Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

STROKE PATIENTS

UPPER LIMB SPASTICITY

Gracies, 2015

Type of study:

Randomized controlled trial

Setting: 34 neurology or rehabilitation clinics in Europe and the USA

Country: Belgium, Czech Republic, France, Hungary, Italy, Poland, Russia, Slovakia, and the USA

Source of funding: Commercial

Inclusion criteria:

• Age 18-80 years
• Hemiparesis for at least 6 months after a stroke or traumatic brain injury
• MAS score in the primary target muscle group (PTMG) of at least 2 for patients who had no previous botulinum toxin A injection in the paretic limb or at least 3 for patients with previous injections of botulinum toxin A in the paretic limb
• DAS score of at least 2 on the principal target of treatment
• Spasticity angle of at least 10° in the PTMG
• Mean Modified Frenchay Scale (MFS) score of 1-8 (over a total possible score of 10)

Exclusion criteria:

• Major limitations in the passive range of motion in the paretic limb
• Physiotherapy initiated less than 4 weeks before the expected enrolment
• Treatment with botulinum toxin A of any type in the previous 4 months
• Anticipated botulinum toxin A treatment in the lower limb during the study
• Previous surgery
• Administration of alcohol or phenol in the study limb
• Any medical disorder increasing the risk of botulinum-toxin-A-related adverse events
• Major neurological impairment that could negatively affect functional performance

N total at baseline:

I1: 80

I2: 79

C: 79

Important prognostic factors²:

Mean age (SD):

I1: 52 (13)

I2: 52 (14)

C: 52 (14)

Sex:

I1: 65% M

I2: 66% M

C: 62% M

Groups comparable at baseline?

Yes

AbobotulinumtoxinA (Dysport)

A single injection session of 500 IU or 1000 IU into the most hypertonic muscle group among the elbow, wrist, or finger flexors, and into at least two additional muscle groups from the elbow, wrist, or finger flexors or shoulder extensors. The only accepted technique for targeting the muscle was electrical stimulation

Placebo

Length of follow-up:

12 weeks

Loss-to-follow-up:

I1: N = 3 (4%)

Reasons: 1 adverse event; 1 moved out of the study area; 1 family reason

I2: N = 4 (5%)

Reasons: 1 adverse event; 2 consent withdrawn; 1 non-compliance

C: N = 7 (9%)

Reasons: 3 adverse events; 1 consent violation; 2 protocol violations; 1 lost to follow-up

Incomplete outcome data:

I1: N = 1 (1%)

Reasons: no baseline or week 4 MAS score

I2: N = 2 (2%)

Reasons: no baseline or week 4 MAS score

C: N = 2 (2%)

Reasons: no baseline or week 4 MAS score

Muscle tone

Measured as the change from baseline in MAS, mean (SE)

Baseline

I1: 3.9 (SD 0.5)

I2: 3.9 (SD 0.4)

C: 3.9 (SD 0.4)

Week 1

I1: -0.9 (0.1)

I2: -0.7 (0.1)

C: -0.2 (0.1)

p<0.0001 compared with placebo

Week 4

I1: -1.2 (0.1)

I2: -1.4 (0.1)

C: -0.3 (0.1)

p<0.0001 compared with placebo

Week 12

I1: -0.6 (0.1)

I2: -0.7 (0.1)

C: -0.1 (0.1)

p<0.0001 compared with placebo

Range of Motion

“Active range of motion improved for movements opposing finger, wrist, and elbow flexors in the abobotulinumtoxinA 1000 U group but only for finger flexors in the 500 U group.”

Physician Global Assessment

Measured on a 9-point scale from -4 (markedly worse) to 4 (markedly improved), mean (SE)

Week 4

I1: 1.4 (0.1)

I2: 1.8 (0.1)

C: 0.6 (0.1)

p<0.0003 compared with placebo

Week 12

I1: 0.5 (0.1)

I2: 0.9 (0.1)

C: 0.5 (0.1)

p=0.001 for I2 compared with placebo

Functional disability

Measured with Disability Assessment Scale (DAS), improvement in principal therapeutic target from baseline, mean (SE)

Baseline

I1: 2.6 (SD 0.5)

I2: 2.5 (SD 0.5)

C: 2.6 (SD 0.5)

Week 1

I1: -0.4 (0.1)

I2: -0.4 (0.1)

C: -0.4 (0.1)

p>0.05 compared with placebo

Week 4

I1: -0.7 (0.1)

I2: -0.7 (0.1)

C: -0.5 (0.1)

p>0.05 compared with placebo

Week 12

I1: -0.5 (0.1)

I2: -0.6 (0.1)

C: -0.4 (0.1)

p=0.003 for I2 compared with placebo

Safety

Treatment- related adverse event, n (%)

I1: 6 (7%)

I2: 7 (9%)

C: 2 (2%)

Authors’ conclusions: AbobotulinumtoxinA at doses of 500 IU or 1000 IU injected into upper limb muscles provided tone reduction and clinical benefit in hemiparesis. Future research into the treatment of spastic paresis with botulinum toxin should use active movement and function as primary outcome measures.

Adverse event: The most common treatment-emergent adverse event was nasopharyngitis and the most common treatment-related adverse event was muscular weakness (two cases in the 500 IU group and four cases in the 1000 IU group). Other treatment-related adverse events included asthenia (one case in the 500 IU group) and injection site erythema (one case in the 1000 IU group).

Rosales, 2012

Type of study: Randomized controlled trial

Setting: 5 neurological and rehabilitation units

Country: Hong Kong, Malaysia, the Philippines, Singapore, Thailand

Source of funding: Commercial

Inclusion criteria:

• Aged 18-80 years
• Asian ethnicity
• MAS score of 1+ or higher in the elbow or wrist joint
• At least grade 2 according to Medical Research Council criteria in the relevant joint to be eligible

Exclusion criteria:

• Pregnancy/lactation
• Prestrike Rankin score greater than 1
• Known hypersensitivity to test materials or related compounds
• Preexisting neuromuscular junction disease or neurogenic disorder that could induce muscle hypertonus
• Previous treatment with botulinum toxin
• Unable or unwilling to comply with the protocol

N total at baseline:

I: 80

C: 83

Important prognostic factors²:

Mean age (range):

I: 55 (23-79)

C: 54 (17-79)

Sex:

I: 68% M

C: 66% M

Groups comparable at baseline?

Yes

500 U of botulinum neurotoxin type A (Dysport)

The recommended dose distribution was 2 injections of 200 U in a 1 mL volume for the biceps brachii, 1 injection of 100 U in a 0.5 mL volume in the brachioradialis, 1 injection of 100 U in a 0.5 mL volume in the flexor carpi ulnaris, and 1 injection of 100 U in a 0.5 mL volume in the flexor carpi radialis.

Investigators were permitted to adjust the dose per targeted muscle, depending on the level of hypertonicity, as long as the total dosage per patient was 500 U.

Placebo (visually identical)

Length of follow-up:

24 weeks

Loss-to-follow-up:

I: N = 4 (5%)

Reasons: 2 lost to follow-up; 2 died

C: N = 3 (9%)

Reasons: 2 lost to follow-up; 1 died

Incomplete outcome data:

I: N = 4 (5%)

Reasons: 2 lost to follow-up; 2 died

C: N = 3 (9%)

Reasons: 2 lost to follow-up; 1 died

Muscle tone

Measured as the change from baseline in MAS in the most affected joint, mean difference (95%CI) adjusted for country and baseline MAS score

Week 2

MD: -0.66 (-0.84 to -0.49)

Week 4

MD: -0.67 (-0.88 to -0.47)

Week 8

MD: -0.60 (-0.82 to -0.39)

Week 12

MD: -0.66 (-0.88 to -0.43)

Week 24

MD: -0.54 (-0.79 to -0.30)

Hand movements and upper arm function

Measured as the change from baseline in the Functional Motor Assessment Scale, mean difference (95%CI) adjusted for baseline score

Upper-arm function

Week 2

MD: 0.07 (-0.25 to 0.39)

Week 4

MD: 0.08 (-0.29 to 0.44)

Week 8

MD: -0.18 (-0.54 to 0.19)

Week 12

MD: -0.23 (-0.64 to 0.18)

Week 24

MD: -0.30 (-0.75 to 0.15)

Hand movements

Week 2

MD: 0.27 (-0.18 to 0.65)

Week 4

MD: 0.26 (-0.16 to 0.69)

Week 8

MD: 0.20 (-0.27 to 0.67)

Week 12

MD: 0.33 (-0.14 to 0.79)

Week 24

MD: 0.23 (-0.27 to 0.74)

Advanced hand activities

Week 2

MD: -0.18 (-0.44 to 0.07)

Week 4

MD: -0.34 (-0.73 to 0.04)

Week 8

MD: -0.42 (-0.87 to 0.04)

Week 12

MD: -0.24 (-0.72 to 0.23)

Week 24

MD: -0.36 (-0.85 to 0.14)

Pain

Measured as the change from baseline in the Global Pain Scale, mean difference (95%CI) adjusted for baseline scores

Week 2

MD: -3.50 (-9.43 to 2.43)

Week 4

MD: -7.87 (-13.28 to -2.46)

Week 8

MD: -5.84 (-12.61 to 0.94)

Week 12

MD: -5.93 (-12.63 to 0.77)

Week 24

MD: -7.15 (-13.76 to -0.54)

ROM

Measured as voluntary and passive joint range of motion, mean difference (95%CI) adjusted for baseline score

Elbow

Week 2

Active: 2.80 (-3.98 to 9.58)

Passive: 4.07 (1.55 to 6.59)

Week 4

Active: 5.16 (-1.94 to 12.25)

Passive: 4.67 (1.13 to 8.22)

Week 8

Active: 3.78 (-4.29 to 11.85)

Passive: 2.86 (-1.24 to 6.97)

Week 12

Active: 5.06 (-3.05 to 13.18)

Passive: 2.14 (-2.15 to 6.42)

Week 24

Active: 5.23 (-2.87 to 13.34)

Passive: 4.52 (1.13 to 7.90)

Wrist

Week 2

Active: 0.34 (-5.50 to 6.19)

Passive: 2.78 (-4.19 to 9.75)

Week 4

Active: 0.71 (-5.45 to 6.88)

Passive: 7.31 (0.68 to 13.94)

Week 8

Active: 3.21 (-3.48 to 9.90)

Passive: 6.08 (-0.18 to 12.34)

Week 12

Active: 3.80 (-3.77 to 11.36)

Passive: 6.43 (-0.74 to 13.59)

Week 24

Active: 2.73 (-6.31 to 11.77)

Passive: 9.40 (2.43 to 16.38)

Safety

A total of 84 adverse events were reported: 31 serious and 53 nonserious. There was o clinically relevant difference in the distribution of adverse events (36 [43%] in the placebo group and 48 [57%] in the BoNT-A group) or of serious adverse events (13 [15%] in the placebo group and 18 [21%] in the BoNT-A group).

The sponsor, Ipsen Pharma, provided logistical support, study drugs, support for investigator meetings, central statistical support, and data analysis.

No additional antispasticity medication was permitted after entry. All patients continued with their standard rehabilitation programs throughout the study, as deemed suitable by the attending physician.

