Care standards for Duchenne patients based on international consensus One day workshop supported by CARE-NMD Consortium One day workshop supported by CARE NMD Consortium Outcome measures in DMD Enrico Bertini MD Pediatric Neurologist Pediatric Neurologist, Unit of Neuromuscular and Neurodegenerative Disorders Laboratory of Molecular Medicine Dep.t of Neurosciences Children's Research Hospital "Bambino Gesú”, Rome, Italy [email protected]
Transcript
Care standards for Duchenne patients based on international consensus One day workshop supported by CARE-NMD ConsortiumOne day workshop supported by CARE NMD Consortium
Outcome measures in DMD
Enrico Bertini MDPediatric NeurologistPediatric Neurologist, Unit of Neuromuscular and Neurodegenerative DisordersLaboratory of Molecular MedicineDep.t of NeurosciencespChildren's Research Hospital "Bambino Gesú”, Rome, [email protected]
2 5 4 2.5- 4 y• Frequent falls
Difficulty in climbing stairs and
• Beyond age 7 5 y
climbing stairs and run
• After 5 y: Beyond age 7.5 y increasing walking difficulties
After 5 y: increasing walking difficulties
• Loss of walking ability : mean age
• Loss of walking ability: mean age ability mean age
• Lenghthening of time for appearance of respiratory
d di i l card ac death 0
mortality rate
• Two decades ago no DMA
and cardiac involvement.
Two decades ago no DMA patient survived beyond the age of 18-20 years
Cooperative International Neuromuscular Research Group (CINRG) founded in 1999 The CINRG Coordinating Center is currently located at the Children's National Medical Center in Washington, DCA multi-disciplinary and cross-institutional network of clinicians and scientists with the shared goal of wanting to positivelyimpact the lives of neuromuscular disorder patients and their families.
Participating sites in the CINRG Network
p pToday, CINRG is a global, state-of-the-art 24 site clinical research network that has conducted many studies and has access to over 4,000 neuromuscular patients.
Strength TestingSt e gt est gA multi-disciplinary and cross-institutional network of clinicians and scientists with the shared goal of wanting to positively impact the lives of neuromuscular disorder patients and their families. Today, CINRG is a global, state-of-the-art 24 site clinical research network that has conducted many studies and has access to over4 000 l ti t Th i l f CINRG i t t d th ( ) th i d li i l t f l
Quantitative Muscle Testing (QMT)• Age 5 and up - as able
4,000 neuromuscular patients. The primary goal of CINRG is to study the cause(s), pathogenesis and clinical outcomes of neuromuscular disorders and to conduct well-controlled clinical studies that examine promising, therapeutic interventions that may improve quality of life or extend life for patients.
• Age 5 and up - as able• Test knee and elbow flexors and extensors
and hand grip • For non-ambulatory participants, only hand
i i f dgrip is performed.
Manual Muscle Testing (MMT)• Age 5 and up as able (test introduced at• Age 5 and up - as able (test introduced at
age 4)• MMT performed on 34 muscles (as
described by Brooke)
Goniometry • Non-ambulant only measures elbow
extensionextension
Strength H d h ld Q tit ti M tHand held or Quatitative Myometry
EMEA W k h DMDEMEA Workshop on DMDTREAT-NMD
London, September 25, 2009
• Measures must be statistically robust but should f f falways reflect clinically meaningful changes for
the patients and their caregivers
• Cure the patient and not the test!
