A double‐blind,placebo‐controlled study of prucalopride in elderly patients with chronic constipation

Background Constipation affects up to 50% of the elderly; this study evaluates the efficacy, safety, and tolerability of the selective 5‐HT₄ agonist prucalopride in chronically constipated elderly patients. Methods Three hundred chronic constipation patients aged ≥65 years were randomized to prucalopride (1, 2, or 4 mg once daily) or placebo for 4 weeks. The primary endpoint was the percentage of patients with ≥3 spontaneous complete bowel movements (SCBM) per week. Secondary endpoints included the percentage with an increase of ≥1 SCBM per week, BM frequency, constipation‐related symptoms, quality of life (QoL), safety, and tolerability. Key Results More patients achieved ≥3 SCBM per week with prucalopride than with placebo. This difference was largest and significant during the first week of 4 mg prucalopride (P ≤ 0.05). Significantly more patients in each prucalopride group achieved an increase of ≥1 SCBM per week from baseline vs placebo (e.g. 60% with 1 mg prucalopride vs 34% with placebo at week 4; P ≤ 0.05). More patients had improvement in PAC‐QOL satisfaction score of ≥1 with 1 mg prucalopride than with placebo (P ≤ 0.05); the same was true for PAC‐SYM stool symptoms (1 and 4 mg prucalopride; P ≤ 0.05). Treatment‐emergent adverse events were similar between groups: the most frequently reported with prucalopride were headache and gastrointestinal events. There were no clinically significant differences between prucalopride and placebo for vital signs, laboratory assessments, or ECG variables. Conclusions & Inferences Prucalopride, in the dose‐range tested (1–4 mg once daily), has beneficial effects on bowel movements, symptoms, and QoL, and is safe and well‐tolerated in elderly patients with chronic constipation.     

A randomized,placebo‐ and active‐controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder

Vieta E, Nuamah IF, Lim P, Yuen EC, Palumbo JM, Hough DW, Berwaerts J. A randomized, placebo‐ and active‐controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder.
Bipolar Disord 2010: 12: 230–243. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: To evaluate the antimanic efficacy and safety of paliperidone extended‐release (ER) tablets in patients with bipolar I disorder. Methods: This study included a 3‐week, double‐blind, acute treatment phase (paliperidone ER versus placebo, with quetiapine as control), and a 9‐week, double‐blind, maintenance phase (paliperidone ER versus quetiapine). Patients [n = 493; Young Mania Rating Scale (YMRS) score ≥ 20] were randomized (2:2:1) to flexibly dosed paliperidone ER (3–12 mg/day), quetiapine (400–800 mg/day), or placebo for the acute treatment phase. During the maintenance phase, patients assigned to placebo were switched to paliperidone ER but not included in analysis of efficacy. Results: Paliperidone ER was superior to placebo at the 3‐week endpoint {primary outcome; least‐squares mean difference in change from baseline in YMRS scores [95% confidence interval (CI)]: ?5.5 (?7.57; ?3.35); p < 0.001} and noninferior to quetiapine at the 12‐week endpoint [least‐squares mean difference (95% CI): 1.7 (?0.47; 3.96)]. The median mode dose during the 12‐week treatment period was 9 mg for paliperidone ER and 600 mg for quetiapine. The most common (≥ 10%) treatment‐emergent adverse events during the 12‐week period were: headache (16%), somnolence (10%), and akathisia (10%) for paliperidone ER; somnolence (21%), sedation and dry mouth (17% each), headache (14%), and dizziness (13%) for quetiapine. Body weight increase ≥ 7% from baseline to 12‐week endpoint was 8% with paliperidone ER and 17% with quetiapine. A higher percentage of paliperidone ER (13.9%) versus quetiapine patients (7.5%) ‘switched to depression’ at the12‐week endpoint. Conclusions: Paliperidone ER (3–12 mg/day) was efficacious and tolerable in the treatment of acute mania.     

