- Email: [email protected]
Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry
Accepted Manuscript Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry Angelo Antonini, Werner Poewe, K. Ray Chaudhuri, Robert Jech, Barbara Pickut, Zvezdan Pirtošek, Jozsef Szasz, Francesc Valldeoriola, Christian Winkler, Lars Bergmann, Ashley Yegin, Koray Onuk, David Barch, Per Odin, on behalf of the GLORIA study co-investigators PII:
S1353-8020(17)30350-4
DOI:
10.1016/j.parkreldis.2017.09.018
Reference:
PRD 3427
To appear in:
Parkinsonism and Related Disorders
Received Date: 28 April 2017 Revised Date:
16 August 2017
Accepted Date: 18 September 2017
Please cite this article as: Antonini A, Poewe W, Chaudhuri KR, Jech R, Pickut B, Pirtošek Z, Szasz J, Valldeoriola F, Winkler C, Bergmann L, Yegin A, Onuk K, Barch D, Odin P, on behalf of the GLORIA study co-investigators, Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2017.09.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Antonini, Poewe, et al. 1
Levodopa-carbidopa intestinal gel in advanced Parkinson’s: final results of the
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GLORIA registry
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Angelo Antonini, MD, PhD*,a Werner Poewe, MD*,b K. Ray Chaudhuri, MD, DSc,c Robert Jech, MD, PhD,d Barbara Pickut, MD, MPH,e Zvezdan Pirtošek, MD, PhD,f Jozsef Szasz, MD, PhD,g Francesc Valldeoriola, MD,h Christian Winkler, MD, PhD,i Lars Bergmann, MD,j Ashley Yegin, MD,j Koray Onuk, MD,j David Barch, MD,j Per Odin, MD, PhDk, on behalf of the GLORIA study co-investigators. a
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Department of Neurosciences, University of Padua, and IRCCS Hospital San Camillo, Venice, Italy; b Medical University of Innsbruck, Innsbruck, Austria; c King’s College and King’s College Hospital, London, United Kingdom; d Department of Neurology and Center of Clinical Neurosciences, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic; e University Hospital Antwerp, Antwerp, Belgium, and Michigan State University and Mercy Health Hauenstein Neurosciences, Grand Rapids, MI, USA; f University Medical Center Ljubljana, Ljubljana, Slovenia; g University of Medicine and Pharmacy Tirgu-Mures, Emergency Clinical County Hospital Mures, Tîrgu Mureș, Romania; h Clinical and Provincial Hospital of Barcelona, Barcelona, Spain; i Lindenbrunn Hospital, Coppenbrügge, Germany; j AbbVie Inc., North Chicago, IL, USA; k Lund University, Lund, Sweden
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Corresponding authors: Angelo Antonini Parkinson and Movement Disorders Unit IRCCS Hospital San Camillo, Viale Alberoni 70, Venice, Italy Phone: +39 (02) 57993319 e-mail: [email protected] Werner Poewe Department of Neurology Medical University of Innsbruck Anichstrasse 35, 6020 Innsbruck, Austria Phone: +43 512 504-23850 Email: [email protected]
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* These authors contributed equally to the manuscript
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Key Words: Parkinson’s disease, levodopa-carbidopa intestinal gel, motor symptoms, non-motor symptoms, routine patient care Manuscript type: Full Length Article Manuscript word count: 2619/3000 limit
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ABSTRACT
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Introduction: This registry evaluated the 24-month safety and efficacy of levodopa-
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carbidopa intestinal gel (LCIG) treatment in advanced Parkinson’s disease (PD) patients
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under routine clinical care.
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Methods: Motor fluctuations, dyskinesia, non-motor symptoms, quality of life, and
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safety were evaluated. Observations were fully prospective for treatment-naïve patients
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(60% of patients) and partially retrospective for patients with ≤ 12 months of pre-
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treatment with LCIG (40% of patients). Hours of “On” and “Off” time were assessed with
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a modified version of the Unified Parkinson’s Disease Rating Scale part IV items 32 and
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39.
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Results: Overall, 375 patients were enrolled by 75 movement disorder centers in 18
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countries and 258 patients completed the registry. At 24 months LCIG treatment led to
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significant reductions from baseline in “Off” time (hours/day) (mean±SD = -4.1±3.5,
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P<0.001), “On” time with dyskinesia (hours/day) (-1.1±4.8, P=0.006), Non-Motor
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Symptom Scale total (-16.7±43.2, P<0.001) and individual domains scores, and
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Parkinson’s Disease Questionnaire-8 item total score (-7.1±21.0, P<0.001). Adverse
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events deemed to have a possible/probable causal relationship to treatment drug/device
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were reported in 194 (54%) patients; the most frequently reported were decreased
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weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device
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issues (4.8%), and polyneuropathy (4.5%).
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Conclusions: LCIG treatment led to sustained improvements in motor fluctuations,
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non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal
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domains, as well as quality of life in advanced PD patients over 24 months. Safety
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events were consistent with the established safety profile of LCIG.
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INTRODUCTION
Levodopa is the most efficacious drug for the treatment of Parkinson’s disease
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(PD), but the long-term use of standard oral administration is associated with the development of disabling motor complications in most patients. Fluctuations in motor
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response are related to fluctuating peripheral levodopa plasma levels and are often
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associated with a variety of non-motor symptoms [1-4]. These motor and non-motor
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complications are aggravated by erratic gastric emptying, and substantially impact daily
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activities, social interactions, and patient quality of life (QoL) [5, 6].
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Levodopa-carbidopa intestinal gel (LCIG, also carbidopa-levodopa enteral
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suspension in the United States, CLES) is continuously delivered to the upper intestine
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ensuring more stable levodopa plasma levels than standard oral levodopa therapy [7,
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8]. This reduces motor response fluctuations and has also been shown to improve non-
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motor complaints commonly associated with chronic oral levodopa treatment [9-14].
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To date only a few studies have assessed the long-term safety and efficacy of
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LCIG treatment in routine clinical care and a majority of these studies included a limited
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number of patients or lacked systematic collection of efficacy data and adverse events
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[11, 15-19]. The objective of the GLORIA registry (global long-term registry on efficacy
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and safety of LCIG in patients with advanced Parkinson's disease in routine care) was
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to prospectively evaluate the long-term effectiveness of LCIG on motor and non-motor
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symptoms (NMS), QoL, and safety in a large cohort of advanced PD patients.
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METHODS
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Study design
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In this 24-month (M), multi-national, non-interventional, observational registry, advanced PD patients with persistent motor complications received LCIG treatment at
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75 movement disorder centers across 18 countries (Australia, Austria, Belgium,
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Bulgaria, Czech Republic, Denmark, France, Germany, Greece, Ireland, Italy,
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Netherlands, Norway, Romania, Slovenia, Spain, Switzerland, and United Kingdom).
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The study protocol was approved by national and/or local independent ethics
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committees and health authorities at each participating institution and country. All
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patients provided written informed consent before enrollment in the registry.
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LCIG treatment was initiated via a temporary nasojejunal (NJ) tube to verify drug efficacy and optimize dose before being administered through PEG-J (according to local
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label and reimbursement criteria). Concomitant medications were permitted at the
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discretion of the treating physician.
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Patients
Enrolled participants were male and female advanced PD patients with persistent
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severe motor complications that were eligible for LCIG treatment according to European
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Commission Summary Product Characteristics and national reimbursement criteria.
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Clinical observations were recorded prospectively for up to 24M for LCIG-naïve 5
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patients. For patients who had received LCIG for ≤ 12M before enrollment in the
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registry, clinical observations were collected retrospectively up to the day of registry
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enrollment followed by prospective documentation for a total observation period of 24M.
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Efficacy and safety outcomes were comparable between the retrospective and
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prospective cohorts (Supplemental Table 1).
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Efficacy
Efficacy outcomes included the mean change from baseline to study visit in the
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Unified Parkinson’s Disease Rating Scale (UPDRS) parts II, III, and IV; “Off” time and
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the dyskinesia items from UPDRS part IV. UPDRS IV items 39 and 32 were modified by
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using the rating instructions for the corresponding parts 4.3 and 4.1 of the MDS-UPDRS
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to allow for calculation of actual hours of “Off” time and “On” time with dyskinesias.
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UPDRS was conducted in the “On” state. NMS were assessed using the NMS Scale
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(NMSS) and patient reported QoL measures included the disease-specific 8-item
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Parkinson’s Disease Questionnaire (PDQ-8) and the generic EuroQoL- 5 Dimensions
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(EQ-5D) descriptive score and visual analog scale (VAS). Efficacy assessments were
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collected at baseline before LCIG treatment initiation with temporary NJ (concomitant
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PD medications were administered at the discretion of threating physician), at discharge
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from hospital following PEG-J placement (D1), 6M, 12M, 18M, and 24M.
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Primary efficacy analyses included all patients who had a baseline efficacy
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evaluation, received ≥ 1 dose of LCIG and ≥ 1 post-baseline safety and efficacy
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evaluation (N=329). Safety analyses included all patients who received ≥ 1 dose of
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LCIG and had ≥ 1 post-baseline safety evaluation (N=356). Last visit was defined as a 6
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patient’s last reported study visit. ANOVA over time and paired t-tests were performed
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for the comparison of all efficacy outcomes to baseline. The targeted enrollment for
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adequate sample size was 400 patients. Missing data was accounted for using survey
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methodology.
