Clinical Trial Outcomes AbobotulinumtoxinA for the ... · Upper limb spasticity is a common feature of many conditions arising from stroke, brain injury or progressive neurological

847Clin. Invest. (Lond.) (2014) 4(9), 847–865 ISSN 2041-6792

Clinical Trial Outcomes

part of

AbobotulinumtoxinA for the treatment of upper limb spasticity

Wolfgang H JostDepartment of Neurology, University of

Freiburg, 79106 Freiburg, Germany

Tel.: +49 7834 971 111

Fax: +49 7834 971 340

[email protected]

10.4155/CLI.14.74 © Wolfgang Jost

Clin. Invest. (Lond.)

Clinical Trial Outcomes4

9

2014

Upper limb spasticity is a common feature of many conditions arising from stroke, brain injury or progressive neurological illness and can cause significant disability. Current guidelines recommend first-line treatment with botulinum neurotoxin type A. This paper provides a comprehensive overview of one type of botulinum neurotoxin type A – abobotulinumtoxinA – including its mechanism of action, efficacy and safety. Overall, there is a wealth of evidence supporting the clinical efficacy of abobotulinumtoxinA in the management of spasticity. Key findings from randomized controlled and open-label naturalistic studies support abobotulinumtoxinA as an efficacious long-term treatment for upper limb spasticity, with benefits extending to overall patient function as well as direct improvements in muscle tone.

Keywords: abobotulinumtoxinA • botulinum toxin • Dysport® • spasticity • upper limb

Spasticity, characterized by excess muscle tone and exaggerated tendon jerks, is a com-mon feature of the upper motor neuron syn-drome and is seen in a variety of diseases and conditions. For example, spasticity is estimated to affect 17–36% of patients with stroke [1–3], over half of patients with multiple sclerosis [4] or spinal cord injury [5,6] and up to a third of patients with traumatic brain injury [7]. The underlying pathophysiology of spas-ticity is complex and not well understood. Whereas it was once defined as a “velocity dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflexes” [8]. This definition has been heavily criticized as it only recognizes one motor loop and does not account for the complexity of changes that allow task performance after brain injury [9]. The burden of disability associated with spasticity can exert an immense impact on patient quality of life, as well as greater dependability on the caregiver and increased societal costs [10,11].

Key treatment goals in the management of spasticity are to maintain muscle length and enable normal positioning of the limbs

to prevent secondary soft tissue shortening [11,12]. Treatment options include conservative (physical and occupational therapies), oral and intrathecal medications, local injections of botulinum toxin (BoNT) and surgery. For patients with moderate-to-severe spasticity, physical treatments alone are often not effec-tive enough, and therefore early intervention with pharmacological agents is advised [11].

Management of upper limb spasticity with botulinum neurotoxin type ABotulinum neurotoxin type A (BoNT-A) is an acknowledged mainstay pharmacological treatment for the management of spasticity [11,13]. A robust body of evidence supports the use of BoNT-A as an effective focal interven-tion for reduction of spasticity. Guidelines consistently recommend that BoNT-A should be offered as a treatment option in adult spasticity as standard clinical practice [11–13].

The efficacy and safety of three of the commercially available BoNT-A prepara-tions (abobotulinumtoxinA, Ipsen Biopharm Ltd, Wrexham, UK; incobotulinumtoxinA Merz Pharmaceuticals, Frankfurt am Main,

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848 Clin. Invest. (Lond.) (2014) 4(9) future science group

Clinical Trial Outcomes Jost

Germany and onabotulinumtoxinA Allergan, Inc., CA, USA) in treating spasticity have each been well established and there are numerous reviews regarding the efficacy and safety of the BoNT-A class for spas-ticity [12,14–16]. However, very few papers have looked at the efficacy and safety of specific products. This is important, as the injection dosing schemes (units used, volume of injection, and so on) of each product are not interchangeable. It is essential that practitioners under-stand the specifics of each product, as the lack of direct product comparability is a potential source of confu-sion. This review provides an overview of the use of abobotulinumtoxinA (Dysport®) in the management of upper limb spasticity (ULS).

In ULS, injections can be made into a variety of muscles to reduce muscle tone (Figure 1). Aside from improved muscle tone, patients may expect to experience improvement in function, increased ease of care and comfort, prevention of musculoskeletal complications and general cosmesis [17–19].

AbobotulinumtoxinA (Dysport)The clinical development of BoNT-A began around 1970, when it was investigated for use as a nonsurgical alternative for the treatment of strabismus [20,21]. Since then, various BoNT-A products have been developed, each with their own characteristics. One of the first to be developed was given the commercial name Dysport, which was developed by the Centre for Applied Micro-biology Research in Porton Down. In 2009, in order to reinforce the inherent differences and lack of inter-changeability between different BoNT-A products, the US FDA recommended that all BoNT products be given a new established drug name specific to each drug product. Dysport was given the name abobotulinum-toxinA, and this unique name for the drug has been adopted in many other countries.

The abobotulinumtoxinA neurotoxin complex is composed of the active neurotoxin and associated proteins that stabilize and protect the neurotoxin.

The active neurotoxin is produced by fermentation of Clostridium botulinum type A, Hall strain and puri-fied from the culture supernatant by a series of pro-prietary precipitation, dialysis and chromatography steps. Since approval in 1990, all abobotulinumtoxinA batches have been produced using essentially the same method and have been reported to have a high degree of consistency [22].

Mechanism of actionLike all other BoNT-A products, abobotulinumtoxinA is a muscle relaxant agent that achieves its therapeutic effects on spasticity through the blockade of acetylcho-line (ACh) release [23,24]. Following injection of abobot-ulinumtoxinA to the target muscle, the BoNT-A com-plex rapidly dissociates to separate associated proteins (hemagglutinin and nontoxic/nonhemagglutinin) from the neurotoxin [25,26]. The neurotoxin then diffuses and spreads to reach the target nerve terminals. Although various dermatologic studies [27–29] have reported dif-ferences in the diffusion characteristics of the different BoNT-A formulations, this has been disputed by sev-eral studies conducted under more strictly comparable laboratory conditions [30]. Once injected into tissue, there is a rapid dissociation between neurotoxin and associated proteins [26] and therefore there is no direct relationship between the complex size and the diffusion characteristics of abobotulinumtoxinA [30].

Thereafter, a four-step sequence of physiological events leads to the inhibition of ACh release: cell sur-face binding to peripheral nerve terminals; internal-ization (endocytosis); translocation and proteolysis. During the proteolysis step, the neurotoxin cleaves the SNAP-25 protein thereby impairing function of the neuroexocytosis machinery [31] and preventing ACh release. The main physiologic effect is the chemically induced loss of nerve input to the treated muscle, which results in a measurable decrease of the compound mus-cle action potential (muscle function) and consequent localized reduction of muscle activity. Very impor-tantly, the effects of BoNT are not permanent; a final step in the sequence of physiological events associated with BoNT-A action is the gradual resumption of trans-mission as the neuromuscular junction recovers from the blockade of exocytosis and as new nerve endings are formed [32,33].

Efficacy of abobotulinumtoxinA in the management of ULS: evidence from clinical trialsThe efficacy and safety of abobotulinumtoxinA in ULS has been established by several trials in the clinical development program and by further indepen-dent research. Official dosing recommendations for

Figure 1. Muscles involved in upper limb spasticity. Image courtesy of Ipsen Pharma (Boulogne, France).

Biceps brachii

Flexor carpiradialisFlexor carpi

radialis

Flexor carpiulnarisFlexor carpi

ulnaris

Flexor digitorumsuperficialis

Flexor digitorumsuperficialis

www.future-science.com 849future science group

AbobotulinumtoxinA for the treatment of upper limb spasticity Clinical Trial Outcomes

abobotulinumtoxinA in ULS are largely based on the studies by Bakheit and colleagues who conducted two randomized placebo-controlled trials in patients with poststroke spasticity [34,35].

Pivotal studiesThe first study was a dose-ranging trial to find effec-tive and safe dose [34]. In this study, patients (n = 82) were randomized to receive injections with placebo (PBO), or three doses of abobotulinumtoxinA: 500, 1000 or 1500 U. Injections were made into the biceps brachii, flexor digitorum profundus, flexor digitorum superficialis, flexor carpi ulnaris and flexor carpi radia-lis using anatomic landmarks for guidance. Week 4 results showed a significant reduction in muscle tone as measured on the Modified Ashworth Scale (MAS) for all three abobotulinumtoxinA doses. Although not significantly different between groups, the authors noted an increase in range of motion at the elbow, wrist and fingers for all study groups. Importantly, the study found that 15.8% of the group who received 1500 U of abobotulinumtoxinA reported loss of the ability to voluntarily extend their fingers. The authors concluded that treatment with abobotulinumtoxinA at doses of 500, 1000 and 1500 U is effective and safe; however, for those individuals with residual voluntary movement in the affected limb, the optimal dose of abobotulinum-toxinA is 1000 U to achieve adequate spasticity control without negatively impacting voluntary movement.

