Pragmatic Clinical Trial

Applications must propose pragmatic clinical trials to test paradigms to detect cognitive impairment, including dementia, with adequate power in up to 3 populations including at least two specified populations that experience health disparities.

older African Americans, Hispanics and other populations that experience health disparities than among older whites.
Paradigms proposed must be supported by rigorous preliminary data that justifies proceeding to a pragmatic clinical trial.
race/ethnicity (African Americans, Hispanic/Latinos, Asian Americans, American Indians/Alaska Natives, Native Hawaiians and other Pacific Islanders), low socioeconomic status, rural populations, and sexual and gender minorities (lesbian, gay, bisexual and transgender).

Definition of a Pragmatic Clinical Trial

According to Califf and Sugarman, there are “three key attributes of PCTs: (1) an intent to inform decision-makers (patients, clinicians, administrators, and policy-makers), as opposed to elucidating a biological or social mechanism; (2) an intent to enroll a population relevant to the decision in practice and representative of the patients or populations and clinical settings for whom the decision is relevant; and (3) either an intent to (a) streamline procedures and data collection so that the trial can focus on adequate power for informing the clinical and policy decisions targeted by the trial or (b) measure a broad range of outcomes. Given these attributes, a common-sense definition for a PCT would thus be as follows:

Designed for the primary purpose of informing decision-makers regarding the comparative balance of benefits, burdens and risks of a biomedical or behavioral health intervention at the individual or population level. (Califf and Sugarman 2015).

large efficient study in real world provides evidence for adoption of an intervention into clinical practice
EHR | outcomes important to decision makers | interventions in routinbe clinical workflow | diversity study populations

Responsive Characteristics

Applications must propose pragmatic clinical trial(s).
Applications should identify and evaluate the risks and consequences of over- or under-detection of cognitive impairment using the proposed paradigm(s).
Pragmatic clinical trials involving populations that experience health disparities must identify the major (hypothesized) barriers resulting in delay and/or lack detection of cognitive impairment, including dementia, in the specific population, and clearly indicate which of these barriers are proposed to be overcome by using the paradigm.
Proposed pragmatic clinical trials must be sufficiently powered to definitively test proposed paradigms in at least three U.S. populations for detecting cognitive impairment, including dementia, in aging populations, at least two of which must be populations that experience health disparities.
Attention should be paid to consideration of when the paradigm(s) should and should not be used (e.g. settings, state of the patient).
Applicants should make their paradigm(s) available for others to utilize after the funding period, including how the paradigm(s) will be made available and with minimum cost and burden.
Projects should include a paradigm or paradigms that have preliminary evidence of efficacy and safety in the populations to be included in the trial.
Projects should address potential longer term goals for establishing feasibility and effectiveness, and how the proposed research will facilitate those goals by establishing an essential foundation for future efforts. Specifically, applicants must provide descriptions of: (i) how the research will yield information critical for next steps, including for widespread implementation of developed paradigm(s); (ii) how, including via utilizing paradigm(s) further developed and validated under this FOA, together with other appropriate strategies, it will be possible to fully assess the need and the potential impact in the United States for routinely detecting cognitive impairment, including dementia, in everyday clinical settings, including in primary care.
For applications that propose pragmatic clinical trials that are ancillary studies, the application must provide evidence that data collection on any additional outcome measures proposed in the ancillary study must be completed within the timeline of the parent study (analysis can extend beyond the parent study timeline).

UO1 Template

https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-22-009.html

The purpose of this funding opportunity announcement (FOA) is to invite pragmatic clinical trial applications to test paradigms designed to address the unmet need to detect cognitive impairment, including dementia, in large and diverse populations seen in primary care across the United States when a patient, relative, or care provider indicates concern. Applications must propose pragmatic clinical trials to test paradigms to detect cognitive impairment, including dementia, with adequate power in up to 3 populations including at least two specified populations that experience health disparities. Clinical paradigms proposed for pragmatic clinical trials should have rigorous supporting preliminary data and utilize tools that are simple to use, standardized, integrated into the electronic medical record (EMR) workflow, and ideally take five minutes or less to administer in a primary care clinical setting. Paradigms must provide standardized and implementable turnkey guidance via the EMR to the care provider for follow-up based on results of either “no objective cognitive impairment detected” or “cognitive impairment possible or detected”.

Applications Not-Responsive to this FOA

This FOA is only for studies related to humans; animal or other disease model studies are not responsive to this FOA.