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Safety
Adverse drug reactions (ADRs), which included all adverse events with a
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reasonable possibility of being causally related to the treatment drug or device as
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determined by the investigator, were recorded for the duration of the registry and for 28
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days following a patient’s last reported study visit. ADRs were coded according to the
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Medical Dictionary for Regulatory Activities (MedDRA) [20] and categorized by the study
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investigator as mild, moderate or severe and as having an unlikely, possible or probable
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relationship to LCIG treatment. Serious ADRs and product complaints were monitored
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and recorded. Gastrointestinal (GI)-related ADRs reported by the investigator were
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categorized post hoc by the authors as either procedure-related, device-related, or
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“other” type of GI reaction not directly related to the procedure or device (e.g. decreased
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weight, nausea). Daily levodopa equivalent dose (LED) was calculated for the reported
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administration of LCIG and concomitant oral PD treatment for each study visit,
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according to published conversion factors [21].
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RESULTS Of the 375 patients enrolled, 258 (69%) completed the registry (Supplemental Figure 1). The mean ± SD exposure to PEG-J was 640.7 ± 198.3 days. Patient 7
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demographics, PD characteristics, and baseline assessments of motor symptoms,
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NMS, and QoL are summarized in Table 1. Over the course of the study, the
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percentage of patients receiving LCIG as a monotherapy ranged between 36-40%
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(36%, n=98/273 at M18; 40%, n=126/316 at M6) (Supplemental Table 2). The most
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common concomitant medications across all study visits were oral levodopa and
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dopamine agonists. Among patients that received LCIG as a monotherapy, the mean
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daily LED ranged from 1509 ± 719 mg at D1 (n=126) to a maximum of 1795 ± 878 mg
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at M18 (n=98). The mean daily LED for patients with LCIG combination therapy ranged
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from 1960 ± 873 mg at D1 (n=225) to a maximum of 2013 ± 880 mg at M6 (n=189)
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(Supplemental Table 2).
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Efficacy
At last visit, LCIG-treated patients showed significant reductions in “Off” time
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compared to baseline (modified UPDRS IV item 39, mean change from baseline ± SD=-
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3.9 ± 3.5 hours/day, 95% CI=[-4.4, -3.5], P<0.001, n=207) (Figure 1A). Significant and
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sustained reductions in “On” time with dyskinesia (modified UPDRS IV item 32) were
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also observed at last visit (-1.1 ± 4.7, 95% CI=[-1.8, -0.5], P<0.001, n=211) (Figure 1B).
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Additional improvements observed at last visit included UPDRS IV item 33 (dyskinesia
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severity, -0.9 ± 1.3, 95% CI=[-1.1, -0.7], P<0.001, n=188), UPDRS IV item 34
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(dyskinesia-related pain, -0.6 ± 1.2, 95% CI=[-0.8, -0.4], P<0.001, n=187), and UPDRS
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IV item 35 (early morning dystonia, -0.2 ± 0.6, 95% CI=[-0.2, -0.1], P<0.001, n=250).
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UPDRS II and III scores (assessed when “On”, Supplemental Table 3) showed
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significant reductions compared to baseline through 18M (-2.0 ± 9.1, 95% CI=[-3.4, -
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0.5], P=0.007) and 24M (-1.9 ± 11.8, 95% CI=[-3.6, -0.2], P=0.026), respectively. The NMSS total score was significantly reduced from baseline at all study visits
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with a mean change of -14.4 ± 44.8 at last visit (95% CI=[-20.3, -8.5], P<0.001, n=227)
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(Figure 2A). At last visit, 5/9 NMSS domain scores were significantly reduced compared
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to baseline: cardiovascular (last visit: mean change from baseline=-0.6 ± 4.1, 95% CI=[-
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1.1, -0.0], P=0.044), sleep/fatigue (-4.5 ± 10.6, 95% CI=[-5.9, -3.1], P<0.001),
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mood/cognition (-2.8 ± 14.7, 95% CI = [-4.7, -0.9], P=0.004), gastrointestinal tract (-2.2
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± 7.3, 95% CI=[-3.1, -1.2], P<0.001), and miscellaneous (-1.5 ± 9.9, 95% CI=[-2.8, -
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0.2], P=0.022) (Figure 2B and Supplemental Table 3).
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Quality of life, as measured by the PDQ-8, was significantly improved in LCIG-
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treated patients at every study visit (last visit: -5.3 ± 20.7, 95% CI=[-8.2, -2.5], P<0.001,
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n=205) (Figure 2C). Significant improvements were maintained through last visit in three
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PDQ-8 items: item 1 (difficulty getting around in public places, -0.4 ± 1.4, 95% CI=[-0.6,
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-0.2], P<0.001), item 7 (had painful muscle cramps and pain, -0.3 ± 1.4, 95% CI=[-0.5, -
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0.1], P=0.002), and item 8 (felt embarrassed by having PD, -0.5 ± 1.4, 95% CI=[-0.7, -
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0.3], P<0.001) (Supplemental Table 4). Significant improvements were observed in the
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EQ-5D descriptive and VAS scores compared to baseline (18M: EQ-5D, 0.06 ± 0.34,
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95% CI=[0.0, 0.1], P=0.025; last visit: VAS, 11.9 ± 28.3, 95% CI=[7.9, 15.9], P<0.001)
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(Supplemental Table 4).
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Overall, 194 (54.5%, N=356) patients experienced one or more ADRs (Table 2). The most frequently reported ADRs during the PEG-J treatment period were decreased
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weight (6.7%, n=24), device-related infections (5.9%, n=21), device dislocations (4.8%,
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n=17), device issues (4.8%, n=17), and polyneuropathy (4.5%, n=16) (Table 2). Thirty-
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nine percent of patients (n=139/356) reported ≥ 1 GI-related ADR during the PEG-J
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treatment period, of which procedure-related ADRs were reported in 35 patients (9.8%),
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device-related in 93 (26%), and other GI ADRs in 63 (18%). These ADRs were
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generally transient, with the highest prevalence of GI-related ADRs (13.5%) and serious
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GI-related ADRs (4.5%) occurring during the first 2 weeks of LCIG treatment post-PEG-
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J placement (Supplemental Figure 2).
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Serious ADRs occurred in 109 (30.6%) patients and 55 (15.4%) patients had a severe ADR (Table 2). Device dislocation was the most frequently reported serious
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ADR during the PEG-J treatment period (2.2%, n=8). Twenty-five (7.0%) patients
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experienced at least one ADR that led to discontinuation of LCIG treatment and device
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dislocation was the only ADR leading to discontinuation reported by more than 1 patient
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(n=2, 0.6%).
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Twenty-nine deaths (8%, N=356) occurred during the registry period: 23 were deemed unrelated to treatment, 5 possibly related, and 1 probably related (Table 2). Of
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the possibly related deaths, 2 were the result of pneumonia followed by septic shock
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and/or organ failure on treatment days 463 and 452, 1 occurred on treatment day 511
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and was the result of pneumonia followed by a stroke, 1 occurred on treatment day 425
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and was the result of a fatal seizure, and 1 occurred on treatment day 645 and was the
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result of unknown causes following a small bowel obstruction that occurred 3 weeks
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before patient death. The patient death deemed probably related to treatment occurred
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after 646 days of treatment and was the result of a small bowel perforation and
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peritonitis.
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DISCUSSION
This primary analysis of the GLORIA registry represents the largest cohort of advanced PD patients treated with LCIG and provides evidence for the long-term
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effectiveness in reducing motor fluctuations and dyskinesia during routine clinical care.
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In addition, there were improvements in QoL and a variety of non-motor symptoms, and
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the safety profile was overall satisfactory.
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LCIG led to sizable reductions in the amount of time patients spent in the “Off”
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state. On average, patients maintained at least a 50% reduction in “Off” time at every
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study visit. This reduction in “Off” time observed was well above the 1-hour change that
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is deemed clinically relevant [22] and was consistent with other published open-label
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studies and randomized controlled trials on LCIG [9-11]. “Off” time improvements occurred alongside reductions in the proportion of “On”
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time spent with dyskinesia. The average “On” time with dyskinesia was reduced by 25%
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at 24M. Importantly, this was observed despite increased total levodopa equivalent
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dose following the switch from oral levodopa to LCIG and increases in LED over the
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24M follow-up period. This is consistent with literature suggesting that switching to
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continuous levodopa delivery improves not only motor fluctuations but also reduces pre-
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existing dyskinesia [2, 6, 9, 23, 24]. Increases in the daily levodopa dose are common in
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clinical practice when switching from oral PD medications to LCIG and similar
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magnitudes of LED increase have been previously reported [17]. The continuous nature
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of levodopa delivery with LCIG often allows for an increase in LED for optimal motor
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symptom control while limiting many of the undesirable side effects associated with high
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oral levodopa dose. Given that GLORIA was a registry and not a controlled, clinical trial,
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there were no specific requirements for dose optimization prior to LCIG initiation.
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Procedures in this registry reflected the 'real-world' routine clinical setting, where
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treating physicians determined that all oral treatment options had been exhausted and
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LCIG was now indicated.
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however they were only significant through M18 (UPDRS II) while change at M24 in the
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UPDRS III score falls below the minimal clinically important difference threshold. These
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data are similar to those reported in previous studies examining LCIG treatment,
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including Palhagen et al. (2016) [27], and may reflect worsening/progression of the
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disease. It is important to note that QoL remained improved over all time points in a
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stable manner which is consistent with other studies on LCIG [9, 10, 27] Consistent with the interim analysis of this registry [12] and the EuroInf study
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[25], LCIG led to a significant reduction in NMS burden at 24M. NMS domains that
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showed persistent improvement over the entire follow-up period included the
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cardiovascular, sleep/fatigue, mood/cognition, gastrointestinal tract, and
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“miscellaneous” domains. Notably, disturbances in sleep/fatigue, which have a strong
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impact on QoL, showed the greatest magnitude of improvement at 24M, arguing for
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improved sleep quality as motor fluctuations improved [26].
