Probiotics as Adjunctive Migraine Prophylaxis

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of multi-strain probiotics as an adjunctive treatment for episodic migraine

Detailed Description
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This is a phase 2 and single center, randomized, placebo-controlled double-blind clinical Trial. Episodic migraine patients according to International Headache Society criteria will be allocated randomly into two treatment arms. One group will receive active probiotics and another group will receive placebo for treatment phase. Both groups of patients will consume the treatment twice daily for 12 weeks and assessment will be made at baseline, baseline, week 4, 8 and 12

Official Title
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The Effectiveness and Tolerability of Multi-Strain Probiotics as Adjunctive Preventive Treatment of Episodic Migraine: A Single Centre, Randomised, Double- Blind, Sham-Controlled Phase 2 Trial (PROBIOTICS -EM).

Conditions
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Migraine, Episodic Migraine

Intervention / Treatment
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* Dietary Supplement: (Microbial cell preparation) probiotics
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects fulfilling criteria for episodic migraine as per the Third Edition of The International Headache Society (ICHD-3) (Table 1) Patients diagnosed with episodic migraine (4 or more episodes per month) for a minimum of 3 months. On a steady treatment regimen: preventive and acute migraine medications and therapies unchanged over the last 3 months Adult patients Age > 18 years old A signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study including any known and potential risks and available alternative treatments. Exclusion Criteria: Lactose intolerance Previous history of small and large bowel surgery Use of probiotics or antibiotics in 2 weeks before baseline visit. Patients with medical conditions such as severe hypertension, infections, Malignancy, cardiovascular and cerebrovascular diseases, epilepsy, degenerative central nervous system diseases, renal failure, hepatic failure, bleeding diathesis and serious mental illnesses Headache with red flags symptoms that may suggest organic secondary headaches. Onset of headache more than 50 years Prior GI infection in the previous 3-months Morbid obesity (BMI >40) Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Parallel Assignment
Interventional Model Description: Two-arm parallel assignment involves two groups of participants. One group receives probiotics , and the other group receives placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Double-blind, placebo-controlled interventional study<br>Active treatment group will receive a 3-gram sachet of probiotics containing multi-strain of lactobacillus and Bifidobacterium 30 Colony Forming Unit x 109 to be taken twice daily for 12 weeks. | Dietary Supplement: (Microbial cell preparation) probiotics<br>* Lactobacillus acidophilus (107mg), Lactobacillus casei subsp (107mg), Lactobacillus lactis (107mg), Bifidobacterium bifidum (107mg), Bifidobacterium infantis (107mg) and Bifidobacterium longum (107mg)<br>* Other names: Hexbio;|
| Placebo Comparator: Placebo<br>Patients will be given placebo sachet (exactly the same packaging as active comparator) to be taken 1 sachet twice daily for 12 weeks. | Other: Placebo<br>* Placebo sachet with no microbial cell preparation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in mean monthly migraine days (MMD). | The MMD will be calculated using the MMD recorded by patients in a headache diary from each of the months of the double-blind treatment phase. | Baseline, week 4, 8 and 12 post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in mean monthly migraine attacks | The mean monthly migraine attacks will be calculated using the monthly migraine attack recorded by patients in headache diaries from each of the months of the double-blind treatment phase | Baseline, week 4, 8 and 12 post treatment | 
| Reduction mean monthly migraine days(MMD) | Proportion of subjects with at least a 50% reduction from baseline in MMD | 12 weeks post treatment | 
| Change from baseline in mean monthly pain intensity of migraine attacks | The mean monthly pain intensity will be based on the record of the maximal pain intensity by means of a verbal scale (i.e., 0 =no headache; 1 = mild headache; 2 = moderate headache; 3 = severe headache) prior to taking symptomatic medication | Baseline, week 4, 8 and 12 post treatment | 
| Adverse events in response to probiotics | Frequency and adverse events in response to (probiotics) | Week 4, 8 and 12 treatment | 
| Change from baseline in mean Migraine Induced Disability Assessment Score (MIDAS) | Change from baseline in mean Migraine Induced Disability Assessment Score (MIDAS) in migraine patients in response to probiotics | Week 0 and 12 post treatment | 
| Change from baseline in mean Depression, Anxiety and Stress Scale (DASS21) | Change from baseline in mean Depression, Anxiety and Stress Scale (DASS21) score in migraine patients in response to probiotics | Week 0 and 12 post treatment | 
| Change from baseline in mean Migraine-Specific Quality-of-Life Questionnaire (MSQ V2) score | Change from baseline in mean Migraine-Specific Quality-of-Life Questionnaire (MSQ V2) score in migraine patients in response to probiotics | Week 0 and 12 post treatment | 
| Serum Highly sensitive C-Reactive Protein (hs-CRP) | Highly sensitive C-Reactive Protein (hs-CRP) level changes in migraine patients in response to probiotics | Week 0 and 12 post treatment | 
| Serum Interleukin 6 (IL- 6) | Interleukin 6 (IL- 6) level changes in migraine patients in response to probiotics | Week 0 and 12 post treatment | 
| Serum Tumour Necrosis Factor Alpha (TNF-alpha) | Tumour Necrosis Factor Alpha (TNF-alpha) level changes in migraine patients in response to probiotics | Week 0 and 12 post treatment | 
| Satisfaction measures of efficacy, tolerability, safety, and expectations of probiotics among the participants | A 5-point, Likert scale will be used to evaluate satisfaction with probiotics in migraine prevention | Week 0 and 12 post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Episodic migraine, probiotics, effectiveness, preventive treatment, randomized controlled trial.