Onabotulinum Toxin A (Botox) for the Treatment of Persistent Post-Stroke and Vascular Headache
Onabotulinum Toxin A (Botox) for the Treatment of Persistent Post-Stroke and Vascular Headache
Post stroke headache occurs in approximately 10-23% of all stroke patients. Its onset is
 shortly after experiencing a stroke, or stroke like event, and persists for at least three
 months. These headaches have features which resemble migraine or occur in people who have a
 previous history of migraine that was once infrequent. Botox is a treatment that is currently
 approved for the treatment of chronic migraine, that is migraine headaches occurring for at
 least 15 days a month for at least 3 months. Given the clinical similarity in character and
 frequency of post stroke headache and migraine, and the fact that stroke affects structures
 like the blood vessels in the brain that are also affected in migraine, this study is to
 investigate the possible role that Botox would have in the treatment of Post-Stroke Headache.
The proposed study will be a randomized, open-label, comparator controlled study
 investigating the safety and efficacy of Botox in Persistent Post "Stroke" (encompassing
 ischemic stroke, hemorrhagic stroke, CVST, Cervical Vessel Dissection and RCVS) headache
 patients relative to Placebo with or without concomitant standard pharmacologic and
 Non-pharmacologic treatments.

 The study population will be a stratified random sample of stroke patients fulfilling the
 inclusion criteria and consenting to study. The study groups will consist of 40 patients
 randomly allocated to receiving Botox according to the treatment regime specified below and
 40 patients randomly allocated to Non-Botox standard treatments, to a total study population
 of 80 patients.

 A Screening Questionnaire will be developed allowing for the identification of
 persistent/chronic post stroke headache and the classification into novel vs previous stable
 migraine sub-groups. Such dichotomization will not affect randomization process up and until
 one sub-group total had been met. If one arm is met prematurely, the Data and Safety
 Monitoring Committee will inform study investigators and only patients of the remaining
 sub-population will be randomized post- screening (stratified random sampling).

 To facilitate Data collection and monitoring. Patients will be seen in face to face
 encounters every 12 weeks with interim phone interviews every 4 weeks. A cross platform
 mobile based application (Migraine Buddy, Healint Analytics)15 will be utilized with patient
 subjects to allow for documentation of migraine attacks including severity and the facility
 of real-time documentation of temporal profile, migraine triggers, and medications as well as
 facility for remote monitoring by study investigators. Subjects will be taught how to use
 application to export data to study investigators in order to allow timely a communication of
 potential adverse and serious adverse events.

 Additionally, the investigators will be undergoing a retrospective analysis of headache
 patients treated at the Grey Nuns Community Hospital Stroke Clinic in order to add to the
 literature regarding the clinical characteristics and putative treatment effects in this
 unique patient population.

 Treatment Protocol:

 Botox 200 IU vials for 40 patients for the duration of study (4 treatment cycles); Treatment
 will be based on the PREEMPT study full treatment and follow the pain protocol to a total of
 195 IU in standard injection sites.
Inclusion Criteria:

 1. Adult patients (>18 y) fulfilling ICHD-3 criteria* of persistent post
 stroke/hemorrhagic stroke headache; persistent headache post dissection* and post RCVS
 persistent headache will be enrolled at 3 months or greater of persistence of
 symptoms.

 For the purposes of this study, as suggested elsewhere in the literature, the initial
 onset of headache will be considered for study if occurring within 72 hours prior to
 and 7 days post sentinel vascular event ("Stroke"). The 72 hours prior criteria
 allowing for inclusion of patients of intracerebral hemorrhage who are known to have
 anticipatory headache as well as alternate ischemic syndromes in which new onset
 headache may anticipate stroke symptoms such as dissection and reversible
 cerebro-vasoconstriction syndrome.

 2. The syndrome of post CVST headache patients will only be enrolled after symptoms have
 persisted for a minimum of 6 months and after relevant imaging demonstrates a
 resolution of potentially structural contribution from the sentinel event (i.e.
 recanalization or chronic thrombo- sis with a normal opening pressure on lumbar
 puncture).

 -  Note the patients of post dissection persistent headaches may be enrolled despite
 the absence of an identified ischemic lesion, i.e. in the setting of TIA or new
 onset headache without embolic symptoms but with a history of the (stabilized)
 vascular injury associated with the syndrome.

 -  Note the co-existence of medication overuse headache will not be a
 contraindication to randomization.

 Exclusion Criteria:

 1. Tension type Post Stroke Persisting Headache, Post stroke pain syndrome such as the
 Thalamic syndrome of Dejerine-Roussy, or any headache semiology that does not fulfill
 diagnostic criteria for chronic migraine, will be excluded.

 2. Contraindications to Botox, neuromuscular illness or documented hyper- sensitivity
 will preclude randomization of patients.

 3. Concurrent active systemic illness, such as sepsis, chronic infective processes,
 neoplastic syndromes, or autoimmune syndromes. (Headache secondary to medical illness,
 even if occurring post-stroke).

 4. Subjects must be screened for coexistent (including psychiatric) conditions to exclude
 illnesses that may influence the conduct or results of the trial. Subjects with
 coexisting conditions, such as depression, may be included if they are defined a
 priori, stable on current treatment regimens (with no anticipated changes in
 management that may interfere with study results), and recorded throughout the study.
 One of the secondary outcome measures in the study investigates the potential impact
 on concurrent symptoms of depression. However, the stability of symptoms treatment and
 concomitant medications should be assessed prior to inclusion in the study. If factors
 are identified which might interfere with patient compliance, follow up or confound
 results, such patients should be excluded. Other common reasons for exclusion include
 severe depression and overuse of alcohol or illicit drugs, as defined by the
 Diagnostic and Statistical Manual of Mental Disorders, 5th edition.

 5. CGRP inhibitors will be contraindicated during the period of study.