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Given the characteristics of this registry (which included some retrospective data) the safety analyses cannot be directly compared to previous studies, however the most
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frequently reported ADRs were consistent with the established safety profile of LCIG [9-
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11, 28]. Device and procedure-related events were the most frequently reported ADRs
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and were generally transient, occurring at highest prevalence within the first 2 weeks
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post-PEG-J placement. These data emphasize the need for close monitoring in the
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immediate post-PEG-J placement period. Additionally, the GI-related ADRs were
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consistent with the known long-term complications of the PEG-J procedure [29]. Given
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the demographics of the registry population, LCIG procedure and treatment was
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generally well tolerated, with a low rate of discontinuation due to ADR (7.0%) that was
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consistent with previously published reports [10]. Of the 29 deaths that occurred during
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the registry, 5 were deemed possibly related to treatment and 1 was probably related to
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treatment. The determination of possibly related deaths was based upon the
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investigator’s judgment that there was reasonable support for an association between
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the treatment and an event (e.g. pneumonia); however, a causal relationship between
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treatment and death was undetermined. The 1 probably related death, resulting from of
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a fatal small bowel perforation, occurred after 646 days of treatment and underscores
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the invasiveness and inherent risks of chronic PEG-J use in an elderly population.
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Timely investigations of a patient’s abdominal complaints and the involvement of GI
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specialists and interdisciplinary care and management teams may reduce the inherent
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risks of chronic PEG-J use in the elderly.
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This registry provides important clinical data related to the use of LCIG to treat advanced PD patients, however there are some limitations associated with the registry
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design. These limitations include the registry’s open-label design and the lack of a
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control group, which does not allow for comparative efficacy and safety assessments.
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This limitation is particularly relevant in evaluating the significance of LCIG on NMS as a
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recent double-blind randomized study examining the effects of rotigotine and placebo
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on NMS severity in PD patients with severe non-motor disability demonstrated similar
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improvements (>30%) in both the treatment and placebo study groups [30]. Additional
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limitations include the statistical method employed for the efficacy analyses, which did
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not carry the last observation forward, and the partially retrospective nature of data
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collection for 40% of the enrolled patients, which resulted in some missing data during
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the documentation period.
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In conclusion, LCIG treatment in advanced PD patients in routine care led to significant and sustained reductions in motor fluctuations and NMS burden and
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improvements in QoL, despite natural PD progression over the 2-year follow-up. The
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safety results were consistent with the previously established safety profile of LCIG.
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ACKNOWLEDGEMENTS
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This work was funded by AbbVie Inc. AbbVie participated in the study design, research,
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data collection, analysis, and interpretation of data, writing, reviewing, and approving
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the publication. Medical writing support was provided by Amy M. Spiegel of AbbVie, Inc.
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The EDC system used to collect clinical data was provided by Koehler eClinical Ltd.,
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Freiburg, Germany. The statistical analysis was performed by Koehler eClinical, funded
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by AbbVie.
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STUDY FUNDING
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This study was sponsored by AbbVie Inc. (North Chicago, IL, USA), which participated
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in the study design, research, data collection, analysis and interpretation of the data,
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writing, reviewing, and approving the publication.
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AUTHOR CONTRIBUTIONS AND DISCLOSURES
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Dr. Antonini was as a study investigator and has received compensation for consultancy
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and speaker related activities from Acadia, Sunovion, UCB, Boston Scientific, Angelini,
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Medtronic, GE, Boehringer Ingelheim, AbbVie, Zambon. He also received research
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support from Mundipharma. Dr. Antonini’s contributions include study concept and
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design, acquisition and interpretation of the data, and review and critique of the
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manuscript.
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Dr. Poewe was a study investigator and has received compensation from AbbVie, Astra
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Zeneca, Teva, Novartis, GSK, Boehringer-Ingelheim, UCB, Orion Pharma, Zambon and
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Merz Pharmaceuticals (consultancy and lecture fees in relation to clinical drug
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development programmes for PD) outside the submitted work. He has received
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royalties from Thieme, Wiley Blackwell and Oxford University Press. Dr. Poewe’s
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contributions include study concept and design, acquisition and interpretation of the
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data, and review and critique of the manuscript.
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Dr. Chaudhuri was a study investigator and has received honorarium from UCB,
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AbbVie, Britannia, Mundipharma, Boehringer Ingelheim, and GSK Pharmaceuticals for
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lecturing at symposia. He has acted as a consultant for UCB, AbbVie, Britannia,
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Neuronova and Mundipharma. He has received research funding from Parkinson’s UK,
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NIHR, PDNMG, as well as educational grants from UCB, Britannia, AbbVie, GSK
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Pharmaceuticals, Boehringer Ingelheim, and Neuronova. Dr. Chaudhuri receives
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royalties from Oxford University Press and holds intellectual property rights for the Kings
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Parkinson’s Pain Scale and Parkinson’s Disease Sleep Scale 2. Dr. Chaudhuri’s
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contributions include acquisition and interpretation of the data, and review and critique
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of the manuscript.
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Dr. Jech was a study investigator and received honoraria from AbbVie, Medtronic,
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Ipsen, Allergan, Cardion for consultancies and lectures. Dr. Jech’s contributions include
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acquisition and interpretation of the data, and review and critique of the manuscript.
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Dr. Pickut was a study investigator and has received compensation from AbbVie, GSK,
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St. Jude Medical, and Teva for advisory boards, consultancy and speaker-related
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activities, and research support from Novartis. Dr. Pickut’s contributions include
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acquisition of the data, and review and critique of the manuscript.
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Dr. Pirtosek was a study investigator and has received compensation from AbbVie for
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speaker related activities. Dr. Pirtosek’s contributions include acquisition and
386
interpretation of the data, and review and critique of the manuscript.
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ACCEPTED MANUSCRIPT Antonini, Poewe, et al.
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Dr. Szasz was a study investigator and received compensation from AbbVie, Novartis,
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UCB, Boehringer-Ingelheim, GSK, Ever, Lundbeck, Teva, Pfizer for speaker activities.
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Dr. Szasz’s contributions include acquisition and interpretation of the data, and review
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and critique of the manuscript.
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Dr. Valldeoriola was a study investigator and received honoraria from AbbVie,
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Medtronic, Boston Scientific, UCB Pharma and Italfármaco for professional advice and
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lectures. Dr. Valldeoriola’s contributions include acquisition and interpretation of the
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data, and review and critique of the manuscript.
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Dr. Winkler was a study investigator and has participated in advisory boards for AbbVie,
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UCB, and BIAL, and has received lecture fees from AbbVie, LicherMT, and BIAL. Dr.
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Winkler’s contributions include acquisition and interpretation of the data, and review and
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critique of the manuscript.
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Dr. Bergmann is an employee of AbbVie and holds AbbVie stock and/or stock options.
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Dr. Bergmann’s contributions include acquisition and interpretation of the data, and
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review and critique of the manuscript.
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Dr. Yegin is a former employee of AbbVie. Dr. Yegin’s contributions include acquisition
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and interpretation of the data, and review and critique of the manuscript.
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Dr. Onuk is an employee of AbbVie and holds AbbVie stock and/or stock options. Dr.
411
Onuk’s contributions include acquisition and interpretation of the data, and review and
412
critique of the manuscript.
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Dr. Barch is an employee of AbbVie and holds AbbVie stock and/or stock options. Dr.
415
Barch’s contributions include interpretation of the data and review and critique of the
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manuscript.
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Dr. Odin was a study investigator and has received compensations for consultancy and
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speaker related activities from AbbVie, Britannia, Boehringer-Ingelheim, Nordic
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Infucare, UCB and Zambon. PO has received royalties from Uni-Med Verlag.Dr. Odin’s
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contributions include study concept and design, acquisition and interpretation of the
422
data, and review and critique of the manuscript.
