Selection Of Subjects For Clinical Trials Research Articles

Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer's Disease.

Background:Age may affect treatment outcome in trials of mild probable Alzheimer’s disease (AD).Objective:We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD.Methods:Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation (“on”) or sham DBS-f (“off”) for 12 months.Results:The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the “on” and “off” groups in the intent to treat (ITT) population. There was a significant age by time interaction with the Alzheimer’s Disease Assessment Scale; ADAS-cog-13 (p = 0.028). Six of the 12 enrolled participants < 65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7%of the 30 participants≥65 years old regardless of treatment assignment (p = 0.005). While not significant, post-hoc analyses favored DBS-f “off” versus “on” over 12 months in the < 65 age group but favored DBS-f “on” versus “off” in the≥65 age group on all clinical metrics. On the integrated Alzheimer’s Disease rating scale (iADRS), the effect size contrasting DBS-f “on” versus “off” changed from +0.2 (favoring “off”) in the < 65 group to –0.52 (favoring “on”) in the≥65 age group.Conclusion:The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials.

Fair and equitable subject selection in concurrent COVID-19 clinical trials

Clinical trials emerged in rapid succession as the COVID-19 pandemic created an unprecedented need for life-saving therapies. Fair and equitable subject selection in clinical trials offering investigational therapies ought to...

The combined effects of microglia activation and brain glucose hypometabolism in early-onset Alzheimer\u2019s disease

BackgroundEarly-onset Alzheimer’s disease (EOAD) is characterized by young age of onset (< 65 years), severe neurodegeneration, and rapid disease progression, thus differing significantly from typical late-onset Alzheimer’s disease. Growing evidence suggests a primary role of neuroinflammation in AD pathogenesis. However, the role of microglia activation in EOAD remains a poorly explored field. Investigating microglial activation and its influence on the development of synaptic dysfunction and neuronal loss in EOAD may contribute to the understanding of its pathophysiology and to subject selection in clinical trials. In our study, we aimed to assess the amount of neuroinflammation and neurodegeneration and their relationship in EOAD patients, through positron emission tomography (PET) measures of microglia activation and brain metabolic changes.MethodsWe prospectively enrolled 12 EOAD patients, classified according to standard criteria, who underwent standard neurological and neuropsychological evaluation, CSF analysis, brain MRI, and both [18F]-FDG PET and [11C]-(R)-PK11195 PET. Healthy controls databases were used for statistical comparison. [18F]-FDG PET brain metabolism in single subjects and as a group was assessed by an optimized SPM voxel-wise single-subject method. [11C]-PK11195 PET binding potentials were obtained using reference regions selected with an optimized clustering procedure followed by a parametric analysis. We performed a topographic interaction analysis and correlation analysis in AD-signature metabolic dysfunctional regions and regions of microglia activation. A network connectivity analysis was performed using the interaction regions of hypometabolism and [11C]-PK11195 PET BP increases.ResultsEOAD patients showed a significant and extended microglia activation, as [11C]-PK11195 PET binding potential increases, and hypometabolism in typical AD-signature brain regions, i.e., temporo-parietal cortex, with additional variable frontal and occipital hypometabolism in the EOAD variants. There was a spatial concordance in the interaction areas and significant correlations between the two biological changes. The network analysis showed a disruption of frontal connectivity induced by the metabolic/microglia effects.ConclusionThe severe microglia activation characterizing EOAD and contributing to neurodegeneration may be a marker of rapid disease progression. The coupling between brain glucose hypometabolism and local immune response in AD-signature regions supports their biological interaction.

Disease activity in chronic inflammatory demyelinating polyneuropathy

IntroductionEvaluation of disease status in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is often done by a combination of clinical evaluation and electrodiagnostic studies. A CIDP disease activity status (CDAS) was developed to standardize outcomes in CIDP patients. We aimed to determine if the CDAS was concordant with classical evaluation and whether CDAS enables benchmarking of CIDP. MethodsWe performed a retrospective chart review of 305 CIDP patients and identified 206 patients with >1 visit and applied the CDAS to this cohort. We examined relationships between the CDAS and classical evaluation as to outcomes and compared our cohort to other CIDP cohorts who had CDAS. ResultsWe found that the CDAS mirrored disease severity as measured by electrophysiology and vibration perception thresholds in that CDAS class 5 had more severe neuropathy. Our results are similar to other cohorts in the middle CDAS strata with the exception of fewer subjects in CDAS 1 and more in CDAS 5. The only demographic factor predicting CDAS 5 in our cohort was age, and the overall treatment response rate using the CDAS classification was 79.3%. ConclusionsCDAS appears to have sufficient face-validity as a grading system to assess disease activity in relation to treatment status. The use of CDAS appears to allow benchmarking of patients with CIDP that may be useful in subject selection for clinical trials and also to highlight differences in practice.

Prevalence of Submandibular Gland Synucleinopathy in Parkinson's Disease, Dementia with Lewy Bodies and other Lewy Body Disorders.

Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson's disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders. To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of subjects with PD and other Lewy body disorders. Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α-synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer's disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA). Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects. These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers.

