A study of once-a-week donepezil transdermal system's bioequivalence to oral donepezil in healthy volunteers: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article published in the Journal of Alzheimer's Disease. It describes an adhesive patch placed on the skin's surface, also referred to as a transdermal delivery system (or TDS), that delivers donepezil (called donepezil TDS going forward) through the skin of patients with mild, moderate, and severe dementia of the Alzheimer's type. This summary focuses on how fast and how much of the medication donepezil enters the body through the skin, and how it compares with taking a pill form of donepezil by mouth (oral donepezil). This summary also looks at how much donepezil is circulating through the body with the use of the once-a-week donepezil TDS versus the once-a-day donepezil pill. We show that the same amount of donepezil circulates through the body when donepezil TDS is used once a week as when a participant takes an oral donepezil pill once a day. WHY IS THIS STUDY IMPORTANT?: Dementia is a term used to describe a person's decreasing ability to remember, think, or make decisions necessary to successfully complete daily activities. Alzheimer's disease is a disorder that progresses slowly, with the symptoms of dementia getting worse over many years. When viewed under a microscope, the visible features of Alzheimer's disease within the brain are protein deposits called plaques between brain cells and protein strands within brain cells that appear as tangles. One of the many features that cannot be seen with the naked eye in the Alzheimer's brain is the low level of a chemical called acetylcholine that allows certain nerve cells in the brain involved with memory to communicate with one another. Donepezil, a drug that is widely used to treat dementia associated with Alzheimer's disease, increases the amount of acetylcholine in the brain. Donepezil is usually in pill form and taken by mouth. However, one problem with taking oral donepezil is that it can cause stomach or intestinal side effects like diarrhea, nausea, and vomiting. These side effects may be bad enough that people stop taking their medication. In 2022, for the first time, the United States Food and Drug Administration approved a donepezil TDS marketed under the name Adlarity. Donepezil TDS is for use in patients who have mild, moderate, and severe dementia caused by Alzheimer's disease. It is applied once a week to skin on the patient's back, upper buttocks, or thigh. Donepezil TDS allows the drug donepezil to be absorbed into the body directly through the skin, which means that the drug does not go through the digestive system. This means that many stomach and intestinal side effects (the undesirable effects of the drug) can potentially be reduced. WHAT WERE THE RESULTS?: In healthy volunteers, we showed that donepezil TDS allows a similar amount of the drug into the body as the oral donepezil pill. This is done using a type of examination known as pharmacokinetics (how much, how fast, and how steadily donepezil is taken into the bloodstream). In healthy participants, donepezil TDS had overall fewer stomach and intestinal side effects (like constipation, diarrhea, nausea, and vomiting) than the oral donepezil pill, although more participants reported abdominal pain with donepezil TDS than with oral donepezil. Donepezil TDS also had fewer instances of nervous system side effects (like dizziness and sleepiness) than the oral donepezil pill. These findings support using donepezil TDS to treat patients with Alzheimer's disease.

Long-Term Safety, Tolerability, and Efficacy of a Transdermal Donepezil Patch in Patients with Severe Alzheimer's Disease.

BACKGROUND: Oral formulations are not suitable for demented patients with dysphagia, those refuse to take tablets, or those with drug compliance problem. However, only oral formulations of donepezil hydrochloride are approved for the treatment of severe Alzheimer's disease in Japan. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of long-term application of a 55.0 mg transdermal donepezil patch switched from a 10 mg oral donepezil hydrochloride tablet, for the treatment of patients with severe Alzheimer's disease. METHODS: A 52-week, multicenter, open-label, uncontrolled (phase III) study (jRCT2080224612) was conducted in Japan between April 2019 and August 2021. A 10 mg donepezil hydrochloride tablet was administered once a day for four weeks; a 55.0 mg donepezil patch was then applied once a day for 52 weeks in patients with severe Alzheimer's disease. RESULTS: Of 64 patients received the patch, 45 completed the 52-week period. The overall discontinuation rate was 29.7% (19/64). Among the 19 patients discontinued, six patients 9.4% (6/64) discontinued due to adverse events. The incidence of adverse events at application sites was 67.2% (43/64), including application site erythema 29.7% (19/64), application site pruritus 25.0% (16/64), and contact dermatitis 20.3% (13/64). Adverse events were mild and did not increase with time, demonstrating a favorable safety profile. Cognitive function, measured using the Mini-Mental State Examination, was maintained for up to 24 weeks. CONCLUSIONS: Adverse events were considered manageable in a clinical setting. The long-term application of a 55.0 mg donepezil patch once a day was feasible treatment in patients with severe Alzheimer's disease.