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CO-INVESTIGATOR APPENDIX
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The authors would like to acknowledge the following non-author, GLORIA study investigators for their contributions: Ene Amalia, University Emergency Hospital,
428
Bucharest, Romania; Guy Arnold, Sindelfingen Hospital, Department of Neurology,
429
Sindelfingen, Germany; Ovidiu Bajenaru, University Department of Clinical
430
Neurosciences, University of Medicine and Pharmacy "Carol Davila", Bucharest,
431
Romania; Bruno Bergmans, AZ St-Jan Brugge-Oostende AV, Brugge, Belgium; Kari
432
Anne Bjornara, Drammen Hospital, Drammen, Norway; Jeff Blackie, John Hunter
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Hospital , Newcastle, Australia; Matthias Bode, Odense University Hospital, Odense,
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Denmark; Paul Bourgeois, Department of Neurology AZ Groeninge, Kortrijk, Belgium;
435
Stephan Bohlhalter, Neurology and Neurorehabilitation Center, Luzern, Switzerland;
436
Ioan Buraga, Colentina Hospital, Bucharest, Romania; Pierre R. Burkhard, Geneva
437
University Hospitals, Geneva, Switzerland; Philippe Busson, Centre Hospitalier
438
Avranches Granvilles, Avranches, France; Matilde Calopa, Neurology Service. Hospital
439
Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalonia, Spain; Jesper Clausen,
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Rigshospitalet/Glostup, Denmark; Erik Hvid Danielsen, Dept of Neurology, Aarhus
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University Hospital , Aarhus, Denmark; Luc Defebvre, Movement Disorder Department,
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Parkinson’s disease Expert Center, Université of Lille, Lille, France;Valerie Delvaux,
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University of Liege, Belgium; Sophie Dethy, chu-Tivoli, La Louviere, Belgium; Espen
444
Dietrichs, Dept of Neurology, Oslo University Hospital and University of Oslo, Oslo,
445
Norway; Oriol De Fabregues, Vall d'Hebron University Hospital, Autonomous University
446
of Barcelona, Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Ransmayr
447
Gerhard, Dept. of Neurology 2, Kepler University Hospital, Linz, Austria; Graziano
448
Gusmaroli, SC Neurologia - Ospedale degli Infermi di Biella, Biella, Italy; Kirsten Hahn,
449
Practice Dr. Hahn, Berlin, Germany; Björn Hauptmann, Neurologisches Zentrum, Bad
450
Segeberg, Germany; Tove Henriksen, University Hospital of Bispebjerg, Copenhagen,
451
Denmark; Jorge Hernandez-Vara, Neurology Department, Hospital Universitari Vall
452
D´Hebron, Barcelona, Spain; A. Jeanjean, Université catholique de Louvain, Louvain-la-
453
Neuve, Belgium; Michaela Kaiserova, Department of Neurology, Faculty of Medicine
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and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic;
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Jan Kassubek, Department of Neurology, University of Ulm, Ulm, Germany; Thomas
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Kimber, Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia;
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Spyridon Konitsiotis, Department of Neurology, Faculty of Medicine, University of
458
Ioannina, Greece; Rejko Krüger, Luxembourg Centre for Systems Biomedicine,
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University of Luxembourg, and Centre Hospitalier de Luxembourg, Luxembourg; and
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Centre for Neurology, University of Tübingen, Germany, Esch-sur-Alzette, Luxembourg
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and Tübingen, Germany; Jaime Kulisevsky, Sant Pau Hospital, Barcelona, Spain; Jo
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Leenders, Sint-Dimpa Ziekenhuis, Geel, Belgium; Christofer Lundqvist, Akershus
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University Hospital and University of Oslo, Oslo, Norway; F. Ory Magne, Toulouse
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University hospital, France; Pietro Marano, Nuova Casa di Cura D'Anna, Palemro, Italy;
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Ivan Milanov, University Neurological Hospital "St. Naum", Sofia, Bulgaria; Nicola
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Modugno, IRCCS Neuromed, Pozzilli (IS), Italy; Anjum Misbahuddin, Essex Centre for
467
Neurological Sciences, Romford, UK; Martin Nevrly, Department of Neurology,
468
University Hospital and Faculty of Medicine and Dentistry of Palacky University ,
469
Olomouc, Czech Republic; Zikos Panayiotis, 251 Hellenic Air Force Hospital, Athens
470
Greece; Kenn Freddy Pedersen, Neurology department, Stavanger University Hospital,
471
Stavanger, Norway; Stephen W. Pedersen, Department of neurology Glostrup hospital
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University of Copenhagen, Glostrup, Denmark; Lacramioara Perju-Dumbrava,
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University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj-Napoca, Cluj-Napoca,
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Romania; M.M. Ponsen, Meander Medical Center, Amersfoort, Netherlands; Bogdan O.
475
Popescu, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania;
476
Michel Rijntjes, Department of Neurology, University Clinic Freiburg, Freiburg,
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Germany; V. Puente, Neurology Department, Institut Hospital del Mar d’Investigacions
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Mediques, Universitat Autonoma de Barcelona, Hospital del Mar, Barcelona, Spain;
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Christoph Redecker, Department of Neurology, Jena University Hospital, Jena,
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Germany; Christoph Schrader, Hannover Medical School, Hannover, Germany;
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Mariachiara Sensi, Neurology Department Arcispedale S.Anna, Ferrara, Italy; Mihaela
482
Simu, UMF"Victor Babes”, Timisoara, Romania; Cleanthe Spanaki, University Of Crete,
483
School Of Medicine, Neurology Department, Iraklio, Greece; Alexander Storch,
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University of Rostock, Rostock, Germany; Anette Storstein, Haukeland University
485
Hospital, Bergen, Norway; Volker Tomantschger, Gailtal-Klinik Hermagor,
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Hermagor,Austria; Chris van der Linden, Department of Neurology, St. Lucas Hospital
487
Ghent, Ghent, Belgium; T. van Laar, University Medical Center Groningen, Groningen,
488
Netherlands; F. Viallet, Service de Neurologie, CH du pays d'Aix, Aix en Provence,
489
France; Tatiana Witjas, University Hospital Timone, Marseille, France; Martin Wolz,
490
Elblandklinikum Meissen , Meissen, Germany; Maurizio Zibetti, Department of
491
Neuroscience, University of Torino, Torino, Italy; Michel Van Zandijcke, AZ Sint-Jan
492
Brugge, Brugge, Belgium.
493
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Figure Legends
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Figure 1. Motor symptom efficacy. Mean change from baseline of daily hours of A.
631
"Off" time (modified UPDRS Part IV Items 39) and B. "On" time with dyskinesia
632
(modified UPDRS Part IV Item 32). Error bars indicate SD. Asterisks indicate statistical
633
significance compared to baseline in a paired t test at the P<0.01 (**) and P<0.001 (***)
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levels. UPDRS = Unified Parkinson's Disease Rating Scale; BL = baseline; D1 =
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discharge from hospital post-PEG-J placement; M = month; LV = patient’s last reported
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study visit.
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Figure 2. Non-motor symptom efficacy. Mean change from baseline in A. NMSS total
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score, B. NMSS domain scores over 2-year follow-up, and C. PDQ-8 total score. Error
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bars indicate SD. NMSS = Non-Motor Symptom Scale, PDQ-8 = Parkinson’s Disease
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Questionnaire 8-item, BL = baseline; D1 = discharge from hospital post-PEG-J
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placement; M = month; LV = patient’s last reported study visit. P<0.05 (*), P<0.01 (**),
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and P<0.001 (***)
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ACCEPTED MANUSCRIPT
Table 1. Baseline demographics and disease characteristics
Characteristic
Value 66.4 ± 8.8
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Age, years, mean ± SD Sex, n (%) Male
220 (58.7)
Female
155 (41.3)
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LCIG History, n (%) LCIG-naïve
Baseline LED, mg/day, mean ± SD PD duration, years, mean ± SD Hoehn & Yahr, mean ± SD During “On”
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During “Off”
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LCIG ≤ 12M before enrollment
225 (60) 150 (40) 1319 ± 617 12.7 ± 6.3
2.8 ± 0.8 4.0 ± 0.9
UPDRS Part IV, hours/day, mean ± SD Modified item 39: “Off” time
6.0 ± 3.2
Modified item 32: Time with dyskinesia
4.3 ± 3.8 16.5 ± 9.8
UPDRS Part III (motor examination), mean ± SD
24.6 ± 12.0
NMSS, total score, mean ± SD
69.2 ± 42.1
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UPDRS Part II (activities of daily living), mean ± SD
PDQ-8 Total Score (quality of life), mean ± SD
46.8 ± 18.6
EQ-5D score, mean ± SD
0.4 ± 0.32
EQ-VAS score, mean ± SD
48.0 ± 21.3
PD medications reported at baseline, n (%) Levodopa
367 (97.9)
Dopamine agonists
253 (67.5)
COMT inhibitors
212 (56.5)
ACCEPTED MANUSCRIPT
MAO-B inhibitors
133 (35.5)
Amantadine
102 (27.2)
Other oral
50 (13.3)
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LCIG = levodopa-carbidopa intestinal gel, LED = levodopa equivalent dose, PD = Parkinson’s disease, UPDRS = Unified Parkinson’s Disease Rating Scale, NMSS = Non-motor symptom scale,PDQ-8 = Parkinson’s Disease Questionnaire 8-item, EQ-5D = Euro Quality of Life 5 Dimensions, EQ-VAS = Euro Quality of Life Visual Analog Scale, COMT = catechol-Omethyltransferase, MAO-B = monoamine oxidase
ACCEPTED MANUSCRIPT
Table 2. Safety Summarya
n (% of N=356)
Patients with at least one ADR
194 (55)
Patients with at least one GI-related ADR Patients with at least one serious ADR
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55 (15)
Deaths
ADRs occurring in ≥ 3% of patients Weight decreased Device related infection Device dislocation
Polyneuropathy Device lead issue
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Unrelated to treatment
Probably related to treatment
139 (39) 109 (31)
Patients with at least one severe ADR
Possibly related to treatment
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Safety
29 (8.1) 23 (6.5) 5 (1.4) 1 (0.3)
24 (6.7) 21 (5.9) 17 (4.8) 17 (4.8) 16 (4.5) 14 (3.9) 13 (3.7)
Abdominal pain
13 (3.7)
Hallucination
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12 (3.4)
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Serious ADRs occurring in ≥ 1% of patientsb Device dislocation
8 (2.2)
Device issue
7 (2.0)
Parkinson’s disease
7 (2.0)
Parkinsonism
7 (2.0)
Medical device complication
6 (1.7)
Device malfunction
5 (1.4)
Device occlusion
5 (1.4)
Abdominal pain
4 (1.1)
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Hallucination
4 (1.1)
Pneumonia
4 (1.1)
Polyneuropathy
4 (1.1)
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Gastrointestinal and gastrointestinal procedure-related ADRs are italicized. a Data indicates incidence of ADRs b During 24 months of LCIG infusion via PEG-J ADR = adverse drug reaction (adverse events with a possible/probable relationship to the treatment drug or device), GI = gastrointestinal, LCIG = levodopa-carbidopa intestinal gel, PEGJ = percutaneous endoscopic gastrojejunostomy
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Highlights:
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Long-term registry of LCIG treatment in patients with advanced Parkinson’s disease LCIG was delivered over 24 months in a routine clinical care setting LCIG treatment reduced “Off” time and dyskinesia time over 2 years LCIG treatment improved non-motor symptoms and quality of life over 2 years Adverse drug reactions were consistent with the established safety profile of LCIG
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• • • • •
S1353-8020(17)30350-4
DOI:
10.1016/j.parkreldis.2017.09.018
Reference:
PRD 3427
To appear in:
Parkinsonism and Related Disorders
Received Date: 28 April 2017 Revised Date:
16 August 2017
Accepted Date: 18 September 2017
Please cite this article as: Antonini A, Poewe W, Chaudhuri KR, Jech R, Pickut B, Pirtošek Z, Szasz J, Valldeoriola F, Winkler C, Bergmann L, Yegin A, Onuk K, Barch D, Odin P, on behalf of the GLORIA study co-investigators, Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2017.09.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Antonini, Poewe, et al. 1
Levodopa-carbidopa intestinal gel in advanced Parkinson’s: final results of the
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GLORIA registry
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Angelo Antonini, MD, PhD*,a Werner Poewe, MD*,b K. Ray Chaudhuri, MD, DSc,c Robert Jech, MD, PhD,d Barbara Pickut, MD, MPH,e Zvezdan Pirtošek, MD, PhD,f Jozsef Szasz, MD, PhD,g Francesc Valldeoriola, MD,h Christian Winkler, MD, PhD,i Lars Bergmann, MD,j Ashley Yegin, MD,j Koray Onuk, MD,j David Barch, MD,j Per Odin, MD, PhDk, on behalf of the GLORIA study co-investigators. a
