PMID- 37152360 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230509 IS - 2589-5370 (Electronic) IS - 2589-5370 (Linking) VI - 59 DP - 2023 May TI - Efficacy and safety of vixotrigine in idiopathic or diabetes-associated painful small fibre neuropathy (CONVEY): a phase 2 placebo-controlled enriched-enrolment randomised withdrawal study. PG - 101971 LID - 10.1016/j.eclinm.2023.101971 [doi] LID - 101971 AB - BACKGROUND: No pharmacological treatments are specifically indicated for painful small fibre neuropathy (SFN). CONVEY, a phase 2 enriched-enrolment study, evaluated the efficacy and safety of vixotrigine, a voltage- and use-dependent sodium channel blocker, in participants with idiopathic or diabetes-associated painful SFN. METHODS: CONVEY was a phase 2, multicentre, placebo-controlled, double-blind (DB), enriched-enrolment, randomised withdrawal study. The study was conducted at 68 sites in 13 countries (Europe and Canada) between May 17, 2018, and April 12, 2021. Following a 4-week open-label period in which 265 adults with painful SFN (a mixture of large and small fibre neuropathy was not exclusionary) received oral vixotrigine 350 mg twice daily (BID), 123 participants (with a >/=30% reduction from baseline in average daily pain [ADP] score during the open-label period) were randomised 1:1:1 to receive 200 mg BID, 350 mg BID or placebo for a 12-week double-blind (DB) period. Primary endpoint was change from baseline in ADP at DB Week 12. Secondary endpoints included the proportion of participants with a >/=30% reduction from baseline in ADP and the proportion of Patient Global Impression of Pain (PGIC) responders at DB Week 12. Treatment-emergent adverse events (AEs) were monitored. Statistical significance was set at 0.10 (2-sided). The trial was registered on ClinicalTrials.gov (NCT03339336) and on ClinicalTrialsregister.eu (2017-000991-27). FINDINGS: A statistically significant difference from placebo in least squares mean reduction in ADP score from baseline to DB Week 12 was observed with vixotrigine 200 mg BID (-0.85; SE, 0.43; 95% CI, -1.71 to 0.00; p = 0.050) but not 350 mg BID (-0.17; SE, 0.43; 95% CI, -1.01 to 0.68; p = 0.70). Numerically, but not statistically significantly, more participants who received vixotrigine vs placebo experienced a >/=30% ADP reduction from baseline (68.3-72.5% vs 52.5%), and only the 350 mg BID group had significantly more PGIC responders vs placebo (48.8% vs 30.0%; odds ratio = 2.60; 95% CI, 0.97-6.99; p = 0.058) at DB Week 12. AEs were mostly mild to moderate in the vixotrigine groups. The most common AEs (>/=5% of vixotrigine-treated participants) in the DB 200 mg BID and 350 mg BID vixotrigine groups were falls, nasopharyngitis, muscle spasm, and urinary tract infection. INTERPRETATION: In our study, vixotrigine 200 mg BID, but not 350 mg BID, met the primary endpoint; more vixotrigine-treated participants experienced a >/=30% reduction from baseline in ADP at DB Week 12. Vixotrigine (at both dosages) was well tolerated in participants with SFN. FUNDING: Biogen, Inc. CI - (c) 2023 The Authors. FAU - Faber, Catharina G AU - Faber CG AD - Department of Neurology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, P. Debeyelaan 25, Maastricht 6229 HX, the Netherlands. FAU - Attal, Nadine AU - Attal N AD - INSERM U987, Ambroise Pare Hospital, APHP, Boulogne-Billancourt F-92100, France. AD - Universite UVSQ Paris-Saclay, Versailles 78000, France. FAU - Lauria, Giuseppe AU - Lauria G AD - Third Neurology Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan 20133, Italy. AD - Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Festa del Perdono 7, Milan 20122, Italy. FAU - Dworkin, Robert H AU - Dworkin RH AD - Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. FAU - Freeman, Roy AU - Freeman R AD - Department of Neurology, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02115, USA. FAU - Dawson, Katherine T AU - Dawson KT AD - Biogen, Cambridge, MA 02142, USA. FAU - Finnigan, Helen AU - Finnigan H AD - Biogen, Maidenhead SL6 4AY, UK. FAU - Hajihosseini, Amirhossein AU - Hajihosseini A AD - Biogen, Cambridge, MA 02142, USA. FAU - Naik, Himanshu AU - Naik H AD - Biogen, Cambridge, MA 02142, USA. FAU - Serenko, Michael AU - Serenko M AD - Biogen, Cambridge, MA 02142, USA. FAU - Morris, Christopher J AU - Morris CJ AD - Biogen, Cambridge, MA 02142, USA. FAU - Kotecha, Mona AU - Kotecha M AD - Biogen, Cambridge, MA 02142, USA. LA - eng SI - ClinicalTrials.gov/NCT03339336 PT - Journal Article DEP - 20230427 PL - England TA - EClinicalMedicine JT - EClinicalMedicine JID - 101733727 PMC - PMC10154969 OTO - NOTNLM OT - Clinical trial OT - Diabetic peripheral neuropathy OT - Nav inhibitor OT - Painful neuropathy OT - Sodium channel blocker OT - Tolerability COIS- C.G.F. discloses grants from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant for PAIN-Net, molecule-to-man pain network (grant no. 721841), from Grifols and Lamepro for a trial on IVIg in small fibre neuropathy, and from Prinses Beatrix Spierfonds and serving on steering committees and advisory boards for Biogen Inc, Vertex Pharmaceuticals Incorporated, Lilly, and OliPass for studies in small fibre neuropathy. N.A. discloses grants from DOLORisk (European Union's Horizon) and honoraria from Pfizer Inc, Sanofi, Novartis AG, Grunenthal, Air Liquide, and Merz outside the submitted work and from Biogen Inc for scientific advice on vixotrigine over the past 3 years. G.L. discloses support from the European Commission, Italian Ministry of Health, Lombardy Foundation for Biomedical Research (FRRB), and Italian Research Foundation for Amyotrophic Lateral Sclerosis (AriSLA) and scientific advisory for CSL Behring, Biogen Inc, Vertex Pharmaceuticals Incorporated, Chromocell Corporation, Janssen Pharmaceuticals, Inc, Lilly, and the Bracco Group. R.H.D. discloses research grants and contracts received from the US Food and Drug Administration and the US National Institutes of Health in the past 5 years and compensation for serving on advisory boards or consulting on clinical trial methods from Abide, Acadia, Adynxx, Analgesic Solutions, Aptinyx, Aquinox, Asahi Kasei, Astellas, Beckley, Biogen, Biohaven, Biosplice, Boston Scientific, Braeburn, Cardialen, Celgene, Centrexion, Chiesi, Chromocell, Clexio, Collegium, Concert, Confo, Decibel, Editas, Eli Lilly, Endo, Ethismos (equity), Eupraxia, Exicure, Glenmark, Gloriana, Grace, Hope, Lotus, Mainstay, Merck, Mind Medicine (equity), Neumentum, Neurana, NeuroBo, Novaremed, Novartis, OCT, OliPass, Pfizer, Q-State, Reckitt Benckiser, Regenacy (also equity), Sangamo, Sanifit, Scilex, Semnur, SIMR Biotech, Sinfonia, SK Biopharmaceuticals, Sollis, SPRIM, Teva, Theranexus, Toray, Vertex, Vizuri, and WCG. R.F. discloses personal compensation and/or stock options for serving on scientific advisory boards for AlgoRx, Allergan, Applied Therapeutics, Clexio, Collegium, CND Life Sciences, Glenmark, GW Pharma, GlaxoSmithKline, Eli Lilly, Lundbeck, Maxona, Novartis, NeuroBo, Regenacy, Vertex, and Worwag. K.T.D., H.F., M.S., C.J.M., and M.K. are employees of and may hold stock and/or stock options in Biogen Inc. A.H. and H.N. are former employees of Biogen. A.H. is currently employed by Pfizer, Inc, and H.N. by Sumitovant Biopharma. EDAT- 2023/05/08 06:41 MHDA- 2023/05/08 06:42 PMCR- 2023/04/27 CRDT- 2023/05/08 04:01 PHST- 2023/01/18 00:00 [received] PHST- 2023/03/30 00:00 [revised] PHST- 2023/04/03 00:00 [accepted] PHST- 2023/05/08 06:42 [medline] PHST- 2023/05/08 06:41 [pubmed] PHST- 2023/05/08 04:01 [entrez] PHST- 2023/04/27 00:00 [pmc-release] AID - S2589-5370(23)00148-7 [pii] AID - 101971 [pii] AID - 10.1016/j.eclinm.2023.101971 [doi] PST - epublish SO - EClinicalMedicine. 2023 Apr 27;59:101971. doi: 10.1016/j.eclinm.2023.101971. eCollection 2023 May.