Notice of Changes to RFA-AG-19-020 "Clinical Trial on Effects of Statins in Older Adults without Clinical Cardiovascular Disease (U19 Clinical Trial Required)"

Notice Number: NOT-AG-18-038

Key Dates
Release Date: November 8, 2018

Related Announcements
RFA-AG-19-020

Issued by
National Institute on Aging (NIA)

National Heart, Lung, and Blood Institute (NHLBI)

National Institute of Neurological Disorders and Stroke (NINDS)

Purpose

This Notice is being issued to inform potential applicants of changes to RFA-AG-19-020 "Clinical Trial on Effects of Statins in Older Adults without Clinical Cardiovascular Disease (U19 Clinical Trial Required)". NIA is increasing its funding contribution (commitments from NHLBI and NINDS are remaining the same). As a result, the key dates, scope, funds available and anticipated number of awards, award budget, and application instructions are being revised as described below.

These changes will ensure that the future clinical trial will be sufficiently powered to assess effects of statins on mild cognitive impairment and dementia (MCI+D) in the study population defined in the RFA. It is anticipated that achieving this power may require enrollment of substantially more than the originally projected 17,000 participants. Having a larger number of participants is important for several reasons:

  • A larger number of participants will increase power on the primary outcome and will provide for a greater power to assess effects of statins in a priori defined subgroups (e.g. minorities, older age groups, participants with frailty, etc.).
  • A larger sample size is crucial for assessing effects of statins on the important secondary outcomes of MCI+D and composite of clinical cardiovascular disease events. The narrower confidence intervals around the hazard ratios for treatment that the larger sample will provide, even if no significant effect on dementia or MCI+D is found, will provide more definitive evidence of benefit or lack of benefit.
  • The larger sample size and associated increase in funding will provide for enhanced ascertainment of MCI+D outcomes, further increasing power for measuring effects on MCI+D by ensuring that fewer events have been missed. All participants who fail a screening test will not only be referred to a healthcare professional, but they will also be contacted by the study staff to confirm the diagnosis in addition to review of the electronic health records.

The following revisions have been made to RFA-AG-19-020 (revised text is italicized):

Part 1. Overview Information, Key Dates

Open Date (Earliest Submission Date): January 4, 2019

Letter of Intent Due Date(s): January 4, 2019

Application Due Date(s): February 4, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications  allowed for this funding opportunity announcement are due on this date. No late applications will be accepted for this Funding Opportunity Announcement. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Scientific Merit Review: May 2019

Advisory Council Review: August 2019

Earliest Start Date: September 2019

Expiration Date: February 5, 2019

Part 2. Full Text of Announcement, Section I. Funding Opportunity Description

Scope of Research Requested

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 the intervention on two co-secondary outcomes: 1) a composite of clinical CVD events (acute myocardial infarction, ischemic stroke or transient ischemic attack, heart failure, death attributed to cardiovascular disease) and 2) MCI+D with 90% power to detect a risk reduction of 15%. 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 from at least 17,000 of the participants 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.

Part 2. Full Text of Announcement, Section II. Award Information

Funds Available and Anticipated Number of Awards: The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. NIA intends to commit up to $6.0 million in direct costs in FY 2019 to fund one award. Across the seven-year project period, issuing IC and partner components intend to commit an estimated $60.2 million in direct costs to fund one award.

Award Budget: Application budgets cannot exceed $60.2 million in direct costs across seven years and need to reflect the actual needs of the proposed project.

Part 2. Full Text of Announcement, Section IV. Application and Submission Information

PHS 398 Research Plan (Overall)

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 two co-secondary outcomes: a composite of clinical CVD events (acute myocardial infarction, ischemic stroke or transient ischemic attack, heart failure, death attributed to cardiovascular disease) and MCI+D with 90% power to detect a 15% effect. 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.

The plan should detail assumptions about obtaining bio-specimens at baseline from at least 17,000 participants, and in subset of participants at periodic intervals during the trial for the masked determination of LDL cholesterol levels by arm.

PHS 398 Research Plan (Vanguard Phase)

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. Regarding the outcomes, detailed description of how the primary composite study outcome and two co-secondary outcomes -- a composite of clinical CVD events and MCI+D -- 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%.

All other aspects of this FOA remain unchanged.

Inquiries

Please direct all inquiries to:

Sergei Romashkan, MD, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-435-3047
Email: romashks@nia.nih.gov