Placebo-Controlled Clinical Trial of IncobotulinumtoxinA for Sialorrhea in Children: SIPEXI

Abstract

Background and objectives: To investigate the efficacy and safety of repeated injections of incobotulinumtoxinA (incoBoNT/A) for treatment of chronic sialorrhea (drooling) associated with neurologic disorders (e.g., cerebral palsy, traumatic brain injury) or intellectual disability in children and adolescents in a prospective phase III study (SIPEXI [Sialorrhea Pediatric Xeomin Investigation]).

Methods: The study enrolled 2- to 17-year-old patients with sialorrhea due to neurologic disorders or intellectual disability. Patients received body weight-dependent doses of incoBoNT/A (20-75 U). A main period with 1 injection cycle (placebo-controlled, double-blind, 6- to 17-year-olds) was followed by an open-label extension with up to 3 further cycles. An additional cohort of 2- to 5-year-olds received active treatment throughout the study. Coprimary endpoints were the change in unstimulated salivary flow rate (uSFR) from baseline to week 4 and the carers' Global Impression of Change Scale (GICS) rating at week 4. Adverse events were recorded.

Results: In the main period, 220 patients aged 6-17 years were randomized and treated (148 patients in incoBoNT/A group, 72 patients in placebo group). A total of 35 patients aged 2-5 years received incoBoNT/A (no placebo). A total of 214 patients aged 6-17 years and 33 patients aged 2-5 years continued treatment in the open-label extension period. For the 6- to 17-year-olds, a significant difference between incoBoNT/A and placebo was seen in mean uSFR decrease (difference -0.06 g/min; p = 0.0012) and the carers' GICS rating (difference 0.28 points; p = 0.032) at week 4, in favor of active treatment. The secondary endpoints consistently supported these results. A sustained benefit was observed during the extension. Incidences of adverse events were comparable between incoBoNT/A and placebo and did not increase notably with repeated injections. The most common adverse events were respiratory infections. Efficacy and safety were also favorable in the uncontrolled cohort of 2- to 5-year-olds.

Discussion: Both co-primary efficacy endpoints were reached and superiority of incoBoNT/A over placebo was confirmed. IncoBoNT/A (up to 75 U, up to 4 cycles) is an effective and well-tolerated treatment for sialorrhea associated with neurologic disorders in children.

Trial registration information: Clinicaltrials.gov: NCT02270736 (clinicaltrials.gov/ct2/show/results/NCT02270736); EU Clinical Trials Register: 2013-004532-30 (clinicaltrialsregister.eu/ctr-search/search?query=2013-004532-30).

Classification of evidence: This study provides Class I evidence that injection of incobotulinumtoxinA decreases drooling in children aged 6 to 17 years with neurologic disorders.

Figure 1. Disposition of Patients for the Main Period (MP) and Open-Label Extension (OLEX) of the Study

With patient numbers for each treatment arm and phase. Multiple reasons for discontinuation were possible.

Figure 2. Carers' Global Impression of Change Scale (GICS) Mean Ratings at the Main Period (MP) Visits (Active Treatment Compared to Placebo)

Results for the incobotulinumtoxinA group shown in green, placebo in gray. Means are least squares (LS) means (adjusted) from mixed model repeated measures analysis. Week 4 (4 weeks after MP injection) was the time point of the primary analysis. GICS 7-point scale ranges from −3 (very much worse) to +3 (very much improved). Data based on full analysis set (6–17 years). Error bars show SE. *p < 0.05, **p < 0.01, ***p ≤ 0.001.

Figure 3. Unstimulated Salivary Flow Rate (uSFR, g/min), Mean Changes From Study Baseline to all Main Period and Open-Label Extension (OLEX) Period Visits

Each week 4 visit (4 weeks after respective injection) in dark blue; each week 16 visit in light blue. Data based on full analysis set/safety evaluation set (6–17 years), subset of patients who received incobotulinumtoxinA (incobotulinumtoxinA) throughout the study (no placebo). Error bars show SE. Means are unadjusted.

Figure 4. Carers' Global Impression of Change Scale (GICS) Mean Ratings at all Main Period and Open-Label Extension (OLEX) Period Visits

Each week 4 visit (4 weeks after respective injection) in dark red; each week 16 visit in light red. GICS 7-point scale from −3 (very much worse) to +3 (very much improved). Data based on full analysis set/safety evaluation set (6–17 years), subset of patients who received incobotulinumtoxinA throughout the study (no placebo). Error bars show SE. Means are unadjusted.