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Background Botulinum neurotoxin (BoNT) is an effective treatment for chronic sialorrhea; however, reliable and robust evidence supporting long-term efficacy and safety is lacking. This study investigated the efficacy and safety of repeated incobotulinumtoxinA injections for chronic sialorrhea over 64 weeks. Methods Adults with sialorrhea were randomized (2:2:1) to incobotulinumtoxinA 75 U, incobotulinumtoxinA 100 U (n = 74 each), or placebo (n = 36) in the double-blind, placebo-controlled main period (NCT02091739). Eligible subjects entered the extension period and received dose-blinded incobotulinumtoxinA 75 or 100 U in three further 16±2-week injection cycles. Efficacy and safety assessments in subjects who received incobotulinumtoxinA throughout the study included unstimulated salivary flow rate (uSFR), subjects' Global Impression of Change Scale (GICS), Drooling Severity and Frequency Scale (DSFS), modified Radboud Oral Motor Inventory for Parkinson's Disease (mROMP) drooling, speech, and swallowing symptom scores, and incidence of adverse events (AEs). Results In total, 173/184 subjects (94%) completed the main period and entered the extension period; 141 subjects received incobotulinumtoxinA 75 U (n = 69) or 100 U (n = 72) in both periods. Mean uSFR decreased consistently with repeated incobotulinumtoxinA 75 and 100 U treatment and by −0.16 and −0.17, respectively, at the end-of-study visit. Subjects’ GICS, DSFS, and mROMP drooling scores also improved at all assessments. mROMP speech and swallowing scores remained stable. The most common treatment-related AEs during the extension period were dry mouth (4.4% and 11.1%) and dysphagia (1.5% and 4.2%). Conclusions Data support long-term efficacy and safety of repeated incobotulinumtoxinA treatment for sialorrhea, with no additional safety concerns reported over 64 weeks.

Introduction: Intractable sialorrhea results from various causes, including Parkinson's disease (PD). The pivotal, double-blind, randomized, Phase 3 SIAXI study (NCT02091739) assessed the efficacy and safety of incobotulinumtoxinA (botulinum neurotoxin type A [BoNT-A] free from complexing proteins) 75 U and 100 U for the treatment of sialorrhea. Methods: Adults included in the main phase (MP) had chronic, troublesome sialorrhea due to PD, atypical Parkinsonism, stroke, or traumatic brain injury (TBI) and were randomized (2:2:1) to a single injection cycle (16±2 weeks) of incobotulinumtoxinA 75 U or 100 U, or placebo (PBO) distributed in bilateral parotid and submandibular glands (dose ratio of 3:2). Co-primary endpoints were change in unstimulated salivary flow rate (uSFR) and subjects' Global Impression of Change Scale (GICS) at Week 4. Safety was also assessed. Results: One hundred eighty-four subjects were randomized to either incobotulinumtoxinA 75 U (n=74), 100 U (n=74), or PBO (n=36) in the MP. Primary drooling etiologies were: PD (70.7%), atypical Parkinsonism (8.7%), stroke (17.9%), and TBI (2.7%). Injection was guided by anatomic landmarks in 39.2%, 44.6%, and 50.0%, and ultrasonography in 60.8%, 55.4%, and 50.0% of subjects in the incobotulinumtoxinA 75 U, 100 U, and PBO groups, respectively. At week 4, incobotulinumtoxinA 100 U significantly improved uSFR, and subjects' GICS scores were significantly higher vs PBO (both, P

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.