Clinical trial NCT04112043
Conditions: Hypertension
Keywords: systolic blood pressure (SBP) cardiovascular (CV) disease
Sponsor: University of Florida
Start date: 2020-07-28; Completion date: 2023-05-26
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
More than 80% of older adults have hypertension, with higher prevalence of high systolic blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death. Novel compound, nicotinamide riboside may enhance the effects of exercise therapy in hypertensive older adults.

Detailed description:
More than 80% of older adults have hypertension, with a higher prevalence of high systolic blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death. Because drug therapy that lowers SBP is associated with side effects such as hypotension, syncope, and kidney dysfunction, there is a great need for effective lifestyle SBP-lowering interventions for the older population that can replace drug therapy. While aerobic exercise is a recommended lifestyle intervention for controlling SBP and preventing CV disease naturally, in older adults it has been shown to be less effective in vascular-tissue remodeling because of arterial stiffness, resulting in less efficient SBP control. Reduced bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the deacetylase sirtuin1 (SIRT1), may contribute to age-related vascular dysfunction via oxidative stress and reduced nitric oxide (NO). Exercise-induced overexpression of NAD+-dependent SIRT1 improves the bioavailability of NO. Preclinical evidence suggests that poor vascular function improvement in response to exercise in older mice is caused by insufficient NAD+ levels to stimulate SIRT1 activity. Importantly, replenishment of NAD+ levels induced vascular remodeling, improved vascular function, and reduced SBP in mice. An objective of this study, therefore, is to test a combination of aerobic exercise and nicotinamide riboside, a compound that replenishes NAD+ levels, to optimize exercise's SBP-lowering effect in hypertensive older adults. Initial human clinical trials demonstrated that nicotinamide riboside supplementation (1,000 mg/day) was safe and showed a higher potential to reduce SBP and arterial stiffness in participants with elevated SBP. As we have preclinical evidence that combining NAD+ replenishment with exercise is an ideal strategy for improving vascular function, our central hypothesis is that the intervention of aerobic-exercise training combined with nicotinamide riboside supplementation will reduce SBP in hypertensive older adults more effectively than will exercise alone. We will enroll 54 participants ≥ 55 years and older into either: (1) 1,000 mg/day of nicotinamide riboside plus 3 days/week of supervised, center-based walking exercise (n=18), or (2) the same exercise program combined with placebo (n=18), or (3) 1,000 mg/day of nicotinamide riboside alone (n=18). All participants will undergo daytime continuous SBP at baseline, 3 weeks, and 6 weeks, and arterial-stiffness measurements by pulse-wave velocity at baseline and at 6 weeks. Elevated SBP will be determined as daytime average equal to or above 130 mmHg, measured by the 24-hour blood-pressure device. To our knowledge, this study will be the first attempt to enhance exercise therapy with nicotinamide riboside in hypertensive older adults. We believe that nicotinamide riboside is "the missing piece of the puzzle" in improving vascular remodeling and SBP management in older adults. Preliminary evidence from this pilot study may support a full-scale Phase III clinical trial in hypertensive older adults. The ultimate goal of this line of research is to find adjuvant strategies to improve the exercise's SBP-lowering effects in older adults.

Arms: arm 1: 1,000 mg/day of NR combined with three days/week of supervised, center-based walking exercise (n=18) arm 2: 1,000 mg/day of Placebo combined with three days/week of supervised, center-based walking exercise (n=18) arm 3: 1,000 mg/day of NR
Interventions: intervention 1: Walking Exercise intervention 2: Nicotinamide Riboside (NR)
Intervention descriptions: intervention 1: Participants randomized to this intervention 3 days/week of supervised, center-based walking exercise. intervention 2: Participants randomized to this intervention will receive 1,000 mg/day of NR.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 NCT04112043  
Nicotinamide riboside as an 
Enhancer of Exercise Therapy 
in hypertensive older adults  
- The NEET Trial  
PI: Robert T. Mankowski, PhD 
2-9-2023 
 


Protocol NEET Trial, IRB201900746 
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Study Protocol and Statistical Analysis Plan 
1. Project Title: 
Nicotinamide riboside as an Enhancer of Exercise Therapy in hypertensive older adults – The NEET Trial. 
2. Investigators: 
Robert Mankowski, PhD 
Stephen Anton, PhD 
Christiaan Leeuwenburgh, PhD 
Demetra Christou, PhD 
Bhanuprasad Sandesara, MD 
Peihua Qiu, PhD 
3. Abstract:   
More than 80% of older adults have hypertension, with higher prevalence of high systolic blood 
pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death. Because drug 
therapy that lowers SBP is associated with side effects such as hypotension, syncope, and kidney 
dysfunction, there is a great need for effective lifestyle SBP-lowering interventions for the older 
population that can replace drug therapy. While aerobic exercise is a recommended lifestyle 
intervention for controlling SBP and preventing CV disease naturally, in older adults it has been shown 
to be less effective in vascular-tissue remodeling because of arterial stiffness, resulting in less efficient 
SBP control. Reduced bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the 
deacetylase sirtuin1 (SIRT1), may contribute to age-related vascular dysfunction via oxidative stress 
and reduced nitric oxide (NO). Exercise-induced overexpression of NAD+-dependent SIRT1 improves 
the bioavailability of NO. Preclinical evidence suggests that poor vascular-function improvement in 
response to exercise in older mice is caused by insufficient NAD+ levels to stimulate SIRT1 activity. 
Importantly, replenishment of NAD+ levels induced vascular remodeling, improved vascular function, 
and reduced SBP in mice. An objective of this study, therefore, is to test a combination of aerobic 
exercise and nicotinamide riboside, a compound that replenishes NAD+ levels, to optimize exercise’s 
SBP-lowering effect in hypertensive older adults. Initial human clinical trials demonstrated that 
nicotinamide riboside supplementation (1,000 mg/day) was safe and showed a higher potential to 
reduce SBP and arterial stiffness in participants with elevated SBP. As we have preclinical evidence 
that combining NAD+ replenishment with exercise is an ideal strategy for improving vascular function, 
our central hypothesis is that the intervention of aerobic-exercise training combined with nicotinamide 
riboside supplementation will reduce SBP in hypertensive older adults more effectively than will 
exercise alone. We will enroll 54 participants ≥ 55 years and older into either: (1) 1,000 mg/day of 
nicotinamide riboside plus 3 days/week of supervised, center-based walking exercise (n=18), or (2) the 
same exercise program combined with placebo (n=18), or (3) 1,000 mg/day of nicotinamide riboside 
alone (n=18). All participants will undergo daytime continuous SBP at baseline, 3 weeks, and 6 weeks, 
and arterial-stiffness measurements by pulse-wave velocity at baseline and at 6 weeks. Elevated SBP 
will be determined as daytime average equal to or above 130 mmHg, measured by the 24-hour blood-
pressure device. To our knowledge, this study will be the first attempt to enhance exercise therapy with 
nicotinamide riboside in hypertensive older adults. We believe that nicotinamide riboside is “the missing 
piece of the puzzle” in improving vascular remodeling and SBP management in older adults. 
Preliminary evidence from this pilot study may support a full-scale Phase III clinical trial in hypertensive 
older adults. The ultimate goal of this line of research is to find adjuvant strategies to improve the 
exercise’s SBP-lowering effects in older adults. 


