Uniwersytet Medyczny w Łodzi Medical University of Lodz https://publicum.umed.lodz.pl Long-term incobotulinumtoxinA treatment for chronic sialorrhea: Efficacy and safety over 64 weeks, Publikacja / Publication Jost Wolfgang H., Friedman Andrzej, Michel Olaf, Oehlweind Christian, Sławek Jarosław, Bogucki Andrzej Stanisław, Ochudło Stanisław, Banach Marta, Pagan Fernando, Flatau-Baqué Birgit DOI wersji wydawcy / Published http://dx.doi.org/10.1016/j.parkreldis.2019.11.024 version DOI Adres publikacji w Repozytorium URL / Publication address in https://publicum.umed.lodz.pl/info/article/AML69dcd7bdf8cf4510bea56202e30c5b6c/ Repository Data opublikowania w Repozytorium 2020-02-06 / Deposited in Repository on Rodzaj licencji / Type of licence Attribution (CC BY) Jost Wolfgang H., Friedman Andrzej, Michel Olaf, Oehlweind Christian, Sławek Jarosław, Bogucki Andrzej Stanisław, Ochudło Stanisław, Banach Marta, Pagan Fernando, Flatau-Baqué Birgit, Dorsch Ulrike, Csikós János, Blitzer Andrew: Long- Cytuj tę wersję / Cite this version term incobotulinumtoxinA treatment for chronic sialorrhea: Efficacy and safety over 64 weeks, Parkinsonism & Related Disorders, Elsevier Ltd, vol. 70, 2020, pp. 23-30, DOI:10.1016/j.parkreldis.2019.11.024 Parkinsonism and Related Disorders 70 (2020) 23–30 Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis Long-term incobotulinumtoxinA treatment for chronic sialorrhea: Efficacy and safety over 64 weeks T ∗ Wolfgang H. Josta, , Andrzej Friedmanb, Olaf Michelc, Christian Oehlweind, Jaroslaw Slaweke,f, Andrzej Boguckig, Stanislaw Ochudloh, Marta Banachi, Fernando Paganj, Birgit Flatau-Baquék, Ulrike Dorschk, János Csikósl, Andrew Blitzerm,n,o a Parkinson-Klinik Ortenau, Wolfach, Germany b Department of Neurology, Faculty of Health Science, Medical University of Warsaw, Warsaw, Poland c Department of Otorhinolaryngology, University Hospital Brussels, Vrije Universiteit Brussel, Brussels, Belgium d Neurological Outpatient Clinic for Parkinson's Disease and Deep Brain Stimulation, Gera, Germany e Department of Neurological-Psychiatric Nursing, Medical University of Gdansk, Gdansk, Poland f Neurology Department, St Adalbert Hospital, Gdansk, Poland g Department of Extrapyramidal Diseases, Medical University of Łódź, Łódź, Poland h Department of Neurology and Stroke Unit, Medical University of Silesia, Katowice, Poland i Department of Neurology, Collegium Medicum, Jagiellonian University Medical College, Krakow, Poland j Department of Neurology, Georgetown University Hospital, Washington DC, USA k Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany l Formerly of Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany m Department of Otolaryngology/Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA n Department of Neurology, Icahn School of Medicine at Mt. Sinai, New York, NY, USA o NY Center for Voice and Swallowing Disorders, New York, NY, USA ARTICLE INFO ABSTRACT Keywords: Background: Botulinum neurotoxin (BoNT) is an effective treatment for chronic sialorrhea; however, reliable Botulinum toxin and robust evidence supporting long-term efficacy and safety is lacking. This study investigated the efficacy and Parkinson's disease/Parkinsonism safety of repeated incobotulinumtoxinA injections for chronic sialorrhea over 64 weeks. Drooling Methods: Adults with sialorrhea were randomized (2:2:1) to incobotulinumtoxinA 75 U, incobotulinumtoxinA IncobotulinumtoxinA 100 U (n = 74 each), or placebo (n = 36) in the double-blind, placebo-controlled main period (NCT02091739). Sialorrhea 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 in- cidence 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 sialor- rhea, with no additional safety concerns reported over 64 weeks. ∗ Corresponding author. Kreuzbergstraße 12–16, Wolfach, 77709, Germany. E-mail addresses: [email protected] (W.H. Jost), [email protected] (A. Friedman), [email protected] (O. Michel), [email protected] (C. Oehlwein), [email protected] (J. Slawek), [email protected] (A. Bogucki), [email protected] (S. Ochudlo), [email protected] (M. Banach), [email protected] (F. Pagan), [email protected] (B. Flatau-Baqué), [email protected] (U. Dorsch), [email protected] (J. Csikós), [email protected] (A. Blitzer). https://doi.org/10.1016/j.parkreldis.2019.11.024 Received 27 August 2019; Received in revised form 15 November 2019; Accepted 26 November 2019 1353-8020/ © 2019 Published by Elsevier Ltd. Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-26 W.H. Jost, et al. Parkinsonism and Related Disorders 70 (2020) 23–30 1. Introduction (Fig. 1B), guided by ultrasound or anatomical landmarks at the in- vestigator's discretion [21]. Until recently, treatment approaches for chronic, troublesome sia- lorrhea in adults were based on multidisciplinary, short-term symptom 2.2. Study population management [1], and no pharmacological agents had US Food and Drug Administration (FDA) or European Medicines Agency (EMA) ap- The full inclusion and exclusion criteria have been described pre- proval for this indication. Therapy options ranged from conservative viously [21]. Eligibility criteria for continued treatment in the exten- (e.g., speech therapy, oral motor and swallowing training), to more sion period were: subject and physician's shared agreement regarding interventional/aggressive treatment methods, including off-label use of clinical need for continued treatment; no clinically relevant dysphagia pharmacological agents (e.g., oral anticholinergics), offering transient (modified Radboud Oral Motor Inventory for Parkinson's disease relief with a risk of unwanted side effects. In treatment-resistant cases, [mROMP] Swallowing Symptoms Item A score ≤2 and ≤ 3 on Item C radiation therapy or surgery (e.g. laryngectomy [2], salivary glands [24]); absence of medically relevant moderate or severe treatment-re- removal, ligation or replacement of the submandibular ducts) were lated adverse events (AEs); no infection or inflammation in the planned options, as reviewed in Refs. [1,3,4]. injection sites. Repeat incobotulinumtoxinA treatment could be post- Botulinum neurotoxin (BoNT) injections into the salivary glands poned for up to 2 weeks in subjects who did not meet the eligibility offer an alternative approach for the reduction of saliva production and criteria; however, subjects could be withdrawn if not met within 18 secretion [4]. The safety and efficacy of BoNT-A and -B for the im- weeks of the first injection. provement of sialorrhea in subjects with neurological disorders have The study was conducted in accordance with the ethical principles been reported in numerous studies [5–20]. However, there is no con- of the Declaration of Helsinki. The protocol, informed consent forms, sensus in the literature regarding the BoNT doses used, the selection of and other appropriate study-related documents were reviewed and salivary glands for treatment, the use of guidance techniques – such as approved by the local independent ethics committees, and institutional ultrasound or anatomical landmarks – or the selection of efficacy end- review boards. All subjects provided written informed consent. points. Furthermore, reliable and robust evidence is lacking to support the efficacy and safety of BoNT for the long-term treatment of chronic 2.3. Outcome measures sialorrhea. The pivotal, Phase III SIAXI study, was the first well-controlled 2.3.1. Efficacy study to assess the long-term efficacy and safety of 2.3.1.1. Unstimulated salivary flow rate. The unstimulated salivary flow incobotulinumtoxinA (a BoNT-A free from complexing proteins; rate (uSFR) was measured from direct saliva collection using the swab Xeomin®, Merz Pharmaceuticals, GmbH) for dual salivary gland method, as described previously [21], at baseline, 4, and 16 weeks post- blockade for the treatment of chronic sialorrhea in subjects with injection in Cycles 1–4 and at the end-of-study visit. The changes from Parkinson's disease (PD) or other neurological disorders, excluding the main period baseline were assessed. those with moderate-severe dysphagia. The results of the 16 ± 2-week placebo-controlled main period showed a statistically significant re- 2.3.1.2. Global Impression