Effects of treatment cessation and re-treatment in randomized controlled trials of prucalopride in patients with chronic idiopathic constipation

Background

Prucalopride is a selective, high-affinity serotonin type 4 receptor agonist approved for the treatment of chronic idiopathic constipation (CIC) in adults. We investigated the impact of prucalopride cessation and re-treatment on efficacy and safety.

Methods

Data were from two randomized controlled trials in adults with CIC. In a dose-finding trial, complete spontaneous bowel movements (CSBMs) and treatment-emergent adverse events (TEAEs) were assessed during a 4-week run-out period after a 4-week treatment period (TP; prucalopride 0.5–4 mg once daily or placebo). In a re-treatment trial, CSBMs and TEAEs were assessed during two 4-week TPs (prucalopride 4 mg once daily or placebo) separated by a 2- or 4-week washout period.

Key Results

In the dose-finding trial (N = 234; 43–48 patients/group), mean CSBMs/week and the proportion of responders (≥3 CSBMs/week) were higher with prucalopride than placebo during the TP, but similar in all groups 1–4 weeks after treatment cessation. TEAEs were less frequent following treatment cessation. In the re-treatment trial (efficacy analyses: prucalopride, n = 189; placebo, n = 205), the proportion of responders was similar in both TPs and significantly higher (p ≤ 0.001) with prucalopride (TP1, 38.6%; TP2, 36.0%) than placebo (TP1, 10.7%; TP2, 11.2%). Most patients who responded to prucalopride in TP1 responded again in TP2 (71.2%). TEAEs were less frequent in TP2 than TP1.

Conclusions and Inferences

Prucalopride cessation resulted in a loss of clinical effect to baseline levels within 7 days. Similar efficacy and safety were observed between TP1 and TP2 after prucalopride was re-initiated following a washout period.     

Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized,placebo‐controlled study

Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society     

A mixture of Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of the irritable bowel syndrome – A randomized controlled trial with primary care physicians

Abstract Therapy trials with bacterial compounds in irritable bowel syndrome (IBS) have produced conflicting results. This study was performed in 1988 and 1989, and was re‐analysed according to current IBS standards. Two hundred ninety‐seven patients with lower abdominal symptoms diagnosed as IBS were treated for 8 weeks by the compound ProSymbioflor^® (Symbiopharm GmbH, Herborn, Germany), an autolysate of cells and cell fragments of Enterococcus faecalis and Escherichia coli, or placebo in a double‐blinded, randomized fashion. Patients were seen weekly by the physician, who assessed the presence of core IBS symptoms. Responders had at least a 50% decrease in global symptom score (GSS) and in abdominal pain score (APS) reports at ≥1 visit during treatment. The responder rate in GSS to the drug was 102/149 (68.5%) in comparison to placebo with 56/148 (37.8%) (P < 0.001), the improvement in APS was 108/149 (72.5%) and 66/148 (44.6%) respectively (P = 0.001). The number‐needed‐to‐treat was 3.27 for GSS and 3.59 for the APS report. Kaplan–Meier analysis revealed a mean response time of 4–5 weeks for active treatment and more than 8 weeks for placebo (P < 0.0001). Treatment of IBS with the bacterial lysate ProSymbioflor is effective and superior to placebo in reducing typical symptoms of IBS patients seen by general practitioners.     

Randomized,double‐blind,pilot evaluation of intravenous glutathione in Parkinson's disease

