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Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994. From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4·04 h (SE 0·65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2·14 h (0·66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference −1·91 h [95% CI −3·05 to −0·76]; p=0·0015). Mean on-time without troublesome dyskinesia increased by 4·11 h (SE 0·75) in the intestinal gel group and 2·24 h (0·76) in the immediate-release oral group (difference 1·86 [95% CI 0·56 to 3·17]; p=0·0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study. AbbVie.

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (−2·75 [0·50] vs −0·96 [0·49] h; difference −1·79 h, −3·03 to −0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild–moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. AbbVie.

Background. Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa administration and clinical benefits to patients with advanced Parkinson’s disease (PD). This report evaluates long-term safety and efficacy of high-dose LCIG in PD patients. Methods. Data were collected from several prospective, phase III clinical studies and an observational registry. The phase III program (N = 412) included four multicenter studies: a 12-week, randomized, double-blind study and three open-label studies extending ≥12 months. GLORIA (N = 375) was a 24-month, multicountry, observational registry. LCIG safety (adverse effects (AEs)/adverse drug reactions (ADRs)) and efficacy (modified Unified Parkinson’s Disease Rating Scale (UPDRS) part IV item 32 and 39 scores for “On” time with dyskinesia and “Off” time) were assessed in patients who received ≥2000 mg/day vs <2000 mg/day LCIG. Results. A total of 72 of 412 (17.5%) patients required dosages ≥2000 mg/day LCIG in the phase III program and 47 of 375 (12.5%) patients in GLORIA. Baseline demographics and disease severity were similar between dosage groups with more men in the high-dosage group. Compared with the <2000 mg/day dosage group, patients requiring ≥2000 mg/day LCIG had higher rates of AEs/ADRs including polyneuropathy; improvements in “Off” time and discontinuations due to AEs were similar between dosage groups and lower for discontinuations due to ADRs reported in GLORIA. Conclusions. Patients who require ≥2000 mg/day LCIG exhibited a safety profile comparable to the established safety/tolerability of LCIG with similar clinical improvements. Higher AEs were noted but within what is accepted for LCIG. Continuous administration of LCIG is beneficial to advanced PD patients who require very high doses of levodopa.

Background. Nonmotor symptoms (NMS) are common in advanced Parkinson’s disease (APD) and reduce health-related quality of life. Objective. The aim of the study was to evaluate levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) on NMS in APD. Methods. INSIGHTS was a phase 3b, open-label, randomized, multicenter study in patients with APD (LCIG or OMT, 26 weeks) (NCT02549092). Primary outcomes assessed were total NMS (NMS scale (NMSS) and PD sleep scale (PDSS-2)). Key secondary outcomes included the Unified PD Rating Scale (UPDRS) Part II, Clinical Global Impression of Change (CGI-C), and PD Questionnaire-8 (PDQ-8). Additional secondary measures of Patient Global Impression of Change (PGIC), King’s PD Pain Scale (KPPS), and Parkinson Anxiety Scale (PAS) also were evaluated. Finally, safety was assessed. Results. Out of 89 patients randomized, 87 were included in the analysis (LCIG, n = 43; OMT, n = 44). There were no significant differences in NMSS or PDSS-2 total score changes (baseline to Week 26) between LCIG and OMT; within-group changes were significant for NMSS (LCIG, p<0.001; OMT, p=0.005) and PDSS-2 (LCIG, p<0.001; OMT, p<0.001). Between-group treatment differences were nominally significant for UPDRS Part II (p=0.006) and CGI-C (p<0.001) at Week 26 in favor of LCIG; however, statistical significance could not be claimed in light of primary efficacy outcomes. PGIC (Week 26) and KPPS (Week 12) scores were nominally significantly reduced with LCIG versus OMT (p<0.001; p<0.05). There were no significant differences in PDQ-8 or PAS. Adverse events (AEs) were mostly mild to moderate; common serious AEs were pneumoperitoneum (n = 2) and stoma-site infection (n = 2) (LCIG). Conclusions. There were no significant differences between LCIG versus OMT in NMSS or PDSS-2; both LCIG and OMT groups significantly improved from baseline. AEs were consistent with the known safety profile.

