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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">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</title><author><name sortKey="Mandel, Jonas" sort="Mandel, Jonas" uniqKey="Mandel J" first="Jonas" last="Mandel">Jonas Mandel</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Bertrand, Viviane" sort="Bertrand, Viviane" uniqKey="Bertrand V" first="Viviane" last="Bertrand">Viviane Bertrand</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Lehert, Philippe" sort="Lehert, Philippe" uniqKey="Lehert P" first="Philippe" last="Lehert">Philippe Lehert</name><affiliation><nlm:aff id="Aff2">Faculty of Medicine, University of Melbourne, Melbourne, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3">Faculty of Economics, UCL Mons, Louvain, Belgium</nlm:aff></affiliation></author><author><name sortKey="Attarian, Shahram" sort="Attarian, Shahram" uniqKey="Attarian S" first="Shahram" last="Attarian">Shahram Attarian</name><affiliation><nlm:aff id="Aff4">Centre de référence des maladies neuromusculaires et de la SLA, Pôle des neurosciences Cliniques, AP-HM et Aix Marseille Université, Marseille, France</nlm:aff></affiliation></author><author><name sortKey="Magy, Laurent" sort="Magy, Laurent" uniqKey="Magy L" first="Laurent" last="Magy">Laurent Magy</name><affiliation><nlm:aff id="Aff5">CHU de Limoges Hôpital Dupuytren, Limoges, France</nlm:aff></affiliation></author><author><name sortKey="Micallef, Joelle" sort="Micallef, Joelle" uniqKey="Micallef J" first="Joëlle" last="Micallef">Joëlle Micallef</name><affiliation><nlm:aff id="Aff6">CIC-Centre de Pharmacologie Clinique et D’Evaluations Thérapeutiques, AP-HM et Aix Marseille Université, Marseille, France</nlm:aff></affiliation></author><author><name sortKey="Chumakov, Ilya" sort="Chumakov, Ilya" uniqKey="Chumakov I" first="Ilya" last="Chumakov">Ilya Chumakov</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Scart Gres, Catherine" sort="Scart Gres, Catherine" uniqKey="Scart Gres C" first="Catherine" last="Scart-Grès">Catherine Scart-Grès</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Guedj, Mickael" sort="Guedj, Mickael" uniqKey="Guedj M" first="Mickael" last="Guedj">Mickael Guedj</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Cohen, Daniel" sort="Cohen, Daniel" uniqKey="Cohen D" first="Daniel" last="Cohen">Daniel Cohen</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26070802</idno><idno type="pmc">4482281</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482281</idno><idno type="RBID">PMC:4482281</idno><idno type="doi">10.1186/s13023-015-0293-y</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000980</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000980</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">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</title><author><name sortKey="Mandel, Jonas" sort="Mandel, Jonas" uniqKey="Mandel J" first="Jonas" last="Mandel">Jonas Mandel</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Bertrand, Viviane" sort="Bertrand, Viviane" uniqKey="Bertrand V" first="Viviane" last="Bertrand">Viviane Bertrand</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Lehert, Philippe" sort="Lehert, Philippe" uniqKey="Lehert P" first="Philippe" last="Lehert">Philippe Lehert</name><affiliation><nlm:aff id="Aff2">Faculty of Medicine, University of Melbourne, Melbourne, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3">Faculty of Economics, UCL Mons, Louvain, Belgium</nlm:aff></affiliation></author><author><name sortKey="Attarian, Shahram" sort="Attarian, Shahram" uniqKey="Attarian S" first="Shahram" last="Attarian">Shahram Attarian</name><affiliation><nlm:aff id="Aff4">Centre de référence des maladies neuromusculaires et de la SLA, Pôle des neurosciences Cliniques, AP-HM et Aix Marseille Université, Marseille, France</nlm:aff></affiliation></author><author><name sortKey="Magy, Laurent" sort="Magy, Laurent" uniqKey="Magy L" first="Laurent" last="Magy">Laurent Magy</name><affiliation><nlm:aff id="Aff5">CHU de Limoges Hôpital Dupuytren, Limoges, France</nlm:aff></affiliation></author><author><name sortKey="Micallef, Joelle" sort="Micallef, Joelle" uniqKey="Micallef J" first="Joëlle" last="Micallef">Joëlle Micallef</name><affiliation><nlm:aff id="Aff6">CIC-Centre de Pharmacologie