The same investigators further evaluated the effi-cacy and safety of 1000 U abobotulinumtoxinA in 59 patients [35]. In this placebo-controlled study, patients randomized to abobotulinumtoxinA treatment received 1000 U in 2 ml of normal saline of abobotulinum-toxinA injected into the biceps brachii (300–400 U), flexor digitorum superficialis (150–250 U) and 150 U each into the flexor digitorum profundus, flexor carpi ulnaris and flexor carpi radialis, again using anatomic landmarks for guidance. The benefits of abobotulinum-toxinA injection in reducing muscle tone (MAS) were confirmed at week 4 of the study. Functional outcome measures, including active range of motion, Barthel Index and goal attainment did not show significance between group differences. However, global assess-ments of benefit (clinician and patient rated) demon-strated significant improvements for patients receiving abobotulinumtoxinA. The authors attributed this dis-crepancy to “the poor sensitivity of global functional outcome assessment scales in this situation.”

Randomized controlled trialsIn 2008 the American Academy of Neurology con-ducted an evidence-based review of 14 random-ized controlled trials (RCTs) of BoNT treatment for

spasticity, of which eight studies evaluated abobotu-linumtoxinA (including the pivotal trials described above) [13]. Since then, at least six more RCTs (some of which have had an open-label design) have been completed and published. Tables 1–7 present an over-view of the 14 RCTs conducted to evaluate the efficacy and safety of abobotulinumtoxinA in the management of ULS [19,34–46].

All but one of the studies showed significant ben-efits of abobotulinumtoxinA versus placebo on the reduction of muscle tone as assessed by the MAS. The studies generally showed that clinically significant (≥1 point on MAS) [47] reductions in muscle tone were achieved within 2 weeks after injection. The trial by Hesse and colleagues was the only one not to show a significant difference in MAS and the authors attrib-uted this finding to restricted selection of subjects with severe spasticity (mean MAS scores = 3), as well as the fact that the subjects did not participate in postinjec-tion rehabilitation [45]. Nevertheless, the study showed significant improvements for abobotulinumtoxinA plus electrical stimulation in activities of daily living (cleaning the palm, cutting fingernails and putting affected arm through sleeve), which might be a very important goal for many patients.

When taken together, the 14 studies also show that, as well as improving muscle tone, treatment with abo-botulinumtoxinA can, in some patients, also be helpful in improving associated reactions, disability, pain and caregiver burden (Tables 1–7).

By contrast, it was harder for the individual studies to demonstrate meaningful effects of abobotulinum-toxinA on functional improvement. Interestingly, meta-analytic approaches that combine data from many studies to produce a larger population of patients have found that reducing spasticity in the arm is associ-ated with significant improvements in arm function. In the first exploratory meta-analysis conducted by Fran-cis and colleagues in 2004, the authors used the MAS (elbow, wrist and fingers) from two RCTs to calculate a ‘Composite Spasticity Index’ and compared this with a ‘Composite Functional Index’ that had been similarly derived from the arm section of the Barthel Activities of Daily Living Index (dressing, grooming and feeding) and three subjective measures (putting arm through sleeve, cleaning palm, cutting fingernails) [48]. Using this targeted meta-analytic approach, the analysis found that there was a clear relationship between the changes in spasticity and in arm function in patients treated with abobotulinumtoxinA at 500 or 1000 U, but not in those treated with placebo or 1500 U. This led the authors to conclude, “…a moderate dose of BoNT reduces spasticity sufficiently to allow function to improve, without causing a substantial decrease in


Clinical Trial Outcomes JostTa

ble

1. P

ivo

tal t

rial

s o

f ab

ob

otu

linu

mto

xin

A.

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Bak

hei

t et

al.

(20

00

)

Ran

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

-co

ntr

olle

d,

do

se-r

ang

ing

stu

dy

Key

elig

ibili

ty c

rite

ria

:Pa

tien

ts w

ith

m

od

erat

e–s

ever

e m

usc

le s

pas

tici

ty p

ost

h

emip

leg

ic s

tro

ke;

≥3 m

on

ths

afte

r ce

reb

rova

scu

lar

even

t;

mu

scle

to

ne

sco

re

≥2 o

n M

AS

in w

rist

, el

bo

w a

nd

fin

ger

fl

exo

rs

Key

exc

lusi

on

cri

teri

a:

Mu

scle

co

ntr

actu

res;

p

revi

ou

s tr

eatm

ent

wit

h B

oN

T

Inje

ctio

ns

wer

e m

ade

into

th

e m

oto

r en

dp

late

zo

ne

of

the

bic

eps

bra

chii,

fl

exfo

r d

igit

oru

m

pro

fun

du

s,

flex

or

dig

ito

rum

su

per

fici

alis

, flex

or

carp

i uln

aris

an

d

flex

or

carp

i rad

ialis

Plac

ebo

(n

= 1

9)

AB

O 5

00

U (

n =

22

)A

BO

10

00

U (

n =

22

)A

BO

150

0 U

(n

= 1

9)

•Tr

eatm

ent

wit

h A

BO

(al

l th

ree

do

ses)

sig

nifi

can

tly

red

uce

d M

AS

sco

res

in a

ny

join

t at

wee

k 4

com

par

ed w

ith

PB

O•

The

nu

mb

er o

f p

atie

nts

wh

o h

ad

an im

pro

vem

ent

of

the

MA

S in

all

thre

e jo

ints

was

sta

tist

ical

ly h

igh

er

for

AB

O (

all d

ose

s) t

han

in t

he

pla

ceb

o g

rou

p (

p <

0.0

2)

•A

ll A

BO

do

ses

sig

nifi

can

tly

imp

rove

d M

AS

in e

lbo

w a

nd

wri

st

ove

r 16

wee

ks

(all

p <

0.0

5).

AB

O

100

0 U

sig

nifi

can

tly

red

uce

d M

AS

in fi

ng

ers

(p =

0.0

4)

•A

ll g

rou

ps

had

no

nsi

gn

ifica

nt

incr

ease

s in

RO

M (

acti

ve a

nd

p

assi

ve)

at t

he

elb

ow

, wri

st a

nd

fi

ng

ers

•N

o s

tati

stic

ally

sig

nifi

can

t d

iffe

ren

ces

ob

serv

ed f

or

mea

sure

s o

f p

ain

an

d f

un

ctio

nal

ass

essm

ent

AEs

like

ly

rela

ted

to

AB

O:

skin

ras

hes

(n

= 6

), fl

u-

like

sym

pto

ms

(n =

3).

Red

uce

d

acti

ve R

OM

wit

h

150

0 U

do

se,

du

e to

exc

essi

ve

wea

ken

ing

of

mu

scle

s

“Tre

atm

ent

wit

h A

BO

re

du

ces

mu

scle

to

ne

in

pat

ien

ts w

ith

po

stst

roke

u

pp

er li

mb

sp

asti

city

. Tr

eatm

ent

was

eff

ecti

ve a

t d

ose

s o

f A

BO

of

500,

10

00

and

150

0 U

. Th

e o

pti

mal

d

ose

fo

r tr

eatm

ent

of

pat

ien

ts w

ith

res

idu

al

volu

nta

ry m

ove

men

ts in

th

e u

pp

er li

mb

ap

pea

rs

to b

e 10

00

U i s

saf

e in

th

e d

ose

s u

sed

in t

his

stu

dy”

[34]

Bak

hei

t et

al.

(20

01)

Ran

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

-co

ntr

olle

d

stu

dy

Key

elig

ibili

ty c

rite

ria

: Pa

tien

ts w

ith

m

od

erat

e–s

ever

e m

usc

le s

pas

tici

ty

≥3 m

on

ths

po

st

hem

iple

gic

str

oke

; m

usc

le t

on

e sc

ore

≥2

on

MA

S in

at

leas

t tw

o o

f th

e w

rist

, el

bo

w a

nd

fin

ger

fl

exo

rs a

nd

sco

re

(≥1

in r

emai

nin

g a

rea

)

Key

exc

lusi

on

cri

teri

a:

Mu

scle

co

ntr

actu

res;

tr

eatm

ent

wit

h B

oN

T w

ith

in 6

mo

nth

s

Inje

ctio

ns

wer

e m

ade

into

th

e b

icep

s b

rach

ii fl

exo

r d

igit

oru

m

sup

erfi

cial

is,

flex

or

dig

ito

rum

p

rofu

nd

us,

flex

or

carp

i uln

aris

an

d

flex

or

carp

i rad

ialis

Plac

ebo

(n

= 3

2)

AB

O 1

00

0 U

(n

= 2

7)

•A

BO

tre

atm

ent

resu

lted

in

sig

nifi

can

t re

du

ctio

n in

MA

S in

an

y jo

int

at w

eek

4 co

mp

ared

wit

h P

BO

(p

= 0

.00

4)

•N

o s

ign

ifica

nt

dif

fere

nce

s b

etw

een

g

rou

ps

in c

han

ge

fro

m b

asel

ine

to

wee

k 4

for

acti

ve o

r p

assi

ve R

OM

•Pa

tien

t an

d p

hys

icia

n g

lob

al

asse

ssm

ents

of

ben

efit

sho

wed

“s

om

e o

r m

uch

imp

rove

d”

for

sig

nifi

can

tly

mo

re A

BO

-tre

ated

p

atie

nts

(92

.3 a

nd

88

.4%

)

AEs

po

ssib

ly

rela

ted

to

A

BO

incl

ud

ed

fati

gu

e,

tire

dn

ess

and

p

ain

in t

he

arm

fo

llow

ing

th

e in

ject

ion

“Tre

atm

ent

wit

h [

AB

O

100

0 U

] re

du

ces

mu

scle

to

ne

in p

atie

nts

wit

h

po

stst

roke

up

per

lim

b

spas

tici

ty. T

his

eff

ect

is

sust

ain

ed f

or

at le

ast

16 w

eek

s. A

BO

is s

afe

in t

he

do

se u

sed

in t

his

st

ud

y”

[35]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le.

