NIA and NHLBI request input on the need for research studies to evaluate potential effects of types of blood pressure reducing agents on the development of mild cognitive impairment and dementia.
There have been recommendations in the literature (e.g., van Dalen JW et al., 2021; DSilva EA et al., 2022; Marcum ZA et al., 2022; Marcum ZA et al., 2023) for additional research on the hypothesis that, compared to anti-hypertensive drugs that inhibit type 2 and 4 angiotensin II receptors, anti-hypertensive drugs that stimulate type 2 and 4 angiotensin II receptors reduce the incidence of mild cognitive impairment and/or dementia in older adults with hypertension. This hypothesis could be further explored in observational studies using causal interferences methods, randomized trials primarily focused on psychometric outcomes, or phase 3 trials on mild cognitive impairment and/or dementia.
This Request for Information (RFI) solicits comments and suggestions on the aforementioned approaches, their combinations, or novel ideas that are most appropriate at this stage of our scientific knowledge. NIA and NHLBI seek input from all interested stakeholders, including researchers, clinicians, academic institutions, medical institutions, professional organizations or societies, as well as other interested members of the public. Organizations are strongly encouraged to submit a single response that reflects the view of their organization and membership as a whole. A synopsis of your preferred option or options would be welcomed.
Since phase 3 trials are expensive and may not be feasible even if scientifically they are the most robust way to test an important hypothesis that will impact treatment guidelines, we have listed several specific topics of interest related to a phase 3 trial below. Respondents may address one or more of the topics and are encouraged to provide detailed descriptions, examples, publications, and additional information regarding context that will help clarify their response(s).
- Whether there is sufficient scientific evidence for the need of a phase 3 trial to compare the effects of anti-hypertensive drugs that stimulate type 2 and 4 angiotensin II receptors to the effects of anti-hypertensive drugs that inhibit type 2 and 4 angiotensin II receptors on the incidence of mild cognitive impairment and/or dementia in older adults with hypertension.
- Additional evidence or data analyses that would be valuable to assess the need for and feasibility of such a trial.
- The feasibility of a phase 3 trial.
- For a trial design that focuses on those who are not currently taking anti-hypertensive medications and have not done so for the past five years, whether there are enough older adults with hypertension who are currently not taking any anti-hypertension medications to participate in a phase 3 trial. Specifically:
- For a trial that includes current participants that are not on anti-hypertensives, the proportions of older adults with hypertension of certain ages (e.g., 65, 70, 75 years and older) currently taking anti-hypertensive drugs.
- The proportions of treatment-naïve patients with hypertension of certain ages (e.g., 65, 70, 75 years and older) who started anti-hypertensives annually over the past 5 years.
- Among these older adults who are currently taking anti-hypertensive medications, the proportions of those who take exclusively drugs stimulating type 2 and 4 angiotensin II receptors; drugs inhibiting type 2 and 4 angiotensin II receptors; or a combination of the two drug classes.
- The rates of long-term compliance with the prescribed treatment regimens for hypertension in these populations.
- Whether a primary prevention trial design is the best approach to evaluate the efficacy of drugs that inhibit type 2 and 4 angiotensin II receptors in reducing the incidence of mild cognitive impairment and/or dementia in older adults with hypertension.
- If so, the data that exist to inform the duration the trial needs to be to detect a meaningful effect.
- The most important hypothesis to be tested in such a phase 3 clinical trial.
- The specific primary endpoints or outcomes that are the most important to be tested in such a phase 3 trial.
- The scientific justification for primary endpoints.
- The effect size for these endpoints that is supported by the scientific literature.
- What the sample size of a phase 3 trial should be.
- The temporal relationship between the initiation or change in anti-hypertensive treatment and impact on trial outcomes.
- The specific secondary endpoints, including endpoints other than cognitive, that are the most important to be included in the trial, and the scientific justification for their inclusion.
- The most important inclusion and exclusion criteria (e.g., whether the trial should be limited to those who are initiating anti-hypertensive medications, what the inclusion criteria should be for age, etc.).
- The approaches that can be put in place to support the recruitment and enrollment of diverse participants to ensure underrepresented groups are included.
- The most important aspects for a study design that will best test the scientific hypothesis of the study. For example, if a trial is designed, whether there should be any standard treatment protocols, or whether the treatment decisions, beside the randomly assigned drugs that stimulate or inhibit type 2 and 4 angiotensin II receptors, should be left to the individual study investigators.
Submitting a Response
Comments should be submitted electronically by email to: firstname.lastname@example.org. Responses must be received by 11:59:59 pm (ET) on 12/31/2023.
This RFI is for planning purposes only and should not be construed as a policy, solicitation for applications, or as an obligation on the part of the Government to provide support for any ideas identified in response to it. Please note that the Government will not pay for the preparation of any information submitted or for its use of that information. Please do not include any proprietary, classified, confidential, or sensitive information in your response.