Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol

Bas C Stunnenberg, Willem Woertman, Joost Raaphorst, Jeffrey M Statland, Robert C Griggs, Janneke Timmermans, Christiaan G Saris, Bas J Schouwenberg, Hans M Groenewoud, Dick F Stegeman, Baziel G M van Engelen, Gea Drost, Gert Jan van der Wilt, Bas C Stunnenberg, Willem Woertman, Joost Raaphorst, Jeffrey M Statland, Robert C Griggs, Janneke Timmermans, Christiaan G Saris, Bas J Schouwenberg, Hans M Groenewoud, Dick F Stegeman, Baziel G M van Engelen, Gea Drost, Gert Jan van der Wilt

Abstract

Background: To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously.

Methods/design: We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT.

Discussion: The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases.

Trial registration: ClinicalTrials.gov Identifier: NCT02045667.

Figures

Figure 1
Figure 1
Study design individual N-of-1 trials.

References

    1. Rodwell C, Aymé S. 2014 report on the state of the art of rare disease activities in Europe. 2014.
    1. Cleland JC, Griggs RC. Treatment of neuromuscular channelopathies: current concepts and future prospects. Neurotherapeutics. 2008;5(4):607–12. doi: 10.1016/j.nurt.2008.09.001.
    1. Lochmuller H, Griggs RC. New treatments for neuromuscular disease: optimism and obstacles. Neurotherapeutics. 2008;5(4):497–8. doi: 10.1016/j.nurt.2008.08.010.
    1. Venance SL, Herr BE, Griggs RC. Challenges in the design and conduct of therapeutic trials in channel disorders. Neurotherapeutics. 2007;4(2):199–204. doi: 10.1016/j.nurt.2007.01.004.
    1. Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, et al. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009;96(1):20–6. doi: 10.1016/j.ymgme.2008.10.003.
    1. Gupta S, Faughnan ME, Tomlinson GA, Bayoumi AM. A framework for applying unfamiliar trial designs in studies of rare diseases. J Clin Epidemiol. 2011;64(10):1085–94. doi: 10.1016/j.jclinepi.2010.12.019.
    1. Facey K, Granados A, Guyatt G, Kent A, Shah N, van der Wilt GJ, et al. Generating health technology assessment evidence for rare diseases. Int J Technol Assess Health Care. 2014;30(4):416–22. doi: 10.1017/S0266462314000464.
    1. Trip J, Drost G, Ginjaar HB, Nieman FH, van der Kooi AJ, De Visser M, et al. Redefining the clinical phenotypes of non-dystrophic myotonic syndromes. J Neurol Neurosurg Psychiatry. 2009;80(6):647–52. doi: 10.1136/jnnp.2008.162396.
    1. Trivedi JR, Bundy B, Statland J, Salajegheh M, Rayan DR, Venance SL, et al. Non-dystrophic myotonia: prospective study of objective and patient reported outcomes. Brain. 2013;136(Pt 7):2189–200. doi: 10.1093/brain/awt133.
    1. College voor Zorgverzekeringen . Beoordeling stand van de wetenschap en praktijk. Diemen: Publ Nr 254; 2007.
    1. College voor Zorgverzekeringen . Geneesmiddelbeoordeling Mexiletine bij M. Becker (2006-0611) Diemen: College voor Zorgverzekeringen; 2006.
    1. Trip J, Drost G, Van Engelen BG, Faber CG. Drug treatment for myotonia. Cochrane Database Syst Rev. 2006;1
    1. Statland JM, Bundy BN, Wang Y, Rayan DR, Trivedi JR, Sansone VA, et al. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA. 2012;308(13):1357–65. doi: 10.1001/jama.2012.12607.
    1. Gabler NB, Duan N, Vohra S, Kravitz RL. N-of-1 trials in the medical literature: a systematic review. Med Care. 2011;49(8):761–8. doi: 10.1097/MLR.0b013e318215d90d.
    1. Irwig L, Glasziou P, March L. Ethics of n-of-1 trials. Lancet. 1995;345(8948):469. doi: 10.1016/S0140-6736(95)90578-2.
    1. Guyatt G, Sackett D, Adachi J, Roberts R, Chong J, Rosenbloom D, et al. A clinician’s guide for conducting randomized trials in individual patients. CMAJ. 1988;139(6):497–503.
    1. Guyatt G, Sackett D, Taylor DW, Chong J, Roberts R, Pugsley S. Determining optimal therapy–randomized trials in individual patients. N Engl J Med. 1986;314(14):889–92. doi: 10.1056/NEJM198604033141406.
    1. Guyatt GH, Heyting A, Jaeschke R, Keller J, Adachi JD, Roberts RS. N of 1 randomized trials for investigating new drugs. Control Clin Trials. 1990;11(2):88–100. doi: 10.1016/0197-2456(90)90003-K.
    1. Guyatt GH, Jaeschke R. N-of-1 randomized trials–where do we stand? West J Med. 1990;152(1):67–8.
    1. Huber AM, Tomlinson GA, Koren G, Feldman BM. Amitriptyline to relieve pain in juvenile idiopathic arthritis: a pilot study using Bayesian metaanalysis of multiple N-of-1 clinical trials. J Rheumatol. 2007;34(5):1125–32.
    1. Nathan PC, Tomlinson G, Dupuis LL, Greenberg ML, Ota S, Bartels U, et al. A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N-of-1 trials design. Support Care Cancer. 2006;14(3):268–76. doi: 10.1007/s00520-005-0875-7.
    1. Zucker DR, Ruthazer R, Schmid CH, Feuer JM, Fischer PA, Kieval RI, et al. Lessons learned combining N-of-1 trials to assess fibromyalgia therapies. J Rheumatol. 2006;33(10):2069–77.
