Long-Term Incobotulinumtoxina Treatment for Chronic

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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

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Parkinsonism and Related Disorders

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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 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.

∗ 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.

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1. Introduction (Fig. 1B), guided by ultrasound or anatomical landmarks at the investigator's discretion [21]. Until recently, treatment approaches for chronic, troublesome sialorrhea 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 of Change Scale score. The subjects' Global duction in unstimulated salivary flow rate (uSFR) and an improvement Impression of Change Scale (GICS) score (or carers’ GICS entry, if the in subjects' Global Impression of Change Scale (GICS) score versus subject was unable to answer) was measured on a 7-point Likert scale placebo 4 weeks post-injection in the incobotulinumtoxinA 100 U from −3 (very much worse) to +3 (very much improved) [21] at 4 and group, with improvements persisting throughout the observation period 8 weeks post-injection in Cycles 2–4, and at the end-of-cycle/end-of- [21]. These data led to the first FDA and EMA approvals of a BoNT study visits. The number of GICS responders (GICS entries ≥1 point) formulation for the treatment of chronic sialorrhea in adults [22,23]. were assessed. Here we present previously unpublished efficacy and safety results from the entire 64-week observation period of SIAXI for subjects who re- 2.3.1.3. Drooling severity and Frequency Scale scores. Investigators used ceived incobotulinumtoxinA 75 or 100 U in the main period and ex- the Drooling Severity and Frequency Scale (DSFS) [25] to rate the tension period. change in drooling severity (using a 5-point Likert scale from 1 [dry; never drools] to 5 [profuse; hands, tray and objects wet]) and frequency 2. Methods (using a 4-point Likert scale from 1 [never] to 4 [constantly]), and the DSFS sum score (maximum score of 9 from the sum of the two 2.1. Study design and treatments subscales) [21] from the main period baseline to 4 weeks post- injection in Cycles 2–4. SIAXI (clinicaltrials.gov NCT02091739) was a prospective, randomized, double-blind, parallel-group, Phase III study with an extension 2.3.1.4. mROMP drooling and speech symptoms and EuroQoL 5-dimension, period [21]. The study investigated the long-term efficacy and safety of 3-level scores. See Supplementary Materials. incobotulinumtoxinA 75 and 100 U for the treatment of chronic, troublesome sialorrhea over a total duration of 64 weeks (range 56–72 2.3.2. Safety weeks) in adults (18–80 years of age) with PD, atypical Parkinsonism, 2.3.2.1. Adverse events. The occurrence of AEs, treatment-related AEs, stroke or traumatic brain injury. and serious AEs (SAEs) was reported by injection cycle. Subjects were Eligible subjects who completed the main period (Cycle 1) con- actively questioned for the occurrence of AEs of special interest (AESIs) tinued into the extension period where all subjects received dose- potentially indicating toxin spread. Dry mouth had to be reported as an blinded incobotulinumtoxinA in three further 16 ± 2-week injection AESI when it was considered severe, serious, or irreversible. cycles (Cycles 2–4; Fig. 1A). Subjects who received in- cobotulinumtoxinA in the main period remained on their assigned dose, 2.3.2.2. mROMP swallowing symptoms scores, dental health, and while placebo recipients were randomized 1:1 to receive either in- neutralizing antibodies. See Supplementary Materials. cobotulinumtoxinA 75 U or 100 U at the beginning of the extension period (Cycle 2). Here, data are presented for those subjects who re- 2.4. Statistical analysis ceived incobotulinumtoxinA for the entire study duration. Each incobotulinumtoxinA treatment was administered in four in- Efficacy and safety endpoints were assessed in subjects who re- jections into bilateral parotid and submandibular salivary glands ceived incobotulinumtoxinA in the main period and continued active

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Fig. 1. (A) Study design and (B) injection sites and incobotulinumtoxinA doses administered. Equivalent volumes were injected in all treatment groups to ensure blinding. aThe total dose could be reduced by 25% at the investigator's discretion in the 3rd/4th injection cycles in case of safety concerns in the preceding injection cycle, as an alternative to the withdrawal of the patient due to AEs. Dose reduction (still blinded) was allowed only once and in only one step. AE, adverse event; SCR, screening; T, telephone contact. treatment in the extension period (excluding main period placebo (ultrasound or anatomical landmark guidance). subjects). Descriptive summary statistics were reported for eﬃcacy outcome measures. AEs were analyzed by frequency, with data pre- 3. Results sented by cycle based on those subjects who received incobotulinumtoxinA in the respective cycle. 3.1. Study population Additional exploratory analyses of uSFR, subjects’ GICS, and DSFS eﬃcacy outcomes and safety were conducted for each injection cycle, Baseline characteristics for the full study population have been re- stratifying the subject population by injection guidance technique ported previously and were similar across treatment groups [21],

