Disease Drug Trials Research Articles

Functional Magnetic Resonance Imaging in Alzheimer's Disease Drug Trials: A Mini-Review.

Alzheimer's disease (AD) is a progressive neurodegenerative pathology that leads to cognitive decline and dementia, particularly in older adults. It disrupts brain structure and function, with neurotoxic amyloid-β (Aβ) plaques being a primary pathological hallmark. Pharmacotherapeutic trials targeting Aβ and other AD pathological features aim to slow disease progression. Functional magnetic resonance imaging (fMRI) is a non-invasive tool that visualizes brain functional activity, aiding in evaluating the efficacy of AD drugs in clinical trials. This mini-review explores the role of fMRI in evaluating the impact of AD pharmacotherapeutic clinical trials conducted in the past seven years. Literature was systematically searched using two databases. The risk of bias was assessed with the Revised Cochrane risk-of-bias tool (RoB-2) for randomized clinical trials (RCTs). Four studies using fMRI to investigate AD drug efficacy were included. Cholinesterase, glutamatergic, and serotonergic drugs showed significant positive effects on brain functional activity, especially within the default mode network. Functional connectivity (FC) changes due to drug intake were linked to cerebellar and cholinergic decline in AD, correlating with improved global cognition and fMRI task performance. Recent RCTs demonstrate fMRI's ability to reveal longitudinal FC pattern changes in response to AD drug treatments across disease stages. Positive FC changes in distinct brain regions suggest potential compensatory mechanisms from drug intake. However, these drugs have limited efficacy, necessitating further research to enhance specific pharmacological interventions for clinical application.

Changes in Drug Clinical Trials of Thyroid Diseases in China, 2009-2022.

The incidence rate of thyroid diseases increased worldwide. This study aims to overview the changing landscape of drug clinical trials on thyroid disease during 2009-2022. The detailed information of thyroid disease drug trials registered on the National Medical Products Administration (NMPA) Registration and Information Disclosure Platform for Drug Clinical Studies was searched and collected. The thyroid drug clinical trials were analyzed by the characteristics, time trends, indications, and geographical distribution. Sixty-five thyroid disease drug clinical trials were launched from 2009 to 2022 in China, which included 21 trials in nontumorous thyroid disease and 44 trials in thyroid carcinoma. The number of registered trials of thyroid diseases including thyroid carcinoma and nontumorous thyroid disease increased steadily from 2009 to 2020. Bioequivalence studies accounted for the largest proportion (32[49.2%]), while phase I and Phase II studies both only accounted for 18.5% (12/65). A significant difference was observed in the trials phase, and randomization between thyroid carcinoma and nontumorous thyroid disease. In terms of clinical indications and drug mechanisms, the number of trials in multi-target tyrosine kinase inhibitors for thyroid carcinoma (n=35) ranked first, followed by thyroid hormone for hypothyroidism (n=7), thyrotropin for thyroid carcinoma (n=6). Sixty-five trials were led by 36 principal investigator (PI) units, and more than 30% of PI-leading units were located in Shanghai (n=7) and Beijing (n=4). During the past 13 years, the development of thyroid diseases drugs trials has achieved certain progress in thyroid carcinoma, especially the molecular targeted therapy, yet the development of drug trials on nontumorous thyroid disease was very slow.

Randomizing for Alzheimer's disease drug trials should consider the cancer history of participants.

Journal Article Accepted manuscript Randomizing for Alzheimer’s disease drug trials should consider the cancer history of participants Get access Viswanath Das, Viswanath Das Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic Correspondence to: Viswanath Das, PhD, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic E-mail: viswanath.das@upol.cz Search for other works by this author on: Oxford Academic PubMed Google Scholar Marián Hajdúch Marián Hajdúch Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic Search for other works by this author on: Oxford Academic PubMed Google Scholar Brain, awad177, https://doi.org/10.1093/brain/awad177 Published: 27 May 2023 Article history Received: 24 March 2023 Accepted: 17 April 2023 Published: 27 May 2023

Diversity in Alzheimer’s Disease drug trials: The importance of eligibility criteria

