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Safety and tolerability of donepezil 23?mg with or without intermediate dose titration in patients with Alzheimer's disease taking donepezil 10?mg: a multicenter, randomized, open-label, parallel-design, three-arm, prospective trial.

ABSTRACT: BACKGROUND:High-dose donepezil is currently prescribed for patients with Alzheimer's disease (AD) who showed poor or waning response to a lower dose at the risk of increasing cholinergic side effects. However, the adverse events (AEs) depending on the method of dose escalation have not been clarified yet. This study aimed to find out whether dose titration before escalating to donepezil 23?mg is preferred. We investigated safety and tolerability of donepezil 23?mg during the first 12?weeks of dose escalation in patients with moderate to severe AD. METHODS:This study was a 12-week, multicenter, randomized, open-label prospective trial. We included patients with moderate to severe AD who were treated with a stable dose of donepezil 10?mg/day. Patients were randomized into 3 groups according to the dose escalation method: 15?mg of donepezil for 4?weeks before escalating to 23?mg (group 1), 10?mg and 23?mg on alternate days for 4?weeks prior to escalation (group 2), and direct escalation to 23?mg (group 3). Safety analyses included incidence, severity, timing of AEs, relationship to the study drug, and premature study discontinuation due to AEs between the groups. RESULTS:Among 175 enrolled, 110 patients completed the study. Baseline characteristics were similar among the groups. Using safety population (N?=?160), cholinergic gastrointestinal symptoms including anorexia and nausea were the most common AEs and titration groups showed significantly fewer cases of nausea as compared with those in no-titration group. CONCLUSIONS:In this study, dose titration before escalating to donepezil 23?mg/day showed better safety in terms of cholinergic AEs. We suggest that dose titration during the first 4?weeks can be recommended for patients with moderate to severe AD. TRIAL REGISTRATION:Clinicaltrials.gov , NCT02550665. Retrospectively registered on 15 Sep 2015.

SUBMITTER: Hong YJ

PROVIDER: S-EPMC6492390 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Safety and tolerability of donepezil 23 mg with or without intermediate dose titration in patients with Alzheimer's disease taking donepezil 10 mg: a multicenter, randomized, open-label, parallel-design, three-arm, prospective trial.

Hong Yun Jeong YJ Han Hyun Jeong HJ Youn Young Chul YC Park Kyung Won KW Yang Dong Won DW Kim SangYun S Kim Hwa Jung HJ Kim Ji Eun JE Lee Jae-Hong JH

Alzheimer's research & therapy 20190501 1

<h4>Background</h4>High-dose donepezil is currently prescribed for patients with Alzheimer's disease (AD) who showed poor or waning response to a lower dose at the risk of increasing cholinergic side effects. However, the adverse events (AEs) depending on the method of dose escalation have not been clarified yet. This study aimed to find out whether dose titration before escalating to donepezil 23 mg is preferred. We investigated safety and tolerability of donepezil 23 mg during the first 12 wee ...[more]

PMID: 31039806

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Project description:BackgroundDonepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD), was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d.MethodSafety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs) and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434) included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed.ResultsThe safety population comprised 1434 patients: donepezil 23 mg/d (n = 963); donepezil 10 mg/d (n = 471); completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively). AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group), nausea (1.9% and 0.4%), diarrhea (1.7% and 0.4%), and dizziness (1.1% and 0.0%). The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%).DiscussionThe 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs, similar to those observed in studies with a dose increase from 5 to 10 mg/d.ConclusionThe good safety and predictable tolerability profile for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe AD.