25 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 including the underlying drooling etiology (Supplementary Table 1). A 3.2.4. mROMP drooling and speech symptoms and EuroQoL 5-dimension, total of 173 subjects completed the main period and continued treat- 3-level scores ment in the extension period; most (123 [71.1%]) had sialorrhea due to Mean (SD) mROMP drooling scores improved consistently from PD (Supplementary Table 1). Of these, 151 subjects (87.3%, including main period baseline to 4 weeks post-injection in all injection cycles those who received placebo in the main period) completed the exten- (Supplementary Fig. 2A). mROMP speech symptom scores remained sion period; 22 (12.7%) discontinued. The main reasons for dis- stable throughout the study (Supplementary Fig. 2B). There were small continuation in the extension period were death (n = 5, all unrelated to improvements in mean EuroQoL 5-dimension, 3-level visual analog treatment), AEs (n = 12), and withdrawal by subject (n = 12; scale scores throughout the study (See Supplementary Materials). Supplementary Fig. 1). A total of 148 subjects, 68.9% male, mean (standard deviation [SD]) 3.3. Safety age 65.6 (11.6) years received either incobotulinumtoxinA 75 U (n = 74) or 100 U (n = 74) in a single injection cycle in the main 3.3.1. Adverse events period. Of these, 141 subjects completed the main period and continued The overall incidence of AEs was 61/140 (43.6%), 47/132 (35.6%), treatment with incobotulinumtoxinA 75 U (n = 69) or 100 U (n = 72) and 51/127 (40.2%) in Cycles 2, 3, and 4, respectively and was similar in the extension period. One patient in the 75 U group missed the in- in both dose groups (Fig. 3). AEs were of mild or moderate intensity in jection in Cycle 2 but was injected in Cycles 3 and 4. the majority of subjects. The majority of subjects (> 97%) received the dose they were During the extension period, the most frequently reported AE was randomized to receive in all injection cycles. The planned dose was dry mouth, reported by 3 (4.4%) and 9 (12.5%) subjects who received reduced for safety reasons in five subjects. More than half of all injec- incobotulinumtoxinA 75 U and 100 U, respectively. Two subjects, one tions were guided by ultrasound device in all cycles (Cycle 1: 56.5%, in each dose group, reported one instance each of aspiration pneu- Cycle 2: 56.4%, Cycle 3: 54.6%, Cycle 4: 55.4%). monia, deemed unrelated to treatment by the investigator. Treatment-related AEs were reported by 10/140 (7.1%), 8/132 3.2. Efficacy (6.1%), and 5/127 (3.9%) subjects in Cycles 2, 3, and 4, respectively (Fig. 3). Most events were resolved at the end of the study. The most 3.2.1. Unstimulated salivary flow rate frequent treatment-related AEs in the incobotulinumtoxinA 75 U and Mean uSFR was reduced consistently with repeated 100 U groups were dry mouth, reported by 3 (4.4%) and 8 (11.1%), incobotulinumtoxinA treatment at both doses from the main period dysphagia reported by 1 (1.5%) and 3 (4.2%), and speech disorder baseline (mean [SD] uSFR incobotulinumtoxinA 75 U, 0.42 [0.28] g/ reported by 2 (2.9%) and zero subjects, respectively, over the course of min; 100 U, 0.40 [0.27] g/min) at all visits (Fig. 2A). The greatest the extension period. improvements were reported 4 weeks post-injection in all injection SAEs were reported by 14/140 (10.0%), 12/132 (9.1%), and 7/127 cycles, with mean [SD] reductions with incobotulinumtoxinA 75 and (5.5%) subjects in Cycles 2, 3 and 4, respectively. Of these, one subject 100 U, respectively, of − 0.20 [0.18] and − 0.22 [0.23] g/min at Week in the incobotulinumtoxinA 75 U group reported speech disorder and 4 of Cycle 4. one subject in the 100 U group reported dysphagia related to treatment. Sustained