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Department of Neurosciences, University of Padua, and IRCCS Hospital San Camillo, Venice, Italy; b Medical University of Innsbruck, Innsbruck, Austria; c King’s College and King’s College Hospital, London, United Kingdom; d Department of Neurology and Center of Clinical Neurosciences, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic; e University Hospital Antwerp, Antwerp, Belgium, and Michigan State University and Mercy Health Hauenstein Neurosciences, Grand Rapids, MI, USA; f University Medical Center Ljubljana, Ljubljana, Slovenia; g University of Medicine and Pharmacy Tirgu-Mures, Emergency Clinical County Hospital Mures, Tîrgu Mureș, Romania; h Clinical and Provincial Hospital of Barcelona, Barcelona, Spain; i Lindenbrunn Hospital, Coppenbrügge, Germany; j AbbVie Inc., North Chicago, IL, USA; k Lund University, Lund, Sweden
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Corresponding authors: Angelo Antonini Parkinson and Movement Disorders Unit IRCCS Hospital San Camillo, Viale Alberoni 70, Venice, Italy Phone: +39 (02) 57993319 e-mail: [email protected] Werner Poewe Department of Neurology Medical University of Innsbruck Anichstrasse 35, 6020 Innsbruck, Austria Phone: +43 512 504-23850 Email: [email protected]
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* These authors contributed equally to the manuscript
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Key Words: Parkinson’s disease, levodopa-carbidopa intestinal gel, motor symptoms, non-motor symptoms, routine patient care Manuscript type: Full Length Article Manuscript word count: 2619/3000 limit
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ABSTRACT
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Introduction: This registry evaluated the 24-month safety and efficacy of levodopa-
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carbidopa intestinal gel (LCIG) treatment in advanced Parkinson’s disease (PD) patients
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under routine clinical care.
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Methods: Motor fluctuations, dyskinesia, non-motor symptoms, quality of life, and
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safety were evaluated. Observations were fully prospective for treatment-naïve patients
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(60% of patients) and partially retrospective for patients with ≤ 12 months of pre-
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treatment with LCIG (40% of patients). Hours of “On” and “Off” time were assessed with
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a modified version of the Unified Parkinson’s Disease Rating Scale part IV items 32 and
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39.
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Results: Overall, 375 patients were enrolled by 75 movement disorder centers in 18
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countries and 258 patients completed the registry. At 24 months LCIG treatment led to
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significant reductions from baseline in “Off” time (hours/day) (mean±SD = -4.1±3.5,
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P<0.001), “On” time with dyskinesia (hours/day) (-1.1±4.8, P=0.006), Non-Motor
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Symptom Scale total (-16.7±43.2, P<0.001) and individual domains scores, and
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Parkinson’s Disease Questionnaire-8 item total score (-7.1±21.0, P<0.001). Adverse
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events deemed to have a possible/probable causal relationship to treatment drug/device
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were reported in 194 (54%) patients; the most frequently reported were decreased
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weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device
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issues (4.8%), and polyneuropathy (4.5%).
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Conclusions: LCIG treatment led to sustained improvements in motor fluctuations,
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non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal
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domains, as well as quality of life in advanced PD patients over 24 months. Safety
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events were consistent with the established safety profile of LCIG.
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INTRODUCTION
Levodopa is the most efficacious drug for the treatment of Parkinson’s disease
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(PD), but the long-term use of standard oral administration is associated with the development of disabling motor complications in most patients. Fluctuations in motor
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response are related to fluctuating peripheral levodopa plasma levels and are often
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associated with a variety of non-motor symptoms [1-4]. These motor and non-motor
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complications are aggravated by erratic gastric emptying, and substantially impact daily
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activities, social interactions, and patient quality of life (QoL) [5, 6].
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Levodopa-carbidopa intestinal gel (LCIG, also carbidopa-levodopa enteral
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suspension in the United States, CLES) is continuously delivered to the upper intestine
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ensuring more stable levodopa plasma levels than standard oral levodopa therapy [7,
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8]. This reduces motor response fluctuations and has also been shown to improve non-
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motor complaints commonly associated with chronic oral levodopa treatment [9-14].
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To date only a few studies have assessed the long-term safety and efficacy of
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LCIG treatment in routine clinical care and a majority of these studies included a limited
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number of patients or lacked systematic collection of efficacy data and adverse events
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[11, 15-19]. The objective of the GLORIA registry (global long-term registry on efficacy
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and safety of LCIG in patients with advanced Parkinson's disease in routine care) was
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to prospectively evaluate the long-term effectiveness of LCIG on motor and non-motor
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symptoms (NMS), QoL, and safety in a large cohort of advanced PD patients.
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METHODS
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Study design
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In this 24-month (M), multi-national, non-interventional, observational registry, advanced PD patients with persistent motor complications received LCIG treatment at
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75 movement disorder centers across 18 countries (Australia, Austria, Belgium,
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Bulgaria, Czech Republic, Denmark, France, Germany, Greece, Ireland, Italy,
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Netherlands, Norway, Romania, Slovenia, Spain, Switzerland, and United Kingdom).
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The study protocol was approved by national and/or local independent ethics
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committees and health authorities at each participating institution and country. All
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patients provided written informed consent before enrollment in the registry.
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LCIG treatment was initiated via a temporary nasojejunal (NJ) tube to verify drug efficacy and optimize dose before being administered through PEG-J (according to local
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label and reimbursement criteria). Concomitant medications were permitted at the
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discretion of the treating physician.
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Patients
Enrolled participants were male and female advanced PD patients with persistent
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severe motor complications that were eligible for LCIG treatment according to European
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Commission Summary Product Characteristics and national reimbursement criteria.
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Clinical observations were recorded prospectively for up to 24M for LCIG-naïve 5
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patients. For patients who had received LCIG for ≤ 12M before enrollment in the
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registry, clinical observations were collected retrospectively up to the day of registry
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enrollment followed by prospective documentation for a total observation period of 24M.
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Efficacy and safety outcomes were comparable between the retrospective and
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prospective cohorts (Supplemental Table 1).
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Efficacy
Efficacy outcomes included the mean change from baseline to study visit in the
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Unified Parkinson’s Disease Rating Scale (UPDRS) parts II, III, and IV; “Off” time and
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the dyskinesia items from UPDRS part IV. UPDRS IV items 39 and 32 were modified by
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using the rating instructions for the corresponding parts 4.3 and 4.1 of the MDS-UPDRS
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to allow for calculation of actual hours of “Off” time and “On” time with dyskinesias.
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UPDRS was conducted in the “On” state. NMS were assessed using the NMS Scale
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(NMSS) and patient reported QoL measures included the disease-specific 8-item
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Parkinson’s Disease Questionnaire (PDQ-8) and the generic EuroQoL- 5 Dimensions
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(EQ-5D) descriptive score and visual analog scale (VAS). Efficacy assessments were
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collected at baseline before LCIG treatment initiation with temporary NJ (concomitant
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PD medications were administered at the discretion of threating physician), at discharge
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from hospital following PEG-J placement (D1), 6M, 12M, 18M, and 24M.
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Primary efficacy analyses included all patients who had a baseline efficacy
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evaluation, received ≥ 1 dose of LCIG and ≥ 1 post-baseline safety and efficacy
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evaluation (N=329). Safety analyses included all patients who received ≥ 1 dose of
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LCIG and had ≥ 1 post-baseline safety evaluation (N=356). Last visit was defined as a 6
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patient’s last reported study visit. ANOVA over time and paired t-tests were performed
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for the comparison of all efficacy outcomes to baseline. The targeted enrollment for
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adequate sample size was 400 patients. Missing data was accounted for using survey
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methodology.
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Safety
Adverse drug reactions (ADRs), which included all adverse events with a
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reasonable possibility of being causally related to the treatment drug or device as
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determined by the investigator, were recorded for the duration of the registry and for 28
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days following a patient’s last reported study visit. ADRs were coded according to the
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Medical Dictionary for Regulatory Activities (MedDRA) [20] and categorized by the study
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investigator as mild, moderate or severe and as having an unlikely, possible or probable
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relationship to LCIG treatment. Serious ADRs and product complaints were monitored
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and recorded. Gastrointestinal (GI)-related ADRs reported by the investigator were
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categorized post hoc by the authors as either procedure-related, device-related, or
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“other” type of GI reaction not directly related to the procedure or device (e.g. decreased
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weight, nausea). Daily levodopa equivalent dose (LED) was calculated for the reported
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administration of LCIG and concomitant oral PD treatment for each study visit,
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according to published conversion factors [21].
