Transcript A randomised controlled trial to evaluate the clinical

Spasticity and the Botulinum Toxin for the
Upper Limb after Stroke (BoTULS) trial
Helen Rodgers
Professor of Stroke Care
Spasticity
Upper limb spasticity is a significant problem post stroke.
www.wemove.com
Spasticity
• But what is spasticity….?
• Narrow definition: “velocity dependent increase in stretch
reflexes”
• Wider definition including:
– Spasticity as above
– Spastic dystonia
– Co-contraction
– Hyperreflexia/clonus
– Spasms
– Associated reactions
What we recognise
clinically
“disordered sensorimotor control, resulting from an upper motor
neurone lesion, presenting as intermittent or sustained
involuntary activation of muscles”
Problems caused by spasticity
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Deformity
Pain
Spasms
‘Passive’ functional limitations (e.g. hand
hygiene, dressing a sleeve)
• ‘Active’ functional limitations (e.g reaching
and grasping)
Treatment of spasticity
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Removal of exacerbating factors eg pain
Oral medication eg baclofen
Intrathecal medication (baclofen, phenol)
Phenol nerve blocks
Physical therapy
Botulinum toxin
Botulinum toxin
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Protein produced by bacteria Clostridium botulinum
Causes botulism….
But used therapeutically since 1970’s
Temporarily blocks neuromuscular transmission
Injection weakens muscles
Developed as a treatment for conditions with “overactive
muscles”
– Squints, dystonias, spasticity
– Cosmetic uses: wrinkles
Botulinum toxin mechanism of action
2
1
4
3
5
De Paiva A et al, Functional repair of
motor endplates after botulinum
neurotoxin type A poisoning, Proc
Natl Acad Sci USA, 16;96(6):3200-5,
1999
Botulinum toxin for upper limb spasticity
post stroke
• First used 1989 in observational study - encouraging results
• Since then,15 published RCTs (prior to BoTULS)
• RCTs of varying methodological quality and size
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Unclear randomisation processes
Unclear blinding processes
Unclear if groups differed only in respect to botulinum toxin injections
Unclear if intention to treat analyses carried out
Often no power calculations
Smallest n = 15, largest n = 126
• Plus, variable inclusion criteria, botulinum toxin injection patterns
and dosage, outcome measures, follow up times.
Measurement in rehabilitation research
•
Need to measure functional limitation (and quality of life) as well
as impairment (e.g. Spasticity)
1. Measurement of spasticity – “overactive muscles”
Traditionally by Modified Ashworth Scale – but measures biomechanical
changes as well as spasticity. And, this scale only validated at elbow
0
1
1+
2
3
4
No increase in muscle tone
Slight increase in muscle tone, manifested by a catch and
release or by minimal resistance at the end of the range of
motion when the affected part(s) is moved in flexion or extension
Slight increase in muscle tone, manifested by a catch, followed
by minimal resistance throughout the remainder (less than half)
of the range of movement (ROM)
More marked increase in muscle tone through most of the ROM,
but affected part(s) easily moved
Considerable increase in muscle tone, passive movement
difficult
Affected part(s) rigid in flexion or extension
Measurement in rehabilitation research
2. Measurement of functional limitation
i. Global ADL scales – but lack sensitivity to focal changes
Barthel Index
Measurement in rehabilitation research
2. Measurement of functional limitation
ii. “Laboratory” like scales – but lack information about “real world” limitation
Action
Research Arm
Test (ARAT)
iii. Scales believed to capture “real world” limitation
Botulinum toxin for upper limb spasticity
post stroke: results of previous RCTs
• All show spasticity (muscle tone on Modified
Ashworth Scale…) decreases after botulinum
toxin injection
Botulinum toxin for upper limb spasticity post
stroke: results of previous RCTs
Functional limitation assessed in different ways:
i. 4 trials analysed specific basic functional tasks and all showed
improvement – “passive function”
• opening hand to clean palm
• opening hand to cut fingernails
• placing arm down a sleeve
ii. 6 trials used a scale to report physician and/or patient “global
assessment of benefit” and all showed improvement
iii. a variety of tools to assess “active function” and global ADL were
used but inconsistent results seen – only 1 trial showed
improvement
Botulinum toxin for upper limb spasticity post
stroke: results of previous RCTs
• No improvements in quality of life
• Only 2 trials have evaluated repeated botulinum toxin
injections showing spasticity decreases
• No trial has standardised “other rehabilitation treatments”
Botulinum toxin for upper limb spasticity
post stroke: results of previous RCTs
• Only strong evidence from previous trials is that
botulinum toxin can produce short term
decrease in spasticity
BoTULS
Botulinum Toxin for the
Upper Limb after Stroke
Primary objective
To compare the upper limb (UL) function of
participants with spasticity due to stroke who
receive:
• botulinum toxin injection(s) plus an UL therapy
programme (intervention group)
• UL therapy programme alone (control group)
One month after study entry.