improvements and remaining efficacy were reported 16 Upon active questioning, the incidence of treatment-related AESIs weeks post-injection in all injection cycles (Fig. 2A). At the end-of-study was 3/140 (2.1%), 6/132 (4.5%), and 2/127 (1.6%) in Cycles 2, 3, and visit, the mean (SD) improvements in uSFR from main period baseline 4, respectively, and was generally similar in both dose groups (Fig. 3). in subjects who received incobotulinumtoxinA 75 U and 100 U were − These included 3 events of speech disorder and 1 each of dry mouth and 0.16 (0.21) and − 0.17 (0.23) g/min, respectively (mean [SD] uSFR dysphagia in subjects who received incobotulinumtoxinA 75 U, and 5 incobotulinumtoxinA 75 U, 0.26 [0.24]; 100 U, 0.22 [0.18] g/min). events of dry mouth, 4 of dysphagia, and 1 of worsening constipation in There was no clear trend in favor of either ultrasound or anatomical those who received incobotulinumtoxinA 100 U. landmark guidance techniques. Mean uSFR was consistently reduced There were no major differences in the pattern of AEs between in- with both incobotulinumtoxinA doses from the main period baseline to jection cycles, and no increase in the incidence of any AEs with addi- 4 weeks post-injection in all four injection cycles with both guidance tional injections. Two subjects who received incobotulinumtoxinA in techniques (Table 1). the main period, and the extension period died during Cycle 4 of causes unrelated to study treatment (Fig. 3). Also, the incidence of AEs over all 3.2.2. Global Impression of Change Scale score the injection cycles with incobotulinumtoxinA treatment was generally Subjects' GICS scores showed improvement at all visits in the ex- similar with ultrasound and anatomical landmark guidance (data not tension period, being generally highest at 4 and 8 weeks post-injection are shown). in each cycle in both dose groups. Remaining efficacy was shown at 16 weeks post-injection, prior to reinjection in the extension period, and 3.3.2. mROMP swallowing symptom scores, dental health, and neutralizing was sustained until the end-of-study visit (Fig. 2B). Similar improve- antibodies ments were demonstrated for the carers’ GICS scores (data not shown). mROMP swallowing symptom scores remained stable throughout Throughout the extension period, 61.8%–82.4% of subjects were the study. Further details and results of additional safety analyses of responders on the subjects’ GICS. GICS response rates were generally dental health and neutralizing antibodies are listed in the highest at 4 and 8 weeks post-injection in each cycle, decreasing Supplementary Materials. slightly after that. There was no consistent trend in favor of either injection guidance 4. Discussion technique. However, subjects’ GICS scores at 4 weeks post-injection were generally higher in the ultrasound guidance group (Table 1). SIAXI was the first randomized controlled trial of incobotulinumtoxinA for the treatment of chronic sialorrhea. Results of 3.2.3. Drooling severity and Frequency Scale scores the placebo-controlled main period previously showed a reduction in From the main period baseline to 4 weeks post-injection in each uSFR and improvement in drooling measured by GICS that was main- injection cycle, there was an improvement in DSFS sum score as well as tained at Week 16 post-injection [21]. Significant improvements in the subscores for drooling severity and frequency (Fig. 2C–E). Similar DSFS were also observed up to 12 weeks post-injection [21]. The results trends were reported for both dose groups. There was no clear trend in presented here for subjects who received incobotulinumtoxinA 75 U or favor of either injection technique (Table 1). 100 U over four 16 ± 2-week injection cycles show a consistent