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RESULTS Of the 375 patients enrolled, 258 (69%) completed the registry (Supplemental Figure 1). The mean ± SD exposure to PEG-J was 640.7 ± 198.3 days. Patient 7
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demographics, PD characteristics, and baseline assessments of motor symptoms,
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NMS, and QoL are summarized in Table 1. Over the course of the study, the
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percentage of patients receiving LCIG as a monotherapy ranged between 36-40%
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(36%, n=98/273 at M18; 40%, n=126/316 at M6) (Supplemental Table 2). The most
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common concomitant medications across all study visits were oral levodopa and
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dopamine agonists. Among patients that received LCIG as a monotherapy, the mean
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daily LED ranged from 1509 ± 719 mg at D1 (n=126) to a maximum of 1795 ± 878 mg
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at M18 (n=98). The mean daily LED for patients with LCIG combination therapy ranged
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from 1960 ± 873 mg at D1 (n=225) to a maximum of 2013 ± 880 mg at M6 (n=189)
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(Supplemental Table 2).
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Efficacy
At last visit, LCIG-treated patients showed significant reductions in “Off” time
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compared to baseline (modified UPDRS IV item 39, mean change from baseline ± SD=-
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3.9 ± 3.5 hours/day, 95% CI=[-4.4, -3.5], P<0.001, n=207) (Figure 1A). Significant and
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sustained reductions in “On” time with dyskinesia (modified UPDRS IV item 32) were
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also observed at last visit (-1.1 ± 4.7, 95% CI=[-1.8, -0.5], P<0.001, n=211) (Figure 1B).
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Additional improvements observed at last visit included UPDRS IV item 33 (dyskinesia
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severity, -0.9 ± 1.3, 95% CI=[-1.1, -0.7], P<0.001, n=188), UPDRS IV item 34
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(dyskinesia-related pain, -0.6 ± 1.2, 95% CI=[-0.8, -0.4], P<0.001, n=187), and UPDRS
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IV item 35 (early morning dystonia, -0.2 ± 0.6, 95% CI=[-0.2, -0.1], P<0.001, n=250).
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UPDRS II and III scores (assessed when “On”, Supplemental Table 3) showed
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significant reductions compared to baseline through 18M (-2.0 ± 9.1, 95% CI=[-3.4, -
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0.5], P=0.007) and 24M (-1.9 ± 11.8, 95% CI=[-3.6, -0.2], P=0.026), respectively. The NMSS total score was significantly reduced from baseline at all study visits
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with a mean change of -14.4 ± 44.8 at last visit (95% CI=[-20.3, -8.5], P<0.001, n=227)
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(Figure 2A). At last visit, 5/9 NMSS domain scores were significantly reduced compared
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to baseline: cardiovascular (last visit: mean change from baseline=-0.6 ± 4.1, 95% CI=[-
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1.1, -0.0], P=0.044), sleep/fatigue (-4.5 ± 10.6, 95% CI=[-5.9, -3.1], P<0.001),
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mood/cognition (-2.8 ± 14.7, 95% CI = [-4.7, -0.9], P=0.004), gastrointestinal tract (-2.2
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± 7.3, 95% CI=[-3.1, -1.2], P<0.001), and miscellaneous (-1.5 ± 9.9, 95% CI=[-2.8, -
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0.2], P=0.022) (Figure 2B and Supplemental Table 3).
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Quality of life, as measured by the PDQ-8, was significantly improved in LCIG-
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treated patients at every study visit (last visit: -5.3 ± 20.7, 95% CI=[-8.2, -2.5], P<0.001,
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n=205) (Figure 2C). Significant improvements were maintained through last visit in three
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PDQ-8 items: item 1 (difficulty getting around in public places, -0.4 ± 1.4, 95% CI=[-0.6,
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-0.2], P<0.001), item 7 (had painful muscle cramps and pain, -0.3 ± 1.4, 95% CI=[-0.5, -
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0.1], P=0.002), and item 8 (felt embarrassed by having PD, -0.5 ± 1.4, 95% CI=[-0.7, -
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0.3], P<0.001) (Supplemental Table 4). Significant improvements were observed in the
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EQ-5D descriptive and VAS scores compared to baseline (18M: EQ-5D, 0.06 ± 0.34,
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95% CI=[0.0, 0.1], P=0.025; last visit: VAS, 11.9 ± 28.3, 95% CI=[7.9, 15.9], P<0.001)
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(Supplemental Table 4).
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Overall, 194 (54.5%, N=356) patients experienced one or more ADRs (Table 2). The most frequently reported ADRs during the PEG-J treatment period were decreased
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weight (6.7%, n=24), device-related infections (5.9%, n=21), device dislocations (4.8%,
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n=17), device issues (4.8%, n=17), and polyneuropathy (4.5%, n=16) (Table 2). Thirty-
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nine percent of patients (n=139/356) reported ≥ 1 GI-related ADR during the PEG-J
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treatment period, of which procedure-related ADRs were reported in 35 patients (9.8%),
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device-related in 93 (26%), and other GI ADRs in 63 (18%). These ADRs were
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generally transient, with the highest prevalence of GI-related ADRs (13.5%) and serious
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GI-related ADRs (4.5%) occurring during the first 2 weeks of LCIG treatment post-PEG-
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J placement (Supplemental Figure 2).
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Serious ADRs occurred in 109 (30.6%) patients and 55 (15.4%) patients had a severe ADR (Table 2). Device dislocation was the most frequently reported serious
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ADR during the PEG-J treatment period (2.2%, n=8). Twenty-five (7.0%) patients
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experienced at least one ADR that led to discontinuation of LCIG treatment and device
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dislocation was the only ADR leading to discontinuation reported by more than 1 patient
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(n=2, 0.6%).
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Twenty-nine deaths (8%, N=356) occurred during the registry period: 23 were deemed unrelated to treatment, 5 possibly related, and 1 probably related (Table 2). Of
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the possibly related deaths, 2 were the result of pneumonia followed by septic shock
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and/or organ failure on treatment days 463 and 452, 1 occurred on treatment day 511
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and was the result of pneumonia followed by a stroke, 1 occurred on treatment day 425
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and was the result of a fatal seizure, and 1 occurred on treatment day 645 and was the
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result of unknown causes following a small bowel obstruction that occurred 3 weeks
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before patient death. The patient death deemed probably related to treatment occurred
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after 646 days of treatment and was the result of a small bowel perforation and
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peritonitis.
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DISCUSSION
This primary analysis of the GLORIA registry represents the largest cohort of advanced PD patients treated with LCIG and provides evidence for the long-term
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effectiveness in reducing motor fluctuations and dyskinesia during routine clinical care.
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In addition, there were improvements in QoL and a variety of non-motor symptoms, and
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the safety profile was overall satisfactory.
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LCIG led to sizable reductions in the amount of time patients spent in the “Off”
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state. On average, patients maintained at least a 50% reduction in “Off” time at every
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study visit. This reduction in “Off” time observed was well above the 1-hour change that
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is deemed clinically relevant [22] and was consistent with other published open-label
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studies and randomized controlled trials on LCIG [9-11]. “Off” time improvements occurred alongside reductions in the proportion of “On”
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time spent with dyskinesia. The average “On” time with dyskinesia was reduced by 25%
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at 24M. Importantly, this was observed despite increased total levodopa equivalent
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dose following the switch from oral levodopa to LCIG and increases in LED over the
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24M follow-up period. This is consistent with literature suggesting that switching to
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continuous levodopa delivery improves not only motor fluctuations but also reduces pre-
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existing dyskinesia [2, 6, 9, 23, 24]. Increases in the daily levodopa dose are common in
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clinical practice when switching from oral PD medications to LCIG and similar
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magnitudes of LED increase have been previously reported [17]. The continuous nature
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of levodopa delivery with LCIG often allows for an increase in LED for optimal motor
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symptom control while limiting many of the undesirable side effects associated with high
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oral levodopa dose. Given that GLORIA was a registry and not a controlled, clinical trial,
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there were no specific requirements for dose optimization prior to LCIG initiation.
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Procedures in this registry reflected the 'real-world' routine clinical setting, where
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treating physicians determined that all oral treatment options had been exhausted and
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LCIG was now indicated.
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however they were only significant through M18 (UPDRS II) while change at M24 in the
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UPDRS III score falls below the minimal clinically important difference threshold. These
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data are similar to those reported in previous studies examining LCIG treatment,
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including Palhagen et al. (2016) [27], and may reflect worsening/progression of the
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disease. It is important to note that QoL remained improved over all time points in a
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stable manner which is consistent with other studies on LCIG [9, 10, 27] Consistent with the interim analysis of this registry [12] and the EuroInf study
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[25], LCIG led to a significant reduction in NMS burden at 24M. NMS domains that
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showed persistent improvement over the entire follow-up period included the
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cardiovascular, sleep/fatigue, mood/cognition, gastrointestinal tract, and
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“miscellaneous” domains. Notably, disturbances in sleep/fatigue, which have a strong
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impact on QoL, showed the greatest magnitude of improvement at 24M, arguing for
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improved sleep quality as motor fluctuations improved [26].