Objectives: Levodopa-carbidopa intestinal gel (LCIG) was developed to reduce motor complications in Parkinson’s disease (PD) caused by pulsatile levodopa plasma concentrations following oral levodopa administration. Dyskinesia and ‘wearing off’ symptoms can vary between Asian and Caucasian patients with PD, thus highlighting the importance of assessing the effectiveness of LCIG in an Asian population. Efficacy and safety of LCIG were previously assessed in a 12-week open-label study; we report the efficacy and safety of at least 52 weeks of LCIG treatment in Japanese, Taiwanese, and Korean patients with advanced PD in the ongoing extension study. Methods: In this interim analysis of a phase III, open-label, multicenter extension study in Japan, South Korea, and Taiwan [ClinicalTrials.gov identifier: NCT02082249/JapiCTI-142482], the mean change from baseline to final visit in ‘off’ time, as reported in the PD symptom diary, was normalized to a 16-h waking day. Changes in Parkinson’s Disease Questionnaire-39 (PDQ-39) summary index and domains scores were also analyzed. Adverse events (AEs) were recorded. Results: Of the 28 patients enrolled (21 Japanese, 3 Taiwanese, 4 Korean), 27 completed at least 52 total weeks of treatment, and 25 patients were continuing in the study at data cutoff. The mean [standard deviation (SD)] ‘off’ time was significantly reduced by 4.6 (3.1) h/day (p < 0.001, n = 28). Patients experienced significant improvements in quality of life, as recorded by the mean change from baseline in PDQ-39 summary index (p < 0.001). All patients had at least one AE; three patients (11%) discontinued due to an AE. There were two deaths (sepsis and drowning), both of which the investigator considered unrelated to LCIG treatment. Conclusions: These data suggest that LCIG treatment is efficacious, safe, and well tolerated in Japanese, Taiwanese, and Korean patients with advanced PD, thus confirming the consistency of LCIG treatment in patients with advanced PD.

Levodopa-carbidopa intestinal gel (LCIG, carbidopa-levodopa enteral suspension in the United States) is a treatment option for advanced Parkinson’s disease (PD) patients with motor fluctuations. The objective of this investigation was to identify the baseline characteristics predictive of treatment response, measured by improvement in motor symptom severity, in advanced PD patients treated with LCIG during a 54-week, open-label phase 3 study. Patients with ≥1 h improvement from baseline in “Off” time were categorized as “Responders”; whereas those with <1 h improvement, any worsening, or no post-baseline assessment were “Non-Responders”. A subgroup of Responders with ≥3 h improvement in “Off” time was also examined; this subgroup was identified as “Robust Responders”. Baseline demographics and disease characteristics were analyzed and their predictive relationship to change from baseline in normalized “Off” time was assessed. Out of the 324 patients included in the analysis, 272 (84.0%) were categorized as Responders and 52 (16.0%) were Non-Responders. A majority of patients (65.7%) had ≥3 h improvement in “Off” time. In general, baseline characteristics were similar between Non-responders, Responders, and the subgroup of Robust Responders. A conditional tree-structured regression analysis identified baseline “Off” time as the only factor that had significant effect on Responder and Robust Responder status. The safety profile of LCIG was similar between patient groups. Overall, this analysis showed that 84% of LCIG-treated advanced PD patients had ≥1 h improvement in “Off” time and the number-needed-to-treat to observe one patient responder was 1.19 patients. Notably, Responders and Robust Responders to LCIG were observed across the range of baseline demographics and clinical characteristics examined.

In a previous multinational, randomized, double-blind, double-dummy study, levodopa–carbidopa intestinal gel (LCIG) was tolerable and significantly improved ‘off’ time in advanced Parkinson’s disease (PD) patients. However, efficacy and safety in the Asian population has not yet been demonstrated. In this open-label study, efficacy and safety of LCIG were assessed in Japanese, Korean, and Taiwanese advanced PD patients with motor complications not adequately controlled by available PD medication. The patients were treated with LCIG monotherapy for 12 weeks. The primary end point was the mean change from baseline to week 12 in ‘off’ time, as reported in the PD Symptom Diary, normalized to a 16 h waking day and analyzed by a mixed-model repeated-measures analysis. Adverse events (AEs) were recorded. Thirty-one patients were enrolled (23 Japanese, 4 Taiwanese, 4 Korean) and 28 (90%) completed the study. For those who completed the study, the mean (s.d.) total daily levodopa dose from LCIG was 1,206.3 (493.6) mg/day at final visit ( n =28); last observation carried forward ( n =30) was 1,227.6 (482.8) mg/day. There was a significant mean change (s.d.) of −4.6 (3.0) hours of ‘off’ time from baseline (mean (s.d.)=7.4 (2.3)) to week 12 ( n =29), P <0.001. All the patients had an AE, with the most frequently reported being incision site pain (42%); 1 (3.2%) discontinued treatment because of an AE and later died because of sepsis, which the investigator considered unrelated to LCIG treatment. These results suggest that LCIG is efficacious and tolerable in Japanese, Taiwanese, and Korean advanced PD patients. Drug delivery: Intestinal gel proves effective in Asian population Continous intestinal administration of Parkinson’s disease drugs in a gel formulation is effective and tolerable in Asian patients. Previous studies have demonstrated the efficacy and safety of levodopa-carbidopa intestinal gel (LCIG) in primarily Caucasian patients with advanced PD. Because Asian patients develop dyskinesias more frequently than Caucasians and require lower doses of levodopa to control PD symptoms, Miho Murata at the National Center of Neurology and Psychiatry in Tokyo and colleagues investigated the effects of LCIG in 31 patients from Japan, Korea and Taiwan. After a 12 week treatment course they found significant improvements in motor symptoms and in quality of life. Despite the high incidence of adverse effects, the discontinuation rate was low suggesting that LCIG is tolerable in Asian patients with advanced PD.

