Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding AbbVie.
Pregabalin is a novel compound that has been shown to have efficacy in the treatment of generalised anxiety disorder and is licensed for the treatment of the disorder in the European Union.
The ...current study was designed to evaluate the safety and efficacy of pregabalin, an alpha(2)delta-ligand, in the treatment of generalised anxiety disorder in people 65 years and older.
This was a double-blind, randomised (2:1), placebo-controlled, 8-week trial of pregabalin, in flexible doses of 150-600 mg/day, in the treatment of DSM-IV generalised anxiety disorder with a baseline Hamilton Rating Scale for Anxiety (HRSA) total score >/=20. The primary outcome was end-point (week 8 or last visit, with last observation carried forward (LOCF)) change in HRSA total score.
A total of 273 patients (women, 78%; mean age, 72 years (s.d.=6); mean baseline HRSA total score, 26 (s.d.=4.6)) were randomised and received study treatment. On the primary intent-to-treat LOCF analysis, pregabalin was associated with a 2-point greater reduction in HRSA total score than placebo (12.87 v. 10.7; P<0.05). In a post hoc repeated measures mixed-effect model analysis, pregabalin was associated with significantly greater improvement than placebo in the HRSA total score from week 2 (-9.8 (s.d.=0.6) v. -7.2 (s.d.=0.8); P=0.0052) through week 8 (-14.4 (s.d.=0.6) v. -11.6 (s.d.=0.8); P=0.0070). Significant improvement was observed in the pregabalin group on both the HRSA psychic and somatic anxiety factors. There was a significantly greater decrease from baseline in mean Hamilton Rating Scale for Depression (HRSD) score with pregabalin compared with placebo (-5.48 (s.d.=0.46) v. -4.02 (s.d.=0.59); P=0.041). Pregabalin was well-tolerated, with almost all adverse events in the mild-to-moderate range, and self-limiting (median duration of 4-16 days). Discontinuations due to adverse events were similar for pregabalin (10.7%) and placebo (9.4%).
Pregabalin, in doses of 150-600 mg/day, was a safe and effective treatment of generalised anxiety disorder in patients 65 years and older. The anxiolytic efficacy of pregabalin had an early onset (by 2 weeks) and significantly improved both psychic and somatic symptoms of anxiety.
Motor complications of Parkinson’s disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa–carbidopa intestinal gel (LCIG) is infused ...continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-
O
-methyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for ≥30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total levodopa and carbidopa doses were 1,580 (403) and 395 (101) mg, respectively. Mean (SD)
C
avg
(μg/mL) were 2.9 (0.84) for levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation defined as (
C
max
−
C
min
)/
C
avg
in levodopa, 3-OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2–16 of infusion. Accordingly, the within-subject coefficients of variation in levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported ≥1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.
Levodopa-carbidopa intestinal gel (LCIG) is delivered continuously via intrajejunal percutaneous gastrostomy tube.
To examine long-term safety, efficacy and quality of life of LCIG in an open-label ...extension study.
Patients received 52 weeks of open-label LCIG treatment following a 12-week double-blind, double-dummy trial in which they were randomized to either LCIG or immediate-release oral levodopa-carbidopa. Patient cohort designation was by receipt of LCIG in the preceding trial randomization (continuing-LCIG vs. LCIG-naïve patients).
Sixty-two of 66 subjects in the double-blind proceeded to the open-label extension. Most subjects (95%) reported ≥1 adverse event (AE); only 3 subjects (4.8%) discontinued due to AEs. AE incidence declined gradually over 52 weeks. Serious AEs were reported by 23%. LCIG-naïve patients (N = 29) showed a decrease in "Off" time and an increase in "On" time without troublesome dyskinesia (change from baseline to final visit in mean SD hours = -2.34 2.78 P < 0.001 and 2.19 3.70 P = 0.005, respectively), while continuing-LCIG patients (N = 33) showed sustained "Off" time duration and further improvement in "On" time without troublesome dyskinesia (-0.42 2.67 P = 0.377 and 1.00 2.58 P = 0.036, respectively). The majority of patients in both groups (LCIG-naïve, continuing-LCIG, respectively) were rated 'Much Improved' or 'Very Much Improved' at final visit on the Clinical Global Impression-Improvement scale (69.0%, 69.7%).
