Clinical trial NCT02318446: Efficacy Study of Folic Acid Supplementation in Adolescent Epileptics
Official title: Efficacy Study of Folic Acid Supplementation on Homocysteine Levels in Adolescent Epileptics Taking Antiepileptic Drugs: A Single Blind Randomized Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Epilepsy
Keywords: Anti-epileptic drugs
Folic acid
Homocysteine
Lead sponsor: Maharashtra University of Health Sciences
Sponsor class: OTHER
First posted: 2014-12-17
Enrollment: 36
Sex: ALL
Minimum age (years): 10
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The present study is planned to study effect of folic acid supplementation on homocysteine levels and CV risk factors such as BP and lipids in adolescent epileptics taking anti-epileptic drugs (AEDs).

Detailed description: Scientific background, significance and impact value of the project:

Homocysteine is a thiol-containing amino acid formed as an intermediate product during the methionine metabolism. Re-methylation pathway recycles Homocysteine back to methionine and requires vitamin B12 and folic acid as cofactors. \[1\] The concentration of circulating total homocysteine is a sensitive marker of inadequate folate and vitamin B12 status. Elevated homocysteine concentrations are associated with an increased risk for cardiovascular (CV) disease. \[2\] The total homocysteine level is the lowest in children and an increase with age is higher in male sex. \[2\] The cutoffs for homocysteine level in adolescent range from 4.3 to 9.9 µmol/l, and hyperhomocysteinemia is defined as homocysteine \>10.9 µmol/l. \[3\] Lower folate and higher homocysteine concentrations may put adolescent on AEDs at special risk for atherosclerosis in their adulthood. \[4\] This demands early intervention as Asian Indian adolescents are genetically more exposed to cadiovascular disease(CVD) risks, AED therapy is an additional risk for developing future CVDs. Adolescent epileptics on AED have to take it for long time, and homocysteine elevation itself has got epileptogenic potential and can cause the risk developing refractory epilepsy. \[5\] Literature search reveals several studies depicting role of vitamin B12 in regulation of blood homocysteine levels. \[6, 7\] However, the studies confirming role of folic acid supplementation in hyperhomocysteinemia and related CV diseases are fewer and scarce in AEDs induced hyperhomocysteinemia. Few studies have reported negative correlation between hyperhomocysteinemia and low folic acid levels in patients on AEDs. \[8\] At the same time few studies have reported effectiveness of folic acid supplementation to normalize the homocysteine levels. \[9\] Considering the results of various studies many doctors are now prescribing folic acid along with AEDs, although there is a scarcity of data from India. In this context, the present study is planned to study effect of folic acid supplementation on homocysteine levels and CV risk factors such as BP and lipids in adolescent epileptics taking AEDs.

Eligibility criteria: Inclusion Criteria:

* Diagnosed epileptic patients of either sex with age between 10-19 yrs (\<19yrs), coming to the medicine Out Patient /In Patient Departments and undergoing AED therapy for more than 6 months.
* Epileptics with high homocysteine levels i.e. \> 10.9 µmol/L (Normal homocysteine levels are 4.3-9.9 µmol/L for male and 3.3-7.2 µmol/L for female adolescent and a high homocysteine concentration is deaned as at least 11.4 µmol/L for male and at least 10.4 µmol/L for female. Gender mean of high homocysteine concentration is 10.9 µmol/L) \[5\]

Exclusion Criteria:

* Pregnancy and lactation
* Patients with diabetes, Ischemic heart disease (IHD), stroke, malignancy and psychiatric diseases are excluded from study.
* The patients receiving vitamin supplements or who had clinical evidence for an acute illness, renal dysfunction, thyroid dysfunction, chronic inflammatory diseases, inborn errors of homocysteine, cobalamin or folate metabolism, or any other condition known to interfere with homocysteine metabolism will be excluded
* Patients who are already involved in any other trial.
* Patients not willing to fill consent/ assent form are also excluded from study.

Primary outcomes:
measure: Decrease in serum homocysteine levels by 2 µmol/l
timeFrame: 1 month
Secondary outcomes:
measure: Change in baseline serum lipids
timeFrame: 1 month
measure: Change in baseline systolic blood pressure
timeFrame: 1 month
Other outcomes:
Locations:
city: Pune
country: India
facility: Smt. Kashibai Navale Medical College and General Hospital
state: Maharashtra
Study officials:
affiliation: Smt. Kashibai Navale Medical College and General Hospital
name: UMA A. BHOSALE, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hoffer LJ. Homocysteine remethylation and trans-sulfuration. Metabolism. 2004 Nov;53(11):1480-3. doi: 10.1016/j.metabol.2004.06.003.
citation: Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1992 Jan;55(1):131-8. doi: 10.1093/ajcn/55.1.131.
citation: Selhub J, Jacques PF, Rosenberg IH, Rogers G, Bowman BA, Gunter EW, Wright JD, Johnson CL. Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991-1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med. 1999 Sep 7;131(5):331-9. doi: 10.7326/0003-4819-131-5-199909070-00003.
citation: Osganian SK, Stampfer MJ, Spiegelman D, Rimm E, Cutler JA, Feldman HA, Montgomery DH, Webber LS, Lytle LA, Bausserman L, Nader PR. Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health. JAMA. 1999 Apr 7;281(13):1189-96. doi: 10.1001/jama.281.13.1189.
citation: Cheng LS, Prasad AN, Rieder MJ. Relationship between antiepileptic drugs and biological markers affecting long-term cardiovascular function in children and adolescents. Can J Clin Pharmacol. 2010 Winter;17(1):e5-46. Epub 2010 Jan 4.
citation: Sato Y, Ouchi K, Funase Y, Yamauchi K, Aizawa T. Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Endocr J. 2013;60(12):1275-80. doi: 10.1507/endocrj.ej13-0332. Epub 2013 Sep 8.
citation: Satyanarayana A, Balakrishna N, Pitla S, Reddy PY, Mudili S, Lopamudra P, Suryanarayana P, Viswanath K, Ayyagari R, Reddy GB. Status of B-vitamins and homocysteine in diabetic retinopathy: association with vitamin-B12 deficiency and hyperhomocysteinemia. PLoS One. 2011;6(11):e26747. doi: 10.1371/journal.pone.0026747. Epub 2011 Nov 1.
citation: Coppola G, Ingrosso D, Operto FF, Signoriello G, Lattanzio F, Barone E, Matera S, Verrotti A. Role of folic acid depletion on homocysteine serum level in children and adolescents with epilepsy and different MTHFR C677T genotypes. Seizure. 2012 Jun;21(5):340-3. doi: 10.1016/j.seizure.2012.02.011. Epub 2012 Mar 16.
citation: Linnebank M, Moskau S, Semmler A, Widman G, Stoffel-Wagner B, Weller M, Elger CE. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol. 2011 Feb;69(2):352-9. doi: 10.1002/ana.22229. Epub 2011 Jan 19.
citation: De Lourdes Levy M, Larcher V, Kurz R; Ethics Working Group of the Confederation of European Specialists in Paediatrics (CESP). Informed consent/assent in children. Statement of the Ethics Working Group of the Confederation of European Specialists in Paediatrics (CESP). Eur J Pediatr. 2003 Sep;162(9):629-33. doi: 10.1007/s00431-003-1193-z. Epub 2003 Jul 19.
citation: Age limits and adolescents. Paediatr Child Health. 2003 Nov;8(9):577-8. doi: 10.1093/pch/8.9.577. No abstract available.