{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T03:27:17Z","timestamp":1792985237663,"version":"4.5.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T00:00:00Z","timestamp":1634342400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T00:00:00Z","timestamp":1634342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Charcot\u2013Marie\u2013Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen\/naltrexone\/D-sorbitol [mg]: 6\/0.70\/210 or 3\/0.35\/105) in treating subjects with mild to moderate CMT1A.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5\u00a0mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15\u00a0months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference:\u2009\u2212\u20090.37 points; 97.5%\u00a0CI [\u2212\u20090.68 to\u2009\u2212\u20090.06]; <jats:italic>p<\/jats:italic>\u2009=\u20090.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot\u2013Marie\u2013Tooth disease type 1A.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-021-02040-8","type":"journal-article","created":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T18:35:53Z","timestamp":1634409353000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot\u2013Marie\u2013Tooth type 1A"],"prefix":"10.1186","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-4694","authenticated-orcid":false,"given":"Shahram","family":"Attarian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Brannagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Van Damme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian P.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Casanovas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jafar","family":"Kafaie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Tard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie C.","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"P\u00e9r\u00e9on","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Walk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amro","family":"Stino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"de Visser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camiel","family":"Verhamme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Amato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Magy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Statland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Felice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,16]]},"reference":[{"key":"2040_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1385\/NMM:8:1-2:3","volume":"8","author":"D Pareyson","year":"2006","unstructured":"Pareyson D, Scaioli V, Laur\u00e0 M. Clinical and electrophysiological aspects of Charcot\u2013Marie\u2013Tooth disease. NeuroMol Med. 2006;8:3\u201322.","journal-title":"NeuroMol Med"},{"issue":"11","key":"2040_CR2","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.nmd.2014.06.433","volume":"24","author":"NE Johnson","year":"2014","unstructured":"Johnson NE, Heatwole CR, Dilek N, Sowden J, Kirk CA, Shereff D, et al. Quality-of-life in Charcot\u2013Marie\u2013Tooth disease: the patient\u2019s perspective. Neuromuscul Disord. 2014;24(11):1018\u201323.","journal-title":"Neuromuscul Disord"},{"issue":"1","key":"2040_CR3","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1007\/s11910-010-0158-7","volume":"11","author":"\u00c1 Patzk\u00f3","year":"2011","unstructured":"Patzk\u00f3 \u00c1, Shy ME. Update on Charcot\u2013Marie\u2013Tooth disease. Curr Neurol Neurosci Rep. 2011;11(1):78\u201388.","journal-title":"Curr Neurol Neurosci Rep"},{"key":"2040_CR4","unstructured":"Abrams CK. GJB1 disorders: Charcot Marie Tooth neuropathy (CMT1X) and central nervous system phenotypes. In: Adam M, Ardinger H, Pagon R, et al., editors. GeneReviews. Seattle (WA); p. 1\u201323. Available from: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1374\/#cmtx.Clinical_Characteristics."},{"issue":"12","key":"2040_CR5","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1007\/s00415-006-0260-6","volume":"253","author":"HME Bienfait","year":"2006","unstructured":"Bienfait HME, Verhamme C, van Schaik IN, Koelman JHTM, de Visser BWO, de Haan RJ, et al. Comparison of CMT1A and CMT2: similarities and differences. J Neurol. 2006;253(12):1572\u201380.","journal-title":"J Neurol"},{"issue":"12","key":"2040_CR6","first-page":"1CD011952","volume":"2015","author":"B Gess","year":"2015","unstructured":"Gess B, Baets J, de Jonghe P, Reilly MM, Pareyson D, Young P. Ascorbic acid for the treatment of Charcot\u2013Marie\u2013Tooth disease. Cochrane Database Syst Rev. 2015;2015(12):1CD011952.","journal-title":"Cochrane Database Syst Rev"},{"issue":"10","key":"2040_CR7","doi-asserted-by":"publisher","first-page":"2641","DOI":"10.1111\/j.0953-816X.2004.03368.x","volume":"19","author":"V Magnaghi","year":"2004","unstructured":"Magnaghi V, Ballabio M, Cavarretta ITR, Froestl W, Lambert JJ, Zucchi I, et al. GABAB receptors in Schwann cells influence proliferation and myelin protein expression. Eur J Neurosci. 