Safety and efficacy of tofacitinib for the treatment of patients with juvenile idiopathic arthritis: preliminary results of an open-label, long-term extension study.

OBJECTIVES: We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study. METHODS: Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0. RESULTS: Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48. CONCLUSIONS: In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48. TRIAL REGISTRATION NUMBER: NCT01500551.

Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA). METHODS: This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434. FINDINGS: Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study. INTERPRETATION: The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections. FUNDING: Pfizer.

Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research.

The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross-validation across cohorts and laboratories.

Efficacy and safety of pregabalin versus levetiracetam as adjunctive therapy in patients with partial seizures: a randomized, double-blind, noninferiority trial.

OBJECTIVES: To assess the comparative efficacy and safety of pregabalin and levetiracetam for the reduction of seizure frequency in patients with partial seizures. METHODS: This was a randomized, double-blind, flexible-dose, parallel-group noninferiority study of pregabalin and levetiracetam (randomized 1:1) as adjunctive treatment in adult patients with refractory partial seizures. The study included a 6-week baseline phase, 4-week dose-escalation phase, and 12-week maintenance phase. The primary endpoint was the proportion of patients with a ≥ 50% reduction in 28-day seizure rate during the 12-week maintenance phase, as compared with baseline. Noninferiority of pregabalin was declared if the lower limit of the 95% confidence interval (CI) for the difference in responder rates was greater than the prespecified noninferiority margin of -12%. A key secondary endpoint was the percent change from baseline in 28-day seizure rate during the dose-escalation and maintenance phases. RESULTS: Five hundred nine patients were randomized to pregabalin (n = 254) or levetiracetam (n = 255) and 418 (208 pregabalin, 210 levetiracetam) completed the maintenance phase. With both pregabalin and levetiracetam, the proportion of patients with a ≥ 50% reduction in 28-day seizure rate was 0.59 (difference between groups [95% CI], 0.00 [-0.08 to 0.09]). Because the lower bound of the 95% CI was greater than the prespecified noninferiority margin of -12%, pregabalin was not inferior to levetiracetam. There was no significant difference between pregabalin and levetiracetam in the percent change in 28-day seizure rate (median difference [95% CI], 4.1 [-2.6 to 10.9], p = 0.3571). In a post hoc analysis, the proportion of patients who were seizure-free for the maintenance phase was lower with pregabalin (8.4%) than with levetiracetam (16.2%), p = 0.0155. Safety profiles were similar and consistent with prior trials. SIGNIFICANCE: These results indicate that pregabalin is noninferior, and has a similar tolerability, to levetiracetam as adjunctive therapy in reducing seizure frequency in patients with partial seizures.

Adjunctive use of controlled-release pregabalin in adults with treatment-resistant partial seizures: a double-blind, randomized, placebo-controlled trial.

OBJECTIVES: To assess the efficacy and tolerability of add-on pregabalin controlled-release formulation (PGB-CR) (doses of 165 or 330 mg/day) in patients with partial-onset seizures (POS). METHODS: This was a randomized, double-blind (DB), parallel-group study of PGB-CR once-daily as adjunctive treatment in adults with treatment-resistant partial seizures. After an 8-week baseline period, eligible patients were randomized (1:1:1) to placebo, PGB-CR 165 mg, or PGB-CR 330 mg for 14 weeks, including a 2-week dose escalation. Primary endpoint was the loge -transformed 28-day seizure rate for all POS with observable component during the full 14-week double-blind treatment phase. Secondary endpoints included the 50% responder rate and percent change from baseline in 28-day POS rate. RESULTS: Three hundred twenty-three patients were randomized and received treatment; placebo (n = 110), PGB-CR 330 mg (n = 100), PGB-CR 165 mg (n = 113); and 287 (88.9%) completed the trial. The primary efficacy analysis result, expressed as percent reduction from placebo, was 13.1% and 1.0% for PGB-CR 330 mg and PGB-CR 165 mg, respectively, and was not statistically significant (p = 0.091, 0.908). The proportion of 50% responders was similar for placebo (35.8%) and 165 mg PGB-CR (37.8%) and nominally higher for 330 mg PGB-CR (45.9%, p = 0.125 compared to placebo). The LS mean estimates of the percent change from baseline for placebo (-5.7%) was nominally smaller than 165 mg PGB-CR (-15.0%, p = 0.540) and 330 mg PGB-CR (-31.5%, p = 0.079); however, the median percent changes from baseline were not as well differentiated (placebo, -35.4%; 165 mg PGB-CR, -38.0%; 330 mg PGB-CR -43.4%). Rates of adverse events (AEs) were low for placebo and study drug; the most frequent reported AEs were dizziness, somnolence, and fatigue, consistent with the immediate-release formulation. SIGNIFICANCE: Results from this trial did not demonstrate that PGB-CR is effective in reducing seizure frequency below that of placebo. Both doses of PGB-CR were shown to be safe and well-tolerated.

