Clinical trial NCT05598723: BOTOX® vs. XEOMIN® for Chronic Migraine
Official title: A Randomized, Double-Blind Study on the Effect of OnabotulinumtoxinA (BOTOX®) vs. IncobotulinumtoxinA (XEOMIN®) Botulinum Toxin in Adults With Chronic Migraine
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Chronic Migraine
Keywords: Botox
Xeomin
onabotulinumtoxinA
incobotulinumtoxinA
Botulinum Toxin
refrigeration
HIT-6
Lead sponsor: Naval Medical Center Camp Lejeune
Sponsor class: FED
First posted: 2022-10-28
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, double blind, prospective, parallel-group study (non-inferiority trial)
Primary purpose: TREATMENT

Brief summary: Chronic migraine (CM) is a disabling disorder that sidelines active duty personnel and diminishes their quality of life. It affects 1.3% to 2.4% of the general population. These numbers increase in active duty personnel, especially those returning from deployment, as well as in veterans. Furthermore, these numbers are 4-5 times higher in military members who experienced at least one mild traumatic brain injury. CM leads to impaired cognition and poor decision-making. These impairments on critical active duty tasks could have a significant impact on task readiness and military performance. Therefore, CM presents a challenge for the "return to duty" mission. Currently, onabotulinumtoxinA is the only FDA-approved prophylactic treatment for CM; however, this treatment requires refrigeration, to which there is little access for the forward-deployed members who have limited access to adequate storage for this treatment. Therefore, it is imperative to identify a CM treatment that does not require refrigeration. Furthermore, in light of the ongoing COVID-19 pandemic and resulting international shortages in critical medication production and delivery, it is imperative to identify more than one treatment option for the management of CM. In this study, we will test the efficacy of incobotulinumtoxinA, a neurotoxin that, unlike onabotulinumtoxinA, does not require refrigeration, but is an effective off-label alternative for the treatment of migraine. OnabotulinumtoxinA and incobotulinumtoxinA are comparable in strength, with a conversion ratio of 1:1.

Detailed description: One hundred and twenty-eight male and female active duty personnel, adult dependent and retiree patients from the Navy Medical Center at Camp Lejeune who meet the International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria of ≥15 headache days per month lasting 4 hours or longer will participate in the trial. Subjects will be group-allocated randomly, 64 to onabotulinumtoxinA and 64 to incobotulinumtoxinA. Injections of either treatment will occur twice, 12 weeks apart, in the head and neck regions. The primary treatment efficacy measurement will be the mean change in headache days 12 to 24 weeks post-treatment. Participants will complete an electronic diary to report headache days, their severity, and adverse effects or unforeseen events. A baseline will be established four weeks prior to the first botulinumtoxinA (Botox or Xeomin) administration using the number of headache days and two questionnaires, Headache Impact Test-6 (HIT-6) and the Migraine Specific Quality (MSQ) Questionnaire, which assess headache impact and Health-Related Quality of Life (HRQOL), respectively. These questionnaires will also be administered at weeks 12 and 24 of the study. The baseline, 12-, and 24-week analysis will be performed using a time vs. treatment repeated measures analysis of variance for headache days. Secondary outcomes (total scores of both the HIT-6 and MSQ) will be analyzed similarly.

Eligibility criteria: Inclusion Criteria:

* Between ages of 18-89
* 15 or more headaches days experienced per month lasting 4 hours or longer
* Department of Defense (DoD) Beneficiary/TriCare Eligible
* Failure, contraindication or intolerance to two migraine medications from two different classes.
* Able to provide informed consent and be able to read and write English.
* Able to read, comprehend, and complete the assessment and diary
* Women must provide a negative urine pregnancy test

Exclusion Criteria:

* Currently pregnant, breastfeeding, or planning to become pregnant
* Allergic to botulinum toxin or to any of the ingredients of the medication
* Has myasthenia gravis, amyotrophic lateral sclerosis, or Eaton Lambert syndrome, mitochondrial disease, fibromyalgia, any temporomandibular disfunction, or any other significant disease that might interfere with neuromuscular function.
* Uncontrolled epilepsy defined as more than 1 generalized seizure in any month within the 3 months prior to the day 0 visit
* Those on oral anticoagulation
* Previous botulinum toxin treatment on the cephalic/upper lumbar region within 6 months for any indication
* Localized infections on face, neck or on antibiotics for areas in this region
* Unable to attend study follow up visits for any reason (i.e. Training, deployment, or PCS)
* Use of any prophylactic headache medication between -4 weeks and week 0 visits
* Any person taking chronic pain medication for a chronic indication
* Any diagnosed psychiatric condition which would prohibit a participant from completing the trial in its totality.

