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CTRI Number  CTRI/2023/04/051915 [Registered on: 24/04/2023] Trial Registered Prospectively
Last Modified On: 06/11/2024
Post Graduate Thesis  Yes 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   Role of Brivaracetam use for Treatment of Episodic Migraine (ROBUST-EM) 
Scientific Title of Study   Role of Brivaracetam use for Treatment of Episodic Migraine (ROBUST-EM): A Randomised Double-Blind Placebo-Controlled Study”. 
Trial Acronym  ROBUST-EM 
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr debashish Chowdhury 
Designation  Director Professor and Head of Department 
Affiliation  GB Pant Institute of Post Graduate Medical Education and Research, New Delhi 
Address  Department of Neurology, Maulana Azad Medical College and associated GB Pant Institute of Post Graduate Medical Education and Research, New Delhi

New Delhi
DELHI
110002
India 
Phone  9718599306  
Fax    
Email  debuchoke@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Manju yadav 
Designation  Senior Resident 
Affiliation  GB Pant Institute of Post Graduate Medical Education and Research, New Delhi 
Address  Department of Neurology, Maulana Azad Medical College and associated GB Pant Institute of Post Graduate Medical Education and Research, New Delhi

New Delhi
DELHI
110002
India 
Phone  8368487948  
Fax    
Email  mishty@gmail.com  
 
Details of Contact Person
Public Query  
Name  Dr Manju Yadav 
Designation  Senior Resident 
Affiliation  GB Pant Institute of Post Graduate Medical Education and Research, New Delhi 
Address  Department of Neurology, Maulana Azad Medical College and associated GB Pant Institute of Post Graduate Medical Education and Research, New Delhi

New Delhi
DELHI
110002
India 
Phone  8368487948  
Fax    
Email  mishty125@gmail.com  
 
Source of Monetary or Material Support  
GB Pant Institute of Post Graduate Medical Education and Research, New Delhi 110002 
 
Primary Sponsor  
Name  GB Pant Institute of Post Graduate Medical Education and Research, New Delhi 110002 
Address  Jawahar Lal Nehru Marg, New Delhi-110002 
Type of Sponsor  Government medical college 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Manju Yadav  GB Pant Institute of Post Graduate Medical Education and Research  room no 504,Neurology department,5th floor, academic block. Jawaharlal Nehru Marg
New Delhi
DELHI 		 8368487948

mishty125@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Institutional Ethical Committee, MAMC  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: G430||Migraine without aura,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Tablet Brivaracetam   There will be three intervention(oral route of administration) groups: Brivaracetam 50mg/day; Brivaracetam 100mg /day and placebo(in two divided doses). patients shall be given treatment according to their group in double blind phase for 12 weeks. it will be followed by open label for another 12 weeks, where they will be given option to continue oral Brivaracetam upto 100mg/day. After 24 weeks an attempt to stop the treatment shall be made as per clinical judgement of the investigator and the final follow-up of the patient shall be undertaken at 36 weeks. 
Comparator Agent  Tablet Placebo  There will be three intervention(oral route of administration) groups: brivaracetam 50mg/day; brivaracetam 100mg /day and placebo(in two divided doses). patients shall be given treatment according to their group in double blind phase. it will be followed by open label where the will be given option to continue brivaracetam upto 100mg/day. Results of brivaracetam group will be compared among themselves and to placebo group 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  65.00 Year(s)
Gender  Both 
Details  1. Adults 18 to 65 years of age who had have a history of migraine with or without aura (as defined by ICHD-3) for at least 12 months before screening.
2. Patients should be experiencing at least 4 and fewer than 15 migraine headache days during the 4weeks of the baseline phase (as obtained by the paper headache diary).
3. Patients should be experiencing fewer than 15 headache days per month during the last 3 months before baseline the phase (as obtained by history from the patient).
4. Patients must demonstrate at least 80% adherence to reporting with the headache diary during the baseline phase.
 