Clinique et D’Evaluations Thérapeutiques, AP-HM et Aix Marseille Université, Marseille, France</nlm:aff></affiliation></author><author><name sortKey="Chumakov, Ilya" sort="Chumakov, Ilya" uniqKey="Chumakov I" first="Ilya" last="Chumakov">Ilya Chumakov</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Scart Gres, Catherine" sort="Scart Gres, Catherine" uniqKey="Scart Gres C" first="Catherine" last="Scart-Grès">Catherine Scart-Grès</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Guedj, Mickael" sort="Guedj, Mickael" uniqKey="Guedj M" first="Mickael" last="Guedj">Mickael Guedj</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author><author><name sortKey="Cohen, Daniel" sort="Cohen, Daniel" uniqKey="Cohen D" first="Daniel" last="Cohen">Daniel Cohen</name><affiliation><nlm:aff id="Aff1">Pharnext SAS, Issy-les-Moulineaux, France</nlm:aff></affiliation></author></analytic><series><title level="j">Orphanet Journal of Rare Diseases</title><idno type="eISSN">1750-1172</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Raeymaekers, P" uniqKey="Raeymaekers P">P Raeymaekers</name></author><author><name sortKey="Timmerman, V" uniqKey="Timmerman V">V Timmerman</name></author><author><name sortKey="Nelis, E" uniqKey="Nelis E">E Nelis</name></author><author><name sortKey="De Jonghe, P" uniqKey="De Jonghe P">P De Jonghe</name></author><author><name sortKey="Hoogendijk, Je" uniqKey="Hoogendijk J">JE Hoogendijk</name></author><author><name sortKey="Baas, F" uniqKey="Baas F">F Baas</name></author><author><name sortKey="Barker, Df" uniqKey="Barker D">DF Barker</name></author><author><name sortKey="Martin, Jj" uniqKey="Martin J">JJ Martin</name></author><author><name sortKey="De Visser, M" uniqKey="De Visser M">M De 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Orphanet J Rare Dis</journal-id><journal-id journal-id-type="iso-abbrev">Orphanet J Rare Dis</journal-id><journal-title-group><journal-title>Orphanet Journal of Rare Diseases</journal-title></journal-title-group><issn pub-type="epub">1750-1172</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26070802</article-id><article-id pub-id-type="pmc">4482281</article-id><article-id pub-id-type="publisher-id">293</article-id><article-id pub-id-type="doi">10.1186/s13023-015-0293-y</article-id><article-categories><subj-group subj-group-type="heading"><subject>Letter to the Editor</subject></subj-group></article-categories><title-group><article-title>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</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" equal-contrib="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-1893-8411</contrib-id><name><surname>Mandel</surname><given-names>Jonas</given-names></name><address><email>jmandel@pharnext.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Bertrand</surname><given-names>Viviane</given-names></name><address><email>viviane.bertrand@pharnext.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Lehert</surname><given-names>Philippe</given-names></name><address><email>philippe.lehert@gmail.com</email></address><xref ref-type="aff" rid="Aff2"></xref><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Attarian</surname><given-names>Shahram</given-names></name><xref ref-type="aff" rid="Aff4"></xref></contrib><contrib contrib-type="author"><name><surname>Magy</surname><given-names>Laurent</given-names></name><xref ref-type="aff" rid="Aff5"></xref></contrib><contrib contrib-type="author"><name><surname>Micallef</surname><given-names>Joëlle</given-names></name><xref ref-type="aff" rid="Aff6"></xref></contrib><contrib contrib-type="author"><name><surname>Chumakov</surname><given-names>Ilya</given-names></name><address><email>ilya.chumakov@pharnext.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Scart-Grès</surname><given-names>Catherine</given-names></name><address><email>catherine.scart-gres@pharnext.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Guedj</surname><given-names>Mickael</given-names></name><address><email>mickael.guedj@pharnext.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Cohen</surname><given-names>Daniel</given-names></name><address><email>jmandel@pharnext.