Kaji, 2010a

Type of study:

Randomized controlled trial

Setting:

Patients with focal spasticity of the wrist and fingers after stroke from 19 national institutions

Country: Japan

Source of funding: Commercial

Inclusion criteria:

• Aged 20-80 years
• At least 40 kg in weight
• Stroke ≥ 6 months ago
• Modified Ashworth Scale score of at least 3 for wrist flexors, and at least 2 for finger flexors
• Score of 2 or higher in 1 of 4 domains on the Disability Assessment Scale (DAS)

Exclusion criteria:

• Bilateral hemiplegia or quadriplegia
• Fixed contractures in the wrist or fingers
• Prior treatment with phenol/ethanol block, muscle afferent block (MAB), intrathecal baclofen or any botulinum toxin serotype
• Current use of peripheral muscle relaxants

N total at baseline:

I: 51

C: 26

Important prognostic factors²:

Mean age (SD):

I: 63 (9)

C: 63 (11)

Sex:

I: 71% M

C: 54% M

Groups comparable at baseline?

Yes, except sex

Single set of intramuscular injections with botulinum toxin type A (Botox) with a total dose of 200 U

The following muscles were injected: flexor carpi radialis, flexor carpi ulnaris, flexor digitorum profundus and flexor digitorum superficialis. Patients with thumb spasticity (MAS >2) were additional injected with a total dose of 40 U in the flexor pollicis longus and adductor pollicis.

An electromyography (EMG) or a nerve stimulator, and an EMG injection needle were used to identify proper muscles and facilitate injection in all patients.

Placebo (visually identical)

Length of follow-up:

12 weeks

Loss-to-follow-up:

I: N = 4 (8%)

Reasons: 1 subject’s request, 3 adverse event

C: N = 1 (4%)

Reasons: 1 adverse event

Incomplete outcome data:

Week 4

I: N = 0 (0%)

C: N = 0 (0%)

Week 8

I: N = 3 (6%)

C: N = 2 (8%)

Week 12

I: N = 4 (8%)

C: N = 1 (4%)

Reasons unclear at each time point

Muscle tone:

Measured with the MAS, mean change from baseline (SE)

Wrist

Baseline

I: 3.31 (SD 0.47)

C: 3.18 (SD 0.40)

Week 4

I: -1.05 (0.13)

C: -0.48 (0.13)

P=0.006

Week 8

I: -1.01 (0.14)

C: -0.35 (0.12)

P=0.002

Week 12

I: -0.83 (0.12)

C: -0.20 (0.08)

P<0.001

Fingers

Baseline

I: 3.08 (SD 0.66)

C: 3.09 (SD 0.54)

Week 4

I: -0.92 (0.11)

C: -0.37 (0.13)

P=0.003

Week 8

I: -0.86 (0.11)

C: -0.35 (0.16)

P=0.004

Week 12

I: -0.67 (0.10)

C: -0.26 (0.12)

P=0.016

Functional disability

Measured with Disability Assessment Scale (DAS), improvement in principal therapeutic target from baseline, mean change from baseline (SE)

Baseline

I: 2.24 (SD 0.71)

C: 2.27 (SD 0.47)

Week 4

I: -0.82 (0.11)

C: -0.31 (0.12)

P=0.002

Week 8

I: -0.79 (0.11)

C: -0.38 (0.13)

P=0.018

Week 12

I: -0.70 (0.10)

C: -0.32 (0.11)

P=0.014

Clinical global impression (CGI):

Measured by Numeric Rating Scale, mean change (SE) from  baseline

Investigator

Baseline

I: -1.29 (SD 1.51)

C: -3.00 (SD 0.89)

Week 4

I: 1.80 (0.20)

C: 0.50 (0.23)

P<0.001

Week 8

I: 1.33 (0.28)

C: 0.42 (0.23)

P=0.003

Week 12

I: 0.94 (0.28)

C: 0.32 (0.22)

P=0.032

Patient

Baseline

I: -1.43 (SD 1.97)

C: -1.55 (SD 2.07)

Week 4

I: 1.53 (0.25)

C: 0.65 (0.38)

P=0.043

Week 8

I: 1.52 (0.23)

C: 0.54 (0.27)

P=0.006

Week 12

I: 1.32 (0.25)

C: 0.92 (0.39)

P=0.096

Physical/occupational therapist

Baseline

I: -1.27 (SD 1.74)

C: -2.64 (SD 1.03)

Week 4

I: 1.08 (0.21)

C: 0.62 (0.24)

P=0.122

Week 8

I: 0.98 (0.21)

C: 0.63 (0.20)

P=0.348

Week 12

I: 0.74 (0.21)

C: 0.64 (0.20)

P=0.961

Safety

Reported as investigator-determined treatment-related adverse events

I: 2 (4%)

C: 2 (8%)

Authors’ conclusions: BoNTA reduced spasticity in upper limb muscles and improved ADL performance in terms of limb position and dressing. BoNTA is safe and effective in the treatment of post-stroke upper limb spasticity.

Comment: Role of the sponsor is unclear. Majority of authors are employed by the sponsor

Shaw, 2010

Type of study:

Randomized controlled trial

Setting: Twelve stroke services

Country: United Kingdom

Source of funding: Commercial

Inclusion criteria:

• Age over 18 years
• At least 1 month since stroke
• Upper limb spasticity [Modified Ashworth

Scale19 > 2 at the elbow and/or spasticity at the hand, wrist or shoulder (there is no validated measure of spasticity at these sites)]

• Reduced upper limb function (ARAT score 0-56)
• Able to comply with the requirements of the protocol and upper limb therapy programme
• Informed consent given by participant of legal representative

Exclusion criteria:

• Significant speech or cognitive impairment which impeded ability to perform the ARAT assessment
• Other significant upper limb impairment
• Evidence of fixed contracture
• Pregnancy or lactating
• Female at risk of pregnancy and not willing to take adequate precautions against pregnancy for the duration of the study
• Other diagnosis likely to interfere with rehabilitation or outcome assessments
• Other diagnosis which may contribute to upper limb spasticity
• Contraindications to intramuscular injection
• Religious objections to blood products
• Contraindication to botulinum toxin type A
• Use of botulinum toxin to the upper limb in the previous three months
• Known allergy or hypersensitivity to any of the test compounds
• Previous enrolment in this study

N total at baseline:

I: 170

C: 163

Important prognostic factors²:

Median age (IQR):

I: 67 (58 to 74)

C: 66 (59 to 72)

Sex:

I: 65% M

C: 71% M

Groups comparable at baseline?

Yes

Botulinum toxin type A (Dysport) and 4-week upper limb therapy program (1 hour twice per week provided by study therapist).

Dysport is available as a white lyophilised powder for reconstitution containing 500 units of C. botulinum type A toxin– haemagglutinin complex together with 125 μg of a 20% albumin solution and 2.5 mg lactose in a clear glass vial. The maximum dose of botulinum toxin that could be administered at any one time point was 1000 units.

Participants could receive further injections or therapy if required.

4-week upper limb therapy program (1 hour twice per week provided by study therapist).

Participants could receive further therapy if required.

Length of follow-up:

N=208 (62%) followed for 12 months

N=125 (38%) followed for three months

Loss-to-follow-up:

At 3 months

I: N = 7 (4%)

Reasons: 4 withdrawn; 1 died; 2 not done

C:

N = 12 (7%)

Reasons: 6 withdrawn; 2 died; 4 not done

Incomplete outcome data:

Week 4

I: N = 0 (0%)

C: N = 0 (0%)

Week 8

I: N = 3 (6%)

C: N = 2 (8%)

Week 12

I: N = 4 (8%)

C: N = 1 (4%)

Reasons unclear at each time point

Muscle tone:

Measured with the MAS in the elbow, mean change from baseline (95%CI)

One month

I: -0.6 (-0.8 to -0.4)

C: -0.1 (-0.2 to 0.1)

Difference: -0.5 (-0.8 to -0.3)

Three months

I: -0.3 (-0.4 to -0.1)

C: -0.1 (-0.3 to 0.1)

Difference: -0.2 (-0.5 to 0.1)

Twelve months (n=188)

I: -0.3 (-0.5 to -0.1)

C: -0.2 (-0.5 to 0.1)

Difference: -0.1 (-0.4 to 0.2)

Functionality

Measured with grip strength, kg, mean change from baseline (95%CI)

One month

I: 0.5 (0.0-1.0)

C: 0.6 (0.2-1.1)

Difference: -0.2 (-0.8 to 0.5)

Three months

I: 1.9 (1.1-2.8)

C: 0.9 (0.4-1.5)

Difference: 1.0 (0.0 to 2.0)

Twelve months (n=189)

I: 1.5 (0.7-2.4)

C: 1.6 (0.7-2.6)

Difference: -0.1 (-1.4 to 1.1)

Measured with ARAT, mean change from baseline (95%CI)

One month

I: 2.2 (1.3-3.0)

C: 1.5 (0.8-2.2)

Difference: 0.7 (-0.4 to 1.8)

Three months

I: 3.0 (2.0-4.2)

C: 1.3 (0.4-2.1)

Difference: 1.8 (0.4 to 3.2)

Twelve months (n=189)*

I: Unclear

C: Unclear

Difference: Unclear

Pain

Measured as upper limb pain and scored from 0 to 10, mean change from baseline (95%CI)

One month

I: -1.3 (-1.9 to -0.8)

C: -1.1 (-1.6 to -0.6)

Difference: -0.3 (-1.0 to 0.5)

Three months

I: -1.6 (-2.2 to 1.1)

C: -1.2 (-1.8 to -0.6)

Difference: -0.4 (-1.2 to 0.3)

Twelve months (n=189)

I: -2.2 (-2.9 to -1.4)

C: -0.8 (-1.5 to 0.1)

Difference: -1.4 (-2.4 to -0.3)

Safety

Indicated as serious adverse events

I: 52 (30%)

C: 50 (32%)

Authors’ conclusions: The addition of botulinum toxin type A to an upper limb therapy program to treat spasticity due to stroke did enhance improvement in muscle tone at 1 month, upper limb strength at 3 months, upper limb functional activities related to undertaking specific basic functional tasks at 1, 3 and 12 months, and upper limb pain at 12 months. Botulinum toxin was well tolerated and side effects were minor.

*Reported mean and confidence interval did not match in both control and intervention group

Kanovsky, 2009

Type of study:

Randomized controlled trial

Setting:

Patients with focal spasticity of the wrist and finger flexors after stroke from 23 centres

Country: Czech Republic, Hungary, Poland

Source of funding: Commercial

Inclusion criteria:

• > 18 years
• Stroke ≥ 6 months ago
• Ashworth Scale score of at least 2 in wrist, and finger flexor muscles
• Score of 2 or higher in 1 of 4 domains on the Disability Assessment Scale (DAS)
• Antispastic medication with centrally acting muscle relaxants and/or benzodiazepine medication and physical and occupational therapy regimens were permitted if they had been stable in the 2 weeks before screening; no treatment changes were allowed during the study
• Stable spasticity and disability ratings four weeks before randomization

Exclusion criteria:

• Spasticity of any other origin than stroke
• Bilateral upper limb paresis
• Botulinum toxin treatment within the last 4 months
• Previous or planned treatment with phenol or alcohol injection or surgery in the target limb
• Fixed contracture
• Other muscle hypertonia
• Neuromuscular disorders such as Lambert-Eaton syndrome, myasthenia gravis, or amyotrophic lateral sclerosis
• Current treatment with intrathecal baclofen
• Severe atrophy of the target muscles
• Hypersensitivity to the study medication
• Pregnant or lactating women
• Women without adequate contraception

N total at baseline:

I: 73

C: 75

Important prognostic factors²:

Mean age (SD):

I: 58 (10)

C: 53 (13)

Sex:

I: 62% M

C: 67% M

Groups comparable at baseline?

Yes

Single set of intramuscular injections with botulinum neurotoxin type A NT 201 (Xeomin) with a maximum dose of 400 units

Appropriate localization of the needle in the muscle targeted for treatment was assured by means of electrical stimulation or recording of electromyography signal (EMG).