Protocol NEET Trial, IRB201900746 
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4. Background:  
More than 80% of older adults are diagnosed with hypertension and thus are at high risk of 
atherosclerosis, cardiovascular (CV) events, and death [1]. Systolic blood pressure (SBP) is the most 
common form of hypertension and is considered more important than diastolic blood pressure (BP) as 
an independent CV disease risk factor [2]. SBP equal to or above 130 mmHg needs treatment, as even 
10-mmHg elevation doubles the risk of a heart attack [3]. Because successful reduction of SBP with 
medication is often accompanied by side effects such as hypotension, syncope and kidney dysfunction 
[2], there is a great need for effective lifestyle SBP-lowering interventions in the older population. 
The major contributors to high SBP are decline in endothelial function, decline in capillary vessel 
density, and arterial stiffening, which are profound changes in vascular aging [4, 5]. Reduced 
bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the deacetylase sirtuin1 
(SIRT1), may contribute to age-related vascular dysfunction via oxidative stress and reduced nitric 
oxide (NO) [6]. Endothelial dysfunction reduces bioavailability of NO, which increases arterial stiffness 
and elevates SBP [6]. Interventions that elevate NAD+ levels and increase SIRT1 activity may be 
critical for improving therapies that target endothelial dysfunction and arterial stiffness to manage SBP 
and prevent CV disease in older adults.  
While aerobic exercise is recommended for SBP control and CV disease prevention [7], it has been 
shown to be less effective in lowering SBP in older adults because of arterial stiffness [8]. Preclinical 
evidence suggests that age-related lower vascular function improvement in response to exercise may 
be caused by insufficient levels of NAD+ to stimulate SIRT1 activity and induce vascular remodeling for 
SBP reduction [9]. In particular, preclinical evidence showed that in old mice with replenished NAD+ by 
administration of nicotinamide mononucleotide (NMN), exercise was more effective in stimulating 
SIRT1 activity and restoring endothelial function and capillary density, compared to mice with lower 
NAD+ levels [9]. Such findings suggest that replenishment of NAD+ levels with metabolites (e.g., 
nicotinamide riboside (NR) or NMN) may be the key to enhancing vascular function in response to 
aerobic-exercise training and, thus, reducing SBP in older adults more effectively. 
In healthy, men and women aged 55 to 79 years, 6 weeks of supplementation with 1,000 mg/day of NR 
was well-tolerated and increased NAD+ levels in peripheral blood [10]. Importantly, NR 
supplementation produced trends towards reductions of SBP as well as arterial stiffness compared to 
placebo [10]. A post-hoc analysis of the same study sample showed trends towards larger reductions 
after NR supplementation in individuals with higher SBP (9 mmHg lower after NR compared to placebo 
among participants with 120–139 mmHg SBP) and arterial stiffness (41.5 centimeters per second 
(cm/s)) [10]. We believe that promising results from Martens et al., study and promising preclinical 
evidence from Das et al., that showed a combination of NAD+ replenishment and exercise was an 
optimal strategy to most effectively improve vascular function and reduce SBP in older mice, support 
our novel proposal that a combination of NR and aerobic exercise (NREx) will be more effective than 
either NR or exercise alone (exercise and placebo - PLEx) in hypertensive older adults. Thus, our 
central hypothesis is that the intervention of aerobic-exercise training combined with NR 
supplementation will reduce SBP in older adults who have high SBP more effectively than will exercise 
alone. 
To test our central hypothesis, we will recruit 54 older adults ≥55 years old with high 24-hour 
average SBP and follow them for 6 weeks in a double-blind fashion. Participants will be randomly 
assigned to receive either (1) 1,000 mg/day of NR plus 3 days/week of supervised, center-based 
walking exercise, or (2) the same exercise program combined with placebo, or (3) 1,000 mg/day of NR 
alone. Inclusion of all treatment groups will be important for detecting the potential benefit of NREx. 
High SBP will be determined at screening as daytime average above or equal to 130 mmHg and below 
160 mmHg, measured by the 24-hour BP device. All enrolled participants will undergo daytime 
continuous SBP measurements at baseline, 3 weeks, and 6 weeks, and arterial-stiffness 
measurements by pulse-wave velocity (PWV) at baseline and 6 weeks. 


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5. Specific Aims: 
The objective of this study is to conduct a pilot study to refine and finalize elements critical to 
conducting a future, definitive randomized, controlled trial (RCT). We propose to recruit 54 persons 
aged ≥ 55 years with SBP ≥130 mmHg and <160 mmHg for 6 weeks. Participants will be randomly 
assigned to receive either (1) 1,000 mg/day of NR plus 3 days/week of supervised, center-based 
walking exercise, or (2) the same exercise program combined with placebo, or (3) 1,000 mg/day of NR 
alone. Inclusion of all treatment groups will be important for detecting the potential benefit of NREx. 
High SBP will be determined at screening as daytime average above or equal 130 mmHg and below 
160 mmHg, measured by the 24-hour BP device. All enrolled participants will undergo daytime 
continuous SBP measurements at baseline, 3 weeks, and 6 weeks, and arterial-stiffness 
measurements by pulse-wave velocity (PWV) at baseline and 6 weeks. This study will enable us to 
address the following aims, all of which are of critical importance for designing a full-scale trial. 
Aim 1. To obtain critical data necessary to project the sample size needed for a full-scale trial 
using the change in SBP, as the primary outcome and; 
Aim 2. Using the change in arterial stiffness, as the secondary outcome. 
6. Research Plan: 
 
We propose to conduct a randomized, controlled pilot trial to test if nicotinamide riboside improves an 
effect of aerobic exercise training on cardiovascular function among hypertensive older adults. Following 
study entry, participants (N = 54) will be randomly assigned to either NREx, NR or PLEx groups for 6 
weeks. Exercise groups will be involved in three center-based walking training sessions per week. We 
anticipate that up to an additional 20 individuals enrolled may discontinue participation in the project prior 
to completion, and that we may have to screen up to 250 additional individuals to reach our recruitment 
goal of 54 subjects.  
 
6.1 Participants: Eligible participants will be males or females ≥ 55 years of age with daytime average 
SBP ≥ 130mmHg and < 160 mmHg. 
 
