAEs) in the active group versus the placebo group [ Time Frame: week 1 through week 12 in the post-injection period ]
  All adverse events and serious adverse events occurring in the 3 months follow up are registered in an electronic case report form (CRF). Frequency of AE and SAE are compared between the placebo group and the treatment group
• Difference in change from baseline week 5-8 in mean number of cluster headache attacks per week during weeks 9-12 post-intervention in the active group versus the placebo group [ Time Frame: week 9 through week 12 in the post-injection period ]
  Change from baseline to weeks 9-12 post-intervention in number of cluster headache attacks per week in the active group versus the placebo group. The number of cluster headache attacks is collected in a headache diary
• Difference in change from baseline week 5-8 in mean number of cluster headache attacks per week at weeks 5-8 post-intervention in the active group versus the placebo group, in the prespecified subgroups [ Time Frame: week 5 through week 8 in the post-injection period ]
  Change from baseline to weeks 5 - 8 post-intervention in number of cluster headache attacks per week comparing high versus low attack frequency and low versus high attack frequency variation in the entire baseline period. Comparisons are done between the active and the placebo group. The number of cluster headache attacks is collected in a headache diary
• Difference in change from baseline week 5-8 in mean number of cluster headache attacks per week during weeks 9-12 post-intervention in the active group versus the placebo group, in the prespecified subgroups [ Time Frame: week 9 through week 12 in the post-injection period ]
  Change from baseline to weeks 9-12 post-intervention in number of cluster headache attacks per week comparing high versus low attack frequency and high versus low attack frequency variation in the entire baseline period. Comparisons are done between the active and the placebo group. The number of cluster headache attacks is collected in a headache diary
• Difference in the number of therapeutic responders in the active group versus the placebo group. [ Time Frame: week 5 through week 8 in the post-injection period ]
  Number of therapeutic responders as defined as a ≥ 30% reduction in attack frequency, intensity or both during weeks 5 - 8 post-intervention compared to baseline week 5-8. The number in the placebo and intervention group are compared
• Difference in the number of attack frequency responders [ Time Frame: week 5 through week 8 in the post-injection period ]
  Number of attack frequency responders as defined as a ≥ 30% reduction in attack frequency during weeks 5-8 post-intervention compared to baseline. The number in the placebo and intervention group are compared
• Difference in change from baseline week 5-8 in mean attack intensity week 5 - 8 post-intervention in the active group versus the placebo group. [ Time Frame: week 5 through week 8 in the post-injection period ]
  Mean attack intensity (10-point numerical response scale - NRS) week 5-8 post intervention compared to baseline in the intervention group versus the placebo group.

• Number of therapeutic responders [ Time Frame: 5-8 weeks post-intervention ]
  Number of therapeutic responders as defined as a ≥ 50% reduction in attack frequency, intensity or both during weeks 5 - 8 post-intervention compared to baseline. The number in the placebo and intervention group are compared
• Number of attack frequency responders [ Time Frame: week 5-6 post-intervention ]
  Number of attack frequency responders as defined as a ≥ 50% reduction in attack frequency during weeks 5 - 8 post-intervention compared to baseline.The number in the placebo and intervention group are compared
• Mean attack intensity [ Time Frame: week 5-8 post-intervention ]
  Mean attack intensity (10-point numerical response scale - NRS) week 5 - 8 post intervention compared to baseline in the intervention group versus the placebo group.
• Number of days with cluster headache [ Time Frame: week 1-4, week 5-8 and week 9-12 post-intervention ]
  Number of days with cluster headache at baseline compared to the week 1-4, week 5-8 and week 9-12 post-injection in the intervention group versus the placebo group
• Patient Global Impression of Improvement (PGI-I) [ Time Frame: week 12 post-intervention ]
  The Patient Global Impression of Improvement (PGI-I) is a global index used to rate the subjective treatment response (transition scale). The PGI-I score is collected at the last visit
• Quality of Life with EQ-5D-5L [ Time Frame: week 12 post-intervention ]
  The EQ-5D-5L is a life quality assessment tool which consists the EQ-5D descriptive system (5 questions addressing the five dimensions mobility, self-care, usual activities, pain/discomfort and anxiety) AND the EQ visual analogue scale (EQ-VAS) which records the patient's self-rated health. The EQ-5D-5L score is collected at the first visit (inclusion) and at the last visit
• mean attack duration [ Time Frame: weeks 1-4, 5-8 and 9-12 post-intervention ]
  attack duration of each headache attack is registered. The mean cluster headache attack in the baseline period, is compared to the mean cluster headache attack in weeks 1-4, 5-8 and 9-12 post-intervention
• Number of attacks requiring use of rescue medication) [ Time Frame: weeks 1-4, 5-8 and 9-12 post-intervention ]
  Number of days with registered use of any headache related rescue medication (including triptans and oxygen) in weeks 1-4, 5-8 and 9-12 post-intervention compared to the baseline period
• Number of responders using concomitant calcitonin gene-related peptide (CGRP) antagonists [ Time Frame: week 5-8 post-intervention ]
  Current use of CGRP-antagonists is registered at inclusion. Change in number of cluster headache attacks per week is compared between participants in the intervention group with simultaneous CGRP-antagonist use and those that do not use CGRP-antagonists.
• Autonomic symptoms [ Time Frame: weeks 1-4, 5-8 and 9-12 post-intervention ]
  The most prominent autonomic symptom/sign (if any) is registered in the headache diary when headache. Frequency of concomitant autonomous symptoms in week 1-4, week 5-8 and week 9-12 post-intervention are compared to the frequency at baseline
• Number of adverse effects (AEs) and serious adverse effects (SAEs) [ Time Frame: week 5-8 post-intervention ]
  All adverse events occurring in the 3 months follow up are registered in an electronic CRF. Frequencies in treatment group and placebo group are compared
• Number of days with headache [ Time Frame: weeks 1-4, 5-8 and 9-12 post-intervention ]
  The number of days with headache in the last four weeks of the baseline period is compared with the number in weeks 1-4, 5-8 and 9-12 post-intervention
• Time from injection to onset of effect [ Time Frame: week 1-12 post-intervention ]
  Number of weeks from injection to the first week of 50% reduction in the number of cluster headache attacks
• Acceptability of treatment: numeric rating scale (NRS) score [ Time Frame: within 10 minutes ]
  patients are asked to provide a numeric rating scale (NRS) score from 0-10 immediately after injection. The patient are asked to give the maximum pain score during the injection, and than to score present pain intensity

• Drug: Botulinum toxin type A
  Botulinum toxin 25 Allergan units in 0.5 ml Sodium Chloride (NaCl) 0.9 % Braun. One injection in the headache side of the face, targeted at the sphenopalatine ganglion (SPG)
  Other Name: botox
• Drug: placebo
  0.5 ml Sodium Chloride (NaCl) 0.9% Braun. One injection in the headache side of the face, targeted at the sphenopalatine ganglion (SPG)
  Other Name: Sodium Chloride

• Experimental: Botox injections towards SPG
  Botulinum Toxin type A injections
  Intervention: Drug: Botulinum toxin type A
• Placebo Comparator: Controls
  placebo injections
  Intervention: Drug: placebo

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.

• St. Olavs Hospital
• University College, London
• Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
• Catholic University of Valencia
• University Hospital, Essen