Effect of lacosamide in peripheral neuropathic pain: study protocol for a randomized, placebo-controlled, phenotype-stratified trial

Malin E Carmland, Melissa Kreutzfeldt, Jakob V Holbech, Niels T Andersen, Troels S Jensen, Flemming W Bach, Søren H Sindrup, Nanna B Finnerup, Malin E Carmland, Melissa Kreutzfeldt, Jakob V Holbech, Niels T Andersen, Troels S Jensen, Flemming W Bach, Søren H Sindrup, Nanna B Finnerup

Abstract

Background: Neuropathic pain is a common pain condition that has a major negative impact on health-related quality of life. However, despite decades of research, it remains difficult to treat neuropathic pain. Lacosamide is a sodium-channel blocker that is efficacious in animal models of neuropathic pain. In humans, its effect in neuropathic pain is inconclusive, based on inconsistent results and very large placebo responses. Previous trials have not used patient stratification or looked for predictors for response.

Methods: This study will be conducted as a multicenter, randomized, double-blind, placebo-controlled, parallel, phase 2, proof-of-concept, phenotype-stratified study. The study will enroll 108 patients with peripheral neuropathic pain who will be randomized to a 12-week treatment with lacosamide or placebo up to 400 mg/day in a 2:1 ratio. The primary objective is to compare the change in the mean value of the patients' daily ratings of average pain intensity from baseline to the last week of treatment in patients with and without the irritable nociceptor phenotype in the per-protocol population. A supportive objective is to compare the effect of lacosamide with that of placebo in the two phenotypes. Secondary and tertiary outcomes include the Patient Global Impression of Change, pain relief, presence of 30% and 50% pain reduction, sleep disturbance, depression, and anxiety.

Discussion: We will examine the concept of individualized therapy based on phenotyping, and expect that this study will provide important information on the usefulness of lacosamide in the treatment of peripheral neuropathic pain.

Trial registration: ClinicalTrials.gov, NCT03777956 . Registered on 18 December 2018.

Keywords: Lacosamide; Neuropathic pain; Precision medicine; Randomized controlled trial.

Conflict of interest statement

MEC, JVH, SHS, and NTA declare no competing interests. NBF has received honoraria for serving on advisory boards or speaker panels from Teva, Novartis, Astellas, Grünenthal, Mitshubishe Tanabe, Merck, and Novartis. TSJ has received honoraria for serving on advisory boards from Pfizer, Grünenthal, and Aptinyx. FWB has received honoraria for serving on advisory boards from Novartis and TEVA.

Figures

Fig. 1
Fig. 1
Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) figure. Schedule of enrolment, interventions, and assessment. 1The 3-week follow-up includes a 1-week tapering down and a 2-week follow-up with no medication. Telephone call after the 3-week follow-up. In the case of unresolved side effects at this call, an additional call is scheduled after 1–4 weeks. 2Patients treated with pregabalin will come for an extra visit. ECG electrocardiogram, PGIC Patient Global Impression of Change
Fig. 2
Fig. 2
Primary and supportive objectives. IN irritable nociceptor, NIN non-irritable nociceptor, R randomization
Fig. 3
Fig. 3
Study design. Blue arrows, visits; red arrows, telephone calls. IN irritable nociceptor, NIN non-irritable nociceptor, QST quantitative sensory testing, R randomization, V visit

References

    1. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002. doi: 10.1038/nrdp.2017.2.
    1. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173. doi: 10.1016/S1474-4422(14)70251-0.
    1. Smith SM, Dworkin RH, Turk DC, Baron R, Polydefkis M, Tracey I, et al. The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations. J Pain. 2017;18(7):757–777. doi: 10.1016/j.jpain.2017.02.429.
    1. Attal N, Bouhassira D, Baron R, Dostrovsky J, Dworkin RH, Finnerup N, et al. Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome? Eur J Pain. 2011;15(5):441–443. doi: 10.1016/j.ejpain.2011.03.005.
    1. Demant DT, Lund K, Vollert J, Maier C, Segerdahl M, Finnerup NB, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain. 2014;155(11):2263–2273. doi: 10.1016/j.pain.2014.08.014.
    1. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012;153(6):1193–1198. doi: 10.1016/j.pain.2012.02.021.
    1. Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain. 2004;108(3):248–257. doi: 10.1016/j.pain.2003.12.024.
    1. Beyreuther BK, Freitag J, Heers C, Krebsfanger N, Scharfenecker U, Stohr T. Lacosamide: a review of preclinical properties. CNS Drug Rev. 2007;13(1):21–42. doi: 10.1111/j.1527-3458.2007.00001.x.
    1. McCleane G. Lacosamide for pain. Expert Opin Investig Drugs. 2010;19(9):1129–1134. doi: 10.1517/13543784.2010.511174.
    1. Rauck RL, Shaibani A, Biton V, Simpson J, Koch B. Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study. Clin J Pain. 2007;23(2):150–158. doi: 10.1097/01.ajp.0000210957.39621.b2.
    1. Shaibani A, Fares S, Selam JL, Arslanian A, Simpson J, Sen D, et al. Lacosamide in painful diabetic neuropathy: an 18-week double-blind placebo-controlled trial. J Pain. 2009;10(8):818–828. doi: 10.1016/j.jpain.2009.01.322.
    1. Wymer JP, Simpson J, Sen D, Bongardt S. Efficacy and safety of lacosamide in diabetic neuropathic pain: an 18-week double-blind placebo-controlled trial of fixed-dose regimens. Clin J Pain. 2009;25(5):376–385. doi: 10.1097/AJP.0b013e318196d2b6.
    1. Ziegler D, Hidvegi T, Gurieva I, Bongardt S, Freynhagen R, Sen D, et al. Efficacy and safety of lacosamide in painful diabetic neuropathy. Diabetes Care. 2010;33(4):839–841. doi: 10.2337/dc09-1578.
    1. de Greef BT, Hoeijmakers JGJ, Geerts M, Oakes M, Church TJE, Waxman SG, et al. Lacosamide in patients with Nav1.7 mutation-related small fiber neuropathy: a randomized controlled trial. Brain. 2019;142:263–275. doi: 10.1093/brain/awy329.
    1. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, et al. Quantitative sensory testing: a comprehensive protocol for clinical trials. Eu J Pain. 2006;10(1):77–88. doi: 10.1016/j.ejpain.2005.02.003.
    1. Finnerup NB, Haroutounian S, Kamerman P, Baron R, Bennett DL, Bouhassira D, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain. 2016;157(8):1599–1606. doi: 10.1097/j.pain.0000000000000492.
    1. Helme RD, Finnerup NB, Jensen TS. Hyperpathia: “to be or not to be: that is the question”. Pain. 2018;159(6):1005–1009. doi: 10.1097/j.pain.0000000000001149.
    1. Gassmann-Mayer C, Jiang K, McSorley P, Arani R, Dubrava S, Suryawanshi S, et al. Clinical and statistical assessment of suicidal ideation and behavior in pharmaceutical trials. Clin Pharmacol Ther. 2011;90(4):554–560. doi: 10.1038/clpt.2011.144.
    1. European Medicines Agency. Withdrawal assessment report for Lacosamide Pain UCB Pharma [Assessment report]. European Medicines Agency; 2008 [Doc. Ref: EMEA/CHMP/658067/2008]. Available from: . Accessed 14 Dec 2018.
    1. Senn S. Statistical pitfalls of personalized medicine. Nature. 2018;563:619–621. doi: 10.1038/d41586-018-07535-2.

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