| CTRI Number |
CTRI/2024/06/069336 [Registered on: 20/06/2024] Trial Registered Prospectively |
| Last Modified On: |
04/06/2024 |
| Post Graduate Thesis |
Yes |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Parallel Group, Placebo Controlled Trial |
|
Public Title of Study
|
Is Greater Occipital Nerve Block Together with Botulinum Toxin Injection a Better Treatment Than Either of These Treatments Alone in Patients with Refractory Migraine |
|
Scientific Title of Study
|
Combination Treatment of Greater Occipital Nerve Block and Botulinum Toxin for Resistant Migraine: A Randomized Double-Blind Placebo-Controlled Study (COMBO-GONBOT Study)) |
| Trial Acronym |
COMBO-GONBOT Study |
|
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 Postgraduate Medical Education and Research, New Delhi |
| Address |
Department of Neurology, Maulana Azad Medical College and Associated GB Pant Institute of Postgraduate Medical Education and Research, Jawaharlal Nehru Marg, New Delhi
Central
DELHI
110002
India |
| Phone |
9718599306 |
| Fax |
|
| Email |
debuchoke@gmail.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Mahak Golani |
| Designation |
Senior Resident |
| Affiliation |
GB Pant Institute of Postgraduate Medical Education and Research, New Delhi |
| Address |
Department of Neurology, Maulana Azad Medical College and Associated GB Pant Institute of Postgraduate Medical Education and Research, Jawaharlal Nehru Marg, New Delhi
Central
DELHI
110002
India |
| Phone |
9582029372 |
| Fax |
|
| Email |
mahakgolani@gmail.com |
|
Details of Contact Person
Public Query
|
| Name |
Dr Mahak Golani |
| Designation |
Senior Resident |
| Affiliation |
GB Pant Institute of Postgraduate Medical Education and Research, New Delhi |
| Address |
Department of Neurology, Maulana Azad Medical College and Associated GB Pant Institute of Postgraduate Medical Education and Research, Jawaharlal Nehru Marg, New Delhi
Central
DELHI
110002
India |
| Phone |
9582029372 |
| Fax |
|
| Email |
mahakgolani@gmail.com |
|
|
Source of Monetary or Material Support
|
| GB Pant Institute of Postgraduate Medical Education and Research, Jawaharlal Nehru Marg, New Delhi, India-110002 |
|
|
Primary Sponsor
|
| Name |
GB Pant Institute of Postgraduate Medical Education and Research, New Delhi |
| Address |
GB Pant Institute of Postgraduate Medical Education and Research, Jawaharlal Nehru Marg, New Delhi-110002. |
| Type of Sponsor |
Government medical college |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 1 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Mahak Golani |
GB Pant Institute of Postgraduate Medical Education and Research, New Delhi |
Department of Neurology, Headache Clinic, Room no 328, D Block, GB Pant Institute of Postgraduate Medical Education and Research, Jawaharlal Nehru Marg, New Delhi-110002
Central
DELHI |
9582029372
mahakgolani@gmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 1 |
| Name of Committee |
Approval Status |
| Institutional Ethics Committee, Maulana Azad Medical College and Associated Hospitals |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: G430||Migraine without aura, (2) ICD-10 Condition: G431||Migraine with aura, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
GONB (Greater Occipital Nerve Block) and BoT-A (Botulinum Toxin) |
GONB with 2% lidocaine(2ml) every 4 weeks and BoT-A (5U, 0.1ml) at 31 sites
as per PREEEMPT design) every 12 weeks
GONB Injection Protocol:
GONB shall be administered using a standardized procedure. The site of injection shall be marked i.e. approximately two thirds of the distance on a line drawn from the center of the mastoid to the external occipital protuberance only if these points exhibited conspicuous pain sensitivity to pressure. Prior to giving injection of GONB, on the marked point and an area surrounding it with 3cm diameter, lignocaine jelly will be applied topically to mask the effect of numbness following the GONB. Injection will be given on both left and right sides after 10 minutes of topical application of lidocaine. The patient will be positioned properly by slight neck flexion. The injection site will be cleaned with spirit to give GONB under aseptic precaution. One third of the injection will be injected in that area, one third slightly medially and one third slightly laterally. The patients will receive GONB with 2ml of 2% lidocaine.