Table 3.1.1. Inclusion and exclusion criteria. 
Inclusion Criteria  
• 
Age 55 years and older   
• 
Daytime average of systolic blood pressure of ≥ 130 mmHg and < 160 mmHg.  
• 
Sedentary lifestyle, defined as < 150 min/wk of moderate physical activity as assessed by the CHAMPS 
questionnaire.  
• 
Willingness to be randomized to either treatment group 
• 
Willingness to participate in all study procedures 
Exclusion criteria  
• 
Failure to provide informed consent. 
• 
Pregnant 
• 
Change in blood pressure therapy (type or dose) within the last 3 months- Temporary Exclusion 
• 
Daytime average of systolic blood pressure ≥160 mmHg. 
• 
Regular consumption of nicotinamide riboside supplement 
• 
Current involvement in supervised rehabilitation program  


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• 
Absolute contraindication(s) to exercise training according to American College of Sports Medicine 
guidelines [11] 
• 
Daytime average of systolic blood pressure below 130mm Hg or Diastolic BP ≥ 100mm Hg. 
• 
Peripheral vascular disease; peripheral neuropathy; retinopathy 
• 
Severe cardiac disease, including NYHA Class III or IV congestive heart failure, clinically significant 
aortic stenosis, history of cardiac arrest, use of a cardiac defibrillator, or uncontrolled angina;   
• 
Myocardial infarction or stroke within past year 
• 
Significant cognitive impairment, including known dementia diagnosis or a Mini-Mental State Examination 
exam score < 24  
• 
Progressive, degenerative neurologic disease, e.g., Parkinson’s Disease, multiple sclerosis; 
• 
Severe rheumatologic or orthopedic diseases, e.g., awaiting joint replacement, active inflammatory 
disease; 
• 
Severe pulmonary disease, requiring steroid therapy or the use of supplemental oxygen; 
• 
Hip fracture, hip or knee replacement, or spinal surgery within past 4 months; 
• 
Other significant co-morbid conditions that would impair ability to participate in the exercise-based 
intervention 
• 
Simultaneous participation in another intervention trial 
 
6.2 Recruitment: Participant recruitment will be coordinated in conjunction with the OAIC Clinical 
Research Core, led by co-investigator Dr. Stephen Anton. We will develop a targeted recruitment 
approach based on previous experiences utilizing methods of recruitment that include direct mailings, 
newspaper classified and print ads, community luncheons and health fairs, as well as clinic referrals. We 
have been extremely successful in implementing this approach in past studies 
 
6.3 Screening and Study Entry: Participants deemed eligible based on an initial phone screening by our 
front desk manager, will be encouraged to consult with their physician and invited to an in-person 
screening visit. During this visit, potential participants will first be asked to give their informed consent 
and then will be screened for study entry criteria. Initial screening procedures will include a review of 
their medical history, medication use, a physical exam or nursing assessment, physical activity levels, 
cognitive function (assessed by the Mini-Mental State Exam), measurement of vital signs, height and 
weight, BMI (calculated in database only), collection of demographics information, single 24-hour 
ambulatory SBP monitoring (daytime average SBP≥130 mmHg and <160 mmHg – qualifying criterion), 
and urine collection for a pregnancy test. If all study entry criteria are met, participants will be scheduled 
to return to the clinic for baseline assessments. In addition, the study participants will be asked to sign 
Medical Records Release Authorization if they qualify. This Authorization will be used exclusively to 
obtain medical records to acquire facts, details, and outcomes of Serious Adverse Events that occurred 
during the study and have to be reported to the sponsor and/or IRB. 
 
6.4 Baseline Assessment and Randomization: If all study entry criteria are met, participants will be 
scheduled to return to the clinic for baseline assessments prior to randomization. Participants who have 
not yet had a physical evaluation or nursing assessment will complete this before undergoing physical 
tests. Participants will be asked to provide a fasting blood sample for evaluation of clinical safety lab 
values. We will also collect urine samples (first sample collected between 8 am to 11 am and another 
sample collected between 5 pm to 8 pm) at this visit, which will be slow frozen in a -80 freezer and 
analyzed after data collection is complete. The first sample will be collected when the participant comes 
in the morning to participate in the in-person visit. Then, the study coordinator will provide the urine 
sample collection cup for the participant to bring back home to collect the second urine sample. The 
study coordinators can help transport the second urine sample or, if the participant prefer, the 
participant could bring the urine sample back to the study coordinator. In addition, vital signs and weight 


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will be measured, as well as exercise capacity with the 6-Minute Walk Test and self-assessed 
functionality with the Late Life Function and Disability Instrument (LLFDI). Participants will also be given 
the 24-h BP device to complete the 24-hour ambulatory recording and will have their arterial stiffness 
assessed. We will also collect adverse events and update medication changes. Finally, the study 
coordinator will provide participants with a supplement intake form to take home to record when the 
supplement is taken. Staff members will then discuss randomization procedures with participants. The 
participants will receive a return envelope/box to return the ambulatory BP device after the 24-hour 
recording. 
 
6.5 Exercise Intervention: After random assignment to either the NREx or the PLEx groups, participants 
will engage in a three-days a week, center-based walking exercise intervention for 6 weeks. Following a 
brief warm-up, participants will be instructed to walk for 30 minutes at a 5-6 on the CR10 scale with 
encouragement for 10 minutes to be vigorous (7-8 on CR10 scale). Sessions will also include balance 
training to promote cool-down. Participants will be introduced to exercises in such a way that they begin 
with lighter intensity and gradually increase. The progressive nature of the intervention is designed to 
minimize discomfort and prevent injury. Blood pressure will be measured prior to each exercise 
session; the participant will not complete the session that day if he or she has an in-person SBP >200 
mmHg or DBP >110 mmHg (AHA guidelines for exercise contraindication) measured at the exercise 
center. 
 
6.6. Supplementation: Participants will be randomly assigned to receive, in a double-blind fashion, 
either 1,000 mg/day of encapsulated NR (Niagen®) or placebo. The company ChromaDex (Irvine, CA) 
will provide both the NR and placebo capsules for the proposed study. Placebo capsules will be 
identical to those including NR. As noted above, a 6-week NR study of Martens et al. demonstrated that 
NR supplementation at a dose of 1,000 mg/day was safe in rather healthy middle-aged and older 
adults. Subjects will ingest NR (NIAGEN®; 500 mg, twice per day; ChromaDex, Inc.) or alike looking 
placebo capsules [10]. The participants will be provided with capsules sufficient for at least 3 weeks. 
The second 3-week portion of the capsules will be dispensed at 3-week follow-up visits by a study 
coordinator. A study coordinator will be given a jar with the study product by an unblinded staff person 
not-involved in this study. The not-involved staff member will be is possession of the identified 
randomization list and will provide this list after completing the enrollment and outcome measure 
analyses. The participants will receive a supplement intake diary to note the taken pills and a study 
coordinator will count the remaining pills at 3 and 6-week visits. 
 
