A Randomized Study Evaluating the Efficacy and Safety of Timolol Ophthalmic Solution as an Acute Treatment of Migraine

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy (headache freedom at 2 hours) of Timolol 0.5% ophthalmic solution compared to placebo in acute treatment of migraine headache. And to assess the safety and tolerability of Timolol 0.5% ophthalmic solution in treatment of acute migraine headache.

Detailed Description
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Oral beta-blockers are a class of medications frequently used to control blood pressure, angina, and heart irregularities. Certain oral beta-blockers such as propranolol and timolol are used on a daily basis to prevent migraines. However, propranolol and timolol tablets have not been shown to be effective as an acute treatment to stop attacks of migraine because of their longer onset of action. We propose that, since beta-blocker eye drops, unlike tablets are quickly absorbed through the covering of the eye and lining of the nose and can be detected in the bloodstream within minutes, can be beneficial and efficacious in the treatment of headache abortion. Timolol is a non-selective beta-adrenoreceptor antagonist. Oral timolol (20-30 mg daily) has been studied in 3 randomized controlled trials and have been found to reduce headache frequency by more than 50% when compared to placebo. It has been approved by FDA for prophylactic use in migraine patients and had level A evidence to support this indication. The prophylactic benefit of beta-blockers in migraine treatment is not completely understood. It may be related to the effect of beta-blockers on central autonomic vascular tone center, which in turn modulate the cerebrovascular reactivity to sensory stimulation.Propranolol, a beta-adrenergic blocker modulates serotonergic transmission, regulates peri aqueductal pathway activation and prevents central sensitization, normalizes neuronal excitability in the CNS, and blocks cortical spreading depression (CSD). Topical ocular beta blockers have been reported to be successful in retinal arteriolar spasm, retinal migraines causing visual field defects, migraines causing oculomotor nerve palsy, and as abortive agents in migraine patients. Topical timolol maleate solution 0.5% reaches a concentration of 0.5 ng/ml in the plasma within 4 hours of first dose after being used twice daily for 7 days. Topical beta-blockers so far have been noted to be effective for acute migraine episodes only in case reports. We believe that this pilot study, to evaluate the efficacy and safety of a timolol eye drop for acute treatment of migraine headaches, will open doors for future trials and larger studies. If successful, this will be able establish the use of beta-blocker eye drops which is a simple, painless and low cost acute treatment of migraine. The aim of this study is to determine the efficacy of timolol eye drops for the acute treatment of migraine.

Official Title
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A Randomized, Double-Blinded, Placebo-Controlled, Cross Over Study Evaluating the Efficacy and Safety of Timolol Ophthalmic Solution as an Acute Treatment of Migraine

Conditions
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Migraine

Intervention / Treatment
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* Drug: Timolol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of migraine, with or without aura, according to ICHD-2 criteria (Appendix A) for at least 1 year prior to screening; experience an average of 1 to 8 migraines per month. Females must be practicing an effective method of birth control before entry and throughout the study, or be surgically sterile, or be postmenopausal Females of child-bearing potential must have a negative urine pregnancy test Subjects should be able to demonstrate the ability to properly administer study medication Subjects should be able and willing to read and comprehend written instructions and complete the diary information required by the protocol Subjects must be capable, in the opinion of the Investigator, of providing informed consent or assent to participate in the study Subjects (and their legally acceptable representatives, if applicable) must provide an informed consent indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study Exclusion Criteria: Inability to distinguish other headaches from migraine Experiences headache of any kind at a frequency greater than or equal to 15 days per month Current use of medication for migraine prophylaxis that has not been stable (no dose adjustment) for 30 days prior to screening Chronic opioid therapy for headaches (> 3 consecutive days in the 30 days prior to screening) Hemiplegic migraine History, symptoms or signs of ischemic cardiac, cerebrovascular or peripheral vascular syndromes History of glaucoma and/or current treatment with prescription eye drops History of naso-lacrimal duct (tear duct problem to patients) obstruction or surgery for such Active treatment by ophthalmologist or optometrist for any severe ophthalmic disease or problem Any physical problems or co-ordination difficulty or eye avoidance sensitivity (squeezer) that would preclude proper installation of eye drops in either or both eyes History of uncontrolled asthma, COPD, or reversible airway disease which in the opinion of the investigator would be worsened by the use of beta blockers History of clinically symptomatic bradycardia, congestive heart failure, or hypotension Uncontrolled Diabetes Mellitus Uncontrolled Hyperthyroidism History (within 2 years) of drug or alcohol abuse Systemic disease, which in the opinion of the Investigator, would contraindicate participation History of a neurological or psychiatric condition, which in the opinion of the Investigator would contraindicate participation History of hypersensitivity or intolerance to beta-blockers eye drops Pregnant or lactating women Have taken any investigational medication within 12 weeks before randomization, or are scheduled to receive an investigational drug Subjects, who in opinion of the Investigator, should not be enrolled in the study because of the precautions, warnings or contra-indications sections of the timolol Package Insert

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Timolol<br>Participants will be given 0.5% timolol ophthalmic solution to use after migraine onset. Participants will put 2 drops of solution in each eye after migraine and then again 2 hours later. | Drug: Timolol<br>* Timolol is a clear solution supplied in a plastic ophthalmic dispenser.<br>* Other names: beta blocker eye drops;|
| Placebo Comparator: Group 2: Placebo<br>Participants will be given matching placebo (0.9% normal saline solution) to use after migraine onset. Participants will put 2 drops of solution in each eye after migraine and then again 2 hours later. | Drug: Placebo<br>* Placebo is normal saline solution that will be supplied in container matched to Timolol container.<br>* Other names: inactive drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache Severity | Measure of the change in severity using visual analogue pain scale ranging from 0-10 with zero being no pain and ten being worst pain. Scale will be completed after each migraine episode over course of participation in study, up to 8 weeks. | Headache/ pain severity at onset and at 120 minutes post intervention use | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Reaction From Using Timolol Eye Drops | Measured by number of adverse events experienced by the participants from the intervention. Each adverse event was counted as one. | 8 weeks | 
| Number of Participants Satisfied With Intervention | Measured by patient-reported satisfaction questionnaire. Satisfaction level was looked at as satisfactory and very satisfactory compared to neutral and unsatisfied. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Headache, Acute migraine headache