BoT-A injection Protocol:
BoT-A will be injected as per the PREEEMPT protocol. A fixed dose regimen of 155 units at 31 specified sites (5 units each) will be used. 50-unit vials of BoT-A will be diluted with 1ml of 0.9% of normal saline and filled up in insulin syringes. Four such syringes will be filled. Syringe 1: 35 units (0.7ml) for frontalis, corrugator and procerus muscles; syringe 2: 40 units (0.8ml) for temporalis muscles; syringe 3: 50 units (1ml) for paraspinal and occipital muscles and syringe 4: 30 units ( 0.6ml) for trapezius muscles.
All patients will be administered GON block initially followed 1 hour later by BoT-a on the same day. |
| Comparator Agent |
GONB (Greater Occipital Nerve Block) and Sham BoT-A (Botulinum Toxin) |
GONB with 2% lidocaine(2ml) every 4 weeks and sham BoT-A (using normal
saline) every 12 weeks.
GONB Injection Protocol: GONB shall be administered using a standardized procedure. The site of injection shall be marked i.e. approximately two thirds of the distance on a line drawn from the center of the mastoid to the external occipital protuberance only if these points exhibited conspicuous pain sensitivity to pressure. Prior to giving injection of GONB, on the marked point and an area surrounding it with 3cm diameter, lignocaine jelly will be applied topically to mask the effect of numbness following the GONB. Injection will be given on both left and right sides after 10 minutes of topical application of lidocaine. The patient will be positioned properly by slight neck flexion. The injection site will be cleaned with spirit to give GONB under aseptic precaution. One third of the injection will be injected in that area, one third slightly medially and one third slightly laterally. The patients will receive GONB with 2ml of 2% lidocaine.
Sham BoT-A injection Protocol: Sham BoT-A with 0.9% normal saline will be injected using similar injectors and volume and sites except for the four sites at the frontalis , two sites at the corrugators and one site at the procerus muscles where 2.5 units of BoT-A will be added to normal saline (0.05ml of BoT-A and 0.05 ml of normal saline) to mask the effect of smoothing of frontalis, corrugators and procerus muscles due to BoT-A injection.
All patients will be administered GON block initially followed 1 hour later by sham BoT-A on the same day. |
| Comparator Agent |
Sham GONB (Greater Occipital Nerve Block) and BoT-A (Botulinum Toxin) |
Sham GONB (using 2ml normal saline) every 4 weeks and BoT-A (5U at 31
sites as per PREEEMPT design) every 12 weeks.
Sham GONB Protocol:
Sham GONB with 2ml of normal saline will be administered using the same protocol. Prior to giving injection of sham GONB, on the marked point and an area surrounding it with 3cm diameter, lignocaine jelly will be applied topically for masking the effect of numbness
BoT-A injection Protocol: BoT-A will be injected as per the PREEEMPT protocol. A fixed dose regimen of 155 units at 31 specified sites (5 units each) will be used. 50-unit vials of BoT-A will be diluted with 1ml of 0.9% of normal saline and filled up in insulin syringes. Four such syringes will be filled. Syringe 1: 35 units (0.7ml) for frontalis, corrugator and procerus muscles; syringe 2: 40 units (0.8ml) for temporalis muscles; syringe 3: 50 units (1ml) for paraspinal and occipital muscles and syringe 4: 30 units ( 0.6ml) for trapezius muscles. All patients will be administered Sham GON block initially followed 1 hour later by BoT-a on the same day.
|
|
|
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)12 for at least 12 months before screening and fulfils the European Headache Federation (EHF) consensus criteria for resistant migraine.
2. Patients should be experiencing ≥8 days/month of disabling headache for at least 3 months (as defined by EHF criteria).
3. Patients with failure to three treatment classes of drugs (with established evidence for migraine prevention) given at an appropriate dose for an appropriate duration (as defined by EHF consensus criteria).
4. Patients with medication overuse [overuse of triptans, ergot derivatives, analgesics, and combination drugs (any combination of those above or simple analgesics with opiates or butalbital)] will be permitted to participate in this study.
|
|
| ExclusionCriteria |
| Details |
1. Patients older than 50 years at migraine onset
2. Patients who have previously received and failed BoT-A and GONB treatments during the last 6 months or less prior to the inclusion.
3. Patients who had previously received anti-CGRP-mAbs three months or less before their enrolment.
4. Patients who had received neuromodulation devices and undergone procedures such as multiple nerve blocks used for migraine prophylaxis.
5. Patients who had received investigational medications and devices for migraine prevention.
6. All patients with a clinical phenotype of episodic or chronic migraine but on further investigation, found to have a secondary cause for their headaches will be excluded.
