Prucalopride in the treatment of chronic constipation in patients from the Asia‐Pacific region: a randomized,double‐blind,placebo‐controlled study

Background The study evaluated efficacy and safety of the 2 mg dose of prucalopride compared to placebo in patients with chronic constipation (CC) from the Asia‐Pacific region. Methods Randomized, placebo‐controlled, parallel‐group, phase III study with 2‐week run‐in, 12‐week treatment phase, and 1‐week follow‐up. Adult patients with CC (≤2 spontaneous bowel movements per week) received 2 mg prucalopride or placebo, once‐daily, for 12 weeks. Primary efficacy measure was percentage of patients with average of ≥3 spontaneous complete bowel movements (SCBMs) per week (Responders) during the 12‐week treatment. A key secondary endpoint was Responders during first 4 weeks of treatment. Other efficacy assessments were based on patient diaries, their assessments of symptoms and quality of life, and investigator’s assessment on efficacy of treatment. Safety assessments included adverse events, laboratory values, and cardiovascular events. Key Results Efficacy and safety were evaluated for 501 patients who received study drug. On the primary endpoint, prucalopride was significantly more effective than placebo with 83 (33.3%) vs 26 (10.3%) patients having a weekly average of ≥3 SCBMs during the 12‐week treatment (P < 0.001). Respective percentages were 34.5%vs 11.1% over first 4 weeks (P < 0.001). On other secondary endpoints, clinical improvement was generally larger and statistically superior (P < 0.001) in the prucalopride group. Most frequently reported adverse events were diarrhea, nausea, abdominal pain, and headache. Conclusion & Inferences Prucalopride 2 mg given once‐daily significantly improved bowel function, associated symptoms, and satisfaction in CC over a 12‐week treatment period, and was safe and well tolerated by patients in the Asia‐Pacific region.     

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.     

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.     

Psychometric performance and clinical meaningfulness of the Patient Assessment of Constipation – Quality of Life questionnaire in prucalopride (RESOLOR®) trials for chronic constipation

Background The Patient Assessment of Constipation–Quality of Life (PAC‐QOL) is a self‐reported questionnaire measuring health‐related quality of life (HRQL) of constipated patients and was used as secondary endpoint in three identical double‐blind, randomized, placebo‐controlled Phase III clinical trials. These 12‐week trials in subjects with severe chronic constipation evaluated the effects of prucalopride, a selective 5‐HT₄ agonist given orally once daily. Methods To consolidate the main treatment effect results observed in the prucalopride trial populations, analyses were undertaken on the pooled data of the three trials to confirm the psychometric properties of the PAC‐QOL and to provide guidance for the interpretation of the clinical significance of its scores. Key Results The evaluation of the psychometric properties confirmed the PAC‐QOL reliability, validity and responsiveness to measure the impact of chronic constipation symptoms on HRQL in the prucalopride trials. The 1‐point improvement in PAC‐QOL scores used as target response level for the main treatment effect analyses was validated as a relevant definition of response for treatment group comparisons. Cumulative distribution curves, drawn for each treatment group to provide more complete information on treatment effects than single minimal important difference point estimates, demonstrated consistent superior effects of prucalopride over placebo on all PAC‐QOL scores. Conclusions & Inferences The PAC‐QOL questionnaire is a useful measurement tool to assess, from a patient perspective, the potential therapeutic value of chronic constipation treatments in clinical trials and, by directly reflecting the patient’s own perspective on constipation and its treatment, eventually also for informing daily medical practice.     

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     

Plecanatide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: Post hoc analyses of placebo-controlled trials in adults with severe constipation

Background

Patients with chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) often experience severe symptoms. The current aim was to evaluate plecanatide in adults with CIC or IBS-C with severe constipation.