Primary outcome measure:
Action Research Arm Test
Grasp
Grip
Pinch
Gross
movements
Secondary objectives
• To evaluate impairment (1, 3, 12 months):
1. Muscle tone (spasticity)
0
1
1+
2
3
4
No increase in muscle tone
Slight increase in muscle tone, manifested by a catch and release or by
minimal resistance at the end of the range of motion when the affected
part(s) is moved in flexion or extension
Slight increase in muscle tone, manifested by a catch, followed by minimal
resistance throughout the remainder (less than half) of the range of
movement (ROM)
More marked increase in muscle tone through most of the ROM, but
affected part(s) easily moved
Considerable increase in muscle tone, passive movement difficult
Affected part(s) rigid in flexion or extension
3. Arm strength: Motricity Index
2. Grip strength
Secondary objectives
• To evaluate functional limitation (1, 3, 12):
2. Dexterity: Nine hole peg test
4. Barthel ADL Index
3. Basic arm activities
How difficult has it been for you
to perform the following tasks?
No
difficulty
Little
difficulty
Moderate
difficulty
A great
deal of
difficulty
Unable to
perform
activity
a. Put your affected arm through the
sleeve of a garment
5
4
3
2
1
b. Open the hand of your affected
limb for cleaning your palm
5
4
3
2
1
c. Open the hand of your affected
limb for cutting your fingernails
5
4
3
2
1
d. Use cutlery with your affected
hand
5
4
3
2
1
Secondary objectives
• To evaluate quality of life/participation
restriction (1, 3, 12 months):
– Euroqol EQ-5D
– Stroke Impact Scale
– Oxford Handicap Scale
– Pain
Methods
Multicentre RCT (ran July 05-June 08)
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North Tyneside
Wansbeck
Hexham
Newcastle
Sunderland
Gateshead
South Tyneside
Durham
Carlisle
Bishop Auckland
Hartlepool/North Tees
Study flowchart
Target population
Adults with upper limb spasticity and reduced upper limb function due to
stroke > 1 month previously
Screening assessment
Baseline assessment
CENTRAL RANDOMISATION
Website
Study flowchart
INTERVENTION
Botulinum toxin + 4 week upper limb therapy
programme (one hour twice per week provided
by study therapist)
CONTROL
4 week upper limb therapy programme
(one hour twice per week provided by study
therapist)
1 month
Blinded assessment: outcome measures
3 month
Blinded assessment: outcome measures
Clinical assessment by study therapist. If required:
I : further botulinum toxin and UL therapy. C: further UL therapy
6 month and 9 month
Clinical assessment by study therapist. If required:
I : further botulinum toxin and UL therapy. C: further UL therapy
12 month
Blinded assessment: outcome measures
Clinical assessment by study therapist. If further spasticity treatment
required, refer to local services or regional spasticity clinic
Trial treatments: botulinum toxin
• Injected according to spasticity pattern
• Commonly chosen muscles:
– Hand – FDS, FDP, FPL
– Wrist – FCR, FCU
– Elbow – biceps, brachioradialis
– Shoulder – pec major
Trial treatments: therapy
What is the clinical effect and cost-effectiveness of treating upper limb spasticity
due to stroke with botulinum toxin?
What is the clinical effect and cost-effectiveness of treating upper limb
spasticity due to stroke with botulinum toxin?
HTA
UPPER LIMB THERAPY PROGRAMME One
• Menu 1: ARAT 0-3.
Stretching, passive and
active assisted upper limb
movement, hygiene and
positioning
• Menu 2: ARAT 4-56.
Stretching, intensive task
orientated practice
• 1 hour, 2x/week for 4
weeks
Frederike van Wijck & Julia Mackenzie
Version 8
27/11/06
______________________________________________________________
CONTENT
Page
PART I
UPPER LIMB THERAPY PROGRAMME One
1.
Introduction
2
2.
Criteria for the therapy programme
2
3.
Content of the therapy programme
3
4.
Programme structure and principles of skill acquisition
4
4.1
4
5.
Introduction
4.2
Demonstration
4
4.3
Organisation of practice
4
4.4
Organisation of augmented feedback
5
4.5
Equipment
6
Upper limb therapy programme: template
7
Appendix 1.1: Task variations
8
Appendix 1.2: Programme Samples
11
PART II
UPPER LIMB THERAPY PROGRAMME HOME
1.
Introduction
16
2.
16
Specifications
HTA
UPPER LIMB THERAPY PROGRAMME Two
Frederike van Wijck
Version 5
28/11/06
______________________________________________________________
CONTENT
2
2.
Criteria for the therapy programme
2
3.
Content of the therapy programme
2
4.