A phase 2a study investigating the effects of ritlecitinib on brainstem auditory evoked potentials and intraepidermal nerve fiber histology in adults with alopecia areata.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Putting the Alzheimer's cognitive test to the test I: traditional psychometric methods.

BACKGROUND: The Alzheimer's Disease Assessment Scale-Cognitive Behavior section (ADAS-Cog) is the most commonly used cognitive test in AD clinical trials. However, there are concerns about its use in early-stage disease. Herein we examine those concerns using traditional psychometric methods. METHODS: We analyzed ADAS-Cog data (n = 675) based on six psychometric properties: data completeness; scaling assumptions; targeting; reliability; validity; and responsiveness. RESULTS: At the scale-level, criteria tested for data completeness, scaling assumptions (item total correlations 0.33-0.59), targeting (no floor/ceiling effects), reliability (Cronbach's α = 0.74), and validity (correlation with MMSE = -0.70) were satisfied. Responsiveness (baseline to 12 months; n = 145) was moderate to high (effect size = -0.73). However, 8 of 11 ADAS-Cog components had substantial ceiling effects (range 32%-83%), and decreased responsiveness associated with low to moderate effect sizes (0.14-0.65). CONCLUSION: In our study, many patients with AD found large portions of the ADAS-Cog too easy. Future research should consider modifying the ADAS-Cog or developing a new test.

Putting the Alzheimer's cognitive test to the test II: Rasch Measurement Theory.

BACKGROUND: The Alzheimer's Disease Assessment Scale-Cognitive Behavior section (ADAS-Cog) is the most widely used measure of cognitive performance in AD clinical trials. This key role has rightly brought its performance under increased scrutiny with recent research using traditional psychometric methods, questioning the ADAS-Cog's ability to adequately measure early-stage disease. However, given the limitations of traditional psychometric approaches, herein we use the more sophisticated Rasch Measurement Theory (RMT) methods to fully examine the strengths and weaknesses of the ADAS-Cog, and identify potential paths toward its improvement. METHODS: We analyzed AD Neuroimaging Initiative (ADNI) ADAS-Cog data (675 measurements across four time-points over 2 years) from the AD participants. RMT analysis was undertaken to examine three broad areas: adequacy of scale-to-sample targeting; degree to which, taken together, the ADAS-Cog items adequately perform as a measuring instrument; and how well the scale measured the subjects in the current sample. RESULTS: The 11 ADAS-Cog components mapped-out a measurement continuum, worked together adequately, and were stable across different time-points and samples. However, the scale did not prove to be a good match to the patient sample supporting previous research. RMT analysis also identified problematic "gaps" and "bunching" of the components across the continuum. CONCLUSION: Although the ADAS-Cog has the building blocks of a good measurement instrument, this sophisticated analysis confirms limitations with potentially serious implications for clinical trials. Importantly, and unlike traditional psychometric methods, our RMT analysis has provided important clues aimed at solving the measurement problems of the ADAS-Cog.

Establishing the psychometric underpinning of cognition measures for clinical trials of Alzheimer's disease and its precursors: a new approach.

The Alzheimer's disease (AD) Cognitive Behavior Section (ADAS-Cog) is the most commonly used cognitive test in clinical trials of AD. Recent trials have focused on people earlier in the course of disease; however, there are concerns about using the ADAS-Cog at this crucial stage. Using data from the Alzheimer's disease Neuroimaging Initiative study, we used a range of traditional psychometric tests to evaluate those concerns. This issue of Alzheimer's & Dementia includes two articles that evaluate the ADAS-Cog. These articles report evaluations using two psychometric approaches: traditional methods and new methods. In this review, we provide accompanying background information to this program of research.

Magnetic resonance imaging-measured atrophy and its relationship to cognitive functioning in vascular dementia and Alzheimer's disease patients.

