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Disclosures

Trial design and outcomes for inherited neuropathy studies D. Pareyson IRCCS Foundation C.Besta Neurological Institute Milan, Italy MSG Meeting, Buffalo, NY September 22, 2009. Disclosures. No conflict of interest

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  1. Trial design and outcomes for inherited neuropathy studiesD. Pareyson IRCCS Foundation C.Besta Neurological Institute Milan, ItalyMSG Meeting, Buffalo, NYSeptember 22, 2009

  2. Disclosures • No conflict of interest • Conducting a trial of ascorbic acid in CMT1A funded by Telethon-Italy and AIFA (Italian Medicines Agency) • No honorary from any company • Travel grants + meeting participation from Kedrion

  3. Highly heterogeneous, different pathogenic mechanisms • Slowly progressive disease • Variability in disease severity and course • Some forms very rare Need • Natural history studies • Long study duration, large samples of pts. • Multicenter studies • Reliable and responsive OM

  4. Charcot-Marie-Tooth 1A (CMT1A) • Most frequent CMT type (40-50% all CMT) • Animal models available • Down-regulation of PMP22 expression • Progesteron antagonists, Neurotrophin-3 (NT3), ascorbic acid beneficial in animal models • Opened clinical trial phase

  5. Holland, 12 patients 12-25 yrs, MCV Germany, 50 children placebo, 3 grams Czech Rep. 60 patients placebo, 1.5 gr - CMTNS Italy-UK, 272 patients placebo, 1.5 grams 2 years - CMTNS US, 120 patients Placebo, 4 grams 2 years - CMTNS France, 180 patients placebo, 1 gram, 3 grams, 1 year - CMTNS Australia, 81 children, 1 year

  6. Clinical OM used in CMT • Impairment • Strength assessment: MRC, myometers • Sensory assessment: INCAT sensory sum score (ISS), Semmes-Weinstein monofilaments • Composite: CMTNS, NIS • VAS for pain, fatigue, cramps, etc. • Disability • Walking: 10 meter timed walking, Ambulation index • Upper limbs: 9 hole peg test (9HPT), Box and Block test, Functional dexterity test, Jebsen test, Sollerman hand function test, Shape texture identification test, DASH • Global: ONLS, Barthel Index, Rankin scale • Qol • SF36, RAND

  7. 168th ENMC WorkshopOutcome measures and clinical trials in CMT September 18-20, 2009 136th ENMC Workshopon CMT1A April 8-10, 2005 Naarden International panel of experts (clinicians, neuroepidemiologist, pharmacologist, basic researchers). Agreement on outcome measures, trial design, etc.

  8. Recommended core outcome measures 136th, 2005 • CMT neuropathy score (CMTNS) • Quantitative motor strength assessment • VAS for pain and fatigue • 10-meter timed walking • Overall Neuropathy Limitations Scale (ONLS) • SF-36 • Electrophysiology: Non-dominant side • CV of CMTNS nerves; • motor nerves 2 upper limb, 1 lower limb (peroneal), (MCV, DL, CMAP); 1 sensory (ulnar, SAP ampl., SCV)

  9. Anglo-Italian study CMT-TRIAAL & CMT-TRAUK MRC Centre for Neuromuscular Disease MRC Centre for Neuromuscular Disease Reliability study before starting N° patients recruited = 272 2 YEARS

  10. January 2006: FIRST PATIENT SCREENED March 2006 - March 2007 December 2007 INTERIM ANALYSIS (March 2009 Italy, July 2009 UK) TRIAL CLOSURE, FINAL ANALYSIS SCREENING genetically confirmed, symptomatic CMT1A patients RANDOMIZATION ASCORBIC ACID 1,5 g/day PLACEBO 6 MONTH FOLLOW-UP* 6 MONTH FOLLOW-UP 12 MONTH FOLLOW-UP 12 MONTH FOLLOW-UP 18 MONTH FOLLOW-UP 18 MONTH FOLLOW-UP WE ARE HERE 24 MONTH FOLLOW-UP 24 MONTH FOLLOW-UP

  11. Age: mean 42.54, SD 13.13, range 18-70 yrs.

  12. CMT Neuropathy Score (CMTNS) • Composite scale (Shy et al. Neurology 2005;64:1209) • Symptoms • Sensory in legs only = 1 • Motor arms and legs =2 • Signs • Sensory, vibration and pin = 2 • Motor arms and legs = 2 • Electrophysiology • Motor and sensory amplitude ulnar or median nerve =2 Score = 0-36

  13. RELIABLE CHANGE SENSITIVE (Shy, 2008) 0.686 / year progression in CMT1A adults

  14. Trial with Ascorbic acid in CMT1A Italy-UK Basal assessment (n = 271 pts.) 0-10 mild = 26%; 11-20 moderate = 65%; >20 severe = 9%