Project description:BackgroundDonepezil (23 mg/day) is approved by the US Food and Drug Administration for the treatment of patients with moderate to severe Alzheimer's disease (AD). Approval was based on results from a 24-week, randomized, double-blind study of patients who were stable on donepezil 10 mg/day and randomized 2:1 to either increase their donepezil dose to 23 mg/day or continue taking 10 mg/day. The objective of this study was to assess the long-term safety and tolerability of donepezil 23 mg/day in patients with moderate to severe AD.MethodsPatients who completed the double-blind study and were eligible could enroll into a 12-month extension study of open-label donepezil 23 mg/day. Clinic visits took place at open-label baseline and at months 3, 6, 9, and 12. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs); changes in weight, electrocardiogram, vital signs, and laboratory parameters; and discontinuation due to AEs.Results915 double-blind study completers were enrolled in the open-label extension study and 902 comprised the safety population. Mean treatment duration in this study was 10.3 ± 3.5 months. In total, 674 patients (74.7%) reported at least one AE; in 320 of these patients (47.5%) at least one AE was considered to be possibly or probably study drug related. The majority of patients reporting AEs (81.9%) had AEs of mild or moderate severity. There were 268 patients (29.7%) who discontinued early, of which 123 (13.6%) were due to AEs.Patients increasing donepezil dose from 10 mg/day in the double-blind study to 23 mg/day in the extension study had slightly higher rates of AEs and SAEs than patients who were already receiving 23 mg (78.0% and 16.9% vs 72.8% and 14.0%, respectively). The incidence of new AEs declined rapidly after the first 2 weeks and remained low throughout the duration of the study.ConclusionThis study shows that long-term treatment with donepezil 23 mg/day is associated with no new safety signals. The elevated incidence of AEs in patients increasing the dose of donepezil from 10 mg/day to 23 mg/day was limited to the initial weeks of the study.

Project description:IntroductionProgressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function.MethodsIn the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated.ResultsAt week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores.ConclusionsPatients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.ClinicalTrials.gov identifier: NCT00478205.

Project description:IntroductionKnee osteoarthritis (OA) is a common painful disorder. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat knee pain. Lorecivivint (LOR), a novel IA cdc2-Like Kinase (CLK)/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase (DYRK) inhibitor thought to modulate Wnt and inflammatory pathways, has appeared safe and demonstrated improved patient-reported outcomes compared with placebo. While LOR is proposed for stand-alone use, in clinical practice, providers might administer LOR in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study assessed potential short-term safety, tolerability and pharmacokinetic (PK) interactions between IA LOR and triamcinolone acetonide (TCA) administered 7 days apart.MethodsHealthy volunteers were randomized to Treatment Sequence 1 (IA 40 mg TCA followed by IA 0.07 mg LOR) or Treatment Sequence 2 (IA 0.07 mg LOR followed by IA 40 mg TCA). Treatment-emergent adverse events (TEAEs) were categorized by "epoch", with epoch 1 spanning from first until second injection, and epoch 2 spanning from second injection until end of study. Plasma PK was assessed pre injection and out to 22 days after to assess PK treatment interaction.ResultsA total of 18 TEAEs were reported by 11 (27.5%) of 40 enrolled participants, and there were no serious adverse events. Thirteen TEAEs were reported in Treatment Sequence 1 and five in Treatment Sequence 2, similarly distributed between epochs 1 and 2. In all participants and at all time points, plasma LOR concentrations were below the limit of quantification (0.100 ng/mL). Geometric mean concentrations and PK parameters for TCA were similar between treatment sequences.ConclusionNo safety signals were observed. There were no quantifiable plasma concentrations of LOR in either Treatment Sequence. The PK of TCA was unaffected by previous LOR injection. These results suggest that IA administration of LOR and TCA in close time proximity is unlikely to pose a safety concern.Trial registrationClinicalTrials.gov identifier, NCT04598542.

Project description:IntroductionThe US Food and Drug Administration approved a 23 mg daily dose of donepezil for treatment of moderate to severe Alzheimer's disease (AD) based on outcomes from a large trial comparing the 23 mg/day dose with the standard 10 mg/day dose. Results from this study indicated that after 24 weeks, donepezil 23 mg/day provided significant cognitive benefits over donepezil 10 mg/day, measured using the Severe Impairment Battery (SIB). In the analyses reported herein, we further characterize the range of cognitive domains impacted by treatment with donepezil 23 mg/day.MethodsA post hoc analysis was conducted using data from a 24-week, randomized, double-blind trial comparing donepezil 23 mg/day versus 10 mg/day in 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20). Changes from baseline to week 24 in the nine SIB domain scores were analyzed in the intent-to-treat (ITT) population (baseline MMSE 0 to 20), in patients with more severe baseline AD (MMSE 0 to 16), and in severity strata based on baseline MMSE scores (0 to 5, 6 to 10, 11 to 15, 16 to 20).ResultsIn the ITT population, changes in six of the nine SIB domains favored donepezil 23 mg/day over donepezil 10 mg/day. LS mean treatment differences were significant for the language, visuospatial ability, and construction domains. In the more advanced cohort of patients (MMSE 0 to 16 at baseline), LS mean treatment differences were statistically significant favoring donepezil 23 mg/day in five of the nine domains: language, memory, visuospatial ability, attention, and construction. Descriptive analysis of LS mean changes in SIB domain scores in the four baseline severity strata showed variable patterns of response; overall, cognitive benefits of donepezil 23 mg/day were greatest in patients with MMSE scores of 0 to 15.ConclusionsThese results suggest that donepezil 23 mg/day provides benefits over 10 mg/day across a range of cognitive domains. The magnitude of benefit and domains impacted varied depending on the stage of AD; significant benefits with higher dose donepezil were most apparent at more advanced stages of AD and were most prominent in the language domain.

