Regulatory Decision Summary for Botox

 

Symptomatic treatment of upper limb spasticity in pediatric patients 2 years of age or older

The efficacy of Botox for the treatment of pediatric upper limb (PUL) spasticity in pediatric patients 2 years of age or older was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 12-week study (NCT01603602).

The study included 234 pediatric patients with upper limb spasticity due to cerebral palsy or stroke, and baseline MAS score ≥ 2 for the principal muscle group (PMG), which is either for elbow flexors or wrist flexors, in three treatment groups (77 in Botox 6 Units/kg, 78 in Botox 3 Units/kg and 79 in placebo). The patients were injected a total dose of 3 Units/kg (maximum 100 Units) or 6 Units/kg (maximum 200 Units) or placebo in PMG and then followed for 12 weeks. All patients also received weekly standardized occupational therapy (OT) sessions from Week 2 through Week 11. The primary efficacy endpoint was the average change from baseline in MAS score in PMG at Weeks 4 and 6.

Eligible patients could enter an open-label extension study, in which they received up to five treatments at doses up to 10 Units/kg (maximum 340 Units), if treating more than one limb.

The efficacy of Botox (3 U/kg and 6 U/kg) in treatment of PUL spasticity was demonstrated by the statistically significant improvement in the primary efficacy endpoint, i.e. up to 0.71 MAS grade more in the reduction in LS mean MAS-B change from baseline in PMG at Weeks 4 and 6 in the Botox groups than that in the placebo group. The clinical meaningfulness of the primary treatment effect is further suggested by the observation that compared to the placebo, the Botox groups had a higher rate of responders who achieved at least 2 grade reduction in MAS score from baseline in the PMG at Weeks 4 and 6. The difference was up to 32% (Botox 6 U/kg - placebo). The increased treatment effects were observed between Week 2 and Week 8 after injection.

Symptomatic treatment of lower limb spasticity in pediatric patients 2 years of age or older

The efficacy and safety of Botox for the treatment of pediatric lower limb (PLL) spasticity in pediatric patients 2 years of age or older were evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 12-week study (NCT01603628).

The study included 384 pediatric patients with lower limb spasticity due to cerebral palsy and baseline MAS score ≥ 2 for the ankle plantar flexors in the study limb in three treatment groups (128 Botox 8 Units/kg, 126 Botox 4 Units/kg and 128 placebo). The patients were intramuscularly injected a total dose of 4 Units/kg (maximum 150 Units) or 8 Units/kg (maximum 300 Units) or placebo in the gastrocnemius, soleus and tibialis posterior in the study limb and then followed for 12 weeks. All patients also received weekly standardized physical therapy (PT) sessions from Week 2 through Week 11. The primary endpoint was the average of the change from baseline in MAS ankle score at week 4 and week 6.

Eligible patients could enter an open-label extension study, in which they received up to five treatments at doses up to 10 Units/kg (maximum 340 Units), if treating more than one limb.

The efficacy of Botox (4 U/kg and 8 U/kg) in treatment of PLL spasticity was demonstrated by a small but statistically significant improvement in the primary efficacy endpoint, i.e., up to 0.26 MAS grade more in the reduction in LS mean change from baseline in MAS-B ankle score at Weeks 4 and 6 in the Botox groups than that in the placebo group. Such level of improvement is similar to that observed in Botox treatment of adult lower limb spasticity in clinical trials. The clinical meaningfulness of the observed treatment effect appears suggested by the observation that compared to the placebo, the Botox groups had higher rates of responders who achieved at least 2 grade reduction in MAS score from baseline in MAS-B ankle score at all post-injection visits up to Week 8. The difference was up to 14% (Botox 8 U/kg - placebo) at Week 4. The increased treatment effects were observed between Week 2 and Week 8 after injection.

Strong placebo effects in treatment of PUL spasticity and PLL spasticity

There was a clear placebo effect in all efficacy variables in the above mentioned clinical studies in symptomatic treatment of PUL spasticity and PLL spasticity. Such effect was often stronger than the treatment effect of the Botox treatment, indicating that Botox should not be intended as a replacement for usual standard of care regimens in treatment of pediatric focal spasticity by Botox.

Safety

The safety of Botox in the treatment of paediatric lower and upper limb spasticity are assessed in an integrated analysis of 933 Botox-treated pediatric patients (Overall Safety Population) from 9 clinical studies. Botox was well tolerated in pediatric patients 2 years of age or older in treatment of PUL spasticity and PLL spasticity. The safety of Botox in the treatment has no noticeable difference with the established safety profile of Botox in treatment of approved indications, including adult lower and upper limb spasticity.

In the pivotal clinical trials, the observed frequency of distant spread of toxin was about 1.2% in treatment of PUL spasticity with Botox up to 6 U/kg but below 0.4% in treatment of PLL spasticity with Botox up to 8 U/kg.

Methods to Ensure Efficacy and Minimize Risk

In order to ensure adequate efficacy in treatment of pediatric focal spasticity and mitigate the risk of serious adverse events, the following issues are specifically addressed in the Product Monograph.

1. Botox should not be intended as a replacement for usual standard of care regimens in treatment of adult focal spasticity and pediatric focal spasticity
2. When combining indications, the maximum cumulative dose of Botox in a 3-month interval should generally not exceed 10 Units/kg or 340 Units, whichever is lower, in pediatric patients.

Conclusion

Overall, the benefit/risk ratio of Botox in treatment of focal spasticity in pediatric patients 2 years of age or older is considered favorable.