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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
wolfgang.jost@uniklinik-freiburg.de
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,
For reprint orders, please contact reprints@future-science.com
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
850 Clin. Invest. (Lond.) (2014) 4(9) future science group
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.
www.future-science.com 851future science group
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.
852 Clin. Invest. (Lond.) (2014) 4(9) future science group
Clinical Trial Outcomes JostTa
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.
www.future-science.com 853future science group
AbobotulinumtoxinA for the treatment of upper limb spasticity Clinical Trial Outcomes
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.).
854 Clin. Invest. (Lond.) (2014) 4(9) future science group
Clinical Trial Outcomes Jost
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.
www.future-science.com 855future science group
AbobotulinumtoxinA for the treatment of upper limb spasticity Clinical Trial OutcomesTa
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.
856 Clin. Invest. (Lond.) (2014) 4(9) future science group
Clinical Trial Outcomes JostTa
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.
www.future-science.com 857future science group
AbobotulinumtoxinA for the treatment of upper limb spasticity Clinical Trial OutcomesTa
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.
858 Clin. Invest. (Lond.) (2014) 4(9) future science group
Clinical Trial Outcomes JostTa
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.
www.future-science.com 859future science group
AbobotulinumtoxinA for the treatment of upper limb spasticity Clinical Trial OutcomesTa
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.
860 Clin. Invest. (Lond.) (2014) 4(9) future science group
Clinical Trial Outcomes Jost
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.
www.future-science.com 861future science group
AbobotulinumtoxinA for the treatment of upper limb spasticity Clinical Trial Outcomes
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
862 Clin. Invest. (Lond.) (2014) 4(9) future science group
Clinical Trial Outcomes Jost
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.
www.future-science.com 863future science group
AbobotulinumtoxinA for the treatment of upper limb spasticity Clinical Trial Outcomes
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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