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><label></label>Pharnext SAS, Issy-les-Moulineaux, France</aff><aff id="Aff2"><label></label>Faculty of Medicine, University of Melbourne, Melbourne, Australia</aff><aff id="Aff3"><label></label>Faculty of Economics, UCL Mons, Louvain, Belgium</aff><aff id="Aff4"><label></label>Centre de référence des maladies neuromusculaires et de la SLA, Pôle des neurosciences Cliniques, AP-HM et Aix Marseille Université, Marseille, France</aff><aff id="Aff5"><label></label>CHU de Limoges Hôpital Dupuytren, Limoges, France</aff><aff id="Aff6"><label></label>CIC-Centre de Pharmacologie Clinique et D’Evaluations Thérapeutiques, AP-HM et Aix Marseille Université, Marseille, France</aff></contrib-group><pub-date pub-type="epub"><day>13</day><month>6</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>13</day><month>6</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>10</volume><elocation-id>74</elocation-id><history><date date-type="received"><day>24</day><month>4</month><year>2015</year></date><date date-type="accepted"><day>4</day><month>6</month><year>2015</year></date></history><permissions><copyright-statement>© Mandel et al. 2015</copyright-statement><license license-type="open-access"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0">http://creativecommons.org/licenses/by/4.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><p>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.</p></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Charcot-Marie-Tooth</kwd><kwd>CMT1A</kwd><kwd>CMTNS</kwd><kwd>ONLS</kwd><kwd>PXT3003</kwd><kwd>Meta-analysis</kwd><kwd>Ascorbic acid</kwd><kwd>Clinical trials</kwd><kwd>Randomized</kwd><kwd>Double blind</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2015</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Letter to the editor</title><p>Charcot-Marie-Tooth disease Type 1A (CMT1A, OMIM: 118220, Orphanet: ORPHA101081) is a rare, inherited, peripheral neuropathy caused by duplication of the gene PMP22 [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>], whose over-expression induces dysmyelination, axonal loss and muscle wasting [<xref ref-type="bibr" rid="CR3">3</xref>, <xref ref-type="bibr" rid="CR4">4</xref>]. Two treatments have been recently investigated in seven 1- or 2-year randomized, double blind, placebo-controlled clinical trials: Ascorbic Acid (AA) [<xref ref-type="bibr" rid="CR5">5</xref>–<xref ref-type="bibr" rid="CR12">12</xref>] and PXT3003, a combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol [<xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR14">14</xref>]. Now that all these trials have been completed, and as recommended at the 168<sup>th</sup> ENMC international workshop [<xref ref-type="bibr" rid="CR15">15</xref>], we report the results of a first meta-analysis assessing the disease progression after one year under Placebo, AA or PXT3003.</p></sec><sec id="Sec2" sec-type="materials|methods"><title>Methods</title><p>We conducted a literature search through PubMed and ClinicalTrials.gov for randomized, placebo-controlled clinical trials lasting 12 months or more using ‘‘Charcot-Marie-Tooth type 1A disease’’ and its synonyms’ ‘‘hereditary motor and sensory neuropathy’’, ‘‘peroneal muscular atrophy’’ and ‘‘distal spinal muscular atrophy’’ as the search terms. MEDLINE search terms are given in <xref rid="Sec5" ref-type="sec">Appendix</xref>. We also checked the bibliography of identified trials. The outcomes of interest were the change from baseline in CMTNS [<xref ref-type="bibr" rid="CR16">16</xref>] and ONLS [<xref ref-type="bibr" rid="CR17">17</xref>] after one year of treatment or Placebo, hence only trials measuring CMTNS or ONLS were selected. CMTNS and ONLS are considered as the main clinical scales for impairment and disability, respectively, in CMT1A disease [<xref ref-type="bibr" rid="CR15">15</xref>]. Studies measuring at least one of these two outcomes were selected. In both measures, an increasing score is considered as deterioration.</p><p>The estimated mean changes from baseline and corresponding standard errors were extracted from the publications. When not available, standard errors were deduced from confidence intervals. Studies not providing sufficient information were excluded from the meta-analysis.