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| Drug | AbobotulinumtoxinA (Dysport Therapeutic) |
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| Indication | For the symptomatic treatment of lower-limb spasticity in pediatric patients 2 years of age and older |
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| Reimbursement Request | As per indication |
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| Dosage Form | Sterile lyophilized powder for solution for injection, 300 U and 500 U per vial |
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| NOC Date | December 21, 2017 |
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| Manufacturer | Ipsen Biopharmaceuticals Canada Inc. |
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Introduction
Spasticity is a condition characterized by a velocity-dependent increase in muscle tone that results in tightness or stiffness of the muscles and can interfere with speech, gait, and normal movement.1 The most common cause of spasticity in children is cerebral palsy (CP). “Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitations, which are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, and behaviour, by epilepsy, and by secondary musculoskeletal problems.”2,3
4,5 Typical deformities arising from lower-limb spasticity (LLS) in children with CP include hip adduction and flexion, knee flexion, and equinus foot deformity.6 Other causes of spasticity include stroke, brain injury, spinal cord injury.1 In a study conducted in Quebec, spasticity affects up to 92.8% of children with CP. In this study, 31.6% were spastic hemiplegia, 35.2% were spastic quadriplegia, and 25.9% were spastic diplegia.7 Another study estimated the prevalence rates of CP in Northern Alberta among five-year-old children to be 2.22 (95% confidence interval [CI], 2.12 to 2.32) per 1,000 five-year-old children.5
Usually, treatment is required only if the spasticity causes disruptive or painful symptoms, limits function, or contributes to the development of musculoskeletal complications such as contracture and/or bony malalignment. The management of LLS includes both pharmacological and non-pharmacologic treatments. Non-pharmacological treatments include physiotherapy and splinting. Pharmacological treatments include oral medications (such as benzodiazepines and imidazolines), intrathecal baclofen, or focal chemodenervation treatments (such as botulinum toxin A [BoNTA] intramuscular injections), and/or surgical interventions (such as selective dorsal rhizotomy and orthopedic surgeries).8,9 Multiple therapies are often used concomitantly. Treatment goals in the management of LLS include increasing strength and voluntary motor control, improving and maintaining joint mobility, reducing spasticity, improving gait, increasing the ease of performing the basic activities of daily living, preventing skeletal deformity, and reducing and preventing pain. BoNTA injections are recommended treatment options for pediatric LLS to improve physical functioning through reduction of muscle tone.10,11 Spasticity in children with CP is associated with reduced motor function, reduced muscle strength and a reduction in mobility, which impact quality of life and the ability to perform activities of daily living.12–15 In the American Academy of Neurology guidelines, BoNTA is recommended as an effective and generally safe treatment with level A evidence for the treatment of localized/segmental spasticity that warrants treatment in the pediatric population.16 In Canada, there are currently two BoNTA products approved for the treatment of LLS in pediatric patients: abobotulinumtoxinA (aboBoNTA; trade name Dysport Therapeutic),17 and onabotulinumtoxinA (onaBoNTA; trade name Botox).18
AboBoNTA has a Health Canada–approved indication for the symptomatic treatment of LLS in pediatric patients two years of age and older and for upper-limb spasticity (ULS) and cervical dystonia (spasmodic torticollis) in adults.17 The CADTH Common Drug Review (CDR) previously reviewed aboBoNTA for the treatment of cervical dystonia and, in July 2017, the CADTH Canadian Drug Expert Committee (CDEC) recommended that aboBoNTA be reimbursed for reducing the subjective symptoms and objective signs of cervical dystonia (spasmodic torticollis) in adults with or without botulinum toxin (BoNT) treatment experience in a manner similar to the public plan listings for other BoNTA products and with a reduction in price. CDR previously reviewed aboBoNTA for the symptomatic treatment of focal spasticity affecting the upper limbs in adults and, in September 2017, CDEC recommended that aboBoNTA be reimbursed in a manner similar to other BoNTA products for the treatment of ULS and with a cost saving condition.
The objective of this report is to perform a systematic review of the beneficial and harmful effects of aboBoNTA for the symptomatic treatment of LLS in pediatric patients two years of age and older.