Each muscle for the clinical patterns flexed wrist and clenched fist had to be treated. Other spastic muscles were treated as individually needed.

Placebo (visually identical)

Length of follow-up:

12 weeks

Loss-to-follow-up:

I: N = 2 (3%)

Reasons: 1 consent withdrawn, 1 adverse event (paraparesis)

C: N = 1 (1%)

Reasons: 1 death due intracranial hematoma

Incomplete outcome data:

I: N = 0 (0%)

C: N = 0 (0%)

Muscle tone

Measured as a reduction of at least 1 point of the Ashworth Scale, n %

Flexed wrist

Week 2

I: 45 (62)

C: 22 (30)

RR 2.05, 95%CI: 1.38-3.03

Week 4

I: 50 (68)

C: 27 (37)

RR 1.85, 95%CI: 1.32-2.60

Week 8

I: 49 (67)

C: 22 (30)

RR 2.23, 95%CI: 1.52-3.27

Week 12

I: 31 (42)

C: 18 (25)

RR 1.72, 95%CI: 1.06-2.79

Clenched fist

Week 2

I: 50 (69)

C: 22 (29)

RR 2.33, 95%CI: 1.59-3.43

Week 4

I: 50 (69)

C: 27 (36)

RR 1.90, 95%CI: 1.35-2.67

Week 8

I: 44 (60)

C: 27 (36)

RR 1.67, 95%CI: 1.17-2.39

Week 12

I: 35 (48)

C: 23 (31)

RR 1.56, 95%CI: 1.03-2.37

Functional disability

Measured with Disability Assessment Scale (DAS), improvement in principal therapeutic target from baseline

Significant differences in week 2, 4, 8, and 12 were found in favor of the active arm (p≤0.005)

Impact on physical carer burden

Measured with the Carer burden scale

Superiority of NT 201 over placebo was observed for the

items putting the affected arm through a sleeve (P = 0.021) and

for cleaning the palm of affected hand (P = 0.028)

at week 4

Safety

Indicated as adverse events

I: 21 (29%)

C: 20 (27%)

Authors’ conclusions: Botulinum neurotoxin led to statistically significant improvements in muscle tone and disability and was well tolerated in patients with post-stroke upper limb spasticity. During the entire treatment period, the proportion of treatment responders with improved muscle tone was consistently higher in the botulinum neurotoxin group compared with placebo for all 5-treated muscle groups (flexors of the wrist, finger, elbow, and thumb as well as forearm pronators).

Comment: Sponsor was involved in authorship of the paper.

McCrory, 2009

Type of study:

Randomized, controlled trial

Setting: Patients with upper limb spasticity after stroke from six national centres

Country: Australia

Source of funding:

Commercial

Inclusion criteria:

• > 18 years
• Stroke ≥ 6 months ago
• MAS score of at least 2 in 2 out of 3 of wrist, elbow, and finger flexor muscles and at least 1 in the third area
• Cognitive and communicative able
• In case of oral anti-spasticity medication, stable dosage in the month prior to the study
• Stable spasticity and disability ratings four weeks before randomization

Exclusion criteria:

• Established severe contracture or other neurological impairments
• Receiving concurrent aminoglycoside antibiotics
• Received botulinum toxin treatment within the past 120 days
• Previously treated with phenol or intrathecal baclofen for arm spasticity

N total at baseline:

I: 54

C: 42

Important prognostic factors²:

Mean age (SD):

I: 59 (12)

C: 58 (14)

Sex:

I: 59% M

C: 62% M

Groups comparable at baseline?

Yes

Single treatment with intramuscular injection with BoNT-A (Dysport) into the principal spastic muscles of the distal upper limb (restricted to muscles acting at elbow, wrist and finger joints) with a total dose range of 750-1000 units

The selection of muscles, use of single or multiple injection sites within a given muscle, and electromyography or nerve/muscle stimulation to assist accurate placement were all at the clinicians’ discretion.

Patients received re-treatment at week 12, which was not considered in this table.

Placebo (visually equivalent)

Length of follow-up:

24 weeks (Follow-up till week 12 was considered for this table)

Loss-to-follow-up:

Intervention:

N=1 (2%)

Reasons: 1 withdrew

Control:

N=4 (10%)

Reasons: 3 withdrew; 1 protocol violation

Incomplete outcome data:

Week 8

I: N=0

C: N=3

Week 12

I: N=1

C: N=4

Reasons: 4 withdrew; 1 protocol violation

Pain

Measured in the hand, wrist and elbow “at rest” and “on movement” using a (100-mm) visual analogue scale, mean change (SE) from baseline

Baseline

I: 44.3 (6.3)

C: 36.0 (5.7)

P=0.34

Week 8

I: -9.9 (5.4)

C: -4.9 (5.8)

Mean difference: 5.07 (95%CI: -10.9 to 21.0)

Depression

Measured using the Hospital Anxiety and Depression Rating Scale (HADs), mean change (SE) from baseline

Baseline

I: 5.7 (0.4)

C: 5.2 (0.6)

P=0.48

Week 8

I: 0.0 (0.3)

C: -0.3 (0.4)

Mean difference: -0.3 (95%CI: -1.24 to 0.68)

Achievement of individual goals

Measured using Goal Attainment Scaling (GAS), mean change (SE) from baseline

Baseline

I: 28.7 (0.7)

C: 29.5 (0.9)

P=0.49

Week 8

I: 3.5 (1.3)

C: 0.2 (1.1)

Mean difference: 3.30 (95%CI: -0.36 to 6.80)

Spasticity

Measured during passive range of movement at the elbow, wrist and finger joints using the MAS, mean change (SE) from baseline

Baseline

I: 7.1 (0.2)

C: 6.9 (0.2)

P=0.35

Week 8

I: -1.8 (0.2)

C: -0.3 (0.2)

Mean difference: -1.47 (95%CI: -2.10 to -0.84)

Hand movements and upper arm function

Measured with the Modified Motor Assessment Scale (MMAS), mean change (SE) from baseline

Baseline

I: 1.1 (0.2)

C: 1.5 (0.3)

P=0.28

Week 8

I: 0.3 (0.2)

C: 0
Mean difference: 0.32 (95%CI: -0.15 to 0.79)

Patient and carer burden

Measured using the Patient Disability Scale (PDS) and the Carer Burden Scale (CBS), mean change (SE) from baseline

PDS

Baseline

I: 1.8 (0.1)

C: 1.8 (0.1)

P=0.81

Week 8

I: -0.2 (0.1)

C: -0.3 (0.1)

Mean difference: -0.05 (95%CI: -0.28 to 0.18)

CBS

Baseline

I: 1.5 (0.1)

C: 1.9 (0.2)

P=0.19

Week 8

I: -0.2 (0.1)

C: -0.1 (0.1)

Mean difference: 0.06 (95%CI: -0.48 to 0.60)

Patient functional outcome measure (PFOM)

Chosen by patients as the activity in the PDS as their preferred activity to improve, n (%) improved from baseline

Week 8

I: 20 (37%)

C: 6 (15%)

P=0.02

Global assessment of benefit

Measured by asking to rate the overall benefit on a 5-point Likert scale by the patient and the investigator, n (%)

Investigator

Week 12

I: 31 (58%)

C: 12 (32%)

P=0.01

Patient

Week 12

I: 32 (60%)

C: 13 (34%)

P=0.01

Safety

Indicated as experiencing at least 1 treatment-related adverse event

I: 6%

C: 10%

Authors’ conclusions: Botulinum toxin type A was found to be safe and efficacious in reducing upper limb spasticity and improving the ability to achieve personal goals. No consistent difference in reduction of pain or depression was observed. However, these symptoms were not prominent among the study population and the groups were not well matched with respect to pain at baseline.

Comment: Sponsor had no influence on the interpretation of data and the final conclusions drawn. Sponsor is an author of the paper.

Brashear, 2002

Type of study: Randomized, placebo-controlled trial

Setting: Patients with focal spasticity of the wrist and fingers after stroke

Country: United States of America

Source of funding:

Commercial

Inclusion criteria:

• At least 21 years
• Stroke ≥ 6 months ago
• Ashworth Scale score 3 or 4 for wrist flexor tone
• Ashworth Scale score of 2 or higher for finger flexor tone
• Disability Assessment Scale score of 2 or 3

Exclusion criteria:

• Fixed contracture or profound muscle atrophy in the spastic limb
• Prior or planned treatment with any botulinum toxin serotype, or with phenol, alcohol or surgery
• Change in oral medication for spasticity
• Treatment with intrathecal baclofen
• Treatment with agents affecting neuromuscular transmission
• Pregnant or lactating women
• Women planning to become pregnant during the course of the study

N total at baseline:

I: 64

C: 62

Important prognostic factors²:

Mean age (range):

I: 61 (23-88)

C: 62 (23-87)

Sex:

I: 44% M

C: 56% M

Groups comparable at baseline?

Yes

Single treatment with intramuscular injection of Botulinum toxin A (Botox) with a total dose of 200 to 240 IU

50 units injected in each of four wrist and finger muscles with optional injections in one or two thumb muscles

Placebo (visually identical)

Length of follow-up:

12 weeks

Loss-to-follow-up:

Intervention:

N=0 (0%)

Control:

N=4 (6%)

Reasons: Unknown

Incomplete outcome data:

Unclear

Functional disability:

Measured with the Disability Assessment Scale with the principal therapeutic target chosen by subject and study investigator, mean (95%CI)

Baseline

I: 2.70

C: 2.52

P=0.04

Mean change from baseline

Week 6

I: -0.94 (-1.16 to -0.72)

C: -0.31 (-0.48 to -0.14)

P<0.001

Week 12

I: -0.88 (-1.12 to -0.63)

C: -0.46 (-0.67 to -0.24)

P=0.02

Muscle tone:

Measured with the Ashworth Scale, mean change in score from baseline (95%CI)

1. Wrist flexor:

Baseline

I: 3.11

C: 3.13

P=0.79

Week 6

I: -1.66 (-1.87 to -1.44)

C: -0.48 (-0.66 to -0.30)

P<0.001

Week 12

I: -1.07 (-1.30 to -0.84)

C: -0.31 (-0.48 to -0.14)

P<0.001

2. Finger flexor

Baseline

I: 3.06

C:3.05

P>0.99

Week 6

I: -1.34 (-1.60 to -1.07)

C: -0.32 (-0.50 to -0.14)

P<0.001

Week 12

I: -0.78 (-1.05 to -0.51)

C: -0.12 (-0.32 to -0.08)

P<0.001

3. Thumb flexor

Baseline

I: 2.46

C: 2.28

P=0.28

Week 6

I; -1.31 (-1.63 to -0.98)

C: -0.62 (-0.95 to -0.28)

P=0.09

Week 12

I: -0.92 (-1.27 to -0.56)

C: -0.31 (-0.62 to -0.01)

P=0.02

Global Assessment:

Measured with the Global Assessment Scale, mean change from pre-treatment status (95%CI)

1. Physician:

Week 6

I: 1.77 (1.55-1.99)

C: 0.57 (0.35-0.78)

P<0.001

Week 12

I: 1.09 (0.80-1.38)

C: 0.50 (0.29-0.72)

P<0.001

2. Patient or caregiver’s:

Week 6

I: 1.60 (1.30-1.89)

C: 0.63 (0.40-0.85)

P<0.001

Week 12

I: 1.05 (0.76-1.34)

C: 0.48 (0.25-0.72)

P=0.002

Safety:

There were no significant differences between the study groups in the incidence of specific adverse events.

Neutralizing antibodies:

Defined as a positive test for neutralizing antibodies to botulinum toxin A

In total N=93 measured

I: positive N=1

C: positive N=0

Authors’ conclusions:

Intramuscular injections of botulinum toxin A reduce spasticity of the wrist and finger muscles and associated disability in patients who have had a stroke.