7. Pregnant women, patients with known allergies against lidocaine or BoT-A, patients with history of moderate to severe anxiety or depression, psychosis and chronic liver, kidney and heart diseases.
|
|
|
Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Sequentially numbered, sealed, opaque envelopes |
|
Blinding/Masking
|
Participant, Investigator and Outcome Assessor Blinded |
|
Primary Outcome
|
| Outcome |
TimePoints |
| Change in mean disabling headache days per 28 days compared with baseline at the end of week 24 |
24 weeks |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| Proportions of patients achieving more than 50% reduction in disabling headache days per 28 days compared with baseline at the end of week 24 |
24 weeks |
| Change in mean migraine days per 28 days compared with baseline at the end of week 24. (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) |
24 weeks |
| 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 24 |
24 weeks |
| Change in mean total duration of disabling headache [cumulative headache hours (CHH)] per 28 days compared with baseline at the end of week 24 |
24 weeks |
| Change in mean Numerical Pain Rating Scale per 28 days compared with baseline at the end of week 24 |
24 weeks |
| Change in mean HIT-6 (Headache Impact Test) score per 28 days compared with baseline at the end of week 24 |
24 weeks |
| Change in mean MIDAS (Migraine Disability Assessment) score per 28 days at the end of week 24 |
24 weeks |
| Change in migraine specific quality of life score per 28 days compared with baseline at the end of week 24 |
24 weeks |
| Change in clinical global impression severity (CGI-S) score per 28 days compared with baseline at the end of week 24 |
24 weeks |
| Clinical global impression improvement (CGI-I) score per 28 days at the end of week 24 |
24 weeks |
| Proportions of patients in each group having treatment emergent adverse events including serious adverse events at the end of week 24 |
24 weeks |
|
|
Target Sample Size
|
Total Sample Size="84"
Sample Size from India="84"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 3 |
|
Date of First Enrollment (India)
|
15/07/2024 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="1"
Months="6"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Not Applicable |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
N/A |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
|
Brief Summary
|
A
small but sizeable proportion of migraine patients do not respond to the
standard established medications which are called as resistant and refractory
migraine as defined by EHF criteria 2020. Currently
the treatment options for resistant migraine include BoT-A, GON blocks and
anti-CGRP mAbs. However
when used alone they are efficacious in only about 50% of the patients. Hence,
combination treatments are being tried. A
combination of anti-CGRP mAbs and BoT-A is very expensive
and is prohibitive for most of the patients in the developing world. In
contrast, GONB treatment is very cheap, easily available and require little
expertise to administer. Efficacy
and tolerability of a combination treatment of GONB and BoT-A for prevention of
resistant migraine is unknown.Hence,
this randomized controlled trial (RCT) was devised using the International
Headache society guidelines to find the efficacy and the tolerability of the
combination of GONB and BoT-A in patients with
resistant migraine. Aims of this study are: - 1.To find out the efficacy of combination treatment of 4 weekly GONB with 12 weekly BoT-A at 24 weeks for
the prevention of resistant migraine as compared with either treatment as monotherapy.
2. To find out the effects of combination treatment of 4
weekly GONB with 12 weekly BoT-A at 24 weeks on patient reported outcomes such as
headache impact, disability, and migraine specific quality of life.
3. To find out the tolerability of combination treatment of
4 weekly GONB with 12 weekly BoT-A at 24 weeks for the prevention of resistant migraine
as compared with either treatment as monotherapy.
Methodology: This
randomized, double-blind, placebo-controlled, parallel-group study will consist
of a baseline period of 4 weeks followed by a double-blind treatment phase
(DBTP) for 24 weeks. There will be three intervention groups during the DBTB: Group
A: GONB with BoT-A, Group
B: GONB and sham BoT-A (using normal saline), Group
C: BoT-A with sham GONB (using normal saline). Following
the screening of eligible patients, the baseline data (4 weeks) will be captured by using the headache diary. Randomization
shall be done by computer-based block randomization chart and patients will be
allocated to the three intervention groups. The patients will be followed up for 24 weeks. The primary end point would be Change
in mean disabling headache days per 28 days compared with baseline at the end
of week 24. Efficacy
variables such as 4 weekly disabling headache days, migraine days, AMT days, CHH,
pain severity [rated by numeric rating scale (NRS); higher score denoting
greater severity of pain], 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 24 weeks during DBTP. 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 and 24 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 12 and 24 weeks after
randomization. Acute
migraine treatment (acetaminophen, NSAIDs, antiemetics, triptans, ditans and
ergots) shall be allowed throughout the study. The patients shall be told to
take acute medication after 30 minutes of onset of moderate to severe headache
attacks. They will be also educated to reduce the medication overuse and be
encouraged to use stratified acute care. |