title: Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial.
abstract: BACKGROUND
  Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study.
  
  
  METHODS
  We did a double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a trial in 25 secondary care centres in Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK. After a 7-day run-in phase, eligible patients aged 18-80 years with confirmed trigeminal neuralgia received open-label, BIIB074 150 mg three times per day, orally, for 21 days. Patients who met at least one response criteria were then randomly assigned (1:1) to BIIB074 or placebo for up to 28 days in a double-blind phase. We used an interactive web response system to assign patients with a computer-generated schedule, with stratification (presence or absence of existing pain medication). Patients, clinicians, and assessors were masked to treatment allocation. The primary endpoint was the difference between groups in the number of patients classified as treatment failure during the double blind phase assessed in the modified intention-to-treat population. We assessed safety in all patients who received one or more doses of BIIB074. This study is registered with ClinicalTrials.gov (NCT01540630) and EudraCT (2010-023963-16).
  
  
  RESULTS
  The first patient was enrolled on April 23, 2012, and the last patient completed the study on February 26, 2014. We enrolled 67 patients into the open-label phase; 44 completed open-label treatment, and 29 were randomly assigned to double-blind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures (p=0·0974). BIIB074 was well tolerated, with similar adverse events in the double-blind phase to placebo. Headache was the most common adverse event with BIIB074 in the open-label phase (in 13 [19%] of 67 patients), followed by dizziness (in six [9%] patients). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074 (in one [7%] of 15 patients for each event), and headache, dizziness, diarrhoea, and vomiting were the most frequent adverse events in patients assigned to placebo (in one [7%] of 14 patients for each event). No severe or serious adverse events were reported in the BIIB074 group during the double-blind phase. One patient assigned to placebo reported intestinal adhesions with obstruction as a severe and serious adverse event, which was considered as unrelated to study medication.
  
  
  CONCLUSIONS
  The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials.
  
  
  BACKGROUND
  Convergence Pharmaceuticals.
authors.affiliation: Facial Pain Unit, Division of Diagnostic, Surgical and Medical Sciences, Eastman Dental Hospital, University College London Hospitals NHS Foundation Trust/University College London, London, UK. Electronic address: j.zakrzewska@ucl.ac.uk.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Zakrzewska
authors.affiliation: Convergence Pharmaceuticals, Cambridge, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Palmer
authors.affiliation: Convergence Pharmaceuticals, Cambridge, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Morisset
authors.affiliation: Convergence Pharmaceuticals, Cambridge, UK.
authors.forename: Gerard Mp
authors.initials: GM
authors.lastname: Giblin
authors.affiliation: Department of Neurology and German Headache Center, University of Duisburg-Essen, Essen, Germany; Center for Neurology, Asklepios Hospitals Schildautal, Seesen, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Obermann
authors.affiliation: Interdisciplinary Orofacial Pain Unit, Clinic KFS-KAB, Center of Dental Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Dominik A
authors.initials: DA
authors.lastname: Ettlin
authors.affiliation: Department of Neurology and Psychiatry, Sapienza University, Roma, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cruccu
authors.affiliation: Danish Headache Centre, Department of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Nordre Ringvej 67, 2600 Glostrup, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Bendtsen
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, and Veterans Affairs Medical Center, West Haven, CT, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Estacion
authors.affiliation: Convergence Pharmaceuticals, Cambridge, UK.
authors.forename: Dominique
authors.initials: D
authors.lastname: Derjean
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, and Veterans Affairs Medical Center, West Haven, CT, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.affiliation: ParamStat, Ash, Canterbury, Kent, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Layton
authors.affiliation: Convergence Pharmaceuticals, Cambridge, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gunn
authors.affiliation: Convergence Pharmaceuticals, Cambridge, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Tate
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007391:International Cooperation; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010647:Phenyl Ethers / Q000494:pharmacology / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D012189:Retrospective Studies; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D016896:Treatment Outcome; D014277:Trigeminal Neuralgia / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D010647:Phenyl Ethers; D026941:Sodium Channel Blockers; D011392:Proline; C000592131:vixotrigine