NIH's new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically using ASSIST or an institutional system-to-system solution; paper applications will not be accepted.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Although statins have been shown to be effective in preventing cardiovascular events in persons with existing cardiovascular disease (CVD) and in persons up to age 75 who are free of CVD, there is significant uncertainty about the risks and benefits of statin treatment in adults over age 75 without CVD, especially those with common age-related conditions (multimorbidity, cognitive and physical decline, and polypharmacy). The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on the Treatment of Blood Cholesterol indicate that there are few data to assess the benefits and risks of statins therapy in individuals over age 75 without CVD. In its 2016 report, the US Preventive Services Task Force agrees with this assessment: " the current evidence is insufficient to assess the balance of benefits and harms of initiating statin use in adults 76 years and older." Both the ACC/AHA and the US Preventive Services Task Force list randomized trials to assess the overall benefits and risks of statins in adults over 75 years of age without clinical CVD as a high-priority research area.

Issues regarding statin use in persons over 75 years without clinical cardiovascular diseases, and the possible value of one or more clinical trials to address these issues, were discussed in detail at the NIA-sponsored workshop "Opportunities for Trials on Effects of Statins in Primary Prevention in Older Adults" in August 2017. Workshop participants included experts in geriatrics, cardiology, pharmacology, biostatistics, and related fields. Several other federal agencies were represented, including the Veterans' Administration, National Cancer Institute and National Heart, Lung and Blood Institute (NHLBI). The review of data presented at the workshop indicated that existing evidence is not sufficient to inform administration of statins to adults 75 years of age and older without clinical cardiovascular disease.

Results of several meta-analyses of randomized controlled trials show that statin therapy is associated with significant reduction in the risk of major incident CVD events in persons over 70 years of age. However, trials informing these meta-analyses did not enroll significant numbers of participants aged over 75 (the mean age of patients included in the meta-analyses was approximately 74 years), and rarely included those older than 80 years. Given the relationship between elevated serum LDL cholesterol and incident CVD risk declines with advancing age, questions remain regarding the size of potential incident CVD risk reduction with statin therapy, if any, at these older ages. In these older age groups, the most common CVD event will likely be heart failure. The majority of these heart failure cases will likely be non-reduced ejection fraction type. Compared to the prevention of myocardial infarction, there is little clinical trial evidence regarding the primary prevention of preserved ejection fraction heart failure in any age group. Furthermore, none of the statin trials on CVD outcomes were sufficiently powered to assess the effects of statins on other important outcomes for older adults such as dementia, functional status, quality of life, incident diabetes or adverse muscular effects. Finally, one of the most important limitations of the existing statins' trials is that elderly who were enrolled in these trials differ markedly from 'real world' older patients, who often have some physical and cognitive challenges, multiple chronic conditions and take numerous medications, and are seen daily in physicians' clinical practices.

Based on data from primarily younger persons on statins' cardiovascular effects, it has been estimated that statin therapy in adults over age 75 without clinical cardiovascular disease could prevent large numbers of cardiovascular events. However, a small to moderate increase in risk for disability or cognitive impairment could offset these cardiovascular benefits. Cardiac biomarkers have predicted the absolute magnitude of cardiovascular benefit from statins and cardiovascular risk in older individuals, and therefore possibly could identify subgroups with superior benefit to harm ratios. Additionally, there remains significant uncertainty about the extent and severity of statin-associated muscle symptoms and how they affect muscle strength, physical activity, performance, and falls in persons age 75 and above.

Data regarding the potential cognitive benefits and risks of statins in older adults is also inconclusive. A recent systematic review and meta-analysis of cognitive test data from clinical trials shows no significant adverse effects of statins on all tests of cognition in either cognitively normal participants or those with Alzheimer's disease despite post-marketing report of statin-related impaired cognition. A Cochrane Review published in 2016 found no evidence that statins given late in life to people at risk for vascular disease prevents cognitive decline or dementia. It is important to note that those at high risk for cognitive impairment, including the very elderly, were not included in significant numbers in these clinical trials assessing the potential effect of statins on incident and/or worsening dementia.