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Fig. 2. (A) Mean uSFR over time, (B) subjects' mean GICS scores over time, and mean change from main period baseline to Week 4 in (C) DSFS sum (D) DSFS severity and (E) DSFS frequency scores in those who received incobotulinumtoxinA in the main period and extension period. aCompared with status immediately before the last injection. Reduction in uSFR and DSFS indicates an improvement in symptoms. GICS score: 3 (very much worse), −2 (much worse), −1 (minimally worse), 0 (no change in function), +1 (minimally improved), +2 (much improved) to +3 (very much improved). BL, baseline; DSFS, Drooling Severity and Frequency Score; EoS, end of study; GICS, Global Impression of Change Scale; uSFR, unstimulated salivary ﬂow rate; W, week.

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Table 1 Key eﬃcacy endpoints stratiﬁed by injection guidance technique in those who received incobotulinumtoxinA in the main period and extension period.

IncobotulinumtoxinA 75 U IncobotulinumtoxinA 100 U

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 1 Cycle 2 Cycle 3 Cycle 4

Mean (SD) change from main period baseline at Week 4 in uSFR, g/min With ultrasound guidance −0.06 (0.15) −0.12 (0.18) −0.15 (0.23) −0.20 (0.21) −0.15 (0.21) −0.16 (0.27) −0.19 (0.31) −0.20 (0.23) With anatomic landmark guidance −0.08 (0.17) −0.17 (0.18) −0.23 (0.20) −0.21 (0.14) −0.10 (0.20) −0.20 (0.21) −0.20 (0.20) −0.25 (0.21) Mean (SD) subjects' GICS score at Week 4a With ultrasound guidance 0.88 (0.78) 1.26 (0.99) 1.54 (1.20) 1.43 (1.17) 1.27 (1.17) 1.25 (1.21) 1.50 (1.06) 1.51 (1.15) With anatomic landmark guidance 0.78 (0.85) 1.38 (1.08) 1.21 (1.47) 1.24 (1.21) 0.85 (0.78) 1.06 (1.15) 0.83 (1.49) 1.37 (1.24) Mean change from main period baseline at Week 4 DSFS sum scoreb With ultrasound guidance −1.27 (1.32) −2.36 (1.42) −2.80 (1.28) −3.26 (1.44) −1.93 (1.42) −2.50 (1.41) −3.05 (1.54) −3.17 (1.54) With anatomic landmark guidance −1.52 (1.40) −2.41 (1.72) −3.00 (1.49) −2.97 (1.57) −1.13 (1.60) −2.29 (1.68) −2.23 (1.57) −2.96 (1.97)

DSFS, Drooling Severity and |Frequency Scale; GICS, Global Impression of Change Scale; SD, standard deviation; uSFR, unstimulated salivary flow rate. a GICS score: 3 (very much worse), −2 (much worse), −1 (minimally worse), 0 (no change in function), +1 (minimally improved), +2 (much improved) to +3 (very much improved). b DSFS sum score ranges from 2 (best) to 9 (worst). reduction in salivary flow rate and increasing improvements in clinical stable throughout the study and no increased risk of dysphagia was outcomes with repeated treatment over time. detected with this scale. The additional drooling assessments, DSFS, and mROMP drooling Strengths of this study include the range of underlying neurological scores showed increasing improvement of sialorrhea, consistent with diseases, the use of two incobotulinumtoxinA doses, and the multiple the analysis of uSFR and GICS scores (primary endpoints in the main injection cycles. Similar efficacy was shown with long-term treatment period). Although uSFR, measured using four adsorbent oral swabs, is a in both incobotulinumtoxinA dose groups, offering physicians the op- direct measure of saliva production, DSFS is a measure of the frequency tion to adapt the dosage for subjects with poor health status who are and severity of symptoms associated with sialorrhea; therefore, DSFS is prone to a higher risk of AEs, especially dry mouth and dysphagia. Also, a useful clinical measure of treatment response that could be applied as exploratory analyses revealed no clear trend in favor of either ultra- a primary endpoint in future studies and clinical practice. sound or anatomical landmark guidance in terms of efficacy and safety Clinical efficacy seen after multiple injections mimics real-world profiles, allowing physicians the flexibility to offer effective treatment outcomes, where, in the experience of the authors, most subjects show with or without additional equipment, including ultrasound. greater improvement after the third or fourth injection. Furthermore, The extension period did not include a placebo control group. Data the high retention rate, and the remaining efficacy as assessed by uSFR from the main