The objective of this study was to evaluate the safety, tolerability, and preliminary efficacy of intravenous glutathione in Parkinson's disease (PD) patients. This was a randomized, placebo‐controlled, double‐blind, pilot trial in subjects with PD whose motor symptoms were not adequately controlled with their current medication regimen. Subjects were randomly assigned to receive intravenous glutathione 1,400 mg or placebo administered three times a week for 4 weeks. Twenty‐one subjects were randomly assigned, 11 to glutathione and 10 to placebo. One subject who was assigned to glutathione withdrew from the study for personal reasons prior to undergoing any postrandomization efficacy assessments. Glutathione was well tolerated and there were no withdrawals because of adverse events in either group. Reported adverse events were similar in the two groups. There were no significant differences in changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores. Over the 4 weeks of study medication administration, UPDRS ADL + motor scores improved by a mean of 2.8 units more in the glutathione group (P = 0.32), and over the subsequent 8 weeks worsened by a mean of 3.5 units more in the glutathione group (P = 0.54). Glutathione was well tolerated and no safety concerns were identified. Preliminary efficacy data suggest the possibility of a mild symptomatic effect, but this remains to be evaluated in a larger study. © 2009 Movement Disorder Society     

Macrogol for the treatment of constipation in Parkinson's disease. A randomized placebo‐controlled study

Chronic constipation is the most frequent symptom of autonomic system involvement in Parkinson's disease (PD). Quite often the symptom is severe and impairs patients' quality of life. The objective of this study is to determine the efficacy and safety of an isosmotic macrogol solution for the treatment of constipation in PD patients, in a double‐blind, placebo‐controlled study. A total of 57 PD patients with constipation were randomly assigned to receive an isosmotic macrogol electrolyte solution (MC‐ES; 29 patients) or placebo (28 patients) for 8 weeks. Treatment efficacy was defined as complete relief of the symptom or a marked improvement of two of the following indicators: stool frequency, straining, stool consistency, use of rectal laxatives as a rescue therapy. The responder rates were significantly higher in the MC‐ES group both at the first (4 weeks; P < 0.0003) and at the final evaluation (8 weeks; P < 0.0012). The frequency of bowel movements (P < 0.002) and stool consistency (P < 0.006) were significantly changed in the MC‐ES group compared to the placebo group. At the final evaluation, a rectal laxative was used by 2 (12.5%) patients on placebo, whereas no use was recorded in the MC‐ES group. Responder rate for straining showed a favorable trend in patients treated with macrogol versus placebo. Unified Parkinson's Disease Rating Scale Part III and Parkinson's Disease Questionnaire (PDQ‐39) did not show any significant modification in either group during the 8‐week treatment period. The results of this placebo‐controlled study show the efficacy of MC‐ES in the treatment of constipation in PD. MC‐ES was well‐tolerated and did not affect the course of PD. © 2006 Movement Disorder Society     

Placebo‐controlled,double‐blind dose‐finding study of entacapone in fluctuating parkinsonian patients

We conducted a multicenter randomized, placebo‐controlled double‐blind parallel‐group study in Japanese Parkinson's disease (PD) patients with wearing‐off motor fluctuations to determine the clinical efficacy and safety of entacapone as an adjunct to concomitant treatment with levodopa and a dopa decarboxylase inhibitor (DCI). We randomized 341 patients to receive entacapone 100 or 200 mg or placebo per dose of levodopa/DCI for 8 weeks. The primary efficacy variable was on time change while awake, determined by patients' diaries. Mean baseline on time in each group was approximately 8 hours. Mean on time change at final assessment was 1.4 hours each for entacapone 100‐mg and 200‐mg groups and by 0.5 hours for the placebo group (P < 0.05). The two entacapone doses were equally efficacious. Adverse events occurred in 79 patients (69.9%) in placebo, 82 (72.6%) in 100 mg, and 98 (86.0%) in 200 mg. The most common adverse event with entacapone was an increase in dyskinesias. The overall safety profile was satisfactory in both entacapone groups. In conclusion, both entacapone 100 and 200 mg were equally effective in increasing on time of PD patients with wearing‐off fluctuations, although the safety and tolerability profile appeared more favorable for the 100‐mg dose. © 2006 Movement Disorder Society     

Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week,randomized, placebo‐controlled study

Objective: To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. Methods: A randomized, double‐blind, 30‐week, placebo‐controlled study of aripiprazole (10 or 30 mg/day) in youths (10–17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double‐blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. Results: Of the 210 subjects who entered the 26‐week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol‐specified last observation carried forward analyses, but not in observed case or mixed‐model repeated measures at week 30. Overall time to all‐cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children’s Global Assessment of Functioning and Clinical Global Impressions‐Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. Conclusions: Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.     