INTRODUCTION:Levodopa-carbidopa intestinal gel (LCIG, carbidopa-levodopa enteral suspension [CLES] in the US) administered via percutaneous gastrojejunostomy (PEG), a jejunal (J) extension tube and an external pump is a long-term treatment option for patients with advanced Parkinson’s disease (aPD). Limited data exists on PEG-J component utilization and replacements during LCIG treatment in a ‘real-world’ setting. This interim analysis investigated the routine clinical practice of PEG-J insertion and component replacements of the device and associated safety.METHODS:DUOGLOBE is an ongoing multinational observational study with 3-year follow-up. This interim analysis included patients who had the PEG-J insertion procedure from 55 global sites. The type of tubing used, frequency of and reasons for tube replacements, and Serious Adverse Events (SAEs) were assessed. This analysis was not powered for statistical comparisons.RESULTS:This interim dataset had 188 patients with PEG-J tube placement (mean duration of PEG-J exposure: 515.8 days); 178 patients with PEG-J tubing manufacturer data were included in this analysis. At initial PEG-J tube placement, 83% (n = 148) of patients received AbbVie-proprietary tubing and 17% (n = 30) received non-AbbVie tubing. Most patients 79% (n = 141) did not require a PEG-J replacement. Patients needing any PEG-J replacement was similar between AbbVie and non-AbbVie tubing (22% and 17%); 5% of patients (n/N = 7/148) with AbbVie tubing required 2 PEG-J replacements (n/N = 0/30 for non-AbbVie tubing). In the first 12 months, Kaplan-Meier estimates demonstrated that 84% of patients did not require a tube replacement with AbbVie tubing (non-AbbVie tubing, 89%). The most common reasons for the first PEG-J replacement for AbbVie tubing was a routine, preplanned procedure (6%), PEG-J dislocation (4%), occlusion and leaking (each 2%), and other (5%); for non-AbbVie tubing PEG-J dislocation (10%) was the only reported reason. Overall, 38% of patients experienced an SAE who had AbbVie tubing (n = 56) and 47% for non-AbbVie tubing (n = 14). Gastrointestinal (GI)-related SAEs were reported in patients [n(%)] with AbbVie tubing [8(5%)] and non-AbbVie tubing [6(20%)]; 1 (1%) and 2 (7%) patients discontinued due to a GI-related AE, respectively.CONCLUSION:This interim analysis of patients in a multinational observational study with LCIG demonstrated that most patients did not require PEG-J tube replacements in a real-world setting and safety was similar to the known safety profile of LCIG.

To determine if age and Parkinson's disease duration at therapy initiation influence the efficacy of levodopa-carbidopa intestinal gel (LCIG) on quality of life and activities of daily living. This analysis assessed subgroups of patients stratified by baseline age, disease duration, hours/day of 'off' time and levodopa equivalent dose. Patients' data were collected from the GLORIA study, a 24-month observational registry evaluating long-term effectiveness of LCIG. LCIG therapy led to sustained improvements in quality of life irrespective of patient age and disease duration at baseline. Improvements in activities of daily living were observed across all subgroups, particularly in younger patients, patients with shorter disease duration and in patients with the highest baseline levodopa equivalent dose.

Background Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer’s dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25–75 mg) and an open-label extension study (75 mg). Methods The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10–24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD ( n  = 77), ABT-126 50 mg QD ( n  = 108), ABT-126 75 mg QD ( n  = 73), donepezil 10 mg QD ( n  = 76), or placebo ( n  = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale—Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies. Results A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (−2.29 ± 0.95; one-sided P  = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, −0.47 ± 0.94 ( P  = 0.309); ABT-126 50 mg, −0.87 ± 0.85 ( P  = 0.153); and ABT-126 75 mg, −1.08 ± 0.94 ( P  = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters. Conclusions In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies. Trial registration ClinicalTrials.gov NCT01527916 , Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935 . Registered 29 August 2012 (open-label extension study).