AbstractBackgroundTo generalize safety and efficacy findings, it is essential that diverse populations are well represented in global Alzheimer’s disease (AD) drug trials. In this review, we aimed to 1) investigate participant diversity in disease‐modifying AD trials over time, 2) identify which eligibility criteria were used and how they were defined, and 3) how the eligibility criteria may have affected participant diversity levels.MethodA systematic review of amyloid and tau trials in Alzheimer’s disease was performed using Medline, Embase, the Cochrane Library, and Clinicaltrials.gov, identifying 2247 records.ResultIn the 101 included AD trials, participants were predominantly white (median percentage: 94.7%, IQR: 81.0%‐96.7%); and this percentage showed no significant increase or decrease over time (2001‐2019). Eligibility criteria such as exclusion of persons with psychiatric illness (78.2%), cardiovascular disease (71.3%) and cerebrovascular disease (68.3%), obligated caregiver attendance (80.2%), and specific MMSE‐scores (90.1%; no significant increase/decrease over time, Fig. 1) may have led to a disproportionate exclusion of ethnoracially diverse individuals. Furthermore, many eligibility criteria—such as those describing diabetes, hepatic disease, and renal conditions—often were not well defined, or the cut‐offs varied considerably across studies.ConclusionEthnoracially diverse participants continue to be underrepresented in AD clinical trials. Several recommendations will be provided, such as the use of internationally recognized clinical classifications and cut‐offs, inclusion of participants with specific medical conditions as long as they are medically stable, and flexibility in requirements regarding caregiver attendance. Furthermore, changes need to be considered to 1) the instruments used in trials (e.g. overreliance on MMSE) and 2) requirements regarding education, literacy, and language.

Diversity in Alzheimer's disease drug trials: The importance of eligibility criteria.

IntroductionTo generalize safety and efficacy findings, it is essential that diverse populations are well represented in Alzheimer's disease (AD) drug trials. In this review, we aimed to investigate participant diversity in disease‐modifying AD trials over time, and the frequencies of participant eligibility criteria.MethodsA systematic review was performed using Medline, Embase, the Cochrane Library, and Clinicaltrials.gov, identifying 2247 records.ResultsIn the 101 included AD trials, participants were predominantly White (median percentage: 94.7%, interquartile range: 81.0–96.7%); and this percentage showed no significant increase or decrease over time (2001–2019). Eligibility criteria such as exclusion of persons with psychiatric illness (78.2%), cardiovascular disease (71.3%) and cerebrovascular disease (68.3%), obligated caregiver attendance (80.2%), and specific Mini‐Mental State Examination scores (90.1%; no significant increase/decrease over time) may have led to a disproportionate exclusion of ethnoracially diverse individuals.DiscussionEthnoracially diverse participants continue to be underrepresented in AD clinical trials. Several recommendations are provided to broaden eligibility criteria.

A blood-based diagnostic test incorporating plasma A\u03b242/40 ratio, ApoE proteotype, and age accurately identifies\xa0brain amyloid status: findings from a multi cohort validity analysis

BackgroundThe development of blood-based biomarker tests that are accurate and robust for Alzheimer’s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status.MethodsWe used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio.ResultsPlasma Aβ42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77–0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82–0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87–0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model.ConclusionsThis mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer’s disease; and may enhance the efficiency of enrolling participants into Alzheimer’s disease drug trials.

Goal attainment scaling as an outcome measure in rare disease trials: a conceptual proposal for validation

BackgroundGoal Attainment Scaling (GAS) is an instrument that is intended to evaluate the effect of an intervention by assessing change in daily life activities on an individual basis. However, GAS has not been validated adequately in an RCT setting. In this paper we propose a conceptual validation plan of GAS in the setting of rare disease drug trials, and describe a hypothetical trial where GAS could be validated.MethodsWe have used the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) taxonomy to deduce which measurement properties of GAS can be evaluated, and how. As individual GAS scores cannot be interpreted outside the context of a RCT, the validation of GAS needs to be done on trial as well as on individual level.ResultsThe procedure of GAS consists of three steps. For the step of goal selection (step 1) and definition of levels of attainment (step 2), face validity may be assessed by clinical experts. For the evaluation of the goal attainment (step 3), the inter and intra rater reliability can be evaluated on an individual level. Construct validity may be evaluated by comparison with change scores on other instruments measuring in the same domain as particular goals, if available, and by testing hypotheses about differences between groups. A difference in mean GAS scores between a group who received an efficacious intervention and a control group is an indication of well-chosen goals, and corroborates construct validity of GAS on trial level. Responsiveness of GAS cannot be evaluated due to the nature of the construct being assessed.ConclusionGAS may be useful as an instrument to assess functional change as an outcome measure in heterogeneous chronic rare diseases, but it can only be interpreted and validated when used in RCTs with blinded outcome assessment. This proposed theoretical validation plan can be used as a starting point to validate GAS in specific conditions.