Comment: Sponsor was responsible for data management and statistical analysis. The interpretation of the data and preparation of the manuscript were performed by all the authors, who had full access to the data. The content of the manuscript and the decision to submit it for publication were not controlled by the sponsor.

Bakheit, 2001

Type of study: Randomized, placebo-controlled trial

Setting: Patients from 7 international centres with upper limb spasticity after a stroke

Country: United Kingdom, Ireland and Germany

Source of funding: Commercial

Inclusion criteria:

• Patients with hemiplegic stroke and severe or moderately severe muscle spasticity with a MAS of two or more in at least two out of the elbow, wrist, and finger flexors and a score of 1 or more in the remaining area

Exclusion criteria:

• Muscle contractures
• Previous treatment with phenol or alcohol nerve blocks or motor joint injections with neurologic agents or with BtxA in the 6 months preceding

N total at baseline:

I: 27

C: 32

Important prognostic factors²:

Mean age ± SD:

I: 64 (13)

C: 67 (11)

Sex:

I: 41% M

C: 47% M

Groups comparable at baseline?

Yes

Single treatment with Botulinum A toxin-haemagglutinin (Dysport) diluted in 2 ml of 0.9% NaCl solution to give 1000 IU

About 300-400 IU of BtxA were injected into the biceps brachii (two sites), 150-250 IU into the flexor digitorum superficialis and 150 IU into each of the flexor digitorum profundus, flexor carpi ulnaris and flexor carpi radialis. Only one site per muscle was injected in the forearm. The injections were placed in the muscle belly using anatomical landmarks.

Placebo (visually identical)

Length of follow-up:

16 weeks

Loss-to-follow-up:

I: N = 1 (2%) before the last scheduled visit of the study at 16 weeks

C: N = 0 (0%)

Reason: Lost to follow-up

Incomplete outcome data:

Outcomes measured at week 16

I: N = 1 (2%) before the last scheduled visit of the study at 16 weeks

C: N = 0 (0%)

Reason: Lost to follow-up

Muscle spasticity:

Measured as the change in MAS from baseline, n (%) decrease in score

Week 4

No change

I: 5 (19)

C: 10 (31)

Decrease of 1

I: 8 (30)

C: 15 (47)

Decrease of 2

I: 7 (26)

C: 3 (9)

Decrease of 3

I: 5 (19)

C: 4 (13)

Decrease of 4

I: 2 (7)

C: 0 (0)

P=0.004

Joint ROM:

Measured with a hand-held goniometer for elbow and wrist. A scale was used for hands. Measured change at week 4 from baseline

Elbow

Active

Not reported; only data from 1 centre available

Passive, mean (SE)

I: 10.3 (3.8)

C: 3.5 (3.9)

Mean difference: 6.8 (95%CI: -3.4 to 16.9)

Wrist

Active, mean (SE)

I: 14.6 (4.3)

C: 9.7 (4.4)

Mean difference: 4.9 (95%CI: -6.5 to 16.3)

Passive, mean (SE)

I: 25.7 (3.8)

C: 17.4 (3.8)

Mean difference: 8.3 (95%CI: -1.6 to 18.2)

Fingers

Active, n (%) increase in score

I: 15 (56%)

C: 11 (34%)

P=0.06

Fingers

Passive, n (%) increase in score

I: 9 (33%)

C: 8 (25%)

P=0.60

Severity of pain:

Measured at the shoulder, arm, wrist and fingers on a four-point scale (0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain)

No statistically significant differences between the study groups

Patient’s functional abilities:

Measured with the Barthel index of activities of daily living

No statistically significant differences between the study groups

Goal attainment scale:

Measured by assessment of attainment of three realistic functional goals

No statistically significant differences between the study groups

Difficulties in functional activities:

Measured by assessing three abilities at week 4

1. Cleaning palm

No or little difficulties

I: 17 (63%)

C: 16 (50%)

Moderate difficulties

I: 3 (11%)

C: 7 (22%)

Great difficulties/cannot do

I: 7 (26%)

C: 9 (28%)

Too small number to perform statistical testing

2. Cutting fingernails

No or little difficulties

I: 2 (7%)

C: 3 (10%)

Moderate difficulties

I: 0 (0%)

C: 1 (3%)

Great difficulties/cannot do

I: 25 (93%)

C: 28 (88%)

Too small number to perform statistical testing

3. Putting arm through sleeve

No or little difficulties

I: 10 (37%)

C: 10 (31%)

Moderate difficulties

I: 8 (30%)

C: 9 (28%)

Great difficulties/cannot do

I: 9 (33%)

C: 13 (41%)

Too small number to perform statistical testing

Global assessment of benefit:

Measured as an overall subjective assessment of treatment by patients and investigators at week 16

Patient

N (%) ‘much improved’ and ‘some improvement’

I: 24 (92%)

C: 16 (50%)

RR 1.85 (95%CI: 1.28-2.66)

Investigator

N (%) ‘much improved’ and ‘some improvement’

I: 23 (88%)

C: 16 (50%)

RR 1.84 (95%CI: 1.28-2.65)

Authors’ conclusions: Treatment with BtxA in a dose of 1000 units reduces muscle tone in patients with post-stroke upper limb spasticity. BtxA is safe in the dose used in this study.

Comment: The role of the sponsor in this study is unclear.

STROKE PATIENTS

LOWER LIMB SPASTICITY

Kaji, 2010b

Type of study: Randomized, placebo-controlled trial

Setting: Patients with lower limb spasticity after stroke from 19 national medical institutions

Country: Japan

Source of funding:

Commercial

Inclusion criteria:

• Aged 20-80 years
• At least 50 kg
• Stroke ≥ 6 months ago
• MAS score of > 3 for ankle flexor

Exclusion criteria:

• Bilateral hemiplegia or quadriplegia
• Fixed contractures of the ankle
• Profound atrophy of the muscles to be injected
• Prior treatment with surgery, phenol/ethanol block, muscle afferent block, intrathecal baclofen, or any botulinum toxin serotype
• Current use of peripheral muscle relaxants
• Pregnant of lactating women
• Women planning to become pregnant during the course of the study

N total at baseline:

I: 58

C: 62

Important prognostic factors²:

Mean age (SD):

I: 62 (9)

C: 62 (9)

Sex:

I: 86% M

C: 74% M

Groups comparable at baseline?

Yes, except for sex

Single treatment with intramuscular injection Botulinum toxin type A (Botox) with a total dose of 300 IU

75 IU were injected per muscle into each of the following: medial head of the gastrocnemius, lateral head of the gastrocnemius, and soleus muscle and tibialis posterior muscle (divided into three sites per muscle).

An EMG or nerve stimulator, and an EMG injection needle were used to identify the proper muscles and facilitate injection in all patients.

Placebo (visually identical)

Length of follow-up:

12 weeks

Loss-to-follow-up:

Intervention:

N=6 (10%)

Reasons: 3 adverse events; 3 subject’ request

Control:

N=1 (2%)

Reasons: 1 protocol violation

Incomplete outcome data:

Week 4

I: N=4

C: N=1

Week 8

I: N=5

C: N=3

Week 12

I: N=5

C: N=2

Reasons per time point unclear

Muscle tone:

Measured with the MAS, mean change from baseline (SE)

Week 4

I: -0.88 (0.09)

C: -0.43 (0.09)

P<0.001

Week 8

I:-0.82 (0.09)

C: -0.43 (0.09)

P<0.001

Week 12

I: -0.56 (0.09)

C: -0.40 (0.07)

P=0.240

Gait pattern scale (physician’s rating scale):

Measured by assessment of 10m walk using the Physician’s Rating Scale, mean change (SE) from baseline

Week 4

I: 0.54 (0.17)

C: 0.63 (0.19)

P=0.688

Week 8

I: 0.61 (0.16)

C: 0.78 (0.24)

P=0.825

Week 12

I: 0.55 (0.17)

C: 0.58 (0.20)

P=0.775

Speed of gait:

Measured by timing (in seconds) the walk over 10m straight, mean change (SE) from baseline

Week 4

I: -6.10 (3.11)

C: -7.37 (2.66)

P=0.209

Week 8

I: -3.14 (4.87)

C: -8.19 (2.41)

P=0.367

Week 12

I: -10.14 (3.70)

C: -8.53 (3.16)

P=0.585

Clinical global impression (CGI):

Measured by Numeric Rating Scale, mean change (SE) from  baseline

Investigator

Week 4

I: 1.09 (0.17)

C: 0.64 (0.14)

P=0.048

Week 8

I: 1.13 (0.18)

C: 0.59 (0.16)

P=0.016

Week 12

I: 0.81 (0.18)

C: 0.52 (0.16)

P=0.166

Patient

Week 4

I: 0.75 (0.21)

C: 0.44 (0.23)

P=0.120

Week 8

I: 1.00 (0.28)

C: 0.70 (0.25)

P=0.281

Week 12

I: 0.49 (0.21)

C: 0.49 (0.28)

P=0.409

Physical/occupational therapist

Week 4

I: 0.64 (0.17)

C: 1.07 (0.18)

P=0.119

Week 8

I: 1.04 (0.24)

C: 1.00 (0.21)

P=0.589

Week 12

I: 1.02 (0.18)

C: 0.97 (0.19)

P=0.600

Safety:

Indicated as investigator-determined treatment-related adverse events

I: 7 (12%)

C: 7 (11%)

Authors’ conclusions: This was the first large-scale trial to indicate that BoNTA significantly reduced spasticity in lower limb muscles.

Both BoNTA and placebo treatment were associated with slight increases in the Physician’s Rating Scale score (i.e., gait pattern scale), and no significant difference was noted between BoNTA and placebo. In addition, the time required for 10-m walking decreased after treatment with either BoNTA or placebo, and no significant difference was noted between the two treatments. A significantly greater increase in the CGI score by the investigator was noted in the BoNTA group compared to the placebo group, but no significant differnecne was noted by the patient of physical/occupational therapist. Since the result of the Physician’s Rating Scale score and speed of gait was not significant in this study, the treatment outcome seems to have fallen short of the expectation of patients and the physical/occupational therapist.

Comment: Role of the sponsor is unclear. Majority of authors are employed by the sponsor

Pittock, 2003

Type of study: Randomized, controlled trial

Setting: Patients with lower limb spasticity after stroke from 29 international centres

Country: Ireland, United Kingdom, Czech Republic, Slovak Republic, Poland, Russia, Germany, Austria, Netherlands, Italy

Source of funding:

Commercial

Inclusion criteria:

• Stroke ≥ 3 months ago
• Hemiparesis
• Spastic equinovarus deformity of the ankle preventing full dorsiflexion
• Ambulatory
• Able to walk more than 5m, but a walking speed of <90% normal over 10m.

Exclusion criteria:

• Fixed contractures
• Prior treatment with surgery, phenol or alcohol
• BoNTA-treatment for leg spasticity in the past 6 months
• Known sensitivity to BoNTA
• Underlying non-stroke-related neurological impairment

N total at baseline:

I1: 59

I2: 60

I3: 60

C: 55

Important prognostic factors²:

Mean age (SD):

I1: 56 (13)

I2: 54 (14)

I3: 54 (10)

C: 55 (11)

Sex:

I1: 61% M

I2: 65% M

I3: 58% M

C: 67% M

Groups comparable at baseline?

Yes

Single treatment with intramuscular injection Botulinum toxin type A-haemagglutinin complex (Dysport) diluted with 1.0 ml 0.9% NaCl giving a total of 4 ml. Three different doses were given:

1. 500 IU

2. 1000 IU

3. 1500 IU

Four sites were injected.