Results and Interpretation
Included Studies
Two placebo-controlled randomized controlled trials (RCTs) (Study 141 and Study 701) met the inclusion criteria for this review. Study 141 was a pivotal trial. Study 141 (N = 241) was a phase III, multi-centre, double-blind, prospective, randomized, placebo-controlled, single treatment cycle study that assessed the efficacy of aboBoNTA compared with placebo in children with dynamic equinus foot deformity associated with CP. Patients were randomized into one of three treatment groups; aboBoNTA 10 U/kg, aboBoNTA 15 U/kg, or placebo in a ratio of 1:1:1, and stratified according to age range (two to nine years and 10 to 17 years) and BoNT-naive or non-naive status, as assessed at baseline. After randomization, aboBoNTA or placebo was administered by intramuscular injections into the gastrocnemius-soleus complex (GSC) of each affected lower limb. The dose of aboBoNTA administered was either 10 U/kg or 15 U/kg per affected GSC, so the total dose was either 10 U/kg or 15 U/kg for unilateral injections and 20 U/kg or 30 U/kg for bilateral injections. The primary outcome was the change from baseline in a Modified Ashworth Scale (MAS) score at week 4. Other outcomes included Physician’s Global Assessment (PGA) score (first secondary outcome) measured at week 4, and goal attainment scaling (GAS) score (second secondary outcome) measured at week 4. MAS and PGA assessed at week 12, Tardieu Scale (TS), Observational Gait Scale (OGS), Faces Pain Scale (FPS), and healthrelated quality-of-life scales (Pediatric Quality of Life Inventory Version [PedsQL]) was assessed at weeks 4 and 12 as tertiary outcomes for exploratory purposes only.
Study 701 (N = 52) was a phase III, multi-centre, double-blind, prospective, randomized placebo-controlled study that compared the efficacy and safety of a single administration of aboBoNTA or placebo in the treatment of pediatric dynamic equinus spasticity associated with diplegic CP. Eligible patients were randomized to receive a single treatment of either aboBoNTA (30 U/kg) or placebo. Study medication was distributed equally between both legs by injection of the gastrocnemius muscle of each limb. Two sites were injected in each muscle. The primary efficacy variable was functional change as assessed by the Gross Motor Function Measure (GMFM) score. Other outcomes assessed were Leeds Videographic Gait Assessment scores, Leeds Functional Mobility Questionnaire results, and subjective functional assessment of gait.
One of the main limitations of Study 141 was that clinically relevant outcomes such as passive and active function outcomes (e.g., TS) and the health-related quality-of-life outcomes (i.e., PedsQL) were analyzed as tertiary outcomes for exploratory purpose only and were not controlled for multiple statistical testing (i.e., increased risk of type I error). In addition, no Canadian sites were included in the study. The clinical expert consulted for this review indicated that patients included in the trial appeared to be limited to ambulatory patients with mild to moderately severe CP. In Study 701, the main limitations were that there was a substantial difference between groups in the baseline GMFM overall and goal-total scores, with aboBoNTA-treated patients being less functionally impaired than placebo-treated patients, which could introduce bias, and no adjustment was made for multiple testing despite secondary end points analyses, which would increase the risk of type I (false-positive) error.
Efficacy
Modified Ashworth Scale
In Study 141 at week 4, the between-group mean difference in change from baseline was statistically significant (−0.49, 95% CI, −0.75 to −0.23, P = 0.0002) in the aboBoNTA 15 U/kg/leg group compared with the placebo group. Likewise, the between-group mean difference in change from baseline for the aboBoNTA 10 U/kg/leg group compared with placebo was statistically significant (−0.38, 95% CI, −0.64 to −0.13, P = 0.0029). One of the clinical experts consulted for this review indicated that a one-point difference in the MAS (in either direction) was clinically relevant, and that the decrease in MAS at week 4 within the aboBoNTA 10 U/kg treatment group of −0.86, and the −0.97 decrease within the aboBoNTA 15 U/kg treatment group are clinically significant. However, the between-group mean difference in change from baseline of −0.38 for the aboBoNTA 10 U/kg/leg group compared with the placebo group, and the between-group mean difference in change from baseline of −0.49 for the aboBoNTA 15 U/kg/leg group compared with the placebo group, while statistically significant, are not clinically significant in the expert’s opinion, as this represents less than half of one gradation on the MAS scale. In contrast, the other clinical expert consulted for this review noted that while a clinically important change in a single patient must be at least a one-point change due to the nature of the MAS, a change between–treatment groups as low as 0.38 would be considered clinically significant when related to a group of patients receiving treatment. MAS scores assessed at week 12 were analyzed as a tertiary outcome for exploratory purposes only. The improvement in MAS score observed for both aboBoNTA groups at week 4 appeared to be maintained at week 12 to a lesser extent. The subgroup analysis for the MAS assessed by previous exposure to botulinum toxin (BoNT) treatment also showed an improvement in both aboBoNTA treatment groups compared with placebo, regardless of prior exposure to BoNT.