  15. CMTNS ♂ ♀ CMTNS: mean ± SD Males 13.3 ± 4.2 Females 14.7 ± 5.0 AGE (yrs): mean ± SD 39.6 ± 12.0 44.8 ± 10.0

  16. CMTNS & age in CMT1A (n = 271) CMT-TRIAAL / CMT-TRAUK score years

  17. Maximal Voluntary Isometric Contraction (MVIC) CMT-TRIAAL & CMT-TRAUK, basal assessment (n = 271 CMT1A patients) Reliability study handgrip Foot plantar flexion 3-point pinch Foot dorsiflex 87.4 ± 42.366.3 ± 31.365.3 ± 53.3100.7 ± 64.7 MEAN VALUE ± SD (Newton)

  18. Strength (myometer) & AGE in CMT1A (n = 271) Score (N) years

  19. Activity limitation ( = Disability) • 10 meter timed walking quantitative mobility and leg function performance test= 9.16 ± 5.2 sec • 9-hole peg test (9-HPT) Time taken to place and remove all 9 pegs • Dominant side = 23.6 ± 7.4 sec • Non-dominant side = 25.3 ± 7.2 sec

  20. ONLS arm score 0-5 + leg score 0-7 = Total 0-12 Graham & Hughes JNNP 2006

  21. 40 30 Percent 20 10 0 0 1 2 3 4 5 6 ONLS (Total Score) Basal assessment: 271 CMT1A pts (AA trial)

  22. Disability & AGE in CMT1A (n = 271) CMT-TRIAAL / CMT-TRAUK score years

  23. VAS for pain 3.68 ± 3.02 cm 271 CMT1A pts. VAS for fatigue 4.87 ± 2.81 cm

  24. VAS for PAIN VAS for FATIGUE ♂ ♀ ♂ ♀

  25. PF is physical functioning, RP role-physical, BP bodily pain, GH general health, EN energy, SF social functioning, RE role-emotional, MH mental health. P values < 0.001 for all comparison except MH (P=0.80). QoL lower in CMT * * * * * * *

  26. Skin biopsy • Consenting patients Mi-Ge-Na, baseline & end of study (n = 53) • Glabrous skin (proximal falanx II finger or V finger tip) • Study: PMP22 mRNA expression (RT-PCR)

  27. CMT-TRIAAL & CMT-TRAUK: largest series ever evaluated and followed according to a standardised protocol. • CMTNS correlates with other disability & QoL outcome measures • CMTNS & other outcome measures correlate with age • No correlation of pain, fatigue, QoL (SF36) with age • Next phase evaluate responsiveness of OM

  28. Sensitivity to change (CMT1A) • CMTNS:0.686 / yr CMT1A (Shy 2008) • MCV (m/s): No or minimal change over time, no correlation with clinical severity • CMAP ampl (mV) • Median -0.141 / yr; ulnar -0.074 / yr (Shy); but also controls’ CMAP decrease over a 5-year period (Verhamme, in press) • Quality of life(SF36, RAND) does not worsen over years in CMT (adaptation?)

  29. CURRENT EVIDENCE • 3 RCT finished • >280 pts (about 190 treated) = None of endpoints reached • Some post-hoc analysis results possibly indicate some efficacy (5 pts. in Australian, CMTES in French trial) • 1 large trial just finished (272), 3 underway (about 220) Total of about 770 pts (450 treated pts, ITT) • Different dosages explored, interesting to compare

  30. Perspectives • Meta-analysis (prospective) • Biomarkers (skin biopsy) • Lessons from these trials for the future • Adequate powering & duration • Adequate primary outcome measure • CMTNS to be improved • ONLS not sensitive to change • MCV not good as primary outcome measure • Outcome measures for children

  31. Hip Knee Ankle flex Angle [°] ext ext Moment [Nm/kg] flex prod Power [W/kg] abs Gait Analysis SKIN BIOPSY MRI

  32. CMT-TRIAAL & CMT-TRAUK Groups Investigators — “C. Besta” National Neurological Institute, Milan: D. Pareyson, E. Salsano, V. Scaioli, C. Ciano, M. Rimoldi, G. Lauria, E. Rizzetto, F. Camozzi; Department of Neurology, Ophthalmology and Genetics, University of Genoa: A. Schenone, M. Grandis, E. Narciso; Department of Neurological and Visual Sciences, Section of Clinical Neurology, University of Verona: N. Rizzuto, G.M. Fabrizi, T. Cavallaro; Department of Neurological Sciences, Federico II University of Naples: L. Santoro, F. Manganelli, M. Nolano; Sacro Cuore Catholic University, Rome: L. Padua, C. Pazzaglia; Department of Medical Sciences, "Magna Graecia" University of Catanzaro: A. Quattrone, P. Valentino; Department of Neurosciences, of Psychiatric and Anesthesiologic Sciences, Messina University: G.Vita, A. Mazzeo, M. Aguenoz; Department of Neuroscience, University of Parma: F. Gemignani, F. Brindani, MRC Centre for Neuromuscular Disease

