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Journal ArticleDOI

Alzheimer's disease progression by geographical region in a clinical trial setting.

TL;DR: Assessment of disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology suggests that in multi- national clinical trials, AD progression or its measurement may differ across geographical regions.
Abstract: To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer’s disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology. Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI). Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline. These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm. ClinicalTrials.gov NCT00594568 – IDENTITY. Registered 11 January 2008. ClinicalTrials.gov NCT00762411 – IDENTITY2. Registered 26 September 2008 ClinicalTrials.gov NCT00905372 – EXPEDITION. Registered 18 May 2009 ClinicalTrials.gov NCT00904683 – EXPEDITION2. Registered 18 May 2009

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TL;DR: The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease clinical trials.
Abstract: Introduction The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study. Methods ADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning will be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition. Results Multimodal analyses will provide insight into AD pathophysiology and disease progression. Discussion ADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.

237 citations

Journal ArticleDOI
TL;DR: Drug development decision making can be improved based on lessons learned from past trials, improved interpretation of animal models, better pharmacologic characterization in phase I and phase II trials, appropriate sample size, diagnosis of AD with biomarker support, optimization of global recruitment, and avoiding inappropriate subgroup analyses can improve drug development success rates.
Abstract: Alzheimer disease (AD) drug development has a high failure rate. Drug development decision making can be improved based on lessons learned from past trials. Improved interpretation of animal models, better pharmacologic characterization in phase I and phase II trials, appropriate sample size, diagnosis of AD with biomarker support, optimization of global recruitment, and avoiding inappropriate subgroup analyses can improve drug development success rates. Alzheimer disease (AD) doubles in frequency every 5 years after the age of 65 years and is becoming increasingly common as the world’s population ages. It is estimated that in the United States alone, the number of patients with AD will burgeon from 5.3 million now to nearly 14 million by 2050.1 To address this impending public health disaster, there is an urgent need to discover and develop new drugs to prevent, delay the onset, slow the progression, or treat the cognitive and behavioral symptoms of AD. AD drug development has proven to be unusually difficult with a 99.6% failure rate in the decade of 2002 to 20122; currently, the success rate continues at the same low level. Each clinical trial provides evidence on a narrow range of questions. For example, does this dose of the test agent, given for a specific period of time (e.g., 18–24 months for disease-modifying therapies [DMTs]), to a defined population (e.g., preclinical AD; prodromal AD; mild, moderate, or severe AD dementia) produce a statistically significant difference compared with placebo in change from baseline on the prespecified primary outcomes, such as those measuring cognition (e.g., the Alzheimer’s Disease Assessment Scale – Cognitive Portion)3 and function (e.g., the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale).4 Questions regarding effects in other populations, other doses, other exposure durations, and effects on other instruments must all be addressed in separate trials. These complex constraints on clinical trials have evolved to allow them to define efficacy in a way that is acceptable to regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency. Regulatory acceptance of the data is the only way to gain marketing approval and make the agent widely available to patients. Each trial is a critical test of a narrow hypothesis and each incorporatesmethodologic decisions that offer valuable

213 citations

Journal ArticleDOI
TL;DR: Attention to disciplined drug development will increase the likelihood of success, decrease the risks associated with AD drug development, enhance the ability to attract investment, and make it more likely that new therapies will become available to those with or vulnerable to the emergence of AD.
Abstract: There is a high rate of failure in Alzheimer’s disease (AD) drug development with 99% of trials showing no drug-placebo difference. This low rate of success delays new treatments for patients and discourages investment in AD drug development. Studies across drug development programs in multiple disorders have identified important strategies for decreasing the risk and increasing the likelihood of success in drug development programs. These experiences provide guidance for the optimization of AD drug development. The “rights” of AD drug development include the right target, right drug, right biomarker, right participant, and right trial. The right target identifies the appropriate biologic process for an AD therapeutic intervention. The right drug must have well-understood pharmacokinetic and pharmacodynamic features, ability to penetrate the blood-brain barrier, efficacy demonstrated in animals, maximum tolerated dose established in phase I, and acceptable toxicity. The right biomarkers include participant selection biomarkers, target engagement biomarkers, biomarkers supportive of disease modification, and biomarkers for side effect monitoring. The right participant hinges on the identification of the phase of AD (preclinical, prodromal, dementia). Severity of disease and drug mechanism both have a role in defining the right participant. The right trial is a well-conducted trial with appropriate clinical and biomarker outcomes collected over an appropriate period of time, powered to detect a clinically meaningful drug-placebo difference, and anticipating variability introduced by globalization. We lack understanding of some critical aspects of disease biology and drug action that may affect the success of development programs even when the “rights” are adhered to. Attention to disciplined drug development will increase the likelihood of success, decrease the risks associated with AD drug development, enhance the ability to attract investment, and make it more likely that new therapies will become available to those with or vulnerable to the emergence of AD.