    1. Spiegelhalter DJ, Freedman LS, Parmar MK. Applying Bayesian ideas in drug development and clinical trials. Stat Med. 1993;12(15–16):1501–11. doi: 10.1002/sim.4780121516.
    1. Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR. Bayesian methods in health technology assessment: a review. Health Technol Assess. 2000;4(38):1–130.
    1. Zucker DR, Schmid CH, McIntosh MW, D’Agostino RB, Selker HP, Lau J. Combining single patient (N-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J Clin Epidemiol. 1997;50(4):401–10. doi: 10.1016/S0895-4356(96)00429-5.
    1. Trip J, Drost G, Verbove DJ, van der Kooi AJ, Kuks JB, Notermans NC, et al. In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia. Eur J Hum Genet: EJHG. 2008;16(8):921–9. doi: 10.1038/ejhg.2008.39.
    1. Trip J, De Vries J, Drost G, Ginjaar HB, Van Engelen BG, Faber CG. Health status in non-dystrophic myotonias: close relation with pain and fatigue. J Neurol. 2009;256(6):939–47. doi: 10.1007/s00415-009-5049-y.
    1. Trip J, Faber CG, Ginjaar HB, Van Engelen BG, Drost G. Warm-up phenomenon in myotonia associated with the V445M sodium channel mutation. J Neurol. 2007;254(2):257–8. doi: 10.1007/s00415-006-0353-2.
    1. Trip J, Pillen S, Faber CG, Van Engelen BG, Zwarts MJ, Drost G. Muscle ultrasound measurements and functional muscle parameters in non-dystrophic myotonias suggest structural muscle changes. Neuromuscul Disord. 2009;19(7):462–7. doi: 10.1016/j.nmd.2009.06.369.
    1. Statland JM, Wang Y, Richesson R, Bundy B, Herbelin L, Gomes J, et al. An interactive voice response diary for patients with non-dystrophic myotonia. Muscle Nerve. 2011;44(1):30–5. doi: 10.1002/mus.22007.
    1. Sansone VA, Ricci C, Montanari M, Apolone G, Rose M, Meola G, et al. Measuring quality of life impairment in skeletal muscle channelopathies. European J Neurol: Off J Eur Fed Neurol Soc. 2012;19(11):1470–6. doi: 10.1111/j.1468-1331.2012.03751.x.
    1. Seesing FM, Drost G, Groenewoud J, van der Wilt GJ, van Engelen BG. Shared medical appointments improve QOL in neuromuscular patients: a randomized controlled trial. Neurology. 2014;83(3):240–6. doi: 10.1212/WNL.0000000000000588.
    1. Ware JE, Jr, Gandek B, Kosinski M, Aaronson NK, Apolone G, Brazier J, et al. The equivalence of SF-36 summary health scores estimated using standard and country-specific algorithms in 10 countries: results from the IQOLA Project. Int Qual Life Assess J Clin Epidemiol. 1998;51(11):1167–70.
    1. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol. 1998;51(11):1055–68. doi: 10.1016/S0895-4356(98)00097-3.
    1. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39(2):142–8.
    1. Hammaren E, Kjellby-Wendt G, Lindberg C. Quantification of mobility impairment and self-assessment of stiffness in patients with myotonia congenita by the physiotherapist. Neuromuscul Disord. 2005;15(9–10):610–7. doi: 10.1016/j.nmd.2005.07.002.
    1. Statland JM, Bundy BN, Wang Y, Trivedi JR, Raja Rayan D, Herbelin L, et al. A quantitative measure of handgrip myotonia in non-dystrophic myotonia. Muscle Nerve. 2012;46(4):482–9. doi: 10.1002/mus.23402.
    1. Drost G, Stunnenberg BC, Trip J, Borm G, McGill KC, Ginjaar HB, et al. Myotonic discharges discriminate chloride from sodium muscle channelopathies. Neuromuscul Disord. 2014 (epub ahead of print), doi:10.1016/j.nmd.2014.09.014.
    1. Streib EW. AAEE minimonograph #27: differential diagnosis of myotonic syndromes. Muscle Nerve. 1987;10(7):603–15. doi: 10.1002/mus.880100704.
    1. Li S, Liu G, Jia J, Liu Y, Pan C, Yu C, et al. Simultaneous determination of ten antiarrhythic drugs and a metabolite in human plasma by liquid chromatography–tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2007;847(2):174–81. doi: 10.1016/j.jchromb.2006.10.013.
    1. Patel A, Rendu A, Moran P, Leese M, Mann A, Knapp M. A comparison of two methods of collecting economic data in primary care. Fam Pract. 2005;22(3):323–7. doi: 10.1093/fampra/cmi027.
    1. Beecham J, Knapp M. Costing psychiatric interventions. In: Thornicroft G, editor. Measuring mental health needs. 2. London: Gaskell; 2001.
    1. Hakkaart-van Roijen L, Tan SS, Bouwmans CAM. Handleiding voor kostenonderzoek, methoden en standaard kostprijzen voor economische evaluaties in de gezondheidszorg. 2010.
    1. Katzberg HD, Barnett C, Merkies IS, Bril V. Minimal clinically important difference in myasthenia gravis: outcomes from a randomized trial. Muscle Nerve. 2014;49(5):661–5. doi: 10.1002/mus.23988.
    1. Wang F, Gelfand AE. A simulation-based approach to Bayesian sample size determination for performance under a given model and for separating models”. Stat Sci. 2002;17(2):193–208. doi: 10.1214/ss/1030550861.
    1. Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian approaches to clinical trials and health-care evaluation. Chichester: John Wiley & Sons; 2004.

Source: PubMed

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