title: Efficacy, safety, and tolerability of lacosamide in patients with gain-of-function Nav1.7 mutation-related small fiber neuropathy: study protocol of a randomized controlled trial-the LENSS study.
abstract: Small fiber neuropathy generally leads to considerable pain and autonomic symptoms. Gain-of-function mutations in the SCN9A- gene, which codes for the Nav1.7 voltage-gated sodium channel, have been reported in small fiber neuropathy, suggesting an underlying genetic basis in a subset of patients. Currently available sodium channel blockers lack selectivity, leading to cardiac and central nervous system side effects. Lacosamide is an anticonvulsant, which blocks Nav1.3, Nav1.7, and Nav1.8, and stabilizes channels in the slow-inactivation state. Since multiple Nav1.7 mutations in small fiber neuropathy showed impaired slow-inactivation, lacosamide might be effective.
  
  
  
  The Lacosamide-Efficacy-'N'-Safety in Small fiber neuropathy (LENSS) study is a randomized, double-blind, placebo-controlled, crossover trial in patients with SCN9A-associated small fiber neuropathy, with the primary objective to evaluate the efficacy of lacosamide versus placebo. Eligible patients (the aim is to recruit 25) fulfilling the inclusion and exclusion criteria will be randomized to receive lacosamide (200 mg b.i.d.) or placebo during the first double-blinded treatment period (8 weeks), which is preceded by a titration period (3 weeks). The first treatment period will be followed by a tapering period (2 weeks). After a 2-week washout period, patients will crossover to the alternate arm for the second period consisting of an equal titration phase, treatment period, and tapering period. The primary efficacy endpoint will be the proportion of patients demonstrating a 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. We assume a response rate of approximately 60 % based on the criteria composed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group for measurement of pain. Patients withdrawing from the study will be considered non- responders. Secondary outcomes will include changes in maximum pain score, the Small Fiber Neuropathy Symptoms Inventory Questionnaire, sleep quality and the quality of life assessment, patients' global impressions of change, and safety and tolerability measurements. Sensitivity analyses will include assessing the proportion of patients having ≥ 2 points average pain improvement compared to the baseline Pain Intensity Numerical Rating Scale scores.
  
  
  
  This is the first study that will be evaluating the efficacy, safety, and tolerability of lacosamide versus placebo in patients with SCN9A-associated small fiber neuropathy. The findings may increase the knowledge on lacosamide as a potential treatment option in patients with painful neuropathies, considering the central role of Nav1.7 in pain.
  
  
  
  ClinicalTrials.gov, NCT01911975 . Registered on 13 July 2013.
authors.affiliation: Department of Neurology, School of Mental Health and Neuroscience, Maastricht University Medical Center, P. Debijelaan 25, P.O. Box 5800, 6202, AZ, Maastricht, The Netherlands. bianca.greef@mumc.nl.
authors.forename: Bianca T A
authors.initials: BT
authors.lastname: de Greef
authors.affiliation: Department of Neurology, School of Mental Health and Neuroscience, Maastricht University Medical Center, P. Debijelaan 25, P.O. Box 5800, 6202, AZ, Maastricht, The Netherlands.|Department of Neurology, St. Elisabeth Hospital, 193 J.H.J. Hamelbergweg, Willemstad, Curaçao.
authors.forename: Ingemar S J
authors.initials: IS
authors.lastname: Merkies
authors.affiliation: Department of Neurology, School of Mental Health and Neuroscience, Maastricht University Medical Center, P. Debijelaan 25, P.O. Box 5800, 6202, AZ, Maastricht, The Netherlands.
authors.forename: Margot
authors.initials: M
authors.lastname: Geerts
authors.affiliation: Department of Neurology, School of Mental Health and Neuroscience, Maastricht University Medical Center, P. Debijelaan 25, P.O. Box 5800, 6202, AZ, Maastricht, The Netherlands.
authors.forename: Catharina G
authors.initials: CG
authors.lastname: Faber
authors.affiliation: Department of Neurology, School of Mental Health and Neuroscience, Maastricht University Medical Center, P. Debijelaan 25, P.O. Box 5800, 6202, AZ, Maastricht, The Netherlands.
authors.forename: Janneke G J
authors.initials: JG
authors.lastname: Hoeijmakers
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D000073659:Gain of Function Mutation; D020022:Genetic Predisposition to Disease; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D009426:Netherlands; D010147:Pain Measurement; D010641:Phenotype; D012107:Research Design; D012307:Risk Factors; D012720:Severity of Illness Index; D000071075:Small Fiber Neuropathy / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000081:Acetamides; D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D000078334:Lacosamide
keywords: Lacosamide; Nav1.7; Painful neuropathy; Randomized controlled trial; SCN9A gene; Small fiber neuropathy