trial design and outcomes for inherited neuropathy studies d. pareyson irccs foundation c.besta...
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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
September 22, 2009
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
• 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
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
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 grams2 years - CMTNS
Germany, 50 childrenplacebo, 3 grams
Czech Rep. 60 patientsplacebo, 1.5 gr - CMTNS
US, 120 patients Placebo, 4 grams2 years - CMTNS
Australia, 81 children, 1 year
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
136th ENMC Workshopon CMT1A
April 8-10, 2005
International panel of experts (clinicians, neuroepidemiologist, pharmacologist, basic
researchers). Agreement on outcome measures, trial design, etc.
168th ENMC WorkshopOutcome measures and clinical trials in
CMT September 18-20, 2009
Naarden
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
MRC Centre for Neuromuscular Disease
N° patients recruited =
272
2 YEARS
Anglo-Italian study
CMT-TRIAAL &
CMT-TRAUK
MRC Centre for Neuromuscular Disease
Reliability study before
starting
SCREENINGgenetically 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 2007INTERIM ANALYSIS
(March 2009 Italy, July 2009 UK)TRIAL CLOSURE, FINAL ANALYSIS WE ARE
HERE
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
CMT neuropathy score (CMTNS) Symptoms Signs ENG
Total score
2.8 ± 1.76.1 ± 2.65.3 ± 1.7
14.2 ± 4.7
0-10 mild = 26%; 11-20 moderate = 65%; >20 severe = 9%
Trial with Ascorbic acid in CMT1A Italy-UK Basal assessment (n = 271 pts.)
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
0,00
2,00
4,00
6,00
8,00
10,00
12,00
14,00
16,00
18,00
18-29 30-39 40-49 50-59 60-70
symptomssignsENGTotal
CMTNS & age in CMT1A (n = 271) CMT-TRIAAL / CMT-TRAUK
years
score
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
0,00
20,00
40,00
60,00
80,00
100,00
120,00
18-29 30-39 40-49 50-59 60-70
grippinchplantar flexdorsiflexion
Strength (myometer) & AGE in CMT1A (n = 271)
years
Score (N)
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
01
02
03
04
0
Per
cen
t
0 1 2 3 4 5 6ONLS (Total Score)
Overall Neuropathy Limitations Scale - ONLS Arm score Leg score
Total score
1.44 ± 0.951.70 ± 0.68
3.14 ± 1.31
Basal assessment: 271 CMT1A pts (AA trial)
0,00
5,00
10,00
15,00
20,00
25,00
30,00
18-29 30-39 40-49 50-59 60-70
ONLS9HPT10MTW
years
scoreDisability & AGE in CMT1A (n = 271) CMT-TRIAAL / CMT-TRAUK
0
10
20
30
40
50
60
70
80
90
PF RP BP GH EN SF RE MH
CMT Patients
Italian Norms
SF-36 QoL questionnaire Physical Composite Score (PCS) Mental Composite Score (MCS)
42,99 ± 10,9846,02 ± 11,50
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
CMTNS tertilesVariableMean 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)
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)
• 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
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?)
Trial Number Dosage Duration
Primary endpoint
results
(Toth 12 5 gopen 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 1803 arms
1 g / 3 g 1 year CMTNS (5) No effectCMTES
Italian UK 272 1.5 g 2 years CMTNS (1.5) Data analysis underway
US 114Futility des.
4 g 2 years CMTNS Underway
Czech 60 1.5 g 2 years CMTNS Underway
German 50children
3 g 2 years Underway
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
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
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
MRI
SKIN BIOPSY
Pow
er
[W/k
g]
Hip Knee Ankle
Mom
en
t [N
m/k
g]
An
gle
[°
]
flex
ext
ext
flex
prod
abs
Gait Analysis
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
9 gastrointestinal disturbances1 gum disease 4 pregnancies2 foot surgery 1 lumbar spine surgery 1 renal stones1 saccharine intolerance
13 retired consent
Drop outs = 32 (11.8%)
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
INCLUSION CRITERIA:
1. Clinical diagnosis of CMT1A
2. Genetic confirmation (17p11.2 duplication)
3. CMT Neuropathy Score between 1 (excluding the electrophysiologicalcomponent) and 35 (including the electrophysiological component)
4. Age 18-70 years
5. Ability to accomplish the primary outcome measures
6. Women of child-bearing age only if they declare not to be pregnant or breastfeeding at the inclusion into the study and to avoid becoming pregnant during thestudy
7. Signed informed patient consent
EXCLUSION CRITERIA:
1. Clinical or echographic diagnosis of nephrolithiasis
2. Positive history of recurrent renal colics
3. One or more episodes of renal colic in the 6 months prior to screening
4. Deficit of Glucose-6P-Dehydrogenase
5. Acquired or hereditary haemochromatosis; thalassemia major; syderoblasticanaemia
6. Treatment with potential therapeutic agents for CMT1A in the three months priorto screening
7. AA consumption in the three months prior to screening
8. Other causes of neuropathy
9. Other neurological disorders, or major comorbidities
10. Limb surgery in the six months prior to screening, or planned before finalassessment
Electrophysiology
• 3 motor nerves
– (ulnar, median, peroneal)
• 1 sensory nerve (ulnar)
Ulnar, Median
Peroneal
CMAP, MCV, DL (fixed distance)SCV, SAP amplorthodromic
Non-dominant side
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
• 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
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)
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
Physical Functioning Role limitation, Phys.Bodily PainGeneral Health
Vitality (Energy)Role limitation, Emot.Social FunctioningMental Health
Physical HealthComposite
Mental HealthComposite
SF-36
QUALITY OF LIFE
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
Manual testing MRC score(271 pts.)
DOMINANT HAND
(R 94%)
NON- DOMINANT
HAND
I INTEROSSEOUS(mean SD) 3.72 ±
0.873.73 ± 0.95
ABDUCTOR POLLICIS BREVIS(mean SD)
3.80 ± 0.97
3.83 ± 0.99
Overwork weakness?
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