The upper and lower sites were determined by palpation of the femoral and calcaneal insertions of the gastrocnemius muscle, 1/4 and 1/3 of the total length from the femoral insertions, respectively. At each site, medial and lateral injections were made. At the upper lateral, lower lateral and medial sites, deep positioning of the needle, penetrating the bulk of the gastrocnemius, enabled the soleus muscle to be injected with 0.5 ml. The needle was partially withdrawn and 0.5 ml injected into the gastrocnemius muscle. The upper medial site was injected last and received 1.0 ml into the gastrocnemius muscle.

Placebo (visually identical)

Length of follow-up:

12 weeks

Loss-to-follow-up:

I1: N=4 (7%)

Reasons: 3 lost to follow-up; 1 open treatment

I2: N=5 (8%)

Reasons: 5 lost to follow-up

I3: N=3 (5%)

Reasons: 1 lost to follow-up; 2 withdrawals (1 severe pain; 1 withdrew consent)

C: N=1 (2%)

Reasons: 1 withdrawal due to severe pain

Incomplete outcome data:

Varied per outcome and time point.

2-min walking test:

Measured as the distance in m covered during 2 min, mean change (SE) from baseline

Week 4

I1: 2.9 (5.0)

I2: 3.7 (5.2)

I3: 5.5 (5.1)

C: 5.1 (4.8)

Week 8

I1: 7.6 (5.3)

I2: 4.9 (5.5)

I3: 7.7 (5.3)

C: 7.1 (4.9)

Week 12

I1: 8.1 (5.3)

I2: 7.7 (5.6)

I3: 8.4 (5.3)

C: 9.1 (4.9)

No statistical significant differences were observed

Difference in step length:

Measured in cm, mean change (SE) from baseline

Week 4

I1: -0.2 (1.7)

I2: -1.9 (1.4)

I3: -0.2 (1.7)

C: -0.6 (1.4)

Week 8

I1: -1.1 (1.6)

I2: -1.6 (1.4)

I3: -0.7 (1.7)

C: -0.1 (1.6)

Week 12

I1: -0.3 (1.7)

I2: -2.5 (1.4)

I3: -1.1 (1.6)

C: -0.3 (1.5)

No statistical significant differences were observed

Stepping rate:

Measured as the number of steps per min, mean change (SE) from baseline

Week 4

I1: 2.7 (4.6)

I2: 2.5 (4.0)

I3: 4.4 (4.0)

C: 3.1 (4.3)

Week 8

I1: 4.3 (4.7)

I2: 3.9 (4.3)

I3: 4.1 (4.1)

C: 3.9 (4.3)

Week 12

I1: 4.4 (4.7)

I2: 7.1 (4.3)

I3: 7.2 (4.0)

C: 5.2 (4.4)

No statistical significant differences were found

Rivermead Motor Assessment:

No statistically significant differences between study groups, data not shown

Active and passive range of movement:

Measured in the affected ankle

No statistically significant differences between study groups, data not shown

Muscle tone:

Measured with the Modified Ashworth Scale, n (%) decrease in score

Week 4

I1: 23 (40)

I2: 23 (40)

I3: 31 (53)

C: 8 (15)

P=0.003

Week 8

I1: 29 (53)

I2: 23 (43)

I3: 35 (57)

C: 14 (26)

P=0.006

Week 12

I1: 27 (48)

I2: 22 (38)

I3: 29 (50)

C: 16 (30)

P=0.249

Pain:

Subjectively assessed in the knee, leg, ankle or foot, n(%) decrease in score

Week 4

I1: 14 (25)

I2: 23 (39)

I3: 20 (34)

C: 11 (20)

P=0.157

Week 8

I1: 20 (35)

I2: 25 (45)

I3: 23 (40)

C: 10 (19)

P=0.063

Week 12

I1: 18 (32)

I2: 22 (41)

I3: 17 (29)

C: 10 (19)

P=0.234

Global assessment of benefit:

Rating by patient and investigator at week 12, n(%) improved

Patient

I1: 43 (75)

I2: 35 (65)

I3: 35 (60)

C: 31 (57)

P>0.05

Investigator

I1: 38 (66)

I2: 36 (65)

I3: 38 (66)

C: 34 (64)

P>0.05

Authors’ conclusions: The greatest benefits were in patients receiving 1500 IU. Significant improvements in spasticity as measured by MAS limb pain and a reduction in the use of walking aids. Although there were clear benefits in subsets of patients, there was no statistically significant benefit of dysport over placebo with respect to walking speed, stepping rate or step length.

Comment: Sponsor was responsible for monitoring of data collection. Additional statistical tests were performed and help was given with manuscript by the sponsor.

STROKE PATIENTS

UPPER AND LOWER LIMB SPASTICITY

Ward, 2014

Type of study:

RCT

and the treatment arms were stratified according

to location of spasticity (UL or LL).

Setting:

Not reported, but probably rehabilitation centre

Country:

Germany, Sweden, the United Kingdom, and Canada

Source of funding:

Allergan employees were involved in: (i) the design and conduct of the study; and (ii) the collection, management, analysis, and interpretation of the study data. The authors had sole control over the preparation, review, and approval of this manuscript. Editorial assistance for preparation of this manuscript was provided by Right Angle Communications, funded by Allergan.

All participating authors had a conflict of interest.

Inclusion criteria:

men and women aged 18–85

years who: had experienced a stroke due to a primary cerebral haemorrhage/ infarction or subarachnoid haemorrhage, leading to a hemiplegia/ hemiparesis, ≥ 3 months before the screening visit

Exclusion criteria:

Patients with a fixed contracture as a result of spasticity and with causes of

spasticity other than stroke

N total at baseline:

Intervention: 139

Control:137

Important prognostic factors:

Age (95% CI):

I: 64.11 (22.6–81.2)

C: 61.86 (26.8–82.4)

Sex:

I: 61.2% M

C: 56.3% M

Groups comparable at baseline?

Yes on the reported variables

onabotulinumtoxinA (BOTOX®, Allergan,

Inc., Irvine, CA, USA) + standard of care (SC) with a minimum inter-injection interval of 12 weeks. A maximum of 800 U of study medication was available to the investigator for any

single treatment session. While minimum doses for each muscle were recommended in the study protocol, the principal investigators agreed

that, in order to reflect clinical practice, individual patients’ dosing

was to be at each investigator’s discretion based upon their clinical

experience. This may not have reflected the manufacturer ’s label.

Each participating centre individually determined SC in terms of available resources and usual practice in that centre. Therefore SC was anticipated to differ between individual patients and centres across the study but for some, this may well have been a more intensive

programme of care than prior to study entry, e.g., physical therapy, occupational therapy and SC focussed on their active functional goal achievement.

placebo + standard care

Each participating centre individually determined SC in terms of available resources and usual practice in that centre. Therefore SC was anticipated to differ between individual patients and centres across the study but for some, this may well have been a more intensive

programme of care than prior to study entry, e.g., physical therapy, occupational therapy and SC focussed on their active functional goal achievement.

Length of follow-up:

52 weeks (22 to 34 weeks double blind. Thereafter open label)

Loss-to-follow-up:

Intervention:

N 16 (12%)

Reasons:

Discontininued onabotulinumtoxin n= 8

Patients request/withdrew consent n=5

Non-compliance with study visits n=1

Administrative reasons n=1

Loss to follow up n=1

Control:

N 28 (20%)

Reasons:

Discontinued placebo n=13

Serious adverse event n=2

Patients request/withdrew consent n=4

Administrative reasons n=2

Died n=5

Did not receive placebo n=1

Serious adverse event n=1

Incomplete outcome data:

Missing data was imputed following the last-case carries forward procedure

Outcome measures and effect size (include 95%CI and p-value if available):

Goal attainment scaling:

Principal active functional

goal achievement at 12 weeks was comparable for patients

receiving onabotulinumtoxinA + SC or placebo + SC.

OR= 1.20 (0.69 to 2.10); p = 0.512

24 weeks

OR= 1.36 (0.81 to 2.29); p = 0.247

Resistance to passive movement (spasticity):

24 weeks, mean change from baseline

I: –4.3 (–5.7 to –2.8)

C: –1.7 (–2.9 to –0.4)

Adverse events (treatment related) double blind phase:

I: n= 14 (10.1%)

C: n=5 (3.7%)

To fill in the evidence table two publications have been consulted. The original publication by Ward et al. 2014 and the published protocol:

Borg J, Ward AB, Wissel J, Kulkarni J, Sakel M, Ertzgaard P, Åkerlund P,

Reuter I, Herrmann C, Satkunam L, Wein T, Girod I, Wright N; BEST Study Group.

Rationale and design of a multicentre, double-blind, prospective, randomized,

European and Canadian study: evaluating patient outcomes and costs of managing

adults with post-stroke focal spasticity. J Rehabil Med. 2011 Jan;43(1):15-22.

doi: 10.2340/16501977-0663. PubMed PMID: 21174051.

The authors did not do a multi level analysis on centre/country level but added the variable as a possible confounder or effect modifier. Neglectingthe multi level

MS PATIENTS

LOWER LIMB SPASTICITY

Gusev, 2008

Type of study: Randomized, controlled trial

Setting: Patients with leg adductor muscle spasticity of both legs with definite or probable MS from 17 international centres

Country: Germany, Poland, and Russia

Source of funding:

Commercial

Inclusion criteria:

• Disabling leg adductor muscle spasticity that would benefit from treatment with botulinum toxin

Exclusion criteria:

• Fixed contractures of the hip
• Scheduled to receive any investigational drug therapy during study or had received such therapy in the 30 days prior to entry into the study
• Acute unstable MS, undergone surgery on the affected muscles or ligaments
• Received botulinum toxin for the treatment of lower limb spasticity in the 12 weeks prior to study entry
• Known sensitivity to botulinum toxin
• Prior treatment with phenol or alcohol
• Receiving medications known to interfere with neuromuscular transmission
• Pregnant or lactating women
• Women without adequate contraception

N total at baseline:

I: 55

C: 51

Important prognostic factors²:

Mean age :

I: 46

C: 45

Sex:

I: 36% M

C: 33% M

Groups comparable at baseline?

Yes

Single treatment with intramuscular injection Botulinum toxin type A-haemagglutinin complex (Dysport) with a max of 750 units per leg and in total of 1,500 units

Three adductor muscles were injected; adductor magnus, adductor longus, adductor brevis. Muscles were located by palpation, and sites of injection guided by standard locations used for electromyography.

Placebo (visually identical)

Length of follow-up:

12 weeks

Loss-to-follow-up:

I: N=1 (2%)

Reason: consent withdrawn

C: N=0 (0%)

Incomplete outcome data:

I: N=1 (2%)

Reason: consent withdrawn

C: N=0 (0%)

Functional disability

Measured as improvement of at least one grade in principal therapeutic target, n (%)

Week 4

I: 16 (29)

C: 15 (29)

P=0.745

Week 8

I: 16 (29)

C: 14 (27)

P=0.469

Week 12

I: 14 (25)

C: 12 (24)

P=0.497

Distance between the knees

Measured at the medial aspect of the joint line using a tape measure of calipers following passive of active abduction

No statistically significant differences between study groups

Muscle tone

Measured with the Modified Ashworth Scale, improvement at least one point

No statistically significant differences between study groups

Upper leg pain

Rating of degree of pain associated with spasticity in upper legs on a four-point scale (0=absent to 3=severe), responders (%)

Week 8

P=0.008

Week 12

P=0.013

Global assessment of benefit

Assessed on a five point scale from much worse to great benefit

No statistically significant differences between study groups, data not shown

Safety

Reported as adverse events

I: 29 (53%)

C: 14 (27%)

Authors’ conclusions: A treatment benefit in favor of BoNT-A, which tended towards significance, was seen for many of the endpoints used in this study, but not for the novel, subjective patient-determined primary outcome measure.