period have shown that incobotulinumtoxinA recipients and GICS score 16 weeks post-injection in all injection cycles, may in- show significantly greater improvement than placebo recipients [21]; dicate a duration of effect beyond 16 weeks. These data are similar to therefore, long-term placebo treatment in this population would be those reported for BoNT injections for the treatment of hyperhidrosis. unethical. Further limitations include the potential progression of the During long-term follow-up, it was found that repeated injections in- underlying disease during the study and the exclusion of subjects with creased the duration of efficacy by more than 50% [26]. Further long- pre-existing moderate-to-severe dysphagia. Severe dysphagia can be term studies are required to identify the duration of response in subjects associated with more severe sialorrhea; however, as dysphagia is a with sialorrhea. known side effect of BoNT treatment, these subjects were excluded to Long-term incobotulinumtoxinA treatment for sialorrhea was well reduce the risk of exacerbating the underlying symptom. Disease pro- tolerated, and the incidence of AEs per treatment cycle during the ex- gression was assessed in participants with PD and atypical Parkin- tension period (35.6–43.6%) was similar to that reported for sonism, with no significant deterioration reported at the end of the incobotulinumtoxinA recipients in Cycle 1 in the main period (44.6%) study (data not shown). [21], with no major differences between the injection cycles in the In conclusion, the results of this long-term study provide evidence pattern of AEs. Dry mouth was the most common AE reported in the for the efficacy and safety of repeated BoNT-A treatment for chronic extension period; however, the incidence did not increase with an in- sialorrhea, with no additional safety concerns reported over 64-weeks creasing number of injection cycles. Dry mouth is frequently reported in of incobotulinumtoxinA treatment. subjects with PD, which may in part explain why it was noted as the most frequent AE in this population. In a recent study, 49% of subjects Financial disclosures reported dry mouth, and dry mouth in combination with slight, mild, moderate, or severe drooling was reported by 18.8%, 22.9%, 14.6%, Wolfgang H. Jost was the Principal Investigator in the SIAXI study and 6.3% of subjects, respectively [27]. Of note, although reduction of and has served as a consultant for AbbVie, Allergan, Bial, Ipsen, Merz saliva production may increase the incidence of dry mouth, mROMP Pharmaceuticals, UCB, and Zambon; Andrzej Friedman was an in- speech symptom scores remained stable throughout the current study, vestigator in the SIAXI study and has served as a consultant for AbbVie, suggesting that sufficient saliva remained to prevent further speech GE, and Roche; Olaf Michel was a Data Safety Monitoring Committee impairment. Indeed, levels of salivation, while reduced from baseline member in the SIAXI study and has served as a speaker for Merz with incobotulinumtoxinA, remained within normal physiological le- Pharmaceuticals; Christian Oehlwein was an investigator in the SIAXI vels across the study [28]. Similarly, results of dental health assessment study and reports no other disclosures; Jaroslaw Slawek was an in- reflected poor dental status due to underlying diseases consistent with a vestigator in the SIAXI study and has served as a consultant and speaker previous study [29], rather than safety issues due to hyposalivation. for Merz Pharmaceuticals, Allergan, and Ipsen; Andrzej Bogucki was an Dysphagia and aspiration pneumonia are also common complica- investigator in the SIAXI study and has served as a consultant for tions in subjects with PD [30]. During the extension period, following AbbVie, GE, UCB, and Ever; Stanislaw Ochudlo was an investigator in active questioning, two subjects reported aspiration pneumonia un- the SIAXI study and reports no other disclosures; Marta Banach was an related to treatment, and treatment-related dysphagia was reported by investigator in the SIAXI study and has served as a consultant for Merz four subjects; however, mROMP swallowing symptom scores remained Pharmaceuticals; Fernando Pagan was an investigator in the SIAXI