Given that increased age, comorbidities and functional limitations are strong risk factors for side effects, older adults' life expectancy could be substantially shorter than the time to benefit for a preventive intervention. Thus, administration of statins may expose participants to immediate risks with little likelihood of them surviving long enough to benefit from treatment. A related issue is the persistence of statins' benefits and under what conditions might statins continue to reduce risk after stopping therapy. In one clinical trial, adherence to treatment as measured by LDL reductions declined after the first year, but statin's beneficial effect increased over time in that incident CVD risk reduction remained significantly lower for five years. This phenomenon raises the question about maintenance of statin therapy in the very old, e.g., whether nonagenarians, or those with a limited life expectancy, who take statins need to continue to do so, particularly in light of the fact that their physiologic status may have changed markedly since they began taking statins, resulting in a higher risk versus benefit ratio.

In summer 2017, participants in NIA's workshop "Opportunities for Trials on Effects of Statins in Primary Prevention in Older Adults" concluded that limited data exist on comprehensive clinical and patient-centered outcomes (e.g., functional status, independence, quality of life, statin-related symptoms) in persons aged 75 years and older to evaluate the net benefit or harm in this population among existing studies. Given the increasing population aged 75 years and older, there is a critical need for a clinical trial of statin therapy in 'real world' older adults without known cardiovascular disease, incorporating outcomes of clinical and patient relevance. These trials are necessary to best inform decisions on initiation of statin treatment in older patients, taking into account risks, comorbidities, and preferences to provide optimal patient-oriented care.

NIA, NHLBI and NINDS request applications for a pragmatic trial from a network or consortium of health care delivery systems (HCS), which together cover most of the geographic regions of the United States, and a data coordinating center to assess the overall risks and benefits of statins in adults = 75 years without clinical cardiovascular disease. Specifically, the proposed trial should be designed to:

• Be conducted in a real-life healthcare delivery system setting (see "Introduction to pragmatic clinical trials" and "Rethinking Clinical Trials: A Living Textbook of Pragmatic Trials").
• Have broad inclusion criteria and use minimization, stratification or another technique to ensure enrollment of a high number of women, minorities, participants with frailty, mobility limitations, cognitive impairment, comorbidities and very old adults.
• Test the effects of moderate- to high-intensity statin (legally marketed in the US and approved by the FDA) vs placebo administered for up to five years in a blinded fashion by the health care providers (members of the HCS participating in the trial).
• Test the effects of interventions on the universal primary health outcome of survival free of dementia and persistent physical disability.
• Test the effects of interventions on a secondary composite cardiovascular outcome. The secondary composite cardiovascular outcome should include acute myocardial infarction, stroke, and heart failure and may include other cardiovascular components such as to death attributed to cardiovascular disease, urgent revascularization, and acute coronary syndrome requiring hospitalization. Characterization of the type of heart failure as well as stroke subtype should be considered.
• Assess the effects of interventions on exploratory outcomes, including but not limited to health-related quality of life, muscle-related symptoms, incident diabetes, hospitalization for any cause, medication adherence, and major sources of health care resource utilization.
• Ascertain the outcomes in a cost-efficient manner with a high degree of accuracy.
• Have sufficient power to assess the effects of interventions with high degree of confidence. The applicants are strongly encouraged to propose a trial that has a 90% power to assess the effects of interventions on both primary and secondary outcomes. Sample size calculations should be designed to accommodate high crossover rates between study treatment groups.
• Obtain biological samples so that analysis of biomarkers predictive of harms and benefits is feasible in the future.
• Periodically obtain sufficient number of biological samples to assess the difference in the serum LDL-cholesterol levels between the two trial arms.
• Include pre-specified analyses with adequate power to assess treatment risks and benefits in important subgroups (e.g., men/women, older/younger, differing baseline health status, differing ethnicity).