Data from the exercise interventions will be collected and stored in the study database. Following each 
session, participants will be asked to provide a rating of perceived exertion (RPE) for the session 
according to the Borg CR10 scale.  
Table 1. Data collection summary by study visit. 
Study phase 
Pre-randomization 
Randomization 
Visit description (FU=follow-up, CO=close-out) 
Screen 
Baseline 
FU 
CO 
Visit number 
1 
2 
3 
4 
Week number 
-2 
0 
3 
(+ or - 7 days) 
6 
(+ or - 7 days) 
Informed consent, review of inclusion/exclusion 
criteria 
X 
 
 
 
Medical history and medications, MSSE 
X 
 
 
 
Height 
X 
 
 
 
Weight 
X 
X 
X 
X 
BMI (calculated in database only) 
X 
 
 
 
Demographics information 
X 
 
 
 
Physical Exam/nursing assessment 
X* 
X* 
 
 
Monitor vital signs 
X 
X 
X 
X 
Ambulatory BP recording 
X 
X 
X 
X 


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6.7 
Adherence to interventions. To enhance adherence to the study interventions (compliance), we will 
utilize empirically-supported techniques which we have successfully utilized in prior studies. Our first 
step will be to fully inform participants of study requirements before randomization and enroll only those 
persons who are willing to complete all study procedures. Undoubtedly, however, issues arise after 
randomization with the potential to limit compliance. Common causes of poor compliance include 
vacations, spouse care, fatigue, and fluctuations in motivation, perceived lack of benefit, physical 
discomfort, and adverse health experiences. First, we have designed the trial, including the 
inclusion/exclusion criteria and physician monitoring, to limit the likelihood of experiencing adverse 
health events in response to the interventions. In addition, care will be taken by the interventionists to 
promote the safe engagement in the exercise intervention. For other issues of non-compliance, we will 
approach this potential problem using a social problem solving model (“toolbox”) approach in dealing 
with individual adherence problems.28 This approach assumes that the process of changing behavior is 
a collaborative effort between the participant and the interventionists, and that behavior change can be 
readily undertaken during the regular weekly contacts that intervention staff will initiate throughout the 
course of the intervention, as well as during face-to-face visits. Our team has successfully applied this 
type of problem-solving approach in promoting adherence to behavioral interventions in prior studies. 
 
6.8 Follow-up and Close-out visits. In addition to baseline and screening visits, assessment visits will be 
conducted at approximately 3 weeks (follow-up) and approximately 6 weeks post-randomization. During 
the 3-week assessment visit, the research team will evaluate participant’s vital signs, measure weight, 
update medical history, collect blood samples for safety markers and inquire about any adverse 
experiences since the last visit. We will also collect urine samples (first sample collected between 8 am 
to 11 am and another sample collected between 5 pm to 8 pm) at these visits, to be analyzed after data 
collection is complete. The first sample will be collected when the participant comes in the morning to 
participate in the in-person visit. Then, the study coordinator will provide the urine sample collection cup 
for the participant to bring back home to collect the second urine sample. The study coordinators can 
help transport the second urine sample or, if the participant prefer, the participant could bring the urine 
sample back to the study coordinator. Blood pressure will be measured prior to completing physical 
function tasks at these visits; the participant will not complete the physical function tasks for that visit if 
he or she has an in-person SBP >200 mmHg or DBP >110 mmHg (AHA guidelines for exercise 
contraindication) at the clinic. The coordinator will collect and count return pills and dispense a new 
supply. At the end of the 3 week visit, the participant will be provided with a 24-Hour Ambulatory Blood 
Pressure Monitor and the measurements will be recorded as in previous visits. During the close-out (6-
week) visit, the team will perform the same evaluations as during the baseline visit, as well as collect 
and count returned pills, and collect supplement intake information from participants. We will also 
collect adverse events and update medication changes. 
 
CHAMPS Questionnaire 
X 
 
 
 
Pregnancy test 
X 
 
 
 
6 minute walk test 
 
X 
 
X 
Late Life Function & Disability Instrument 
 
X 
 
X 
Randomization 
 
X 
 
 
Blood collection 
 
X 
X 
X 
Urine collection 
 
X 
X 
X 
Arterial stiffness 
 
X 
 
X 
 Dispense Supplement Intake Diary 
 
X 
X 
 
Dispense Study Supplement (NR or Placebo) 
 
X 
X 
 
Pill counts, collect diaries, assessment of 
adverse experiences 
 
 
X 
X 
Collection of AEs and update medication 
changes 
 
X 
X 
X 
*The physical exam/nursing assessment can be completed at either Screening Visit 1 or at the Baseline Visit as long as it is 
prior to randomization. 
 


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6.9. Primary and Secondary Outcome Measures.  
 
6.10 Sample size justification. This pilot study will help generate precise estimates of effect variance in 
the population in which a subsequent larger-scale study will be conducted. Published recommendations 
for the design of pilot studies indicate that a sample of 18 participants per randomized arm is typically 
sufficient to estimate a parameter for a future trial [14-16]. The enrollment sample of 54 (n=18 x 3 arms) 
participants is intended to provide preliminary data necessary to indicate feasibility of a larger trial and 
to provide descriptive estimates of effects. Based on our experience from the past and current clinical 
trials conducted at our institute, we do not expect an attrition higher than 15%, therefore, we increased 
a group size to n=18, which will give us sufficient sample sizes for the pilot purposes after drop-out 
(n=15 x 3 groups). The data will also provide for nominal estimation (using a 95% CI) of mean changes 
in dependent variables within each arm. By assuming the mean decrease in SBP after a 6-week of 
intervention to be 20 mmHg, 10 mmHg and 15 mmHg in the three groups of NREx, PLEx and NR, 
respectively, and the standard deviation of the SBP decreases to be 10 [16], the sample size of 15 
participants for each group can guarantee a power of 85% to detect the difference between the NREx 
and PLEx groups and a power of about 80% to detect the differences among the three groups. We 
expect that the differences of the arterial-stiffness measurements among the three groups are larger 
than those of SBP. Thus, the power numbers for that measure will be larger as well.  
 