Project description:BackgroundTreatment of Alzheimer's disease with acetylcholinesterase inhibitors can result in symptomatic benefits, but patients often show variable responses. The objective of this post hoc analysis was to investigate relationships between easily identifiable baseline characteristics/demographics and cognitive response in patients treated with either donepezil 23 mg/d or 10 mg/d and to identify factors potentially influencing response.MethodsA post hoc analysis was conducted using data from a large, 24-week, randomized, double-blind, international study enrolling patients with moderate to severe Alzheimer's disease (baseline Mini-Mental State Examination [MMSE], 0-20) (NCT 00478205). Cognitive changes in subgroups of patients based on selected baseline and demographic characteristics were compared using the least squares mean changes in Severe Impairment Battery scores at Week 24. Univariate and multivariate analyses were also performed.ResultsDonepezil 23 mg/d provided statistically significant incremental cognitive benefits over donepezil 10 mg/d irrespective of baseline functional severity, measured by scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living-severe version (P < 0.05). When patients were categorized by baseline cognitive severity (MMSE score), significant benefits of donepezil 23 mg/d over 10 mg/d were seen in both subgroups when based on MMSE scores of 0-9 versus 10-20 (P < 0.02 and P < 0.01, respectively), and in the more severe subgroup when based on MMSE scores of 0-16 versus 17-20 (P < 0.0001 and P > 0.05). Statistically significant incremental cognitive benefits of donepezil 23 mg/d over 10 mg/d were also observed regardless of age, gender, weight, or prestudy donepezil 10 mg/d treatment duration (P < 0.05). In the multivariate analysis, the only significant interaction was between treatment and baseline MMSE score.ConclusionsThe cognitive benefits of donepezil 23 mg/d over 10 mg/d were achieved regardless of the patient's age, gender, weight, duration of prior donepezil 10 mg/d, and functional severity. The influence of baseline cognitive severity on response seemed to be dependent on the level of impairment, with cognitive benefits of donepezil 23 mg/d over 10 mg/d most apparent in those patients at a more advanced stage of disease. These data may be useful in helping practicing physicians make informed decisions for their patients with advanced Alzheimer's disease.

Project description:BACKGROUND:The current maintenance dose (10,000 AUeq/monthly) of a subcutaneous allergoid for house dust mite (HDM) immunotherapy has previously shown significant clinical efficacy in patients with HDM induced allergic rhinitis or rhinoconjunctivitis. In order to comply with the 2009 EMA guidelines on immunotherapy products, a study was conducted to evaluate the safety, tolerability and short-term treatment effects of up-dosing regimens with high doses (up to 40,000 AUeq) of allergoid HDM immunotherapy. METHODS:In total 48 patients with HDM-allergic rhinitis or rhinoconjunctivitis (29 M/19 F; 18-53 years) were included and enrolled into one of three up-dosing regimens (1:4:4): 1) a regular regimen with up-dosing to 40,000 AUeq followed by two maintenance doses (total duration 17 weeks), 2) an intermediate regimen (14 weeks) or 3) a fast regimen (11 weeks). Safety and tolerability were evaluated by monitoring of early and late local reactions and systemic reactions. In addition, short-term effects were assessed by conjunctival provocation test (CPT) and levels of serum allergen-specific IgE, IgG and IgG4. RESULTS:Thirty-nine patients completed the study according to protocol. No early local reactions occurred. Late local reactions (LLR) were observed in 12% of the injections. In total, 31 systemic reactions, all grade 1, were reported of which two needed oral antihistamine treatment. No grade 2 or higher systemic reactions were observed. Six patients (15%) did not reach the highest dose due to LLR and/or systemic reactions needing antihistamines (20% in the regular regimen, 16% in the intermediate regimen and 13% in the fast regimen). At the end of the study, an improvement in the CPT was observed in 82.1% of patients, indirectly indicating an early treatment effect at the current dose and higher doses. In addition, IgG4 immunoglobulin levels were significantly increased in all groups following treatment. CONCLUSIONS:In this open-label study, allergoid HDM immunotherapy in doses up to 40,000 AUeq was generally well tolerated and no clinically relevant safety issues were identified. In the safety aspects of the three up-dosing regimens no clinically relevant differences were encountered. Therefore, these dose ranges and up-dosing regimens can be safely included in future dose-finding efficacy studies.