Objectives of outcome measure development
• Selection of measures
• Promoting natural history data
• Improving methods of analysis
• Identification of new clinical measures
• Identification of non clinical measures
List of measures in DMDList of measures in DMD• 6 minute Walk Test (6MWT)
• North Star Ambulatory Assessment (NSAA)y ( )
• Motor Function Measure (MFM)
• Timed Tests (TTs)
• Hand held or Quatitative MyometryHand held or Quatitative Myometry
• Upper limbs scale
• PEDsQoL
Importance of experience with th lti t i t i l PTCthe multicentric trial PTC
DMDDMD• 6 MWT is a reliable and sensitive measure• 6 MWT is a reliable and sensitive measure
• Time test are reliable• Time test are reliable
• Activity monitoring is useless• Activity monitoring is useless
• Hand held myometry correlates• Hand held myometry correlates
6 minutes walk test in DMD (PTC study)
• 6 minute walk test• Measure of endurance and fatigabilityMeasure of endurance and fatigability• Measure the distance covered along a
fix turn of 20-25 metres in 6 minutes
Validated in the PTC t i l DMDPTC trial on DMD
Regulatory, Disease, and Feasibility Considerations Supported Use of the 6-Minute Walk Test (6MWT) as the Primary Outcome Measure
• Progressive loss of walking ability is a critical g g yfunctional concern in DBMD
• Stabilizing or slowing the decline of walking bilit ld t li i ll i f lability would represent a clinically meaningful
benefit for boys with DBMD • The 6MWT is accepted by regulatoryer
s→
• The 6MWT is accepted by regulatory authorities and has been responsive to therapy in other neuromuscular disorders
←25
met
e
• 6MWT results are sufficiently reproducible and discerning to use in a controlled clinical study Short term observational data indicated that the
←
• Short-term observational data indicated that the 6MWT is feasible and reliable in boys with DBMD*
McDonald et al, Muscle & Nerve, 2010, April
Statistics Were Based on 6MWD Data from the Observational Study in DBMD and from Studies inObservational Study in DBMD and from Studies in
Other Disorders*• Hypothesis
– Mean change in 6MWD over 48 weeks will be 30 m longer in at least one of the ataluren treatment arms than in the placebo armleast one of the ataluren treatment arms than in the placebo arm
– Variability (standard deviation) of change in 6MWD will be 50 m
• Calculations and assumptionsp– Power ≥85%– 2-sided significance level = 0.05– Estimated 10% premature discontinuation rate
• Planned sample size– 165 total (55 per treatment arm)
* McDonald et al, Muscle & Nerve, 2010, April
The Study Was Well Conducted and Patients Were Evenly Distributed Across the Treatment Arms by Stratification Factorsy
The study was well conducted
• Only 1 patient discontinued prematurelyOnly 1 patient discontinued prematurely
• Missing data were few
Compliance to study drug was >97%
Stratification FactorPlacebo
N=57Low Dose
N=57High Dose
N=60
Age group<9 y 56% 56% 57%
≥9 y 44% 44% 43%≥9 y 44% 44% 43%
Corticosteroid useYes 70% 72% 72%
No 30% 28% 28%No 30% 28% 28%
6MWD≥350 m 60% 56% 55%
<350 m 40% 44% 45%
6MWD, median Range
354 m159-533 m
362 m75-525 m
368 m90-554 m
Estimated Treatment Effect of 30 Meters Is Consistent with Those Observed in Registration Trials of Other Drugs in OtherThose Observed in Registration Trials of Other Drugs in Other
Indications
Drug IndicationTherapy Duration
Mean Baseline
Mean Δ6MWDDifference (SD*)Drug Indication Duration,
wksBaseline 6MWD, m
Difference (SD )Relative to Placebo
0Tracleer(bosentan)
10 pulmonary HTN 16 335 44 (NA)
Aldurazyme MPS I 26 344 38 (68)Aldurazyme(laronidase) MPS I 26 344 38 (68)
Elaprase(id lf ) MPS II 52 395 30 (61)(idursulfase) MPS II 52 395 30 (61)
* SD is standard deviation of change from baseline to the final assessment
The 6MWD Range and Associated Variability of Change From Baseline Increased Over Time
250
300
Change From Baseline Increased Over Time
250
300
100
150
200
150
200
250
0
50
100
MW
D (m
)
0
50
100
MW
D (m
)
-150
-100
-50
hang
e in
6
150
-100
-50
ange
in 6
M
-250
-200
150
Placebo (N=57)
Ch
-250
-200
-150
Pl b (N 57)
Cha
