1 / 50

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

benjy
Download Presentation

Disclosures

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related