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 (XV1), 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 (XV1), 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 |
---|