Clinical trial NCT04064814: Evaluation of Efficacy and Safety of add-on Alpha-lipoic Acid on Migraine Prophylaxis in Adolescent Population
Official title: Evaluation of Efficacy and Safety of add-on Alpha-lipoic Acid on Migraine Prophylaxis in Adolescent Population: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Adolescent Migraine
Keywords: Adolescent Migraine
Flunarizine
Alpha Lipoic Acid
Thiol Level
Calcitonin gene regulated peptide
Lead sponsor: All India Institute of Medical Sciences, Bhubaneswar
Sponsor class: OTHER
First posted: 2019-08-22
Enrollment: 60
Sex: ALL
Minimum age (years): 10
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, open Label , active controlled study
Primary purpose: PREVENTION

Brief summary: Migraine causes a substantial impact on the physical and mental health of a child and it is a major cause for time-off school leading to impaired academic performance. Therefore prophylactic treatment is suggested for adolescents with frequent or disabling migraine, aiming at improving the function, quality of life and reducing disability.

The most commonly used non-pharmacological agents for the prophylactic management of migraine in adolescents are nutraceuticals. Amongst all nutraceuticals, most commonly used agents for prophylaxis are coenzyme Q10, magnesium, riboﬂavin, feverfew and butterbur .

Alpha-lipoic acid (ALA) or 6,8-thioctic acid, is an endogenous molecule which functions as an important co-factor for various enzyme complexes in mitochondria and plays an important role in energy metabolism.ALA is a nutraceutical agent which also has neuroprotective and anti-inﬂammatory effects. It has been proved that the thiol level remains low in migraine patients.

However, only one study has been done by Ali et al in the pediatric population where the combination of ALA and topiramate has shown promising results but the study result is not generalizable due to its inherent limitations.

So, the study has been planned with an aim to evaluate the efficacy and safety of ALA as add-on therapy with flunarizine in the adolescent age group

Detailed description: Migraine causes a substantial impact on the physical and mental health of a child and it is a major cause for time-off school leading to impaired academic performance. Therefore prophylactic treatment is suggested for adolescents with frequent or disabling migraine, aiming at improving the function, quality of life and reducing disability. Pharmacological agents commonly used for migraine prophylaxis in adolescents are topiramate, cyproheptadine, amitriptyline, valproate, propranolol and flunarizine. These preventive medications are effective first-line treatment but the associated adverse effects have limited their use amongst the adolescent population. In this clinical scenario nutraceuticals may be an alternative option.

The most commonly used non-pharmacological agents for the prophylactic management of migraine in adolescents are nutraceuticals. Amongst all nutraceuticals, most commonly used agents for prophylaxis are coenzyme Q10, magnesium, riboﬂavin, feverfew and butterbur . Despite being largely used for prophylaxis of adolescent migraine, sufficient evidences are lacking which support the safety and efficacy of these agents. The findings from the previous studies on riboflavin and coenzyme Q10 are conflicting and inconclusive. Thus there is a need for a clinically effective nutraceutical in migraine prophylaxis.

Alpha-lipoic acid (ALA) or 6,8-thioctic acid, is an endogenous molecule which functions as an important co-factor for various enzyme complexes in mitochondria and plays an important role in energy metabolism. ALA is a nutraceutical agent which also has neuroprotective and anti-inﬂammatory effects. It has been proved that the thiol level remains low in migraine patients. In some recent studies, ALA has been found to be beneficial in migraine prophylaxis in adults. However, only one study has been done by Ali et al in the pediatric population where the combination of ALA and topiramate has shown promising results but the study result is not generalizable due to its inherent limitations.

From the literature search, it is evident that there is a lack of data on the efficacy and safety of ALA as a prophylactic agent in migraine. So, the study has been planned with an aim to evaluate the efficacy and safety of ALA as add-on therapy with flunarizine in the adolescent age group. The choice of flunarizine as standard prophylactic therapy in the present study is supported by the fact that flunarizine is efficacious and safer in the adolescent population due to its fewer adverse effects in comparison to topiramate and propranolol.

Eligibility criteria: Inclusion Criteria:

* Patients with "15 or more headache days per month with at least 8 days having migraine features for at least 3 months (according to the criteria of the International Classification of Headache Disorders, 3rd edition \[beta version\], or ICHD-3 beta)."
* Adolescent migraineurs aged 10 to 19 years of age of either sex.
* Patients who have not taken any prophylactic treatment within the last three months before their inclusion in the study.
* Patients and/or parents have given informed written consent/assent.