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Fig. 3. Summary of adverse events during the extension period in subjects who received incobotulinumtoxinA in the main period and extension period. (A) Injection cycle 2, (B) injection cycle 3, and (C) injection cycle 4. aFatal SAE of cardio-respiratory arrest, unrelated to study treatment; bFatal SAEs of psychomotor hyperactivity, de- lusion, dopamine dysregulation syndrome, and altered state of consciousness, unrelated to study treatment. AEs were defined as AEs with onset or worsening at or after the first injection of the extension period up to and including 16 weeks after the last injection of the extension period, or last study visit, whichever was later. AESIs were classified based on a pre-defined list of AEs that could potentially indicate toxin spread (Medical Dictionary for Regulatory Activities version 19.1), regardless of whether an AE was regarded as treatment-related by the investigator. Additionally, AEs describing “dry mouth” considered severe, serious, or irreversible were reported as AESIs. AE, adverse event; AESI, adverse event of special interest; SAE, severe adverse event.

29 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 study and has received research grants from US World Meds and Teva results of treatment with botulinum toxin, Park. Relat. Disord. 7 (2001) 329–332. Neuroscience; educational grants from Medtronic; acted as a consultant [7] W.H. Jost, Treatment of drooling in Parkinson's disease with botulinum toxin, Mov. Disord. 14 (1999) 1057. for Acadia, Adamas, Merz Pharmaceuticals, and Teva Neuroscience; [8] C.E. Jackson, G. Gronseth, J. Rosenfeld, R.J. Barohn, R. Dubinsky, C.B. Simpson, and was a speaker for Acadia, Adamas, Teva, Merz Pharmaceuticals, et al., Randomized double-blind study of botulinum toxin type B for sialorrhea in and US World Meds; Birgit Flatau-Baqué and Ulrike Dorsch are em- ALS patients, Muscle Nerve 39 (2009) 137–143. [9] G. Lagalla, M. Millevolte, M. Capecci, L. Provinciali, M.G. Ceravolo, Botulinum ployees of Merz Pharmaceuticals; János Csikós is a former employee of toxin type A for drooling in Parkinson's disease: a double-blind, randomized, pla- Merz Pharmaceuticals; Andrew Blitzer was an investigator in the SIAXI cebo-controlled study, Mov. Disord. 21 (2006) 704–707. study and has received research funding from Allergan and Merz [10] G. Lagalla, M. Millevolte, M. Capecci, L. Provinciali, M.G. Ceravolo, Long-lasting fi Pharmaceuticals; and acted as a consultant for Merz Pharmaceuticals. bene ts of botulinum toxin type B in Parkinson's disease-related drooling, J. Neurol. 256 (2009) 563–567. [11] A. Lipp, T. Trottenberg, T. Schink, A. Kupsch, G. Arnold, A randomized trial of Author's roles botulinum toxin A for treatment of drooling, Neurology 61 (2003) 1279–1281. [12] M. Porta, M. Gamba, G. Bertacchi, P. Vaj, Treatment of sialorrhoea with ultrasound guided botulinum toxin type A injection in patients with neurological disorders, J. Wolfgang H. Jost, Andrzej Friedman, Jaroslaw Slawek, Birgit Neurol. Neurosurg. Psychiatry 70 (2001) 538–540. Flatau-Baqué, Ulrike Dorsch, János Csikós, and Andrew Blitzer [13] D.A. Restivo, M. Panebianco, A. Casabona, S. Lanza, R. Marchese-Ragona, F. Patti, were involved in the study concept and design, and the acquisition, et al., Botulinum toxin A for sialorrhoea associated with neurological disorders: evaluation of the relationship between effect of treatment and the number of glands analysis, and interpretation of study data. They have also been involved treated, Toxins (Basel) 10 (2018) E55. in the critical revision of the manuscript for important intellectual [14] K. Dashtipour, R. Bhidayasiri, J.J. Chen, B. Jabbari, M. Lew, D. Torres-Russotto, content. Olaf Michel, Christian Oehlwein, Andrzej Bogucki, RimabotulinumtoxinB in sialorrhea: systematic review of clinical trials, J Clin Mov Disord 4 (2017) 9. Stanislaw Ochudlo, Marta Banach, and Fernando Pagan were in- [15] S. Isaacson, C. Jackson, E. Molho, R. Trosch, W. Ondo, T. Clinch, MYSTICOL: a volved in the acquisition and interpretation of study data, and have multisite, double-blind, randomized, placebo-controlled trial of been involved in the critical revision of the manuscript for important rimabotulinumtoxinB for the treatment of sialorrhea in Parkinson's disease (PD) and fi other neurological conditions, Neurology 88 (16 Suppl) (2017) P3.026. intellectual content. All authors have approved the nal version for [16] J. Martínez-Poles, V. Nedkova-Hristova, J.B. Escribano-Paredes, S. García-Madrona, submission. E. Natera-Villalba, C. Estévez-Fraga, et al., Incobotulinumtoxin A for sialorrhea in neurological disorders: a real-life experience, Toxins (Basel) 10 (2018) E217. Funding [17] K. Huss, S. Berweck, A.S. Schroder, V. Mall, I. Borggrafe, F. Heinen, Interventional- neuropaediatric spectrum of treatments with botulinumtoxin neurotoxin type A, free of complexing proteins: effective and safe application - three exemplary cases, This study was supported by Merz Pharmaceuticals GmbH, Neuropediatrics 39 (2008) P077. Frankfurt am Main, Germany. [18] P. Kossmehl, B. Freudenberg, J. Wissel, Experience with a new botulinum toxin type A formulation in the treatment of sialorrhoea, Abstract Presented at the 4th Annual Congress of the International Society of Physical and Rehabilitation Medicine Acknowledgments (ISPRM), 12-15 June 2007, Seoul, Korea, 2007. [19] G. Castelnovo, M. de Verdal, D. Renard, V. Boudousq, L. Collombier, Comparison of different sites of injections of incobotulinumtoxin (XEOMIN®) into the major sali- The authors wish to thank the subjects and study investigators. This vary glands in drooling, Mov. Disord. 28 (Suppl) (2013) S167. study was supported by Merz Pharmaceuticals GmbH, Frankfurt am [20] A. South, H. 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