Clinician's Guide to Using Ozanimod for the Treatment of Ulcerative Colitis.

The emergence of advanced therapies [eg, biologics, Janus kinase inhibitors] over the past few decades has revolutionised the treatment of ulcerative colitis. However, the limitations of these therapies leave an unmet need for safer and more effective or convenient treatment options. There is growing interest in the development of novel oral small molecule therapies for the treatment of ulcerative colitis. Ozanimod is an oral small molecule therapy that is approved in the USA, the European Union, and other countries as the first sphingosine 1-phosphate receptor modulator for the treatment of moderately to severely active ulcerative colitis in adults. This review provides guidance for ozanimod use for the treatment of ulcerative colitis, based on the prescribing information, clinical trial and real-world data, and the authors' clinical experiences. This guidance outlines patient characteristics to consider when deciding if ozanimod treatment is suitable and describes how to educate patients on risks and best practices. It also details the nature and frequency of monitoring during treatment, which should be adapted to the individual patient based on pre-existing risk factors and events that possibly occur during treatment. This review also provides insights into the patient characteristics and clinical scenarios best suited for ozanimod treatment, based on its efficacy, safety profile, and risks compared with other therapies.

Efficacy and Safety of a Transdermal Donepezil Patch in Patients with Mild to Moderate Alzheimer's Disease: Open-Label, Extension Study.

BACKGROUND: In Japan, only oral formulation of donepezil hydrochloride is approved for the treatment of Alzheimer's disease. OBJECTIVE: To evaluate safety and efficacy of a donepezil patch 27.5 mg application for 52 weeks in patients with mild-to-moderate Alzheimer's disease; and to evaluate safety on switching from donepezil hydrochloride tablets. METHODS: This 28-week, open-label study (jRCT2080224517) is an extension of a 24-week double-blind (donepezil patch 27.5 mg versus donepezil hydrochloride tablet 5 mg) noninferiority study. The patch group (continuation group) continued administration of the patch and the tablet group (switch group) switched to the patch in this study. RESULTS: A total of 301 patients participated (156 patients continued using patches; 145 patients switched). Both groups showed similar course on the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and ABC dementia scales. At weeks 36 and 52, changes in ADAS-Jcog from week 24 [mean (standard deviation)] were 1.4 (4.8) and 2.1 (4.9) in the continuation group, and 1.0 (4.2), and 1.6 (5.4) in the switch group. The incidence of adverse events at application site in the continuation group over 52 weeks was 56.6% (98/173). Erythema, pruritus, and contact dermatitis at application site were observed in more than 10 patients each. There was no additional adverse event of clinical concern, and no increase in their incidence from the double-blind study. During the four weeks following switching, no patient discontinued or suspended administration due to adverse events. CONCLUSION: Application of the patch for 52 weeks was well tolerated and feasible, including switching from tablets.

Adverse Drug Event Profile Associated with Anti-dementia Drugs: Analysis of a Spontaneous Reporting Database.