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Given the characteristics of this registry (which included some retrospective data) the safety analyses cannot be directly compared to previous studies, however the most
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frequently reported ADRs were consistent with the established safety profile of LCIG [9-
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11, 28]. Device and procedure-related events were the most frequently reported ADRs
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and were generally transient, occurring at highest prevalence within the first 2 weeks
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post-PEG-J placement. These data emphasize the need for close monitoring in the
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immediate post-PEG-J placement period. Additionally, the GI-related ADRs were
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consistent with the known long-term complications of the PEG-J procedure [29]. Given
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the demographics of the registry population, LCIG procedure and treatment was
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generally well tolerated, with a low rate of discontinuation due to ADR (7.0%) that was
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consistent with previously published reports [10]. Of the 29 deaths that occurred during
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the registry, 5 were deemed possibly related to treatment and 1 was probably related to
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treatment. The determination of possibly related deaths was based upon the
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investigator’s judgment that there was reasonable support for an association between
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the treatment and an event (e.g. pneumonia); however, a causal relationship between
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treatment and death was undetermined. The 1 probably related death, resulting from of
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a fatal small bowel perforation, occurred after 646 days of treatment and underscores
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the invasiveness and inherent risks of chronic PEG-J use in an elderly population.
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Timely investigations of a patient’s abdominal complaints and the involvement of GI
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specialists and interdisciplinary care and management teams may reduce the inherent
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risks of chronic PEG-J use in the elderly.
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This registry provides important clinical data related to the use of LCIG to treat advanced PD patients, however there are some limitations associated with the registry
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design. These limitations include the registry’s open-label design and the lack of a
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control group, which does not allow for comparative efficacy and safety assessments.
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This limitation is particularly relevant in evaluating the significance of LCIG on NMS as a
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recent double-blind randomized study examining the effects of rotigotine and placebo
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on NMS severity in PD patients with severe non-motor disability demonstrated similar
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improvements (>30%) in both the treatment and placebo study groups [30]. Additional
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limitations include the statistical method employed for the efficacy analyses, which did
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not carry the last observation forward, and the partially retrospective nature of data
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collection for 40% of the enrolled patients, which resulted in some missing data during
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the documentation period.
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In conclusion, LCIG treatment in advanced PD patients in routine care led to significant and sustained reductions in motor fluctuations and NMS burden and
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improvements in QoL, despite natural PD progression over the 2-year follow-up. The
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safety results were consistent with the previously established safety profile of LCIG.
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ACKNOWLEDGEMENTS
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This work was funded by AbbVie Inc. AbbVie participated in the study design, research,
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data collection, analysis, and interpretation of data, writing, reviewing, and approving
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the publication. Medical writing support was provided by Amy M. Spiegel of AbbVie, Inc.
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The EDC system used to collect clinical data was provided by Koehler eClinical Ltd.,
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Freiburg, Germany. The statistical analysis was performed by Koehler eClinical, funded
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by AbbVie.
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STUDY FUNDING
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This study was sponsored by AbbVie Inc. (North Chicago, IL, USA), which participated
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in the study design, research, data collection, analysis and interpretation of the data,
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writing, reviewing, and approving the publication.
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AUTHOR CONTRIBUTIONS AND DISCLOSURES
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Dr. Antonini was as a study investigator and has received compensation for consultancy
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and speaker related activities from Acadia, Sunovion, UCB, Boston Scientific, Angelini,
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Medtronic, GE, Boehringer Ingelheim, AbbVie, Zambon. He also received research
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support from Mundipharma. Dr. Antonini’s contributions include study concept and
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design, acquisition and interpretation of the data, and review and critique of the
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manuscript.
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Dr. Poewe was a study investigator and has received compensation from AbbVie, Astra
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Zeneca, Teva, Novartis, GSK, Boehringer-Ingelheim, UCB, Orion Pharma, Zambon and
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Merz Pharmaceuticals (consultancy and lecture fees in relation to clinical drug
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development programmes for PD) outside the submitted work. He has received
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royalties from Thieme, Wiley Blackwell and Oxford University Press. Dr. Poewe’s
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contributions include study concept and design, acquisition and interpretation of the
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data, and review and critique of the manuscript.
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Dr. Chaudhuri was a study investigator and has received honorarium from UCB,
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AbbVie, Britannia, Mundipharma, Boehringer Ingelheim, and GSK Pharmaceuticals for
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lecturing at symposia. He has acted as a consultant for UCB, AbbVie, Britannia,
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Neuronova and Mundipharma. He has received research funding from Parkinson’s UK,
368
NIHR, PDNMG, as well as educational grants from UCB, Britannia, AbbVie, GSK
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Pharmaceuticals, Boehringer Ingelheim, and Neuronova. Dr. Chaudhuri receives
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royalties from Oxford University Press and holds intellectual property rights for the Kings
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Parkinson’s Pain Scale and Parkinson’s Disease Sleep Scale 2. Dr. Chaudhuri’s
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contributions include acquisition and interpretation of the data, and review and critique
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of the manuscript.
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Dr. Jech was a study investigator and received honoraria from AbbVie, Medtronic,
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Ipsen, Allergan, Cardion for consultancies and lectures. Dr. Jech’s contributions include
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acquisition and interpretation of the data, and review and critique of the manuscript.
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Dr. Pickut was a study investigator and has received compensation from AbbVie, GSK,
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St. Jude Medical, and Teva for advisory boards, consultancy and speaker-related
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activities, and research support from Novartis. Dr. Pickut’s contributions include
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acquisition of the data, and review and critique of the manuscript.
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Dr. Pirtosek was a study investigator and has received compensation from AbbVie for
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speaker related activities. Dr. Pirtosek’s contributions include acquisition and
386
interpretation of the data, and review and critique of the manuscript.
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ACCEPTED MANUSCRIPT Antonini, Poewe, et al.
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Dr. Szasz was a study investigator and received compensation from AbbVie, Novartis,
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UCB, Boehringer-Ingelheim, GSK, Ever, Lundbeck, Teva, Pfizer for speaker activities.
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Dr. Szasz’s contributions include acquisition and interpretation of the data, and review
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and critique of the manuscript.
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Dr. Valldeoriola was a study investigator and received honoraria from AbbVie,
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Medtronic, Boston Scientific, UCB Pharma and Italfármaco for professional advice and
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lectures. Dr. Valldeoriola’s contributions include acquisition and interpretation of the
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data, and review and critique of the manuscript.
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Dr. Winkler was a study investigator and has participated in advisory boards for AbbVie,
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UCB, and BIAL, and has received lecture fees from AbbVie, LicherMT, and BIAL. Dr.
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Winkler’s contributions include acquisition and interpretation of the data, and review and
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critique of the manuscript.
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Dr. Bergmann is an employee of AbbVie and holds AbbVie stock and/or stock options.
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Dr. Bergmann’s contributions include acquisition and interpretation of the data, and
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review and critique of the manuscript.
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Dr. Yegin is a former employee of AbbVie. Dr. Yegin’s contributions include acquisition
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and interpretation of the data, and review and critique of the manuscript.
409
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Dr. Onuk is an employee of AbbVie and holds AbbVie stock and/or stock options. Dr.
411
Onuk’s contributions include acquisition and interpretation of the data, and review and
412
critique of the manuscript.
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Dr. Barch is an employee of AbbVie and holds AbbVie stock and/or stock options. Dr.
415
Barch’s contributions include interpretation of the data and review and critique of the
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manuscript.
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Dr. Odin was a study investigator and has received compensations for consultancy and
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speaker related activities from AbbVie, Britannia, Boehringer-Ingelheim, Nordic
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Infucare, UCB and Zambon. PO has received royalties from Uni-Med Verlag.Dr. Odin’s
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contributions include study concept and design, acquisition and interpretation of the
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data, and review and critique of the manuscript.