Applications that propose clinical trials to test drug interventions are not-responsive to this FOA.
Delayed-Onset Trials.
Applications that do no include at least two populations that experience health disparities.
Applications that are not focused on pragmatic clinical trials for implementing rapid (10 minutes of primary care provider time or less) paradigm(s) for detecting cognitive impairment, including dementia in large human populations in the United States are not responsive.
Applications that do not link the proposed paradigm(s) to the EMR.
Applications that do not link the proposed paradigm(s) to billing.
Applications which do not include paradigms for detecting cognitive impairment, including dementia, which already have evidence of efficacy in the studied populations are not responsive.
Applications that do not indicate how they will make their paradigm(s) available for others to utilize both during the funding period (e.g., at a minimum, to other consortium members), and after, including how and with minimum burden, are not responsive.
Applications that focus on related topics that are not central to the goals of this FOA, such as differentiating among cognitive domains, determining the degree of cognitive impairment and whether the cognitive impairment detected does or does not meet criteria for dementia, and differentiating among different dementia disorders, are not responsive.
Applications that propose mechanistic clinical trials or BESH clinical trials are not responsive.

James Comments

diagnostic work up for patients that would be referred for dementia. I think this would require more work, although my time is currently limited.

I really think that a fantastic grant would be to apply your zCor and all those subjects who score “at risk” get a biomarker assessment of an MRI of the brain to assess cerebrovascular disease burden, which may be what zCor picks up the most, as it seems to identify cardiovascular risks that would contribute to vascular dementia.
In addition, since our tests can detect Alzheimer’s several years, if not a decade before development of symptoms, we could screen all high risk subjects with amyloid PET scans or spinal taps (see the attached document) to assess for underlying AD.
One limitation of biomarkers to predict specific diseases processes is that only Alzheimer’s can be detected early on. We don’t have biomarkers for other major dementias. But since Alzheimer’s is the most common in the elderly, I think it would still be worthwhile.
I’m also sending you a nice paper on the overview of diagnosis of Alzheimer’s Disease, which has elements of what I discuss in the diagnostic work up.

How early can we diagnose Alzheimer disease

DX workup

Letter of Support

Letters of support from participating HCS are required.

memory center
CRI
geriatric clinics

Resource Sharing

Applications funded under this FOA are expected to provide a specific plan for sharing paradigm(s), including tool(s), with Consortium collaborators , and very broadly with others at the conclusion of this 5 year program, consistent with achieving the goals of the program.

Availability of Appropriate Institutional Resources

Applicants must provide strong evidence of the availability of appropriate institutional resources, and suitable patient populations, providers, clinics, or facilities (depending on unit of randomization). Documentation of availability of eligible participants, clinic sites, or units of randomization, presented in tabular format must be provided. The application must include relevant information that addresses the feasibility of recruiting participants who are eligible for the pragmatic trial implementation study. Specifically, applicants must provide evidence that each recruiting center in the study or trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the submitted protocol. For multisite applications, information must be provided for each participating site.

Recruitment

The participant recruitment and retention plans must include a discussion of the availability of participants for the proposed study and the ability of enrollment sites to recruit and retain the proposed number of participants meeting the eligibility criteria, including women and minority participants as applicable. Data supporting recruitment and retention estimates must be provided. Evidence should be provided that relevant stakeholders (e.g., potential participants, referring and treating physicians, patient groups) have sufficient equipoise, consider the question to be important and the study acceptable.

For a multicenter trial, applicants should survey the potential clinical sites to ensure that recruitment targets can be met. Present the survey results using a table where the rows represent potential clinical sites and the columns include responses to questions from the survey. The survey questions will depend on the nature of the trial and the protocol-specified screening procedures but might include these:

Has the PD/PI previously recruited patients with this disease into a clinical trial?
Does this site have all necessary equipment to complete eligibility evaluations?
If not, how far (in miles) will patients need to travel to complete eligibility evaluations?
What is the total number of patients seen at this site in the past 12 months?
How many of these appear to meet the pre-screening eligibility criteria?
How many of these are likely to be found fully eligible and consent to be enrolled?
Do the sites have appropriate demographics to comply with the Inclusion of women and minorities NIH Policy?
Is there a clear plan for recruitment of diverse patients, based on the patient population seen at that facility or in the local community?