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

A button to access the online ASSIST system is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

Most applicants will use NIH's ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Sergei Romashkan, MD
National Institute on Aging (NIA)
Telephone: 301-435-3047
Fax: 301-402-1784
Email: [email protected]

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12
Core (Use for: Administrative and Trial Management; Data Coordinating Center (DCC); Recruitment and Retention; Biorepository and Laboratory; and Clinical Sites)	6
Project (Use for: Protocol Refinement and Study Start-up Phase; Vanguard Phase; Trial Implementation Phase; Statistical Analysis Plan)	6

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: required, maximum 1
• Administrative and Trial Management: required, maximum 1
• Data Coordinating Center (DCC): required, maximum 1
• Recruitment and Retention: required, maximum 1
• Biorepository and Laboratory: required, maximum 1
• Clinical Sites: required, maximum 1
• Protocol Refinement and Study Start-up Phase: required, maximum 1
• Vanguard Phase: required, maximum 1
• Trial Implementation Phase: required, maximum 1
• Statistical Analysis Plan: required, maximum 1

When preparing your application in ASSIST, use Component Type 'Overall'.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application. The PD(s)/PI(s) of the clinical trial must be experienced in multi-center clinical trial coordination and management, including success in meeting milestones and timelines, and have expertise in the content area of the proposed clinical trial. The experience of each PD/PI must be carefully documented, and roles and responsibilities must be well defined. In addition, the responsibilities and authority of each PD/PI must be specified. The application must ensure that a multidisciplinary team of appropriate personnel are proposed at the participating HCSs to facilitate the implementation of all aspects of the clinical trial.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Specific Aims: Describe the overall scientific objective of the proposed trial; the individual aims of the proposed study; how the individual components contribute to these aims; and the overall trial objective. For example, one of the aims could propose to test the effects of moderate- to high-intensity statin which is legally marketed in the US and approved by the FDA vs placebo on the primary universal health outcome of survival free of dementia and persistent physical disability and on a composite secondary cardiovascular outcome. The secondary composite cardiovascular outcome should include acute myocardial infarction, stroke, and heart failure and may include other cardiovascular components such as to death attributed to cardiovascular disease, urgent revascularization, and acute coronary syndrome requiring hospitalization. Characterization of the type of heart failure as well as stroke subtype should be considered. Exploratory outcomes, including but not limited to health-related quality of life, muscle-related symptoms, incident diabetes, hospitalization for any cause, medication adherence, and major sources of health care resource utilization could also be proposed.

Research Strategy: The scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention should be well supported by preliminary data, clinical and/or preclinical studies, information in the literature and/or knowledge of biological mechanisms. For trials focusing on clinical or public health endpoints, the need for a trial testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy should be justified. For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, the need for a trial to advance scientific understanding should also be justified. Focus on the project as a whole to address (i) the importance of the problem to the field that the proposed trial addresses, (ii) how this trial will improve scientific knowledge and clinical practice in geriatrics and cardiology, (iii) how the preventive interventions in target population will be changed if the proposed aims are achieved. Describe the preliminary data on which the trial is based. The applicants are required to include both a description and a table or graph of the overall project timeline and key milestones. The overall study timeline should include a description of key milestones that need to be met throughout the lifecycle of the clinical trial to ensure its success and to advance through the defined study phases described as projects elsewhere in this FOA. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound.

The applicants should clearly define and justify selection of the target population. It is expected that the study will enroll adults 75 years of age and older without clinical cardiovascular disease. The study should propose and justify selection of broad inclusion criteria and use of minimization, stratification or another technique that would result in enrollment of a high number of women, minorities, participants with frailty, mobility limitations, cognitive impairment, comorbidities and very old adults

The applicants are required to justify their proposed definitions of the primary and secondary outcomes and their components. Selection and definitions of the exploratory outcomes, if any, should also be justified.

Letters of Support: A strong commitment to the proposed trial by the leadership of the participating healthcare delivery systems should be demonstrated by including letters of support from the participating HCS signed by individuals with financial authority within the systems.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan for the trial. The Data Sharing Plans for the individual Cores and Projects are not expected.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Section 3 - Protection and Monitoring Plans

3.1 Protection of Human Subjects

Address all ethical issues and issues related to human subject safety oversight for the pragmatic trial (see: NIA Implementation of Policies for Human Intervention Studies, NIH Clinical Trials) including developing informed consent documents or opt-out consents (if applicable).

3.2 Is this a multi-site study that will use the same protocol to conduct non-exempt human subjects research at more than one domestic site?