2004;19(10):2641\u20139.","journal-title":"Eur J Neurosci"},{"key":"2040_CR8","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1385\/JMN:28:1:89","volume":"28","author":"V Magnaghi","year":"2006","unstructured":"Magnaghi V, Ballabio M, Consoli A, Lambert JJ, Roglio I, Melcangi RC. GABA Receptor-mediated effects in the peripheral nervous system. J Mol Neurosci. 2006;28:65\u201376.","journal-title":"J Mol Neurosci"},{"issue":"2","key":"2040_CR9","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/0304-3835(96)04119-5","volume":"101","author":"SD Hytrek","year":"1996","unstructured":"Hytrek SD, McLaughlin PJ, Lang CM, Zagon IS. Inhibition of human colon cancer by intermittent opioid receptor blockade with naltrexone. Cancer Lett. 1996;101(2):159\u201364.","journal-title":"Cancer Lett"},{"issue":"32","key":"2040_CR10","doi-asserted-by":"publisher","first-page":"23171","DOI":"10.1074\/jbc.M610896200","volume":"282","author":"TT Leskel\u00e4","year":"2007","unstructured":"Leskel\u00e4 TT, Markkanen PMH, Pietil\u00e4 EM, Tuusa JT, Pet\u00e4j\u00e4-Repo UE. Opioid receptor pharmacological chaperones act by binding and stabilizing newly synthesized receptors in the endoplasmic reticulum. J Biol Chem. 2007;282(32):23171\u201383.","journal-title":"J Biol Chem"},{"issue":"2","key":"2040_CR11","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1055\/s-1999-13967","volume":"65","author":"M Zhu","year":"1999","unstructured":"Zhu M, Li RC. Receptor binding activities of Schefflera triterpenoids and oligosaccharides. Planta Med. 1999;65(2):99\u2013103.","journal-title":"Planta Med"},{"issue":"1","key":"2040_CR12","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/jnr.20874","volume":"84","author":"S Loreti","year":"2006","unstructured":"Loreti S, Vilar\u00f3 MT, Visentin S, Rees H, Levey AI, Tata AM. Rat Schwann cells express M1\u2013M4 muscarinic receptor subtypes. J Neurosci Res. 2006;84(1):97\u2013105. https:\/\/doi.org\/10.1002\/jnr.20874.","journal-title":"J Neurosci Res"},{"issue":"37","key":"2040_CR13","doi-asserted-by":"publisher","first-page":"35159","DOI":"10.1074\/jbc.M301924200","volume":"278","author":"M Howard","year":"2003","unstructured":"Howard M, Fischer H, Roux J, Santos BC, Gullans SR, Yancey PH, et al. Mammalian osmolytes and S-nitrosoglutathione promote Delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) protein maturation and function. J Biol Chem. 2003;278(37):35159\u201367.","journal-title":"J Biol Chem"},{"issue":"1","key":"2040_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.abb.2009.09.007","volume":"491","author":"R Kumar","year":"2009","unstructured":"Kumar R. Role of naturally occurring osmolytes in protein folding and stability. Arch Biochem Biophys. 2009;491(1):1\u20136.","journal-title":"Arch Biochem Biophys"},{"issue":"1","key":"2040_CR15","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1186\/s13023-014-0201-x","volume":"9","author":"I Chumakov","year":"2014","unstructured":"Chumakov I, Milet A, Cholet N, Primas G, Boucard A, Pereira Y, et al. 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(1):201.","journal-title":"Orphanet J Rare Dis"},{"key":"2040_CR16","first-page":"47","volume":"7","author":"R Hajj","year":"2019","unstructured":"Hajj R, Prukop T, Wernick S, Ewers D, Brureau A, Cholet N, et al. Baclofen, naltrexone and sorbitol all contribute to the efficacy of PXT3003 in CMT1A rats. EMJ Neurol. 2019;7:47\u20139.","journal-title":"EMJ Neurol"},{"issue":"1","key":"2040_CR17","doi-asserted-by":"publisher","first-page":"e0209752","DOI":"10.1371\/journal.pone.0209752","volume":"14","author":"T Prukop","year":"2019","unstructured":"Prukop T, Stenzel J, Wernick S, Kungl T, Mroczek M, Adam J, et al. Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot\u2013Marie\u2013Tooth disease 1A (CMT1A). PLoS ONE. 2019;14(1):e0209752.","journal-title":"PLoS ONE"},{"key":"2040_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13023-014-0199-0","volume":"9","author":"S Attarian","year":"2014","unstructured":"Attarian S, Vallat J, Magy L, Funalot B, Gonnaud P, Lacour A, et al. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol ( PXT3003) in patients with Charcot\u2013Marie\u2013Tooth disease type 1A. Orphanet J Rare Dis. 2014;9:1\u201315.","journal-title":"Orphanet J Rare Dis"},{"key":"2040_CR19","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1136\/jnnp.2005.081547","volume":"77","author":"RC Graham","year":"2006","unstructured":"Graham RC, Hughes RAC. A modified peripheral neuropathy scale: the overall Neuropathy Limitations Scale. J Neurol Neurosurg Psychiatry. 2006;77:973\u20136.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2040_CR20","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1212\/01.wnl.0000297553.36441.ce","volume":"70","author":"ME Shy","year":"2008","unstructured":"Shy ME, Chen L, Swan MER, Taube BR, Krajewski KM, Herrmann D, et al. Neuropathy progression in Charcot\u2013Marie\u2013Tooth disease type 1A. Neurology. 