Continuing-LCIG patients continued to derive benefit from LCIG while the magnitude of improvement among LCIG-naïve patients was similar to that observed for patients on LCIG in the preceding double-blind study. The overall AE profile was consistent with previous phase 3 clinical trials involving the LCIG system.
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.
Abstract Background: Esreboxetine is an investigational, highly selective norepinephrine reuptake inhibitor that has been reported to have antinociceptive effects in preclinical pain models. ...Objective: This study assessed the efficacy and safety profile of esreboxetine in the management of fibromyalgia. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial in patients aged ≥18 years who met American College of Rheumatology criteria for fibromyalgia. Eligible patients were required to have a score ≥40 mm on the 100-mm visual analog scale of the Short-Form McGill Pain Questionnaire at screening and randomization, and a mean score ≥4 on an 11-point pain rating scale (from 0 = no pain to 10 = worst possible pain) based on the weekly mean pain score in the week before randomization. After a 1-week baseline period and a 2-week, single-blind, placebo run-in period, patients were randomized to receive esreboxetine or placebo for 8 weeks, followed by a 1-week follow-up period. Esreboxetine dosing was started at 2 mg/d and was escalated by 2 mg/d every 2 weeks until attainment of a dose of 8 mg/d or the maximum tolerated dose. The primary efficacy outcome was the change from baseline to week 8 in weekly mean pain scores, as derived from patients' daily pain ratings on the 11-point scale. Additional primary efficacy outcomes included changes in the Fibromyalgia Impact Questionnaire (FIQ) total score and the Patient Global Impression of Change (PGIC). The safety profile was evaluated based on observed and spontaneously reported adverse events, laboratory tests, and other safety measures. Results: One hundred thirty-four patients were randomized to each study group, but 1 patient in the placebo group did not receive treatment. Thus, the study population consisted of 267 patients (89.5% female; 88.4% white; mean age, ∼50 years range, 20–84 years). Twenty-seven patients in each group discontinued the study. Adverse events were the most common reason for discontinuation in the esreboxetine group (11 patients), compared with 3 discontinuing due to adverse events in the placebo group. Patient default (withdrawal of consent and loss to follow-up) was the most common reason for discontinuation in the placebo group (13 patients), compared with 10 in the esreboxetine group. The esreboxetine group had significantly greater improvement in the weekly mean pain score compared with the placebo group (mean SE change from baseline: −1.55 0.16 vs −0.99 0.16, respectively; P = 0.006). A significantly greater percentage of patients in the esreboxetine group reported a ≥30% reduction in pain scores compared with the placebo group (37.6% 50/133 vs 22.6% 30/133; P = 0.004). Esreboxetine was associated with significant improvement compared with placebo in the FIQ total score (mean change from baseline: −15.63 1.56 vs −8.07 1.54; P < 0.001). On the PGIC, significantly more patients in the esreboxetine group than in the placebo group reported their condition much or very much improved (odds ratio = 2.42; 90% CI, 1.549-3.786; P < 0.001). Esreboxetine also was associated with significant improvements in secondary outcomes compared with placebo. These included fatigue, as reflected in scores on the Multidimensional Assessment of Fatigue (mean SE change from baseline: −6.39 0.75 vs −2.82 0.75, respectively; P < 0.001), and scores on measures of patient function and health-related quality of life, including the 36-item Short Form Health Survey (SF-36) Physical Component Summary (mean change from baseline: 4.36 0.59 vs 1.86 0.59; P = 0.002), the SF-36 Mental Component Summary (mean change from baseline: 4.25 0.83 vs 1.81 0.83; P = 0.019), and the Sheehan Disability Scale total score (mean change from baseline: −6.50 0.64 vs −2.79 0.61; P < 0.001). Numerically more patients in the esreboxetine group than in the placebo group reported at least one adverse event (71.6% vs 57.1%), most commonly constipation (17.2% vs 5.3%), insomnia (15.7% vs 3.0%), dry mouth (15.7% vs 2.3%), and headache (10.4% vs 2.3%). Conclusions: In this 8-week trial in patients with fibromyalgia, esreboxetine was associated with significant reductions in pain scores compared with placebo. It was also associated with improvements in outcomes relevant to fibromyalgia, including the PGIC, function, and fatigue. ClinicalTrials.gov identifier: NCT00357825.
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