Predicted economic damage from a quick, simple Alzheimer's disease cure

The estimated 5.8 million Alzheimer’s disease patients in the U.S. require an enormous share of national healthcare expenditures. Other nations face similar economic burdens. There have been great efforts, thus far unsuccessful, to discover an effective therapeutic, with 1081 Alzheimer’s disease drug trials completed as of May 2019. The pessimism thus engendered has forestalled contingency planning for the potential major economic repercussions of a simple, quick cure. Yet, promising new research spotlighting the possible “trigger” role of infectious agents might allow some or all cases of Alzheimer’s disease to be halted, reversed, or prevented with an antibiotic or antiviral compound, possibly even one already approved by drug regulators for other uses. The sudden advent of such an unexpected therapy would theoretically have dramatic impacts, both detrimental and beneficial, on the American economy. The damages would include a $414 billion shrinkage of Medicaid, Medicare and other revenues to all six sectors comprising the healthcare provider category. Nursing homes and skilled nursing facilities are projected to suffer the greatest loss of annual revenue: $51 billion and $16 billion, respectively. This would cause the loss of an estimated 654,000 jobs. Facility mortgage and commercial loan repayments could stop. Other adverse consequences would include detrimental effects on reserves for Social Security and pensions, cutbacks in dementia research funding, and reduced donations to Alzheimer’s disease advocacy groups. Insurance company reserves for fixed payment annuities already sold could be jeopardized. However, an Alzheimer’s disease cure would also create economic beneficiaries. Medicare and Medicaid would save up to a projected $195 billion annually. Life insurance companies and unpaid caregivers would also benefit financially. By identifying the healthcare sectors likely to be detrimentally impacted by a simple, quick Alzheimer’s disease cure, contingency plans can be made in the U.S. and other countries to assist the foreseeable painful transitions for staff and facilities.

Heterogeneity of Alzheimer\u2019s disease: consequence for drug trials?

BackgroundAlzheimer’s disease is a heterogenous disorder with multiple phenotypes and genotypes, although they eventually converge to a final common clinicopathological endpoint. However, Alzheimer’s disease drug trials do not account for the heterogeneity of the disease in trial design, impeding development of effective drugs.DiscussionAlzheimer’s disease drug trials commonly have wide inclusion criteria that subsume multiple subtypes of the condition, with varying genotypes, phenotypes, and clinical courses. The outcome variables used in many trials may not be sensitive for the particular disease subtype and trials may not follow patients for the appropriate length of time necessary for the subtype of disease. Methods of stratifying treatment trial design to account for disease heterogeneity using algorithms incorporating demographics, neuroimaging, genetics, and clinical phenotypes, as well as more tailored outcome measures, are proposed to allow for personalized, precision medicine in Alzheimer’s disease therapeutics development.SummaryApproaching Alzheimer’s disease as a heterogenous disorder will likely improve yield in the search for effective treatments for the condition.

Expanding rare disease drug trials based on shared molecular etiology.

Current clinical trial approaches in rare disease test one drug on one indication defined by a clinical phenotype. For targeted drugs, grouping patients by molecular etiology would make much more sense.