6.11 Safety monitoring plan. To ensure participant safety in the proposed study, we will adapt procedures 
that we have implemented successfully in other studies including LIFE,46,47 Weight Loss + Exercise,48 and 
Task Specific Exercise.49 As he has for a number of our prior studies, Dr. Bhanuprasad Sandesara will 
serve as the Study Physician who is responsible for assessment, monitoring and interventions for health 
events. To maximize participant safety we will follow a standardized screening protocol. Accordingly, all 
potential participants will undergo screening for cardiovascular and other major diseases by means of a 
health questionnaire, medication inventory, and physical exam/nursing assessment. Those with 
conditions that meet the exclusion criteria described in section 6.1 as determined by Dr. Sandesara will 
be excluded. Dr. Sandesara will also review clinically significant abnormal laboratory values and indicate 
the need for study withdrawal if he deems it necessary. Each participant will be instructed to report the 
occurrence of an adverse event at scheduled data collection times (scheduled clinical exams or phone 
interviews). Participants also have access to study clinic personnel at other times to report serious 
adverse events or concerns about the safety of participating in the study. If necessary, Release of 
Medical Records Authorizations signed by the study participants will be used to obtain medical records to 
collect details and outcomes of SAEs for safety and reporting purposes. 
Venipuncture will be performed by a trained and experienced phlebotomist using standard techniques. 
Participants will always have venipuncture performed while seated upright with both feet on the floor.  
24-h BP 
All blood pressure recordings will be performed with validated Oscar 2 monitors, under 
the supervision of trained personnel and according to the manufacturer’s 
recommendations. SBP will be measured every 20 minutes (min) during the day (from 
0700 to 2200 hours), and every 60 min overnight (from 2200 to 0700 hours) [12]. 
Arterial 
Stiffness 
 
Aortic pulse-wave velocity (PWV), commonly measured as carotid to femoral PWV 
(cfPWV), is considered to be the gold standard method of assessing arterial stiffness 
in humans. cfPWV will be measured using the SphygmoCor XCEL system (AtCor 
Medical, New South Wales, Australia). Briefly, cfPWV will be determined by recording 
pressure pulse waves at the carotid and femoral arteries using a high-fidelity 
micromanometer (Millar Instruments, Houston, TX) and calculating the distance 
between the recording sites divided by the time delay between the carotid and the 
femoral pulse waves [13]. 


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Center-based assessments and interventions will be conducted and supervised by trained staff who will 
monitor potential adverse experiences and symptoms. All assessors and interventionists receive CPR 
training and training on management of acute events including syncope, chest pain, acute dyspnea, focal 
neurological symptoms and abnormal vital signs. Portable defibrillators are available at each intervention 
and assessment site and all study staff have on-call access to the study physician and contact numbers 
for emergency services. Institutional and community EMS services will be activated if needed. As 
indicated previously, participants will be taught the importance and proper method of warming-up prior to 
and cooling-down following structured activity sessions. If at any point during an exercise session, 
participants develop chest pain, shortness of breath, or dizziness, they will be instructed to rest and to 
contact the center and their physicians if these symptoms persist or recur with further exercise.  
Blood pressure and heart rate will be measured before and after the resistance training at each center 
based session for pre-exercise safety. The participant will not complete the session that day if he or she 
has an in-person SBP >200 mmHg or DBP >110 mmHg (AHA guidelines for exercise contraindication) 
measured at the exercise center.  
 
Procedures to minimize discomfort include warm-up and cool-down activities. The participants will also be 
introduced to the intervention exercises in a structured way, such that they begin with lighter intensity and 
gradually increase over the course of the first week. During the intervention visits, participants will be 
supervised at all times. Participants will also be instructed to move slowly when rising from a seated or 
lying position to reduce the risk of experiencing orthostatic hypotension. Study staff will be instructed to 
stand in a supportive position when participants are rising to prevent a fall in case of syncope. Exercise 
will be stopped if the participant reports pain, tightness or pressure in the chest, significant shortness of 
breath, feeling faint, lightheaded or dizzy, or significant other medical problems.  
Any significant adverse events will be reported promptly to the IRB and to the NIA Data Safety 
Monitoring Board (DSMB). Otherwise, annual reports will be prepared for both.   
Written informed consent will be obtained after explanation to subjects of all procedures and time 
commitments. The study interviewers will explain to prospective participants the purpose, methods and 
extent of the study. Potential participants will be asked to read the informed consent form and to ask 
questions. The form will be written in simple, easy-to-understand language. Staff members will also 
review all key aspects of the study verbally.  
Confidentiality of data will be maintained by using research identification numbers that uniquely identify 
each individual. Data will be used only in aggregate and no identifying characteristics of individuals will 
be published or presented. Safeguards will be established to ensure the security and privacy of 
participants’ study records. The information collected from participants in this study has a low potential 
for abuse, since the data do not address sensitive issues. Nevertheless, appropriate measures will be 
taken to prevent unauthorized use of study information. The research records will be kept in a locked 
room at the Institute on Aging. The files matching participants' names and demographic information 
with research ID numbers will be kept in a separate room and will be stored in a locked file that uses a 
different key from that of all other files. Only study personnel will have access to these files, and they 
will be asked to sign a document that they agree to maintain the confidentiality of the information. 
After the study is completed, local data will be stored with other completed research studies in a 
secured storage vault. In compliance with the Health Insurance Portability and Accountability Act 
(HIPAA) and the Standards for Privacy of Individually Identifiable Health Information of the Department 
of Health and Human Services, we will access personal health information and medical records only 
after receiving signed informed consent, as described above.  
Finally, the study protocol will be registered at www.ClinicalTrials.gov before study enrollment begins. 
7. Possible Discomforts and Risks: 


