Date: 2016-01-26
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in Pediatrics
Company: Ipsen (France)
Product: Dysport® (abobotulinumtoxin A )
Action
mechanism: protein. Dysport® is an injectable form of botulinum toxin type A (BTX-A), which is isolated and purified from Clostridium BTX-A bacteria. It is supplied as a lyophilized powder. Dysport® was first registered for the treatment of blepharospasm and hemifacial spasm in the United Kingdom in 1990, and is licensed in 82 countries for various indications including: blepharospasm, adult upper and lower limb spasticity, hemifacial spasm, spasmodic torticollis (ST) (previously referred to as cervical dystonia), pediatric lower limb spasticity due to cerebral palsy (CP), axillary hyperhidrosis, and glabellar lines. Dysport® is approved for the treatment of upper limb spasticity and pediatric lower limb spasticity in many international markets, but not in the United States. Dysport® is also approved for the treatment of adult lower limb spasticity in some European countries, but not in the United States.
Disease: lower limb spasticity/dynamic equinus foot deformity in children and in adults
Therapeutic area: Neurological diseases - Neuromuscular diseases
Country: Belgium, Chile, Czech Republic, France, Hungaria, Italy, Mexico, Poland, Russia, Slovakia, USA
Trial
details: The Phase III study conducted in children with cerebral palsy included 235 patients and was multicentric, prospective, double blind, randomized, and placebo-controlled. It was conducted in the USA, France, Turkey, Poland, Mexico and Chile. The purpose of this study in children was to assess the efficacy and safety of Dysport® compared to placebo in improving lower limb spasticity in hemiparetic or diplegic cerebral palsy patients.
The phase III study in adults suffering from lower limb spasticity included 388 patients and was international, multicentric, prospective, double blind, randomized and placebo-controlled. It was conducted in the USA, France, Italy, Belgium, Czech Republic, Poland, Slovakia, Russia and Hungary. The purpose of this study was to assess the efficacy and safety of Dysport® compared to placebo in improving lower limb spasticity in hemiparetic adult patients who had experienced a stroke or a traumatic brain injury.
The primary endpoint for both studies was the improvement of muscle tone in the treated lower limb measured by the Modified Ashworth Scale (MAS). Patients were offered to continue in an open label longterm study wherein they will be receiving additional Dysport® treatment cycles within a total of 15 months. (NCT01249417)
Latest
news: * On January 26, 2016, Ipsen announced that the scientific journal Pediatrics published the detailed results of the phase III randomized study showing both the efficacy and the safety of Dysport® in the treatment of dynamic equinus foot deformity (also known as pediatric lower limb spasticity), a condition associated with cerebral palsy in children. The study met the primary endpoint (Modified Ashworth Scale, MAS) and the first secondary endpoint (Physician Global Assessment, PGA) in children with dynamic equinus foot deformity who received injections of Dysport® in the gastrocnemius and soleus calf muscles. Dysport® showed statistically significant improvement in muscle tone, resulting in an improved overall clinical benefit at week 4 at the two dose levels tested (10 and 15U/kg for unilateral injection or 20 and 30U/kg for bilateral injections). In addition, improvement of spasticity and attainment of overall treatment goals were demonstrated in a statistically and clinically significant manner as compared to placebo at week 4 after injection. Both doses of Dysport® were well tolerated and there was no evidence of a dose relationship for adverse events. The most frequent treatment emergent adverse events were common childhood infections (upper respiratory tract infections). * On October 22, 2015, Ipsen announced additional results from a Phase III study evaluating the investigational use of Dysport® for the treatment of spastic equinus foot. The data will be presented during an oral session on Thursday, October 22 at the “Free Paper Session B: Tone Management Strategies and Pain Control” between 10:50 AM –10:57 AM CT at the 69th Annual Meeting of the American Academy for Cerebral Palsy and Developmental
The Phase III study (NCT01249417) was multi-center, prospective, double blind, randomized, and placebo-controlled. It was conducted in the U.S., Mexico, Chile, Turkey, France and Poland. A total of 241 patients from 27 centers were randomized to treatment with Dysport® 10U/kg/leg (n=80), Dysport® 15U/kg/leg (n=80) or placebo (n=81). The purpose of this study was to assess the efficacy of Dysport® compared to placebo in the treatment of Lower Limb Spasticity in children with cerebral palsy. Muscle tone and spasticity were assessed using the MAS and the Tardieu Scale; patient functionality was assessed using the Physician’s Global Assessment (PGA) and goal attainment scaling (GAS). Study results showed a significant improvement versus placebo on muscle tone at both doses at week 4 post-injection (Primary endpoint – Assessment scale: Modified Ashworth Scale) with abobotulinumtoxinA; mean [95%CI] treatment differences vs. placebo were: -0.49 [-0.75, -0.23] (p=0.0002) for 15U/kg/leg and - 0.38 [-0.64, -0.13] (p=0.003) for 10U/kg/leg. A significant improvement was also observed on the overall clinical improvement (first secondary endpoint - Physician Global Assessment) with mean treatment differences vs. placebo of 0.77 [0.45, 1.10] for 15U/kg/leg and 0.82 [0.50, 1.14] for 10U/kg/leg (both p<0.0001).