3,4‐Diaminopyridine is more effective than placebo in a randomized,double‐blind,cross‐over drug study in LEMS

The purpose of this study was to investigate the clinical and electrophysiological efficacy of 3,4‐diaminopyridine (DAP) in patients with Lambert–Eaton myasthenic syndrome (LEMS) in a randomized, double‐blind, cross‐over drug trial. The diagnosis of LEMS was made based on the combination of fluctuating muscle weakness, diminished or absent reflexes, and more than 60% increment of the compound muscle action potential (CMAP) amplitude after brief exercise or 50‐HZ stimulation on a repetitive nerve stimulation (RNS) test. Evaluations were done at baseline, with placebo, and with 3,4‐DAP (up to 75–80 mg/day). Assignment of placebo or 3,4‐DAP was done in a double‐blinded manner. Measurements included subjective symptoms score, objective clinical measurements [LEMS classification, muscle strength score, quantitative myasthenia gravis (QMG) score] and RNS test and single‐fiber electromyography (SFEMG). The differences between placebo and baseline values (placebo change) were compared with the differences between 3,4‐DAP and baseline or placebo values (DAP change). Seven patients with LEMS (QMG score >9) participated in the study. One patient had major side‐effects with 3,4‐DAP and withdrew from the study. Statistically significant efficacy was noted with DAP change (N = 13) compared with placebo change (N = 7) according to the subjective symptoms score (P = 0.01), LEMS classification (P < 0.001), muscle strength score (P < 0.006), QMG score (P = 0.02), and CMAP (P = 0.03). For long‐term treatment, 2 patients preferred 3,4‐DAP, 1 chose guanidine hydrochloride, 1 preferred pyridostigmine, and 2 chose no treatment. A randomized, double‐blind, cross‐over drug trial of 3,4‐DAP showed significant efficacy over placebo in patients with LEMS. As a long‐term treatment, however, not all patients preferred this drug. Muscle Nerve, 2009     

Multicenter,randomized, double‐blind,active comparator and placebo‐controlled trial of a corticotropin‐releasing factor receptor‐1 antagonist in generalized anxiety disorder

Background: Antagonism of corticotropin‐releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF‐1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double‐blind, placebo‐controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half‐powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2‐2016) with the HAM‐A psychic subscale score for the entire cohort at baseline (FDR‐adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

Long‐term safety and efficacy of levodopa‐carbidopa intestinal gel in advanced Parkinson's disease

Background: Levodopa‐carbidopa intestinal gel (designated as carbidopa‐levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long‐term safety and efficacy outcomes from an open‐label phase 3 treatment program. Methods: PD patients (n = 262) who completed a 12‐week double‐blind study and its 52‐week open‐label extension or a separate 54‐week open‐label study were enrolled in this ongoing phase 3 open‐label, multinational study (NCT00660673). Safety and efficacy assessments were collected every 6 months. Results: Mean total duration of exposure to levodopa‐carbidopa intestinal gel was 4.1 years (range, 1.2 to 6.9 years). The overall discontinuation rate was 34% (average annual discontinuation rate, 10%). Although most patients (94%) reported an adverse event, the rate of adverse events decreased over time; 53% experienced a serious adverse event. Of patients in this extension study, 54% required jejunal tube replacement during the study, and 37% required percutaneous endoscopic gastrostomy tube replacement. Most patients were on levodopa monotherapy. Patients maintained reductions in “off” time and increases in mean “on” time without dyskinesia from initial levodopa‐carbidopa intestinal gel infusion to he study end point (P < 0.001; n = 81). Activities of daily living and quality‐of‐life assessments demonstrated significant improvements that persisted through the study. Conclusions: This long‐term study demonstrates sustained and clinically meaningful benefits from levodopa‐carbidopa intestinal gel in advanced PD patients. Although adverse event rates decreased over time, vigilance is required for device‐related complications and adverse events. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society     