Adverse drug events (ADEs) rates associated with anti-dementia acetylcholinesterase inhibitors are estimated to be 5%-20% and show a wide range of symptoms. No report has examined whether there is a difference in the anti-dementia drugs' ADEs profile. This study aimed to establish whether anti-dementia drugs' ADEs profile differed. Data was based on the Japanese Adverse Drug Event Report (JADER) database. The reporting odds ratios (RORs) was used to analyze data for ADEs from April 2004-October 2021. The target drugs were donepezil, rivastigmine, galantamine, and memantine. The top ten most frequently occurring adverse events were selected. The association between the RORs and antidementia drug ADEs was evaluated, and compared the distribution rate of expression age related to ADEs and each ADEs' timing of onset due to anti-dementia drugs. The primary outcome was RORs. Secondary outcome were expression age and time-to-onset of ADE associated with anti-dementia drugs. A total of 705,294 reports were analyzed. The adverse events incidence differed. Bradycardia, loss of consciousness, falls, and syncope incidence were significantly diverse. The Kaplan-Meier curve results for the cumulative ADEs incidence showed that donepezil had the slowest onset, while galantamine, rivastigmine, and memantine had approximately the same timing of onset.

Efficacy and safety of a transdermal donepezil patch in patients with mild-to-moderate Alzheimer's disease: A 24-week, randomized, multicenter, double-blind, parallel group, non-inferiority study.

AIM: To assess non-inferiority of a donepezil patch 27.5 mg compared with donepezil hydrochloride tablets 5 mg in patients with mild-to-moderate Alzheimer's disease; and to compare the efficacy and safety profiles of a donepezil patch 27.5 mg with donepezil hydrochloride tablets 5 mg. METHODS: This was a 24-week, multicenter, randomized, double-blind, double-dummy, parallel group, non-inferiority (phase III) study carried out in Japan. The primary end-point was the change in the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version from baseline to week 24, with the aim of evaluating the non-inferiority of the donepezil patch 27.5 mg compared with donepezil hydrochloride tablets 5 mg. RESULTS: Of 340 randomized patients, 303 completed the double-blind period. Changes from baseline in the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version at week 24 (least squares mean ± standard error) were -0.7 ± 0.4 (donepezil patch 27.5 mg) and 0.2 ± 0.4 (donepezil hydrochloride tablet 5 mg). The difference in the least squares means (95% confidence interval) was -0.9 (-2.01 to 0.14). The upper bound of the 95% confidence interval for the difference between groups was less than the predefined non-inferiority margin of 2.15. The donepezil patches 27.5 mg also had a safety profile that showed good tolerability comparable with donepezil hydrochloride tablets 5 mg. CONCLUSIONS: Non-inferiority on suppression of cognitive decline was shown for the donepezil patch 27.5 mg when compared with donepezil hydrochloride tablets 5 mg in Japanese patients with mild-to-moderate Alzheimer's disease. Geriatr Gerontol Int 2023; 23: 275-281.

[Abnormal posture of the trunk related to donepezil hydrochloride: report of 2 cases].

Patient 1, an 80-year-old woman with Alzheimer's disease, had been taking donepezil 5 mg for 2 years. Donepezil was increased to 10 mg, and 2 months later, the patient developed dropped head syndrome. MRI and needle EMG abnormality of the neck extensor muscles suggested focal myopathy, but the symptom disappeared within 2 months by discontinuing donepezil. Patient 2, a 78-year-old man with Lewy body dementia, had been taking levodopa and pramipexole (PPX). One month after tapering levodopa, donepezil 3 mg was introduced, and Pisa syndrome (bending of the trunk to the right anterior direction) developed 10 days later. Donepezil and PPX were discontinued and levodopa was increased. Within 5 months, his posture had almost recovered. Cholinesterase inhibitors can induce abnormal posture of the trunk, and clinicians should be aware of this uncommon but important side effect.

Investigation of the Asyogh's rectangular device for learning and memory testing in Wistar rats.