Applicants should propose a consolidated or centralized IRB approach for trial oversight to facilitate the appropriate and timely implementation of the study.

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application, use Component Type 'Core.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List the site or sites that will administer and manage the trial, including site or sites, if any, that will be responsible for site visits to ensure data quality and integrity.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Core Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Core Lead (Trial Director) must be experienced in multi-center clinical trial coordination and management, including success in meeting milestones and timelines. The Trial Director's experience must be documented, and his or her role and responsibilities must be well defined

Budget for the core should reflect actual expenses related to trial administration and management. The applicants should include a $1000/year honorarium for each of seven members of the NIA-appointed Data and Safety Monitoring Board (DSMB) members. The applicants should also budget for expenses related to one in-person DSMB meeting during the Protocol Refinement and Study Start-up Phase, and one in-person meeting and one DSMB teleconference in years 2 through 7 of the study. All in-person meetings will be held in the Washington, DC area.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Aims for this core should define key aspects of administration and management of the trial.

Research Strategy: The application is required to include the Project Management Plan describing the strategy that will be used throughout the trial to ensure that the unique goals of the study are met. Project management should directly support the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. The project management plan must provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time and to successfully manage and mitigate risks.

Letters of Support: If more than one site is proposed for trial administration and management, letters of support from sites other than the Trial Director's site are required.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Core.

Appendix:

Limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Administrative and Trial Management )

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to Project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

This core should perform data management and provide biostatistical support. When preparing your application in ASSIST, use Component Type 'Core.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Data Coordinating Center)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Data Coordinating Center)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Data Coordinating Center)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Data Coordinating Center)

List the site or sites that will perform data management and provide biostatistical support.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Data Coordinating Center)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Core Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Core Lead (DCC Director) must be experienced in biostatistics and have experience in leading efforts of several PhD level biostatisticians..

Budget (Data Coordinating Center)

Budget for the core should reflect actual expenses related to data management and biostatistical support.

DCC Director's role and responsibilities must be well defined and justified.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Data Coordinating Center)

Specific Aims: Aims for this core should define the key aspects of trial's data management and biostatistical support.

Research Strategy: This section should discuss in detail assumptions used in power calculations and provide evidence supporting these assumptions. The applicants are strongly encouraged to propose a trial that has a 90% power to assess the effects of interventions on both primary and secondary outcomes. Sample size calculations should be designed to accommodate high crossover rates between study treatment groups. .

The research strategy section should also demonstrate the compatibility of the electronic health records (EHR) across participating HCSs to ensure rapid and cost-efficient enrollment of study participants and include evidence of ability to collect outcome data within the participating HCSs and from the external sources.

Letters of Support: if more than one site is proposed for data management and biostatistical support, letters of support from sites other than the DCC Director's site are required.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Core.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Data Coordinating Center)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application in ASSIST, use Component Type 'Core.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Recruitment and Retention)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Recruitment and Retention)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Recruitment and Retention)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project/Performance Site Location(s) (Recruitment and Retention)

List the site or sites that will coordinate and lead recruitment and retention efforts. These coordinating site(s) may also recruit and retain the participants but are not necessarily required to do so.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Recruitment and Retention)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Core Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Core Lead must have experience in successfully leading recruitment and retention of participants in large clinical trial or trials. Such experience must be documented, and Core Lead's role and responsibilities must be well defined.

Budget (Recruitment and Retention)

Budget for the core should reflect actual expenses related to recruitment and retention of participants.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Recruitment and Retention)

Specific Aims: Aims for this core should define the key aspects of recruitment and retention of participants.

Research Strategy: This section should include the following:

• Evidence of availability of sufficient number of prospective participants across the participating HCSs
• Evidence of availability of sufficient number of healthcare providers within participating HCSs willing to have their patients randomized to either statin or placebo
• An approach that addresses: 1) the expertise of the individual(s) responsible for screening, approaching and consenting potential participants; 2) the process for identification and screening of study participants; 3) primary and back-up recruitment strategies i.e. use of electronic health records; 4) implementation of the consent process; and 5) participant retention and adherence strategies.