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

Bo

NT:

Bot

ulin

um

tox

in; M

AS:

Mo

difi

ed A

shw

ort

h Sc

ale;

PB

O: P

lace

bo

; RO

M: R

ang

e of

mo

vem

ent.


AbobotulinumtoxinA for the treatment of upper limb spasticity Clinical Trial OutcomesTa

ble

2. R

and

om

ized

co

ntr

olle

d t

rial

s o

f ab

ob

otu

linu

mto

xin

A u

p t

o 1

00

0 U

in u

pp

er li

mb

sp

asti

city

.

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Bh

akta

et

al. (

200

0)

Sin

gle

-cen

ter,

ra

nd

om

ized

, d

ou

ble

-blin

d,

pla

ceb

o-

con

tro

lled

st

ud

y

Key

elig

ibili

ty c

rite

ria

:Pa

tien

ts w

ith

ch

ron

ic

hem

ipar

esis

; fin

ger

or

elb

ow

flex

or

(MA

S >

2)

at le

ast

mo

der

ate

dif

ficu

lty

wit

h t

wo

ou

t o

f ei

gh

t it

ems

defi

nin

g

pat

ien

t d

isab

ility

; at

leas

t 6

mo

nth

s p

ost

stro

ke

Key

exc

lusi

on

cri

teri

a:

Fun

ctio

nal

ly u

sefu

l m

ove

men

t in

th

e p

aret

ic a

rm; p

revi

ou

s tr

eatm

ent

wit

h B

oN

T o

r p

hen

ol b

lock

Inje

ctio

ns

wer

e m

ade

into

th

e b

icep

s b

rach

ii,

bra

chio

rad

ialis

, fl

exo

r d

igit

oru

m

sup

erfi

cial

is,

flex

or

dig

ito

rum

p

rofu

nd

us

and

fl

exo

r ca

rpi u

lnar

is

Plac

ebo

(n

= 2

0)

AB

O 1

00

0 U

(n

= 2

0)

•Pa

tien

ts in

th

e A

BO

gro

up

had

s i

gn

ifica

ntl

y g

reat

er im

pro

vem

ent

in

dis

abili

ty c

om

par

ed w

ith

PB

O f

rom

w

eek

0 to

2 (

p =

0.0

04

) an

d w

eek

6 (p

= 0

.016

). G

reat

er im

pro

vem

ent

was

al

so o

bse

rved

in t

he

AB

O g

rou

p a

t w

eek

12, b

ut

was

no

t si

gn

ifica

nt

•C

areg

iver

bu

rden

was

sig

nifi

can

tly

dec

reas

ed f

rom

wee

k 0

to 2

(p

= 0

.011

),

wee

k 6

(p =

0.0

05)

and

wee

k 1 2

(p

= 0

.027

)•

Fin

ger

flex

or

spas

tici

ty w

as s

ign

ifica

ntl

y im

pro

ved

in t

he

AB

O g

rou

p c

om

par

ed t

he

PBO

gro

up

at

all t

ime

po

ints

(fr

om

wee

k 0

to 2

, p <

0.0

01; w

eek

0 to

6, p

< 0

.001

; w

eek

0 to

12,

p <

0.0

06

)•

Elb

ow

flex

or

spas

tici

ty w

as s

ign

ifica

ntl

y im

pro

ved

in t

he

AB

O g

rou

p c

om

par

ed

wit

h t

he

PBO

gro

up

fro

m w

eek

0 to

2

(p =

0.0

02)

•N

o s

ign

ifica

nt

dif

fere

nce

s b

etw

een

g

rou

ps

for

acti

ve R

OM

, pas

sive

RO

M a

t th

e el

bo

w o

r sh

ou

lder

, mu

scle

str

eng

th

or

pai

n

Pati

ents

in t

he

AB

O g

rou

p

rep

ort

ed s

elf-

limit

ing

arm

pai

n

wit

hin

1 w

eek

of

inje

ctio

n (

n =

2)

and

wo

rsen

ing

o

f m

usc

le s

pas

m

(n =

1) .

No

se

rio

us

AEs

wer

e re

po

rted

. Gri

p

stre

ng

th w

as

red

uce

d w

ith

AB

O

“[A

BO

] is

use

ful f

or

trea

tin

g p

atie

nts

wit

h

stro

ke w

ho

hav

e se

lf

care

dif

ficu

ltie

s d

ue

to a

rm s

pas

tici

ty. T

he

dec

isio

n t

o t

reat

sh

ou

ld

also

incl

ud

e re

lief

of

care

r b

urd

en”

[19]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le.

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

AQ

oL:

Ass

essm

ent

of q

ualit

y of

life

; AR

: Ass

oci

ated

rea

ctio

n; B

oN

T: B

otu

linu

m t

oxin

; GA

S: G

oal

att

ainm

ent

scal

ing

; MA

S: M

od

ified

Ash

wo

rth

Scal

e;

PBO

: Pla

ceb

o; R

OM

: Ran

ge

of m

ove

men

t.



ble

2. R

and

om

ized

co

ntr

olle

d t

rial

s o

f ab

ob

otu

linu

mto

xin

A u

p t

o 1

00

0 U

in u

pp

er li

mb

sp

asti

city

(co

nt.

).

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Bh

akta

et

al. (

200

8)

Ran

do

miz

ed,

pla

ceb

o-

con

tro

lled

st

ud

y

Key

elig

ibili

ty c

rite

ria

: C

on

secu

tive

p

atie

nts

ref

erre

d f

or

man

agem

ent

of

up

per

lim

b s

pas

tici

ty; a

t le

ast

6 m

on

ths

po

stst

roke

Key

exc

lusi

on

cri

teri

a:

Prev

iou

s tr

eatm

ent

wit

h B

oN

T o

r p

hen

ol

blo

ck

Inje

ctio

ns

wer

e m

ade

into

th

e b

icep

s b

rach

ii,

bra

chio

rad

ialis

, fl

exo

r d

igit

oru

m

sup

erfi

cial

is,

flex

or

dig

ito

rum

p

rofu

nd

us

and

fl

exo

r ca

rpi u

lnar

is

Plac

ebo

(n

= 2

0)

AB

O 1

00

0 U

(n

= 2

0)

•Pe

ak A

Rs

(un

wan

ted

invo

lun

tary

m

ove

men

ts)

bet

wee

n w

eek

1 an

d 6

wer

e si

gn

ifica

ntl

y re

du

ced

in t

he

AB

O g

rou

p

com

par

ed w

ith

th

e PB

O g

rou

p (

mea

n

gro

up

dif

fere

nce

: 19.

0; p

≤ 0

.01)

•10

/12

pat

ien

ts in

th

e A

BO

gro

up

rep

ort

ed

a re

du

ctio

n in

th

e in

terf

eren

ce t

hat

AR

h

ave

on

th

eir

dai

ly a

ctiv

itie

s vs

tw

o o

f 12

in

th

e p

lace

bo

gro

up

(p

= 0

.02

)

No

ne

rep

ort

ed“

[AB

O]

red

uce

s as

soci

ated

rea

ctio

ns

and

may

be

a u

sefu

l ad

jun

ct t

o o

ther

re

hab

ilita

tio

n

inte

rven

tio

ns.

Th

e im

pac

t o

f as

soci

ated

re

acti

on

s o

n d

aily

ac

tivi

ties

may

als

o b

e re

du

ced

”

[36]

McC

rory

et

al. (

200

9)

Ran

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

-co

ntr

olle

d

stu

dy

Key

elig

ibili

ty c

rite

ria

:Pa

tien

ts (

aged

≥1

8 ye

ars)

wit

h

mo

der

ate

–sev

ere

spas

tici

ty o

f th

e ar

m

(MA

S sc

ore

≥2

in a

t le

ast

two

of

wri

st,

elb

ow

an

d fi

ng

er

flex

or

and

≥1

in

rem

ain

ing

are

a)

Key

exc

lusi

on

cri

teri

a:

Prev

iou

s tr

eatm

ent

wit

h B

oN

T in

pas

t 12

0 d

ays,

ph

eno

l o

r n

euro

lyti

c o

r in

trat

hec

al b

aclo

fen

; se

vere

co

ntr

actu

res

Inje

ctio

ns

wer

e m

ade

into

th

e b

icep

s b

rach

ii,

bra

chia

lis,

bra

chio

rad

ialis

, tr

icep

s, fl

exo

r d

igit

oru

m

sup

erfi

cial

is,

flex

or

dig

ito

rum

p

rofu

nd

us,

flex

or

carp

i uln

aris

, flex

or

carp

i rad

ialis

an

d

fin

ger

/th

um

b fl

exo

rs

Plac

ebo

(n

= 4

2)

AB

O 7

50–1

00

0 U

(n

= 5

4)

•N

o s

ign

ifica

nt

dif

fere

nce

s b

etw

een

g

rou

ps

for

qu

alit

y o

f lif

e•

No

sig

nifi

can

t d

iffe

ren

ces

bet

wee

n

gro

up

s fo

r p

ain

, mo

od

dis

abili

ty o

r ca

reg

iver

bu

rden

•A

sta

tist

ical

ly s

ign

ifica

nt

fun

ctio

nal

b

enefi

t in

GA

S w

as o

bse

rved

fo

r A

BO

co

mp

ared

wit

h P

BO

fro

m b

asel

ine

to

wee

k 20

(G

AS

chan

ge

: -5.

