A Multicenter,Placebo‐Controlled,Double‐Blind,Randomized Study of Efficacy and Safety of Ocinaplon (DOV 273,547) in Generalized Anxiety Disorder

Preclinical studies demonstrated that ocinaplon, a positive allosteric modulator of GABA_A receptors, possesses anxiolytic‐like actions at doses devoid of the side effects typically associated with benzodiazepines. The aim of this study was to evaluate the effects of ocinaplon in a multicenter, double‐blind proof‐of‐concept trial of male and female outpatients who met DSM‐IV criteria for GAD with no coexisting depression, and had a baseline score of ≥20 on the Hamilton Scale for Anxiety (HAM‐A). Patients with <20% reduction in HAM‐A to placebo in a single‐blind 7‐day run‐in period were randomly assigned to treatment with ocinaplon 90 mg t.i.d. (n = 31) or placebo for 28 days (n = 29). Ocinaplon was more effective than placebo in reducing HAM‐A scores (P= 0.009). Patients assigned to ocinaplon exhibited a mean improvement of 14.2 points (SE = 2.6) on the total score of the HAM‐A scale at the conclusion of the trial, while patients assigned to placebo obtained a mean improvement of 6.3 points (SE = 2.0). A significant (P= 0.023) difference in improvement between ocinaplon and placebo was observed beginning at and continuing from 1‐week after the initiation of dosing. The proportion of patients with treatment‐emergent adverse events (TEAE) was not statistically significant between ocinaplon and placebo. One serious adverse event (SAE) occurred in the ocinaplon group that was considered possibly related to study medication (icterus following transaminase elevations). The patient had preexisting medical conditions that may have contributed to this SAE. A full recovery was observed with no residual effects. The overall safety profile revealed no patterns of TEAEs, including those effects typically associated with other anxiolytic and/or benzodiazepine compounds, such as sedation. Ocinaplon appears to be a well‐tolerated and effective treatment for GAD. It produces a rapid onset of anxiolytic action absent the side effects (e.g., dizziness, sedation) typically reported following anxiolytic doses of benzodiazepines.     

Atomoxetine treatment in adults with attention‐deficit/hyperactivity disorder and comorbid social anxiety disorder

Background: To evaluate the effect of atomoxetine (ATX) on attention‐deficit/hyperactivity disorder (ADHD) and comorbid social anxiety disorder in adults. Methods: Randomized, double‐blind, placebo‐controlled, conducted in adults with ADHD and social anxiety disorder. Patients received 40–100 mg ATX (n=224) or placebo (n=218) for 14 weeks following a 2‐week placebo lead‐in period. Efficacy measures included the Conners' Adult ADHD Rating Scale: Investigator‐Rated: Screening Version (CAARS:Inv:SV), Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression‐Overall‐Severity (CGI‐O‐S), State‐Trait Anxiety Inventory (STAI), Social Adjustment Scale‐Self Report (SAS), and Adult ADHD Quality of Life Scale‐29 (AAQoL). Safety and tolerability were also assessed. Results: ATX mean change (?8.7±10.0) from baseline (29.6±10.4) on CAARS:Inv:SV Total ADHD Symptoms score was significantly greater than placebo mean change (?5.6±10.2) from baseline (31.2±9.4; P<.001). ATX mean change (?22.9±25.3) from baseline (85.3±23.6) on LSAS Total score was significant compared to placebo mean change (?14.4±20.3) from baseline (82.1±21.3; P<.001). The visit‐wise analysis revealed greater improvement on the CAARS:Inv:SV Total ADHD Symptoms score and LSAS Total score for ATX at every time point throughout the study (P values ≤.012). Mean changes in CGI‐O‐S, STAI‐Trait Anxiety scores, and AAQoL Total score were significantly greater for ATX compared to placebo. Mean change for both groups on STAI‐State Anxiety scores was comparable. Improvement on SAS for ATX compared to placebo was not significant. Rates of insomnia, nausea, dry mouth, and dizziness were higher with ATX than with placebo. Discontinuation rates due to treatment‐emergent adverse events were similar between groups. Conclusions: ATX monotherapy effectively improved symptoms of ADHD and comorbid social anxiety disorder in adults and was well tolerated. Depression and Anxiety, 2009. Published 2009 Wiley‐Liss, Inc.     

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.     

Orodispersible sublingual piribedil to abort OFF episodes: A single dose placebo‐controlled,randomized, double‐blind,cross‐over study

S90049, a novel sublingual formulation of the non‐ergoline D₂‐D₃ agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single‐dose double‐blind double‐placebo 3 × 3 cross‐over study. Optimal tested doses were determined during a previous open‐label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (ΔUPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 ± 8 years, PD duration: 12 ± 6 years, UPDRS III OFF: 37 ± 15) participated. S90049 wassuperior to placebo on ΔUPDRS III (?13 ± 12 versus ?7 ± 9 respectively; estimated difference ?5.2, 95% Confidence Interval (CI)[?10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, ΔUPDRS III was similar on S90049 (?21.2 ± 10.1) and apomorphine (?23.6 ± 14.1) (estimated difference: 4.0 95% CI [?2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate. © 2009 Movement Disorder Society     