Comment: This study was supported and coordinated by sponsor.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

STROKE PATIENTS

UPPER LIMB SPASTICITY

Bakheit, 2000

Type of study: RCT [parallel]

Setting: 11 West European centers

Country: Not specifically stated

Source of funding: Industry

Inclusion criteria:

• Hemiplegic stroke
• Severe or moderately severe muscle spasticity (MAS score ≥ 2 in the wrist, elbow, and finger flexors)

Exclusion criteria:

• Muscle contractures of the upper limb joints
• Previous treatment with botulinum toxin, phenol or alcohol nerve blocks, or motor point injections for upper limb spasticity
• De novo treatment with antispasticity drugs

N total at baseline:

Intervention1: 22

Intervention2: 22

Intervention3: 19

Control: 19

Important prognostic factors²:

Age ± SD:

I1: 64 (15)

I2: 60 (9)

I3: 61 (15)

C: 63 (14)

Sex:

I1: 68% M

I2: 55% M

I3: 63% M

C: 63% M

Groups comparable at baseline? Yes

1. Dysport 500

2. Dysport 1000

3. Dysport 1500

Placebo – identical to active drug

Length of follow-up:

16 weeks

Loss-to-follow-up:

Interventions:

N = 0 (0%)

Control:

N = 1 (5%)

Reasons: unclear

Incomplete outcome data:

Interventions:

N = 0 (0%)

Control:

N = 1 (5%)

Reasons: unclear

Muscle tone

Measured with the MAS, change from baseline, mean difference compared to placebo (95%CI)

Elbow

16 weeks

I1: -13.0 (-21.3 to -4.7)

I2: -11.8 (-20.1 to -3.5)

I3: -10.9 (-19.5 to -2.4)

Wrist

16 weeks

I1: -10.8 (-20.3 to -1.2)

I2: -14.4 (-24.0 to -4.8)

I3: -12.2 (-22.1 to -2.2)

Fingers

16 weeks

I1: -5.5 (-15.2 to 4.2)

I2: -10.0 (-19.8 to -0.3)

I3: -7.1 (-17.2 to 3.0)

Joint ROM

Measured on voluntary extension of the elbow and wrist and on passive muscle stretch (with a hand-held goniometer), change in degrees (unclear whether mean with SD or SE)

Passive ROM – Elbow

Week 4

I1: 11.4 (16.8)

I2: 0.9 (26.2)

I3: 16.9 (26.4)

C: 8.2 (27.8)

No statistical significant differences

Passive ROM – Wrist

Week 4

I1: 16.5 (13.0)

I2: 16.7 (26.4)

I3: 14.6 (33.3)

C: 5.3 (36.7)

No statistical significant differences

Active ROM – Elbow

Week 4

I1: 10.1 (41.4)

I2: -1.0 (18.1)

I3: 7.8 (24.8)

C: 9.4 (25.5)

No statistical significant differences

Active ROM – Wrist

Week 4

I1: -6.3 (35.8)

I2: 0.1 (25.3)

I3: 2.4 (14.0)

C: 1.4 (17.2)

No statistical significant differences

Pain

Measured as the severity of muscle pain at the shoulders, wrist and fingers (score; 0 to 3)

Week 4

I1: -1.4 (1.7)

I2: -0.9 (1.8)

I3: -1.2 (1.4)

C: -1.3 (2.7)

No statistical significant differences

Functionality

Measured with the Rivermead Motor Assessment and the Barthel Index of activities of daily living

Rivermead Motor Assessment

Week 4

I1: 0.2 (1.0)

I2: 0.3 (0.7)

I3: 0.1 (0.5)

C: 0.2 (0.7)

No statistical significant differences

Barthel Index

Week 4

I1: 0.1 (1.4)

I2: 0.1 (2.5)

I3: 0.8 (2.6)

C: 0.7 (1.2)

No statistical significant differences

Safety

Measured by recording the reported adverse events, n (%)

I1: 13 (59)

I2: 4 (18)

I3: 8 (42)

C: 8 (42)

No statistical significant differences

The study was sponsored by Ipsen Limited, Maidenhead, Berkshire, UK, who also designed the study in consultation with the senior authors and was responsible for the recruitment of the researchers and monitoring of the data collection. The statistical analysis of the study data was performed by Hartington Statistics and Data Management Limited, London, UK. The sponsors were not involved in the data interpretation or the writing of the manuscript. None of the authors were employees or paid consultants of Ipsen Ltd.

Bhakta, 2000

Type of study: RCT [parallel]

Setting: Patients referred to rehabilitation medicine unit for potential treatment with botulinum toxin

Country: unclear

Source of funding: Industry

Inclusion criteria:

• Stroke with chronic hemiparesis
• Finger or elbow flexor spasticity > 2 MAS and at least moderate difficulty with two out of eight items defining patient disability
• At least six months post stroke

Exclusion criteria:

• Previous treatment with botulinum toxin, phenol nerve blocks

N total at baseline:

Intervention: 20

Control: 20

Important prognostic factors²:

Median age (range):

I: 60 (22-77)

C: 53 (11-72)

Sex:

I: 65% M

C: 50% M

Groups comparable at baseline? Doubtful

Botulinum toxin type A (Dysport) 1000 Mouse Units, divided over elbow, wrist and finger flexors, diluted in 0.9% salin

Placebo (diluted in 0.9% saline)

Length of follow-up:

12 weeks

Loss-to-follow-up:

Intervention:

N = 0 (0%)

Control:

N = 2 (10%)

Reasons; Unable to attend the week 6 assessment

Incomplete outcome data:

Intervention:

N = 0 (0%)

Control:

N = 2 (10%)

Reasons; Unable to attend the week 6 assessment

Muscle tone

Measured with the MAS, change from baseline, median (25, 75 percentile)

Finger flexor

Week 2

I: -2.0 (-3.0 to -0.3)

C: 0 (-0.3 to 0)

P<0.001

Week 6

I: -1.5 (-2.8 to 0)

C: 0 (0 to 0)

P<0.001

Week 12

I: -1.0 (-2.0 to 0)

C: 0 (0 to 0)

P=0.006

Elbow flexor

Week 2

I: -1.0 (-1.0 to 0)

C: 0 (-0.25 to 0)

P=0.002

Week 6

I: -0.5 (-1.0 to 0)

C: 0 (-1.0 to 0)

P=0.42

Week 12

I: 0 (-1.0 to 0)

C: 0 (-1.0 to 0)

P=0.62

Joint ROM

Data reported only in the text.

“At baseline, only 14/40 had voluntary elbow movement and 3/40 voluntary wrist movement. Active ROM was not changed with BT-A in comparison with placebo. Passive elbow extension was recorded as 0 if full extension was possible (+ve values indicating flexion deformity). There was no improvement in overall passive ROM at the elbow or shoulder between groups.”

Pain

Self-completed 0-10 rating of pain, median change from baseline (IQR)

Week 6

I: -2 (-10 to 0)

C: 0 (-5.5 to 0)

No statistical significant differences

Patient disability

Based on eight items rated on a five point Likert scale

Week 2

I: -0.6 (-1.4 to -0.3)

C: -0.5 (-1.0 to -0.2)

P=0.004

Week 6

I: -0.5 (-1.0 to -0.2)

C: -0.1 (-0.5 to 0.1)

P=0.016

Week 12

I: -0.5 (-1.3 to 0)

C: -0.2 (-0.4 to 0.1)

P=0.055

Carer burden

Based on eight items rated on a five point Likert scale

Week 2

I: -0.77 (-1.8 to 0)

C: 0 (-0.4 to 0)

P=0.011

Week 6

I: -1.0 (-1.9 to 0)

C: 0 (-0.3 to 0)

P=0.005

Week 12

I: -1.0 (-2.0 to 0)

C: 0 (-0.3 to 0)

P=0.027

Safety

Data reported in the text

“In the BT-A group, two patients developed self-limiting arm pain within 1 week of injection and one patient reported worsening of muscle spasm. No serious BT-A related adverse events were reported. In the placebo group, one patient reported herpes labialis 7 days postinjection, one patient reported two transient ischaemic attacks 12 days postinjection, and one patient had exacerbation of cardiac failure 4 weeks after treatment.”

Gracies, 2014

Type of study: RCT [parallel]

Setting: Tertiary care center

Country: United States of America

Source of funding: Industry

Inclusion criteria:

• 18 to 80 years
• Overactivity in upper limb muscles resulting from a stroke or traumatic brain injury at least 4 weeks before recruitment
• Elbow flexor overactivity

Exclusion criteria:

• Major elbow flexor contracture
• Cognitive impairment
• Significant cutaneous or joint inflammation in the affected upper limb
• Hypersensitivity to BoNT/B or its components
• Ongoing neuromuscular disease or use of agents interfering with neuromuscular transmission
• Pregnancy or women not using contraceptives
• Anticoagulant treatment with INR > 3.5
• Serious uncontrolled systemic disease

N total at baseline:

Intervention1: 8

Intervention2: 8

Control: 8

Important prognostic factors²:

Age ± SD:

I1: 44 (12)

I2: 46 (17)

C: 61 (13)

Sex:

I1: 62% M

I2: 62% M

C: 50% M

Groups comparable at baseline? Difficult to assess with few participants

RimabotulinumtoxinB (BoNT/B)

1 10000 U total dose, of which a blinded fixed dose of 2500 U was injected into the elbow flexors

2 15000 U total dose, of which a blinded fixed dose of 5000 U was injected into the elbow flexors

Saline placebo

50% of subjects received 2 mL, of which 0.5 mL was injected into the elbow flexors; the other 50% received 3 mL, of which 1 mL was injected into the elbow flexors

Length of follow-up:

3 months

Loss-to-follow-up:

None were lost to follow-up

Muscle tone

Measured with the AS, mean change from baseline (SD)

1 month

I1: -0.14

I2: -0.80

C: 0.00

P=0.13

Active Range of Motion

Measured in the elbow joint

1 month

I1: 9.8

I2: 6.6

C: -9.0

P=0.028

Pain

Measured with GSA (score out of 10), mean change from baseline

1 month

I1: -0.9

I2: -0.1

C: -0.2

P=0.61

Global Self-Assessment

Total score (out of 10), mean change from baseline

1 month

I1: -2.4

I2: 3.1

C: -0.4

Safety

Reported in the text

“No adverse effects associated with either dose of BoNT/B (n=16 subjects) occurred in this study.”

Hesse, 1998

Type of study: RCT [parallel]

Setting: neurological rehabilitation clinic

Country: Germany

Source of funding: Industry

Inclusion criteria:

• Six to twelve months post-stroke
• Upper limb spasticity (grade 3 MAS)
• Nonfunctional extremity with no possible selective movement

Exclusion criteria:

• Fixed contractures
• Previous treatment with BtxA
• Surgical procedures in the study limb
• Severe impairments of cognition

N total at baseline:

Intervention: 6

Control: 6

Important prognostic factors²:

Age ± SD:

I: 54

C: 42

Groups comparable at baseline?

BtxA (Dysport), 1000 units

Injected into the Mm. biceps brachii, brachialis (each 250 units), flexor carpi ulnaris, flexor carpi radialis, flexor digitorum profunus et superficialis (each 125 units) at two sites per muscle, close to the motor point.