Study Timeline

For preparatory activities:

Development of data management system and case report forms, incorporating applicable NINDS Common Data Elements
Integration of the detection paradigm into the HCS HER.
Development of tools for data and quality management
Enrollment, retention, plans to minimize losses to follow-up, and acceptable attrition rates
Development of recruitment and retention strategies
Finalization of protocol, manual of procedures, consent forms, and data management plan
Finalization of planned analyses (including interim analyses, if appropriate)
Finalization of the study data sharing plan
Protocol approval from a Medical Monitor and/or Study Monitoring Committee
Initiation of contracts and training of clinical site personnel (NINDS expects the initiation of all study sites to occur in the start-up stage; if a large number of sites is needed, a plan that describes how additional sites will be added after the initiation of the study should be included)
Initiation of processes for including proposed international clinical sites, if applicable
Plans for site activation, execution of contracts and training of additional clinical sites, including any international sites, if applicable

Funding beyond timelimit Proposed milestones should be included for the entire trial, including any time beyond the five-year award. This information will be used for planning purposes and to support the rationale for the full trial but does not guarantee continued funding beyond the initial funding cycle.

Milestones and timelines will be refined and finalized in consultation with Program staff at the time of award.

For enrollment:

Completion of start-up activities (finalization of protocol, contracting of sites, registration in ClinicalTrials.gov, completion of any final regulatory approvals, etc.)
Earliest possible enrollment date
Enrollment of 25%, 50%, 75% and 100% of the targeted sample size
Completion of all study data collection
Completion of primary endpoint and secondary endpoint data analyses
Completion of final study report
Publication of primary study results
Reporting of results in ClinicalTrials.gov
Submission of final public use dataset to NINDS
If an adaptive design is to be used, indicate when adaptions will be considered.

Protection and Monitoring Plans

Study Team Structure

Study Design

participant eligibility criteria including the demographic characteristics of the people to be tested (such as age, sex, ethnicity), and how it will be determined whether or not a given individual will be selected for testing.
all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the research paradigm.
efficient data management and methods for monitoring quality, methods for monitoring the quality and consistency of paradigm administration, and methods for ensuring participant confidentiality.
informed consent process, and example consent language that describes sharing. Consent should allow sharing of de-identified clinical data and, if applicable, biospecimens, for broad biomedical research.

Statistical Power

Applicants must provide a description of statistical methods including sample size and power calculations, study outcome measures, plans for interim and final analyses, methods of bias control, and methods for handling missing data. Examples of the critical elements of a well-designed study are summarized on the NINDS website.

Review specifics

Neda Cooments

*Pharmacologic interventions do not really slow dementia – though there could be interventions like better chronic disease management for diabetes and hypertension and obesity sleep apnea that could decrease the risk of dementia – that is one of the very cool things to me about this work. *

If you wanted to add – here are some citations with text so you can preview by PMID: - it was pretty easy to find these, and I can find more if you want.

34711638: (prediabetes) Compared with normoglycemia, aHRs (95% CI) were 1.01 (1.01-1.02) in IFG, 1.45 (1.44-1.47) in new-onset diabetes, 1.32 (1.30-1.33) in known diabetes < 5 years, and 1.62 (1.60-1.64) in known diabetes ≥5 years. We found that associations between ischemic heart disease and chronic kidney disease with incident dementia were affected by the presence of diabetes. Ischemic stroke showed a greater association with incident dementia than diabetes.

34768695 (angiotensin receptor blocker medicine a/w decreased dementia)

We selected 21,208 patients from the Taiwan nationwide database from 1 January 2006 to 31 December 2006. We identified ARB users (n = 17,466) and ARB non-users (n = 3742) and their medication possession ratio (MPR). The Cox proportional hazard model was used to estimate hazard ratios (HRs) for the incidence of dementia in ARB users in the CKD population. During the 11-year follow-up period, 2207 dementia events were recorded; multivariate-adjusted hazard ratios for dementia by ARB usage and ARB usage per MPR were 0.578 (95% CI: 0.52-0.643) and 0.996 (95% CI: 0.995-0.998), respectively. This association was observed in almost all subgroups. Dose frequency effect of ARBs was noted; patients with higher MPRs of ARBs generally had higher protection from dementia. Patients with hypertension and CKD who received ARBs had a decreased risk of dementia. Protective effects of ARBs on dementia increased with the frequency of ARB use.

34482601 (vascular disease, MESA study)

African-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aβ positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aβ. Aβ was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline.

Also where are the approaches for specific aims 1-4 explicitly described?

I get that some elements are universal – e.g., study population, recruitment, diagnostic assessments, but we still need aim 1-4 statistical analysis described.

ZCOR_NIH

Wiki for Zero Knowledge Discovery, University of Kentucky, Division of Biomedical Informatics