BACKGROUND: Recent pathological studies report vascular pathology in clinically diagnosed Alzheimer's disease (AD) and AD pathology in clinically diagnosed vascular dementia (VaD). We compared magnetic resonance imaging (MRI) measures of vascular brain injury (white matter hyperintensities [WMH] and infarcts) with neurodegenerative measures (medial-temporal atrophy [MTA] and cerebral atrophy [CA]) in clinically diagnosed subjects with either AD or VaD. We then examined relationships among these measures within and between the two groups and their relationship to mental status. METHODS: Semi-quantitative MRI measures were derived from blind ratings of MRI scans obtained from participants in a research clinical trial of VaD (N = 694) and a genetic epidemiological study of AD (N = 655). RESULTS: CA was similar in the two groups, but differences in the mean of MTA and WMH were pronounced. Infarcts were significantly associated with CA in VaD but not in AD; MTA and WMH were associated with CA in both. WMH was associated with MTA in both groups; however, MRI infarcts were associated with MTA in VaD but not with MTA in AD patients. MTA was strongly associated with Mini-Mental State Examination scores in both groups, whereas evidence of a modest association between WMH and Mini-Mental State Examination scores was seen in VaD patients. CONCLUSIONS: MRI data from two dementia cohorts with differing dementia etiologies find that the clinical consequences of dementia are most strongly associated with cerebral and medial-temporal atrophy, suggesting that tissue loss is the major substrate of the dementia syndrome.

Assessment of cognition in early dementia.

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size.

BACKGROUND AND PURPOSE: We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria. METHODS: This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N=974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale and Clinician's Interview-Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method. RESULTS: Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale (least-squares mean difference, -1.156; 95% CI, -1.98 to -0.33; P<0.01) but not on the Clinician's Interview-Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7%), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group. CONCLUSIONS: Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.

The ADAS-cog in Alzheimer's disease clinical trials: psychometric evaluation of the sum and its parts.

BACKGROUND: The Alzheimer's Disease Assessment Scale Cognitive Behavior Section (ADAS-cog), a measure of cognitive performance, has been used widely in Alzheimer's disease trials. Its key role in clinical trials should be supported by evidence that it is both clinically meaningful and scientifically sound. Its conceptual and neuropsychological underpinnings are well-considered, but its performance as an instrument of measurement has received less attention. Objective To examine the traditional psychometric properties of the ADAS-cog in a large sample of people with Alzheimer's disease. METHODS: Data from three clinical trials of donepezil (Aricept) in mild-to-moderate Alzheimer's disease (n=1421; MMSE 10-26) were analysed at both the scale and component level. Five psychometric properties were examined using traditional psychometric methods. These methods of examination underpin upcoming Food and Drug Administration recommendations for patient rating scale evaluation. RESULTS: At the scale-level, criteria tested for data completeness, scaling assumptions (eg, component total correlations: 0.39-0.67), targeting (no floor or ceiling effects), reliability (eg, Cronbach's α: = 0.84; test-retest intraclass correlations: 0.93) and validity (correlation with MMSE: -0.63) were satisfied. At the component level, 7 of 11 ADAS-cog components had substantial ceiling effects (range 40-64%). CONCLUSIONS: Performance was satisfactory at the scale level, but most ADAS-cog components were too easy for many patients in this sample and did not reflect the expected depth and range of cognitive performance. The clinical implication of this finding is that the ADAS-cog's estimate of cognitive ability, and its potential ability to detect differences in cognitive performance under treatment, could be improved. However, because of the limitations of traditional psychometric methods, further evaluations would be desirable using additional rating scale analysis techniques to pinpoint specific improvements.

The long-term efficacy and tolerability of donepezil in patients with vascular dementia.

OBJECTIVE: To determine the long-term tolerability and efficacy of donepezil in patients with vascular dementia (VaD). METHODS: International, multicentre, open-label, 30-week extension study of two 24-week, randomised, double-blind, placebo-controlled studies. Participants were ambulatory adults (59% female; mean age, 74.7 +/- 0.3) with a diagnosis of possible or probable VaD and without a diagnosis of Alzheimer's disease, who were medically stable and had completed one of two double-blind studies. All patients received donepezil 5 mg/day for the first 6 weeks, then 10 mg/day (clinician approval required). Assessments were performed at week 6 and every 12 weeks thereafter. The main outcome measure was the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-cog). Safety/tolerability measures included adverse events (AEs) and physical and laboratory evaluations. RESULTS: Of 1219 eligible patients, 885 (72.6%) were enrolled, of which 707 (79.9%) completed the study; 127 (14.4%) patients discontinued due to AEs. A mean reduction (0.6-1.15 points) from double-blind study baseline score to week 54 (end of open-label study) on the ADAS-cog was observed for patients who received donepezil continuously for 54 weeks. ADAS-cog scores remained stable in the group that initiated donepezil treatment during the extension study. Most common donepezil-related AEs were nausea (occurring in 5.3%) and diarrhoea (8.8%); no unexpected AEs attributable to donepezil occurred. CONCLUSION: These data suggest that donepezil improves cognition for up to 54 weeks in patients with VaD. Patients initiating donepezil in this extension study did not perform as well on the primary outcome measure as those initiating donepezil in the double-blind study.

Scales as outcome measures for Alzheimer's disease.