Goal Attainment Scaling
In Study 141, patients in both aboBoNTA treatment groups achieved a mean GAS score above 50.0, demonstrating that the overall response was better than expected. However, patients in the placebo group showed a mean GAS score below 50.0. This result was statistically significant in both aboBoNTA treatment groups compared with placebo. GAS scores assessed at week 12 were analyzed as a tertiary outcome for exploratory purposes only. The improvement in GAS score observed for both aboBoNTA groups at week 4 appeared to be maintained at week 12.
Physicians Global Assessment
In Study 141, at week 4, compared with placebo, the treatment-group difference (aboBoNTA minus placebo) of the PGA score was 0.82 (95% CI, 0.50 to 1.14) and 0.77 (95% CI, 0.45 to 1.10) in the aboBoNTA 10 U/kg and aboBoNTA 15 U/kg, respectively. The results of the PGA demonstrated that aboBoNTA (10 U/kg and 15 U/kg) was statistically significantly more effective than placebo (P < 0.0001). At week 12, the between–treatment group difference in change from baseline in the PGA score for aboBoNTA versus placebo (which was a tertiary, exploratory outcome) was numerically lower than what was observed at week 4.
Outcomes, including the TS, OGS, FPS, and PedsQL, were analyzed as tertiary outcomes for exploratory purposes only. The observed improvement in muscle tone at week 4 demonstrated in MAS score, was supported by the results of the TS, which is another efficacy measurement for spasticity. In the TS, the spasticity grade was reduced for both treatment groups at week 4. However, no conclusion could be derived from the TS because it was analyzed as a tertiary outcome end point and for exploratory purpose only, and no controls for multiple statistical testing were used to control for the risk of type I error. As for the FPS and PedsQL, the magnitude of reduction in all groups was negligible.
Study 701 was a relatively small trial that failed to demonstrate statistically significant between-group differences in the overall GMFM score without walking aids or orthoses at week 4. The clinical expert consulted for this review indicated the GMFM is a clinical tool designed to measure a child’s ability to perform gross motor tasks such as sitting, crawling, standing, walking, and running. Treatment of focal or segmental spasticity (plus the small number of patients) is unlikely to improve the whole-body motions utilized for gross motor tasks, which is what the GMFM evaluates. Therefore, the lack of statistical significance with the GMFM score is possibly because it is not sensitive enough to identify differences in single muscle groups treated with aboBoNTA injections. Other functional outcomes were not controlled for multiplicity. The main limitations of Study 701 are that no adjustment was made for multiple testing despite secondary end points analyses, which would increase the risk of type I (false-positive) error. Also, balance may not have been achieved across the baseline variables, suggesting randomization was not successful, which may substantially bias the study results.
In both trials, for all outcomes included in this review, no minimal clinically important differences (MCIDs) were established specific to a pediatric population with LLS and, thus, the clinical significance of the benefit of aboBoNTA compared with placebo for all outcomes assessed was not clear from the literature.
The results from the open-label extension study (Study 147) demonstrating that the efficacy of repeated use of aboBoNTA in reducing the symptoms and signs of LLS appeared to be maintained; however, very little can be concluded regarding the efficacy of aboBoNTA due to the limitations associated with this study, which are mainly its open-label nature (which can potentially bias the reporting of the outcome measures, especially the subjective measures), the lack of a control group, and the limited sample size of what is likely a highly select population. Therefore, no definitive conclusions can be made regarding the long-term efficacy of aboBoNTA (Appendix 6).
In the absence of direct evidence comparing aboBoNTA with other active treatments, the manufactured submitted an indirect treatment comparison (ITC). The results of this analysis suggest that the two BoNTAs (aboBoNTA and onaBoNTA) may have similar treatment effects in pediatric patients with LLS. These results, however, are limited by the small number of studies for some outcomes, the considerable amount of heterogeneity between studies, and the large number of assumptions required to pool the data for analysis. No evidence was available regarding the difference in the duration of effect between aboBoNTA and onaBoNTA.
