A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment

Jonas Mandel, Viviane Bertrand, Philippe Lehert, Shahram Attarian, Laurent Magy, Joëlle Micallef, Ilya Chumakov, Catherine Scart-Grès, Mickael Guedj, Daniel Cohen, Jonas Mandel, Viviane Bertrand, Philippe Lehert, Shahram Attarian, Laurent Magy, Joëlle Micallef, Ilya Chumakov, Catherine Scart-Grès, Mickael Guedj, Daniel Cohen

Abstract

CMT1A is the most common inherited peripheral neuropathy. There is currently no approved treatment. We performed a meta-analysis including four randomized, double-blind, Placebo-controlled clinical trials to assess the disease progression after one year under Placebo, Ascorbic Acid (AA) or PXT3003, a combination of three repurposed drugs. We observed a weak deterioration in patients under Placebo, well below the reported natural disease progression. Patients treated with AA were stable after one year but not significantly different from Placebo. Patients undergoing PXT3003 treatment showed an improvement in CMTNS and ONLS, statistically significant versus Placebo and potentially precursory of a meaningful change in the disease course.

Figures

Fig. 1
Fig. 1
Results of the meta-analysis on the change from baseline after one year. Fixed-effect meta-analysis, with treatment as moderator variable. Difference in changes from baseline between Placebo, AA and PXT3003 were assessed through contrast tests. a Change from baseline in CMTNS under Placebo, AA and PXT3003; b Change from baseline in ONLS under Placebo, AA and PXT3003. *p < 0.05; NS = not-significant