Project description:BackgroundAripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for gluteal administration every 2 months, currently being investigated for the treatment of schizophrenia and bipolar I disorder (BP-I). The objectives of this trial were to evaluate the safety and tolerability of Ari 2MRTU 960, and the similarity of aripiprazole plasma concentrations following administration of Ari 2MRTU 960 or aripiprazole once-monthly 400 mg (AOM 400), in adults with schizophrenia or BP-I.MethodsThis was a 32-week open-label study. Eligible participants were randomized 1:1 to receive Ari 2MRTU 960 every 56 ± 2 days (four injections scheduled) or AOM 400 every 28 ± 2 days (eight injections scheduled). Participants received overlapping oral antipsychotic treatment with the first administration of study drug (there was no oral overlap for participants stabilized on AOM 400). Safety, tolerability, and pharmacokinetics (PK) were evaluated throughout the study. Primary safety endpoints included reported adverse events, injection site reactions, and extrapyramidal symptoms. Primary PK endpoints were plasma concentration of aripiprazole 56 days after the fourth dose of Ari 2MRTU 960 and 28 days after the eighth dose of AOM 400, and area under the concentration-time curve (AUC) from Day 0 to 56 postdose after the fourth dose of Ari 2MRTU 960, or AUC from Day 0 to 28 after the seventh and eighth doses of AOM 400.ResultsOf the 266 participants enrolled (schizophrenia, n = 185; BP-I, n = 81), 132 were randomized to receive Ari 2MRTU 960 and 134 were randomized to receive AOM 400. The majority (66.2%) of participants were male; 72.9% were Black or African American, and mean age was 47.3 years; demographic characteristics and baseline disease characteristics were generally well balanced between groups. Study completion rate was 77.3% in the Ari 2MRTU 960 group and 68.7% in the AOM 400 group. The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (71.2%) and AOM 400 (70.9%). The most frequently reported TEAEs were increased weight (Ari 2MRTU 960: 22.7%; AOM 400: 20.9%) and injection-site pain (Ari 2MRTU 960: 18.2%; AOM 400: 9.0%). The geometric means ratio (GMR) of aripiprazole plasma concentrations on the last day following the final dosing for Ari 2MRTU 960 versus AOM 400 was 1.011 (90% confidence interval [CI] 0.893-1.145), and the GMR of aripiprazole plasma exposure (area under the concentration-time curve) over the fourth Ari 2MRTU 960 dosing interval versus the seventh and eighth AOM 400 dosing intervals was 1.006 (90% CI 0.851-1.190).ConclusionsAri 2MRTU 960 was generally well tolerated in adults with schizophrenia or BP-I, with a safety profile comparable with that of AOM 400, and aripiprazole exposure equivalent to that with AOM 400 (ClinicalTrials.gov identifier: NCT04030143, registered on 23 July 2019).

Dataset Information

Safety and tolerability of donepezil 23?mg with or without intermediate dose titration in patients with Alzheimer's disease taking donepezil 10?mg: a multicenter, randomized, open-label, parallel-design, three-arm, prospective trial.

Publications

Safety and tolerability of donepezil 23 mg with or without intermediate dose titration in patients with Alzheimer's disease taking donepezil 10 mg: a multicenter, randomized, open-label, parallel-design, three-arm, prospective trial.

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