Harms
▬▬▬▬▬ In Study 701, at least one treatment-emergent adverse event (TEAE) was reported in 39%, and 50% of patients in the aboBoNTA and placebo groups, respectively. The most common TEAEs were rhinitis (15% in the aboBoNTA and placebo treatment groups), bronchitis (15%, and 12% in the aboBoNTA and placebo groups, respectively). ▬▬▬▬▬ The only notable harm reported in the placebo group was muscle weakness, which was reported by one patient (1.3%). While epilepsy was reported only by patients who were receiving aboBoNTA, these patients had a history of epilepsy. All five cases were in the aboBoNTA treatment groups and were assessed by the investigator as unrelated to study treatment. ▬▬▬▬▬ In Study 701, two patients in the aboBoNTA group reported urinary incontinence. The open-label extension study (Study 174) results suggested there were no new safety signals identified, with the most common adverse events being nasopharyngitis, pharyngitis, and upper respiratory tract infection. The manufactured submitted an ITC that suggested there is no statistically significant difference in adverse events between aboBoNTA and onaBoNTA or placebo.
Potential Place in Therapya
Spasticity management is typically classified within five general categories, including non-pharmacological techniques (e.g., conventional rehabilitation and bracing), focal chemodenervation (e.g., phenol/alcohol nerve blocks and BoNTA), intrathecal baclofen therapy, oral medications (e.g., baclofen, tizanidine, and dantrolene) and surgical interventions (e.g., selective dorsal rhizotomy).19 Established practice parameters16,20 and standard of care for management of pediatric spasticity would employ interventions from any or all of the general categories, depending on the severity and anatomical distribution of spasticity. Best available intervention evidence, which is dominated by pediatric spasticity-management studies in CP,21 support various treatments in all intervention categories with the exception of non-pharmacological techniques. AboBoNTA resides within the focal chemodenervation category; this category possesses the most robust literature supporting its use in pediatric spasticity management. Focal chemodenervation utilizes treatment of selected spastic muscles to achieve functional and/or structural objectives. OnaBoNTA also resides within this category and has been used for years in Canada under the formal indication for treatment of dynamic equinus foot deformity in pediatric CP patients. Practically, onaBoNTA has also been used for focal spasticity management of ULS and LLS in pediatric patients. As such, aboBoNTA would join onaBoNTA as an additional focal chemodenervation treatment for LLS in pediatric patients two years of age and older.
Children aged two to 17 years of age with problematic LLS from a variety of underlying etiologies such as CP, stroke, brain injury, and spinal cord injury, and clearly identified functional (e.g., improve gait or activities of daily living or ease of care) or structural goals (e.g., delay or prevent contracture development) conducive to focal chemodenervation should receive this drug in practice. Anticipated barriers to consistently identifying appropriate patients who may benefit from this drug include the relative paucity of allied health and medical professionals appropriately trained to evaluate spasticity in children. Treatment availability may also be limited by the number of physicians adequately prepared to complete BoNTA injections in children, including access to injection-guidance technology (e.g., electromyography, electrical stimulation, or ultrasound) as well as suitable and safe procedural sedation for children unable to tolerate awake injections.
Conclusions
Two trials (Study 141 and Study 701) met the inclusion criteria for this review. Both trials were phase III, multi-centre, randomized, double-blind, controlled trials. Study 141 was a pivotal trial. While Study 141 demonstrated that both aboBoNTA doses (10 U/kg and 15 U/kg) were statistically significantly better than placebo for reducing muscle tone at week 4 (as assessed by MAS), there is some uncertainty around the clinical significance of the difference observed between groups, because each of the clinical experts consulted for this review provided different opinions regarding the difference seen in the MAS at week 4 between the aboBoNTA treatment groups and placebo groups. In addition, the clinical significance of the benefit of aboBoNTA compared with placebo for all outcomes assessed was not clear from the literature. Study 701 did not meet its primary end point (change from baseline in overall GMFM core without walking aids or orthoses at week 4). In Study 141, the effect of aboBoNTA on other clinically meaningful outcomes such as health-related quality of life (HRQoL) and patient-reported symptoms was uncertain, mainly because any observed effects were marginal and limited by methodological considerations. Overall adverse events were low, despite a numerically higher incidence of TEAEs in the aboBoNTA groups than in the placebo group. The open-label uncontrolled extension phase of the trial showed a similar efficacy and safety profile for aboBoNTA as reported in the double-blind phase; however, the study had a few limitations, including the open-label nature of the study, the lack of a control group, and the limited sample size. A network meta-analysis submitted by the manufacturer suggested that the two BoNTAs (aboBoNTA, and onaBoNTA) may have similar treatment effects in pediatric patients with LLS; however, the statistical analyses are limited by the large number of assumptions required to estimate the relative efficacy between toxins.
Summary of Key Results in Study 141.
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This information is based on information provided in draft form by the clinical expert consulted by CDR reviewers for the purpose of this review.