6 12 18 24 30 36 42 48-400
-350
-300
33 41 53 64 67 71 87 90SD
Placebo (N 57)
-400
-350
-300
33 41 53 64 67 71 87 90SD
Placebo (N=57)
6 12 18 24 30 36 42 48Time, weeks
6 12 18 24 30 36 42 48400
Time, weeks
North Star Ambulatory Assessment (NSAA)(NSAA)
Thirteen Italian centers participated in the study
Timed itemsTimed items
• 10 meter timed walk/run
• Time to rise from the floor or Gower’s test
Cross correlation of outcome meauresCross correlation of outcome meaures
North Star 6MTW
25
50
unit
250
500
750
1000
met
ers
5.0 7.5 10.0 12.5 15.0 17.50
Age (years)
5.0 7.5 10.0 12.5 15.0 17.50
Age (years)
Upper limbs scaleUpper limbs scale
In other scales items for upper limbs are available but most items are In other scales items for upper limbs are available but most items are age dependent and have been validated in children above 5 years age dependent and have been validated in children above 5 years
MyometryMyometry has been proved to successfully test children with SMA II > 5 years has been proved to successfully test children with SMA II > 5 years but it is not the ideal tool in very weak patientsbut it is not the ideal tool in very weak patients
Egen Klassifikation Scale Version 2 (EK2)
Steffensen 2008
Name DOBDate of assessment Date of spinal surgery Assessor ( please circle)NOTE: *Score the best you have done in the last two weeks especially if there is variation between good and bad days
1 Ability to use wheelchair How do you get around indoors and outdoors? N/AAble to use a manual wheelchair on flat ground, 10m < 1 minute 0Able to use a manual wheelchair on flat ground, 10m > 1 minute 1Unable to use manual wheelchair, requires power wheelchair 2Uses power wheelchair, but occasionally has difficulty steering 3
2 Ability to transfer from wheelchair How do you transfer from your wheelchair to a bed? N/AAble to transfer from wheelchair without help 0Able to transfer independently from wheelchair with use of aid 1Able to transfer independently from wheelchair, with use of aid 1Needs assistance to transfer with or without additional aids (hoist, easy glide) 2Needs to be lifted with support of head when transferring from wheelchair 3
3 Ability to stand Do you sometimes stand? How do you do this? N/AAble to stand with knees supported, as when using braces 0Able to stand with knees and hips supported, as when using standing aids 1Able to stand with full body support 2Unable to be stood 3
4 Ability to balance in the wheelchair Can you bend forwards and to the sides and return to the upright position? N/A4 Ability to balance in the wheelchair Can you bend forwards and to the sides and return to the upright position? N/AAble to push himself upright from complete forward flexion by pushing up with hands 0Able to move the upper part of the body > 30 in all directions from the upright position, but cannot push himself upright as above 1Able to move the upper part of the body < 30 from one side to the other 2Unable to change position of the upper part of the body, cannot sit without total support of the trunk and head 3
5 Ability to move the arms Can you move your fingers, hands and arms against gravity? N/AAble to raise the arms above the head with or without compensatory movements 0Unable to lift the arms above the head, but able to raise the forearms against gravity, ie. hand to mouth with / without elbow support 1Unable to lift the forearms against gravity but able to use the hands against gravity when the forearm is supported 2Unable to lift the forearms against gravity, but able to use the hands against gravity when the forearm is supported 2Unable to move the hands against gravity but able to use the fingers 3
6 Ability to use the hands and arms for eating Can you describe how you eat? N/AAble to eat and drink without elbow support 0Eats or drinks with support at elbow 1Eats and drinks with elbow support; with reinforcement of the opposite hand +or – aids 2Has to be fed 3