The Language of Hope: Therapeutic Intent in Stem-Cell Clinical Trials

Electronic registries for clinical trials present an opportunity for miscommunication of benefits and risks to potential subjects. We explored early phase clinical trials registered on the National Library of Medicine's ClinicalTrials.gov for inappropriate language patterns (terms and statements) that could convey therapeutic intent. We sampled early-phase heart disease clinical trial records involving stem cells registered on Clincaltrials.gov between April 24, 2004, and September 18, 2008, and randomly selected heart disease drug trials from the same period for comparison. Trial sponsorship and location were coded. Textual data were extracted from titles, purpose, outcome measures, and detailed description statements and coded for readability and the presence of therapeutic language. Content and multiple correspondence analyses were employed to explore language patterns suggestive of therapeutic intent. We found statistically significant differences in therapeutic language use between stem cell (n = 72, median statement frequency 3.5, IQR 1–7) and drug trial (n = 72 median statement frequency 1, IQR 0–3.5) records; Mann–Whitney U = 1808.5, p = .001. A correspondence plot, accounting for 65% of data variability, suggests correspondences among patterns of therapeutic language, regional location, and type of sponsorship between the two record types. Individual-, institute-, and government-sponsored stem-cell trials showed a tendency toward high frequency use of therapeutic statements. This study, the first to explore the potential for therapeutic miscommunication in electronic registries, suggests the need for greater scrutiny of language used in registered trials. Recommendations are offered to improve the integrity of records submitted to ClinicalTrials.gov.

Review of outcome measurement instruments in Alzheimer's disease drug trials: psychometric properties of behavior and mood scales.

This article reviews the reliability and validity of eight scales for behavior and mood problems that were identified in a comparative analysis of Alzheimer's disease (AD) drug trials. The scales are the Brief Psychiatric Rating Scale, the Alzheimer's Disease Assessment Scale-noncognitive, the Relative's Assessment of Global Symptomatology, the Consortium to Establish a Registry for Alzheimer's Disease-Behavior Rating Scale for Dementia, the Dementia Behavior Disturbance scale, the Neuropsychiatric Inventory, and two scales for depressive symptoms, the Cornell Scale for Depression in Dementia and the Dementia Mood Assessment Scale. This article also examines methodological limitations in the way the published literature has assessed the psychometric properties of these scales. The aim is to help clinicians and potential trial investigators select appropriate measurement instruments with which to assess behavior and mood problems in AD and to assist AD researchers in the evaluation of the psychometric properties of such scales.

Review of outcome measurement instruments in Alzheimer's disease drug trials: psychometric properties of global scales.

The use of global outcome measures with strong psychometric properties in Alzheimer's disease (AD) drug trials is encouraged. This article focuses on Clinician Global Impression of Change scales, the Clinical Dementia Rating, and the Global Deterioration Scale to provide (1) a review of psychometric properties, (2) a critique of how these properties are assessed in the literature, and (3) a basis for evaluating, from the standpoint of psychometric properties, the appropriateness of using a given global scale in a drug trial. Reported reliability and validity estimates for the aforementioned scales range from fair to very good, but small sample sizes and/or inappropriate measures of correlation weaken the quality of the evidence. There is also a dearth of published information on responsiveness to change. Researchers planning AD drug trials should consider these issues, along with the interval between test administrations for test-retest reliability, to help select appropriate global outcome measurement instruments.

Review of outcome measurement instruments in Alzheimer's disease drug trials: introduction.

This article introduces a four-part series on outcome scales used in Alzheimer's disease drug trials. First, it discusses the division of scales into four domains: cognition, functional ability/quality of life, behavior/mood, and global. Within each domain, the shortcomings of existing literature reviews are outlined, and the need for a more coherent view of the psychometric properties of the scales is emphasized. Second, the key concepts of reliability, validity, and responsiveness to change are defined and explained. This explanation also provides an overview of the statistical techniques used to assess measurement properties. Finally, the methods used to select the scales for review in the subsequent articles are explained, and each article is briefly introduced.

Review of outcome measurement instruments in Alzheimer's disease drug trials: psychometric properties of functional and quality of life scales.

The psychometric properties of functional and quality of life outcome measures that were used for the purpose of showing changes in antidementia drug trials for Alzheimer's disease are described and critiqued. The seven functional scales reviewed for reliability, validity, and responsiveness to change included the Geriatric Evaluation by Relative's Rating Instrument, the Physical Self-Maintenance Scale, the Instrumental Activities of Daily Living, the Blessed Dementia Scale, Part 1 and its revised version, the Interview for Deterioration in Daily Living with Dementia, the Unified Activities of Daily Living, and the Dependence Scale. The Progressive Deterioration Scale and Quality of Life Assessment were classified as quality of life scales. The majority of the scales were found to exhibit serious limitations, such as incomplete reliability and validity assessment for the intended uses. The most pervasive problem was a lack of data on responsiveness to change. It is recommended that further research be conducted to develop new tools or enhance existing measures for the assessment of both quality of life and functional ability.