20; p

< 0

.01)

•M

usc

le s

pas

tici

ty w

as s

ign

ifica

ntl

y re

du

ced

fo

r A

BO

-tre

ated

pat

ien

ts c

om

par

ed w

ith

PB

O-t

reat

ed p

atie

nts

at

all t

ime

po

ints

(p

≤ 0

.001

)•

A s

ign

ifica

ntl

y h

igh

er p

rop

ort

ion

of

bo

th

pat

ien

ts a

nd

inve

stig

ato

rs r

epo

rted

a

ben

efit

fro

m t

reat

men

t in

th

e A

BO

gro

up

vs

pla

ceb

o g

rou

p a

t w

eek

s 12

an

d 2

4 (p

= 0

.01)

Trea

tmen

t-re

late

d

AEs

occ

urr

ed in

5.

5% o

f A

BO

tr

eate

d p

atie

nts

.A

Es r

elat

ed t

o

AB

O w

ere

: ato

pic

re

acti

on

(d

ue

to

alco

ho

l sw

abs)

, ar

m n

um

bn

ess,

el

bo

w t

wit

ch a

nd

th

um

b t

rem

ble

“Alt

ho

ug

h n

o c

han

ge

in q

ual

ity

of

life

was

d

emo

nst

rate

d u

sin

g

the

AQ

oL,

[A

BO

] w

as

fou

nd

to

be

safe

an

d

effi

caci

ou

s in

red

uci

ng

u

pp

er li

mb

sp

asti

city

an

d im

pro

vin

g t

he

abili

ty t

o a

chie

ve

per

son

al g

oal

s”

[37]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le.

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

AQ

oL:

Ass

essm

ent

of q

ualit

y of

life

; AR

: Ass

oci

ated

rea

ctio

n; B

oN

T: B

otu

linu

m t

oxin

; GA

S: G

oal

att

ainm

ent

scal

ing

; MA

S: M

od

ified

Ash

wo

rth

Scal

e;

PBO

: Pla

ceb

o; R

OM

: Ran

ge

of m

ove

men

t.



Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Lam

et

al. (

2012

)

Ra n

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

-co

ntr

olle

d

tria

l in

lon

g-

term

car

e p

atie

nts

wit

h

a 24

-wee

k fo

llow

-up

p

erio

d

Key

elig

ibili

ty c

rite

ria

:Pa

tien

ts in

lon

g-t

erm

ca

re w

ith

sh

ou

lder

ad

du

cto

r, fi

ng

er

flex

or

or

elb

ow

flex

or

spas

tici

ty(M

AS

>2

) an

d a

t le

ast

mo

der

ate

dif

ficu

lty

wit

h t

wo

of

fou

r it

ems

defi

nin

g c

arer

bu

rden

sc

ale

wer

e el

igib

le f

or

the

stu

dy.

Pat

ien

ts h

ad

to h

ave

had

sp

asti

city

fo

r at

leas

t a

year

an

d

be

able

to

to

lera

te

limb

-str

etch

ing

ex

erci

ses

and

lim

b

splin

ts

Key

exc

lusi

on

cri

teri

a:

Pati

ents

wit

h

fun

ctio

nal

ly u

sefu

l m

ove

men

t in

th

e sp

asti

c lim

b o

r ri

gid

af

fect

ed jo

ints

th

at a

re

un

likel

y to

res

po

nd

to

B

oN

T in

ject

ion

wer

e ex

clu

ded

Inje

ctio

ns

wer

e m

ade

into

th

e b

icep

s b

rach

ii,

bra

chio

rad

ialis

, b

rach

ialis

, p

ecto

ralis

maj

or,

fl

exo

r d

igit

oru

m

pro

fun

du

s,fl

exo

r d

igit

oru

m

sup

erfi

cial

is,

add

uct

or

po

llici

s,

flex

or

po

llici

s lo

ng

us

and

flex

or

po

llici

s b

revi

s

Plac

ebo

(n

= 2

5)

AB

O (

n =

30

); m

ax

do

se 1

00

0 U

•A

t w

eek

6 p

ost

inje

ctio

n, 6

0% o

f h

ad a

s i

gn

ifica

nt

fou

r-p

oin

t re

du

ctio

n o

f ca

rer

bu

rden

sca

le (

p <

0.0

01 v

s p

lace

bo

)•

Sig

nifi

can

t im

pro

vem

ent

in g

oal

at

tain

men

t sc

alin

g (

p <

0.0

01 v

s p

lace

bo

)•

Sig

nifi

can

t im

pro

vem

ent

in M

AS,

res

tin

g

ang

le a

nd

pas

sive

ran

ge

of

mo

vem

ent

of

the

thre

e re

gio

ns

(sh

ou

lder

, elb

ow

an

d

fin

ger

s) in

th

e tr

eatm

ent

gro

up

, wh

ich

p

ersi

sted

un

til w

eek

24

No

sta

tist

ical

si

gn

ifica

nce

in

cu

mu

lati

ve

inci

den

ce r

ates

b

etw

een

th

e tr

eatm

ent

and

co

ntr

ol g

rou

ps

reg

ard

ing

th

e p

neu

mo

nia

, b

on

e fr

actu

re,

feve

r, s

oft

tis

sue

swel

ling

, pre

ssu

re

po

int

or

dea

th

“Lo

ng

-ter

m c

are

pat

ien

ts w

ho

wer

e tr

eate

d f

or

up

per

lim

b s

pas

tici

ty

wit

h in

tram

usc

ula

r in

ject

ion

s o

f [A

BO

] h

ad

a si

gn

ifica

nt

dec

reas

e in

th

e ca

reg

iver

b

urd

en. T

he

trea

tmen

t w

as a

lso

ass

oci

ated

w

ith

imp

rove

d s

core

s o

n p

atie

nt-

cen

tere

d

ou

tco

me

mea

sure

s”

[38]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le.

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

AQ

oL:

Ass

essm

ent

of q

ualit

y of

life

; AR

: Ass

oci

ated

rea

ctio

n; B

oN

T: B

otu

linu

m t

oxin

; GA

S: G

oal

att

ainm

ent

scal

ing

; MA

S: M

od

ified

Ash

wo

rth

Scal

e;

PBO

: Pla

ceb

o; R

OM

: Ran

ge

of m

ove

men

t.

Tab

le 2

. Ran

do

miz

ed c

on

tro

lled

tri

als

of

abo

bo

tulin

um

toxi

nA

up

to

10

00

U in

up

per

lim

b s

pas

tici

ty (

con

t.).



Tab

le 3

. Do

se-r

ang

ing

stu

die

s fo

r ab

ob

otu

linu

mto

xin

A.

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Smit

h e

t al

. (20

00

)

Ran

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

co

ntr

olle

d,

do

se-r

ang

ing

st

ud

y

Key

elig

ibili

ty

crit

eria

:Pa

tien

ts w

ith

tr

ou

ble

som

e fl

exo

r sp

asti

city

of

the

affe

cted

up

per

lim

b a

risi

ng

fro

m

stro

ke o

r tr

aum

atic

b

rain

inju

ry >

1 ye

ar

pre

vio

usl

y

Key

exc

lusi

on

cr

iter

ia:

Fixe

d c

on

trac

ture

Inje

ctio

ns

wer

e m

ade

into

th

e m

usc

les

cau

sin

g t

rou

ble

som

e sp

asti

city

incl

ud

ing

bic

eps

bra

chii,

bra

chia

lis, w

rist

flex

ors

an

d fi

ng

er fl

exo

rs (

oth

er

mu

scle

s n

ot

spec

ified

)

Plac

ebo

(n

= 6

)A

BO

50

0 U

(n

= 6

)A

BO

10

00

U (

n =

7)

AB

O 1

500

U (

n =

6)

•A

t 6

wee

ks,

sig

nifi

can

t o

vera

ll re

du

ctio

ns

in M

AS

(co

mb

ined

d

ose

) w

ere

ob

serv

ed a

t th

e fi

ng

ers

and

wri

st a

fter

AB

O

trea

tmen

t (p

< 0

.01

vs p

lace

bo

)•

Pass

ive

RO

M s

ign

ifica

ntl

y in

crea

sed

at

the

wri

st (

p =

0.0

5)