Letters of Support: if more than one site is proposed to recruit participants, letters of support from sites other than the Core Director's site are required.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Core.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Recruitment and Retention)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

This core should manage the acquisition of bloods and any other types of study specimens, and the processing, storage, tracking, and laboratory analyses of bio-specimens with particularly emphasis on those related to the composite secondary cardiovascular outcome. When preparing your application in ASSIST, use Component Type 'Core.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Biorepository and Laboratory)

• Complete only the following fields:
• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Biorepository and Laboratory)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Biorepository and Laboratory)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Biorepository and Laboratory)

List the site or sites that will manage or perform specimen acquisition, processing, storage, tracking, and laboratory analyses.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Biorepository and Laboratory)

In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Core Lead' and provide a valid eRA Commons ID in the Credential field.

In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

The Core Lead or Co-Leads (Biorepository and Laboratory Director) must be experienced in operating a biorepository and performing laboratory analyses. This experience must be documented, and Core Lead's role and responsibilities must be well defined.

Budget (Biorepository and Laboratory)

Budget for the core should reflect actual expenses related to obtaining, processing, storing, and managing bio-specimens, and laboratory analyses. The cost of laboratory analysis for any proposed bio-specimen should be separated from the other costs of collection, processing, managing, tracking or storage of the bio-specimens. The non-laboratory analysis costs and the analysis of the LDL cholesterol during the trial are the priorities. The cost and budgeting for the core should start in the second year of the project except for modest planning cost in year one. The cost of transferring the samples at the study end to a NIH repository such as NHLBI BioLINCC or NIA repository should be included.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Biorepository and Laboratory)

Specific Aims: Aims for this core should define the key aspects of trial's bio-specimen and laboratory plan.

Research Strategy: This section should discuss how study bio-specimens will be collected, processed, managed, tracked, and stored. In the final year, the study will be required to ship the samples to a NIH repository. There should be a discussion of scientific rationale of which bio-specimens will be collected including those most relevant to the secondary cardiovascular composite outcome or its components.

The plan should detail assumptions about obtaining bio-specimens at baseline, and in subset of participants at periodic intervals during the trial for the masked determination of LDL cholesterol levels by arm. This discussion should include the timing sampling and the size of a subset of participants chosen to assess adherence to medication. The plan should discuss the most cost-efficient use of baseline samples, including but not limited to making specimens available for later post intervention analyses in case-control or case-cohort studies to identify biomarkers related to study outcomes or treatment effect including, but not limited to the secondary composite cardiovascular outcome and possibly its components.

The research strategy section should demonstrate throughout the seven years of the study, the ability to:

• Manage and track bio-specimens
• Periodically withdraw samples from the repository
• Sub-aliquot the samples
• Ship samples, if necessary to other laboratories supporting the NIH funded ancillary studies
• Conduct quality assurance analyses for high priority cardiovascular biomarkers
• Measure LDL cholesterol levels in a CLIA certified laboratory
• Integrate the laboratory results with the study data

Plans should be provided for adherence to Good Laboratory Practices (GLP) and use of current best practices for bio-specimen management and quality control (e.g., the National Cancer Institute's Best Practices for Biospecimen Resources or the NHLBI Biorepository Guide). Some exploratory analyses of cardiovascular biomarkers or other biomarkers may be proposed during the post intervention period.

Letters of Support: If more than one site is proposed for the biorepository and laboratory, letters of support from sites other than the Biorepository and Laboratory Director's site are required.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Core.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Biorepository and Laboratory)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application in ASSIST, use Component Type 'Core.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Clinical Sites)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Clinical Sites)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Clinical Sites)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Clinical Sites)

List the healthcare delivery systems that will recruit, follow and retain study participants and implement study protocol.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Clinical Sites)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Core Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Core Lead (Clinical Sites Director) must have experience in successfully coordinating activities of sites participating in multicenter clinical trial or trials. leading recruitment and retention of participants in large clinical trial or trials. Such experience must be documented, and Core Lead's role and responsibilities must be well defined.

Budget (Clinical Sites)

Budget for the core should reflect actual expenses related to implementation of clinical trial at the participating HCSs. Such activities may include but are not limited to verifying participants eligibility, performing baseline and follow-up measurements, if any, ascertainment of outcomes, study drug dispensing, administration and treatment compliance measurement, and other. The actual clinical sites' activities are defined by the study design.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Clinical Sites)

Specific Aims: Aims for this core should define the key aspects of implementation of the study protocol at participating HCSs.

