Biomarker Study: Heart Failure Patients at Risk for Vascular Dementia and Alzheimer's Disease Related Dementia [Supplement of: IND Enabling Studies for a Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Alzheimer's Disease Related Dementia]
试验速览
- 阶段
- 1 期
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Baseline Blood Biomarkers - Neurology 4-Pleax A, pTau-181, and pTau 231 as measured by the Quanterix Simoa Neurology 4-plex A and Simoa pTau-181 and 283 advantage kits
研究概览
简要总结
In order to determine if NfL can be a prognostic biomarker for VCID, participants will undergo a baseline evaluation consisting of neuropsychological testing and a blood draw with a 12-month follow-up consisting of neuropsychological testing and blood draw. After indicated interest in the study, participants will be screened either in person during a regularly scheduled clinic visit or by phone for eligibility. After consenting, participants will be scheduled for a baseline testing session. One session, lasting about 3 hrs, will include neuropsychological testing and a blood draw. After completion of baseline testing, participants who agree to take part in the clinical trial will begin a 12-week treatment of Ang-(1-7) via daily subcutaneous injections. During the drug treatment, participants will be called weekly to ensure that everything is going well with the injections. After participants have completed the 12-week injection period, participants will be scheduled for a second appointment which will include a blood draw and neuropsychological testing. All participant will be scheduled for a 12-month follow-up, which will include a blood draw and neuropsychological testing. Participants will be called every second month by research staff for a brief update on changes to health status, and to increase compliance with the 12-month follow-up.
Our One-Year outcome for this study is to provide early proof-of-concept clinical trial data that will support a larger, more comprehensive NIH funded study on the safety and efficacy of Ang-(1-7) to prevent cognitive impairment in HF patients at risk for developing VCID/ADRD. Our Long-Term outcome is to demonstrate whether plasma NfL exhibits characteristics making it useful as a Prognostic Biomarker to predict cognitive decline in early heart disease-associated VCID and identify pre VCID-symptomatic in individuals with symptomatic HF. Our goal will be to use levels of plasma Nfl as an enrollment enrichment factor in future trials to allow enrollment or stratification of patients more likely to develop VCID or ADRD and be responsive to Ang-(1-7) therapy.
详细描述
The investigators are proposing that neurofilament light (NfL) polypeptide might serve as a prognostic biomarker in blood that can help predict clinical progression in early VCID and identify pre-VCID-symptomatic individuals with stage II-IV heart failure. Our ultimate goal will be to use levels of NfL in blood as an enrollment enrichment factor for clinical trial eligibility criterion to identify patients who are more likely to develop VCID/ADRD. This project will establish baseline and 12-month longitudinal NfL values in heart failure patients at risk for VCID and determine the association between absolute levels of NfL with measures of cognitive function in participants with stages II, III, and IV heart failure. The investigators will also determine whether baseline levels of NfL predict change in cognitive function over a 12 month period. Investigators will examine whether the substance Ang-(1-7) is safe and effective for improving cognitive impairment in heart failure patients. This project will establish if treatment with Ang-(1-7) modifies the absolute levels of plasma Nfl and the change in these values over 12- months.
Recruitment of eligible patients will be approached at the Banner University Medical Center-North Campus Clinic C after patients have been seen for a standard of care clinic visit. Patients being evaluated for heart failure will be seen at Sarver Heart Center. The heart failure patients' medical records may be pre-screened before being are contacted for participation in this project. The cardiologist or clinic staff will introduce the study to the patient and may present the flyer. If the patient indicates to the doctor or clinic staff that he/she would like to learn about the research study, with the participant's permission, the doctor or clinic staff will contact a member of the research staff, who will discuss or schedule a time to discuss participation in detail with the patient. Participants medical records will be accessed to determine cardiovascular health history.
If a patient is interested, trained study staff will go through the Informed Consent Form (ICF) with the patient in an available private room. During the study consent process, the purpose, procedures, and risks of the study will be explained. Each section of the consent form (attached) will be reviewed together with the participant. The researcher will solicit questions and allow ample time for answers. It will be made clear to potential participants that participation in this study is completely voluntary and participants care will not be affected by decisions regarding participation in this study. The participant will also be asked to sign an addendum to the consent form regarding sharing data with colleagues. A copy of the signed consent form will be given to each participant. Signed consent forms will be stored in a locked file cabinet in the lab and then stored in the Psychology Building. The estimated time for recruitment and consenting of subjects at this location will take 30-60 minutes allowing for a time of question/answers. Potential participants who would like more time, will be given an ICF to take home and review the aspects of the study. A visit will be scheduled to complete the consenting in person. Eligible participants may also be contacted by phone to discuss the study, but the ICF would be signed in person.
