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 Journal of Rare Diseases

Volumn 9, Issue 1, 2014, Pages

  Attarian, Shahram ^a   Vallat, Jean Michel ^b   Magy, Laurent ^b   Funalot, Benoît ^b   Gonnaud, Pierre Marie ^c   Lacour, Arnaud ^d   Péréon, Yann ^e   Dubourg, Odile ^f   Pouget, Jean ^a   Micallef, Joëlle ^a   Franques, Jérôme ^a   Lefebvre, Marie Noëlle ^a   Ghorab, Karima ^b   Al Moussawi, Mahmoud ^c   Tiffreau, Vincent ^d   Preudhomme, Marguerite ^d   Magot, Armelle ^e   Leclair Visonneau, Laurène ^d   Stojkovic, Tanya ^f   Bossi, Laura ^g   Lehert, Philippe ^h,i   Gilbert, Walter ^j   Bertrand, Viviane ^k   Mandel, Jonas ^k   Milet, Aude ^k   Hajj, Rodolphe ^k   Boudiaf, Lamia ^k   Scart Grès, Catherine ^k   Nabirotchkin, Serguei ^k   Guedj, Mickael ^k   Chumakov, Ilya ^k   Cohen, Daniel ^k   more..

^a AIX MARSEILLE UNIVERSITY   (France)

^b LIMOGES UNIVERSITY HOSPITAL   (France)

^c HOSPICES CIVILS DE LYON   (France)

^d LILLE UNIVERSITY HOSPITAL   (France)

^e NANTES UNIVERSITY HOSPITAL   (France)

^f PITIÉ SALPÊTRIÈRE HOSPITAL   (France)

^g Admissions   (France)

^h UNIVERSITY OF MELBOURNE   (Australia)

ⁱ UCL Mons ^*  (Belgium)

^j HARVARD UNIVERSITY   (United States)

^k PHARNEXT   (France)

more..

Author keywords

Charcot Marie Tooth; Clinical trial; CMT1A; Combination therapy; Phase 2; Repurposing

Indexed keywords

AGENTS ACTING ON THE PERIPHERAL NERVOUS AND NEUROMUSCULAR SYSTEMS; BACLOFEN PLUS NALTREXONE PLUS SORBITOL; PLACEBO; UNCLASSIFIED DRUG; BACLOFEN; NALTREXONE; SORBITOL;

ABDOMINAL PAIN; ADULT; ARTICLE; CHARCOT MARIE TOOTH NEUROPATHY SCORE; CHARCOT MARIE TOOTH TYPE 1A; CONNECTIVE TISSUE DISEASE; CONTROLLED STUDY; DIARRHEA; DISEASE SEVERITY; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; EXPLORATORY RESEARCH; FATIGUE; FEMALE; GASTROINTESTINAL SYMPTOM; HEADACHE; HEREDITARY MOTOR SENSORY NEUROPATHY; HUMAN; KIDNEY DISEASE; LIMIT OF QUANTITATION; LOW DRUG DOSE; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; MUSCLE SPASM; MUSCULOSKELETAL DISEASE; NAUSEA; NERVOUS SYSTEM ELECTROPHYSIOLOGY; NEUROLOGIC DISEASE; NEUROLOGIC DISEASE ASSESSMENT; OUTCOME ASSESSMENT; OVERALL NEUROPATHY LIMITATIONS SCALE; PHASE 2 CLINICAL TRIAL; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL; SOMNOLENCE; TREATMENT DURATION; URINARY TRACT DISEASE; CHARCOT-MARIE-TOOTH DISEASE; CLINICAL TRIAL; COMBINATION DRUG THERAPY; MIDDLE AGED;

ADULT; BACLOFEN; CHARCOT-MARIE-TOOTH DISEASE; DOUBLE-BLIND METHOD; DRUG THERAPY, COMBINATION; FEMALE; HUMANS; MALE; MIDDLE AGED; NALTREXONE; SORBITOL;

EID: 84979562049     PISSN: None     EISSN: 17501172     Source Type: Journal    
DOI: 10.1186/s13023-014-0199-0     Document Type: Article

References (50)