Methods

Data were analyzed post hoc from randomized, placebo-controlled trials (CIC [n = 2], IBS-C [n = 2]) of plecanatide 3 mg, 6 mg, or placebo administered for 12 weeks. Severe constipation was defined as no complete spontaneous bowel movements (CSBMs) and an average straining score ≥3.0 (CIC; 5-point scale) or ≥8.0 (IBS-C; 11-point scale) during a 2-week screening. Primary efficacy endpoints were durable overall CSBM responders (CIC: ≥3 CSBMs/week, plus increase from baseline of ≥1 CSBM/week, for ≥9 of 12 weeks, including ≥3 of the last 4 weeks) and overall responders (IBS-C: ≥30% reduction from baseline in abdominal pain and ≥1 CSBM/week increase for ≥6 of 12 weeks).

Key Results

Severe constipation was observed in 24.5% (646/2639) and 24.2% (527/2176) of CIC and IBS-C populations, respectively. The CIC durable overall CSBM response rate (plecanatide 3 mg, 20.9%; plecanatide 6 mg, 20.2%; placebo, 11.3%) and IBS-C overall response rate (plecanatide 3 mg, 33.0%; plecanatide 6 mg, 31.0%; placebo, 19.0%) were significantly greater with plecanatide versus placebo (p ≤ 0.01 for all). Median time to first CSBM in CIC and IBS-C populations were significantly shorter with plecanatide 3 mg versus placebo (p = 0.01 for both).

Conclusions and Inferences

Plecanatide was effective in the treatment of severe constipation in adults with CIC or IBS-C.     

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     

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.     

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     

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.     

Influence of 5‐HT4 receptor activation on acetylcholine release in human large intestine with endometriosis

Background The 5‐HT₄ receptor agonist prucalopride enhances large intestinal contractility by facilitating acetylcholine release through activation of 5‐HT₄ receptors on cholinergic nerves and is effective in patients with constipation. Patients with intestinal endometriosis can present with constipation. We investigated in vitro whether large intestinal endometriotic infiltration influences contractility and facilitation of acetylcholine release by prucalopride. Methods Sigmoid colon or rectum circular muscle strips were obtained at the level of an endometriotic nodule with infiltration of the Auerbach plexus, and at a macroscopically healthy site at least 5 cm cranially from the nodule, in patients undergoing laparoscopic colorectal resection because of symptomatic bowel endometriosis. Responses to muscarinic receptor stimulation and to electrical field stimulation (EFS), and the facilitating effect of prucalopride on acetylcholine release were evaluated. Key results The EC50 and E_max of the contractile responses to the muscarinic receptor agonist carbachol did not differ between healthy and lesioned strips. EFS‐induced on‐contractions were not different between the healthy and lesioned strips, while the non‐nitrergic relaxant responses induced by EFS were decreased in the lesioned strips. The facilitating effect of prucalopride on acetylcholine release in healthy strips was similar to that reported before in macroscopically healthy colon tissue of patients with colon cancer; in lesioned strips, the effect of prucalopride was fully maintained in 6/8 patients and absent in two. Conclusions & inferences Large intestinal endometriosis does not lead to a systematic interference with the cholinergic facilitating effect of prucalopride.     

Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia in Japan: A 6‐week,randomized, double‐blind,placebo‐controlled study

Aim

This study aimed to evaluate the efficacy, safety, and tolerability of brexpiprazole compared to placebo in Japanese patients with acute schizophrenia (SCZ).

Methods

We conducted a 6‐week, multicenter, double‐blind, placebo‐controlled, phase 2/3 study in Japan. Patients with acute SCZ were randomized (1:1:1:1) to receive brexpiprazole 1 mg, 2 mg, 4 mg, or placebo once a day. The primary endpoint was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total scores.

Results

In the 459 patients that were randomized, brexpiprazole 2 mg showed a significant improvement versus placebo (treatment difference: ?7.32, P = 0.0124), although brexpiprazole 4 mg showed numerical improvements (treatment difference: ?3.86, P = 0.1959), and brexpiprazole 1 mg showed only minimal change (treatment difference: ?0.63, P = 0.8330). Treatment‐emergent adverse events with an incidence of ≥5% and ≥2 times the rate of placebo in the brexpiprazole groups were vomiting, elevated blood prolactin, diarrhea, nausea, and dental caries. Most treatment‐emergent adverse events were mild or moderate in severity. There were no clinically significant changes in electrocardiogram parameters, bodyweight, laboratory values, or vital signs in the brexpiprazole groups.