•Th

ere

wer

e n

o s

ign

ifica

nt

dif

fere

nce

s b

etw

een

AB

O a

nd

p

lace

bo

on

act

ive

RO

M•

Sig

nifi

can

t im

pro

vem

ents

wer

e o

bse

rved

in fi

ng

er c

url

wh

ile a

t re

st w

ith

AB

O (

com

bin

ed d

ose

) (p

< 0

.001

vs

pla

ceb

o)

•St

atis

tica

lly s

ign

ifica

nt

imp

rove

men

ts in

glo

bal

rat

ing

sc

ale

wer

e o

bse

rved

in 1

5 p

atie

nts

tre

ated

wit

h A

BO

(c

om

bin

ed d

ose

; p <

0.0

2 vs

p

lace

bo

)•

Ther

e w

ere

no

sig

nifi

can

t d

iffe

ren

ces

acro

ss g

rou

ps

for

dre

ssin

g t

ime,

po

stu

ral

alig

nm

ent

and

th

e Fr

ench

ay

arm

tes

t•

Six

ou

t o

f n

ine

amb

ula

nt

pat

ien

ts (

wh

o h

ad a

n

asso

ciat

ed fl

exo

r re

acti

on

in

the

arm

wh

en w

alki

ng

) h

ad

imp

rove

d g

ait

afte

r A

BO

in

ject

ion

into

th

e b

icep

s

AB

O w

as g

ener

ally

w

e ll t

ole

rate

d. A

Es

incl

ud

ed: h

ip p

ain

(n

= 1

); fl

u-l

ike

sym

pto

ms

(n =

1)

“A s

ing

le d

ose

of

[AB

O]

red

uce

d s

pas

tici

ty a

nd

in

crea

sed

pas

sive

ran

ge

of

mo

vem

ent

in t

he

up

per

lim

b o

f p

atie

nts

w

ith

str

oke

an

d h

ead

in

jury

fo

r at

leas

t 6

wee

ks”

.“

[AB

O]

was

wel

l to

lera

ted

an

d p

atie

nts

re

po

rted

ove

rall

imp

rove

men

t b

ut

no

ch

ang

e in

up

per

lim

b f

un

ctio

n w

as

dem

on

stra

ted

”

[39]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le (

wh

en d

efin

ed).

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

MA

S: M

od

ified

Ash

wo

rth

Scal

e; R

OM

: Ran

ge

of m

ove

men

t; V

AS:

Vis

ual a

nalo

g sc

ale.



ble

3. D

ose

-ran

gin

g s

tud

ies

for

abo

bo

tulin

um

toxi

nA

(co

nt.

).

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Sup

pu

tita

da

et a

l. (2

005

)

Ran

do

miz

ed,

do

ub

le-b

lind

, d

ose

-ran

gin

g

stu

dy

Key

elig

ibili

ty

crit

eria

:Pa

tien

ts (

aged

≥1

5 y e

ars)

wit

h

spas

tici

ty o

f an

y ca

use

wh

o w

ere

amb

ula

tory

an

d c

om

pet

ent,

an

d r

ecei

ved

at

leas

t 6

mo

nth

s o

f re

hab

ilita

tive

th

erap

y

Key

exc

lusi

on

cr

iter

ia:

Co

mp

lete

ple

gia

, fi

xed

co

ntr

actu

res

in t

he

stu

dy

limb

, o

bvi

ou

s at

rop

hy

of

the

mu

scle

s in

th

e st

ud

y lim

b

Inje

ctio

ns

wer

e m

ade

into

th

e b

icep

s b

rach

ii, fl

exo

r d

igit

oru

m s

up

erfi

cial

is, fl

exo

r d

igit

oru

m p

rofu

nd

us,

flex

or

carp

i uln

aris

an

d fl

exo

r ca

rpi

rad

ialis

Plac

ebo

(n

= 1

5)

AB

O 3

50 U

(n

= 1

5)

AB

O 5

00

U (

n =

15

)A

BO

10

00

U (

n =

5)

•A

ll th

ree

AB

O d

ose

s re

sult

ed in

a

s ig

nifi

can

t d

ecre

ase

in M

AS

at

wee

k 8

vs p

lace

bo

. Th

e ch

ang

e in

MA

S w

as s

ign

ifica

ntl

y h

igh

er

in b

oth

th

e 50

0 an

d 1

00

0 U

g

rou

ps

com

par

ed w

ith

AB

O

350

U (

p <

0.0

5)

•M

ean

pai

n V

AS

dec

reas

ed

wit

hin

2 w

eek

s p

ost

-tre

atm

ent

and

ap

pro

ach

ed it

s lo

wes

t va

lue

by

wee

k 8

in a

ll th

ree

AB

O g

rou

ps

•C

om

par

ed w

ith

pla

ceb

o,

AB

O 5

00

U d

emo

nst

rate

d

a si

gn

ifica

nt

incr

ease

in t

he

Act

ion

Res

earc

h A

rm t

est

at w

eek

s 8

and

24

(p <

0.0

5)

The

on

ly A

E co

nsi

der

ed r

elat

ed

to A

BO

was

“to

o

mu

ch w

eakn

ess”

(n

= 5

of

5 in

th

e A

BO

10

00

U g

rou

p)

“Th

is s

tud

y su

gg

est

that

tr

eatm

ent

wit

h A

BO

re

du

ces

mu

scle

to

ne

in a

du

lt p

atie

nts

wit

h

up

per

lim

b s

pas

tici

ty.

The

op

tim

al d

ose

fo

r tr

eatm

ent

of

pat

ien

ts

wit

h r

esid

ual

vo

lun

tary

m

ove

men

t in

th

e u

pp

er

limb

ap

pea

rs t

o b

e 50

0 U

”

[40]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le (

wh

en d

efin

ed).

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

MA

S: M

od

ified

Ash

wo

rth

Scal

e; R

OM

: Ran

ge

of m

ove

men

t; V

AS:

Vis

ual a

nalo

g sc

ale.



ble

4. S

tud

ies

of

abo

bo

tulin

um

toxi

nA

fo

r th

e m

anag

emen

t o

f p

ost

stro

ke s

ho

uld

er p

ain

.

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Ko

ng

et

al. (

2007

)

Ran

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

-co

ntr

olle

d

stu

dy

Key

elig

ibili

ty c

rite

ria

:Pa

tien

ts (

aged

21

–80

year

s) w

ith

h

emip

leg

ic s

ho

uld

er

pai

n (

sco

re ≥

4/1

0 o

n

VA

S) a

nd

sh

ou

lder

ad

du

cto

r/el

bo

w fl

exo

r sp

asti

city

(M

AS ≥2

).

Pati

ents

wer

e ≥3

mo

nth

s p

ost

stro

ke

Key

exc

lusi

on

cri

teri

a:

Prev

iou

s h

isto

ry o

f b

ack

or

sho

uld

er p

ain

bef

ore

st

roke

; po

stst

roke

ce

ntr

al p

ain

; pre

vio

us

Bo

NT

trea

tmen

t; r

eflex

sy

mp

ath

etic

dys

tro

ph

y

Inje

ctio

ns

wer

e m

ade

into

th

e p

ecto

ralis

maj

or

and

bic

eps

bra

chii

Plac

ebo

(n

= 9

)A

BO

50

0 U

(n

= 8

)

•N

o s

ign

ifica

nt

dif

fere

nce

s b

etw

een

g

rou

ps

in s

ho

uld

er p

ain

or

pas

sive

sh

ou

lder

ab

du

ctio

n r

ang

e•

Co

mp

ared

wit

h p

lace

bo

, pat

ien

ts

trea

ted

wit

h A

BO

had

sig

nifi

can

tly

gre

ater

imp

rove

men

ts in

sh

ou

lder

ad

du

cter

an

d e

lbo

w fl

exo

r M

AS

at

wee

k 4

( p <

0.0

1), b

ut

no

t at

wee

ks

8 an

d 1

2

Pain

ob

serv

ed in

si

x A

BO

-tre

ated

p

atie

nts

“In

pat

ien

ts w

ith

ch

ron

ic h

emip

leg

ia

pai

n a

sso

ciat

ed w

ith

sh

ou

lder

ad

du

cto

r an

d e

lbo

w fl

exo

r sp

asti

city

, [A

BO

] is

ef

fect

ive

in r

edu

cin

g

spas

tici

ty c

om

par

ed

wit

h p

lace

bo

. Th

is

red

uct

ion

in s

pas

tici

ty

did

no

t im

pac

t o

n

sho

uld

er p

ain

”

[41]

Mar

co e

t al

. (20

07)

Ran

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

-co

ntr

olle

d

stu

dy

Key

elig

ibili

ty c

rite

ria

:Pa

tien

ts w

ith

m

od

erat

e–s

ever

e sh

ou

lder

pai

n a

nd

mu

scle

sp

asti

city

(M

AS ≥3

) p

ost

stro

ke; a

t le

ast

3 m

on

ths

afte

r o

nse

t o

f ce

reb

rova

scu

lar

even

t

Key

exc

lusi

on

cri

teri

a:

Mild

hem

ipar

esis

, co

nco

mit

ant

sho

uld

er

pat

ho

log

y

Inje

ctio

ns

wer

e m

ade

into

th

e p

ecto

ralis

maj

or

Plac

ebo

(n

= 1

5)

AB

O 5

00

U (

n =

14

)