This study aimed to design Asyogh's rectangular device that is used for memory testing in rodents. It was found that scopolamine (3 mg/kg i.p.) and diazepam (1 mg/kg i.p.) caused significant memory deficits in rats, as evidenced by increased transfer latency times. However, these memory deficits were significantly reversed when the rats were pretreated with Donepezil. It further demonstrates that pretreated donepezil is able to effectively restore the memory deficits induced by scopolamine and diazepam, as indicated by the significant recovery in TLT. The present study showed that the device used to measure transfer latency time that was a valuable tool for assessing memory and cognitive function in rodents.

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. OBJECTIVE: To characterize long-term safety and efficacy of ozanimod. METHODS: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. RESULTS: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DAYBREAK. During DAYBREAK, 2143 patients (85.9%) had treatment-emergent adverse events (TEAEs; similar in nature to those in the parent trials), 298 (11.9%) had a serious TEAE, and 75 (3.0%) discontinued treatment due to TEAEs. Serious infections (2.8%), herpes zoster infections (1.7%), confirmed macular edema cases (0.2%), and cardiac TEAEs (2.8%) were infrequent. Adjusted annualized relapse rate was 0.103 (95% confidence interval, 0.086‒0.123). Over 48 months, 71% of patients remained relapse free. Adjusted mean numbers of new/enlarging T2 lesions/scan and gadolinium-enhancing lesions were low and similar across parent trial treatment subgroups. CONCLUSIONS: This long-term extension of ozanimod trials confirmed a favorable safety/tolerability profile and sustained benefit on clinical and magnetic resonance imaging measures of disease activity.

Efficacy of rasagiline monotherapy for early Parkinson disease: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Rasagiline monotherapy is approved in early Parkinson's disease (PD) for motor benefit. However, the efficacy and optimal rasagiline dosage in improving Unified Parkinson's Disease Rating Scale (UPDRS) subscale scores between Japanese and Caucasian individuals remain uncertain. AIMS: To investigate the efficacy of rasagiline monotherapy and evaluate differences between early PD patients in Eastern and Western countries. METHODS: The study design involved the meta-analysis of randomized controlled trials identified using electronic databases. RESULTS: The mean difference (MD) in total UPDRS scores indicated no significant difference between the 1 and 2 mg rasagiline (MD = -0.00, 95% confidence interval (CI) = -0.82 to 0.81). Compared with the placebo, the MD of UPDRS part I scores significantly improved in the 1 mg (MD = -0.33, 95% CI = -0.57 to -0.10) but not in the 2 mg. For UPDRS part II scores, the MD significantly improved in the 1 mg (MD = -0.87, 95% CI = -1.48 to -0.27) and 2 mg (MD = -0.98, 95% CI = -1.28 to -0.68). Regarding the UPDRS part III, the MD significantly improved in both (1 mg: MD = -2.41, 95% CI = -3.26 to -1.56; 2 mg: MD = -2.05, 95% CI = -2.64 to -1.46). The most commonly reported adverse events were headaches, back pain, and dizziness, with no statistical difference between the 1 mg rasagiline and placebo groups. Subgroup analysis revealed similar effects between Asian and Western participants. CONCLUSION: Rasagiline monotherapy at 1 mg per day is recommended for patients with early PD because of the benefits for motor, nonmotor functions, and safety.

P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson's Disease.

Despite levodopa's superior efficacy in reducing the motor symptoms of Parkinson's disease (PD), its risk to induce motor complications requires consideration of the pros and cons of initiating treatment with levodopa-sparing strategies. The current drive toward early levodopa monotherapy is primarily driven by safety and tolerability concerns with dopamine agonists and only mild efficacy of other available approaches. Recently, P2B001, a novel once-daily combination of low-dose, extended-release formulations of pramipexole and rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this drug evaluation, we review the preclinical and current clinical data for P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