7 Ability to turn in bed How do you turn in bed during the night? N/AAble to turn himself in bed with bedclothes 0Able to turn himself in bed with bedclothes 0Needs some help to turn in bed or can turn in some directions 1Unable to turn himself in bed. Has to be turned 0 - 3 times during the night 2Unable to turn himself in bed. Has to be turned > 4 times during the night 3
8 Ability to cough How do you cough when you have to? N/AAble to cough effectively 0Has difficulty to cough and sometimes needs manual reinforcement. Able to clear throat 1Always needs help with coughing. Only possible to cough in certain positions 2Unable to cough Needs suction and/or hyperventilation techniques or IPPB in order to keep airways clear 3Unable to cough, Needs suction and/or hyperventilation techniques or IPPB in order to keep airways clear 3
9 Ability to speak Can you speak so that what you say can be understood if you sit at the back of a large room? N/APowerful speech. Able to sing and speak loudly 0Speaks normally, but cannot raise his voice 1Speaks with quiet voice and needs a breath after 3 to 5 words 2Speech is difficult to understand except to close relatives 3
10 Physical well-being (This relates to respiratory insufficiency only – see manual) N/ANo complaints, feels good 0Easily tires. Has difficulty resting in a chair or in bed 1Has loss of weight, loss of appetite, Scared of falling asleep at night, sleeps badly 2g , pp , g p g , p yExperience additional symptoms: change of mood, stomach ache, palpitations, perspiring, 3
11 Daytime fatigue Do you have to organise your day or take a rest to avoid getting too tired? N/ADoesn’t get tired during day 0Need to limit activity to avoid getting too tired 1Need to limit my activity and have a rest period to avoid getting too tired 2Get tired during day even if I rest and limit activity 3
12 Head Control How much head support do you need in your wheelchair? N/ADoes not need head support 0Does not need head support 0Needs head support when going up and down slope (15° standard ramp) 1Needs head support when driving wheelchair 2When sitting still in a wheelchair needs head support 3
13 Ability to control Joystick What kind of joystick do you use to control your chair? N/AUses a standard joystick without special adaptation 0Uses an adapted joystick or has adjusted wheelchair in order to use joystick 1Uses other techniques for steering than joystick such as blowing sucking systems or scanned driving 2Unable to operate wheelchair Needs another person to operate it 3Unable to operate wheelchair. Needs another person to operate it 3
14 Food Textures Do you have to modify your food in any way in order to eat it? N/AEats all textures of food 0Eats cut up / chunky food or avoids hard/chewy foods 1Eats minced/ pureed food with supplementation as required 2Main intake consists of being tube fed 3
15 Eating a meal (with or without assistance) How long does it take to complete a meal? N/AAble to consume a whole meal in the same time as others sharing the meal 0gAble to consume a whole meal in the same time as others only with encouragement or needs some additional time (approx 10 min) 1Able to consume a whole meal but requires substantially more time compared to others eating the same meal (15 m or more extra) 2Unable to consume a whole meal 3
16 Swallowing Do you ever have problems with swallowing? N/ANever has problems when swallowing and never chokes on food/drink, 0May experience occasional (less than once a month) problems swallowing certain types of food or occasionally chokes 1Has regular trouble swallowing food/drink or chokes on food/drink (more than once a month) 2Has trouble swallowing saliva or secretions 3Has trouble swallowing saliva or secretions 3
17 Hand function Which of these activities can you do? N/ACan unscrew the lid of a water of fizzy drink bottle and break the seal 0Can write two lines or use computer keyboard 1Can write signature or send text or use remote control 2Cannot use hands 3
TOTAL SCORE / 51Comments Any comments including lack of clarity, difficulty scoring etc. E.g. Relating to age – reasons any items were not applicable (N/A) or Swallowing – Perhaps reasons swallowing was a problem or when or how often.
