Introduction: • AbobotulinumtoxinA (Dysport®) is the first botulinum neurotoxin approved by the

US Food and Drug Administration (FDA) for the treatment of children with lower limb spasticity (age 2 and older).

• Currently, FDA approval is indicated only for injections into the gastrocnemius and soleus muscles.1

• AbobotulinumtoxinA has been used outside of the US for over 20 years to treat pediatric lower limb spasticity, including injections into distal and/or proximal muscles in accordance with the individual pattern of impairment.2 As such, the abobotulinumtoxinA doses used per muscle may vary widely in routine practice.3

• A recent Phase III study established the safety and efficacy of abobotulinumtoxinA injections vs. placebo into the gastrocnemius-soleus complex (GSC) for the treatment of dynamic equinus foot deformity.4 This double-blind study was followed by a prospective open-label treatment phase which permitted injections into other lower limb muscles for individualized therapy.

• We aim to provide an overview of the doses used per lower limb muscle in all randomized controlled trials of abobotulinumtoxinA in pediatric lower limb spasticity that permitted injections into muscles other than the GSC.

Methods:Phase III open-label extension study• We present the doses used per muscle from a multicenter, repeated treatment,

open-label study of abobotulinumtoxinA injections into the GSC and other lower limb muscles in children with lower limb spasticity due to CP with a GMFCS Level of I-III.

• During Cycle 1, all patients requiring treatment received 10 U/kg/leg into the GSC, plus hamstrings if clinically necessary. If patients required hamstring injections in Cycle 1, the total dose per lower limb was equally split between the hamstrings and ipsilateral GSC.

• From Cycle 2 onwards, patients requiring re-treatment received doses ranging from 5 to 20 U/kg/leg. Other lower limb muscles (tibialis posterior, hamstrings, hip adductors or iliopsoas) were injected as required (flexible dosing) to a maximum of 30 U/kg or 1000 U, whichever was the lower dose.

Literature search• A systematic review of the literature was performed in April 2016 using the

PubMed, Cochrane Library and EMBASE databases as well as an internal Ipsen Pharma database. The key search terms were: abobotulinumtoxinA (alternative spelling: Abobotulinumtoxin A) Dysport, spasticity, cerebral palsy, pediatric and clinical trial. References were limited to those written in English.

• All references meeting the above criteria were retrieved, and those that included injections into ex-GSC lower limb muscles are included in this review.

ResultsPhase III open-label extension study• Of the 216 patients who entered into the open-label study, 207 received ≥1

abobotulinumtoxinA injection cycle; only 11 patients required a fourth injection within the open-label period and entered Cycle 4.

• During Cycle 1, the median dose of abobotulinumtoxinA in the GSC was 10 U/kg for unilateral injections and 20 Uk/kg for bilateral injections. The median dose for hamstrings was 5 U/kg for unilateral injections and 10 U/kg for bilateral injections.

AbobotulinumtoxinA injection in muscles in pediatric patients with lower limb spasticityMauricio R Delgado,1 Ann Tilton,2 Mark Gormley,3 Philippe Picaut,4 and Gustavo Suarez4

1Texas Scottish Rite Hospital for Children, Dallas, Texas, USA; 2Louisiana State University Health Center and Children’s Hospital New Orleans, New Orleans, Louisiana, USA; 3Gillette Children’s Specialty Healthcare, St Paul, Minnesota, USA; 4Ipsen Biopharmaceuticals, Basking Ridge, NJ, USA and Les Ulis, France.

SP 4

DisclosuresMRD, MG and AT have been investigators in Ipsen-sponsored clinical trials and they or their institutions have received payment for participation. In addition, AT and MG report personal fees from Ipsen for consultancy. PP and GS are employed by Ipsen.

Medical writing: ACP Clinical Communications Ltd/anita@acpclinicalcommunications.com

References1. Dysport® (abobotulinumtoxinA) for Injection [Prescribing Information]. Basking Ridge, NJ. Ipsen Biopharmaceuticals, Inc; 2016; 2. Strobl W, Theologis T, Brunner R, et al. Best clinical practice in botulinum toxin treatment for children with cerebral palsy. Toxins (Basel) 2015;7(5):1629-1648; 3. Hubble J, Schwab J, Hubert C, Abbott CC. Dysport (botulinum toxin type A) in routine therapeutic usage: a telephone needs assessment survey of European physicians to evaluate current awareness and adherence to product labeling changes. Clin Neuropharmacol 2013;36(4):122-127; 4. Delgado MR, Tilton A, Russman B, et al. AbobotulinumtoxinA for Equinus Foot Deformity in Cerebral Palsy: A Randomized Controlled Trial. Pediatrics 2016;137(2):1-9; 5. Moore AP, Ade-Hall RA, Smith CT, et al. Two-year placebo-controlled trial of botulinum toxin A for leg spasticity in cerebral palsy. Neurology 2008;71(2):122-128; 6. Mall V, Heinen F, Siebel A, et al. Treatment of adductor spasticity with BTX-A in children with CP: a randomized, double-blind, placebo-controlled study. Dev Med Child Neurol 2006;48(1):10-13.

Conclusions• These data provide some information on dosage ranges for

abobotulinumtoxinA injections into proximal and distal leg muscles, including hip adductors, that have been used in children with lower limb spasticity due to CP.

• The two repeat-dose studies (Phase III open-label study and Moore et al) allowed flexible dosing, and accordingly there was variability in dosing and injection patterns.5

• Such data highlight the need for tailored, individualized treatment of pediatric lower limb spasticity that is re-assessed at each injection cycle.

Presented at the 71st Annual Meeting of the American Academy for Cerebral Palsy and Developmental Medicine, Montreal, Quebec, Canada, September 13–16, 2017. This study was sponsored by Ipsen.

Table 2. Dosing per muscle in the Moore et al. study.5

Muscle Injection session (months) Median (range)

sites injected

Entry 3 6 9 12 15 18 21

Hip adductors Number patients Number muscles Dose (U/kg): Mean (SD) [range]

N= 4

76.4 (1.8) [3.8–7.5]

N= 5

88.3 (3.6)

[2.7–12.6]

N= 4

77.5 (3.1)

[5.0–12.0]

N= 3

57.7 (1.3)

[6.7–10.0]

N= 6

107.3 (1.8)

[4.6–10.4]

N= 4

68.3 (3.8)

[4.6–14.8]

N= 6

95.9 (1.4) [4.0–7.5]

N= 4

76.0 (2.0) [4.1–8.9]

1 (1-2)

GSCNumber patients Number muscles Dose (U/kg): Mean (SD) [range]

N= 23

34 10.2 (3.6) [7.4–15.3]

N= 26

38 12.9 (4.4) [9.2–20.3]

N= 22

3414.8 (5.9) [6.3–25.2]

N= 19

3017.6 (6.7)

[7.6–30.8]

N= 15

2517.1 (7.2)

[10.4–32.5]

N= 15

23 15.7 (8.5)

[5.9–30.9]

N= 14

2215.2 (6.7)

[4.8–30.0]

N= 15

2614.8 (7.9)

[4.4– 31.4]

3 (2-4)

HamstringsNumber patients Number muscles Dose (U/kg): Mean (SD) [range]

N= 6

117.0 (1.6)

[3.8–8.4]

N= 4

67.9(2.7)

[3.7–10.0]

N= 8

1510.9 (2.5) [6.8–12.7]

N= 9

1811.2 (3.4) [5.1–15.3]

N= 8

1610.9(3.4) [7.5–15.1]

N= 6

912.6 (3.3) [7.5–15.0]

N= 10

1710.8 (3.1) [6.0–15.8]

N= 7

1310.7 (3.0) [5.9–15.2]

2 (1-3)

• Across the treatment cycles, in addition to abobotulinumtoxinA injections into the GSC, 17-24% of patients had injections into the hamstrings (Table 1). During Cycles 2 and 3, 11–12% patients had injections into other lower limb muscles.

• During the study, 150 (73.5%) patients reported ≥1 treatment emergent AE (TEAE). The most frequently reported TEAEs were the common childhood infections of: nasopharyngitis and upper respiratory tract infection, and associated pyrexia.

• The proportion of subjects reporting TEAEs tended to decrease with each treatment cycle (Cycle 1: 56.2%; Cycle 2: 45.8%; Cycle 3: 17.5% & Cycle 4: 12.5%) and the incidence of treatment-related TEAEs was low (10.3%). There were no apparent differences in incidence with regard to dose or number of limbs injected.

• The only treatment-related TEAE reported by ≥2% patients was injection site pain, of which 11 instances were reported by 10 patients.

Literature search• The formal literature search identified 2 randomized, placebo-controlled trials in

which abobotulinumtoxinA was injected into ex-GSC muscles for pediatric CP.