Conclusion

Brexpiprazole was efficacious and well tolerated in Japanese adult patients with acute SCZ.

     

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.     

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     

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.     

A randomized,double‐blind,placebo‐controlled,parallel‐group,enriched‐design study of nabiximols* (Sativex®), as add‐on therapy,in subjects with refractory spasticity caused by multiple sclerosis

Background: Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo‐controlled study of an oral antispasticity agent to use an enriched study design. Methods: A 19‐week follow‐up, multicentre, double‐blind, randomized, placebo‐controlled, parallel‐group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add‐on therapy, in a single‐blind manner for 4 weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12‐week randomized, placebo‐controlled phase. Results: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4 weeks of single‐blind treatment, and 241 were randomized. The primary end‐point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention‐to‐treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P = 0.0002). Secondary end‐points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols. Conclusions: The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.     

Efficacy and safety of perampanel in generalized and focal to bilateral tonic‐clonic seizures: A comparative study of Asian and non‐Asian populations

Perampanel is an approved adjunctive treatment for focal seizures with or without focal to bilateral tonic‐clonic (FBTC) seizures and generalized tonic‐clonic (GTC) seizures. We compared efficacy and safety of perampanel vs placebo in Asian and non‐Asian populations in a post hoc analysis of pooled data from 5 randomized phase 3 studies. Patients (≥12 years old) with focal + FBTC seizures received perampanel 2, 4, 8, or 12 mg or placebo; patients with GTC seizures received perampanel 8 mg or placebo (titration: 4‐6 weeks; maintenance: 13 weeks). Efficacy endpoints included median percentage change in FBTC or GTC seizure frequency per 28 days and 50% responder rate relative to baseline. Median percentage change in FBTC seizure frequency was significantly greater for perampanel 8 and 12 mg than placebo in the Asian population (median difference from placebo: ?30.32%, P = 0.0017; ?30.06%, P = 0.0008, respectively) and perampanel 4, 8, and 12 mg in the non‐Asian population (?35.07%, P = 0.0001; ?37.78%, P < 0.0001; ?34.53%, P < 0.0001, respectively). In both populations, median percentage change in GTC seizure frequency was significantly greater for perampanel 8 mg than placebo (median difference from placebo: Asian, ?37.37%, P = 0.0139; non‐Asian, ?27.04%, P = 0.0006). The 50% responder rates were significantly greater than placebo for perampanel 8 and 12 mg for FBTC seizures (Asian: 58.0%, P = 0.0017 and 58.6%, P = 0.0013, respectively; non‐Asian: 59.3%, P < 0.0001 and 54.3%, P = 0.0050, respectively) and perampanel 8 mg for GTC seizures (Asian: 57.6%, P = 0.0209; non‐Asian: 68.8%, P = 0.0329). Pooled FBTC/GTC seizure data showed generally similar patterns of response to perampanel in both populations. The most frequent treatment‐related adverse events were fatigue, irritability, dizziness, somnolence, and headache. Perampanel was effective, well tolerated, and can be considered a therapeutic option for FBTC/GTC seizures in Asian populations.     

Long‐term safety and effectiveness of brexpiprazole in Japanese patients with schizophrenia: A 52‐week,open‐label study

Aim

This study assessed the long‐term safety, tolerability, and maintenance of the therapeutic effect of brexpiprazole in Japanese patients with schizophrenia.

Methods

This 52‐week, open‐label, flexible‐dose (1–4 mg/day) study included patients with schizophrenia who continued treatment from a short‐term randomized placebo‐controlled fixed‐dose (1, 2, or 4 mg/day) trial and de novo patients who switched from other antipsychotics.