Droxidopa for the Short‐Term Treatment of Symptomatic Neurogenic Orthostatic Hypotension in Parkinson's Disease (nOH306B)

Neurogenic orthostatic hypotension (nOH) results from failure of norepinephrine responses to postural change to maintain standing systolic blood pressure (s‐SBP). Droxidopa is an oral prodrug of norepinephrine. Study nOH306 enrolled patients with Parkinson's disease (PD) and symptomatic nOH. Subjects underwent up to 2 weeks of double‐blind titration of droxidopa or placebo, followed by 8 weeks of double‐blind maintenance treatment (100‐600 mg thrice‐daily). For the initial 51 subjects (study nOH306A, previously reported), the primary efficacy measure, Orthostatic Hypotension Questionnaire (OHQ) composite score, did not demonstrate significant change versus placebo at maintenance week 8. For the subsequent 171 subjects (study nOH306B, reported here), the primary efficacy measure was change versus placebo on item 1 (“dizziness, lightheadedness, feeling faint, or feeling like you might black out”) of the Orthostatic Hypotension Symptom Assessment (OHSA) subsection of the OHQ at maintenance week 1. At week 1, mean (standard deviation) improvement on OHSA item 1 was 2.3 (2.95) for droxidopa versus 1.3 (3.16) for placebo (P = 0.018). In addition, mean increase in s‐SBP at week 1 was 6.4 (18.85) for droxidopa versus 0.7 (20.18) mmHg for placebo (nominal P value: 0.032). Differences in change in OHSA item 1 scores from baseline to maintenance weeks 2, 4, and 8 were not statistically significant. Adverse‐event (AE) incidence was similar across groups, but 12.4% of droxidopa and 6.1% of placebo subjects withdrew because of AEs. The most common AEs on droxidopa (vs. placebo) were headache (13.5% vs. 7.3%) and dizziness (10.1% vs. 4.9%). Study nOH306B demonstrated subjective (OHSA item 1) and objective (s‐SBP) evidence of short‐term droxidopa efficacy (vs. placebo) for symptomatic nOH in PD. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Metabolic effects of adjunctive aripiprazole in clozapine‐treated patients with schizophrenia

Fan X, Borba CPC, Copeland P, Hayden D, Freudenreich O, Goff DC, Henderson DC. Metabolic effects of adjunctive aripiprazole in clozapine‐treated patients with schizophrenia. Objective: This study examined the effects of adjunctive aripiprazole therapy on metabolism in clozapine‐treated patients with schizophrenia. Method: In an 8‐week randomized, double‐blind, placebo‐controlled study, subjects received either aripiprazole (15 mg/day) or placebo. At baseline and week 8, metabolic parameters were assessed by the frequently sampled intravenous glucose tolerance test, nuclear magnetic resonance spectroscopy and whole‐body dual‐energy X‐ray absorptiometry (DXA). Results: Thirty subjects completed the study (16 in the aripiprazole group and 14 in the placebo group). Glucose effectiveness measured by the frequently sampled intravenous glucose tolerance test improved significantly in the aripiprazole group (0.003 ± 0.006 vs. ?0.005 ± 0.007/min, P = 0.010). The aripiprazole group showed significant reductions in both plasma low‐density lipoprotein (LDL) levels (?15.1 ± 19.8 vs. 4.4 ± 22.5 mg/dl, P = 0.019) and LDL particle numbers (?376 ± 632 vs. ?36 ± 301 nm , P = 0.035). Further, there was a significant reduction in the lean mass (?1125 ± 1620 vs. 607 ± 1578 g, P = 0.011) measured by whole‐body DXA scan in the aripiprazole group. All values were expressed as mean ± standard deviation, aripiprazole vs. placebo. Conclusion: Adjunctive therapy with aripiprazole may have some metabolic benefits in clozapine‐treated patients with schizophrenia.     

A double‐blind,placebo‐controlled trial of rosiglitazone for clozapine‐induced glucose metabolism impairment in patients with Schizophrenia

Objective: The primary purpose of this 8‐week double‐blind, placebo‐controlled trial of rosiglitazone 4 mg/day was to examine its effect on insulin sensitivity index (SI) and glucose utilization (SG) in clozapine‐treated subjects with schizophrenia with insulin resistance. Method: Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI. Results: Controlling for the baseline, comparing the rosiglitazone group with placebo group, there was a non‐significant improvement in SG (0.016 ± 0.006–0.018 ± 0.008, effect size = 0.23, P = 0.05) with a trend of improvement in SI in the rosiglitazone group (4.6 ± 2.8–7.8 ± 6.7, effect size = 0.18, P = 0.08). There was a significant reduction in small low‐density lipoprotein cholesterol (LDL‐C) particle number (987 ± 443–694 ± 415, effect size = 0.30, P = 0.04). Conclusion: Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine.     

Electrophysiology in chronic inflammatory demyelinating polyneuropathy with IGIV

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) received immune globulin intravenous, 10% caprylate/chromatography purified (IGIV‐C, Gamunex; n = 59) or placebo (n = 58) every 3 weeks for up to 24 weeks (first period) in a randomized, double‐blind, parallel‐group, response‐conditional, crossover study. Motor and sensory nerves were assessed at baseline and endpoint/week 24. A nonsignificant trend toward improvement in the proximal amplitude of the most severely affected motor nerve was observed with IGIV‐C (0.69 ± 1.86 mV) versus placebo (0.47 ± 2.29 mV), and a greater improvement of 1.08 ± 2.15 mV with IGIV‐C versus 0.46 ± 2.03 mV with placebo (P = 0.089) was observed with exclusion of data from Erb's point stimulation. Greater improvements from baseline favoring IGIV‐C were observed for 127/142 electrophysiologic parameters. The averaged motor amplitudes from all motor nerves significantly improved with IGIV‐C versus placebo [treatment difference, 0.62 mV; 95% confidence interval (CI), 0.05, 1.20; P = 0.035], and conduction block decreased significantly (treatment difference, ?5.54%; 95% CI, ?10.43, ?0.64; P = 0.027), particularly in the lower limbs. Overall, the data suggest that IGIV‐C improves electrophysiologic parameters in CIDP. Muscle Nerve, 2009     

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.     

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.     

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.     

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     

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     

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.     

Randomized,controlled trial of rasagiline as an add‐on to dopamine agonists in Parkinson's disease

Dopamine agonists (DA) are often used as first‐line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase‐B (MAO‐B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18‐week, randomized, double‐blind, placebo‐controlled trial of rasagiline 1 mg/d as an add‐on to DA therapy (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The modified intent‐to‐treat (ITT) population included 321 subjects whose mean ± SD age was 62.6 ± 9.7, and duration of PD was 2.1 ± 2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, ?2.4 ± 0.95; 95% confidence interval [CI], ?4.3, ?0.5; P = 0.012). Mean improvement (LS mean ± SE) was ?3.6 ± 0.68 in the rasagiline group and ?1.2 ± 0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society     

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 Prospective Open‐Label Trial of Lamotrigine Monotherapy in Children and Adolescents with Bipolar Disorder

Aim: To evaluate the safety and efficacy of lamotrigine monotherapy as an acute treatment of bipolar mood elevation in children with bipolar spectrum disorders. Method: This was a 12‐week, open‐label, prospective trial of lamotrigine monotherapy to assess the effectiveness and tolerability of this compound in treating pediatric bipolar disorder. Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impressions‐Improvement scale (CGI‐I), Children's Depression Rating Scale (CDRS), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self‐reports, vital signs weight monitoring, and laboratory analysis. Results: Thirty‐nine children with bipolar disorder (YMRS at entry: 31.6 ± 5.5) were enrolled in the study and 22 (56%) completed the 12‐week trial. Lamotrigine was slowly titrated to an average endpoint dose of 160.7 ± 128.3 in subjects <12 years of age (N = 22) and 219.1 ± 172.2 mg/day in children 12–17 years of age (N = 17). Treatment with lamotrigine was associated with statistically significant levels of improvement in mean YMRS scores (?14.9 ± 9.7, P < 0.001) at endpoint. Lamotrigine treatment also resulted in significant improvement in the severity of depressive, attention‐deficit/hyperactivity disorder (ADHD), and psychotic symptoms. Lamotrigine was generally well tolerated with marginal increase in body weight (47.0 ± 18.0 kg vs. 47.2 ± 17.9 kg, P= 0.6) and was not associated with abnormal changes in laboratory parameters. Several participants were discontinued due to skin rash; in all cases, the rash resolved shortly after discontinuation of treatment. No patient developed Steven Johnson syndrome. Conclusions: Open‐label lamotrigine treatment appears to be beneficial in the treatment of bipolar disorder and associated conditions in children. Future placebo‐controlled, double‐blind studies are warranted to confirm these findings.     

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.     

A phase 2a,randomized, double‐blind 28‐day study of TZP‐102 a ghrelin receptor agonist for diabetic gastroparesis

Background Gastroparesis causes significant morbidity and treatment options are limited. TZP‐102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double‐blind, placebo‐controlled trial in patients with diabetic gastroparesis. Methods A total of 92 outpatients were randomized to once‐daily administrations of 10‐mg (n = 22), 20‐mg (n = 21), 40‐mg (n = 23) TZP‐102 or placebo (n = 26). The primary endpoint was the change from baseline in gastric half‐emptying time (T_½) utilizing ¹³C‐breath test methodology and secondary endpoints included symptom improvement using patient‐reported gastroparesis symptom scores (PAGI‐SYM questionnaire) and patient and physician overall treatment evaluations (OTE). Key Results Gastric T½ changes were not statistically significant between TZP‐102 and placebo after 28 days of treatment at any dose. Clinical improvements (?1.0 to ?1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI‐SYM, which was significant vs placebo for all TZP‐102 doses combined. Improvements became evident after 1 week of treatment. Significantly, more patients given TZP‐102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP‐102 doses were well‐tolerated with no adverse cardiac, weight, or glucose control outcomes. Conclusions & Inferences TZP‐102 for 28 days, at doses of 10–40 mg once daily, was well‐tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient‐defined outcomes in determining therapeutic benefit.