A placebo‐controlled trial of the 5‐HT1A agonist R‐137696 on symptoms,visceral hypersensitivity and on impaired accommodation in functional dyspepsia

Abstract Acute studies suggested a therapeutic benefit for fundus‐relaxing drugs in functional dyspepsia (FD) with visceral hypersensitivity (VH) to gastric distention or impaired accommodation (IA), but long‐term studies are lacking. R‐137696 is a serotonin‐1A (5‐HT_1A) receptor agonist which relaxes the proximal stomach in man. Our aim was to investigate the influence of R‐137696 on symptoms in FD with VH or IA. Randomized, double‐blind, placebo‐controlled, parallel group study of 4 weeks R‐137696 2 mg t.i.d. in FD with VH or IA. Symptoms were assessed using the patient assessment of upper gastrointestinal symptom severity index (PAGI‐SYM) total score and individual symptom subscales. Barostat studies were performed before and after 4 weeks of treatment. Fifty‐three patients (33 VH and 20 IA), 18 men, mean age 40 ± 13 years were recruited. Twenty‐four received placebo and 29 received R‐137696. In VH patients, both placebo and R‐137696 improved total symptom scores, with a tendency for superiority of placebo (?1.12 vs?0.51, P = 0.07). Placebo was superior for the subscales of early satiety, bloating, fullness and discomfort (all P < 0.05). In IA, both placebo and R‐137696 had no significant influence on total or individual symptom scores (?0.08 and ?0.27). In VH, both placebo and R‐137696 increased the discomfort volume, without a statistical difference between both arms (+120 and +164 mL). In IA, both placebo and R‐137696 enhanced accommodation, without a statistical difference between both (+77 and +159 mL). Adverse events were similar for drug and placebo. A 4‐week administration of the fundus‐relaxing 5‐HT_1A agonist R‐137696 failed to significantly improve symptoms, VH or gastric accommodation compared to placebo.     

Randomized,placebo‐controlled trial of incobotulinumtoxina for upper‐limb post‐stroke spasticity

Introduction: Efficacy and safety of incobotulinumtoxinA in post‐stroke upper‐limb spasticity were studied. Methods: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non‐primary patterns were flexible within predefined ranges. Results: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least‐squares mean change ± standard error: –0.9 ± 0.06 (n = 171) vs. –0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1‐point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. Conclusions: IncobotulinumtoxinA significantly improved upper‐limb spasticity and associated disability, and was well‐tolerated. Muscle Nerve 53: 415–421, 2016     

Trial of dextromethorphan/quinidine to treat levodopa‐induced dyskinesia in Parkinson's disease

Background : Nondopaminergic pathways represent potential targets to treat levodopa‐induced dyskinesia in Parkinson's disease (PD). This pilot‐study (NCT01767129) examined the safety/efficacy of the sigma‐1 receptor‐agonist and glutamatergic/monoaminergic modulator, dextromethorphan plus quinidine (to inhibit rapid dextromethorphan metabolism), for treating levodopa‐induced dyskinesia. Methods : PD patients were randomized to dextromethorphan/quinidine (45 mg/10 mg twice daily)/placebo in two 2‐week double‐blind, crossover treatment periods, with intervening 2‐week washout. After 14 days, a 2‐hour intravenous levodopa‐infusion was administered. Patient examinations were videotaped before infusion (“off” state) and every 30 minutes during and afterwards until patients returned to “off.” The primary endpoint was dyskinesia‐severity during infusion measured by Unified Dyskinesia Rating Scale part 3 area‐under‐curve scores (blinded expert rated). Additional endpoints included other dyskinesia/motor assessments, global measures of clinical‐change, and adverse‐events. Results : A total of 13 patients were randomized and completed the study (efficacy‐evaluable population). Dyskinesia‐severity was nonsignificantly lower with dextromethorphan/quinidine than placebo during infusion (area‐under‐curve 966.5 vs 1048.8; P = .191 [efficacy‐evaluable patients]), and significantly lower in a post‐hoc sensitivity analysis of the per‐protocol‐population (efficacy‐evaluable patients with ≥ 80% study‐drug‐compliance, n = 12) when measured from infusion start to 4‐hours post–infusion completion (area‐under‐curve 1585.0 vs 1911.3; P = .024). Mean peak dyskinesia decreased significantly from infusion‐start to return to “off” (13.3 vs 14.9; P = .018 [efficacy‐evaluable patients]). A total of 9 patients rated dyskinesia “much/very much improved” on dextromethorphan/quinidine versus 1‐patient on placebo. Dextromethorphan/quinidine did not worsen PD‐motor scores, was generally well tolerated, and was associated with more frequent adverse events. Conclusion : This study provides preliminary evidence of clinical benefit with dextromethorphan/quinidine for treating levodopa‐induced dyskinesia in PD. Larger studies with a longer treatment duration need to corroborate these early findings. © 2017 International Parkinson and Movement Disorder Society     