•Pa

tien

ts in

th

e A

BO

gro

up

sh

ow

ed a

si

gn

ifica

ntl

y g

reat

er p

ain

imp

rove

men

t vs

pla

ceb

o a

t 1,

3 a

nd

6 m

on

ths

(p =

0.0

35)

•Pa

tien

ts in

th

e A

BO

gro

up

sh

ow

ed

incr

ease

d s

ho

uld

er a

bd

uct

ion

fro

m t

he

firs

t w

eek

un

til m

on

th 6

. Ho

wev

er, t

he

bet

wee

n g

rou

p d

iffe

ren

ce a

t m

on

th 6

w

as n

ot

stat

isti

cally

sig

nifi

can

t•

Pati

ents

in t

he

AB

O g

rou

p s

ho

wed

si

gn

ifica

ntl

y g

reat

er im

pro

vem

ents

in

mea

n e

xter

nal

ro

tati

on

of

the

sho

uld

er

vs p

lace

bo

(p

= 0

.041

)•

No

sig

nifi

can

t d

iffe

ren

ces

bet

wee

n

trea

tmen

t g

rou

ps

wer

e o

bse

rved

fo

r sh

ou

lder

flex

ion

or

spas

tici

ty

thro

ug

ho

ut

the

follo

w-u

p

No

imp

ort

ant

AEs

wer

e re

po

rted

“[A

BO

] is

mo

re

effe

ctiv

e th

an

pla

ceb

o in

red

uci

ng

p

ain

an

d im

pro

vin

g

exte

rnal

ro

tati

on

in

pat

ien

ts w

ith

vas

cula

r h

emip

leg

ia w

ith

sp

asti

c sh

ou

lder

pai

n”

[42]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le (

wh

en d

efin

ed).

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

Bo

NT:

Bot

ulin

um

tox

in; M

AS:

Mo

difi

ed A

shw

ort

h Sc

ale;

RO

M: R

ang

e of

mo

vem

ent;

VA

S: V

isua

l ana

log

scal

e.



ble

4. S

tud

ies

of

abo

bo

tulin

um

toxi

nA

fo

r th

e m

anag

emen

t o

f p

ost

stro

ke s

ho

uld

er p

ain

(co

nt.

).

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Yel

nik

et

al. (

2007

)

Ran

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

-co

ntr

olle

d,

two

par

alle

l gro

up

st

ud

y

Key

elig

ibili

ty c

rite

ria

: U

pp

er li

mb

sp

asti

city

re

late

d t

o a

cer

ebra

l st

roke

; med

ial r

ota

tor

and

elb

ow

flex

or

spas

tici

ty M

AS ≥1

; lim

ited

pas

sive

RO

M o

f th

e sh

ou

lder

Key

exc

lusi

on

cri

teri

a:

Prev

iou

s tr

aum

atic

or

neu

rolo

gic

al d

isea

se;

retr

acti

on

of ≥1

mu

scle

; p

revi

ou

s tr

eatm

ent

wit

h B

oN

T o

r al

coh

ol i

n

sub

scap

ula

ris

Inje

ctio

ns

wer

e m

ade

into

th

e su

bsc

apu

lari

s m

usc

le

Plac

ebo

(n

= 1

0)

AB

O 5

00

U (

n =

10

)

•Pa

in im

pro

vem

ent

was

see

n in

wee

k 1

in t

he

AB

O 5

00

U g

rou

p a

nd

rea

ched

si

gn

ifica

nce

in w

eek

4 (p

= 0

.025

vs

pla

ceb

o)

•La

tera

l ro

tati

on

was

imp

rove

d w

ith

AB

O

trea

tmen

t•

Spas

tici

ty d

ecre

ased

fo

r u

pp

er li

mb

m

usc

les

No

AEs

rep

ort

ed

to b

e re

late

d t

o

AB

O t

reat

men

t

“Su

bsc

apu

lari

s in

ject

ion

of

[AB

O]

app

ears

to

be

of

valu

e in

th

e m

anag

emen

t o

f sh

ou

lder

pai

n in

sp

asti

c h

emip

leg

ic

pat

ien

ts. T

he

resu

lts

con

firm

th

e ro

le

of

spas

tici

ty in

p

ost

stro

ke s

ho

uld

er

pai

n”

[43]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le (

wh

en d

efin

ed).

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e e v

ent;

Bo

NT:

Bot

ulin

um

tox

in; M

AS:

Mo

difi

ed A

shw

ort

h S c

ale;

RO

M: R

ang

e o f

mo

vem

ent;

VA

S: V

isua

l ana

log

s cal

e.



ble

5. O

pen

-lab

el s

tud

y o

f ab

ob

otu

linu

mto

xin

A.

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Shaw

et

al. (

2010

)

Op

en-l

abel

, p

aral

lel g

rou

p,

ran

do

miz

ed,

con

tro

lled

tri

al

and

eco

no

mic

ev

alu

atio

n

Key

elig

ibili

ty

crit

eria

:Pa

tien

ts w

ith

up

per

lim

b s

pas

tici

ty a

t th

e el

bo

w (

MA

S >

2),

sh

ou

lder

, wri

st o

r h

and

an

d r

edu

ced

u

pp

er li

mb

fu

nct

ion

d

ue

to s

tro

ke ≥

1 m

on

th p

revi

ou

sly

Key

exc

lusi

on

cr

iter

ia:

Oth

er s

ign

ifica

nt

up

per

lim

b

imp

airm

ent;

fi

xed

co

ntr

actu

re;

sig

nifi

can

t sp

eech

o

r co

gn

itiv

e im

pai

rmen

ts; u

se

of

Bo

NT

in p

rio

r 3

mo

nth

s

Inje

ctio

ns

wer

e m

ade

into

th

e fl

exo

r d

igit

oru

m

sup

erfi

cial

is, fl

exo

r d

igit

oru

m p

rofu

nd

us,

fl

exo

r p

olli

cis

lon

gu

s,

fore

arm

flex

ors

, flex

or

carp

i uln

aris

, flex

or

carp

i ra

dia

lis b

icep

s b

rach

ii,

bra

chio

rad

ialis

, pro

nat

or

tere

s an

d p

ecto

ralis

m

ajo

r

Co

ntr

ol (

n =

163

)A

BO

max

10

00

U

(n =

170

)

•N

o s

ign

ifica

nt

dif

fere

nce

b

etw

een

gro

up

s fo

r im

pro

ved

ar

m f

un

ctio

n a

t m

on

ths

1, 3

o

r 12

•Tr

eatm

ent

wit

h A

BO

si

gn

ifica

ntl

y re

du

ced

sp

asti

city

at

th

e el

bo

w v

s co

ntr

ol

(p <

0.0

01)

•C

om

par

ed w

ith

co

ntr

ol,

pat

ien

ts

trea

ted

wit

h A

BO

sh

ow

ed

imp

rove

men

ts in

up

per

lim

b

mu

scle

str

eng

th a

t 3

mo

nth

s (p

= 0

.055

) an

d t

ota

l mo

tor

imp

airm

ent

(p =

0.0

42)

•Pa

rtic

ipan

ts in

th

e A

BO

gro

up

w

ere

mo

re li

kely

to

be

able

to

un

der

take

sp

ecifi

c b

asic

fu

nct

ion

al a

ctiv

itie

s (d

ress

a

slee

ve, c

lean

th

e p

alm

an

d o

pen

th

e h

and

fo

r cu

ttin

g fi

ng

ern

ails

) at

1 m

on

th (

p =

0.0

33)

and

3 m

on

ths

(p =

0.0

27).

Im

pro

vem

ent

was

su

stai

ned

at

12

mo

nth

s fo

r o

pen

ing

th

e h

and

fo

r cl

ean

ing

th

e p

alm

an

d

op

enin

g t

he

han

d f

or

cutt

ing

th

e n

ails

bu

t n

ot

for

oth

er

acti

viti

es•

Pain

rat

ing

was

sig

nifi

can

tly

imp

rove

d in

th

e A

BO

gro

up

vs

con

tro

l at

12 m

on

ths

(p =

0.0

04

),

bu

t n

o s

ign

ifica

nt

dif

fere

nce

s w

ere

seen

at

1 o

r 3

mo

nth

s

Ther

e w

as a

hig

her

in

cid

ence

of

gen

eral

m

alai

se/fl

u-l

ike

/co

ld s

ymp

tom

s in

p

arti

cip

ants

tre

ated

w

ith

AB

O w

ith

a

rela

tive

ris

k o

f 7.

6.O

nly

on

e se

rio

us

AE

(dys

ph

agia

) w

as

po

ten

tial

ly r

elat

ed t

o

AB

O t

reat

men

t

“Th

e ad

dit

ion

of

[AB

O]

to a

n u

pp

er li

mb

th

erap

y p

rog

ram

me

to t

reat

sp

asti

city

d

ue

to s

tro

ke d

id n

ot

enh

ance

imp

rove

men

t in

up

per

lim

b f

un

ctio

n

wh

en a

sses

sed

by

the

pre

spec

ified

pri

mar

y o

utc

om

e m

easu

re a

t 1

mo

nth

. Ho

wev

er,

imp

rove

men

ts w

ere

seen

in m

usc

le t

on

e at

1

mo

nth

, up

per

lim

b

stre

ng

th a

t 3

mo

nth

s,

up

per

lim

b f

un

ctio

nal

ac

tivi

ties

rel

ated

to

u

nd

erta

kin

g s

pec

ific

bas

ic f

un

ctio

nal

tas

ks

at 1

, 3 a

nd

12

mo

nth

s,

and

up

per

lim

b p

ain

at

12 m

on

ths”

[44]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le.