Research Strategy: This section should propose criteria defining performance of the participating HCSs and include a plan describing how performance will be monitored and measured, and what corrective actions will be taken.

Letters of Support: No additional letters of support are required for this Core.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Core.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Clinical Sites)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application in ASSIST, use Component Type 'Project.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Protocol Refinement and Study Start-up Phase)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Protocol Refinement and Study Start-up Phase)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Protocol Refinement and Study Start-up Phase)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Protocol Refinement and Study Start-up Phase)

List the site or sites, including participating healthcare delivery systems that will participate in the protocol refinement and study start-up phase.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Protocol Refinement and Study Start-up Phase)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Project Lead (Study Director) should be the same individual who is proposed as a Core Lead (Study Director) in the Administrative and Trial Management Core.

Budget (Protocol Refinement and Study Start-up Phase)

Budget for the project should reflect actual expenses related to the implementation of the study's protocol refinement and study start-up phase. The applicants should plan for up to four two-day in-person meetings in the Washington, DC area of the Senior/Key persons, members of the study's Steering and other committees during this phase. The applicants may propose and justify fewer in-person meetings. Efficiency of the alternative approaches (e.g., webinars) should be discussed. The applicants should also plan for a one-day in-person meeting in the Washington, DC area of a seven-member NIA-appointed DSMB. The study leadership is required to attend this meeting. A DSMB meeting could be held in conjunction with one of the in-person Steering Committee meetings. The applicants should plan for regular teleconferences/webinars of the Steering and other study committees.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Protocol Refinement and Study Start-up Phase)

Specific Aims: Aims for this project should define the key objectives of the protocol refinement and study start-up phase.

Research Strategy: Given the diverse and complex challenges involved in the design and execution of this trial, the award will provide for up to one-year initial protocol refinement and study start-up phase. The applicants are encouraged, but are not required, to create specialized working groups that will assist in developing their applications. The existence and experience of such collaborative working groups would position the successful applicant to attain the challenging goals of the trial's initial intense protocol refinement and study start-up phase.

The application should include a detailed description of the applicants' plans and proposed staffing for completing activities during this phase, including a detailed time line. Based on its completion of the protocol refinement and study start-up phase, the awardee will recommend the final study protocol, consent documents and manual of procedures, which will be subject to review by the DSMB. The Board's recommendation to NIA and NHLBI to approve the study documents obtained by not later than the end of the initial one-year phase and NIA's and NHLBI's concurrence with the DSMB recommendations is a condition for transitioning to the vanguard phase.

Letters of Support: No letters of support are required for this project.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Project.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Protocol Refinement and Study Start-up Phase)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application in ASSIST, use Component Type 'Project.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Vanguard Phase)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Vanguard Phase)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Vanguard Phase)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Vanguard Phase)

List participating healthcare delivery systems that will implement the vanguard phase.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Vanguard Phase)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Project Lead (Study Director) should be the same individual who is proposed as a Core Lead (Study Director) in the Administrative and Trial Management Core.

Budget (Vanguard Phase)

Budget for the project should reflect actual expenses related to the implementation of the study's vanguard phase. The applicants are expected to plan for one two-day in-person meeting in the Washington, DC area of the Senior/Key persons, members of the study's Steering and other committees during this phase. The applicants should also plan for a one-day in-person meeting in the Washington, DC area and one teleconference of a seven-member NIA-appointed DSMB during this phase. The study leadership is required to attend both DSMB meetings. An in-person DSMB meeting could be held in conjunction with the in-person Steering Committee meeting. The applicants should plan for regular teleconferences/webinars of the Steering and other study committees.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Vanguard Phase)

Specific Aims: Aims for this project should define the key objectives of implementation of the study's protocol during the vanguard phase at participating HCSs.