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The first clinical trial with a 6-week NR supplementation (1000 mg/day) in middle-aged and older adults 
showed that adverse events reported over the course of the study did not differ between the treatment 
group and the placebo. We will test the same supplementation dose and duration provided to us by the 
same company. A different study that tested an effects of a different product but containing NR (500 or 
1000mg/day) and Pterostilbene showed no serious adverse effects among older adults other than 
nausea, fatigue, headaches, diarrhea, stomach discomfort and indigestion. We will inform the potential 
participants that supplementation with similar products containing NR in older adults was associated with 
these side effects and there is always a risk that they may experience these side effects. 
Potential risks are those associated with health information privacy, blood pressure testing, venipuncture 
and participation in exercise training and testing.  
The pregnancy test may provide a false-positive or false-negative result. 
Venipuncture can be associated with pain, bruising, hematoma formation, superficial phlebitis, and rarely 
cellulitis or fainting. The risks of placing a blood pressure cuff on a participant are that it may cause 
pinching, slight bruising, discomfort, or skin irritation from the cuff. The primary risk associated with 
moderate-intensity exercise training is skeletal muscle soreness. There are also other risks that relate to 
falls and fractures, exacerbation of arthritis and other joint conditions, post-exercise hypotension, and 
cardiovascular events. There is a risk that a participant may trip, stumble, or fall during the exercise 
sessions and experience shortness of breath, dizziness, palpitations, chest pain or discomfort, heartburn, 
light headedness, or feeling about to faint. Exercise is contraindicated when resting SBP is >200 mmHg 
or DBP > 110 mmHg. We are recruiting participants with systolic hypertension of ≥ 130mmHg and < 160 
mmHg, therefore, there is no specific increased risk to these participants over the general risks 
associated with moderate-intensity exercise training.  
The DSMB will be set-up and run by the National Institute on Aging.  
Confidentiality:  Data will be used only in aggregate and no identifying characteristics of individuals will 
be published or presented. Confidentiality of data will be maintained by using research identification 
numbers that uniquely identify each individual. Safeguards will be established to ensure the security 
and privacy of participants’ study records. Appropriate measures will be taken to prevent unauthorized 
use of study information. Data other than demographic information will not use names as an identifier. 
The research ID number will be used. The research records will be kept in a locked room in the study 
site. Only trained and certified study personnel will have access to these files, and they will be asked to 
sign a document that they agree to maintain the confidentiality of the information.  Electronic records 
will be stored on a password protected network server maintained by the university information 
technology department.  In compliance with the Health Insurance Portability and Accountability Act 
(HIPAA) and the Standards for Privacy of Individually Identifiable Health Information of the Department 
of Health and Human Services, we access personal health information and medical records only after 
receiving signed informed consent. If a participant does not qualify based on the initial phone pre-
screening, we will delete the individual’s identifying information from the study record immediately, but 
we will keep the other information provided to track the outcome of our calls. 
8. Possible Benefits: 
Importantly, the proposed project should have tangible benefits for participants. These benefits include 
information about their health and assessments of their cardiovascular status. All study participants will be 
encouraged to communicate the results from the study to their primary care providers. Moreover, 
participants in exercise groups will receive supervised exercise training and instruction about how to 
maintain exercise habits at home. Participants in the NR alone group may experience potential benefits of 
the supplementation. We expect that these benefits will improve quality of life for all participants. 


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Potential benefits of NR alone may be lowering systolic blood pressure and improving vascular flexibility, 
but the combination of NR and exercise may have better effects than exercise or NR alone on systolic 
blood pressure reduction and improvement of vascular flexibility in hypertensive older adults. 
9. Conflict of Interest: 
None 
10. Statistical Analysis Plan 
The primary analysis will follow an “intent-to-treat” model. Because repeated measures are obtained on 
individual participants and they are potentially correlated, a mixed-effect linear regression model will be 
used. Differences in outcome measures at the 3-week follow-up (or 6-week close-out) from baseline for 
each individual participant will be used as responses, and two dummy variables representing the three 
treatment groups, age, and gender, and other baseline characteristics of participants will used as 
covariates. A random-effect term will also be included in the model to accommodate within-subject data 
correlation. This analysis will be performed for each outcome variable. The relatively small sample size 
may imbalance pre-randomization covariates. Thus, caution will be taken in the interpretation of 
hypothesis testing results. 
 


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Literature cited  
 
1. 
Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart Disease and 
Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation, 2018. 
137(12): p. e67-e492. 
2. 
Group SR, Wright JT, Jr., Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A Randomized Trial 
of Intensive versus Standard Blood-Pressure Control. N Engl J Med, 2015. 373(22): p. 2103-16. 
3. 
Whelton PK, Carey RM, Aronow WS, Casey DE, Jr., Collins KJ, Dennison Himmelfarb C, et al. 2017 
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, 
Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report 
of the American College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines. Hypertension, 2018. 71(6): p. 1269-1324. 
4. 
AlGhatrif M, Strait JB, Morrell CH, Canepa M, Wright J, Elango P, et al. Longitudinal trajectories of 
arterial stiffness and the role of blood pressure: the Baltimore Longitudinal Study of Aging. 
Hypertension, 2013. 62(5): p. 934-41. 
5. 
Ungvari Z, Tarantini S, Kiss T, Wren JD, Giles CB, Griffin CT, et al. Endothelial dysfunction and 
angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol, 2018. 15(9): p. 555-565. 
6. 
de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, et al. Nicotinamide 
mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. 
Aging Cell, 2016. 15(3): p. 522-30. 
7. 
Tanasescu M, Leitzmann MF, Rimm EB, Willett WC, Stampfer MJ, and Hu FB. Exercise type and 
intensity in relation to coronary heart disease in men. JAMA, 2002. 288(16): p. 1994-2000. 
8. 
Stewart KJ, Bacher AC, Turner KL, Fleg JL, Hees PS, Shapiro EP, et al. Effect of exercise on blood 
pressure in older persons: a randomized controlled trial. Arch Intern Med, 2005. 165(7): p. 756-62. 
9. 
Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, et al. Impairment of an 
Endothelial NAD(+)-H2S Signaling Network Is a Reversible Cause of Vascular Aging. Cell, 2018. 
173(1): p. 74-89 e20. 
10. 
Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic 
nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and 
older adults. Nat Commun, 2018. 9(1): p. 1286. 
11. 
American College of Sports M, Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, Minson CT, Nigg 
CR, et al. American College of Sports Medicine position stand. Exercise and physical activity for older 
adults. Med Sci Sports Exerc, 2009. 41(7): p. 1510-30. 
12. 
Goodwin J, Bilous M, Winship S, Finn P, and Jones SC. Validation of the Oscar 2 oscillometric 24-h 
ambulatory blood pressure monitor according to the British Hypertension Society protocol. Blood Press 
Monit, 2007. 12(2): p. 113-7. 
13. 
Hwang MH, Yoo JK, Kim HK, Hwang CL, Mackay K, Hemstreet O, et al. Validity and reliability of 
aortic pulse wave velocity and augmentation index determined by the new cuff-based SphygmoCor Xcel. J 
Hum Hypertens, 2014. 28(8): p. 475-81. 
14. 
Lancaster GA, Dodd S, and Williamson PR. Design and analysis of pilot studies: recommendations for 
good practice. J Eval Clin Pract, 2004. 10(2): p. 307-12. 
15. 
Browne RH. On the use of a pilot sample for sample size determination. Stat Med, 1995. 14(17): p. 1933-
40. 
16. 
Hertzog MA. Considerations in determining sample size for pilot studies. Res Nurs Health, 2008. 31(2): 
p. 180-91. 
 