Participants will complete the medication training/"test out" procedures at the Sarver clinic with trained clinic staff. The Ang-(1-7) drug will be kept at a Banner Investigational Pharmacy.
Behavioral research will be conducted at the University of Arizona in the psychology building and/or at the Biosciences Research Laboratories (BSRL) Building. Data will be collected on computers using stimulus presentation software and using pen and paper and will take approximately 2 hours and will be analyzed using statistical software. Research assistants will be trained by the principal investigator to help with recruitment and consenting of study participants, conducting study procedures, and data coding and analyses.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
盲法说明
Participants will not know which treatment they're receiving. Research staff and patients care providers will have access to which treatment patients are receiving.
入排标准
- 年龄范围
- 45 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants may be included in the study if they are:
- •45 years old and older
- •Diagnosed at least 90 days prior to enrollment with stable NYHA Class II-IV HF, with symptoms during mild or moderate exercise but not at rest (i.e., shortness of breath),
- •On a stable medical regimen and free from hospitalizations in the prior 30 days,
- •Fluent English speakers.
排除标准
- •Participants will be excluded from the study if there is evidence of:
- •Decompensated heart failure
- •Symptoms or signs of active coronary ischemia
- •Systolic blood pressure <95 mmHg
- •Significant lung disease (FEV1< 1.5 L, pO2 <70 on room air, pCO2 >45)
- •Active substance abuse or a history of substance abuse with cocaine, ecstasy, LSD, or IV drugs
- •History of or current seizure disorder or on medications for seizures (with the exception of childhood febrile seizures)
- •Neurological, psychiatric, or medical illness or injury expected to interfere with cognitive function including but not limited to stroke, head injury, Alzheimer's, Parkinson's, or brain cancer
- •Current depression (Patient Health Questionnaire-9 score >10)
- •Any condition which may prevent the subject from adhering to the study protocol such as significantly impaired vision.\
- •Note: Participants that have contraindications for MRI may be enrolled, but will not take part in the MRI portion of the study.
研究组 & 干预措施
Ang-(1-7)
30 participants will take 100 micrograms of Ang-(1-7) a day via subcutaneous injection for 90 days
干预措施: Angiotensin 1-7 (Drug)
Saline Placebo
10 participants will take 100 micrograms of saline placebo a day via subcutaneous injection for 90 days
干预措施: Saline solution (Drug)
结局指标
主要结局
Baseline Blood Biomarkers - Neurology 4-Pleax A, pTau-181, and pTau 231 as measured by the Quanterix Simoa Neurology 4-plex A and Simoa pTau-181 and 283 advantage kits
时间窗: These measurements will be taken at baseline
We will use the Quanterix Simoa Neurology 4-Plex A (N4PA) Advantage kit to measure Neurology 4-Plex A (GFAP, NF-light, Total Tau, UCH-L1 and the Simoa pTau-181 and 283 Advantage kits to measure pTau-181 and pTau 231.
Baseline evaluations of global cognitive functioning as measured by the Montreal Cognitive Assessment
时间窗: These measurements will be taken at baseline
The Montreal Cognitive Assessment will be used to evaluate global cognitive functioning/ Scores can range from 0 - 30 with higher scores indicating better outcomes.
Baseline evaluations of processing speeds - simple/complex processing speeds as measured by the Deary-Liewald Reaction Time Task
时间窗: These measurements will be taken at baseline
The Deary-Liewald Reaction Time Task will evaluate processing speed - simple/complex processing speed. Scores can range from 200ms - 1500ms with higher scores indicating worse outcomes
Participants quality of life will be assessed as measured by the World Health Organization Quality of Life - BREF (WHOQOL-BREF)
时间窗: These measurements will be taken at the 12 month follow up
The World Health Organization Quality of Life - BREF (WHOQOL-BREF) will be used to assess participant's quality of life. Score can range from 3 to 40 with higher scores indicating better outcomes
Participants disability due to health/mental health conditions will be assessed as measured by the World Health Organization Disability Assessment Schedule 2.0
时间窗: These measurements will be taken at the 12 month follow up
The World Health Organization Disability Assessment Schedule 2.0 will be used to assess participant's disability due to health/mental health conditions. Scores can range from 7 to 36 with higher scores indicating worse outcomes.
