On February 10, 2021, the FDA approved onabotulinumtoxinA (Botox®) for the treatment of pediatric individuals for detrusor overactivity associated with a neurologic condition. The safety and efficacy of onabotulinumtoxinA were evaluated in a multicenter, randomized, double-blind, parallel-group clinical study conducted in individuals from 5 to 17 years of age with urinary incontinence due to detrusor overactivity associated with a neurologic condition and using clean intermittent catheterization. A total of 113 individuals (including 99 with spinal dysraphism such as spina bifida, 13 with spinal cord injury, and 1 with transverse myelitis) who had an inadequate response to or were intolerant of at least one anticholinergic medication were enrolled. These individuals were randomly assigned to 50 Units, 100 Units, or 200 Units, not to exceed 6 Units/kg body weight. The study results demonstrated within group improvements in the primary efficacy variable of change from baseline in daytime urinary incontinence episodes (normalized to 12 hours) at the primary efficacy time point (week 6) for all three Botox® treatment groups. Botox® 200 Units showed an additional reduction in maximum bladder pressure when compared to 50 Units. The most common adverse reactions in the studies were bacteriuria (20%),
urinary tract infection (7%), leukocyturia (7%), and hematuria (3%).
On December 18, 2020, the FDA approved IncobotulinumtoxinA (Xeomin®) for the treatment of pediatric individuals (from 2 to 17 years of age) with chronic sialorrhea. The efficacy and safety of Xeomin were evaluated in a prospective, randomized,
double-blind, placebo-controlled, parallel-group, multicenter
trial that enrolled and treated a total of 216 pediatric individuals from 6 to 17 years of
age with chronic sialorrhea associated with cerebral palsy, other genetic or congenital
disorders, or traumatic brain injury. An additional 35 individuals, from 2 to 5 years of
age, were treated with open-label
Xeomin in the study. The co-primary endpoints among individuals age 6 to 17 years were defined
as the change in unstimulated salivary flow rate (uSFR) from baseline to week 4 and the Global Impression of Change Scale (GICS) score from baseline to week 4,
representing the functional improvement in drooling, as assessed by the
caregiver. Xeomin demonstrated significantly reduced uSFR and improved
GICS versus placebo at week 4 among individuals age 6 to 17 years, and sustained
efficacy over 64 weeks. Improvement in chronic sialorrhea increased with each
injection cycle in comparison to the baseline. GICS scores were comparable among individuals ages 2 to 5 years, who received Xeomin treatment and not placebo throughout the
study. No individuals demonstrated clinical resistance or secondary treatment
failure due to neutralizing antibodies (Nab), supporting the importance of
Xeomin’s unique purification process through XTRACT Technology™. The most common adverse reactions affecting ≥1% of individuals
were bronchitis, headache, and nausea/vomiting. The most
common adverse reaction affecting individuals age 2 to 5 years was
nasopharyngitis.
On October 24, 2019, the FDA approved onabotulinumtoxinA (Botox®) for the treatment of pediatric individuals (from 2 to 17 years of age) with lower limb spasticity. The efficacy and safety of Botox for the treatment of lower limb spasticity in pediatric individuals was evaluated in a randomized, multicenter, double-blind, placebo-controlled study that included 381 pediatric individuals (125 received 4 Units/kg [maximum 150 Units], 127 received 8 Units/kg [maximum 300 Units], and 129 received placebo) with lower limb spasticity (Modified Ashworth Scale [MAS] ankle score of at least 2). Individuals were followed for 12 weeks after injection. The primary efficacy endpoint was average change of spasticity in S score (ankle) at weeks 4 and 6. Secondary efficacy endpoints included clinical global impression ([CGI] - scales that measure symptom severity, treatment response, and the efficacy of treatments), Modified Tardieu Scale ([MTS] that identifies the point in the muscle's range where spasticity is occurring), goal attainment scale** (GAS), and measures of gait. Safety and tolerability of treatments were also assessed. Botox decreased spasticity average S score at weeks 4 and 6 by 1.1 in 8 U/kg group and by 1.0 in 4 U/kg group; both doses were significantly superior to placebo (-0.8, P<0.05). Botox® dose of 8 U/kg significantly improved CGI by 1.6 versus placebo (1.4; P=0.023); Botox® dose of 4 U/kg, 1.5 (P=0.229 vs placebo). Both Botox® groups significantly improved active and passive GAS versus placebo; Botox® dose of 8 U/kg significantly improved measures of gait versus placebo. Rates of patients reporting ≥1 adverse event (AE) were similar across treatment groups: Botox®, 43.3 percent (n=110); placebo, 49.2 percent (n=63). Serious AEs were reported by 1.2 percent (n=3) and 3.1 percent (n=4), respectively. No new safety concerns were identified.