Parkinson's disease is the fastest growing neurologic disorder across the globe. Once diagnosed, it is now generally agreed that there is no clinical rationale to postpone symptomatic treatment in people who develop Parkinson's-related disability. There are three main treatment options available for use in early Parkinson's disease: levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Of these, there is a current push toward using levodopa as the main first-line therapy. This is primarily because of the significant safety and tolerability concerns with dopamine agonists and only mild efficacy of MAO-B inhibitors. Recently, P2B001, a novel drug formulation combining once-daily, extended-release, low dosages of the dopamine agonist pramipexole and the MAO-B inhibitor rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this article, the authors review the preclinical and current clinical data on P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

Compared of efficacy and safety of high-dose donepezil vs standard-dose donepezil among elderly patients with Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: Donepezil is a first-line drug for the treatment of Alzheimer's disease (AD). However, there are no meta-analyses on efficacy and safety of high-dose versus standard-dose donepezil in the treatment of moderate-to-severe AD. RESEARCH DESIGN AND METHODS: We searched for randomized controlled trials (RCTs) from 1993 to May 2021 PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus databases. The outcomes of the meta-analysis included cognitive function, global assessment, and the incidence of adverse events and serious adverse events. RESULTS: Five RCTs (2974 people) were included in this meta-analysis. The improvement of cognitive function was significant among the patients with the treatment of high-dose donepezil [SMD = 0.12, 95% CI: 0.03 ~ 0.22; p = 0.01]. Between the two groups, there was no significant difference in global assessment. Compared with standard-dose donepezil, there was no difference in the incidence of adverse events when high-dose donepezil was used. However, it was found that high-dose donepezil administration increased the risk of heart problems through subgroup analysis of the two serious adverse events. CONCLUSION: High-dose donepezil is more effective than standard-dose donepezil in improving cognitive function of the elderly with moderate-to-severe AD. However, more attention should be paid to patients with heart problems when high-dose donepezil was used.

The association of changes of sleep architecture related to donepezil: A systematic review and meta-analysis.

BACKGROUND: Donepezil had been recognized to have impact on sleep quality in demented patients. However, there was insufficient evidences about the actual effect of donepezil in the sleep architectures. Our meta-analysis aimed to evaluate the changes of sleep architectures related to donepezil use. METHODS: Followed the PRISMA2020 and AMSTAR2 guidelines, electronic search had been performed on the databases of PubMed, Embase, ScienceDirect, ClinicalKey, Cochrane CENTRAL, ProQuest, Web of Science, and ClinicalTrials.gov. The outcome measurement was changes of sleep parameters detected by polysomnography. A random-effects meta-analysis was conducted. RESULTS: Total twelve studies had been involved. The percentage of REM sleep would significantly increase after donepezil treatment (Hedges' g = 0.694, p < 0.001). Compared to placebo/controls, subjects with donepezil would had significantly increased percentage of REM sleep stage (Hedges' g = 0.556, p = 0.018). Furthermore, donepezil was also associated with the decreased stage 2 sleep percentage, sleep efficiency, or total sleep time in different analysis conditions. CONCLUSION: Our meta-analysis provided detailed changes of sleep architectures related to donepezil treatment. Further larger sample size studies with stricter control of potential moderators are needed to clarify these issues.

Inhaled indacaterol/glycopyrronium/mometasone furoate fixed-dose combination in moderate-to-severe asthma.

INTRODUCTION: Fixed-dose long-acting beta2-agonist (LABA)/inhaled corticosteroid (ICS) combinations and add-on therapies as needed are the mainstay for maintenance therapy in asthma. However, more than 40% of patients have an inadequately controlled disease. The development of triple fixed-dose combinations consisting of long-acting muscarinic antagonist (LAMA)/LABA/ICS has paved the way for a new approach to reach therapeutic goals of an optimal control of symptoms and an effective prevention of future exacerbations. AREAS COVERED: A search was conducted on PubMed (MEDLINE), using the MeSH terms [asthma] + [indacaterol] + [glycopyrronium] +[mometasone furoate] + [treatment], until October 2021. Original data from clinical trials, prospective and retrospective studies and reviews were selected. Clinical studies with IND/MF/GLY (Enerzair Breezhaler) are summarized, and its place in current asthma therapy is examined. EXPERT OPINION: Triple therapy has been shown to be an effective and safe therapeutic option for asthma patients who remain uncontrolled despite ICS/LABA combination. The recently approved single-inhaler indacaterol/glycopyrronium/mometasone fixed dose combination has demonstrated to significantly reduce exacerbations, improve FEV1, symptoms and quality of life compared to ICS/LABA, including, salmeterol/fluticasone combination. Moreover, once-daily dosing may improve adherence.