Results

A total of 282 patients (184 de novo and 98 rolled over from short‐term trial) entered the 52‐week treatment with brexpiprazole, and 150 (53.2%) patients completed the week‐52 assessment. Treatment‐emergent adverse events (TEAE) were experienced by 235/281 patients (83.6%), and TEAE reported by ≥10% of all patients were nasopharyngitis (23.1%) and worsening of schizophrenia (22.4%). During the study, most of the TEAE were mild or moderate in severity, and there were no deaths, and no clinically meaningful mean changes in laboratory values, vital signs, or electrocardiogram parameters. Mean scores for the Positive and Negative Syndrome Scale total and Clinical Global Impression–Severity remained stable until week 52.

Conclusion

Brexpiprazole was generally safe and well tolerated and maintained therapeutic effects in the long‐term treatment of Japanese patients with schizophrenia.     

Safety assessment of prucalopride in elderly patients with constipation: a double-blind, placebo-controlled study

Abstract Chronic constipation is common among nursing home residents. The aim of this study was to evaluate safety, tolerability and pharmacokinetics of the selective 5HT₄ receptor agonist prucalopride in elderly, chronically constipated patients in nursing homes. A multicentre, phase II, randomized, double-blind dose-escalation study in 89 elderly constipated nursing home residents treated with placebo, 0.5, 1 or 2 mg prucalopride once daily for 28 days was analysed. Adverse events, vital signs, ECG, Holter monitor and pharmacokinetics were assessed (Clinicaltrials.gov identifier: NCT00627692). Patients' mean age was 83 years; 88% had a history of cardiovascular diseases. Most frequent adverse events, at least possibly related to prucalopride, were diarrhoea and abdominal pain. Relative to placebo, there were no differences in vital signs, ECG corrected QT interval, ECG morphology parameters, or incidence of supraventricular or ventricular arrhythmias on Holter monitoring. Plasma prucalopride concentrations increased proportionally with administered dose. Prucalopride up to 2 mg once daily for 4 weeks was safe and well-tolerated by constipated elderly patients, with no differences vs placebo in ECG or a range of Holter-monitoring parameters.     

Effect of 5‐HT4 receptor agonist mosapride citrate on rectosigmoid sensorimotor function in patients with irritable bowel syndrome

Background The 5‐HT₄ receptor agonist, mosapride citrate, accelerates gastric emptying. However, the effect of mosapride on colonic function has not been well investigated. We examined whether mosapride changes rectosigmoid motility and perception in patients with irritable bowel syndrome (IBS). Methods Thirty‐seven patients with IBS and 18 healthy subjects were studied. All subjects underwent a rectosigmoid barostat test to measure pain perception to intraluminal distention and resting smooth muscle motility for 20 min in the fasting state. Irritable bowel syndrome patients were then randomly assigned to receive either mosapride 15 mg (n = 19) or placebo (n = 18) orally with 200 mL water. Rectosigmoid motility and perception were measured again for 60 min following dosing. Rectosigmoid tone and contractility were evaluated in each 10‐min period. Key Results The pain threshold in the patients was significantly lower than that in controls (P < 0.01). There were no differences between mosapride and placebo groups in pain threshold, barostat bag volume, or number of contractions at baseline. Mosapride significantly decreased the mean bag volume (P < 0.01; group × period interaction by two‐way anova ) and increased the mean number of contractions (P < 0.05) compared with placebo, but did not affect the perception. In IBS patients with constipation (i.e., excluding diarrhea‐predominant subjects), mosapride (n = 13) increased rectosigmoid tone (P < 0.01) and contractions (P < 0.05) more than placebo (n = 14). Conclusions & Inferences Mosapride stimulates colonic motility without any adverse effect. These findings suggest that mosapride may have the potential to treat IBS patients with constipation and/or functional constipation. Further clinical trials are warranted to confirm the efficacy of this agent.