Your SlideShare is downloading. ×
HEREDITARY NEUROPATHIES: MOLECULAR BASIS FOR DISTINCTION AND ...
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

HEREDITARY NEUROPATHIES: MOLECULAR BASIS FOR DISTINCTION AND ...

400

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
400
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
5
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. 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
  • 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. France, 180 patients placebo, 1 gram, 3 grams, 1 year - CMTNS Holland, 12 patients 12-25 yrs, MCV Italy-UK, 272 patients placebo, 1.5 grams 2 years - CMTNS Germany, 50 children placebo, 3 grams Czech Rep. 60 patients placebo, 1.5 gr - CMTNS US, 120 patients Placebo, 4 grams 2 years - 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. 136th ENMC Workshop on CMT1A April 8-10, 2005 International panel of experts (clinicians, neuroepidemiologist, pharmacologist, basic researchers). Agreement on outcome measures, trial design, etc. 168th ENMC Workshop Outcome measures and clinical trials in CMT September 18-20, 2009 Naarden
  • 8. Recommended core outcome measures
    • 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)
    136th, 2005
  • 9. N° patients recruited = 272 2 YEARS Anglo-Italian study CMT-TRI AA L & CMT-TRAUK Reliability study before starting MRC Centre for Neuromuscular Disease MRC Centre for Neuromuscular Disease
  • 10. SCREENING genetically confirmed, symptomatic CMT1A patients RANDOMIZATION ASCORBIC ACID 1,5 g/day PLACEBO 6 MONTH FOLLOW-UP* 12 MONTH FOLLOW-UP 18 MONTH FOLLOW-UP 24 MONTH FOLLOW-UP 6 MONTH FOLLOW-UP 12 MONTH FOLLOW-UP 18 MONTH FOLLOW-UP 24 MONTH FOLLOW-UP January 2006 : FIRST PATIENT SCREENED March 2006 - March 2007 December 2007 INTERIM ANALYSIS (March 2009 Italy, July 2009 UK) TRIAL CLOSURE, FINAL ANALYSIS WE ARE HERE
  • 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. 0-10 mild = 26%; 11-20 moderate = 65%; >20 severe = 9% Trial with Ascorbic acid in CMT1A Italy-UK Basal assessment (n = 271 pts.) 2.8 ± 1.7 6.1 ± 2.6 5.3 ± 1.7 14.2 ± 4.7 CMT neuropathy score (CMTNS) Symptoms Signs ENG Total score
  • 15. 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 ♂ ♀ CMTNS
  • 16. CMTNS & age in CMT1A (n = 271) CMT-TRIAAL / CMT-TRAUK years score
  • 17. handgrip 3-point pinch Foot plantar flexion Maximal Voluntary Isometric Contraction (MVIC) CMT-TRIAAL & CMT-TRAUK, basal assessment (n = 271 CMT1A patients) Foot dorsiflex 87.4 ± 42.3 66.3 ± 31.3 65.3 ± 53.3 100.7 ± 64.7 MEAN VALUE ± SD (Newton) Reliability study
  • 18. Strength (myometer) & AGE in CMT1A (n = 271) years Score (N)
  • 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. Basal assessment: 271 CMT1A pts (AA trial) 0 10 20 30 40 Percent 0 1 2 3 4 5 6 ONLS (Total Score) 1.44 ± 0.95 1.70 ± 0.68 3.14 ± 1.31 Overall Neuropathy Limitations Scale - ONLS Arm score Leg score Total score
  • 22. years score Disability & AGE in CMT1A (n = 271) CMT-TRIAAL / CMT-TRAUK
  • 23. VAS for pain 3.68 ± 3.02 cm 4.87 ± 2.81 cm VAS for fatigue 271 CMT1A pts.
  • 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 42,99 ± 10,98 46,02 ± 11,50 SF-36 QoL questionnaire Physical Composite Score (PCS) Mental Composite Score (MCS)
  • 26. 42.44 (21.79) 41.19 (40.18) 53.45 (26.71) 52.13 (21.57) 43.93 (21.63) 64.01 (24.42) 50.75 (44.05) 64.07 (19.82) 68.20 (23.30) 66.21 (38.33) 67.97 (28.18) 56.37 (22.52) 55.53 (22.18) 74.46 (24.58) 70.21 (39.85) 68.12 (20.74) 75.91 (18.93) 72.02 (34.36) 69.01 (23.48) 61.39 (20.19) 54.75 (18.40) 76.93 (23.88) 68.65 (38.84) 68.68 (16.54) SF36 PF* RP* BP* GH* EN SF* RE MH 27.65 (9.89) 23.60 (5.11) 20.25 (2.89) 9HPT * (sec) 10.69 (4.67) 9.54 (6.65) 7.05 (2.89) T10MW * (sec) 4.16 (0.81) 3.06 (1.06) 2.09 (1.14) ONLS * ≥ 16 (93 pts) 12-15 (94 pts) 0-11 (84 pts) Variable Mean value (SD) CMTNS tertiles
