"Follow the Sutures". A New Procedure for Injection of Botulinum Toxin for Chronic Migraine

"Follow the Sutures". An Open Multicenter, Multinational Pilot Study to Explore Tolerability, Safety and Effect of a New Procedure for Injecting Botulinum Toxin in the Head Against Chronic Migraine

There is no doubt that chronic migraine is a large public health problem, which is both disabling and costly. Many patients and headache doctors see Botulinum toxin (Botox) treatment as a big stride forward, but it is a problem that the effect has been shown in only one study, with a low therapeutic gain. For this reason, before this costly treatment is expanded to potentially several thousand patients in Norway, it would be highly desirable that 1) there is additional good scientific evidence for use of Botox , 2) a more effective treatment procedure is developed, 3) the potential for unblinding is reduced, and 4) the dose, number of injection sites and cost can be halved, and 5) the adverse effects are minimized. These may be the results of this pilot project where injections are given along the sutures, which can open up for a later randomized, blinded and controlled study.

The study is an an open-label, non-con trolled, single-arm and single-center phase II study, at the outpatient clinic of the Department of Neurology and Clinical neurophysiology at St. Olavs Hospital, Trondheim, Norway. The study was originally also planned at the Mayo Clinic, Scottsdale, AZ, USA, but because the study there had not been started before the COVID-19 pandemic, the study was performed only in Trondheim. Potential study participants should be identified among the regular outpatients at the Department of Neurology at St. Olavs hospital. Potential participants should recceive an email with the informed consent form, which should be signed at the screening visit where a detailed medical history and medical examination should be per formed. Patients should complete a paper head ache diary, recording pain intensity and duration, concomitant migraine symptoms (nausea, vomiting, phono- and photophobia), acute medication (type, number of doses) and work absence (yes/no/not relevant). Also, they should record any adverse events. After 7-14 days, they should receive a telephone call from a nurse asking about adverse events and concom itant medication and reminding them to maintain the daily diary. After a baseline period of at least 28 days, diaries should be reviewed at a treatment visit, and each participant should receive injections according to the described procedure. Women of child bearing potential should have a negative pregnancy test before the injections. The duration of the injection procedure should be measure with a stopwatch and immediately after the injections, the patient should be asked to record on a VAS scale (0-10) the level of pain of the procedure and the investigator recorded the degree of bleeding (no, mild, moderate, marked) and any other injection-related adverse events (AEs). Patients should then be asked were asked to keep a headache diary for another 12 weeks or more, before the end of the study visit. During this period, they should receive a call from the study nurse at weeks 2 and 9, reminding to keep the headache diary, and asking about AEs and concomitant medication. They should be also asked whether they had noticed any change in their ability to make forehead wrinkles (no, little, moderate, marked, full paralysis)

Inclusion Criteria:

• Chronic migraine, as defined in the ICHD-3 beta version
• Chronic migraine should have been present for at least ½ year prior to evaluation for study inclusion
• For women of child-bearing potential there must be no pregnancy or planned pregnancy during the study period, and use of highly effective contraception
• Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations

Exclusion Criteria:

• Diseases that are contraindications for use of Botulinum toxin A (Myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, other diseases interfering with neuromuscular function)
• Allergy to Botulinum toxin A
• Other primary or secondary headache disorder, including medication overuse headache (MOH). This means that at least one attempt to withdraw acute medication should have been performed earlier, but without success
• Severe depression or other psychiatric disorder that may interfere with the treatment
• Abuse of alcohol or illicit drugs
• Use of more than one headache prophylactic medication, or change in type and dose of prophylactic medication < 28 days before start of baseline period
• Previous exposure at any time to any botulinum toxin serotype
• Infection at one or more injection site(s)
• Having received extracranial nerve block, cervical facet injection, or other interventional procedure for headache within the prior 3 months
• Use of opioids or barbiturate containing medication(s) > 10 days per month within the preceding 3 months
• Participating in another trial that might affect the current study
• Should not participate in the opinion of the investigator (e.g. not able to comply with study procedures).