In addition, significant improvement in spasticity (tertiary endpoint - using the Tardieu scale) was observed at Week 4. Both doses improved the Tardieu scale spasticity grade Y at 4 Weeks (p<0.001). For the 15U/kg/leg dose, Week 4 improvements were also accompanied by significant improvements in the angle of catch XV3 (p=0.0003) and angle of arrest XV1 (p=0.01). Both doses of Dysport® were well tolerated and there was no evidence of a dose relationship for adverse events (AEs). The most frequent TEAEs (treatment emergent adverse events) were common childhood infections (upper respiratory tract infections). Five patients in the abobotulinumtoxinA groups had an AE of epilepsy recorded versus none in the placebo group, however none was considered related to study treatment and there was an over-representation of epilepsy in the treatment groups. After the completion of this double blind study, patients were offered the option to continue in an open label long-term study where they would receive additional treatment with Dysport®
Medicine (AACPDM) in Austin, Texas. The title of Dr Delgado’s presentation will be “Effect of Abobotulinum toxin A (Dysport®) injections on functioning in children with dynamic equinus foot deformity due to cerebral palsy: analysis of treatment goals, gait and quality of life from a phase 3 study“.
This global, multicenter, double-blind, randomized, placebo-controlled study evaluated the efficacy and safety of Dysport® versus placebo on the mean change from baseline in ankle joint hypertonicity in 241 children with cerebral palsy. Eligible patients were randomized (1:1:1) to injections of Dysport® 10U/kg/leg, Dysport®15U/kg/leg or placebo into the gastrocnemius and soleus muscles (one or both legs injected). The primary endpoint was the change in Modified Ashworth Scale (MAS) from baseline to Week 4. Selected secondary endpoints presented were the mean Goal Attainment Scale (GAS) score at Week 4. At Week 4, muscle tone was improved with Dysport® as measured by the primary endpoint, the Modified Ashworth Scale (MAS). In the intention to treat (ITT) population, the adjusted least squares (LS) mean changes in the MAS score from baseline to Week 4 showed statistically significant differences in favor of the Dysport® 10U/kg/leg treatment group (p=0.0029) and the Dysport® 15U/kg/leg treatment group (p=0.0002) as compared to placebo.
Data presented also included the secondary endpoint of Goal Attainment Scale (GAS). In this study, the most frequently chosen goals were improved walking pattern (70.2% of patients), improved balance (32.3%), and decreased falling (31.1%). As measured by the GAS, where a score of 50 represents goal achieved as expected, patients with Dysport® showed higher goal achievement than the expected score of 50 (GAS of 51.5 for 10U/kg and 50.9 for 15U/kg), whereas patients on placebo did not reach the expected level (GAS score of 46.2). Treatment effects for GAS were significant for both Dysport® groups versus placebo (p=0.0006 and p=0.0031 respectively). The safety profile of both 10U/kg/leg and 15U/kg/leg doses is consistent with previously reported data on Dysport® in pediatric lower limb spasticity. Treatment related adverse events occurred in 8.9% of the placebo group, 7.5% in the Dysport® 10U/kg/leg group, and 6.3% in the Dysport® 15U/kg/leg treatment. The most common treatment related AE was localized muscular weakness (Dysport® 10U/Kg/leg=2; placebo=1).
* On January 26, 2015, Ipsen announced topline results for two double-blind phase III studies of Dysport® (abobotulinumtoxin A) in Pediatric Lower Limb (PLL) spasticity in children with cerebral palsy and in Adult Lower Limb (ALL) spasticity in patients who had experienced a stroke or traumatic brain injury. In the PLL phase III study, conducted in children with hemiparetic or diplegic cerebral palsy, treatment with Dysport® showed a statistically significant response versus placebo in the improvement of muscle tone, as measured by the Modified Ashworth Scale (MAS; primary endpoint), and a statistically significant overall benefit versus placebo, as measured by the Physician Global Assessment (PGA; first secondary endpoint).
In the ALL phase III study, conducted in hemiparetic patients who had experienced a stroke or traumatic brain injury, treatment with Dysport® at the dose of 1500U showed a statistically significant response versus placebo in the improvement of muscle tone, as measured by the Modified Ashworth Scale (MAS; primary endpoint). An overall benefit (measured by the Physician Global Assessment (PGA); first secondary endpoint) versus placebo was observed but did not reach statistical significance according to the pre-specified statistical analysis.
Other spasticity and functional outcome results are currently being analyzed. The safety profile observed in the studies was consistent with the known safety profile of Dysport® in these indications. Comprehensive results from these double-blind studies will be disclosed in the next few months at major international congresses. Ipsen will share these results with key regulatory agencies this year.
Pr. Mauricio Delgado, Principal Investigator of the PLL study stated: “This is the largest pediatric double-blind placebo controlled study demonstrating that Dysport® is an effective and safe treatment for spasticity in children with Cerebral Palsy. Unlike previous studies, this study was designed to demonstrate efficacy through a variety of outcome measures that are of direct relevance to the patient and their family. The study brought together an international and multidisciplinary group of investigators including pediatric neurologists, physiatrists, orthopedic surgeons and physical therapists who got the benefit of using standardized clinical assessments having a positive impact on their clinical practice.”
Pr. Jean Michel Gracies, Principal Investigator of the ALL study stated: “This global doubleblind phase III study provides evidence that Dysport® demonstrates high benefit in adults with stroke or traumatic brain injury causing lower limb spasticity. This study also reveals that it was possible to achieve highly productive collaboration with a very large number of investigators from several countries and health systems. In addition, it must be stressed that this study involved multidisciplinary teams including physical and occupational therapists, particularly involved in patient assessment. These important results reinforce the positioning of Dysport® as an excellent treatment for patients with spastic paresis.”