Research Strategy: A one-year vanguard phase will follow the protocol refinement and study start-up phase. Objectives of this phase are to demonstrate the study's ability to recruit and retain participants; deliver the intervention; ascertain and adjudicate the outcomes. With regard to the outcomes, detailed description of how the primary composite study outcome and secondary composite cardiovascular outcomes will be collected. Any validation studies for the secondary cardiovascular outcome may be initiated for the characterization of the types of heart failure. During this phase, the study will also confirm the loss to follow-up and cross-over rates; the primary and secondary outcome event rates in the control group and the intercluster coefficient of correlation used in sample size and power calculations. If one or more of these differ from the original estimate, the investigators are required to amend the power calculations. At the end of the vanguard phase, the grantees should submit to the DSMB for review at its semi-annual meeting a report justifying transitioning to the study implementation phase. NIA and NHLBI will consider DSMB's recommendations and will use the following criteria to evaluate whether the vanguard phase reached its objectives and the study should continue:

• The actual recruitment rate is not lower than 75% of the target. For rates between 75% and 90% of the target, the DSMB report should include a plan describing in detail how and when the recruitment goal will be met within the allocated study budget.
• The revised study power calculated based upon the observed: a) loss to follow-up and cross over rates; b) the primary and secondary outcome event rates in the control group; c) the intercluster coefficient of correlation; and d) estimated final N is not lower than 85%.

Letters of Support: No letters of support are required for this project.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Project.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Vanguard Phase)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application in ASSIST, use Component Type 'Project.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Trial Implementation Phase)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Trial Implementation Phase)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Trial Implementation Phase)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Trial Implementation Phase)

List the participating healthcare delivery systems that will participate in the trial implementation phase.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Trial Implementation Phase)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Project Lead (Study Director) should be the same individual who is proposed as a Core Lead (Study Director) in the Administrative and Trial Management Core.

Budget (Trial Implementation Phase)

Budget for the project should reflect actual expenses related to the implementation of the study's protocol. The applicants should plan for one annual two-day in-person meeting in the Washington, DC area of the Senior/Key persons, members of the study's Steering Committee and other committees during this phase. The applicants should also plan for a one-day annual in-person meeting in the Washington, DC area of a seven-member NIA-appointed DSMB and one teleconference during this phase. The study leadership is required to attend both DSMB meetings. An in-person DSMB meeting could be held in conjunction with the in-person Steering Committee meeting. The applicants should plan for regular teleconferences/webinars of the Steering and other study committees.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Trial Implementation Phase)

Specific Aims: Aims for this project should define the key objectives of implementation of the study's protocol at participating HCSs.

Research Strategy: The applicants should describe in detail the study protocol (sections included in other Cores and Projects of the application are not required in this project). It is crucial that among other, the applicants propose a plan for ascertaining and adjudicating the outcomes in a cost-efficient manner with a high degree of accuracy. .

Letters of Support: No letters of support are required for this project.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Project.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Trial Implementation Phase)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Section 4 - Protocol Synopsis

Section 4.4. Statistical Design and Power

This section should refer to project Statistical Analysis Plan.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application in ASSIST, use Component Type 'Project.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Statistical Analysis Plan)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Statistical Analysis Plan)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Statistical Analysis Plan)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Statistical Analysis Plan)

The sites should be the same as those providing the biostatistical support (DCC Core).

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Statistical Analysis Plan)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Project Lead should be the same individual who is proposed as a Core Lead (DCC Director) in the DCC Core.

Budget (Statistical Analysis Plan)

No budget for this project is required. All expenses related to the development of the Statistical Analysis Plan (SAP) should be included into the DCC Core's budget.

PHS 398 Research Plan (Statistical Analysis Plan)

Specific Aims: Aims for this project should define the key steps in the development and maintenance of SAP.

Research Strategy: SAP should define the analyses with adequate power to assess treatment risks and benefits in important subgroups (e.g., men/women, older/younger, differing baseline health status, differing ethnicity).

Letters of Support: No letters of support are required for this project.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

A Data Sharing Plan is not expected for this Project.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Statistical Analysis Plan)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following instructions:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

This section should refer to the Recruitment and Retention project.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH's electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the trial to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the trial proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a trial that by its nature is not innovative may be essential to advance a field.