1. Moore et al. Two-year placebo-controlled trial of botulinum toxin A for leg spasticity in

cerebral palsy. Neurology. 2008; 71 (2):122-8.5

2. Mall et al. Treatment of adductor spasticity with BTX-A in children with CP: a randomized, double-blind, placebo-controlled study. Dev Med Child Neurol 2006; 48 (1):10-13.6

Moore et al study• Moore et al. conducted a two-year randomized, double-blind, parallel-group,

placebo-controlled, multi-injection cycle trial of treatment with abobotulinumtoxinA for leg spasticity in children (2–8 years) with CP.5 The majority of patients had diparesis.

• Patients were randomized 1:1 to abobotulinumtoxinA (n=32) or placebo (n=32). Trial injections were administered every 3 months if clinically indicated for a maximum of 8 cycles over 2 years.

• The maximum abobotulinumtoxinA dose was set at 15 U/kg for Cycle 1 and increased by 5 U/kg per cycle up to a maximum of 30 U/kg at Cycle 4. Within these ranges, the blinded clinician and physiotherapist determined the dose administered based on clinical grounds such as spasticity severity, number and distribution of muscles for treatment, and adverse effects or residual weakness from previous injections.

• Injectors could select either a single muscle in one leg or any combination in one or both legs. Criteria for selection of a particular muscle included dynamic spasticity causing a clinical problem, no severe fixed contracture, no recent surgery or injury to that muscle, and no major residual weakness from previous injections. If there were several eligible muscles, they selected combinations likely to be clinically meaningful.

• Muscle patterns injected were similar within the placebo and active treatment groups. Table 2 provides the mean dosing parameters for abobotulinumtoxinA used over the 2-year study period.

• During the study, 150 (73.5%) patients reported ≥1 TEAE; the most frequently reported TEAEs were nasopharyngitis and upper respiratory tract infection, and associated pyrexia, which are common during childhood.

Mall et al study• Mall et al. conducted a randomized, multi-center, double-blind, placebo-controlled

trial in children with a diagnosis of CP (18 months to 10 years) who had bilateral adductor spasticity (Reimer’s migration index <50%); all patients had tetraparesis and most had a GMFCS level greater than grade III.6

• Patients were randomized 1:1 to a single injection of abobotulinumtoxinA (n=33) or placebo (n=28). AbobotulinumtoxinA was administered at a dose of 30 U/kg (maximum 1500 U) injected bilaterally, with 20 U/kg in the adductors and 10 U/kg in the medial hamstrings.

• The most frequently reported AEs were: muscular weakness (n=5 with abobotulinumtoxinA and n=2 with placebo), dysphagia (n=2 with abobotulinumtoxinA and n=1 with placebo) and increased frequency of passing urine (n=2 with abobotulinumtoxinA).

Table 1. Muscles treated and doses per muscleMuscle group; n (%) Open-label

Cycle 1 Cycle 2 Cycle 3 Cycle 4

Number of patients* N=117 unilateralN=84 bilateral

N=98 unilateral N=70 bilateral

N=42 unilateralN=38 bilateral

N=3 unilateralN=5 bilateral

Number of legs injected 285 238 118 13

GSC Number (%) legs injected Median [range] dose (U/kg/leg)

284 (99.6%)10.0 [3.5-16.0]

238 (100%)10.0 [2.5-15.0]

118 (100%)10.0 [3.9-17.0]

13 (100%)10.0 [7.5-15.0]

Hamstrings Number (%) legs injected Median [range] dose (U/kg/leg)

51 (17.9%)5.0 [2.0-10.0]

64 (26.9%)7.5 [2.5-10.0]

26 (22.0%)5.3 [1.5–10.0]

2 (15.4%)**7.5

Tibialis posterior Number (%) legs injected Median [range] dose (U/kg/leg)

- 25 (10.5%)4.0 [1.2–7.5]

8 (10.0%)4.1 [2.3–8.3]

-

Hip adductors Number (%) legs injected Median [range] dose (U/kg/leg)

- 6 (2.5%)2.5 [2.3–6.5]

2 (1.7%)**3.8

-

Iliopsoas Number (%) legs injected Median [range] dose (U/kg/leg)

- 1 (0.4%)2.0

2 (1.7%)**1.9

-

Other lower limb muscle Number (%) legs injected Median [range] dose (U/kg/leg)

- 3 (1.3%)4.0 [2.0–18.0]

- -

* Average dosing data is presented per leg and not per patient because doses for bilateral injections could be split unequally between the 2 legs.

**1 patient injected bilaterally into relevant muscle (i.e. 2 legs). GSC=gastrocsoleus complex.

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