Clinical trial NCT03944876: Botulinum Toxin Type A Blockade of the Sphenopalatine Ganglion in Treatment-refractory Chronic Cluster Headache
Official title: Botulinum Toxin Type A Blockade of the Sphenopalatine Ganglion in Treatment-refractory Chronic Cluster Headache
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Cluster Headache
Keywords: Botulinum Toxin Type A
Sphenopalatine Ganglion Block
Autonomic Nerve Block
Injections
Lead sponsor: Norwegian University of Science and Technology
Sponsor class: OTHER
Collaborators: name: St. Olavs Hospital
name: University College, London
name: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
name: Catholic University of Valencia
name: PRAXISKLINIK ULMENHOF
First posted: 2019-05-10
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 .


Eligibility criteria: 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 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 ≥ two weeks prior to baseline/screening or 5 half-lives, whichever is longer.
2. Subject currently treated with occipital nerve stimulation, deep brain stimulation or other implantable device, that have changed parameters in the last month, or are unable 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 headache medications 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 prescription medicine within 2 months before study drug administration or 5 half-lives, whichever is longer.
7. 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.
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 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.
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 the site of injection based on present symptoms.
17. 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.
18. 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.
19. Patients with comorbid psychiatric disorders with psychotic or other symptoms making compliance with the study protocol difficult, at the discretion of the investigator.
20. 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.
21. Patient with disorders that are known contraindication for Botox® treatment, especially neuromuscular disorders such as motorneuron disorders and myasthenic syndromes
22. 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.
23. 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.
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 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.

Primary outcomes:
measure: 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 treatment group versus the placebo group
timeFrame: week 5 through week 8 in the post-injection period
Secondary outcomes:
measure: Difference in occurrence of adverse events (AEs) and serious adverse events (SAEs) in the active group versus the placebo group
timeFrame: week 1 through week 12 in the post-injection period
measure: 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
timeFrame: week 9 through week 12 in the post-injection period
measure: 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
timeFrame: week 5 through week 8 in the post-injection period
measure: 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
timeFrame: week 9 through week 12 in the post-injection period
measure: Difference in the number of therapeutic responders in the active group versus the placebo group.
timeFrame: week 5 through week 8 in the post-injection period
measure: Difference in the number of attack frequency responders
timeFrame: week 5 through week 8 in the post-injection period
measure: 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.
timeFrame: week 5 through week 8 in the post-injection period
Other outcomes:
Locations:
city: Hamburg
country: Germany
facility: Praxisklinik Ulmenhof
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta (CBNI)
city: Trondheim
country: Norway
facility: St Olavs Hospital
city: Valencia
country: Spain
facility: Department of Neurology, University Clinic Hospital. Catholic University of Valencia
city: London
country: United Kingdom
facility: National Hospital of Neurology and Neurosurgery, University College of London
Study officials:
affiliation: St. Olavs Hospital
name: Geir Bråthen, md phd
role: STUDY_DIRECTOR
References: