Table 4, Details of Included Studies - Clinical Review Report: abobotulinumtoxinA (Dysport Therapeutic)

		Study 141	Study 701
Designs & Populations	Study Design	DB placebo-controlled, phase III RCT	DB placebo-controlled, phase III RCT
Locations	35 centres in 6 countries: US, France, Mexico, Turkey, Poland, and Chile	5 centres (3 in the Czech Republic and 2 in the Slovak Republic)
Randomized (N)	241	52
Inclusion Criteria	Children (aged 2–17 years) with a diagnosis of CP Ambulatory with spastic hemiparesis, paraparesis, diparesis, or tetraparesis characterized by an equinus foot positioning during the stance phase of the gait Able to walk (sufficient to complete a video analysis of 2-dimensional motion) with or without walking aids Had a MAS score of ≥ 2 at the ankle joint of the (most) affected lower limb to be injected Had a spasticity grade (Y) on the TS of 2, 3, or 4 assessed at the ankle joint of the most affected limb to be injected, with a spasticity angle (X) of 10 degrees or more Had been classified as GMFCS level I, II, or III Patients could be BoNT-naive or previously treated, but the last BoNT treatment of any type for any condition must have been more than 6 months prior to study entry Previously established physiotherapy treatment was permitted up to at least the week 12 visit provided it had begun at least four weeks prior to study start and was to continue during the study at the same pre-study frequency and intensity (and provided the patient maintained their usual level of physical activity until the end of the study) A previously established casting/orthoses regimen was permitted until the end of the week 12 visit provided it was used in the same way as before entry into the study	Clinical diagnosis of diplegic cerebral palsy Male or female aged between 2 and 7 years Ambulatory (therapeutic ambulator as a minimum) Considered by the investigator to have the potential to benefit from injection of aboBoNTA into the gastrocnemius muscles Able to achieve passive ankle dorsiflexion of 10 degrees (in both limbs) with the knee straight
Exclusion Criteria	Evidence of non-ambulatory status Major limitation in the passive range of motion at the ankle as defined by maximum ankle dorsiflexion measured by the slow-speed angle of arrest (X_V1), of < 80 degrees (TS angle) in the most affected leg to be injected Significant difference (> 2 cm) between the length of legs Current need for surgery or previous surgery for spasticity of the GSC and/or hamstring muscles (and tendons) in the most affected leg to be injected Serial casting in the past 12 weeks Previous injection of alcohol and/or phenol into the GSC and/or hamstrings in the most affected leg to be injected Severe athetoid or dystonic movements in the targeted lower limb(s) Treatment with any drug that interferes either directly or indirectly with neuromuscular function (e.g., aminoglycoside antibiotics) or neuroblocking drugs used during surgery (e.g., curare) within the last 30 days prior to study treatment Known resistant or sensitivity to BoNT or to any of the components in the formulation or allergy to cow’s milk protein Ongoing treatment with intrathecal baclofen or previous/planned rhizotomy Any medical condition, laboratory or diagnostic procedure finding that might preclude administration of BoNTA	Perceived need for surgery to the affected limbs within six months Requirement for multi-level injections of BoNT Significant foot deformity defined as the inability to obtain a calcaneum-neutral position while measuring maximum passive dorsiflexion Treatment with BoNT within nine months of entry into the study Previous surgery on the affected muscles under investigation Previous treatment with phenol for lowerlimb spasticity Known sensitivity to BoNT Generalized disorder of muscle activity (e.g., myasthenia gravis) Receiving aminoglycoside antibiotics or spectinomycin
Drugs	Intervention	AboBoNTA (10 U/kg or 15 U/kg per GSC injected into each affected leg) injected intramuscularly into six injection sites per affected lower limb (four sites in the gastrocnemius muscle and two sites in the soleus muscle).^a	AboBoNTA 30 U/kg distributed equally between both legs by injecting the gastrocnemius muscle of each limb. Two sites were injected in each muscle. Target sites were at the junction of the proximal quarter and the distal three-quarters of the gastrocnemius.
Comparator(s)	Placebo	Placebo
Duration	Phase
Screening	Day −7 to day 1
Double-blind	12 weeks	16 weeks
Follow-up	Discretionary follow-up at weeks 16, 22, and 28	If treatment effect was maintained at week 16, additional visits at weeks 24 and 36 could be scheduled.
Open-label phase	Patients who required re-treatment at week 12, 16, 22, or 28 were considered to have completed the study and were offered entry into an open-label extension study (Study 147).	NA
Outcomes	Primary End Point	Change in MAS scores from baseline to week 4 in the GSC at the ankle joint of the (most) affected lower limb.	Change in the GMFM overall score, without walking aids/orthoses at week 4 compared with baseline.
Other End Points	Secondary Outcomes Mean PGA score at week 4 Mean GAS score at week 4 Tertiary Outcomes Mean change from baseline to week 12 (and to EOS/EW) in the MAS score in the GSC at the ankle joint of the (most) affected lower limb Proportion of patients with at least one grade reduction in MAS score from baseline to week 4 (and to week 12 and EOS/EW) in the GSC at the ankle joint of the (most) affected lower limb Mean PGA score at week 12 (and EOS/EW) Mean GAS score at week 12 (and EOS/EW) Mean change from baseline to week 4 (and to week 12 and EOS/EW) in the angle of arrest at slow speed (X_V1), angle of catch at fast speed (XV3), spasticity angle (X), and spasticity grade (Y) derived from the TS at the ankle joint of the (most) affected lower limb Mean change from baseline to week 4 (and week 12 and EOS/EW) in the OGS total score Proportion of patients with at least one grade improvement from baseline to week 4 (and to week 12 and EOS/EW) in the “initial foot contact” subsection of the OGS (OGS responders) Mean change from baseline to week 4 (and week 12 and EOS/EW) in lower-limb pain (FPS score) Mean change from baseline to week 12 (and EOS/EW) in the PedsQL score.	GMFM overall score at weeks 8 and 16 GMFM goal-total score at weeks 4, 8, and 16 Leeds Videographic Gait Assessment at weeks 4 and 16 Leeds Functional Mobility Questionnaire at weeks 4 and 16 Subjective functional assessments of gait at weeks 4, 8, and 16 Adverse events.
Notes	Publications	Delgado et al.²³	Kanovsky et al.²⁴