Upper limb therapy programme Two: template
8
Appendix 1.1: Task variations
9
Appendix 1.2: Programme Samples
12
PART II
UPPER LIMB THERAPY PROGRAMME HOME
1.
Introduction
17
2.
Specifications
17
3.
Important notes for participants
18
Important notes for therapists
18
Participants’ guide to their home programme
19
3.
Important notes for participants
16
4.
4.
Important notes for therapists
17
5.
5.
Participants’ guide to their home programme
18
Appendix 2.1: Home therapy programme samples
19
Appendix 2.2: Glossary
24
Page
PART I
UPPER LIMB THERAPY PROGRAMME Two
1.
Introduction
Appendix 2.1: Home therapy programme Two sample
20
Appendix 2.2: Glossary
23
Trial pre-planned statistical analysis
• Primary outcome – ARAT
• Number of “successful” treatments in each group
(control/intervention - ITT) compared (Fisher exact
test)
• Success
– ARAT 0-3 = improve by 3
– ARAT 4-56 = improve by 6
– ARAT > 51 = final score 57
• Power calculation performed on this binary outcome.
332 patients needed to give 80% power to detect a
15% difference in successful treatments between the
groups (two tailed, 5%)
• Secondary outcomes: binary data, fisher exact/chi
square. Remaining data non parametric stats
Trial co-ordination
• Research therapist in each site recruited patients and
delivered therapy
• Patients travelled to either Newcastle or Carlisle to
receive botulinum injections
• Research therapists performed outcome measures
for patients in an adjacent site (blinded)
• Central office in Newcastle co-ordinating activity
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Randomisation via web
Organise injections
Co-ordinate outcome assessment cover
Handle data
Deliver training
Deal with research governance
Generate reports
The challenges of BoTULS
Additional Treatment Costs
Investigational
Medicinal
Product
Ethics
Staff
• Recruitment and training of staff
Staff
• Agenda for Change
• Training
- Therapy programme
- Research methods
- Protocol adherence
- Research governance
Governance
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Local R&D approvals
Acute Trusts and PCT’s
Honorary Contracts
CRB
Sponsorship
Caldicott
Site files
MHRA inspection
ARAT tables
International Stroke Trial
Components of success
Links with
clinical
service
NHS
Management
Research skills
Research
Governance
But equally important….
…..The Team
BoTULS recruitment
July 2005 – March 2008
Total 333
Cumulative Recruitment
350
300
250
200
Cumulative Recruitment
150
100
50
M
N
Ja
n08
S
J
M
M
N
Ja
n07
S
J
M
M
S
J
N
Ja
n06
M
ay
-0
5
0
Randomised n=333
CONSORT flowchart
Intervention n=170
Control n=163
3 Withdrawn
4 Withdrawn
n=167
1 Month assessments
completed n=167
1 Month assessments
completed n=155
1 Withdrawn
1 Died
2 not
done
2 Withdrawn
2 Died
2 not done
1 Died
n=158
3 not done
2 Withdrawn
n=165
3 Month assessments
completed n=163
3 Month assessments
completed n=151
208-7 (withdrawn/died) = 201 patients
eligible for 12 month outcome – patients
recruited after 1/7/2007 followed for only
3 months
n=99
12 Month assessments
completed n=97
1 Died
n=155
4 not done
0 Withdrawn
n=94
12 Month assessments
completed n=92
4 Died
2 not done
Results: Baseline characteristics
Control n=162
Sex
n (%)
male
female
Age
median[ IQR]
Time from stroke to trial randomisation.
median [IQR] days
115
47
Intervention n=170
(71.0)
(29.0)
110
60
(64.7)
(35.3)
66 [59.75-72.25]
67
[58.75-74.0]
280[148.8-1145.8]
324[128.5-1387.5]
n (%)
infarct
intracerebral haemorrhage
subarachnoid haemorrhage
unknown
131
21
3
7
(81.9)
(13.1)
(1.9)
(4.3)
140
25
2
3
(82.8)
(14.8)
(1.2)
(1.8)
Modified Ashworth Score at elbow
median [IQR]
2
[1+-2]
2
[1+-2]
Stroke type
ARAT
median [IQR]
Total
3[3-16]
3
[3-13]
Reminder: primary analysis
• Primary outcome – ARAT at 1 month
• Number of “successful” treatments in each
group (control/intervention) compared (Fisher
exact test)
• Success
– ARAT 0-3 = improve by 3
– ARAT 4-51 = improve by 6
– ARAT >51 = final score 57
Results: Primary outcome
ARAT “success” n (%)
Control n=154
Intervention n=167
P value
30
42
0.232
(19.5)
(25.1)
► No significant difference between the groups
ARAT
Change in score from baseline to 1 month
worse
Rand
better
80
Control
Intervention
Count
60
40
20
0
-17
-13
-8
-6
-4
-2
0
2
4
6
8
10
12
15
17
23
Difference between ARAT score for the affected
side at Screening and 1 Month
31
Results: Secondary outcomes, impairment
Muscle tone (spasticity)
Control
Modified Ashworth Scale at
elbow
median change [IQR]
1 month
3 month
12 month
0
0
0
[-1-1]
[-1-0]
[-1-1]
Intervention
-1
0
0
[-1-0]
[-1-0]
[-1-0]
P
value
0.001
0.145
0.333
Results: Secondary outcomes, impairment
Upper limb strength
Motricity Index (arm
section)
mean change(95%CI)
1 month
3 month
12 month
Control
Intervention
Difference
1.4(-0.9 to 3.7)
1.7(-0.6 to 4.1)
3.6(0.7 to 6.4)
3.6(1.5 to 5.7)
5.2(2.8 to 7.6)
6.1(3.5 to 8.8)
2.2(-0.9 to 5.4)
3.5 (0.1 to 6.8)
2.5(-1.4 to 6.3)
Grip strength: no significant differences
Results: Secondary outcomes, functional limitation
Basic upper limb functional activities
Control
Dressing sleeve improvement by ≥
1
n (%)
1 month
3 month
12 month
Opening hand for cleaning palm
improvement of ≥ 1
n (%)
1 month
3 month
12 month
Opening the hand for cutting nails
improvement of ≥ 1 n (%)
1 month
3 month
12 month
Intervention
P value
38
39
32
(30.4)
(32.0)
(40.5)
65
62
30
(45.1)
(43.7)
(34.9)
0.017
0.057
0.521
41
34
25
(33.1)
(27.9)
(31.6)
65
64
41
(45.5)
(45.1)
(47.7)
0.045
0.005
0.040
31
31
21
(24.8)
(25.4)
(26.9)
52
52
39
(36.6)
(36.9)
(45.3)
0.047
0.048
0.016
No significant differences for nine hole peg test or Barthel ADL index
Results: Secondary outcomes, Qol + pain
Pain
Control
Pain score (0-10)
median change [IQR]
1 month
3 month
12 month
0 [-3-0]
0 [-4-1]
0 [-2.8-1]
Intervention
0
0
-2
[-4-0]
[-4-0]
[-5-0]
P
value
0.600
0.269
0.004
No important significant differences for QoL
measures
BoTULS results summary
• No difference between intervention and
control groups for improvement in arm
function (primary outcome)
• In terms of secondary outcomes, compared to
the control group, participants treated with
botulinum toxin and therapy demonstrated:
– Decreased muscle tone at 1 month
– Improved upper limb strength at 3 months
– Improvements in ability to carry out basic upper
limb functional tasks at 1, 3 and 12 months
– Decreased pain at 12 months
BoTULS results interpretation
Botulinum toxin type A in combination
with an upper limb therapy programme
is unlikely to be useful for improving
active arm function for the majority of
patients after stroke, but may be useful
for improving basic functional activities
and pain.
Why did we not improve active arm
function?
The belief that spasticity results in
active functional limitation is incorrect,
or, for most patients muscle weakness
is the predominate contributor to
functional limitation.
But….study limitations and rehabilitation
research challenges….
Study limitations and rehabilitation
research challenges
1.Was spasticity sufficiently decreased to result
in improved function? Only measured at the
elbow with an imperfect tool.
2. Was the ARAT the most appropriate
functional outcome measure? It doesn’t tell
us whether patients are using their arm more
in everyday life which is important to them.
3. Should the trial only have included people
who could be predicted to improve their arm
function?
Study limitations and rehabilitation
research challenges
4. Was the dosage and pattern of botulinum
toxin injections optimal?
5. Was the combination therapy programme
optimal? Although there is evidence that
“therapy” improves outcome after stroke this
“black box” is hard to unpack.
6. Was the timing of outcome assessment
appropriate? One month may have been too
soon, three and 12 months may have been
too soon or too late.
Summary
• Upper limb spasticity is an important problem
post stroke
• Botulinum toxin is useful for decreasing
spasticity and assisting with basic functional
tasks but previous trials and BoTULS suggest it
is unlikely to help improve active arm function
• Rehabilitation research is challenging and there
are unanswered questions about the optimal
way to use and assess botulinum toxin effects
This project was funded by the NIHR Health Technology Assessment programme. The views and opinions expressed here are
those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health
Thanks to
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Trial participants
Research therapists
Local investigators
Co-ordinating centre staff
Ipsen Ltd who supplied botulinum toxin type A
DMEC (Prof Martin Dennis, Prof Ian Ford, Prof
Marion Walker)
• TSC (Prof Peter Langhorne, Prof Bipin Bhakta, Prof
Anne Forster, Mrs Beryl Fairless)