A randomized,double‐blind,placebo controlled,multi‐center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome

Iron deficiency may exacerbate symptoms in the Restless Legs Syndrome (RLS). We investigated the effect of intravenous iron sucrose or placebo on symptoms in patients with RLS and mild to moderate iron deficit. Sixty patients with primary RLS (seven males, age 46 (9) years, S‐ferritin ≤45 μg/L) recruited from a cohort of 231 patients were randomly assigned in a 12‐months double‐blind, multi‐centre study of iron sucrose 1000 mg (n = 29) or saline (n = 31). The primary efficacy variable was the RLS severity scale (IRLS) score at week 11. Median IRLS score decreased from 24 to 7 (week 11) after iron sucrose and from 26 to 17 after placebo (P = 0.123, N.S. for between treatment comparison). The corresponding scores at week 7 were 12 and 20 in the two groups (P = 0.017). Drop out rate because of lack of efficacy at 12 months was 19/31 after placebo and 5/29 patients after iron sucrose (Kaplan–Meier estimate, log rank test P = 0.0006) suggesting an iron induced superior long term RLS symptom control. Iron sucrose was well tolerated. This study showed a lack of superiority of iron sucrose at 11 weeks but found evidence that iron sucrose reduced RLS symptoms both in the acute phase (7 weeks) and during long‐term follow up in patients with variable degree of iron deficiency. Further studies on target patient groups, dosing and dosing intervals are warranted before iron sucrose could be considered for treatment of iron deficient patients with RLS. © 2009 Movement Disorder Society     

Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized,placebo‐controlled and dose‐finding study

Background Lubiprostone is a prostone analog with a novel mechanism of action involving type‐2 chloride channel activation. The aim of this work was to perform a dose‐finding study for lubiprostone for the treatment of constipation with or without irritable bowel syndrome (IBS) in Japan. Methods A total of 170 patients (128 without IBS and 42 with IBS) with chronic idiopathic constipation (CIC) randomly received a placebo (n = 42) or 16 μg (n = 41), 32 μg (n = 43), or 48 μg (n = 44) of lubiprostone daily for 2 weeks. Key Results There was a statistically significant and dose‐dependent increase in change from baseline in the weekly average number of spontaneous bowel movements at week 1 (placebo: 1.5 ± 0.4; 16 μg: 2.3 ± 0.4, 32 μg: 3.5 ± 0.5; and 48 μg: 6.8 ± 1.1, per week, mean ± SE; P < 0.0001). These primary endpoint results were significant on stratified analysis when patients were limited to those without IBS (P < 0.0001). The primary endpoint in patients with IBS treated with 48 μg of lubiprostone was significantly better than those given placebo (P = 0.0086). Dose dependency was also seen for the secondary efficacy endpoints. Lubiprostone produced no serious side effects. Conclusions & Inferences Our results suggest that lubiprostone produced a steady and effective improvement in the symptoms of CIC with or without IBS in a dose‐dependent manner with a good safety profile and tolerability in a Japanese population.     