</p><p>For each outcome, we performed fixed and DerSimonian-Laird random effects meta-analyses including treatment (Placebo, AA or PXT3003) as moderator factor. The Q-test and I<sup>2</sup> index were used to determine the level of heterogeneity in the random effect model. Comparisons of AA and PXT3003 versus Placebo were performed with tests of contrast of the moderator factor.</p></sec><sec id="Sec3" sec-type="results"><title>Results</title><p>Four studies met the inclusion criteria: three on AA [<xref ref-type="bibr" rid="CR10">10</xref>–<xref ref-type="bibr" rid="CR12">12</xref>] and one on PXT3003 [<xref ref-type="bibr" rid="CR14">14</xref>]. For the PXT3003 trial, only the dose showing a significant effect was considered, <italic>i.e.</italic> the highest dose tested termed ‘PXT3003 HD’. For ONLS in the Pareyson study, values at 24 months were used as values at 12 months were not available. In total, 565 patients were included in these trials: 220 with Placebo, 326 with AA (1, 1.5, 3 or 4 g per day) and 19 with PXT3003 (HD). The Q and I<sup>2</sup> indices for the random effect models did not reveal significant heterogeneity for CMTNS (Q-test <italic>p</italic> = 0.28; I<sup>2</sup> = 10.9 %) nor for ONLS (Q-test <italic>p</italic> = 0.36; I<sup>2</sup> = 11.2 %), justifying reporting the results of the fixed effect models only.</p><p>Results obtained for CMTNS and ONLS scales were consistent (Fig. <xref rid="Fig1" ref-type="fig">1a and b</xref>). After one year, CMT1A patients showed a slight deterioration under Placebo of 0.16 point in CMTNS and 0.06 point in ONLS. The progression of patients under AA appeared stable (−0.04 point in CMTNS and −0.01 point in ONLS) and not significant when compared to Placebo (<italic>p</italic> = 0.390 for CMTNS and <italic>p =</italic> 0.387 for ONLS). Patients taking PXT3003 showed an amelioration in both measures (−0.68 point in CMTNS and −0.21 point in ONLS), significant when compared to Placebo (<italic>p</italic> = 0.048 for CMTNS and <italic>p =</italic> 0.044 for ONLS).<fig id="Fig1"><label>Fig. 1</label><caption><p>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. <bold>a</bold> Change from baseline in CMTNS under Placebo, AA and PXT3003; <bold>b</bold> Change from baseline in ONLS under Placebo, AA and PXT3003. *<italic>p</italic> < 0.05; NS = not-significant</p></caption><graphic xlink:href="13023_2015_293_Fig1_HTML" id="MO1"></graphic></fig></p></sec><sec id="Sec4" sec-type="discussion"><title>Discussion</title><p>The present meta-analysis supports the conclusions made independently within each clinical trial as regards efficacy of treatments and Placebo [<xref ref-type="bibr" rid="CR10">10</xref>, <xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR14">14</xref>]. First, the CMT1A patients of the Placebo groups from studies conducted from 2006 to 2014 deteriorate rather slowly compared to the estimated natural progression of 0.686 point/year in CMTNS reported by Shy and colleagues in 2008 [<xref ref-type="bibr" rid="CR18">18</xref>]. These findings are consistent with the positive placebo effects observed in diabetic neuropathy [<xref ref-type="bibr" rid="CR19">19</xref>] or patient-reported pain outcomes [<xref ref-type="bibr" rid="CR20">20</xref>], although the factors accounting for such a difference remain unclear. Lewis <italic>et al.</italic> [<xref ref-type="bibr" rid="CR12">12</xref>] considered that systematic differences between participants of the different studies may be partially responsible; for instance the mean age and CMTNS are slightly higher in the four clinical trials considered here than in the natural progression study by Shy <italic>et al.</italic> [<xref ref-type="bibr" rid="CR18">18</xref>]. Pareyson and colleagues [<xref ref-type="bibr" rid="CR11">11</xref>] also pointed out that the natural progression study was partly retrospective, and therefore might not be directly comparable with clinical trials. Consequently, we believe that the progression of CMTNS and ONLS under Placebo reported here is more valuable than natural progression estimates for the design of future clinical trials in CMT1A, and less prone to sampling bias that might occur in single independent studies.