The assessment of patient outcomes in clinical trials of new therapeutics for Alzheimer's disease (AD) continues to evolve. In addition to assessing drugs for symptomatic relief, an increasing number of trials are focusing on potential disease-modifying agents. Moreover, participants with AD are being studied earlier in their course of disease. As a result, the limitations of current outcome measures have become more apparent, as has the need for better instruments. In recognition of the need to review and possibly revise current assessment measures, the Alzheimer's Association, in cooperation with industry leaders and academic investigators, convened a Research Roundtable meeting devoted to scales as outcome measures for AD clinical trials. The meeting included a discussion of methodological issues in the use of scales in AD clinical trials, including cross-cultural issues. Specific topics related to the use of cognitive, functional, global, and neuropsychiatric scales were also presented. Speakers also addressed academic and industry initiatives for pooling data from untreated and placebo-treated patients in clinical trials. A number of regulatory topics were also discussed with agency representatives. Panel discussions highlighted areas of controversy, in an effort to gain consensus on various topics.

Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL.

BACKGROUND: Cholinergic deficits might contribute to vascular cognitive impairment. Trials of cholinesterase inhibitors in patients with vascular dementia are difficult because of heterogeneous disease mechanisms and overlap between vascular and Alzheimer's disease (AD) pathology in the age-group recruited. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a genetic form of subcortical ischaemic vascular dementia. It represents a homogeneous disease process, and because of CADASIL's early onset, comorbid AD pathology is rare. We did a multicentre, 18-week, placebo-controlled, double-blind, randomised parallel-group trial to determine whether the cholinesterase inhibitor donepezil improves cognition in patients with CADASIL. METHODS: 168 patients with CADASIL (mean age 54.8 years) were assigned to 10 mg donepezil per day (n=86) or placebo (n=82) by a computer-generated randomisation protocol. Inclusion criteria included a mini-mental state examination (MMSE) score of 10-27 or a trail making test (TMT) B time score at least 1.5 SD below the mean, after adjustment for age and education. The primary endpoint was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Secondary endpoints included scores on the ADAS-cog, MMSE, TMT A time and B time, Stroop, executive interview-25 (EXIT25), CLOX, disability assessment for dementia, and sum of boxes of the clinical dementia rating scale. Analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00103948. FINDINGS: 161 patients were analysed. There was no significant difference between donepezil (n=84) and placebo (n=77) in the primary endpoint. The least-squares mean change from baseline score was -0.81 (SE 0.59) in the placebo group and -0.85 (SE 0.57) in the donepezil group (p=0.956). There was a significant treatment effect favouring donepezil on the following secondary outcomes: TMT B time (p=0.023), TMT A time (p=0.015), and EXIT25 (p=0.022). Ten donepezil-treated patients discontinued treatment due to adverse events compared to seven placebo-treated patients. INTERPRETATION: Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. Our findings may have implications for future trial design in subcortical vascular cognitive impairment.

Performance-based and Observational Assessments in Clinical Trials Across the Alzheimer's Disease Spectrum.

Assessment of the earlier stages of Alzheimer's disease requires different strategies than those previously developed for fully syndromal Alzheimer's disease . This challenge is further magnified in very early stages, where symptomatology may be minimal and functional deficits very subtle to absent. This paper reviews strategies for performance-based assessment of the early stages of Alzheimer's disease, including assessments of cognition, functional capacity, and social cognition. Meetings with an International Society for CNS Clinical Trials and Methodology working group served as the basis for this paper and its companion. The current state of the art of detection and staging-oriented assessments is presented, and information is provided regarding the practicality and validity of these approaches, with a special focus on their usefulness in clinical trials for new medication development.

Outcomes Assessment in Clinical Trials of Alzheimer's Disease and its Precursors: Readying for Short-term and Long-term Clinical Trial Needs.

An evolving paradigm shift in the diagnostic conceptualization of Alzheimer's disease is reflected in its recently updated diagnostic criteria from the National Institute on Aging-Alzheimer's Association and the International Working Group. Additionally, it is reflected in the increased focus in this field on conducting prevention trials in addition to improving cognition and function in people with dementia. These developments are making key contributions towards defining new regulatory thinking around Alzheimer's disease treatment earlier in the disease continuum. As a result, the field as a whole is now concentrated on exploring the next-generation of cognitive and functional outcome measures that will support clinical trials focused on treating the slow slide into cognitive and functional impairment. With this backdrop, the International Society for CNS Clinical Trials and Methodology convened semi-annual working group meetings which began in spring of 2012 to address methodological issues in this area. This report presents the most critical issues around primary outcome assessments in Alzheimer's disease clinical trials, and summarizes the presentations, discussions, and recommendations of those meetings, within the context of the evolving landscape of Alzheimer's disease clinical trials.