Does the trial address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the trial are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Could the results of the proposed pragmatic trial lead to a change of clinical practice?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the pragmatic trial and its primary and secondary outcomes? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI , do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Are the proposed staff's level of effort, expertise, roles and responsibilities sufficient to complete concurrently the multiple parallel activities that will be required in order to test and refine the protocol, both during the protocol development and refinement and vanguard phases, and during the protocol implementation phase?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the trial? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the trial involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Are the recruitment and retention, and the project management plans complete, feasible and realistic?

Does the application adequately address the following, if applicable:

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol, data and specimens collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Does the proposed network or a consortium of participating organizations comprise components with the operational capacity that will be necessary to ensure excellence in conducting all of the project's essential processes?

Are the administrative, data coordinating and enrollment cores appropriate for the trial proposed?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

As applicable for the trial proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

• Do participating HCSs cover most of the geographic regions of the United States?
• Is there convincing evidence of availability of sufficient number of a diverse sample of prospective participants across the participating HCSs?
• Is there convincing evidence of availability of sufficient number of healthcare providers willing to have their patients randomized to either statin or placebo?
• Does the Statistical Analysis Plan propose the pre-specified analyses with adequate power to assess treatment risks and benefits in important subgroups (e.g., men/women, older/younger, differing baseline health status, differing ethnicity?
• Do letters of support from participating HCSs demonstrate strong commitment to the proposed trial by the systems' leadership?

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed trial involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the trial proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NIA in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Aging. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee's business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

Please note the following additional administrative requirements:

• Grant awards will be incrementally funded for a project period of up to seven years no multi-year funded grants will be awarded.
• Progress and financial reporting will be required and reviewed annually.
• Grant awards under this FOA will be excluded from automatic carryover all carryover requests must be reviewed and approved by NIA.
• Grant awards under this FOA will not be provided the authority to automatically extend the final budget period one time for up to 12 months beyond the original performance period expiration date shown in the Notice of Grant Award. All extensions, including the first extension, will require NIA prior approval.
• All funds must be expended within the approved project period.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• All aspects of their study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators. The awardee agrees to accept close coordination, cooperation, and participation of NIA staff in those aspects of scientific and technical management of the study.
• Upon implementation of the protocol, each field center, whether a single institution or a consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, patient management, and data collection.
• Support or other involvement of industry or any other third party in the study--e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIA support; or special access to project results, data, findings, or resources--may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur with the concurrence by NIA Program Officer to ensure objectivity of research.
• Obtaining prior written approval of the NIA Grants Management Specialist in consultation with the NIA Program Officer for a change in any of the key personnel identified in the Notice of Award.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• Have access to data generated under this Cooperative Agreement and will periodically review the data and progress reports. NIA staff may use information obtained from the data for the preparation of internal reports on the activities of the study.
• Serve as a resource to provide scientific/programmatic support during the accomplishment of the clinical trial by participating in the design of the activities, advising in the selection of sources or resources, advising in management and technical performance, or participating in the preparation of publications.
• Participate in the monitoring of issues relating to recruitment, retention and follow-up of study participants, and monitoring of data integrity and quality control through consideration of the annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.
• Assist in the development and modification of study protocols.
• Additionally, an agency program official or IC Program Officer will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• A Steering Committee, composed of the principal investigator, as well as the principal investigators of the various field clinical centers, the Data Coordinating Center and of the specialized core facilities, and NIA and NHLBI Scientific Officers. The NIA and NHLBI Scientific Officers will have voting membership on the SC and, as appropriate, on its subcommittees. The SC will have primary responsibility for facilitating the conduct and monitoring of studies and reporting study results. Awardees will be required to accept and implement the common protocol and procedures approved by the SC. As the components of the SC may be geographically dispersed, the SC should meet with at least monthly conference calls, supplemented as deemed necessary by face to face meetings. Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement all policies governing the study conduct approved by the Steering Committee.

Dispute Resolution:

• Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Sergei Romashkan, MD, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-435-3047
Email: [email protected]

Lawrence J. Fine, MD, DrPH
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0305
Email: [email protected]

Claudia S. Moy, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9135
Email: [email protected]

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9666
Email: [email protected]

John Bladen
National Institute on Aging (NIA)
Telephone: 301-402-7730
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.