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

Bo

NT:

Bot

ulin

um

tox

in; M

AS:

Mo

difi

ed A

shw

ort

h Sc

ale.



ble

6. S

tud

y o

f ab

ob

otu

linu

mto

xin

A g

iven

to

get

her

wit

h e

lect

rica

l sti

mu

lati

on

.

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Hes

se e

t al

. (19

98

)

Ran

do

miz

ed,

do

ub

le-b

lind

, p

lace

bo

-co

ntr

olle

d s

tud

y

Key

elig

ibili

ty c

rite

ria

: Pa

tien

ts w

ith

sev

ere

up

per

lim

b fl

exo

r (e

lbo

w, w

rist

, fin

ger

) sp

asti

city

(M

AS

sco

re ≥

3).

Aff

ecte

d

extr

emit

y h

ad t

o b

e n

on

fun

ctio

nal

Key

exc

lusi

on

cri

teri

a:

Mu

scle

co

ntr

actu

res;

p

revi

ou

s tr

eatm

ent

wit

h B

oN

T, n

euro

lyti

c tr

eatm

ent

or

surg

ery

for

spas

tici

ty

Inje

ctio

ns

wer

e m

ade

into

th

e b

icep

s b

rach

ii,

bra

chia

lis, fl

exo

r d

igit

oru

m s

up

erfi

cial

is,

flex

or

dig

ito

rum

p

rofu

nd

us,

flex

or

carp

i u

lnar

is a

nd

flex

or

carp

i ra

dia

lis

Plac

ebo

(n

= 6

)Pl

aceb

o +

ele

ctri

cal

stim

ula

tio

n (

n =

6)

AB

O 1

00

0 U

(n

= 6

)A

BO

10

00

U +

ele

ctri

cal

stim

ula

tio

n (

n =

6)

•M

usc

le t

on

e re

du

ctio

n

was

mo

st p

red

om

inan

t in

pat

ien

ts t

reat

ed

wit

h A

BO

10

00

U a

nd

el

ectr

ical

sti

mu

lati

on

, p

arti

cula

rly

wit

h t

he

elb

ow

join

t (p

= 0

.011

)•

No

dif

fere

nce

s in

m

usc

le t

on

e o

bse

rved

fo

r fi

ng

er o

r w

rist

•N

o s

ign

ifica

nt

dif

fere

nce

s in

lim

b

po

siti

on

at

rest

acr

oss

g

rou

ps.

Ho

wev

er, t

he

mo

st p

ron

ou

nce

d

imp

rove

men

ts (

flex

ion

fr

om

neu

tral

) w

ere

seen

in p

atie

nts

tr

eate

d w

ith

AB

O

100

0 U

an

d e

lect

rica

l st

imu

lati

on

•Pa

tien

ts t

reat

ed w

ith

A

BO

10

00

U a

nd

el

ectr

ical

sti

mu

lati

on

sh

ow

ed t

he

bes

t sc

ore

s fo

r A

DLs

(cl

ean

ing

th

e p

alm

, cu

ttin

g

fin

ger

nai

ls a

nd

pu

ttin

g

affe

cted

arm

th

rou

gh

sl

eeve

; p =

0.0

04

)

Trea

tmen

t w

as w

ell

tole

rate

d w

ith

no

st

ud

y-re

late

d A

Es

rep

ort

ed

“Th

e p

lace

bo

-co

ntr

olle

d t

rial

fa

vou

rs t

he

con

cep

t th

at

elec

tric

al s

tim

ula

tio

n e

nh

ance

s th

e ef

fect

iven

ess

of

[AB

O]

in

the

trea

tmen

t o

f ch

ron

ic u

pp

er

limb

flex

or

spas

tici

ty a

fter

st

roke

”

[45]

AB

O: A

bo

bot

ulin

um

toxi

nA

; AD

L: A

ctiv

itie

s o f

dai

ly l i

vin

g; A

E: A

dve

rse

e ven

t; B

oN

T: B

otu

linu

m t

oxin

; MA

S: M

od

ified

Ash

wo

rth

S cal

e.



Tab

le 7

. Effi

cacy

of

abo

bo

tulin

um

toxi

nA

in e

arly

str

oke

.

Des

ign

Pati

ent

po

pu

lati

on

Trea

tmen

t (n

)Ef

fica

cy r

esu

lts†

Safe

ty r

esu

lts

Au

tho

r co

ncl

usi

on

sR

ef.

Ro

sale

s et

al.

(201

2)

Mu

ltic

ente

r (A

sian

) ra

nd

om

ized

, p

lace

bo

-co

ntr

olle

d t

rial

Key

elig

ibili

ty c

rite

ria

: A

sian

pat

ien

ts (

aged

18

–80

year

s) w

ere

recr

uit

ed w

ith

in

2–12

wee

ks

afte

r th

eir

firs

t-ev

er s

tro

ke w

ith

im

pai

rmen

t (M

AS

sco

re

of ≥1

in t

he

elb

ow

or

wri

st jo

int.

Pat

ien

t al

so

had

to

hav

e w

eakn

ess

of ≥2

acc

ord

ing

to

MR

C

crit

eria

in t

he

rele

van

t jo

int

Key

exc

lusi

on

cri

teri

a:

Pres

tro

ke R

anki

n s

core

>1

Inje

ctio

ns

wer

e m

ade

into

th

e b

icep

s b

rach

ii,

bra

chio

rad

ialis

, car

pi

uln

aris

an

d t

he

flex

or

carp

i rad

ialis

Plac

ebo

(n

= 8

3)

AB

O 5

00

U (

n =

80

)

•A

t 4

wee

ks

po

stin

ject

ion

, A

BO

sig

nifi

can

tly

imp

rove

d M

AS

sco

res

(mo

st a

ffec

ted

join

t,

wri

st jo

int,

elb

ow

join

t an

d c

om

bin

ed jo

ints

); a

ll p

< 0

.00

01•

Trea

tmen

t ef

fect

-siz

e es

tim

ates

incr

ease

d w

ith

h

igh

er b

asel

ine

MA

S sc

ore

s fr

om

0.4

5 (Q

1) t

o 0

.70

(Q3

)•

Alt

ho

ug

h n

ot

all

par

tici

pan

ts r

epo

rted

pai

n,

AB

O-t

reat

ed p

atie

nts

re

po

rted

red

uct

ion

s in

sp

asti

city

-rel

ated

pai

n

com

par

ed w

ith

bas

elin

e th

rou

gh

ou

t th

e st

ud

y,

and

th

is w

as s

ign

ifica

ntl

y g

reat

er t

han

pla

ceb

o

at w

eek

s 4

and

24

•N

o s

ign

ifica

nt

dif

fere

nce

o

n t

he

Fun

ctio

nal

Mo

tor

Ass

essm

ent

Scal

e

Fou

r A

Es w

ere

rep

ort

ed t

o b

e re

late

d t

o A

BO

tr

eatm

ent:

fat

igu

e (t

wo

eve

nts

),

pyr

exia

an

d

mu

scu

lar

wea

knes

s

“[A

BO

] 50

0 U

can

p

rovi

de

a su

stai

ned

re

du

ctio

n in

p

ost

stro

ke u

pp

er

limb

sp

asti

city

w

hen

co

mb

ined

w

ith

reh

abili

tati

on

in

Asi

an p

atie

nts

w

ho

hav

e m

ild-

to-m

od

erat

e h

yper

ton

icit

y an

d v

olu

nta

ry

mo

vem

ent,

wit

hin

2–

12 w

eek

s o

f st

roke

. Fu

nct

ion

al

use

of

the

arm

an

d h

and

was

no

t af

fect

ed”

[46]

† Res

ult

s in

bo

ld r

epre

sent

th

e p

rim

ary

effi

cacy

var

iab

le (

wh

en d

efin

ed).

AB

O: A

bo

bot

ulin

um

toxi

nA

; AE:

Ad

vers

e ev

ent;

MA

S: M

od

ified

Ash

wo

rth

Scal

e; M

RC

: Med

ical

Res

earc

h C

ou

nci

l.



strength, which may further impede function” [48]. More recently, Foley and colleagues performed a meta-analysis of 16 poststroke BoNT-A RCTs that included some sort of an activity outcome (e.g., Action Research Arm Test, Barthel Index) [49]. This large meta-analysis found that, while there was substantial variation of effect sizes in the individual studies due to the use of differing outcome measures, treatment with BoNT-A was overall associated with moderate improvement in upper-extremity activity capacity or performance after stroke [49].