  33. Drop outs = 32 (11.8%) 9 gastrointestinal disturbances 1 gum disease 4 pregnancies 2 foot surgery 1 lumbar spine surgery 1 renal stones 1 saccharine intolerance 13 retired consent

  34. Sample size • Assumption of: improvement  0.5 in the CMTNS in participants assigned to AA, versus 1 point worsening in the placebo arm at 24 months since enrolment • 90% power, level of significance of 5% (two-tailed) = 113 participants per group to detect the above difference • postulated values of the means (standard deviations) at two years = 13.0 (6.5) for the AA group, 14.5 (6.5) for the placebo group • Assuming an attrition of 20%, at least 272 participants (136 / group) enrolled in 12 months

  35. Electrophysiology Ulnar, Median • 3 motornerves • (ulnar, median, peroneal) • 1 sensory nerve (ulnar) Peroneal CMAP, MCV, DL (fixed distance) SCV, SAP ampl orthodromic Non-dominant side

  36. Paraclinical OM • NERVE CONDUCTION VELOCITIES • CMAP AMPLITUDE • SAP AMPLITUDE • MUNE Motor Unit Number Estimation • QST Quantitative Sensory Testing • MRI • ULTRASOUNDS • GAIT ANALYSIS • BIOMARKERS - SKIN BIOPSY

  37. NIS Neuropathy Impairment Score (weakness, DTRs, sensory loss) • 1 point/year progression in 31 CMT1 patients (Dyck 1989) • 1.386 / year progression in CMT1A adults (Shy 2008) • Padua 2008, Teunissen 2003: • Progression in CMT1A and CMT2 • Quality of life does not worsen over years • CMAP (& SAP) amplitudes: correlation with impairment and disability • Axonal loss as basis of disability and disease progression • MCV no correlation with severity in CMT1A

  38. Electrophysiology (MCV, DL, CMAP ampl, SAP ampl, MUNE) • Change with age (CMT1A): • DL first to change • MCV change after 6 yrs • Change little over years • Dyck 1989 CMT1 • Killian 1996 CMT1A -2.2 (ulnar) and -3.0 (peroneal) m/s over 22 years • Shy 2008 CMT1A median nerve MCV -0.6 m/s/year; ulnar nerve 0.0 m/s/year • CMT1A do not correlate with severity; lower MCV worse prognosis (Birouk 1997, Verhamme 2004) • CMAP • Correlate with disease severity (disability) Krajewski 2000 • (not according to Birouk 1997 and Hoogendijik 1994) • MUNE • Correlation with disability in the hand (Videler, Neurology 2008)

  39. OM validated in CMT:Solari et al. 2008 • Good to excellent intra & inter-examiner reliability in 40 CMT pts of the following OM: • MVIC quantitative strength assessment (hand-held myometer) • Overall Neuropathy Limitations Scale • 10-meter timed walking • 9 hole peg test

  40. Walk-12 Activity limitations Self-administered questionnaire

  41. QUALITY OF LIFE Physical Functioning Role limitation, Phys. Bodily Pain General Health Physical Health Composite SF-36 Vitality (Energy) Role limitation, Emot. Social Functioning Mental Health Mental Health Composite

  42. Choice of the target population • Age: Adults – children? Elderly? • Diagnosis: clinical - molecular diagnosis? • Disease severity: asymptomatic pts? CMTNS: CMT-NE >0 / CMTNS <35 • Exclusion criteria: • Other causes of neuropathies • Other neurological disorders or major comorbidities • Other trials (less than 6 months?) • Pregnancy – breast feeding • Contraindications to specific drugs

  43. Overwork weakness?

  44. CMT-TRIAAL & CMT-TRAUK Groups Investigators — “C. Besta” National Neurological Institute, Milan: D. Pareyson, E. Salsano, V. Scaioli, C. Ciano, M. Rimoldi, G. Lauria, E. Rizzetto, F. Camozzi; Department of Neurology, Ophthalmology and Genetics, University of Genoa: A. Schenone, M. Grandis, E. Narciso; Department of Neurological and Visual Sciences, Section of Clinical Neurology, University of Verona: N. Rizzuto, G.M. Fabrizi, T. Cavallaro; Department of Neurological Sciences, Federico II University of Naples: L. Santoro, F. Manganelli, M. Nolano; Sacro Cuore Catholic University, Rome: L. Padua, C. Pazzaglia; Department of Medical Sciences, "Magna Graecia" University of Catanzaro: A. Quattrone, P. Valentino; Department of Neurosciences, of Psychiatric and Anesthesiologic Sciences, Messina University: G.Vita, A. Mazzeo, M. Aguenoz; Department of Neuroscience, University of Parma: F. Gemignani, F. Brindani, MRC Centre for Neuromuscular Disease

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