Placebo

Length of follow-up:

12 weeks

Loss-to-follow-up:

Not stated

Incomplete outcome data:

Not stated

Muscle tone

Measured with the MAS, mean (SD)

Elbow

Week 0 (baseline)

I: 3.17 (1.17)

C: 2.67 (0.82)

Week 2

I: 2.67 (1.21)

C: 2.67 (0.82)

Week 6

I: 2.67 (1.21)

C: 2.83 (0.75)

Week 12

I: 3.00 (1.27)

C: 2.83 (0.75)

Wrist

Week 0 (baseline)

I: 3.17 (1.17)

C: 2.83 (0.75)

Week 2

I: 2.83 (0.75)

C: 2.67 (0.52)

Week 6

I: 2.83 (0.75)

C: 2.50 (0.55)

Week 12

I: 3.00 (0.89)

C: 2.67 (0.82)

Finger

Week 0 (baseline)

I: 4.17 (0.98)

C: 3.83 (0.75)

Week 2

I: 3.50 (1.38)

C: 3.83 (0.75)

Week 6

I: 3.50 (1.38)

C: 3.67 (0.82)

Week 12

I: 3.67 (1.21)

C: 4.00 (0.63)

Difficulties with activities of daily living

Measured with three indicators, score (0-4 unable), mean (SD)

Cleaning the palm of the affected hand

Week 0 (baseline)

I: 1.67 (0.82)

C: 2.00 (0.90)

Week 2

I: 1.67 (0.82)

C: 2.17 (0.75)

Week 6

I: 1.67 (0.82)

C: 2.17 (0.75)

Week 12

I: 1.67 (0.82)

C: 2.17 (0.75)

Cutting the fingernails of the affected hand

Week 0 (baseline)

I: 1.50 (0.84)

C: 2.33 (0.52)

Week 2

I: 1.50 (0.84)

C:  2.17 (0.75)

Week 6

I: 1.83 (0.98)

C: 2.17 (0.5)

Week 12

I: 1.67 (0.82)

C: 2.33 (0.52)

Putting the affected arm through a sleeve

Week 0 (baseline)

I: 2.17 (0.75)

C: 2.00 (0.63)

Week 2

I: 1.83 (0.75)

C: 2.00 (0.63)

Week 6

I: 1.83 (0.75)

C: 2.00 (0.63)

Week 12

I: 2.17 (0.75)

C: 2.00 (0.63)

Safety

Following stated in the text:

“The treatment was well tolerated by all patients; no study-related side-effects were observed”

Kong, 2007

Type of study:

RCT

Setting:

Outpatient clinic of a tertiary rehabilitation centre

Country:

United Kingdom

Source of funding:

Funded in part by Ipsen Beaufor

Inclusion criteria:

1) Age 21-80 years.

2) More than three months after onset of stroke.

3) Hemiplegic shoulder pain of two weeks duration

or more, with pain severity score of 4 or higher when assessed on a visual analogue scale, with 0 indicating no pain and 10, severe

pain.

4) Shoulder adductor and elbow flexor spasticity of at least 2 or higher on the 5-point Ashworth Scale.

Exclusion criteria:

1) Previous history of shoulder pain/shoulder surgery before stroke.

2) Significant aphasia or cognitive impairment that precluded accurate clinical assessment of visual analogue scale scores.

3) Reflex sympathetic dystrophy.

4) Poststroke central pain.

5) History of neuromuscular disease (e.g. myasthenia gravis or previous BT-A injection).

N total at baseline:

Intervention: 8

Control: 9

Important prognostic factors²:

Age ± SD:

I: 46.3 (9.0)

C: 56 (13.6)

Sex:

I: 43% M

C: 89% M

Groups comparable at baseline?

No, groups were too small to guaranty proper randomization (difference is gender, and nature of stroke)

500 units of BT-A were diluted with 2.5 mL of normal saline, and 250 units of BT-A were injected into the pectoralis major and biceps brachii respectively using anatomical landmarks.

2.5 mL of normal saline without BT-A was used.

Length of follow-up:

12 weeks

Loss-to-follow-up:

Intervention:

N 1 (12.5%)

Reason: fractured his left humerus after a fall, six weeks

after enrolment

Control:

N 0 (0%)

Incomplete outcome data:

Intervention:

N 0 (0%)

Reasons (describe)

Control:

N 0 (0%)

Outcome measures and effect size (include 95%CI and p-value if available):

Shoulder pain (VAS):

12 weeks

I: -3.0 (-3.5 to -0.5)

C: -2.0 (-4.0 to -1.8)

p-value: 0.50

Muscle tone (Ashworth)

12 weeks

I: -1.0 (-2.0 to -1.0)

C: -1.0 (-1.0 to 0)

p-value: 0.14

Passive shoulder abduction

12 weeks

I: +48 (13 to 53)

C: +15 (4 to 31)

p-value: 0.48

Adverse events:

The only reported adverse event was pain during injection, which occurred in 11 patients - six in the BT-A group and five in the placebo group

Marciniak, 2012

Type of study:

RCT

Setting:

multisite academic rehabilitation practice: one urban site and one suburban site

Country:

United States of America

Source of funding:

Funded by an unrestricted educational grant from Allergan, Inc, for which Christina M. Marciniak has been a consultant.

Inclusion criteria:

18 yrs or older, weight of more than 88 lbs, diagnosis

of stroke with resultant hemiplegia or hemiparesis, stable medical illnesses, willingness to remain on a stable dose of antispasticity medication throughout the study and on a stable dose for 3 wks before the study enrollment, received physical therapy or occupational therapy for shoulder pain for at least 2 wks with no change in pain or function, shoulder pain of at least 4 on the visual analog scale for pain rated at the time of the screening visit, an Ashworth grade of 3 or greater for shoulder tone for adductors and internal rotators at the screening visit, no history of BoT-A injections before 1998, ability to appropriately rank pain on a

cognitive function screening tool where the subjects

were asked to rank pain associated with three

painful scenarios, and a negative serum pregnancy test drawn on the day of the injection(s) for women of childbearing potential.

Exclusion criteria:

known allergy or sensitivity to the study medication;

pregnancy, planning pregnancy, or breastfeeding;

women of childbearing potential not using

a reliable means of contraception; concurrent use of aminoglycoside antibiotics, curare-like agents, or other agents that might interfere with neuromuscular function; any medical condition such as myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or other disorders that would put the participant at increased risk with exposure to BoT; infection or dermatologic condition at the injection site; presence of significant fixed contracture of the study limb shoulder; significant inflammation (clinical examination findings such as redness, increased warmth, or swelling) or oedema of the study limb; obesity to the degree that the shoulder landmarks were obscured such that the medication could not safely be injected; planned initiation of new antispasticity medication during the study period; concurrent medical condition that may be the more likely cause of the shoulder pain or that may put the participant at significant increased risk; and significant aphasia to the degree that the assessment tools would not be completely reliable.

N total at baseline:

Intervention: 10

Control: 11

Important prognostic factors²:

Age ± SD:

I: 60.2 ± 7.8

C: 59.8 ± 10.3

Sex:

I: 60% M

C: 63.6% M

Groups comparable at baseline?

No, groups were too small to guaranty proper randomization

two syringes were used to reconstitute two vials of BoT-A, at a concentration of 100 units/1 ml.

The participants had a total

of 100Y150 units (1Y1.5 ml of 100 units/1 ml concentration) injected into the pectoralis major muscle

(or the volume of saline that would correspond to this number of units, in the case of placebo injections). A total of 40Y60 units (or the corresponding saline volume) was injected into the teres major muscle if the shoulder extensors exhibited spasticity of an Ashworth grade of 3 or 4.

Dosing was adjusted on the basis of the Modified Ashworth Scale score and muscle size, as determined by the experienced injectors. Three sites were injected in the pectoralis muscle at the anterior aspect of the shoulder, and one site was injected in the teres major muscle, at the posterior aspect of the shoulder, lateral and superior to the scapular tip. Electromyographic guidance was used for the injections.

2 ml of saline

The participants had a total

of 100Y150 units (1Y1.5 ml of 100 units/1 ml concentration) injected into the pectoralis major muscle

(or the volume of saline that would correspond to this number of units, in the case of placebo injections). A total of 40Y60 units (or the corresponding saline volume) was injected into the teres major muscle if the shoulder extensors exhibited spasticity of an Ashworth grade of 3 or 4.

Dosing was adjusted on the basis of the Modified Ashworth Scale score and muscle size, as determined by the experienced injectors. Three sites were injected in the pectoralis muscle at the anterior aspect of the shoulder, and one site was injected in the teres major muscle, at the posterior aspect of the shoulder, lateral and superior to the scapular tip. Electromyographic guidance was used for the injections.

Length of follow-up:

16 weeks (randomization was opened after 12 weeks. After 12 weeks a total of six participants who were initially in the saline group elected to receive BoT-A.

Loss-to-follow-up:

Intervention:

N 0 (0%)

Control:

N 2 (18%)

Reasons: one because of death from recurrent stroke and one because of hospitalization with bleeding

Incomplete outcome data:

Intervention:

N 0 (0%)

Control:

N 0 (0%)

Outcome measures and effect size (include 95%CI and p-value if available):

Pain:

12 weeks

No significant difference between groups

(data not reported)

Muscle tone (Ashworth)

12 weeks

No significant difference between groups

(data not reported)

Passive range of motion:

12 weeks

No significant difference between groups

(data not reported)

Disability assessment scale:

12 weeks

No significant difference between groups

(data not reported)

Fugl-Meyer Scale:

12 weeks

Significant difference:

P = 0.013

FIM Hygiene:

12 weeks

No significant difference between groups

(data not reported)

Adverse events:

Ten adverse events were reported; these occurred

in seven subjects.

I: treatments for bronchitis and rectal bleeding, and one subject was referred for psychologic follow-up because of the severity of depressive

symptoms reported on the BDI.

C: died at week 8 post injection after a new stroke,

three subjects with dehydration accompanied by urinary tract infections, one

subject who reported anemia requiring transfusion,

and one subject with a seizure.

MS PATIENTS

LOWER LIMB SPASTICITY

Snow, 1990

Type of study:

RCT cross over design

Setting:

Not reported

Country:

Canada

Source of funding:

Injections of botuline toxine were supplied by Smith-Kettlewell Eye Research institute. No other information reported.

Inclusion criteria:

Not reported

Exclusion criteria:

Not reported

N total at baseline:

N= 10 cross over design

Important prognostic factors²:

Not specified per group

Age ± SD:

40.2 (no SD reported)

Sex:

10% M

Groups comparable at baseline?

Yes, it is a cross over design

400 MU (160 ng) was the standard dose for all patients. The toxin was given in divided doses of 50 MU into adductor brevis (total 100 MU), adductor longus (total 100 MU) and adductor magnus (total 200 MU. The site of the injection was guided by the standard locations used for electromyography.

0.9% saline to a concentration of 100 mouse units (MU/ml.

Length of follow-up:

6 weeks (after 3 months cross over)

Loss-to-follow-up:

During saline administration: 1 (10%)

Reason: developed left-sided numbness and hemiparesis

Incomplete outcome data:

Not reported.