Study 141

Study 701

Designs & Populations

Study Design

DB placebo-controlled, phase III RCT

Locations

35 centres in 6 countries: US, France, Mexico, Turkey, Poland, and Chile

5 centres (3 in the Czech Republic and 2 in the Slovak Republic)

Randomized (N)

241

Inclusion Criteria

Children (aged 2–17 years) with a diagnosis of CP
Ambulatory with spastic hemiparesis, paraparesis, diparesis, or tetraparesis characterized by an equinus foot positioning during the stance phase of the gait
Able to walk (sufficient to complete a video analysis of 2-dimensional motion) with or without walking aids
Had a MAS score of ≥ 2 at the ankle joint of the (most) affected lower limb to be injected
Had a spasticity grade (Y) on the TS of 2, 3, or 4 assessed at the ankle joint of the most affected limb to be injected, with a spasticity angle (X) of 10 degrees or more
Had been classified as GMFCS level I, II, or III
Patients could be BoNT-naive or previously treated, but the last BoNT treatment of any type for any condition must have been more than 6 months prior to study entry
Previously established physiotherapy treatment was permitted up to at least the week 12 visit provided it had begun at least four weeks prior to study start and was to continue during the study at the same pre-study frequency and intensity (and provided the patient maintained their usual level of physical activity until the end of the study)
A previously established casting/orthoses regimen was permitted until the end of the week 12 visit provided it was used in the same way as before entry into the study

Clinical diagnosis of diplegic cerebral palsy
Male or female aged between 2 and 7 years
Ambulatory (therapeutic ambulator as a minimum)
Considered by the investigator to have the potential to benefit from injection of aboBoNTA into the gastrocnemius muscles
Able to achieve passive ankle dorsiflexion of 10 degrees (in both limbs) with the knee straight

Exclusion Criteria

Evidence of non-ambulatory status
Major limitation in the passive range of motion at the ankle as defined by maximum ankle dorsiflexion measured by the slow-speed angle of arrest (X_V1), of < 80 degrees (TS angle) in the most affected leg to be injected
Significant difference (> 2 cm) between the length of legs
Current need for surgery or previous surgery for spasticity of the GSC and/or hamstring muscles (and tendons) in the most affected leg to be injected
Serial casting in the past 12 weeks
Previous injection of alcohol and/or phenol into the GSC and/or hamstrings in the most affected leg to be injected
Severe athetoid or dystonic movements in the targeted lower limb(s)
Treatment with any drug that interferes either directly or indirectly with neuromuscular function (e.g., aminoglycoside antibiotics) or neuroblocking drugs used during surgery (e.g., curare) within the last 30 days prior to study treatment
Known resistant or sensitivity to BoNT or to any of the components in the formulation or allergy to cow’s milk protein
Ongoing treatment with intrathecal baclofen or previous/planned rhizotomy
Any medical condition, laboratory or diagnostic procedure finding that might preclude administration of BoNTA

Perceived need for surgery to the affected limbs within six months
Requirement for multi-level injections of BoNT
Significant foot deformity defined as the inability to obtain a calcaneum-neutral position while measuring maximum passive dorsiflexion
Treatment with BoNT within nine months of entry into the study
Previous surgery on the affected muscles under investigation
Previous treatment with phenol for lowerlimb spasticity
Known sensitivity to BoNT
Generalized disorder of muscle activity (e.g., myasthenia gravis)
Receiving aminoglycoside antibiotics or spectinomycin

Drugs

Intervention

AboBoNTA (10 U/kg or 15 U/kg per GSC injected into each affected leg) injected intramuscularly into six injection sites per affected lower limb (four sites in the gastrocnemius muscle and two sites in the soleus muscle).^a

AboBoNTA 30 U/kg distributed equally between both legs by injecting the gastrocnemius muscle of each limb. Two sites were injected in each muscle.

Target sites were at the junction of the proximal quarter and the distal three-quarters of the gastrocnemius.

Comparator(s)

Placebo

Duration

Phase

Screening

Day −7 to day 1

Double-blind

12 weeks

16 weeks

Follow-up

Discretionary follow-up at weeks 16, 22, and 28

If treatment effect was maintained at week 16, additional visits at weeks 24 and 36 could be scheduled.

Open-label phase

Patients who required re-treatment at week 12, 16, 22, or 28 were considered to have completed the study and were offered entry into an open-label extension study (Study 147).

Outcomes

Primary End Point

Change in MAS scores from baseline to week 4 in the GSC at the ankle joint of the (most) affected lower limb.

Change in the GMFM overall score, without walking aids/orthoses at week 4 compared with baseline.

Other End Points

Secondary Outcomes

Mean PGA score at week 4
Mean GAS score at week 4

Tertiary Outcomes

Mean change from baseline to week 12 (and to EOS/EW) in the MAS score in the GSC at the ankle joint of the (most) affected lower limb
Proportion of patients with at least one grade reduction in MAS score from baseline to week 4 (and to week 12 and EOS/EW) in the GSC at the ankle joint of the (most) affected lower limb
Mean PGA score at week 12 (and EOS/EW)
Mean GAS score at week 12 (and EOS/EW)
Mean change from baseline to week 4 (and to week 12 and EOS/EW) in the angle of arrest at slow speed (X_V1), angle of catch at fast speed (XV3), spasticity angle (X), and spasticity grade (Y) derived from the TS at the ankle joint of the (most) affected lower limb
Mean change from baseline to week 4 (and week 12 and EOS/EW) in the OGS total score
Proportion of patients with at least one grade improvement from baseline to week 4 (and to week 12 and EOS/EW) in the “initial foot contact” subsection of the OGS (OGS responders)
Mean change from baseline to week 4 (and week 12 and EOS/EW) in lower-limb pain (FPS score)
Mean change from baseline to week 12 (and EOS/EW) in the PedsQL score.

GMFM overall score at weeks 8 and 16
GMFM goal-total score at weeks 4, 8, and 16
Leeds Videographic Gait Assessment at weeks 4 and 16
Leeds Functional Mobility Questionnaire at weeks 4 and 16
Subjective functional assessments of gait at weeks 4, 8, and 16
Adverse events.

Notes

Publications

Delgado et al.²³

Kanovsky et al.²⁴

From: Results

Cover of Clinical Review Report: abobotulinumtoxinA (Dysport Therapeutic)

Clinical Review Report: abobotulinumtoxinA (Dysport Therapeutic): (Ipsen Biopharmaceuticals Canada Inc.): Indication: For the symptomatic treatment of lower-limb spasticity in pediatric patients 2 years of age and older [Internet].

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Aug.

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Table 4Details of Included Studies