12-week evaluations of executive functions - switching as measured by the Number-Letter Task
时间窗: These measurements will be taken after the 12 week drug course
The Number-Letter task will be used to evaluate executive function - switching. Scores can range from 0.2sec to 10 sec with higher scores indicating worse outcomes
12-week evaluations of executive functions - attention/inhibition as measured by the Flanker Task
时间窗: These measurements will be taken after the 12 week drug course
The Flanker Task will be used to evaluate executive function - attention/inhibition. Scores can range from 200ms - 2000ms with higher scores indicating worse outcomes
Baseline evaluations of associative, verbal memory as measured by the verbal paired associates task (version 2)
时间窗: These measurements will be taken at baseline
The verbal paired associates task (version 2) will be used to evaluate associative, verbal memory. Scores can range from 0 to 36 with higher scores indicating better outcomes.
Baseline evaluations of reading ability/vocabulary as measured by the North American Reading Test
时间窗: These measurements will be taken at baseline
The North American Reading Test will be used to evaluate reading ability/vocabulary. Scores can range from 0 to 61 with higher score indicating better outcomes
Participants heart failure health status will be assessed as measured by the Kansas City Cardiomyopathy Questionnaire
时间窗: These measurements will be taken at the 12 month follow up
The Kansas City Cardiomyopathy Questionnaire. Scores can range from 12 to 118 with higher scores indicating better outcomes
12-week Blood Biomarkers - Neurology 4-Pleax A, pTau-181, and pTau 231 as measured by the Quanterix Simoa Neurology 4-plex A and Simoa pTau-181 and 283 advantage kits
时间窗: These measurements will be taken after the 12 week drug course
We will use the Quanterix Simoa Neurology 4-Plex A (N4PA) Advantage kit to measure Neurology 4-Plex A (GFAP, NF-light, Total Tau, UCH-L1 and the Simoa pTau-181 and 283 Advantage kits to measure pTau-181 and pTau 231.
12-week evaluations of associative, visual memory as measured by the Face Name Associative Memory Test
时间窗: These measurements will be taken after the 12 week drug course
The Face Name Associative Memory Test will be used to evaluate associative, visual memory. Scores can range from 0 to 12 with higher scores indicating better outcomes.
12-week evaluations of reading ability/vocabulary as measured by the North American Reading Test
时间窗: These measurements will be taken after the 12 week drug course
The North American Reading Test will be used to evaluate reading ability/vocabulary. Scores can range from 0 to 61 with higher score indicating better outcomes
12-month evaluations of associative, visual memory as measured by the Face Name Associative Memory Test
时间窗: These measurements will be taken at the 12 month follow up
The Face Name Associative Memory Test will be used to evaluate associative, visual memory. Scores can range from 0 to 12 with higher scores indicating better outcomes.
Baseline evaluations of executive functions - switching as measured by the Number-Letter Task
时间窗: These measurements will be taken at baseline
The Number-Letter task will be used to evaluate executive function - switching. Scores can range from 0.2sec to 10 sec with higher scores indicating worse outcomes
Participants physical activity will be assessed as measured by Rapid Assessment of Physical Activity
时间窗: These measurements will be taken at the 12 month follow up
The Rapid Assessment of Physical Activity will be used to assess participant's physical activity. Scores can range from 1 to 10 with higher scores indicating better outcomes.
Participants independent living skills will be assessed as measured by the Lawton-Brody Instrumental Activities of Daily Living Scale (I.A.D.L)
时间窗: These measurements will be taken at the 12 month follow up
The Lawton-Brody Instrumental Activities of Daily Living Scale (I.A.D.L). Scores can range from 0 to 8 with higher scores indicating better outcomes.
12-month Blood Biomarkers - Neurology 4-Pleax A, pTau-181, and pTau 231 as measured by the Quanterix Simoa Neurology 4-plex A and Simoa pTau-181 and 283 advantage kits
时间窗: These measurements will be taken at the 12 month follow up
We will use the Quanterix Simoa Neurology 4-Plex A (N4PA) Advantage kit to measure Neurology 4-Plex A (GFAP, NF-light, Total Tau, UCH-L1 and the Simoa pTau-181 and 283 Advantage kits to measure pTau-181 and pTau 231.
Baseline evaluations of associative, visual memory as measured by the Face Name Associative Memory Test
时间窗: These measurements will be taken at baseline
The Face Name Associative Memory Test will be used to evaluate associative, visual memory. Scores can range from 0 to 12 with higher scores indicating better outcomes.
Baseline evaluations of pattern separation memory as measured by the Mnemonic Similarity Task
时间窗: These measurements will be taken at baseline
The Mnemonic Similarity Task will be used to evaluate pattern separation memory. Scores can range from 0 to 1.0 with higher scores indicating better outcomes
Baseline evaluations of executive functions - updating/working memory as measured by the Keep Track Task
时间窗: These measurements will be taken at baseline
The Keep Track Task will be used to evaluate executive function - updating/working memory. Scores can range from 0 to 30 with higher scores indicating better performance.