On September 25, 2019, the FDA expanded the use of abobotulinumtoxinA (Dysport®) to include the treatment of upper limb spasticity in pediatric individuals 2 years of age and older.
The efficacy and safety of abobotulinumtoxinA (Dysport®) for the treatment of upper limb spasticity in children with cerebral palsy (CP) was evaluated in a phase III, multicenter, double-blind, prospective, randomized, low-dose controlled, multiple treatment study. A total of 208 botulinum toxin naïve or non-naïve (66 percent had prior treatment with a botulinum toxin) individuals weighing at least 10 kg, with a baseline MAS* of grade 2 or greater at the primary targeted muscle groups (PTMG), were enrolled in the modified intention-to-treat population (mITT). Individuals received Dysport® at the following doses: (16 Units/kg up to maximum of 640 U [n=70] ), Dysport® (8 Units/kg up to maximum of 320 U [n=69] ), or Dysport® (2 Units/kg [n=69] ) injected into the upper limb. The elbow flexors and wrist flexors, respectively, were the PTMG in 57 percent and in 43 percent of individuals.
The primary efficacy endpoint was the mean change from baseline in MAS* in the PTMG at week 6. The secondary efficacy endpoint was the mean Physician Global Assessment (PGA)*** score assessed at week 6. AbobotulinumtoxinA (Dysport®) demonstrated statistically significant improvements from baseline at week 6 with doses of 8 Units/kg and 16 Units/kg, as measured by the MAS* in the elbow or wrist flexors.
The most common adverse reactions (more thanten percent) in pediatric individuals with upper limb spasticity for Dysport were upper respiratory tract infection and pharyngitis.
On June 21, 2019, the FDA approved onabotulinumtoxinA (Botox®) for the treatment of pediatric individuals from 2 to 17 years of age with upper limb spasticity. The approval for upper limb spasticity was based on a randomized, multicenter, double-blind, placebo-controlled study (NCT01249417 ) that included 234 pediatric individuals who received the following doses: (78 individuals received Botox® 3 Units/kg, 77 Botox® 6 Units/kg [maximum 200 Units], and 79 placebo) with upper limb spasticity (MAS* elbow or wrist score of at least 2) because of cerebral palsy or stroke. Individuals were followed up for 12 weeks after injection. Primary endpoints were the average of the change from baseline in MAS* principal muscle group score (elbow or wrist) at week 4 and week 6, and the average of the Clinical Global Impression of Overall Change by Physician (CGI) at week 4 and week 6. The CGI evaluated the response to treatment in terms of how the individual was doing in their life using a nine-point scale ( minus 4=very marked worsening, to plus 4=very marked improvement). Compared to placebo, significant improvements in MAS* change from baseline were observed at all time points for Botox-treated individuals. The CGI scores numerically favored Botox® over placebo, but the difference was not statistically significant.