ICF_001.pdf: 
IRB Project #: 201900746
Page 1 of 13
IRB Version: 02/09/2023
PI Version: 02/09/2023
INFORMED CONSENT FORM
to Participate in Research, and
AUTHORIZATION 
to Collect, Use, and Disclose Protected Health Information (PHI)
INTRODUCTION
Name of person seeking your consent:
Place of employment & position: 
GENERAL INFORMATION ABOUT THIS STUDY
1. Name of Participant ("Study Subject")
___________________________________________________________________
2. What is the Title of this research study (this “Research Study”)?
Nicotinamide riboside as an Enhancer of Exercise Therapy in hypertensive older adults
– The NEET Trial
3. Whom do you call if you have questions about this Research Study (the “Study
Team”)?
Principal Investigator: Robert Mankowski, PhD 352-294-5055
Other research staff:  Study Coordinator 352-273-9212
4. Who is paying for this Research Study?
The sponsor of this study is the National Institute on Aging. ChromaDex is providing
medication (nicotinamide riboside and placebo) for this research study.
5. In general, what do you need to know about this Research Study?
Agreeing to become involved in any research is always voluntary.  By signing this
form, you are not waiving any of your legal rights.  If you decide not to participate in
this research, you will not be penalized in any way and you will not lose any benefits
to which you are entitled. If you have questions about your rights as a research
subject, please call the University of Florida Institutional Review Board (IRB) office at
(352) 273-9600.
a) In general, what is the purpose of the research, how long will you be
involved?  The purpose of this study is to test if nicotinamide riboside improves an
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effect of walking exercise training on cardiovascular function among older adults 
with elevated blood pressure. Participation from initial screening to closeout visit 
will consist of 22 visits (including four study visits and 18 exercise visits) and could 
take up to ten weeks.
b) What is involved with your participation, and what are the procedures to be 
followed in the research? There will be four in-person visits. The visits will vary in 
length and will include monitoring of overall health, blood draws, questionnaires, 
ambulatory blood pressure recording, arterial stiffness testing, group assignment, 
and pill dispensing. You also may be randomly assigned to an exercise group, 
which meets three times per week. 
c) What are the likely risks or discomforts to you?  Potential risks are those 
associated with health information privacy, blood pressure measurement, 
venipuncture, product supplementation, and participation in exercise training and 
testing.
d) What are the likely benefits to you or to others from the research? Benefits 
may include information about your health and assessments of your 
cardiovascular status.   
e) What are the appropriate alternative procedures or courses of treatment, if 
any, that might be helpful to you? If you do not wish to be in this study, please 
tell a study team member and do not sign this form.
Additional and more detailed information is provided within the remainder of this Informed 
Consent form, please read before deciding if you wish to participate in this study.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time.
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY?
6. What will be done as part of your normal clinical care (even if you did not 
participate in this Research Study)? 
No procedures in this study will be part of your normal clinical care.
7.  What will be done only because you are in this Research Study? 
An initial telephone screening indicated that you may be eligible to participate in the 
study. The first study visit (“Screening visit”) will further determine if you are eligible to 
participate. Should you be eligible to participate in the study, you may be asked (by 
random assignment) to participate in a structured physical activity program three days 
a week for 6 weeks. You will be asked to consume the nutritional supplements 
provided to you for 6 weeks and to return to the clinic for additional assessment visits 
to monitor your safety and measure study results.
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This exercise program includes: center-based walking exercise intervention for 6 
weeks. Following a brief warm-up, you will be instructed to walk for 30 minutes at a 
moderate intensity (able to speak freely during exercise) with encouragement for 10 
minutes to be vigorous (unable to speak easily during exercise). Sessions will also 
include balance training to promote cool-down. You will be introduced to exercises in 
such a way that they begin with lighter intensity and gradually increase. The 
progressive nature of the intervention is designed to minimize discomfort and prevent 
injury. 
You will be randomly assigned (like flipping a coin) into one of three groups: exercise 
and 1,000 mg/day of encapsulated NR (Niagen®), or 1,000 mg/day of NR alone, or 
exercise and placebo (an identically appearing pill containing no NR). The placebo is 
a sugar pill with cellulose coating. NR is an alternative form of Vitamin B3 (also known 
as niacin) and is converted into an enzyme with reported beneficial health effects. 
You will be asked to consume your provided supplement daily. You will not know if 
the supplement contains NR or if it is a placebo.  
If you wish to participate, your first visit will be to determine your eligibility for the 
study. Details regarding the tests to be conducted during this screening visit and other 
study visits (if you are eligible) are described below. Visits will take place at the 
University of Florida Clinical and Translational Research Building (CTRB), and the 
physical activity program will take place at the IOA Health Promotion Center.
Once this research study is completed, any information that could identify you might 
be removed from any identifiable private information or identifiable biospecimens 
collected and that, after such removal, the information or biospecimens could be used 
for future research studies or distributed to another investigator for future research 
studies without additional informed consent from you or your legally authorized 
representative.
Screening Visit: The screening visit is expected to take 1 to 2 hours. Details of study 
procedures that will be conducted during this visit are below. The order of these 
procedures may vary based on the schedules of study staff.
Pregnancy test
Women participants aged 55-62 will be asked to complete a urine pregnancy test.
Questionnaires
You will be asked questions about your medical history and medication use. You will 
also be asked to complete a short test of memory and reasoning.
Physical Measurements and Exam
We will take measurements of your height, body weight, BMI (calculated in database 
only), pulse, and blood pressure at the clinic. A medical professional will also give you 
a physical exam/nursing assessment to determine if it is safe for you to participate in 
the study. This may also be done at the baseline visit prior to randomization, depending 
on doctor/nurse availability.
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24-hour Blood Pressure Recording
You will receive a blood pressure monitor to wear on your arm for 24 hours. This monitor 
will measure your blood pressure every 20 minutes during the day (from 7:00 AM until 
10:00 PM) and every 60 minutes overnight (10:00 PM until 7:00 AM). We will give you 
a pre-paid envelope to return this monitor to us after the 24-hour collection has 
completed; this measure will be used to determine eligibility. 
Medical records release authorization
The study team will ask you to sign the Medical Records Release Authorization. We 
would like to have this form signed by you if we need to request your health records if 
you are hospitalized or any health problems worsen and the study team has to report 
details of these events to regulatory authorities (Institutional Review Board, the study 
sponsor, etc.) to ensure your safety during participation in this research study. This 
form will be signed only once – during the Screening Visit. Health information 
collected using this release will be used only for any health events that occur during 
your participation in this research.
At the end of this visit, the study team will determine if you can participate in this 
study. If you are not eligible, this will be your only study visit.
Demographics form
We will collect your background information such as your gender, ethnicity, race, date 
of birth, age, education level, contact information, and emergency contact.
Baseline Visit: Should you be eligible for the study; you will be asked to return to the 
clinic for the baseline study visit. This visit is expected to take 2 to 3 hours and will 
include:
Blood Draw
You will be asked to fast before your appointment because blood will be collected 
during this visit.  We will provide a snack for you before you continue with your visit 
procedures, after we draw your blood. We will collect approximately 2 tablespoons of 
blood from a small vein in your arm or hand.  The purpose of this blood draw is to 
determine levels of certain compounds in your blood that will help us determine some 
details of your health and study eligibility. 
We will also collect urine samples at this visit, to be analyzed after data collection is 
complete. The first urine sample will be collected between 8 am to 11 am when you 
come in the morning to participate in the in-person visit. Then, the study coordinator will 
provide you with the urine sample collection cup to collect the second urine sample 
between 5 pm to 8 pm. The study coordinators can help transport the second urine 
sample from your location to the research building or, if you prefer, you could bring the 
second urine sample back to the research building and hand it to the study coordinator.
Physical measurements
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We will take measurements of your body weight, pulse, and blood pressure at the 
clinic. If not already completed at the Screening Visit, a medical professional will also 
perform a physical exam/nursing assessment prior to randomization to determine if it 
is safe for you to participate in the study.
Questionnaires
You will be asked questions about your perception of your physical abilities. We will 
also ask you if you have had any changes in your health since your last visit.  
Physical Performance Tests
You will be asked to complete tests of your physical ability. You will be asked to walk 
as far as you can for a duration of 6 minutes
24-hour Blood Pressure Recording
You will receive a blood pressure monitor to wear on your arm for 24 hours. This 
monitor will measure your blood pressure every 20 minutes during the day (from 7:00 
AM until 10:00 PM) and every 60 minutes overnight (10:00 PM until 7:00 AM). We will 
give you a pre-paid envelope to return this monitor to us after the 24-hour collection 
has completed. 
Arterial Stiffness Measurement
We will measure the flexibility of your arteries by measuring the pulse in your neck 
and the pulse in your thigh at the same time. We will measure the distance between 
these two points to calculate the flexibility of your arteries. 
Randomization and Study Supplement Distribution
You will be randomized to one of three groups at the end of the Baseline Visit 
(Exercise plus NR study supplement; Exercise plus Placebo; NR study supplement 
alone). You will be provided with your nutritional supplement (NR or placebo) to be 
taken orally until your next appointment. You will be sent home with a 1-month supply 
of study capsules.  You will be asked to take a dose of the capsules twice a day (2 
pills in the morning and 2 pills in the evening).  The instructions will be clearly marked 
on the pill container.  If you forget to take a dose, you will be instructed to skip that 
dose and take your next regularly schedule dose.
Additionally, you will receive a Supplement Intake Diary as well as instructions for 
completing it. We will ask you to return this at future visits.
Collection of AEs and update medication changes
3 Week Visit: This visit is expected to take 1 to 2 hours and will include: 