  • 27. 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)
  • 28.
    • CMT-TRI AA L & 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
  • 29. 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?)
  • 30. No effect MCV median nerve (10 m/s) 1 year 2 g 11 (12-25 yrs) Dutch results Primary endpoint Duration Dosage Number Trial Underway 2 years 3 g 50 children German Underway CMTNS 2 years 1.5 g 60 Czech Underway CMTNS 2 years 4 g 114 Futility des. US Data analysis underway CMTNS (1.5) 2 years 1.5 g 272 Italian UK No effect CMTES CMTNS (5) 1 year 1 g / 3 g 180 3 arms French No effect (5 outliers) MCV median nerve (2.5 m/s) 1 year 30 mg/Kg 81 children Australian Poor tolerability) tolerability 2 years 5 g open label 12 (Toth
  • 31. F lat, CMAP ampl (median n); MVIC 3-point-pinch, foot dorsiflexion; INCAT SS; CMTNS; ODSS ; ADLS; 9HPT ; 50 m timed walking Dutch SECONDARY ENDPOINTS Trial German same as Italian-UK Czech presented tomorrow by Richard Lewis US MVIC handgrip, 3-point-pinch, foot dorsiflexion and plantar flexion; ONLS , 9HPT, T10MW, VAS pain fatigue; SF36 ; electrophysiology, skin biopsy; AA assay; pain Italian UK QMT handgrip, foot dorsiflexion; ODSS; T10MW; VAS ; GCI-S; SF36 . AA assay French FPI; MVIC HHD ; Bruininks-Oseretsky test Functional Motor Proficiency; Functional Power and endurance; Walking ability (GAITRite) Australian CMTNS, CSS, Rankin, AI, electrophysiology (4 motor & 5 sensory nerves) Toth
  • 32. 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
  • 33. 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
  • 34. Gait Analysis MRI SKIN BIOPSY Power [W/kg] Hip Knee Ankle Moment [Nm/kg] Angle [°] flex ext ext flex prod abs
  • 35.  
  • 36. CMT-TRI AA L & 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, &quot;Magna Graecia&quot; 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
  • 37. 9 gastrointestinal disturbances 1 gum disease 4 pregnancies 2 foot surgery 1 lumbar spine surgery 1 renal stones 1 saccharine intolerance 13 retired consent Drop outs = 32 (11.8%)
  • 38. 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
  • 39.  
  • 40. Electrophysiology
    • 3 motor nerves
      • (ulnar, median, peroneal)
    • 1 sensory nerve (ulnar)
    Ulnar, Median Peroneal CMAP, MCV, DL (fixed distance) SCV, SAP ampl orthodromic Non-dominant side
  • 41. 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
  • 42.
    • 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)
    • CMAP (& SAP) amplitudes: correlation with impairment and disability
      • Axonal loss as basis of disability and disease progression
      • MCV no correlation with severity in CMT1A
    • Padua 2008, Teunissen 2003:
      • Progression in CMT1A and CMT2
      • Quality of life does not worsen over years
  • 43. 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)
  • 44. 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
  • 45. Walk-12 Activity limitations Self-administered questionnaire
  • 46. Physical Functioning Role limitation, Phys. Bodily Pain General Health Vitality (Energy) Role limitation, Emot. Social Functioning Mental Health Physical Health Composite Mental Health Composite SF-36 QUALITY OF LIFE
  • 47. 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
  • 48. Overwork weakness? 3.83 ± 0.99 3.80 ± 0.97 ABDUCTOR POLLICIS BREVIS (mean SD) 3.73 ± 0.95 3.72 ± 0.87 I INTEROSSEOUS (mean SD) NON- DOMINANT HAND DOMINANT HAND (R 94%) Manual testing MRC score (271 pts.)
  • 49. CMT-TRI AA L & 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, &quot;Magna Graecia&quot; 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
  • 50.  

×