3,4‐diaminopyridine base effectively treats the weakness of Lambert‐Eaton myasthenia

Introduction: 3,4‐diaminopyridine has been used to treat Lambert‐Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. Methods: We conducted a randomized double‐blind placebo‐controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4‐diaminopyridine base (3,4‐DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in triple timed up‐and‐go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self‐assessment of LEM–related weakness (W‐SAS). Results: Thirty‐two participants were randomized to continuous 3,4‐DAP or placebo groups. None of the 14 participants who received continuous 3,4‐DAP had > 30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P < 0.0001). W‐SAS similarly demonstrated an advantage for continuous treatment over placebo (P < 0.0001). Requirement for rescue and adverse events were more common in the placebo group. Discussion: This trial provides significant evidence of efficacy of 3,4‐DAP in the maintenance of strength in LEM. Muscle Nerve 57 : 561–568, 2018     

Clinical Evaluation of the Daily Assessment of Symptoms‐Anxiety (DAS‐A): A New Instrument to Assess the Onset of Symptomatic Improvement in Generalized Anxiety Disorder

Introduction: Rapid onset of symptomatic improvement is a desirable characteristic of new generalized anxiety disorder (GAD) treatments. A validated rating scale is needed to assess GAD symptoms during the first days of treatment. Aims: To provide clinical data to support the validation of the Daily Assessment of Symptoms‐Anxiety (DAS‐A), a new instrument to assess onset of symptomatic improvement in GAD. Methods: We assessed the ability of the DAS‐A to detect onset of symptomatic improvement during the first week of therapy in 169 GAD patients randomized to paroxetine 20 mg/day, lorazepam 4.5 mg/day, or placebo for 4 weeks. Results: On the primary outcome measure, average change from baseline over the first 6 days of DAS‐A assessments, lorazepam (?14.5 ± 1.8 [LS mean, SE]; P= 0.006 vs. placebo) showed a significant improvement versus placebo (?7.85 ± 1.7), whereas paroxetine (?8.3 ± 1.7; P= 0.83 vs. placebo) did not. Lorazepam produced a significant treatment effect on the DAS‐A at 24 h (P= 0.0004), whereas paroxetine did not (P= 0.5666). Both active drugs produced statistically significant improvement versus placebo on the DAS‐A total change score (last‐observation carried forward method; LOCF, endpoint). On the DAS‐A total change score (observed cases analysis), lorazepam produced statistically significant improvement versus placebo at weeks 1, 2, and 4 (P < 0.05; no week 3 visit), whereas paroxetine, separated from placebo at weeks 2 and 4 (P < 0.05). Both active drugs produced results on the Hamilton Anxiety Rating Scale (HAM‐A) at weeks 1 through 4 that were similar to those found on the DAS‐A. Conclusions: These data indicate that the DAS‐A can detect symptomatic improvement in GAD patients treated with lorazepam during the first week of treatment, and, in a secondary analysis, as early as 24 h.     

Pregabalin in the treatment of post‐traumatic peripheral neuropathic pain: a randomized double‐blind trial

Background: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post‐traumatic peripheral neuropathic pain (including post‐surgical). Methods: Patients with a pain score ≥4 (0–10 scale) were randomized and treated with either flexible‐dose pregabalin 150–600 mg/day (n = 127) or placebo (n = 127) in an 8‐week double‐blind treatment period preceded by a 2‐week placebo run‐in. Results: Pregabalin was associated with a significantly greater improvement in the mean end‐point pain score vs. placebo; mean treatment difference was ?0.62 (95% CI ?1.09 to ?0.15) (P = 0.01). The average pregabalin dose at end‐point was ～326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain‐related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all‐patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end‐point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. Conclusion: Flexible‐dose pregabalin 150–600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post‐traumatic peripheral neuropathic pain.