Trial%20design%20and%20outcomes%20for%20inherited%20neuropathy%20studies%20%20D.%20Pareyson%20%20IRCCS%20Foundation%20%20C.Besta%20Neurological%20Institute%20Milan,%20Italy%20%20MSG%20Meeting,%20Buffalo,%20NY%20September%2022,%202009 - PowerPoint PPT Presentation

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Trial%20design%20and%20outcomes%20for%20inherited%20neuropathy%20studies%20%20D.%20Pareyson%20%20IRCCS%20Foundation%20%20C.Besta%20Neurological%20Institute%20Milan,%20Italy%20%20MSG%20Meeting,%20Buffalo,%20NY%20September%2022,%202009

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Trial design and outcomes for inherited neuropathy studies D. Pareyson IRCCS Foundation C.Besta Neurological Institute Milan, Italy MSG Meeting, Buffalo, NY – PowerPoint PPT presentation

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Title: Trial%20design%20and%20outcomes%20for%20inherited%20neuropathy%20studies%20%20D.%20Pareyson%20%20IRCCS%20Foundation%20%20C.Besta%20Neurological%20Institute%20Milan,%20Italy%20%20MSG%20Meeting,%20Buffalo,%20NY%20September%2022,%202009


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
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
136th ENMC Workshop on CMT1A April 8-10, 2005
168th ENMC Workshop Outcome measures and clinical
trials in CMT September 18-20, 2009
Naarden
International panel of experts (clinicians,
neuroepidemiologist, pharmacologist, basic
researchers). Agreement on outcome measures,
trial design, etc.
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
Anglo-Italian study CMT-TRIAAL CMT-TRAUK
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
    2005641209)
  • 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.)
CMT neuropathy score (CMTNS) Symptoms Signs ENG Total score 2.8 1.7 6.1 2.6 5.3 1.7 14.2 4.7
0-10 mild 26 11-20 moderate 65 gt20 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 42.3 66.3 31.3 65.3
53.3 100.7 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
Basal assessment 271 CMT1A pts (AA trial)
Overall Neuropathy Limitations Scale - ONLS Arm score Leg score Total score 1.44 0.95 1.70 0.68 3.14 1.31
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 lt 0.001 for all comparison
except MH (P0.80).
QoL lower in CMT







SF-36 QoL questionnaire Physical Composite Score (PCS) Mental Composite Score (MCS) 42,99 10,98 46,02 11,50
26
CMTNS tertiles CMTNS tertiles CMTNS tertiles
Variable Mean value (SD) 0-11 (84 pts) 12-15 (94 pts) 16 (93 pts)
ONLS 2.09 (1.14) 3.06 (1.06) 4.16 (0.81)
T10MW (sec) 7.05 (2.89) 9.54 (6.65) 10.69 (4.67)
9HPT (sec) 20.25 (2.89) 23.60 (5.11) 27.65 (9.89)
SF36 PF RP BP GH EN SF RE MH 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) 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) 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)
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-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

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
Trial Number Dosage Duration Primary endpoint results
(Toth 12 5 g open label 2 years tolerability Poor tolerability)
Dutch 11 (12-25 yrs) 2 g 1 year MCV median nerve (10 m/s) No effect
Australian 81 children 30 mg/Kg 1 year MCV median nerve (2.5 m/s) No effect (5 outliers)
French 180 3 arms 1 g / 3 g 1 year CMTNS (5) No effect CMTES
Italian UK 272 1.5 g 2 years CMTNS (1.5) Data analysis underway
US 114 Futility des. 4 g 2 years CMTNS Underway
Czech 60 1.5 g 2 years CMTNS Underway
German 50 children 3 g 2 years Underway
31
Trial SECONDARY ENDPOINTS
Toth CMTNS, CSS, Rankin, AI, electrophysiology (4 motor 5 sensory nerves)
Dutch F lat, CMAP ampl (median n) MVIC 3-point-pinch, foot dorsiflexion INCAT SS CMTNS ODSS ADLS 9HPT 50 m timed walking
Australian FPI MVIC HHD Bruininks-Oseretsky test Functional Motor Proficiency Functional Power and endurance Walking ability (GAITRite)
French QMT handgrip, foot dorsiflexion ODSS T10MW VAS GCI-S SF36. AA assay
Italian UK MVIC handgrip, 3-point-pinch, foot dorsiflexion and plantar flexion ONLS, 9HPT, T10MW, VAS pain fatigue SF36 electrophysiology, skin biopsy AA assay pain
US presented tomorrow by Richard Lewis
Czech same as Italian-UK
German
32
CURRENT EVIDENCE
  • 3 RCT finished
  • gt280 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
SKIN BIOPSY
MRI
35
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36
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,
37
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
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
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40
Electrophysiology
Ulnar, Median
  • 3 motor nerves
  • (ulnar, median, peroneal)
  • 1 sensory nerve (ulnar)

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)
  • 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

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
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
47
Choice of the target population
  • Age Adults children? Elderly?
  • Diagnosis clinical - molecular diagnosis?
  • Disease severity asymptomatic pts? CMTNS
    CMT-NE gt0 / CMTNS lt35
  • 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?
Manual testing MRC score (271 pts.) DOMINANT HAND (R 94) NON- DOMINANT HAND
I INTEROSSEOUS (mean SD) 3.72 0.87 3.73 0.95
ABDUCTOR POLLICIS BREVIS (mean SD) 3.80 0.97 3.83 0.99
49
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,
50
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