Spasticity (no validated score):

Baseline

I: 7.9 ± 4.87

C:6.8 ± 5.26

6 weeks

I: 4.7 ± 4.31

C:7.1 ± 4.77

Significant difference between groups before and after injection

P = 0.009

Hygiene score (no validated score):

6 weeks

Significant improvement in toxin group

p-value = 0.02

Side effects:

No side effects attributable to the toxin were noted at any stage of the study.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

STROKE PATIENTS

UPPER LIMB SPASTICITY

Barnes, 2010

Type of study: Randomized trial

Setting: Patients with stable upper limb spasticity following a stroke, brain injury, multiple sclerosis or cerebral palsy from 32 sites in eight Western European countries

Country: Spain, Italy, Austria, United Kingdom, Germany, Portugal, France, Switserland

Source of funding; Commercial

Inclusion criteria:

• At least 21 years
• Event (i.e. stroke, brain injury, multiple sclerosis, or cerebral palsy) ≥ 6 months ago
• Focal spasticity of wrist flexors or wrist flexors in combination with elbow flexors scoring ≥ 2 on the Ashworth Scale
• Disability in the primary therapeutic target of at least 2
• Patients pretreated with BoNT were included if they had a sufficient therapeutic response following their most recent injection session. The most recent total BoNT ⁄A dose could not have exceeded 400 units of Botox_ or 1600 units of Dysport_ with a maximum dose of 50 units Botox_ or 200 units Dysport_ for flexor carpi ulnaris treatment and 60 units Botox_ and 240 units Dysport_ for flexor carpi radialis treatment.

Exclusion criteria:

• Bilateral upper limb paresis/paralysis
• Botulinum toxin treatment within the last 4 months
• Fixed contracture or other muscle hypertonia in the spastic limb
• Prior or planned treatment with phenol, alcohol or surgery in the target limb
• Neuromuscular disorders
• Treatment with intrathecal baclofen within 4 weeks prior to screening
• Severe atrophy of the target muscles
• Hypersensitivity to the study medication
• Change in oral medication for spasticity
• Treatment with intrathecal baclofen
• Pregnant or lactating women
• Women without adequate contraception

N total at baseline:

I: 97

C: 95

Important prognostic factors²:

Mean age (SD):

I: 55 (15)

C: 55 (14)

Sex:

I: 51% M

C: 65% M

Groups comparable at baseline?

No, proportionally more males in the control group

Single treatment with intramuscular injections with botulinum neurotoxin type A NT 201 (Xeomin) with 100 IU dissolved in 5 ml (high volume group)

Injections could be controlled by EMG, electrical stimulation, or sonography.

The individual injection pattern was adapted to the patient’s needs.

Single treatment with intramuscular injections with botulinum neurotoxin type A NT 201 (Xeomin) with 100 IU dissolved in 2 ml (low volume group)

Injections could be controlled by EMG, electrical stimulation, or sonography.

The individual injection pattern was adapted to the patient’s needs.

Length of follow-up:

20 weeks

Loss-to-follow-up:

I: N = 6 (6%)

Reasons: 2 consent withdrawn, 1 visit scheduling issues, 2 lost to follow-up, 1 other reasons

C: N = 6 (6%)

Reasons: 1 adverse event, 5 visit scheduling issues

Incomplete outcome data:

I: N = 16 (16%)

C: N = 11 (12%)

Reason: major protocol deviations

Functional disability:

Rating of the investigator (on the four-point DAS) of the chosen primary therapeutic target, n (%) showing improvement

Week 4

I: 51 (63%)

C: 44 (52%)

Percentage difference: 10.6% (95%CI: -4.4 to 24.9)

Muscle tone:

Measured with the Ashworth Scale

Data not stratified by treatment group

Global assessment of treatment response:

Measured at week 4

Data not stratified by treatment group

Safety:

Treatment related adverse events

I: 8.3%

C: 10.4%

Authors’ conclusions: NT 201 improved functional disability and muscle tone and was well tolerated in patients with upper limb spasticity of diverse aetiology in both dilutions.

Comment:

Conclusions were not specified by treatment group.

Sponsor performed the statistical analysis and were authors of the paper.

3 cerebral palsy patients were included in the high volume group and 1 MS patient as well.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

STROKE PATIENTS

UPPER LIMB SPASTICITY

Francisco, 2002

Type of study: RCT [parallel]

Setting: Freestanding rehabilitation hospital

Country: United States of America

Source of funding: Non-commercial

Inclusion criteria:

• Spasticity resulting from a nonhemmorrhagic stroke or traumatic brain injury
• At least 1 month postonset of the stroke or traumatic brain injury
• Severe spasticity as defined by a modified Ashworth Scale score ≥ 3 in both the wrist and finger flexors
• Age ≥ 18 year
• Absence of wrist or finger joint contracture
• No known allergy to BTX-A
• No BTX-A injection within 6 months before enrolment

N total at baseline:

Intervention: 7 (6 completed)

Control: 8 (7 completed)

Important prognostic factors²:

Age (range):

I: 46 (27-70)

C: 42 (19-65)

Sex:

I: 67% M

C: 71% M

Groups comparable at baseline? Difficult to judge with few participants

High-volume – 50 units of BTX-A per 1 mL of preservative-free saline and 1.2 mL per muscle

27-gauge Teflon-coated monopolar needle was introduced to the sites, and needle placement was confirmed with an electrical stimulator.

The spastic flexor carpi radialis and ulnaris and the digitorum superficialis and profundus received 60 units each.

On average, patients in the high-volume group received 417 units BTX-A.

Low-volume – 100 units of BTX-A per 1 ml of preservative-free saline and 0.6 ml per muscle.

27-gauge Teflon-coated monopolar needle was introduced to the sites, and needle placement was confirmed with an electrical stimulator.

The spastic flexor carpi radialis and ulnaris and the digitorum superficialis and profundus received 60 units each.

Patients in the low-volume group received, on average, 432 units.

Length of follow-up:

12 weeks

Loss-to-follow-up:

Intervention:

N = 1 (14%)

Reasons: Failed to attend the posttreatment assessments

Control:

N = 1 (13%)

Reasons: Failed to attend the posttreatment assessments

Incomplete outcome data:

Intervention:

N = 1 (14%)

Reasons: Failed to attend the posttreatment assessments

Control:

N = 1 (13%)

Reasons: Failed to attend the posttreatment assessments

Muscle tone

Measured with the MAS, mean change from baseline (SD)

Wrist flexors

Week 4

I: -1.9 (0.7)

C: -1.7 (0.7)

Week 8

I: -1.9 (0.6)

C: -1.9 (0.6)

Week 12

I: -1.6 (0.8)

C: -1.3 (1.1)

Finger flexors

Week 4

I: -1.8 (0.7)

C: -1.3 (0.4)

Week 8

I: -1.9 (0.9)

C: -1.4 (0.7)

Week 12

I: -1.7 (1.2)

C: -0.9 (0.6)

Global Rating Scale

Measures the subjective impressions of change in spasticity (high score indicates worsening of symptoms), mean change from baseline

Patient/caregiver

Week 4

I: -1.7 (0.8)

C: -1.6 (0.5)

Week 8

I: -2.0 (0.6)

C: -3.3 (1.1)

Week 12

I: -3.0 (1.5)

C: -4.9 (1.2)

Investigator

Week 4

I: -1.8 (0.8)

C: -1.7 (0.5)

Week 8

I: -1.7 (0.8)

C: -3.9 (0.7)

Week 12

I: -3.0 (1.3)

C: -4.6 (1.0)

Safety

Following reported in the text:

“There was no adverse event reported by any of the patients.”

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Gracies, 2015

Patients were randomly allocated in a ratio of 1:1:1 […]. Computer-generated randomisation lists were created by a sponsor statistician independent from the study and treatment numbers were assigned when patients entered the study with a 24-h interactive voice response system from an external contract research organisation.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Ward, 2014

Patients were randomized to onabotulinumtoxinA (BOTOX®, Allergan,

Inc., Irvine, CA, USA) + standard of care (SC) or placebo + SC

(in a 1:1 ratio) (Fig. 1) and the treatment arms were stratified according

to location of spasticity (UL or LL).

Unclear, blinding of the allocation was not decribed

Unlikely

Unlikely

Unlikely

Likely; not all pre specified outcomes are reported in the publication

Unclear: 12% and 20% of the participants were lost to follow up. However, data was imputed (imputed a clean data were not reported separately).

Unlikely

Rosales, 2012

Eligible patients were allocated to receive BoNT-A or placebo in a 1:1 ratio according to a predetermined randomization schedule (block size of 4) generated by the sponsor-assigned biostatistician. The sponsor-assigned randomization manager provided treatment allocation codes to the drug supplier and drug safety officer, with the master listing kept confidential and secured by the sponsor representative.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Barnes, 2010

A randomization list was provided by the sponsor using the computerized randomization program RANCODE version 3.6 for block-wise randomization and distribution to the centers, ensuring stratification by center

Unclear

Unclear

Unclear

Unlikely

Unlikely

Unlikely

Unlikely; Although study had a high number of protocol violations in both treatment arms, the results of the PP and ITT analyses were the same

Kaji, 2010a

Eligible patients were randomly assigned to BoNTA or placebo by blocked randomisation with a randomisation ratio of 2:1 within each medical institution. The randomisation code was prepared by a clinical research organisation which was independent of all the clinical staff engaged in the study and access to the randomisation code was maintained at a secure location. The randomisation remained blinded until study completion.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Kaji, 2010b

The person responsible for randomization prepared a randomization code table, and it was concealed from all investigators and all study personnel

Unclear

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Shaw, 2010

Randomisation was by a central independent webbased randomisation service […]. Participants were stratified according to research site and level of upper limb function (ARAT 0-3, ARAT 4-28, ARAT 29-56), and randomised to intervention or control in a 1:1 ratio using permuted block sequences.

Unclear

Likely

Likely

Unlikely

Unlikely

Unlikely

Unlikely

Kanovsky, 2009

[…], patients were randomly assigned to either botuline toxin or placebo by a computer-generated list stratified by the centers.

Unclear

Unlikely

Unlikely

Unclear

Unlikely

unlikely

Unlikely

McCrory, 2009

A computer-generated master list of randomized treatment allocation codes was prepared centrally by an independent organization with a 1:1 proportion of patients assigned to each group. Group assignments was determined independently of the treating team by sequential allocation of treatment packs from the hospital pharmacy with pre-assigned randomization numbers.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Gusev, 2008

[…], eligible patienrs were randomized [1:1] using a computer-generated code. Random computer-generated numbers were attached to individual medication boxes, each containing three vials which were identical in size and appearance.

Unlikely

Unlikely

Unlikely

Unclear

Unlikely

Unlikely

Unlikely

Pittock, 2003

Using computer-generated treatment coding, patients were randomly allocated to one of four treatment groups

Unclear

Unlikely

Unlikely

Unclear

Unlikely

Unlikely

Unlikely

Brashear, 2002

Only statement: randomly assigned, no further information is given

Unclear

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Bakheit, 2001

Randomly assigned to one of the two groups in accordance with a randomization list generated in blocks of four prior to the study and held centrally by a third party.

Unclear

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Trials geincludeerd in de sensitiviteitsanalyse

Bakheit, 2000

Patients were randomized to 1 to 4 study groups

Unclear

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Bhakta, 2000

An individual randomisation code produced by the University medical statistics department

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Francisco, 2002

The allocation schedule was generated by randomly permuting a sequence containing nine assignments to each of the two treatment groups.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Gracies, 2014

Eligible subjects were allocated to 1 of 3 grups (1:1:1 ratio) using a computer-generated randomization list

Unclear

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Hesse, 1998

Patients were randomly assigned to one of four groups.

Unclear

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unlikely

Kong, 2007

Subjects were block-randomized in block sizes of four into either the BT-A or placebo group using a computer-generated sequence. Treatment allocation was revealed only after eligible subjects had consented to participate in the study. In

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Marciniak, 2012

Restricted randomization with random allocation was used. Sealed envelopes were prepared, with one half of the envelopes containing assignment to the placebo group, and one half, to the BoT group. The envelopes disclosing the study group assignment were then opened by the research coordinator preparing the medication at the time of randomization.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear: 18% of the control were lost to follow up

Unlikely

Snow, 1990

A randomized cross-over design was used.

Unclear, blinding of the allocation was not decribed

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear