Tolerability and safety of perampanel: two randomized dose-escalation studies

Krauss GL, Bar M, Biton V, Klapper JA, Rektor I, Vaiciene‐Magistris N, Squillacote D, Kumar D. Tolerability and safety of perampanel: two randomized dose‐escalation studies. Acta Neurol Scand: 2012: 125: 8–15.
© 2011 John Wiley & Sons A/S. Objectives – To evaluate, for the first time in patients with epilepsy, the tolerability and safety of escalating doses of oral perampanel, a novel, selective, non‐competitive AMPA antagonist, as adjunctive therapy for refractory partial‐onset seizures. Materials and methods – Two consecutive, randomized, double‐blind, dose‐escalation studies recruited adults (18–70 years) with uncontrolled partial‐onset seizures receiving one to three concomitant antiepileptic drugs. In study 206, patients were treated for 12 weeks (8‐week dose‐titration, 4‐week dose‐maintenance) with placebo or perampanel (up to 4 mg/day, dosed once‐ or twice‐daily). In study 208, patients received placebo or perampanel once‐daily (up to 12 mg) for 16 weeks (12‐week titration, 4‐week maintenance). Results – Overall, 153 patients were randomized into study 206 (perampanel twice‐daily, n = 51; perampanel once‐daily, n = 51; placebo, n = 51). Study 208 included 48 patients (perampanel once‐daily, n = 38; placebo, n = 10). The highest dose in study 206 – 4 mg/day – was well tolerated, with similar proportions of patients tolerating once‐daily (82.4%) and twice‐daily (82.4%) perampanel and placebo (82.4%) treatments. In study 208 most patients tolerated doses of ≥ 6 mg perampanel once‐daily in a Kaplan–Meier analysis. In both studies, the most common adverse events were CNS‐related; most were of mild/moderate severity. Conclusions – Perampanel was well tolerated across doses of 4–12 mg/day. The studies showed preliminary evidence of efficacy and identified doses to be evaluated in larger clinical studies.     

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.     

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     

Evaluation of adjunctive perampanel in patients with refractory partial‐onset seizures: Results of randomized global phase III study 305

Purpose: To assess the efficacy and safety of once‐daily doses of perampanel 8 and 12 mg when added to 1–3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial‐onset seizures. Methods: Study 305 was a multicenter, double‐blind, placebo‐controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1–3 AEDs. Equal randomization to once‐daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19‐week double‐blind treatment phase comprising a 6‐week titration period, with weekly 2‐mg dose increments, followed by a 13‐week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ≥50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre‐perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty‐six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent‐to‐treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent‐to‐treat analysis) was ?9.7%, ?30.5%, and ?17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was ?32.7% (8 mg), ?21.9 (12 mg), and ?8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ≥10% of patients in any treatment group) treatment‐emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once‐daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial‐onset seizures. These study results also demonstrated that once‐daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.     

The practical impact of altered dosing on perampanel plasma concentrations: Pharmacokinetic modeling from clinical studies

RationalePerampanel is a selective AMPA receptor antagonist approved for adjunctive therapy in patients with refractory partial-onset seizures. Perampanel is metabolized primarily via CYP3A4, yet it has a relatively long half-life of 105 h; it is, therefore, recommended that perampanel be given once daily (preferably at bedtime). Many patients occasionally have less-than-perfect adherence to their drug regimen, and given the known pharmacokinetic interactions of perampanel with commonly used enzyme-inducing antiepileptic drugs (EIAEDs), we explored the effects of a missed dose on steady-state perampanel plasma concentrations and the ramifications of “make up” doses in these patients. Although perampanel is approved for once-daily dosing, some clinicians may elect to give perampanel as a divided dose (i.e., twice daily), so we also sought to examine the pharmacokinetic impact of twice- versus once-daily dosing.MethodsPharmacokinetic simulations were performed using validated perampanel pharmacokinetic parameters, derived from 19 phase I studies in 606 subjects, to investigate the effect on perampanel plasma concentration of (1) missing a dose of perampanel followed by delayed replacement of the missed dose, (2) missing a dose followed by resumption of scheduled therapy, and (3) missing a dose in the presence/absence of carbamazepine. Simulations were done for a typical patient receiving an 8-mg once-daily or a 4-mg twice-daily dose using the nonlinear mixed effects program, NONMEM v7.2, in conjunction with PDx-pop v5.ResultsOur results corroborate that given the pharmacokinetic characteristics of perampanel, a missed dose is unlikely to cause as much fluctuation in plasma concentration as would be expected for a drug with a short half-life. Importantly, simulations suggest that supplementing a missed dose 6–12 h later, followed by continuation of the regular schedule, may not result in any significant “spikes” in perampanel plasma concentrations. Simulations demonstrated that twice-daily dosing offered little advantage in further flattening the concentration–time profile of perampanel in the adherent patient. However, fluctuations in plasma concentrations are minimized by twice-daily dosing in patients receiving concomitant EIAEDs.ConclusionsThese pharmacokinetic simulations suggest that the long half-life of perampanel may be advantageous in conferring a relatively smooth concentration–time profile with a once-daily or twice-daily dosing, even in the presence of concomitant EIAEDs. However, the results of the present study suggest that perampanel replacement is recommended for patients taking an EIAED to mitigate the potential risks associated with reduced exposure. Confirmation of the ultimate clinical impact of these findings will require further study.     

Efficacy,safety, and tolerability of perampanel in Asian and non‐Asian patients with epilepsy

People of different ethnic or racial backgrounds may experience variations in pharmacokinetic and pharmacodynamic responses to drug therapies. Our post hoc analysis evaluated the efficacy, safety, and tolerability of perampanel in Asian and non‐Asian populations with refractory focal seizures with or without focal to bilateral tonic‐clonic (FBTC) seizures. This analysis pooled data from 4 randomized, placebo‐controlled, phase‐3 studies involving patients aged ≥12 years who have focal seizures with or without FBTC seizures. Patients were receiving 2, 4, 8, or 12 mg perampanel (or placebo) by the end of a 6‐week titration period and for a further 13 weeks during the maintenance phase. Efficacy endpoints included median percent change in seizure frequency per 28 days, and 50% and seizure‐freedom responder rates relative to baseline. The median percent change in seizure frequency per 28 days from baseline was significantly greater than placebo for perampanel 8 and 12 mg (?31.1% and ?38.1% change, respectively; each P < 0.0001) in the Asian population, and for perampanel 4, 8, and 12 mg (?21.1% [P = 0.0001], ?26.3% [P < 0.0001], and ?27.7% [P = 0.0001] change, respectively) in the non‐Asian population. The 50% responder rate relative to baseline was significantly greater than placebo for perampanel 8 and 12 mg (40.1% and 43.8%, respectively; each P < 0.0001) in the Asian population, and for perampanel 4, 8, and 12 mg (29.4% [P = 0.0002], 32.8% [P < 0.0001] and 34.5% [P = 0.0001]), respectively, in the non‐Asian population. Seizure‐freedom rate among all patients was 4.9%‐11.7% for perampanel 2, 4, 8, and 12 mg. The most frequently reported treatment‐emergent adverse events (TEAEs) across both populations were dizziness, somnolence, irritability, headache, and fatigue. The most common psychiatric TEAEs were aggression and irritability. Perampanel demonstrated a favorable and similar risk‐benefit profile in both Asian and non‐Asian populations with refractory focal seizures.     

Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial

Background : Compromised iron status is important in restless legs syndrome pathophysiology. We compared the efficacy and tolerability of ferric carboxymaltose (single intravenous dose) versus placebo for restless legs syndrome treatment in iron‐deficient nonanemic patients. Methods : Patients with moderate to severe restless legs syndrome and serum ferritin < 75 μg/L (or serum ferritin 75‐300 μg/L and transferrin saturation < 20%) were randomized to ferric carboxymaltose (1000 mg iron) or placebo. Mean change difference between ferric carboxymaltose and placebo in International Restless Legs Syndrome Severity Scale score from baseline to week 4 was the primary end point; week 12 was a secondary end point. Results : Ferric carboxymaltose treatment (n = 59) led to nonsignificant improvement over placebo (n = 51) in International Restless Legs Syndrome Severity Scale score at week 4 (difference [95% confidence interval], ‐2.5 [‐5.93 to 1.02], P = 0.163), reaching significance by week 12 (‐4.66 [‐8.59 to ‐0.73], P = 0.021). Conclusions : In patients who responded to treatment, ferric carboxymaltose may require more time to stabilize restless legs syndrome than previously assumed. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Confusing placebo effect with natural history in epilepsy: A big data approach

For unknown reasons, placebos reduce seizures in clinical trials in many patients. It is also unclear why some drugs showing statistical superiority to placebo in one trial may fail to do so in another. Using Seizuretracker.com , a patient‐centered database of 684,825 seizures, we simulated “placebo” and “drug” trials. These simulations were employed to clarify the sources of placebo effects in epilepsy, and to identify methods of diminishing placebo effects. Simulation 1 included 9 trials with a 6‐week baseline and 6‐week test period, starting at time 0, 3, 6…24 months. Here, “placebo” reduced seizures regardless of study start time. Regression‐to‐the‐mean persisted only for 3 to 6 months. Simulation 2 comprised a 6‐week baseline and then 2 years of follow‐up. Seizure frequencies continued to improve throughout follow‐up. Although the group improved, individuals switched from improvement to worsening and back. Simulation 3 involved a placebo‐controlled “drug” trial, to explore methods of placebo response reduction. An efficacious “drug” failed to demonstrate a significant effect compared with “placebo” (p = 0.12), although modifications either in study start time (p = 0.025) or baseline population reduction (p = 0.0028) allowed the drug to achieve a statistically significant effect compared with placebo. In epilepsy clinical trials, some seizure reduction traditionally attributed to placebo effect may reflect the natural course of the disease itself. Understanding these dynamics will allow future investigations into optimal clinical trial design and may lead to identification of more effective therapies. Ann Neurol 2015;78:329–336     

Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy

Purpose: To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2‐(2‐oxo‐1‐phenyl‐5‐pyridin‐2‐yl‐1,2‐dihydropyridin‐3‐yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial‐onset seizures. Methods: Perampanel pharmacology was assessed by examining changes in intracellular free Ca²⁺ ion concentration ([Ca²⁺]_i) in primary rat cortical neurones, and [³H]perampanel binding to rat forebrain membranes. Antiseizure activity of orally administered perampanel was examined in amygdala‐kindled rats and in mice exhibiting audiogenic, maximal electroshock (MES)–induced, pentylenetetrazole (PTZ) –induced, or 6 Hz‐induced seizures. Key Findings: In cultured rat cortical neurones, perampanel inhibited α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)–induced increases in [Ca²⁺]_i (IC₅₀ 93 nm vs. 2 μm AMPA). Perampanel had a minimal effect on N‐methyl‐d ‐aspartate (NMDA)–induced increases in [Ca²⁺]_i, and only at a high concentration (30 μm ). [³H]Perampanel binding to rat forebrain membranes was not significantly displaced by glutamate or AMPA but was displaced by the noncompetitive AMPA receptor antagonists CP465022 (K_i 11.2 ± 0.8 nm ) and GYKI52466 (K_i 12.4 ± 1 μm ). In mice, perampanel showed protective effects against audiogenic, MES‐induced, and PTZ‐induced seizures (ED₅₀s 0.47, 1.6, and 0.94 mg/kg, respectively). Perampanel also inhibited 6 Hz electroshock‐induced seizures when administered alone or in combination with other antiepileptic drugs (AEDs). In amygdala‐kindled rats, perampanel significantly increased afterdischarge threshold (p < 0.05 vs. vehicle), and significantly reduced motor seizure duration, afterdischarge duration, and seizure severity recorded at 50% higher intensity than afterdischarge threshold current (p < 0.05 for all measures vs. vehicle). Perampanel caused dose‐dependent motor impairment in both mice (TD₅₀ 1.8 mg/kg) and rats (TD₅₀ 9.14 mg/kg), as determined by rotarod tests. In mice, the protective index (TD₅₀ in rotarod test/ED₅₀ in seizure test) was 1.1, 3.8, and 1.9 for MES‐induced, audiogenic, and PTZ‐induced seizures, respectively. In rat, dog, and monkey, perampanel had a half‐life of 1.67, 5.34, and 7.55 h and bioavailability of 46.1%, 53.5%, and 74.5%, respectively. Significance: These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.     

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.     

Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005)

Objective

Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A_2A receptor antagonist, istradefylline, shows promise for the treatment of PD.

Methods

Istradefylline (40mg/day) was studied in levodopa‐treated PD subjects experiencing prominent wearing‐off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double‐blind, 12‐week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake “off” time, recorded by subjects using a patient PD diary. Secondary end points evaluated “on” time (including “on time with dyskinesia”), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression–Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring.

Results

After randomization, approximately 88% of subjects completed the double‐blind period. Compared with baseline, the decrease of daily awake “off” time for istradefylline was a mean (± standard deviation) of ?10.8 ± 16.6% (95% confidence interval, ?13.46 to ?7.52) and for placebo, ?4.0 ± 15.7% (95% confidence interval, ?7.73–0.31; p = 0.007 using two‐way analysis of variance). This effect corresponded to changes from baseline in total daily awake “off” time of ?1.8 ± 2.8 hours for istradefylline and ?0.6 ± 2.7 hours for placebo (p = 0.005). Treatment‐emergent adverse effects with istradefylline were generally mild.

Interpretation

Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in “off” time without increased troublesome dyskinesia. Ann Neurol 2008

     

Early treatment benefits of ropinirole prolonged release in Parkinson's disease patients with motor fluctuations

We performed a retrospective analysis of the Efficacy And Safety Evaluation in Parkinson's Disease (EASE‐PD) Adjunct Study, assessing the minimum time to symptom improvement after initiation of ropinirole prolonged release (2–24 mg/day) versus placebo in patients with moderate‐to‐advanced PD not optimally controlled with levodopa. Ropinirole prolonged release was superior to placebo at Week 2 for change from baseline in “off” time (adjusted mean treatment difference [AMTD] – 0.7 hours; 95% confidence interval [CI], –1.1, –0.2; P = 0.0029), and “on” time without troublesome dyskinesia (0.4 hours; 95%CI, 0.01, 0.88; P = 0.0444). At Week 4, improvements were seen in change from baseline in Unified Parkinson's Disease Rating Scale total motor score (AMTD, –3.1; 95%CI, –4.4, –1.8; P < 0.0001), activities of daily living score (AMTD, –1.1; 95%CI, –1.7, –0.5; P = 0.0004), and the cardinal symptoms of PD compared with placebo. These analyses indicate that once‐daily, adjunctive ropinirole prolonged release can offer PD symptom control 2 weeks after treatment initiation. © 2010 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.     