 
ExclusionCriteria 
Details  1. Patients older than 50 years at migraine onset.
2. Patients will be excluded if they had no therapeutic response in migraine prevention after an adequate therapeutic trial of >2 of the following medication categories: Category 1: Divalproex sodium, sodium valproate; Category 2: Topiramate; Category 3: Beta blockers; Category 4: Tricyclic antidepressants; Category 5: Serotonin-norepinephrine reuptake inhibitors; Category 6: Flunarizine, verapamil; Category 7: Lisinopril, candesartan. (No therapeutic response will be defined as no reduction in headache frequency, duration, or severity after administration of the medication for ≥6 weeks at the generally accepted therapeutic dose(s) based on the investigator’s assessment. Lack of sustained response to a medication and failure to tolerate a therapeutic dose will not considered to be “no therapeutic response.”)
3. The following medications, devices, or procedures will be excluded: Botulinum toxin (in the head and/or neck region) is excluded within 4 months before the start of the baseline phase and throughout the study.
4. Ergotamine derivatives, steroids, and triptans used for migraine prophylaxis are excluded within 3 months before the start of the baseline phase and throughout the study.
5. Devices and procedures used for migraine prophylaxis are excluded within 2 months before the start of the baseline phase and throughout the study. Investigational medications and devices are excluded throughout the study.
6. Patients also must not have used investigational medications or devices for at least 90 days prior to screening.
7. Patients who were concomitantly using medications for migraine prevention within 3 months before the start of the baseline phase and throughout the study will be excluded.
8. Patients with significant suicidal ideation as analysed by Columbia Suicide Severity Rating Scale (C-SSRS)>2
9. Pregnant women, female patients who are not willing for effective contraception.
10. Patient with known allergies against levetiracetam or brivaracetam, patients with history of moderate to severe anxiety or depression, psychosis and chronic liver, kidney and heart diseases shall be excluded from the study.

 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Case Record Numbers 
Blinding/Masking   Participant, Investigator and Outcome Assessor Blinded 
Primary Outcome  
Outcome  TimePoints 
Change in mean migraine headache days (MHD) per 28 days compared with baseline at the end of week 12 (migraine day is defined as a calendar day when the patient reported ≥4 continuous hours of headache meeting ICHD 3 criteria for migraine; additionally, any calendar day on which acute migraine–specific medication (ergot or triptan) is used shall be counted as a migraine day. A qualified migraine headache is defined as a migraine with or without aura, lasting for ≥30 minutes, and meeting at least one of the following criteria (a and/or b): a) ≥2 of the following pain features: unilateral, throbbing, moderate to severe, exacerbated with exercise/physical activity and b) ≥1 of the following associated symptoms: nausea and/or vomiting, photophobia, and phonophobia)
 		 12 week 
 
Secondary Outcome  
Outcome  TimePoints 
Key Secondary End points
1. Proportions of patients achieving more than 50% reduction in migraine headache days (MHD) per 28 days compared with baseline at the end of week 12

Other Secondary End Points
1. Change in mean number of acute migraine treatment (AMT) days to abort the headache attacks (analgesics/triptans/ergotamines) per 28 days compared with baseline at the end of week 12.
2. Change in mean total duration of migraine headache [cumulative headache hours (CHH)] per 28 days compared with baseline at the end of week 12.
3. Change in mean visual analogue scale (VAS) score per 28 days compared with baseline at the end of week 12.
4. Change in mean HIT-6 (Headache Impact Test) score per 28 days compared with baseline at the end of week 12.
5. Change in mean MIDAS (Migraine Disability Assessment) score per 28 days at the end of week 12.
 		 12 week 
 
Target Sample Size   Total Sample Size="216"
Sample Size from India="216" 
Final Enrollment numbers achieved (Total)= "0"
Final Enrollment numbers achieved (India)="216" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   01/05/2023 
Date of Study Completion (India) 12/09/2024 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="1"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Yet Recruiting 
Recruitment Status of Trial (India)  Completed 
Publication Details    
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - YES
  1. What data in particular will be shared?
    Response - Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).

  2. What additional supporting information will be shared?
    Response -  Study Protocol
    Response - Informed Consent Form
    Response - Clinical Study Report

  3. Who will be able to view these files?
    Response - Researchers who provide a methodologically sound proposal.

  4. For what types of analyses will this data be available?
    Response - To achieve aims in the approved proposal.

  5. By what mechanism will data be made available?
    Response - Proposals should be directed to [mishty125@gmail.com].

  6. For how long will this data be available start date provided 01-01-2026 and end date provided 01-04-2028?
    Response - Beginning 9 months and ending 36 months following article publication.