These post-hoc analyses should be interpreted with caution, and the problem of how to best demonstrate functional improvement in an individual clinical trial has recently become the focus of much debate. A review of upper limb function measurement meth-ods found that none of the methods currently used to assess function after BoNT treatment for upper limb spasticity satisfactorily fulfills all the criteria for a rel-evant outcome measure when used on their own [50]. The MAS is often criticized as being unable to dis-tinguish between spasticity and soft tissue shortening, and experts suggest using the modified Tardieu scale as a better measure of spasticity [51–53]. Guidelines now also recommend that improved and reliable functional outcomes after BoNT-A therapy may be achieved when patient-specific goals that incorporate realistic expectations (e.g., improving passive as well as active functions and reducing pain) are used as functional outcome measures [11]. Emphasis is also placed on the duration of study so as to allow learning, rehabilitation and possibly even allow plasticity to occur [54]. Another aspect of current debate is the screening of suitable patients (inclusion criteria) for entry into clinical trials. Before starting treatment, it is important to assess if the patient has the “potential to improve” with spastic-ity reduction [55]. For example, it has been argued that studies such as the BOTULS study reported by Shaw and colleagues were unlikely to show a great functional benefit of treatment because they did not specifically include patients with the potential for functional change [44]. A patient with significant underlying ple-gia (weakness) is perhaps less likely to gain functional improvements through a reduction in spasticity.

Efficacy in real-world practiceIn addition to randomized controlled studies, the effi-cacy of abobotulinumtoxinA in upper limb spasticity is supported by a number of open-label, ‘real-life practice’ studies. Two studies in particular provide confirmation that beneficial effects observed with abobotulinum-toxinA under clinical trial conditions also extend to real-world practice [18,56]. In their retrospective analysis of their clinics database, Mohammadi and colleagues

reviewed data from 137 patients with spasticity of various aetiologies who received 1221 BoNT-A treat-ments (at least eight consecutive treatments) for up to 12 years [56]. Of the 105 patients who were treated with abobotulinumtoxinA (7.5 years; range: 2–12 years), 16 patients were treated in the upper limb only. In these patients the mean latency between injection and response to abobotulinumtoxinA was 6.8 ± 3.6 days and the treatment effect was observed for a mean duration of 11.6 ± 3.1 weeks [56].

The ULIS-2 study reported by Turner-Stokes and colleagues was a large prospective, multicenter, obser-vational study of patients with poststroke upper limb spasticity that included 456 patients who received one cycle of BoNT-A treatment under routine practice con-ditions [18]. The majority of patients (n = 321; 70%) received treatment with abobotulinumtoxinA. The primary outcome was achievement of the patient’s pri-mary goal using goal attainment scaling (GAS) and the study showed that overall, 363 (79.6%) patients achieved (or overachieved) their primary goal and 355 (75.4%) mainly in terms of passive and active functions and pain reduction [18]. Importantly, GAS T-scores were correlated with global assessment of benefits (patient and investigator rated), as well as reductions in muscle tone. Baseline and mean change from baseline in GAS T-scores were similar between BoNT-A preparations.

Safety & tolerabilityThe safety and tolerability profile of abobotulinum-toxinA is also well established in patients with upper limb spasticity. In the pivotal placebo-controlled trials of patients with upper limb spasticity, the incidence of adverse events (AEs) was generally comparable between abobotulinumtoxinA and placebo and the overall frequency of AEs did not demonstrate a rela-tionship with abobotulinumtoxinA dose [34,35]. Across the clinical trials of abobotulinumtoxinA in patients with spasticity, the most commonly experienced AEs were dysphagia and arm muscle weakness, abnormal gait and accidental injury or falls (Tables 1–7). Less frequently reported AEs that were considered possibly related to single-dose treatment included: skin rashes, flu-like symptoms, fatigue, tiredness and pain in the arm following injection [34,35]. However, these were mostly mild and transient in nature. Repeated treat-ment with abobotulinum toxinA has also been shown to be well tolerated in upper limb spasticity, with no cumulative effect of dosing with abobotulinumtox-inA over multiple treatment cycles [57]. It must how-ever be noted that, in the USA, all BoNT products (including abobotulinumtoxinA) carry a black box warning about the possible risk of spread of the toxin



away from the site of injection to other areas of the body producing symptoms consistent with botulism (including swallowing or breathing difficulties, which can be life-threatening) [58]. Similar warnings and precautions for use are in place for all BoNT in other countries.

Practical considerationsFor the treatment of adult upper limb spasticity, abo-botulinumtoxinA should be initially administered at a recommended dose of up to 1000 U, given as a divided dose at multiple injection sites depending on the affected limb. However, a lower dose may be advisable if target muscles are small or concomitant treatment of other muscle groups is intended. For subsequent treat-ment, the manufacturer recommends that the maxi-mum abobotulinumtoxinA dose should not exceed 1000 U. Injections may be repeated approximately every 16 weeks, or as required to maintain a response, but not more frequently than every 12 weeks. This treatment interval is important for all BoNT-A for-mulations because, although the development of neu-tralizing antibodies is a relatively rare event, studies comparing patient groups with and without antibody-induced therapy failure have shown that shorter dos-ing intervals, more booster injections, higher BoNT-A

doses at each injection series and higher cumulative doses are clinically relevant risk factors for antibody formation [59]. No clinically relevant differences in immunogenicity between the various BoNT-A prod-ucts have been reported. According to published data, only a small number of patients develop antibodies that neutralize the clinical effect of BoNT-A. When a patient develops neutralizing antibodies against a specific serotype, the patient will not respond to any preparation of the same serotype. Other consider-ations include the use of guidance techniques such as electro stimulation, electromyography and ultrasound to improve the accuracy of injections, but a review of these is out of the scope of this article.

Conclusion & future perspectiveIn summary, evidence-based clinical practice guide-lines advocate BoNT-A as a mainstay treatment option for patients with spasticity. Injections of abobotulinum toxinA have been consistently shown to provide significant clinical efficacy in the man-agement of spasticity, as shown in numerous clinical trials and real-life studies. Key findings from clinical studies lend support to abobotulinumtoxinA as an efficacious long-term treatment for spasticity, with benefits extending to overall patient function.

Executive summary

• Spasticity is a common feature of the upper motor neuron syndrome and is seen in a variety of diseases and conditions. When present, the burden of disability associated with spasticity can exert an immense impact on patient quality of life, as well as greater dependability on the caregiver and increased societal costs.

• Botulinum neurotoxin type A is an acknowledged mainstay pharmacological treatment for the management of spasticity.

• The abobotulinumtoxinA neurotoxin complex is produced by fermentation of Clostridium botulinum type A, Hall strain and purified from the culture supernatant by a series of proprietary precipitation, dialysis and chromatography steps.

• Like all other botulinum neurotoxin type A products, abobotulinumtoxinA is a muscle relaxant agent that achieves its therapeutic effects on spasticity through the blockade of acetylcholine release.

• The efficacy and safety of abobotulinumtoxinA in upper limb spasticity has been established by several trials in the clinical development program and by further independent research, including large observational studies.

• All but one of the studies showed significant benefits of abobotulinumtoxinA versus placebo on the reduction of muscle tone as assessed by the Modified Ashworth Scale. The studies generally showed that clinically significant (≥1 point on modified Ashworth scale) reductions in muscle tone were achieved within 2 weeks after injection.

• By contrast, it was harder to demonstrate meaningful effects of abobotulinumtoxinA on functional improvement. However, meta-analytic approaches that combine data from many studies have suggested that reducing spasticity in the arm is associated with significant improvements in arm function.

• In the pivotal placebo-controlled trials, the incidence of adverse events (AEs) was generally comparable between abobotulinumtoxinA and placebo and the overall frequency of AEs did not demonstrate a relationship with abobotulinumtoxinA dose. The most commonly experienced AEs were dysphagia and arm muscle weakness, abnormal gait and accidental injury or falls. Repeated treatment with abobotulinumtoxinA has also been shown to be well tolerated in upper limb spasticity, with no cumulative effect of dosing over multiple treatment cycles.



Within the next years, we will hopefully get the approval to treat any focal spasticity. With support of electromyography and especially sonography the therapeutic results will be optimized.

Financial & competing interests disclosureWH Jost reports acting as a speaker and advisor to Ipsen, Al-

lergan and Merz. In addition to the peer-review process, with

the author(s) consent, the manufacturer of the product(s) dis-

cussed in this article was given the opportunity to review the

manuscript for factual accuracy. Changes were made at the

discretion of the author(s) and based on scientific or edito-

rial merit only. The author has no other relevant affiliations or

financial involvement with any organization or entity with a

financial interest in or financial conflict with the subject mat-

ter or materials discussed in the manuscript. This includes em-

ployment, consultancies, honoraria, stock ownership or op-

tions, expert testimony, grants or patents received or pending

or royalties.

Medical writing support was provided by A Chadha-Patel

(ACP Clinical Communications Ltd, London, UK) funded by

Ipsen Pharma GMbH.

Open AccessThis work is licensed under the Creative Commons Attribu-

tion-NonCommercial 3.0 Unported License. To view a copy

of this license, visit http://creativecommons.org/licenses/by-

nc-nd/3.0/

ReferencesPapers of special note have been highlighted as: • of interest; •• of considerable interest

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Clinical Trial Outcomes AbobotulinumtoxinA for the ... · Upper limb spasticity is a common feature of many conditions arising from stroke, brain injury or progressive neurological