Perampanel for focal epilepsy: insights from early clinical experience

Perampanel is approved for adjunctive therapy of focal epilepsy with or without secondarily generalized seizures in patients aged >12 years. This narrative review uses real‐world and clinical trial data to elucidate perampanel's role in the clinic. Audit data show good tolerability with perampanel and higher freedom‐from‐seizure rates in elderly vs younger patients. When using perampanel in elderly patients, special attention should be given to comorbidities and co‐medication to avoid potential interactions or adverse events. Slower titration is generally recommended, and seizure control should be reassessed at a dose of 4 mg before further dose increases. Perampanel efficacy is similar in adolescents and adults; however, somnolence, nasopharyngitis, and aggression are more frequent in adolescents vs the overall population. Individualized and slow‐dose titration can minimize adverse events. Low serum concentrations of perampanel may occur in patients also receiving some enzyme‐inducing anti‐epileptic drugs; a perampanel dose increase may be required. Adverse events of importance with perampanel include dizziness; anger, aggression, and hostile behavior (particularly in adolescents); and falls (particularly in patients >65 years). An individualized approach to dosing, including slower up‐titration and bedtime dosing, reduces dizziness risk. Other drugs may cause or aggravate dizziness; reducing concomitant drugs may be necessary when up‐titrating perampanel. It would seem clinically appropriate to give due consideration to avoiding use in patients with a history of anger or hostile/aggressive behavior. The possibility of such behaviors should be discussed with patients before starting perampanel, with monitoring during up‐titration. Slower up‐titration of perampanel in older patients helps reduce fall risk.     

Efficacy and safety of tolcapone in levodopa-treated Parkinson's disease patients with “wearing-off” phenomenon: a multicentre,double-blind,randomized, placebo-controlled trial

To assess the effect of tolcapone added to levodopa plus benserazide or carbidopa on the “wearing-off” phenomenon in patients with Parkinson's disease, we undertook a double-blind, randomized, placebo-controlled, parallel-group study of tolcapone 50, 200, or 400 mg three times daily (t.i.d.) for 6 weeks in addition to levodopa therapy. We studied 154 parkinsonian patients, aged 40 years or more, who presented with the “wearing-off” phenomenon despite “optimal” antiparkinsonian therapy. The main outcome measures were “on”- and “off”-time, Investigator's Global Assessments, Subscales of the Unified Parkinson's Disease Rating Scale, changes in levodopa dosage, and safety and tolerability. Tolcapone was more effective than placebo in reducing the “wearing-off” phenomenon between baseline and week 6 at all three dosages. Tolcapone 200 mg t.i.d. increased “on”-time from 37.9% of the waking day to 50.8% (p < 0.01) and reduced “off”-time from 26.7% of the waking day to 16.4% (p < 0.05). Tolcapone treatment was generally well tolerated at all dosages. Initial exacerbation of adverse dopaminergic effects was controlled by levodopa dosage adjustment; at week 6, the mean total daily levodopa dosage had decreased by 80 mg, from 694 mg at baseline, in the tolcapone 200 mg t.i.d. group (p < 0.01). We conclude that the addition of tolcapone to levodopa plus a decarboxylase inhibitor effectively and safely reduces the “wearing-off” phenomenon in parkinsonian patients.     

Use of perampanel in children and adolescents with Lennox–Gastaut Syndrome

AimReport the use of perampanel treatment in children with Lennox–Gastaut syndrome (LGS).MethodWe conducted a prospective study of 13 LGS patients (seven male; mean age, 12.8 years) treated with adjunctive perampanel therapy. Perampanel was initiated at 2 mg/day and titrated to a median maximum dose of 6 mg/day.ResultsAfter a mean follow-up duration of 10.8 months (range, 1–24 months), nine patients (69.2%) were responders (≥ 50% reduction in total seizure frequency) and nine (69.2%) were rated by their physician as “much improved” or “very much improved”. Four patients (30.8%) discontinued perampanel due to the lack of efficacy (n = 2) and seizure aggravation (n = 2). No patients discontinued due to other adverse events (AEs). AEs were reported for six patients (46.2%) and comprised decreased activity/social interaction (n = 3), behavior disturbance with agitation (n = 2), and/or fatigue (n = 2). All AEs became manageable after perampanel dosing was decreased. Improvements in cognitive function and/or behavior were reported for seven patients (53.8%). Introduction of perampanel allowed the dose reduction and/or discontinuation of other treatments in seven patients (53.8%).InterpretationPerampanel was efficacious and generally well tolerated as an adjunctive treatment for seizures associated with LGS, supporting further research in this area.     