Surgery please record date and type of surgeryDate of starting assisted ventilation and type HeightWeightFVCFVC%FVC%Brooke score
Applied in heathy children as early as 30 to 48 months with a full scoreof 18
EQUIPMENT NEEDED:EQUIPMENT NEEDED: -Adjustable table top to fit-Adjustable table top to fit
individual being tested-Paper with drawn 2 circles 10
cm apartcm apart-Pen-Coin (1 ∈)-Weights: 500 gr sand weight 2-Weights: 500 gr sand weight, 2
x 100gr and 1 x 50 gr in plastic pouch
-Fabric pouch to hold weightsFabric pouch to hold weights- Plastic cup- 33cl can with small diameter/2
handled non spill cupa d ed o sp cup- Light with button- Plastic snaps/fasteners on
fabric
Item #1 COMPLETE THE PATHItem #1 COMPLETE THE PATH
0 Unable to0 Unable to complete the path
1 Able to complete the pathcomplete the path but needs to stop or raises pen fromor raises pen from paper
2 Able to complete the pathcomplete the path without stops
Item #2 MOVE WEIGHT :Item #2 MOVE WEIGHT :
0 Unable to moveweightweight
1 Abl t lift d1 Able to lift andmove 250 grweight for 10 cmweight for 10 cm
2 Abl t lift d2 Able to lift andmove 500 grweight for 10 cmweight for 10 cm
Item #3 BRING COIN TO CUP ON TABLE :
0 Unable to bring0 Unable to bring coin
1 Able to bring coin to cup lying horizontally
2 Able to bring2 Able to bring coin into cup placed verticallyplaced vertically
Item # 4 BRING COIN/100 gr WEIGHT TO LIFTED CUP
0 Unable tobring coin to cup
1 Able to bring1 Able to bringcoin into cup
2 Able to bringi ht i tweight into cup
Item #5 LIFT CAN TO MOUTH :Item #5 LIFT CAN TO MOUTH :
0 Unable to lift can to mouth
1 Able to lift can to mouth with 2 hands
2 Able to lift can to mouth with 1 hand
Item #6 BRING ELBOWS TO SHOULDER HEIGHT FROM TABLE
0 Unable to lift0 Unable to liftelbows atshoulder heightshoulder height
1 Able to lift elbowsat shoulder height
2 Able to lift elbows2 Able to lift elbows45° aboveshouldershoulder
Item #7 BRING WEIGHT FROM LAP TO SHOULDER LEVEL
0 Unable to lift weight0 Unable to lift weightfrom thighs to elbowheightheight
1 Able to lift weight from1 Able to lift weight fromthighs in front to elbowheight at wrist length(on table)
2 Able to lift weight fromthighs in front atshoulder height andshoulder height andwrist length
Item #8 open ziploc:Item #8 open ziploc:
0 Unable to open
S bj t t bili th lid ith h d i t b d1 Subject stabilizes the lid with one hand or against bodyand pries lid off with other hand
S bj t t bili th lid ith h d b t t i t2 Subject stabilizes the lid with one hand but not againstbody and pries lid off with other hand
Item #9 PUSH BUTTON :Item #9 PUSH BUTTON :
0 Unable to light the0 Unable to light thebutton or uses 2hands
1 Able to light thegbuttonmomentarily with1 h d1 hand
2 Abl t li ht th2 Able to light thebutton permanentlywith 1 handwith 1 hand
Summary O t A b l t DMDOutcome measures Ambulant DMD
PREVIOSULY VALIDATED
NATURAL HISTORY LONGITUDINAL DATA
PREVIOUSLY USED IN CLINICAL TRIALS
NEW METHODS OF ANALYSIS:
6MWT YES Not in DMD PTC 124;
AN
T
6MWT YES Not in DMD Italian data for 12 months available
PTC 124;
GSK ex51
North Star YES, UK ITALY Yes, UK, Italy GSK ex51 Rasch
AM
BU
LA MFM YES, F yes Data available forRasch
MYOMETRY YES
SAM YES no PTC 124A SAM YES no PTC 124
PEDSQL (NM) Yes No No
Summary Outcome measures non Ambulant DMD
PREVIOSULY VALIDATED
NATURAL HISTORY LONGITUDINAL DATA
PREVIOUSLY USED IN CLINICAL TRIALS
NEW METHODS OF ANALYSIS:
U li b Yes Not in DMD no
AN
T
Upper limb module
Yes Not in DMD no
MFM No No no no
AM
BU
LA MYOMETRY No yes no
EK scale YES YES no
Moviplate no no noiMoviplate no no noi
9 Hole Peg Test no No No
Identification of new clinical measuresIdentification of new clinical measures
Need to address DMD patients at early ages(between age 2-5 years)(between age 2-5 years)
•Analysis of Griffith scale for DMD children
Development of Moviplate
MRI/MRS as Outcome measures
New tools for assessing upper limbs: moviplate
Upper limbs?Upper limbs?
MFM EK scale
Jebsen scale9 hole pegs
Upper limb moduleMoviplate
Transforming Rating Scales Raw data (top row) to interval data (bottomRaw data (top row) to interval data (bottom