References

    1. Raeymaekers P, Timmerman V, Nelis E, De Jonghe P, Hoogendijk JE, Baas F, Barker DF, Martin JJ, De Visser M, Bolhuis PA. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscul Disord. 1991;1:93–7. doi: 10.1016/0960-8966(91)90055-W.
    1. Lupski JR, Wise CA, Kuwano A, Pentao L. Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. Nat Genet. 1992;1:29–33. doi: 10.1038/ng0492-29.
    1. Pareyson D, Scaioli V, Laurà M. Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:3–22. doi: 10.1385/NMM:8:1-2:3.
    1. Bird T. Charcot-Marie-Tooth Neuropathy Type 1. GeneReviews. 2014.
    1. Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J, Thirion X, Robaglia-Schlupp A, Pellissier JF, Fontés M. Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med. 2004;10:396–401. doi: 10.1038/nm1023.
    1. Kaya F, Belin S, Bourgeois P, Micaleff J, Blin O, Fontés M. Ascorbic acid inhibits PMP22 expression by reducing cAMP levels. Neuromuscul Disord. 2007;17:248–53. doi: 10.1016/j.nmd.2006.12.008.
    1. Verhamme C, de Haan R, Vermeulen M, Baas F, de Visser M, van Schaik I. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial. BMC Med. 2009;7:70. doi: 10.1186/1741-7015-7-70.
    1. Burns J, Ouvrier R, Yiu E, Joseph P, Kornberg A, Fahey M, Ryan M. Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial. Lancet Neurol. 2009;8:537–44. doi: 10.1016/S1474-4422(09)70108-5.
    1. Toth C. Poor tolerability of high dose ascorbic acid in a population of genetically confirmed adult Charcot-Marie-Tooth 1A patients. Acta Neurol Scand. 2009;120:134–8. doi: 10.1111/j.1600-0404.2008.01134.x.
    1. Micallef J, Attarian S, Dubourg O, Gonnaud P-M, Hogrel J-Y, Stojkovic T, Bernard R, Jouve E, Pitel S, Vacherot F, Remec J-F, Jomir L, Azabou E, Al-Moussawi M, Lefebvre M-N, Attolini L, Yaici S, Tanesse D, Fontes M, Pouget J, Blin O. Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2009;8:1103–10. doi: 10.1016/S1474-4422(09)70260-1.
    1. Pareyson D, Reilly MM, Schenone A, Fabrizi GM, Cavallaro T, Santoro L, Vita G, Quattrone A, Padua L, Gemignani F, Visioli F, Laurà M, Radice D, Calabrese D, Hughes RAC, Solari A. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol. 2011;10:320–8. doi: 10.1016/S1474-4422(11)70025-4.
    1. Lewis RA, McDermott MP, Herrmann DN, Hoke A, Clawson LL, Siskind C, Feely SME, Miller LJ, Barohn RJ, Smith P, Luebbe E, Wu X, Shy ME. High-Dosage Ascorbic Acid Treatment in Charcot-Marie-Tooth Disease Type 1A: Results of a Randomized, Double-Masked, Controlled Trial. JAMA Neurol. 2013;70:981–7. doi: 10.1001/jamaneurol.2013.3178.
    1. Chumakov I, Milet A, Cholet N, Primas G, Boucard A, Pereira Y, Graudens E, Mandel J, Laffaire J, Foucquier J, Glibert F, Bertrand V, Nave K-A, Sereda MW, Vial E, Guedj M, Hajj R, Nabirotchkin S, Cohen D. Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy. Orphanet J Rare Dis. 2014;9:201. doi: 10.1186/s13023-014-0201-x.
    1. Attarian S, Vallat J-M, Magy L, Funalot B, Gonnaud P-M, Lacour A, Péréon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre M-N, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Grès C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014;9:199. doi: 10.1186/s13023-014-0199-0.
    1. Reilly MM, Shy ME, Muntoni F, Pareyson D. 168th ENMC International Workshop: outcome measures and clinical trials in Charcot-Marie-Tooth disease (CMT) Neuromuscul Disord. 2010;20:839–46. doi: 10.1016/j.nmd.2010.08.001.
    1. Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, Li J, Lewis RA, Reilly M. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology. 2005;64:1209–14. doi: 10.1212/01.WNL.0000156517.00615.A3.
    1. Graham RC, Hughes RAC. A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale. J Neurol Neurosurg Psychiatry. 2006;77:973–6. doi: 10.1136/jnnp.2005.081547.
    1. Shy ME, Chen L, Swan ER, Taube R, Krajewski KM, Herrmann D, Lewis RA, McDermott MP. Neuropathy progression in Charcot-Marie-Tooth disease type 1A. Neurology. 2008;70:378–83. doi: 10.1212/01.wnl.0000297553.36441.ce.
    1. Tesfaye S, Tandan R, Bastyr EJ, Kles KA, Skljarevski V, Price KL. Factors that impact symptomatic diabetic peripheral neuropathy in placebo-administered patients from two 1-year clinical trials. Diabetes Care. 2007;30:2626–32. doi: 10.2337/dc07-0608.
    1. Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;(1):CD003974.
    1. Murphy SM, Herrmann DN, McDermott MP, Scherer SS, Shy ME, Reilly MM, Pareyson D. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011;16:191–8. doi: 10.1111/j.1529-8027.2011.00350.x.
    1. Sadjadi R, Reilly MM, Shy ME, Pareyson D, Laura M, Murphy S, Feely SME, Grider T, Bacon C, Piscosquito G, Calabrese D, Burns TM. Psychometrics evaluation of Charcot-Marie-Tooth Neuropathy Score (CMTNSv2) second version, using Rasch analysis. J Peripher Nerv Syst. 2014;19:192–6. doi: 10.1111/jns.12084.
    1. Mannil M, Solari A, Leha A, Pelayo-Negro AL, Berciano J, Schlotter-Weigel B, Walter MC, Rautenstrauss B, Schnizer TJ, Schenone A, Seeman P, Kadian C, Schreiber O, Angarita NG, Fabrizi GM, Gemignani F, Padua L, Santoro L, Quattrone A, Vita G, Calabrese D, Young P, Laurà M, Haberlová J, Mazanec R, Paulus W, Beissbarth T, Shy ME, Reilly MM, Pareyson D, Sereda MW. Selected items from the Charcot-Marie-Tooth (CMT) Neuropathy Score and secondary clinical outcome measures serve as sensitive clinical markers of disease severity in CMT1A patients. Neuromuscul Disord. 2014;24:1003–17. doi: 10.1016/j.nmd.2014.06.431.

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