Brain metabolic maps in Mild Cognitive Impairment predict heterogeneity of progression to dementia

[18F]FDG-PET imaging has been recognized as a crucial diagnostic marker in Mild Cognitive Impairment (MCI), supporting the presence or the exclusion of Alzheimer's Disease (AD) pathology. A clinical heterogeneity, however, underlies MCI definition. In this study, we aimed to evaluate the predictive role of single-subject voxel-based maps of [18F]FDG distribution generated through statistical parametric mapping (SPM) in the progression to different dementia subtypes in a sample of 45 MCI. Their scans were compared to a large normal reference dataset developed and validated for comparison at single-subject level. Additionally, Aβ42 and Tau CSF values were available in 34 MCI subjects. Clinical follow-up (mean 28.5 ± 7.8 months) assessed subsequent progression to AD or non-AD dementias. The SPM analysis showed: 1) normal brain metabolism in 14 MCI cases, none of them progressing to dementia; 2) the typical temporo-parietal pattern suggestive for prodromal AD in 15 cases, 11 of them progressing to AD; 3) brain hypometabolism suggestive of frontotemporal lobar degeneration (FTLD) subtypes in 7 and dementia with Lewy bodies (DLB) in 2 subjects (all fulfilled FTLD or DLB clinical criteria at follow-up); and 4) 7 MCI cases showed a selective unilateral or bilateral temporo-medial hypometabolism without the typical AD pattern, and they all remained stable. In our sample, objective voxel-based analysis of [18F]FDG-PET scans showed high predictive prognostic value, by identifying either normal brain metabolism or hypometabolic patterns suggestive of different underlying pathologies, as confirmed by progression at follow-up. These data support the potential usefulness of this SPM [18F]FDG PET analysis in the early dementia diagnosis and for improving subject selection in clinical trials based on MCI definition.

P.8.a.013 The challenge of subject selection in clinical trials

Although illusions, hallucinations and delusions did not play a prominent role in James Parkinson's original clinical descriptions, the longitudinal view of disease progression he advocated has important lessons for the study of such symptoms today. A focus on longitudinal progression rather than individual symptoms led to the concept of PD psychosis—a spectrum of positive symptoms in Parkinson's disease. The publication of criteria for PD psychosis in 2007 helped unify the disparate set of symptoms, raising their profile and resulting in a rapid expansion of literature focussing on clinical aspects, mechanisms, and treatment. Here we review this literature and the evolving view of PD psychosis. Adding to previous evidence of a prospective risk for dementia and the move to supervised care, key recent developments include: recognition of prevalence increase with disease duration; a broadening of symptoms included in PD psychosis; better characterization of higher visual and cognitive dysfunction risk factors; structural, functional, and neurotransmitter imaging biomarker evidence; and approval of pimavanserin in the United States for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research that promise a better understanding of the clinical management of PD psychosis and its role as a biomarker for PD stage and progression.

Poster 26: Word Reading Compared to Demographics-Based Estimates of Premorbid IQ in Early Huntington Disease

Background Irregular word pronunciation is a common method of estimating premorbid intellect, because it is resistant to neurological insult/deterioration. However, emerging research suggests word reading ability declines in some neurodegenerative diseases, resulting in an underestimation of premorbid IQ. Misrepresentation of predisease intellect may affect clinical diagnosis and confound the selection of participants for clinical trials. An alternative method is the use of a demographically-based equation to estimate intelligence. Aim To compare the WRAT Reading Subtest (a pronunciation measure) and the Barona Index (a demographically-based regression equation) as estimates of premorbid IQ in individuals with mild to moderate Huntington disease (HD). Method Using participants (n = 73) pooled from two clinical trials and an outpatient HD clinic, we examined WRAT and Barona standard scores and their discrepancy, along with demographic and clinical characteristics. Results Mean age was 47.6 years (SD = 11.7), total functional capacity (TFC) was 9.6 (SD = 3.0), and total motor score (TMS) was 32.7 (SD = 15.8). Average WRAT standard score was 91.9 (SD = 11.9), while Barona was 108.0 (SD = 7.2), with a mean discrepancy of 16.1 (SD = 10.7; range –42.3 to +6.3). Although true premorbid IQ is unknown, this sample overrepresented higher levels of education (i.e., ∼22% of the sample had 16+ years, while ∼8% had p Discussion The WRAT produced premorbid IQ estimates lower than the Barona for 93% of participants and was below expectations given the sample's mean education. Unlike the Barona, the WRAT was associated with impaired motor functioning, suggesting that it may decline with disease. Therefore, the Barona Index may be a more appropriate measure of premorbid intelligence in persons with HD and should be considered for subject selection in clinical trials and clinical evaluation.

Subject Selection for Clinical Trials

Subject Selection for Clinical Trials

Skewed distributions--new outcome measures.

The traditional measure of caries, the DMF index, either as prevalence or incidence of disease, has become highly positively skewed among children and young adults. Most discussion of skewed distributions has focused on the properties of statistical analyses using such data or the implications for sample sizes and subject selection in clinical trials. This paper examines the full range of epidemiologic studies, their aims and constitutive interest in order to identify the measurement problems associated with skewed DMF index data. Constitutive interests include: description; documentation; explanation and prediction; evaluation; advocacy; and, experimentation. 'New' outcome measures that would assist in reaching the aims and constitutive interests of the epidemiology of caries include caries severity grading, variants of prevalence, extent and severity and their combination into case definitions, and weighting of the components of the DMF index. Research questions for each area of 'new' outcome measures are identified as steps in the codifying of their use in the epidemiology of caries.

The selection of healthy volunteers for clinical investigation: the case for volunteer pools

Discussions on the healthy volunteer in clinical investigation do not attempt to define normality. In 34 healthy volunteers, 1653 biochemical and haematological tests were performed. The incidence of abnormal results was 11%. Only 4 subjects had all tests within normal limits and when these repeated only 1 subject still had all results within normal limits. The authors recommend that a stable volunteer pool, with regular physical examinations and blood tests, would provide a large, serial data base for use in subject selection for clinical trials. Attention should be given to human error. Protocols should be realistic, while ensuring the safety of volunteers.