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

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

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

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

RELIABLE

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

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

ONLS

arm score 0-5+

leg score 0-7=

Total 0-12

Graham & Hughes JNNP

2006

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

VAS for pain3.68 ± 3.02 cm

4.87 ± 2.81 cmVAS for fatigue

271 CMT1A pts.

02

46

810

vasd

olor

e0

1 2

VAS for PAIN

♂ ♀

02

46

810

vasf

atica

01 2

VAS for FATIGUE

♂ ♀

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

Walk-12

Activity limitations

Self-administered questionnaire

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