Primary outcomes:
measure: Headache days per month
timeFrame: 24 weeks + Baseline
Secondary outcomes:
measure: Differences in headache impact
timeFrame: 24 weeks vs. Baseline
measure: Differences in Health-Related Quality of Life
timeFrame: 24 weeks vs. Baseline
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Naval Medical Center Camp Lejeune
state: North Carolina
Study officials:
affiliation: Naval Medical Center Camp Lejeune
name: Jacqueline S Buckley, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015 Apr 29;35(17):6619-29. doi: 10.1523/JNEUROSCI.0373-15.2015.
citation: Sandrini G, De Icco R, Tassorelli C, Smania N, Tamburin S. Botulinum neurotoxin type A for the treatment of pain: not just in migraine and trigeminal neuralgia. J Headache Pain. 2017 Dec;18(1):38. doi: 10.1186/s10194-017-0744-z. Epub 2017 Mar 21.
citation: May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016 Aug;12(8):455-64. doi: 10.1038/nrneurol.2016.93. Epub 2016 Jul 8.
citation: Schwedt TJ. Chronic migraine. BMJ. 2014 Mar 24;348:g1416. doi: 10.1136/bmj.g1416.
citation: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;33(9):629-808. doi: 10.1177/0333102413485658. No abstract available.
citation: Do TP, Hvedstrup J, Schytz HW. Botulinum toxin: A review of the mode of action in migraine. Acta Neurol Scand. 2018 May;137(5):442-451. doi: 10.1111/ane.12906. Epub 2018 Feb 6.
citation: Carruthers A, Carruthers J. Botulinum toxin products overview. Skin Therapy Lett. 2008 Jul-Aug;13(6):1-4.
citation: Frevert J, Dressler D. Complexing proteins in botulinum toxin type A drugs: a help or a hindrance? Biologics. 2010 Dec 9;4:325-32. doi: 10.2147/BTT.S14902.
citation: Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, Diener HC, Brin MF; PREEMPT 1 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010 Jul;30(7):793-803. doi: 10.1177/0333102410364676. Epub 2010 Mar 17.
citation: Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, Silberstein SD, Brin MF; PREEMPT 2 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010 Jul;30(7):804-14. doi: 10.1177/0333102410364677. Epub 2010 Mar 17.
citation: Rendas-Baum R, Bloudek LM, Maglinte GA, Varon SF. The psychometric properties of the Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ) in chronic migraine patients. Qual Life Res. 2013 Jun;22(5):1123-33. doi: 10.1007/s11136-012-0230-7. Epub 2012 Jul 15.
citation: Ion I, Renard D, Le Floch A, De Verdal M, Bouly S, Wacongne A, Lozza A, Castelnovo G. Monocentric Prospective Study into the Sustained Effect of Incobotulinumtoxin A (XEOMIN(R)) Botulinum Toxin in Chronic Refractory Migraine. Toxins (Basel). 2018 Jun 1;10(6):221. doi: 10.3390/toxins10060221.
citation: Kwong WJ, Pathak DS. Validation of the eleven-point pain scale in the measurement of migraine headache pain. Cephalalgia. 2007 Apr;27(4):336-42. doi: 10.1111/j.1468-2982.2007.01283.x.
citation: Bagley CL, Rendas-Baum R, Maglinte GA, Yang M, Varon SF, Lee J, Kosinski M. Validating Migraine-Specific Quality of Life Questionnaire v2.1 in episodic and chronic migraine. Headache. 2012 Mar;52(3):409-21. doi: 10.1111/j.1526-4610.2011.01997.x. Epub 2011 Sep 19.
citation: Wilderman I, Tallarigo D, Pugacheva-Zingerman O. A Qualitative Study to Explore Patient Perspectives of Prophylactic Treatment with OnabotulinumtoxinA for Chronic Migraine. Pain Ther. 2021 Dec;10(2):1523-1536. doi: 10.1007/s40122-021-00316-2. Epub 2021 Sep 14.
citation: Stark C, Stark R, Limberg N, Rodrigues J, Cordato D, Schwartz R, Jukic R. Real-world effectiveness of onabotulinumtoxinA treatment for the prevention of headaches in adults with chronic migraine in Australia: a retrospective study. J Headache Pain. 2019 Jul 15;20(1):81. doi: 10.1186/s10194-019-1030-z.
citation: Kawata AK, Shah N, Poon JL, Shaffer S, Sapra S, Wilcox TK, Shah S, Tepper SJ, Dodick DW, Lipton RB. Understanding the migraine treatment landscape prior to the introduction of calcitonin gene-related peptide inhibitors: Results from the Assessment of TolerabiliTy and Effectiveness in MigrAINe Patients using Preventive Treatment (ATTAIN) study. Headache. 2021 Mar;61(3):438-454. doi: 10.1111/head.14053. Epub 2021 Feb 16.
citation: Kreidler SM, Muller KE, Grunwald GK, Ringham BM, Coker-Dukowitz ZT, Sakhadeo UR, Baron AE, Glueck DH. GLIMMPSE: Online Power Computation for Linear Models with and without a Baseline Covariate. J Stat Softw. 2013 Sep;54(10):i10. doi: 10.18637/jss.v054.i10.
citation: Yiannakopoulou E. Serious and long-term adverse events associated with the therapeutic and cosmetic use of botulinum toxin. Pharmacology. 2015;95(1-2):65-9. doi: 10.1159/000370245. Epub 2015 Jan 21.
citation: Kessler KR, Skutta M, Benecke R. Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency. German Dystonia Study Group. J Neurol. 1999 Apr;246(4):265-74. doi: 10.1007/s004150050345.
citation: Fisher CM. Late-life migraine accompaniments--further experience. Stroke. 1986 Sep-Oct;17(5):1033-42. doi: 10.1161/01.str.17.5.1033.
citation: Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin. 2004 Jul;20(7):981-90. doi: 10.1185/030079904125003962.