Ozanimod: A First-in-Class Sphingosine 1-Phosphate Receptor Modulator for the Treatment of Ulcerative Colitis.

OBJECTIVE: To review the pharmacological and clinical profile of ozanimod in the treatment of ulcerative colitis (UC). DATA SOURCES: A PubMed search was conducted from inception to July 2021 using the keywords ozanimod, ulcerative colitis, and sphingosine 1-phosphate receptor modulator. Information was also extracted from published abstracts and the package insert. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 studies and relevant literature on ozanimod pharmacological and clinical profiles were reviewed. DATA SYNTHESIS: Ozanimod approval was based on True North, a phase 3 trial evaluating ozanimod's efficacy and safety in the treatment of moderate to severe UC. Compared with placebo, ozanimod led to clinical remission in a significantly higher proportion of patients in both the induction and maintenance phase. Additionally, for secondary end points of clinical response, endoscopic improvement, corticosteroid-free remission, and mucosal healing, ozanimod performed significantly better than placebo. Common adverse events included infections, headaches, hypertension, bradycardia, and liver enzyme elevations. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Ozanimod is the first sphingosine 1-phosphate modulator to be approved for UC and is administered orally. Its efficacy profile is comparable with other UC medications. However, its safety profile is unique, requiring extensive assessments prior to initiation of and during treatment. Thus, it is unclear how ozanimod will be positioned in UC treatment. CONCLUSION: Ozanimod is another option in the growing arsenal of UC treatment. Although it offers a novel mechanism of action and is administered orally, there are important safety, dosing, and pharmacokinetic factors to consider prior to initiation and use.

Real-world Safety and Efficacy of Indacaterol/Glycopyrronium in Japanese Patients with Chronic Obstructive Pulmonary Disease: A 52-week Post-marketing Surveillance.

Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with chronic obstructive pulmorary disease (COPD) in a real-world setting in Japan. Methods This 52-week, multicentre, post-marketing surveillance conducted in Japan between December 2013 and August 2019 included patients using IND/GLY for the first time to relieve airway obstructive disorder-related symptoms. Safety outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs during the 52-week period. The incidence of priority variables, including cardiovascular/cerebrovascular (CCV) AEs, ß-adrenergic-related or anticholinergic AEs and cough, was also assessed. Safety outcomes were also evaluated in elderly patients. Efficacy outcomes included a physician's global assessment, COPD assessment test (CAT) and lung function test. Results Of the 1,167 patients registered, 1,108 were included in the safety and efficacy analysis. In the safety analysis population, the incidence of AEs was 13.54%, that of SAEs was 4.69%, that of ADR was 3.61%, and that of serious ADRs was 0.36% over 52 weeks. CCV AEs, ß-adrenergic-related and anticholinergic AEs and cough were reported as 2.62%, 1.99% and 0.63%, respectively. The physician's global assessment showed that the overall response rate at the last assessment was 74.19%. The mean (95% confidence interval) CAT scores decreased from the start of treatment to Week 52 with IND/GLY [-6.9 (-7.8 to -6.1)]. The lung function (FEV1 and FVC) improved over time from the start of IND/GLY to Week 52. Conclusion IND/GLY demonstrated a good long-term safety profile in a real-world setting in Japanese patients with COPD, with beneficial effects in terms of the lung function and symptoms in clinical use.