138 citations

Journal ArticleDOI
TL;DR: Alzheimer’s disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed.
Abstract: Alzheimer's disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds. Once an optimized agent is available and has been assessed for efficacy and toxicity in animals, it progresses through Phase I testing with healthy volunteers, Phase II learning trials to establish proof-of-mechanism and dose, and Phase III confirmatory trials to demonstrate efficacy and safety in larger populations. Phase III is followed by Food and Drug Administration review and, if appropriate, market access. Trial populations include cognitively normal at-risk participants in prevention trials, mildly impaired participants with biomarker evidence of AD in prodromal AD trials, and subjects with cognitive and functional impairment in AD dementia trials. Biomarkers are critical in trials of DMTs, assisting in participant characterization and diagnosis, target engagement and proof-of-pharmacology, demonstration of disease-modification, and monitoring side effects. Clinical trial designs include randomized, parallel group; delayed start; staggered withdrawal; and adaptive. Lessons learned from completed trials inform future trials and increase the likelihood of success.

110 citations

Journal ArticleDOI
TL;DR: A considerable amount of data, with an adequate representativeness in terms of sex/gender distribution, seem to be already available for dedicated analyses on this topic and a greater effort should be made to collect and report data on those factors interacting with sex and gender that may significantly influence clinical manifestations, outcomes, and trajectories over time of AD patients.

62 citations

References
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Journal ArticleDOI
TL;DR: A simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely.

76,181 citations


"Alzheimer's disease progression by ..." refers background in this paper

  • ...worse) [21], and the Neuropsychiatric Inventory (NPI; range 0 to 144, higher scores worse) [22,23]....

    [...]

01 Jan 2002
TL;DR: The Mini-Mental State (MMS) as mentioned in this paper is a simplified version of the standard WAIS with eleven questions and requires only 5-10 min to administer, and is therefore practical to use serially and routinely.
Abstract: EXAMINATION of the mental state is essential in evaluating psychiatric patients.1 Many investigators have added quantitative assessment of cognitive performance to the standard examination, and have documented reliability and validity of the several “clinical tests of the sensorium”.2*3 The available batteries are lengthy. For example, WITHERS and HINTON’S test includes 33 questions and requires about 30 min to administer and score. The standard WAIS requires even more time. However, elderly patients, particularly those with delirium or dementia syndromes, cooperate well only for short periods.4 Therefore, we devised a simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely. It is “mini” because it concentrates only on the cognitive aspects of mental functions, and excludes questions concerning mood, abnormal mental experiences and the form of thinking. But within the cognitive realm it is thorough. We have documented the validity and reliability of the MMS when given to 206 patients with dementia syndromes, affective disorder, affective disorder with cognitive impairment “pseudodementia”5T6), mania, schizophrenia, personality disorders, and in 63 normal subjects.

70,887 citations

Journal ArticleDOI
TL;DR: The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.
Abstract: We developed a new instrument, the Neuropsychiatric Inventory (NPI), to assess 10 behavioral disturbances occurring in dementia patients: delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions. Both the frequency and the severity of each behavior are determined. Information for the NPI is obtained from a caregiver familiar with the patient's behavior. Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable. The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.

6,662 citations


"Alzheimer's disease progression by ..." refers background in this paper

  • ...worse) [21], and the Neuropsychiatric Inventory (NPI; range 0 to 144, higher scores worse) [22,23]....

    [...]

Journal ArticleDOI
TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

3,726 citations


"Alzheimer's disease progression by ..." refers background in this paper

  • ...Moreover, AD is a complex disease with multiple risk factors including advancing age, lower education level, and carrying the ε4 allele of the apolipoprotein E (APOE) gene as well as other specific genetic loci [6-10]....

    [...]

Journal ArticleDOI
TL;DR: The output of the 1994 Xth Alzheimer's Disease International meeting in Edinburgh in 1994 reflects the international experience of the disorder in self‐help groups in Eastern Europe, difficulties of epidemiological studies in India and the complex interplay between staff attitude and residents' sexuality in nursing homes in the USA.
Abstract: Editors Note: This editorial and the subsequent three papers, ‘Alzheimer's Disease in Poland’, ‘Sexual Expression and Dementia’ and ‘Prevalence of Dementia in a Rural Setting: A Report from India’, reflect the output of the 1994 Xth Alzheimer's Disease International meeting in Edinburgh in 1994, emphasizing the international experience of the disorder in self-help groups in Eastern Europe, difficulties of epidemiological studies in India and the complex interplay between staff attitude and residents' sexuality in nursing homes in the USA. © 1997 John Wiley & Sons, Ltd.

1,973 citations