1. Kochański A: Molecular genetics studies in polish Charcot-Marie-Tooth families. Folia Neuropathol 2005, 42:65-73.
2. Patzkó A, Shy ME: Update on Charcot-Marie-Tooth disease. Curr Neurol Neurosci Rep 2011, 11:78-88.
3. Pareyson D, Scaioli V, Laurà M: Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med 2006, 8:3-22.
4. Bird TD: Charcot-Marie-Tooth Neuropathy Type 1. In 2014. GeneReviews® 1998 (Updated 2014) [ http://www.ncbi.nlm.nih.gov/books/NBK1205/ ]
5. Gess B, Schirmacher A, Boentert M, Young P: Charcot-Marie-Tooth disease: frequency of genetic subtypes in a German neuromuscular center population. Neuromuscul Disord 2013, 23:647-51.
6. Foley C, Schofield I, Eglon G, Bailey G, Chinnery PF, Horvath R: Charcot-Marie-Tooth disease in Northern England. J Neurol Neurosurg Psychiatry 2012, 83:572-3.
7. 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, 1:93-97.
8. 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.
9. 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.
10. Kaya F, Belin S, Bourgeois P, Micaleff J, Blin O, Fontés M: Ascorbic acid inhibits PMP22 expression by reducing cAMP levels. Neuromuscul Disord 2007, 17:248-253.
11. Schenone A, Nobbio L, Monti Bragadin M, Ursino G, Grandis M: Inherited neuropathies. Curr Treat Options Neurol 2011, 13:160-79.
12. Gess B, Röhr D, Fledrich R, Sereda MW, Kleffner I, Humberg A, Nowitzki J, Strecker J-K, Halfter H, Young P: Sodium-dependent vitamin C transporter 2 deficiency causes hypomyelination and extracellular matrix defects in the peripheral nervous system. J Neurosci 2011, 31:17180-92.
13. 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.
14. 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, 8:537-544.
15. 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, 120:134-138.
16. 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, 8:1103-1110.
17. 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, 10:320-328.
18. 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, 70:981-987.
19. Ainsworth C: Networking for new drugs. Nat Med 2011, 17:1166-1168.
20. Sereda M, Griffiths I, Pühlhofer A, Stewart H, Rossner MJ, Zimmerman F, Magyar JP, Schneider A, Hund E, Meinck HM, Suter U, Nave KA: A transgenic rat model of Charcot-Marie-Tooth disease. Neuron 1996, 16:1049-1060.
21. 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, 28:89-102.
22. Stein C, Lang LJ: Peripheral mechanisms of opioid analgesia. Curr Opin Pharmacol 2009, 9:3-8.
23. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J: Clinical development success rates for investigational drugs. Nat Biotechnol 2014, 32:40-51.
24. Reagan-Shaw S, Nihal M, Ahmad N: Dose translation from animal to human studies revisited. FASEB J 2008, 22:659-661.
25. 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, 64:1209-1214.
26. Reilly MM, de Jonghe P, Pareyson D: 136th ENMC International Workshop: Charcot-Marie-Tooth disease type 1A (CMT1A)8-10 April 2005, Naarden, The Netherlands. Neuromuscul Disord 2005, 2006(16):396-402.
27. 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, 20:839-846.
28. Komyathy K, Neal S, Feely S, Miller LJ, Lewis RA, Trigge G, Siskind CE, Shy ME, Ramchandren S: Anterior tibialis CMAP amplitude correlations with impairment in CMT1A. Muscle Nerve 2013, 47:493-496.
29. 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, 16:191-198.
30. Graham RC, Hughes RAC: A modified peripheral neuropathy scale: the overall neuropathy limitations scale. J Neurol Neurosurg Psychiatry 2006, 77:973-976.
31. Solari A, Laurà M, Salsano E, Radice D, Pareyson D: Reliability of clinical outcome measures in Charcot-Marie-Tooth disease. Neuromuscul Disord 2008, 18:19-26.
32. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, Berman LB: The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985, 132:919-923.
33. Hogrel J-Y, Payan CA, Ollivier G, Tanant V, Attarian S, Couillandre A, Dupeyron A, Lacomblez L, Doppler V, Meininger V, Tranchant C, Pouget J, Desnuelle C: Development of a French isometric strength normative database for adults using quantitative muscle testing. Arch Phys Med Rehabil 2007, 88:1289-1297.
34. Senn S: Testing for baseline balance in clinical trials. Stat Med 1994, 13:1715-1726.
35. O'Brien P: Procedures for comparing samples with multiple endpoints. Biometrics 1984, 40:1079-1087.
36. Logan BR, Tamhane AC: On O' Brien' s OLS and GLS tests for multiple endpoints. Lect Notes-Monograph Ser 2006, 47:76-88.
37. Ruberg SJ: Contrasts for identifying the minimum effective dose. J Am Stat Assoc 1989, 84:816-822.
38. Tamhane AC, Hochberg Y, Dunnett CW: Multiple test procedures for dose finding. Biometrics 1996, 52:21-37.
39. Peace KE: One-sided or two-sided p values: which most appropriately address the question of drug efficacy? J Biopharm Stat 1991, 1:133-138.
40. Fisher LD: The use of one-sided tests in drug trials: an FDA advisory committee member's perspective. J Biopharm Stat 1991, 1:151-156.
41. Zhang J, Yu KF: What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998, 280:1690-1691.
42. Chakraborty H, Gu H: A Mixed Model Approach for Intent-to-Treat Analysis in Longitudinal Clinical Trials with Missing Values, RTI Press Publication No. MR-0009-0903. Research Triangle Park, NC: RTI International; 2009.
43. Shy ME, Rose MR: Charcot-Marie-Tooth disease impairs quality of life: why? And how do we improve it? Neurology 2005, 65(6):790-791.
44. Padua L, Aprile I, Cavallaro T, Commodari I, Pareyson D, Quattrone A, Rizzuto N, Vita G, Tonali P, Schenone A: Relationship between clinical examination, quality of life, disability and depression in CMT patients: Italian multicenter study. Neurol Sci 2008, 29:157-162.
45. Button KS, Ioannidis JPA, Mokrysz C, Nosek BA, Flint J, Robinson ESJ, Munafò MR: Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci 2013, 14:365-376.
46. 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.
47. Dyck PJ, Karnes JL, Lambert EH: Longitudinal study of neuropathic deficits and nerve conduction abnormalities in hereditary motor and sensory neuropathy type 1. Neurology 1989, 39:1302-1302.
48. Verhamme C, van Schaik IN, Koelman JHTM, de Haan RJ, Vermeulen M, de Visser M: Clinical disease severity and axonal dysfunction in hereditary motor and sensory neuropathy Ia. J Neurol 2004, 251:1491-7.
49. Verhamme C, van Schaik IN, Koelman JHTM, de Haan RJ, de Visser M: The natural history of Charcot-Marie-Tooth type 1A in adults: a 5-year follow-up study. Brain 2009, 132(Pt 12):3252-62.
50. Thomas PK, Marques W, Davis MB, Sweeney MG, King RHM, Bradley JL, Muddle JR, Tyson J, Malcolm S, Harding AE, Street RH: The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 1997, 120(3):465-478.