In July 2016, FDA approved Dysport® for lower limb spasticity in pediatric individuals. The safety and efficacy of Dysport for the treatment of lower limb spasticity due to cerebral palsy causing dynamic equinus foot deformity in pediatric individuals from 2 to 17 years of age was evaluated in a double-blind, placebo-controlled, multicenter study. A total of 235 (158 Dysport® and 77 placebo) toxin-naive or non-naive individuals with a MAS* of grade 2 or greater at the ankle plantar flexors were enrolled to receive Dysport® at the following doses: 10 Units/kg/leg (n=79), Dysport® 15 Units/kg/leg (n=79) or placebo (n=77) injected into the gastrocnemius and soleus muscles. Forty-one percent of individuals (n=66) were treated bilaterally and received a total lower limb Dysport® dose of either 20 Units/kg (n=37) or 30 Units/kg (n=29). The primary efficacy endpoint was the mean change from baseline in MAS* in ankle plantar flexor at week 4; a co-primary endpoint was the mean PGA*** score at week 4.
Study results showed an improvement in Dysport® group versus placebo on muscle tone at both doses at week 4 post-injection (Primary endpoint – Assessment scale: MAS)*. The PGA treatment differences versus placebo were also significant. The most frequent treatment-emergent adverse events were common childhood infections (upper respiratory tract infections).
On October 15, 2010, the FDA approved onabotulinumtoxinA (Botox®) for prophylaxis of headaches in adults with chronic migraine headache (at least 15 days per month with headache lasting at least 4 hours per day). The approval for chronic migraine was based on results of the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) program, which consisted of two double-blind, placebo-controlled clinical trials that included 1384 adults from 122 centers in North America and Europe. In both of these studies, individuals receiving onabotulinumtoxinA (Botox®) had a significantly greater decrease in the frequency of headache days from baseline compared with placebo at 24 weeks: 7.8 and 9.2 fewer days for the treated groups versus 6.4 and 6.9 days for the placebo groups, respectively. Treated individuals also had a total cumulative reduction in headache hours by 107 and 134 hours, respectively, compared with 70 and 95 hours for the placebo groups.
On April 29, 2009, abobotulinumtoxinA (Dysport®) was approved by the FDA for the treatment of cervical dystonia. AbobotulinumtoxinA (Dysport®) was evaluated in two randomized, double-blind, placebo-controlled, single-dose, parallel group studies in treatment-naïve cervical dystonia individuals. A total of 252 individuals were enrolled. The primary assessment of efficacy was based on the total Toronto Western Spasmodic. Torticollis Rating Scale (TWSTRS) change from baseline at week 4 for both studies. The scale evaluates the severity of dystonia, individual perceived disability from dystonia, and pain. The adjusted mean change from baseline in the TWSTRS total score was statistically significantly greater for the abobotulinumtoxinA (Dysport®) group than the placebo group at weeks 4 in both studies.
On December 8, 2000, the FDA approved rimabotulinumtoxinB (Myobloc®) for the treatment of cervical dystonia. The approval for cervical dystonia was based on two phase III, randomized, multicenter, double-blind, placebo-controlled studies. Both studies enrolled only adult individuals who had a history of receiving botulinum toxin type A. Study #301 enrolled individuals who were perceived as having an acceptable response to type A toxin, while Study #302 enrolled only individuals who had secondarily lost responsiveness to type A toxin. Study #301 enrolled 109 individuals, and 77 individuals were enrolled into Study #302. Individual evaluations continued for 16 weeks postinjection. The primary efficacy outcome variable for both studies was the TWSTRS Total Score (scale range of possible scores is 0-87) at week 4. The secondary endpoints were the Patient Global and Physician Global Assessments of change at Week 4. TWSTRS Total Score at Week 4 and Patient Global Assessment among subgroups by gender or age showed consistent treatment-associated effects across these subgroups.
*Modified Ashworth Scale (MAS) score measures resistance during passive soft-tissue stretching and is used as a simple measure of spasticity. Scoring (0 = No increase in muscle tone to 4 = Affected part(s) rigid in flexion or extension).
**The GAS is a functional five-point scale used to measure progress towards individual therapy goals.
***The Physician Global Assessment (PGA) is a 5- or 6-point scoring system used to assess disease severity.
COSMETIC SERVICES
Cosmetic services are those provided to improve an individual's physical appearance, from which no significant improvement in physiologic function can be expected. Emotional and/or psychological improvement alone does not constitute improvement in physiologic function.
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issues by leading professional organizations and government entities.