A Double‐Blind,Randomized, Placebo and Active‐Controlled Study of Nebicapone for the Treatment of Motor Fluctuations in Parkinson's Disease

To determine the efficacy, safety and tolerability of nebicapone, a new catechol‐O‐methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8‐week double‐blind, placebo‐ and active‐controlled, parallel‐group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty‐two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4–8 daily doses) were enrolled and 250 patients were eligible for intention‐to‐treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8‐week change from baseline in absolute “Off” time duration noted in self‐scoring diaries. At 8 weeks of treatment the mean daily “Off” time decreased significantly compared to placebo for nebicapone 150 mg (?106 min; 95%CI: ?192; ?21) and entacapone 200 mg (?81 min; 95%CI: ?142; ?19). The decrease in “Off” time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment‐emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.     

Amantadine extended release for levodopa‐induced dyskinesia in Parkinson's disease (EASED Study)

ADS‐5102 is a long‐acting, extended‐release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy, and tolerability of ADS‐5102 in Parkinson's disease (PD) patients with levodopa‐induced dyskinesia. This was a randomized, double‐blind, placebo‐controlled, parallel‐group study of 83 PD patients with troublesome dyskinesia assigned to placebo or one of three doses of ADS‐5102 (260 mg, 340 mg, 420 mg) administered daily at bedtime for 8 weeks. The primary efficacy analysis compared change from baseline to week 8 in Unified Dyskinesia Rating Scale (UDysRS) total score for 340 mg ADS‐5102 versus placebo. Secondary outcome measures included change in UDysRS for 260 mg, 420 mg, Fatigue Severity Scale (FSS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), patient diary, Clinician's Global Impression of Change, and Parkinson's Disease Questionnaire (PDQ‐39). ADS‐5102 340 mg significantly reduced dyskinesia versus placebo (27% reduction in UDysRS, P = 0.005). In addition, ADS‐5102 significantly increased ON time without troublesome dyskinesia, as assessed by PD patient diaries, at 260 mg (P = 0.004), 340 mg (P = 0.008) and 420 mg (P = 0.018). Adverse events (AEs) were reported for 82%, 80%, 95%, and 90% of patients in the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. Constipation, hallucinations, dizziness, and dry mouth were the most frequent AEs. Study withdrawal rates were 9%, 15%, 14%, and 40% for the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. All study withdrawals in the active treatment groups were attributable to AEs. ADS‐5102 was generally well tolerated and resulted in significant and dose‐dependent improvements in dyskinesia in PD patients. © 2015 Adamas Pharmaceuticals, Inc. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Clinical pattern and risk factors for dyskinesias following fetal nigral transplantation in Parkinson's disease: A double blind video‐based analysis

The objective of this study is to assess dyskinesias in 34 Parkinson's disease patients randomized to receive bilateral fetal nigral transplantation with 4 donors per side (12), 1 donor per side (11), or placebo (11). Videotape recordings were performed at the baseline, 3, 6, 12, 18, and 24 month visits during the “practically defined off” (12 hours after last evening dopaminergic therapy) and “best on” (best response following morning dopaminergic therapy) states. Videotapes were analyzed in random order by a blinded investigator. Dyskinesias during “best on” (on‐medication dyskinesia) were observed in all, but 1 patient at baseline, and in all patients at each subsequent visit. There were no differences between groups. No patient had dyskinesia at baseline in “practically‐defined off” (“off‐medication” dyskinesia). Following transplantation, off‐medication dyskinesia was observed in 13 of 23 patients, but not in any patient in the placebo group (P = 0.019). There was no difference in dyskinesia score between patients in the 1 and 4 donor groups. On‐medication dyskinesias were typically generalized and choreiform, whereas off‐medication dyskinesias were usually repetitive, stereotypic movements in the lower extremities with residual Parkinsonism in other body regions. Off‐medication dyskinesias are common following transplantation and may represent a prolonged form of diphasic dyskinesias. © 2008 Movement Disorder Society