Risk for Cardiovascular Adverse Events Associated With Sphingosine-1-Phosphate Receptor Modulators in Patients With Multiple Sclerosis: Insights From a Pooled Analysis of 15 Randomised Controlled Trials.

Background: All agents engaging sphongosine-1-phospate receptors (S1PRs) will have some cardiovascular effect. This study aimed to elucidate the risk of cardiovascular adverse events (AEs) in patients with multiple sclerosis (MS) treated with S1PR modulators (S1PRMs). Methods: We systematically searched the PubMed, EMBASE, and Cochrane Library databases for randomised controlled trials (RCTs) published through January 5, 2021. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. Sensitivity analyses and meta-regression were performed. Results: Seventeen RCTs (12 for fingolimod; 3 for ozanimod; 2 for siponimod) involving 13,295 patients were included. Compared with the control treatment, S1PRMs significantly increased the risk of cardiovascular AEs (RR, 2.21; 95% CI, 1.58-3.10; I2, 75.6%). Notably, the high-risk cardiovascular AEs associated with S1PRMs were primarily bradyarrhythmia (RR, 2.92; 95% CI, 1.91-4.46; I2, 30.8%) and hypertension (RR, 2.00; 95% CI, 1.49-2.67; I2, 56.5%). Subgroup analysis results were consistent with the primary outcomes except that ozanimod was associated with a higher risk of hypertension only (RR, 1.76; 95% CI, 1.10-2.82; I2, 0.0%), while siponimod was associated with a higher risk of bradyarrhythmia only (RR, 2.75; 95% CI, 1.75-4.31; I2, 0.0%). No significant inter-subgroup differences were observed (Pinteraction > 0.05). Conclusions: S1PRM use increased the risk of cardiovascular AEs by 1.21 times in patients with MS, and increased risks for bradyarrhythmia and hypertension were at 2.92- and 2.00-fold, respectively. These findings can help clinicians assess the risk of cardiovascular AEs in patients treated with S1PRMs. Systematic Review Registration: The PROSPERO ID is CRD42020183215.

Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed. RESULTS: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod. CONCLUSIONS: Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).

Effects of Body Weight on the Safety of High-Dose Donepezil in Alzheimer's Disease: Post hoc Analysis of a Multicenter, Randomized, Open-Label, Parallel Design, Three-Arm Clinical Trial.

BACKGROUND: Donepezil 23 mg is considered for Alzheimer's disease (AD) to optimize cognitive benefits; however, increased adverse events (AEs) can negatively influence drug adherence. We investigated whether body weight (BW) differs based on the presence of AEs, and which baseline factors were relevant to the safety of high-dose donepezil. METHODS: This study was a post hoc analysis of a multicenter randomized trial between 2014 and 2016. We included patients with moderate to severe AD treated with 10 mg/day of donepezil, and the daily dose was escalated to 23 mg with/without dose titration. Dose titration indicates 15 mg/day of donepezil before escalation or 10 mg and 23 mg/day on alternate days before escalation during the first 4 weeks. The patients were divided into 2 groups based on occurrence of AEs of special interest (AESIs) to compare baseline characteristics. We also assessed relationships between BW and AESIs. RESULTS: Among the 160 participants in the safety population, the baseline BWs differed between the AESI (+) (n = 67) and AESI (-) (n = 93) groups. Baseline BW was inversely correlated with the occurrence of AESIs (p = 0.020), and this relationship was prominent in the no-dose titration group (p = 0.009) but absent in the dose-titration groups (p > 0.05). CONCLUSIONS: BW is the most important factor that correlated with cholinergic AEs. Hence, stepwise dose titration should be considered, particularly in patients with low BW, to minimize the inverse relationship between BW and the occurrence of AEs ("Clinicaltrials.gov" No. NCT02550665 registered on September 15, 2015).