</p><p>Second, the progression of patients under different dosages of AA appears quite stable, and does not reach statistical significance versus Placebo. The difference between AA and Placebo is far below the order of magnitude expected for sample size calculation in the three AA clinical trials. As it happens, the <italic>a posteriori</italic> power to detect this difference as significant does not exceed 15 % (assuming an SD in CMTNS of 5, a correlation between baseline and final values of 0.8, and an ANCOVA analysis at a two-sided 5 % level). In this context, designing a confirmatory Phase 3 study for a treatment showing such stabilization in CMT1A would require a much larger sample size and longer study duration, making it clearly unrealizable. It confirms the idea that an effective treatment for this disease should bring an improvement, rather than the mere ability to slow or stabilize the disease progression [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR14">14</xref>]. Even if this effect seems quite marginal, a standardized re-analysis of all AA patient-level data would be of great interest.</p><p>Lastly, this meta-analysis supports an improvement in both CMTNS and ONLS with PXT3003 treatment, statistically significant when compared to Placebo. This improvement could herald an early, meaningful change in the disease course.</p><p>Conducting a meta-analysis of clinical trials in CMT1A is challenging because of the small number of studies and of the heterogeneity of study protocols in terms of recruitment criteria, study duration, balance of groups, and statistical analysis. In addition, our study evaluates CMTNS in a context where a second version (CMTNSv2) has been proposed to reduce floor/ceiling effects and eventually to improve the scale’s sensitivity to change [<xref ref-type="bibr" rid="CR21">21</xref>]. The current version of the CMTNSv2 has also been questioned recently through a Rasch analysis by Sadjadi <italic>et al.</italic> [<xref ref-type="bibr" rid="CR22">22</xref>] and a ‘weighted’ alternative has been suggested. In parallel, Mannil <italic>et al.</italic> [<xref ref-type="bibr" rid="CR23">23</xref>] proposed a CMTNSMod by adding three functional measures (9-hole peg test, foot dorsiflexion and walk test) while removing Ulnar SNAP, Pin Sensibility, Vibration and Strength of Arms. None of these modified versions has been evaluated yet in natural history or therapeutic trials. Despite these limitations, the present study provides a set of relevant observations, consistently obtained on both CMTNS and ONLS, to be used for the design of future clinical trials in CMT1A.</p></sec></body><back><app-group><app id="App1"><sec id="Sec5"><title>Appendix</title><sec id="Sec6"><title>PubMed MEDLINE Search Strategy</title><p>randomized controlled trial [Title/Abstract] OR controlled clinical trial [Title/Abstract] OR placebo-controlled clinical trial [Title/Abstract] OR clinical trial [Title/Abstract] OR randomized clinical trials [mh] OR clinical trials [mh] OR random allocation [mh] OR double-blind [mh] OR double blind[mh] OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR follow-up study [mh] OR prospective study [mh])) NOT (animals [mh] NOT human [mh])</p><p>AND ((Charcot-Marie-Tooth [Title/Abstract] OR CMT [Title/Abstract] OR hmsn [Title/Abstract] OR hereditary motor and sensory neuropathy [Title/Abstract] OR peroneal muscular atrophy [Title/Abstract]) AND (1A [Title/Abstract] OR type 1A [Title/Abstract]))</p></sec></sec></app></app-group><glossary><title>Abbreviations</title><def-list><def-item><term>CMT1A</term><def><p>Charcot-Marie-Tooth disease type 1A</p></def></def-item><def-item><term>CMTNS</term><def><p>Charcot-Marie-Tooth neuropathy score</p></def></def-item><def-item><term>ONLS</term><def><p>Overall neuropathy limitation scale</p></def></def-item><def-item><term>AA</term><def><p>Ascorbic acid</p></def></def-item><def-item><term>SD</term><def><p>Standard deviation</p></def></def-item></def-list></glossary><fn-group><fn><p>Jonas Mandel and Mickael Guedj contributed equally to this work.</p></fn><fn><p><bold>Competing interests</bold></p><p>JM, VB, IC, CSG, MG and DC are present employees of Pharnext and have shares in the company. VB, MG, IC and DC hold patent applications by Pharnext. PL is consultant on behalf of Pharnext.</p></fn><fn><p><bold>Authors’ contributions</bold></p><p>JM, MG and PL designed and implemented the statistical analysis. JM and MG participated equally in the achievement of the manuscript. 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