2008;70:378\u201383.","journal-title":"Neurology"},{"issue":"7404","key":"2040_CR21","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1136\/bmj.326.7404.1427","volume":"326","author":"MR Law","year":"2003","unstructured":"Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326(7404):1427\u201331.","journal-title":"BMJ"},{"key":"2040_CR22","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.nmd.2006.03.008","volume":"16","author":"MM Reilly","year":"2006","unstructured":"Reilly MM, de Jonghe P, Pareyson D. 136th ENMC International Workshop: Charcot\u2013Marie\u2013Tooth disease type 1A (CMT1A)8\u201310 April 2005, Naarden, The Netherlands. Neuromuscular Disord. 2006;16:396\u2013402.","journal-title":"Neuromuscular Disord"},{"issue":"12","key":"2040_CR23","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.nmd.2010.08.001","volume":"20","author":"MM Reilly","year":"2010","unstructured":"Reilly MM, Shy ME, Muntoni F, Pareyson D. 168th ENMC international workshop: outcome measures and clinical trials in Charcot\u2013Marie\u2013Tooth disease (CMT). Neuromuscular Disord. 2010;20(12):839\u201346. https:\/\/doi.org\/10.1016\/j.nmd.2010.08.001.","journal-title":"Neuromuscular Disord"},{"issue":"1","key":"2040_CR24","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.nmd.2007.09.006","volume":"18","author":"A Solari","year":"2008","unstructured":"Solari A, Laur\u00e0 M, Salsano E, Radice D, Pareyson D. Reliability of clinical outcome measures in Charcot\u2013Marie\u2013Tooth disease. Neuromuscul Disord. 2008;18(1):19\u201326.","journal-title":"Neuromuscul Disord"},{"issue":"12","key":"2040_CR25","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.1111\/ene.12783","volume":"22","author":"G Piscosquito","year":"2015","unstructured":"Piscosquito G, Reilly MM, Schenone A, Fabrizi GM, Cavallaro T, Santoro L, et al. Responsiveness of clinical outcome measures in Charcot\u2013Marie\u2013Tooth disease. Eur J Neurol. 2015;22(12):1556\u201363.","journal-title":"Eur J Neurol"},{"key":"2040_CR26","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1002\/sim.4780111304","volume":"11","author":"L Frison","year":"1992","unstructured":"Frison L, Pocock SJ. Repeated measures in clinical trials: analysis using mean summary statistics and its implications for design. Stat Med. 1992;11:1685\u2013704.","journal-title":"Stat Med"},{"key":"2040_CR27","first-page":"1002","volume":"1","author":"TM Morgan","year":"2013","unstructured":"Morgan TM, Case LD. Conservative sample size determination for repeated measures analysis of covariance. Ann Biometrics Biostat. 2013;1:1002.","journal-title":"Ann Biometrics Biostat"},{"key":"2040_CR28","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/S1474-4422(11)70025-4","volume":"10","author":"D Pareyson","year":"2011","unstructured":"Pareyson D, Reilly MM, Schenone A, Fabrizi GM, Cavallaro T, Santoro L, et al. Ascorbic acid in Charcot\u2013Marie\u2013Tooth disease type 1A (CMT-TRI AA L and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol. 2011;10:320\u20138.","journal-title":"Lancet Neurol"},{"key":"2040_CR29","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1177\/2515245918808784","volume":"2","author":"DS Sauder","year":"2019","unstructured":"Sauder DS, DeMars CE. An updated recommendation for multiple comparisons. Adv Methods Pract Psychol Sci. 2019;2:26\u201344.","journal-title":"Adv Methods Pract Psychol Sci"},{"key":"2040_CR30","doi-asserted-by":"publisher","first-page":"353","DOI":"10.4097\/kja.d.18.00242","volume":"5","author":"S Lee","year":"2018","unstructured":"Lee S, Lee DK. Multiple comparison test and its imitations what is the proper way to apply the multiple comparison test? KJA Korean J Anesthesiol. 2018;5:353\u201360.","journal-title":"KJA Korean J Anesthesiol"}],"updated-by":[{"DOI":"10.1186\/s13023-024-03110-3","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000}}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-02040-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-021-02040-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-02040-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T21:01:44Z","timestamp":1712005304000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-021-02040-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,16]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["2040"],"URL":"https:\/\/doi.org\/10.1186\/s13023-021-02040-8","relation":{"correction":[{"id-type":"doi","id":"10.1186\/s13023-024-03110-3","asserted-by":"object"}]},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,16]]},"assertion":[{"value":"28 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 April 2024","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1186\/s13023-024-03110-3","URL":"https:\/\/doi.org\/10.1186\/s13023-024-03110-3","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was conducted in accordance with the Declaration of Helsinki and was approved by the appropriate ethics committee for each study center. All participants provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publications"}},{"value":"All authors were either paid as consultants by Pharnext or work at institutions that received funds from Pharnext to complete the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"433"}}