Baseline evaluations of executive functions - attention/inhibition as measured by the Flanker Task
时间窗: These measurements will be taken at baseline
The Flanker Task will be used to evaluate executive function - attention/inhibition. Scores can range from 200ms - 2000ms with higher scores indicating worse outcomes
12-week evaluations of associative, verbal memory as measured by the verbal paired associates task (version 2)
时间窗: These measurements will be taken after the 12 week drug course
The verbal paired associates task (version 2) will be used to evaluate associative, verbal memory. Scores can range from 0 to 36 with higher scores indicating better outcomes.
12-week evaluations of processing speeds - simple/complex processing speeds as measured by the Deary-Liewald Reaction Time Task
时间窗: These measurements will be taken after the 12 week drug course
The Deary-Liewald Reaction Time Task will evaluate processing speed - simple/complex processing speed. Scores can range from 200ms - 1500ms with higher scores indicating worse outcomes
Participants sleep quality will be assessed as measured by the Pittsburgh Sleep Quality Index
时间窗: These measurements will be taken at the 12 month follow up
The Pittsburgh Sleep Quality Index will be used to assess sleep quality. Scores can range from 0 to 21 with higher scores indicating worse outcomes
12-week evaluations of pattern separation memory as measured by the Mnemonic Similarity Task
时间窗: These measurements will be taken after the 12 week drug course
The Mnemonic Similarity Task will be used to evaluate pattern separation memory. Scores can range from 0 to 1.0 with higher scores indicating better outcomes
12-week evaluations of executive functions - updating/working memory as measured by the Keep Track Task
时间窗: These measurements will be taken after the 12 week drug course
The Keep Track Task will be used to evaluate executive function - updating/working memory. Scores can range from 0 to 30 with higher scores indicating better performance.
12-week evaluations of global cognitive functioning as measured by the Montreal Cognitive Assessment
时间窗: These measurements will be taken after the 12 week drug course
The Montreal Cognitive Assessment will be used to evaluate global cognitive functioning/ Scores can range from 0 - 30 with higher scores indicating better outcomes.
12-month evaluations of processing speeds - simple/complex processing speeds as measured by the Deary-Liewald Reaction Time Task
时间窗: These measurements will be taken at the 12 month follow up
The Deary-Liewald Reaction Time Task will evaluate processing speed - simple/complex processing speed. Scores can range from 200ms - 1500ms with higher scores indicating worse outcomes
12-month evaluations of associative, verbal memory as measured by the verbal paired associates task (version 2)
时间窗: These measurements will be taken at the 12 month follow up
The verbal paired associates task (version 2) will be used to evaluate associative, verbal memory. Scores can range from 0 to 36 with higher scores indicating better outcomes.
12-month evaluations of executive functions - updating/working memory as measured by the Keep Track Task
时间窗: These measurements will be taken at the 12 month follow up
The Keep Track Task will be used to evaluate executive function - updating/working memory. Scores can range from 0 to 30 with higher scores indicating better performance.
12-month evaluations of executive functions - switching as measured by the Number-Letter Task
时间窗: These measurements will be taken at the 12 month follow up
The Number-Letter task will be used to evaluate executive function - switching. Scores can range from 0.2sec to 10 sec with higher scores indicating worse outcomes
12-month evaluations of reading ability/vocabulary as measured by the North American Reading Test
时间窗: These measurements will be taken at the 12 month follow up
The North American Reading Test will be used to evaluate reading ability/vocabulary. Scores can range from 0 to 61 with higher score indicating better outcomes
12-month evaluations of executive functions - attention/inhibition as measured by the Flanker Task
时间窗: These measurements will be taken at the 12 month follow up
The Flanker Task will be used to evaluate executive function - attention/inhibition. Scores can range from 200ms - 2000ms with higher scores indicating worse outcomes
12-month evaluations of global cognitive functioning as measured by the Montreal Cognitive Assessment
时间窗: These measurements will be taken at the 12 month follow up
The Montreal Cognitive Assessment will be used to evaluate global cognitive functioning/ Scores can range from 0 - 30 with higher scores indicating better outcomes.
12-month evaluations of pattern separation memory as measured by the Mnemonic Similarity Task
时间窗: These measurements will be taken at the 12 month follow up
The Mnemonic Similarity Task will be used to evaluate pattern separation memory. Scores can range from 0 to 1.0 with higher scores indicating better outcomes
次要结局
未报告次要终点
研究者
Lee Ryan
Professor and Department Head
University of Arizona