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CO-INVESTIGATOR APPENDIX
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The authors would like to acknowledge the following non-author, GLORIA study investigators for their contributions: Ene Amalia, University Emergency Hospital,
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Bucharest, Romania; Guy Arnold, Sindelfingen Hospital, Department of Neurology,
429
Sindelfingen, Germany; Ovidiu Bajenaru, University Department of Clinical
430
Neurosciences, University of Medicine and Pharmacy "Carol Davila", Bucharest,
431
Romania; Bruno Bergmans, AZ St-Jan Brugge-Oostende AV, Brugge, Belgium; Kari
432
Anne Bjornara, Drammen Hospital, Drammen, Norway; Jeff Blackie, John Hunter
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Hospital , Newcastle, Australia; Matthias Bode, Odense University Hospital, Odense,
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Denmark; Paul Bourgeois, Department of Neurology AZ Groeninge, Kortrijk, Belgium;
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Stephan Bohlhalter, Neurology and Neurorehabilitation Center, Luzern, Switzerland;
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Ioan Buraga, Colentina Hospital, Bucharest, Romania; Pierre R. Burkhard, Geneva
437
University Hospitals, Geneva, Switzerland; Philippe Busson, Centre Hospitalier
438
Avranches Granvilles, Avranches, France; Matilde Calopa, Neurology Service. Hospital
439
Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalonia, Spain; Jesper Clausen,
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Rigshospitalet/Glostup, Denmark; Erik Hvid Danielsen, Dept of Neurology, Aarhus
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University Hospital , Aarhus, Denmark; Luc Defebvre, Movement Disorder Department,
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Parkinson’s disease Expert Center, Université of Lille, Lille, France;Valerie Delvaux,
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University of Liege, Belgium; Sophie Dethy, chu-Tivoli, La Louviere, Belgium; Espen
444
Dietrichs, Dept of Neurology, Oslo University Hospital and University of Oslo, Oslo,
445
Norway; Oriol De Fabregues, Vall d'Hebron University Hospital, Autonomous University
446
of Barcelona, Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Ransmayr
447
Gerhard, Dept. of Neurology 2, Kepler University Hospital, Linz, Austria; Graziano
448
Gusmaroli, SC Neurologia - Ospedale degli Infermi di Biella, Biella, Italy; Kirsten Hahn,
449
Practice Dr. Hahn, Berlin, Germany; Björn Hauptmann, Neurologisches Zentrum, Bad
450
Segeberg, Germany; Tove Henriksen, University Hospital of Bispebjerg, Copenhagen,
451
Denmark; Jorge Hernandez-Vara, Neurology Department, Hospital Universitari Vall
452
D´Hebron, Barcelona, Spain; A. Jeanjean, Université catholique de Louvain, Louvain-la-
453
Neuve, Belgium; Michaela Kaiserova, Department of Neurology, Faculty of Medicine
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and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic;
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Jan Kassubek, Department of Neurology, University of Ulm, Ulm, Germany; Thomas
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Kimber, Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia;
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Spyridon Konitsiotis, Department of Neurology, Faculty of Medicine, University of
458
Ioannina, Greece; Rejko Krüger, Luxembourg Centre for Systems Biomedicine,
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University of Luxembourg, and Centre Hospitalier de Luxembourg, Luxembourg; and
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Centre for Neurology, University of Tübingen, Germany, Esch-sur-Alzette, Luxembourg
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and Tübingen, Germany; Jaime Kulisevsky, Sant Pau Hospital, Barcelona, Spain; Jo
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Leenders, Sint-Dimpa Ziekenhuis, Geel, Belgium; Christofer Lundqvist, Akershus
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University Hospital and University of Oslo, Oslo, Norway; F. Ory Magne, Toulouse
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University hospital, France; Pietro Marano, Nuova Casa di Cura D'Anna, Palemro, Italy;
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Ivan Milanov, University Neurological Hospital "St. Naum", Sofia, Bulgaria; Nicola
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Modugno, IRCCS Neuromed, Pozzilli (IS), Italy; Anjum Misbahuddin, Essex Centre for
467
Neurological Sciences, Romford, UK; Martin Nevrly, Department of Neurology,
468
University Hospital and Faculty of Medicine and Dentistry of Palacky University ,
469
Olomouc, Czech Republic; Zikos Panayiotis, 251 Hellenic Air Force Hospital, Athens
470
Greece; Kenn Freddy Pedersen, Neurology department, Stavanger University Hospital,
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Stavanger, Norway; Stephen W. Pedersen, Department of neurology Glostrup hospital
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University of Copenhagen, Glostrup, Denmark; Lacramioara Perju-Dumbrava,
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University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj-Napoca, Cluj-Napoca,
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Romania; M.M. Ponsen, Meander Medical Center, Amersfoort, Netherlands; Bogdan O.
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Popescu, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania;
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Michel Rijntjes, Department of Neurology, University Clinic Freiburg, Freiburg,
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Germany; V. Puente, Neurology Department, Institut Hospital del Mar d’Investigacions
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Mediques, Universitat Autonoma de Barcelona, Hospital del Mar, Barcelona, Spain;
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Christoph Redecker, Department of Neurology, Jena University Hospital, Jena,
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Germany; Christoph Schrader, Hannover Medical School, Hannover, Germany;
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Mariachiara Sensi, Neurology Department Arcispedale S.Anna, Ferrara, Italy; Mihaela
482
Simu, UMF"Victor Babes”, Timisoara, Romania; Cleanthe Spanaki, University Of Crete,
483
School Of Medicine, Neurology Department, Iraklio, Greece; Alexander Storch,
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University of Rostock, Rostock, Germany; Anette Storstein, Haukeland University
485
Hospital, Bergen, Norway; Volker Tomantschger, Gailtal-Klinik Hermagor,
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Hermagor,Austria; Chris van der Linden, Department of Neurology, St. Lucas Hospital
487
Ghent, Ghent, Belgium; T. van Laar, University Medical Center Groningen, Groningen,
488
Netherlands; F. Viallet, Service de Neurologie, CH du pays d'Aix, Aix en Provence,
489
France; Tatiana Witjas, University Hospital Timone, Marseille, France; Martin Wolz,
490
Elblandklinikum Meissen , Meissen, Germany; Maurizio Zibetti, Department of
491
Neuroscience, University of Torino, Torino, Italy; Michel Van Zandijcke, AZ Sint-Jan
492
Brugge, Brugge, Belgium.
493
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[30] A. Antonini, L. Bauer, E. Dohin, W. H. Oertel, O. Rascol, H. Reichmann, M. Schmid,
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Figure Legends
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Figure 1. Motor symptom efficacy. Mean change from baseline of daily hours of A.
631
"Off" time (modified UPDRS Part IV Items 39) and B. "On" time with dyskinesia
632
(modified UPDRS Part IV Item 32). Error bars indicate SD. Asterisks indicate statistical
633
significance compared to baseline in a paired t test at the P<0.01 (**) and P<0.001 (***)
634
levels. UPDRS = Unified Parkinson's Disease Rating Scale; BL = baseline; D1 =
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discharge from hospital post-PEG-J placement; M = month; LV = patient’s last reported
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study visit.
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Figure 2. Non-motor symptom efficacy. Mean change from baseline in A. NMSS total
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score, B. NMSS domain scores over 2-year follow-up, and C. PDQ-8 total score. Error
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bars indicate SD. NMSS = Non-Motor Symptom Scale, PDQ-8 = Parkinson’s Disease
641
Questionnaire 8-item, BL = baseline; D1 = discharge from hospital post-PEG-J
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placement; M = month; LV = patient’s last reported study visit. P<0.05 (*), P<0.01 (**),
643
and P<0.001 (***)
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ACCEPTED MANUSCRIPT
Table 1. Baseline demographics and disease characteristics
Characteristic
Value 66.4 ± 8.8
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Age, years, mean ± SD Sex, n (%) Male
220 (58.7)
Female
155 (41.3)
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LCIG History, n (%) LCIG-naïve
Baseline LED, mg/day, mean ± SD PD duration, years, mean ± SD Hoehn & Yahr, mean ± SD During “On”
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During “Off”
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LCIG ≤ 12M before enrollment
225 (60) 150 (40) 1319 ± 617 12.7 ± 6.3
2.8 ± 0.8 4.0 ± 0.9
UPDRS Part IV, hours/day, mean ± SD Modified item 39: “Off” time
6.0 ± 3.2
Modified item 32: Time with dyskinesia
4.3 ± 3.8 16.5 ± 9.8
UPDRS Part III (motor examination), mean ± SD
24.6 ± 12.0
NMSS, total score, mean ± SD
69.2 ± 42.1
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UPDRS Part II (activities of daily living), mean ± SD
PDQ-8 Total Score (quality of life), mean ± SD
46.8 ± 18.6
EQ-5D score, mean ± SD
0.4 ± 0.32
EQ-VAS score, mean ± SD
48.0 ± 21.3
PD medications reported at baseline, n (%) Levodopa
367 (97.9)
Dopamine agonists
253 (67.5)
COMT inhibitors
212 (56.5)
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MAO-B inhibitors
133 (35.5)
Amantadine
102 (27.2)
Other oral
50 (13.3)
AC C
EP
TE D
M AN U
SC
RI PT
LCIG = levodopa-carbidopa intestinal gel, LED = levodopa equivalent dose, PD = Parkinson’s disease, UPDRS = Unified Parkinson’s Disease Rating Scale, NMSS = Non-motor symptom scale,PDQ-8 = Parkinson’s Disease Questionnaire 8-item, EQ-5D = Euro Quality of Life 5 Dimensions, EQ-VAS = Euro Quality of Life Visual Analog Scale, COMT = catechol-Omethyltransferase, MAO-B = monoamine oxidase
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Table 2. Safety Summarya
n (% of N=356)
Patients with at least one ADR
194 (55)
Patients with at least one GI-related ADR Patients with at least one serious ADR
SC
55 (15)
Deaths
ADRs occurring in ≥ 3% of patients Weight decreased Device related infection Device dislocation
Polyneuropathy Device lead issue
TE D
Device issue
M AN U
Unrelated to treatment
Probably related to treatment
139 (39) 109 (31)
Patients with at least one severe ADR
Possibly related to treatment
RI PT
Safety
29 (8.1) 23 (6.5) 5 (1.4) 1 (0.3)
24 (6.7) 21 (5.9) 17 (4.8) 17 (4.8) 16 (4.5) 14 (3.9) 13 (3.7)
Abdominal pain
13 (3.7)
Hallucination
EP
Medical device complication
12 (3.4)
AC C
Serious ADRs occurring in ≥ 1% of patientsb Device dislocation
8 (2.2)
Device issue
7 (2.0)
Parkinson’s disease
7 (2.0)
Parkinsonism
7 (2.0)
Medical device complication
6 (1.7)
Device malfunction
5 (1.4)
Device occlusion
5 (1.4)
Abdominal pain
4 (1.1)
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Hallucination
4 (1.1)
Pneumonia
4 (1.1)
Polyneuropathy
4 (1.1)
AC C
EP
TE D
M AN U
SC
RI PT
Gastrointestinal and gastrointestinal procedure-related ADRs are italicized. a Data indicates incidence of ADRs b During 24 months of LCIG infusion via PEG-J ADR = adverse drug reaction (adverse events with a possible/probable relationship to the treatment drug or device), GI = gastrointestinal, LCIG = levodopa-carbidopa intestinal gel, PEGJ = percutaneous endoscopic gastrojejunostomy
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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Highlights:
EP
TE D
M AN U
SC
RI PT
Long-term registry of LCIG treatment in patients with advanced Parkinson’s disease LCIG was delivered over 24 months in a routine clinical care setting LCIG treatment reduced “Off” time and dyskinesia time over 2 years LCIG treatment improved non-motor symptoms and quality of life over 2 years Adverse drug reactions were consistent with the established safety profile of LCIG
AC C
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