Clinical Trial Design Considerations

SMA Type I Clinical Trial Design Considerations
Outcome measure for non ambulant patients
by: Eugenio Mercuri
Catholic University, Rome

Comments on the non ambulant phenotype
o Patients with type II SMA or type III who are not able to walk 10 M independently
o Wide variability
o Standards of care available
o Relatively stable condition within 12-18 months
o No consistent endpoint or life altering event
o Need for defining clinically meaningful changes over time in possible trials

Which outcome measures?
* most measures (timed items, 6 minute walk) not applicable to non ambulant patients with neuromuscular disorders
* muscle strength measurements have been used but are not adequate for very weak children
* Recent studies (after 2005) mainly used functional scales
Why functional scales?
* measures of function more sensitive than strength measurements in weak patients
* More clinically meaningful: patients, families and doctor do have difficulties in identifying generic increase in muscle strength if disjointed from measurements of daily life activity that “mean” something.

* Unlike other measures such as myometry or pulmonary function, functional scales can be reliably used in young children from 30 months

Which functional scales?

* There are a number of functional scales available for non ambulant patients with SMA
* In the last few years TREAT NMD and ICC have promoted a series of workshops in Europe and in the US to find a consensus on outcome measures among all the experts on outcome measures and on trials in SMA

Combined TREAT NMD/ICC
* TREAT NMD consensus further discussed with ICC representatives for outcome measures
* In a recent combined meeting in Boston (June 2008) involving both TREAT NMD and ICC representatives a more general consensus was reached for all three forms of SMA, identifying the Hammersmith Motor Functional scale as the most appropriate and specific scale for type II and more generally, for non ambulant patients

Why the Hammersmith scale?
* Disease specific (developed for and validated in non ambulant SMA children)
* Easy, little equipment,
* Short
* Not stressful for children
* Easily used in routine practice

Evidence from literature: ICC review of the literature
AMBULATORY PROBABILITIES
HAMMERSMITH FUNCTIONAL MOTOR SCALE
UPPER EXTREMITY GRADE
SMA FUNCTION RATING SCALE (SMAFRS)
SCOTT SCALE
JEBSEN TEST OF HAND FUNCTION
STANDARDIZED PROTOCOL
FUNCTIONAL MOTOR SCALE
GROSS MOTOR FUNCTION MEASURE (GMFM)
MOTOR FUNCTION MEASURE SCALE (MFM)
EXPANDED HAMMERSMITH FUNCTIONAL MOTOR SCALE
EK SCALE
Method Studies* (Cross-Sectional)
Natural History (Cross-Sectional)
Natural History (Longitudinal)
Clinical Trials
Outcome Measures
Validation studies available
Validation in
* UK (Main et al, 2003)
* Italy (Mercuri et al, 2007)
* US (PNCR data, PC SMA)
* Excellent interobserver reliability
* Very simple instructions, manual available, ideal for multicentric studies

Widely used across the world
* ICC survey on outcome measures (2008)
* ICC Survey Parameters
* Sent to International SMA Community (ICC and TREAT-NMD lists) in February, 2008
* 35 Sites responded
* 22 Countries were represented
* 858 patient exposures (estimated)
* 27 sites
o Ljubljana, Slovenia
o Ankara, TR
o Messina, IT
o Birmingham, UK
o Oswestry, UK
o Rome, Italy
o Bristol, UK
o Warsaw, Poland
o Freiburg, Germany
o Kharkiv, Ukraine
o Rio de Janeiro, Brazil
o Philadelphia, PA USA
o Boston, MA USA
o New York, NY USA
o Chicago, IL USA
o Salt Lake City, Utah USA
o Philadelphia, PA USA
o Salt Lake City, Utah USA
o Chicago, IL USA
o Sydney, Australia

Natural history data available
* 3 and 6-month data available in 110 non ambulant Italian children age 30 months 12 years
* 6, 12 and 18 month data available in 17 patients (Pediatric Neuromuscular Clinical Research Network (PNCR) .
* Similar data collected by the Project Cure SMA network
* No significant changes between baseline and any of the 6,12, 18 months assessment
* According to these data the diseases is relatively stable over 3, 6, 12 and 18 months periods with minimal changes
* Non ambulant patients generally do not have obvious increases in their scores
* Less than 10% has an increase > 2 points

Already used in trials
* Salbutamol (published)
* Phenylbutyrate (double blind) (published)
* Valproate (just completed)

Is this clinically meaningful?
* Difficult to define what is clinically meaningful
* No clear life altering events that could be predicted
* Relatively stable condition
* Quite wide variability in functional abilities and in possible improvements
What is clinically meaningful for families
* Questionnaire developed by ICC
* 91 families of children with non ambulant SMA
* Families were asked if they were happy to participate to clinical trials and what would be the reason for participating into a trial
* THE CURE!
* Stabilization of the disease over long periods of time
* Any improvement of functional activities

(short term studies)

* While in the long run stabilization would be acceptable by families, in a short trial (1 year) any improvement would be considered beneficial
Primary endpoint: Hammersmith scale
* Evidence from literature
* Validation studies
* Widely used across Europe and US
* Natural history data available
* Already used in trials on non ambulant SMA patients
Secondary measures
* Electrophysiology measure: CMAP
* QOL measure
* Caregiver assessment questionnaire
* Growth parameters
* Pulmonary Function: excellent outcome measure

Reliable, already used in clinical trials but can only be reliably performed in children above the age of 5
* Strength reliable in most patients but can only be reliably performed in children above the age of 5
Summary

Clinical Trial Design Considerations.ppt