  7. Any URL or additional information regarding plan/policy for sharing IPD? 
    Additional Information - nil
Brief Summary
Modification(s)  

Levetiracetam(LEV), an antiseizure medication with a good safety profile appears to be effective in treating migraine with and without aura. Brivaracetam (BRV), a congener of LEV is also used as an anti seizure medication, displays a higher affinity to its binding site synaptic vesicle protein 2A (SV2A), has higher potency and efficacy, favourable pharmacokinetic profile with lesser prevalence of adverse effects when compared with LEV. Therefore, BRV is potentially a good candidate drug for investigating its efficacy and safety for migraine prevention. 

We therefore aim to conduct a double-blind, placebo-controlled study for its role in episodic migraine prevention.

All patients fulfilling inclusion and exclusion criteria will be evaluated as per a detailed structured proforma covering all aspects of clinical characteristics of headache including detailed family history. This study will consist of a baseline period of 4 weeks followed by a double-blind treatment phase (DBTP) for 12 weeks and then an open-label treatment phase (OLTP) for another 12 weeks. 

The study tests three hypotheses, namely 100mg and 50mg of oral brivaracetam is superior to placebo and 100mg of oral brivaracetam is better than 50 mg of placebo. So , A planned enrolment of 72 patients per treatment group ( BRV 50mg, BRV 100mg, Placebo) shall be done for 3 groups.

 

METHODS-During the OLTP, the patients will be given an option of continuing with the brivaracetam at a dose of 50-100mg/day for next 12 weeks. Physicians will have discretion to adjust the dose as per the clinical response. After 24 weeks, an attempt to stop the treatment shall be made as per clinical judgement of the investigator. The final follow-up of the patient shall be undertaken at 36 weeks. All patients will be evaluated as per a detailed structured proforma covering all aspects of clinical characteristics of headache including detailed family history. If indicated, contrast enhanced MRI (Brain), Magnetic Resolution Angiography (MRA), Magnetic Resolution Venography (MRV) and Cerebrospinal fluid (CSF) study will be done in selected cases with red flags to rule out a secondary cause. For the detection of psychiatric co-morbidity, a screening questionnaire (PHQ questionnaire) will be used. Depression and anxiety will be rated by Hamilton Depression rating scale (HAM-D) and anxiety by GAD-7. Impact of headache will be assessed by Headache impact test (HIT6) and headache related disability will be assessed by Migraine disability assessment test (MIDAS) and VAS scale for severity of headache. Systemic co-morbid conditions will be noted.  There will a baseline phase of 4 weeks followed by DBTP of 5 visits (-0 weeks to 12 weeks) to be followed by OLTP of 3 visits (weeks 16, 20 and 24) .There will be a final visit at 36 weeks following drug withdrawal at 24 weeks. Thus, there will be 10 visits in total.

Efficacy variables such as 4 weekly migraine days, AMT days, CHH, VAS (an 11-item score from 0-10 with higher score indicating greater severity), and 6-item headache impact test (HIT-6) score (higher score indicating greater disability), a 3-dimension migraine specific quality of life (MSQOL) score (higher score indicating worse quality of life), and clinical global impression severity (CGI-S) score that rates the clinician’s view of the patient’s global functioning (higher score indicating greater severity) shall be documented using a paper headache diary at the baseline phase and every subsequent 4 weeks till 12 weeks during DBTP and then during OLTP.  Baseline migraine disability assessment score (MIDAS) (a five-item self-administered questionnaire with a higher score indicating greater disability), will be calculated based on 3months data prior to randomization and measured at 12 weeks after randomization. Clinical global impression improvement (CGI-I) score that rates the clinician’s view of the patient’s global improvement following start of treatment (higher score indicating greater worsening) will be measured at 4, 8 and 12 weeks after randomization. Patients will also require reporting telephonically or by what’s app message about the occurrence of any moderate to severe headache and acute treatment taken, if any, on the same day of the attack so that it can be double checked with the filled paper diary later. Statistical analysis will be done with SPSS version 17

 

 
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