Exclusion Criteria:

* Patient with headache other than migraine.
* Patients who were on corticosteroids
* Treatment with any test drugs in the preceding three months from the start of the trial.
* If there is any history of interventions or devices used for the treatment of migraine, such as transcranial magnetic stimulation and nerve blocks during the 3 months before screening.
* Any other accompanying systemic illness; abnormalities revealed on neurologic examination.
* Psychiatric disturbances, history of epilepsy , learning disabilities, head trauma or use of other drugs acting on the central nervous system, including, smoking, alcohol consumption or any illicit drug abuse

Primary outcomes:
measure: Mean monthly migraine attack rate
timeFrame: 12 weeks
Secondary outcomes:
measure: Responder rate
timeFrame: 12 weeks
measure: The number of days with migraine headache
timeFrame: 12 weeks
measure: The mean severity of acute attacks
timeFrame: 12 weeks
measure: The number of days with nausea or vomiting
timeFrame: 12 weeks
measure: The headache disability will be assessed by pedMIDAS (pediatric migraine disability assessment score)
timeFrame: 12 weeks
measure: The relapse rate among the responders after stoppage of prophylactic therapy .
timeFrame: 12 weeks
measure: Serum thiol levels
timeFrame: 12 weeks
measure: Serum CGRP
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Bhubaneswar
country: India
facility: AIIMS
state: Odisha
Study officials:
affiliation: Additional Professor
name: Rituparna Maiti, MD
role: STUDY_DIRECTOR
References:
citation: Karsan N, Prabhakar P, Goadsby PJ. Premonitory Symptoms of Migraine in Childhood and Adolescence. Curr Pain Headache Rep. 2017 Jul;21(7):34. doi: 10.1007/s11916-017-0631-y.
citation: Eiland LS, Jenkins LS, Durham SH. Pediatric migraine: pharmacologic agents for prophylaxis. Ann Pharmacother. 2007 Jul;41(7):1181-90. doi: 10.1345/aph.1K049. Epub 2007 Jun 5.
citation: O'Brien HL, Kabbouche MA, Hershey AD. Treating pediatric migraine: an expert opinion. Expert Opin Pharmacother. 2012 May;13(7):959-66. doi: 10.1517/14656566.2012.677434. Epub 2012 Apr 14.
citation: D'Onofrio F, Raimo S, Spitaleri D, Casucci G, Bussone G. Usefulness of nutraceuticals in migraine prophylaxis. Neurol Sci. 2017 May;38(Suppl 1):117-120. doi: 10.1007/s10072-017-2901-1.
citation: Wang J, Tang J, Zhou X, Xia Q. Physicochemical characterization, identification and improved photo-stability of alpha-lipoic acid-loaded nanostructured lipid carrier. Drug Dev Ind Pharm. 2014 Feb;40(2):201-10. doi: 10.3109/03639045.2012.753901. Epub 2013 Jan 22.
citation: Magis D, Ambrosini A, Sandor P, Jacquy J, Laloux P, Schoenen J. A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache. 2007 Jan;47(1):52-7. doi: 10.1111/j.1526-4610.2006.00626.x.
citation: Sorge F, De Simone R, Marano E, Nolano M, Orefice G, Carrieri P. Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-controlled, crossover study. Cephalalgia. 1988 Mar;8(1):1-6. doi: 10.1046/j.1468-2982.1988.0801001.x.
citation: Abu-Arafeh I, Hershey AD, Diener HC, Tassorelli C; Clinical Trials Standing Committee and the Child and Adolescent Standing Committee of the International Headache Society. Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine in children and adolescents, 1st edition. Cephalalgia. 2019 Jun;39(7):803-816. doi: 10.1177/0333102419842188. Epub 2019 Apr 4.
citation: Sorge F, Marano E. Flunarizine v. placebo in childhood migraine. A double-blind study. Cephalalgia. 1985 May;5 Suppl 2:145-8. doi: 10.1177/03331024850050S227.
citation: Kenney D, Jenkins S, Youssef P, Kotagal S. Patient Use of Complementary and Alternative Medicines in an Outpatient Pediatric Neurology Clinic. Pediatr Neurol. 2016 May;58:48-52.e7. doi: 10.1016/j.pediatrneurol.2015.11.003. Epub 2016 Jan 11.