Measurement of pulse, blood pressure and body weight at the clinic

Collection of another blood sample after you have fasted the evening before

Collection of urine samples (same as the procedure at the baseline visit)
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
Questions about any adverse experiences or changes in your health since last 
visit

Return any unused study supplement (including empty bottles).

You will be provided with your nutritional supplement (NR or placebo) to take 
until your next appointment

We will collect the diary you completed after the last visit and dispense a new 
one to complete. 

24-Hour BP recording: As in previous visits, you will receive a blood pressure 
monitor to wear on your arm for 24 hours. This monitor will measure your blood 
pressure every 20 minutes during the day (from 7:00 AM until 10:00 PM) and 
every 60 minutes overnight (10:00 PM until 7:00 AM). We will give you a pre-
paid envelope to return this monitor to us after the 24-hour collection has 
completed.

We will collect adverse events and update medication changes.
6 Week (close-out) Visit: This will be the final study visit. It is expected to take 2 to 3 
hours and will include:

Measurement of pulse, blood pressure and body weight at the clinic

Collection of another blood sample after you have fasted the evening before

Collection of another urine samples (same as the procedure at the baseline 
visit)

Questions about any adverse experiences or changes in your health since last 
visit

Questions about your perception of your physical abilities (as during Baseline 
Visit)

Perform tests of physical performance (as during Baseline Visit)

24-hour BP recording: As in previous visits, you will receive a blood pressure 
monitor to wear on your arm for 24 hours. This monitor will measure your blood 
pressure every 20 minutes during the day (from 7:00 AM until 10:00 PM) and 
every 60 minutes overnight (10:00 PM until 7:00 AM). We will give you a pre-
paid envelope to return this monitor to us after the 24-hour collection has 
completed.  

Arterial Stiffness Measurement (as done at Baseline Visit)

Return any unused study supplement (including empty bottles). 

We will collect the diary you completed after your previous visit. 

We will collect adverse events and update medication changes.
If you have any questions now or at any time during the study, please contact one of 
the research team members listed in question 3 of this form.
8. What identifiable health information will be collected about you and how will it be 
used?
The Research Team will collect 

Name
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
Social Security Number for compensation purposes

Contact Information

Date of Birth

Emergency Contact Information

Laboratory results

Information about your health and medical history

Information about medication you are taking

Information about your vital signs and body measurements

Information about your physical abilities

Information about your mental abilities
The Research Team may collect this information from other healthcare providers, 
such as laboratories, which are a part of this research, as well as healthcare providers 
that are not part of this research (other doctors, hospitals or clinics). Other 
professionals at the University of Florida or Shands Hospital who provide study-
related care, and the University of Florida Institutional Review Board (IRB), may also 
collect your health information. 
The Research Team listed in question 3 above will use or share your health 
information as described below to carry out this research study. 
9. With whom will this health information be shared?
This health information may be shared with:

the study sponsor (listed in Question 4 of this form).

United States governmental agencies which are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health 
and Human Services, and the Office of Human Research Protections.

Government agencies which are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state, and local 
health departments.

The IRB that reviewed this Research Study and ensures your rights as a Study 
Subject are protected 
Otherwise, your identifiable health information will not be shared without your 
permission unless required by law or a court order. Once your health information is 
shared with those listed above, it is possible that they could share it without your 
permission because it would no longer be protected by the federal privacy law. 
 
10. How long will you be in this Research Study?
You may be in this study for up to 10 weeks.
This Authorization to use and share your health information expires at the end of the 
study, unless you revoke it (take it back) sooner.
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11.How many people are expected to take part in this Research Study?
We expect to screen about 315 participants in order to reach a goal of 54 participants 
to complete the study.
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND 
WHAT ARE YOUR OPTIONS?
12.What are the possible discomforts and risks from taking part in this Research 
Study?
Risks of NR Supplementation
Previous clinical trials on NR supplementation have shown side effects among older 
adults to include nausea, tiredness, headaches, diarrhea and stomach discomfort. 
We expect these side effects to be mild and the chance of experiencing these side 
effects is low. 
Risks of Testing Mobility Performance, walking exercise sessions and Other Walking 
Tasks
There is a risk of falling during walking and balance tests. Falls can lead to injuries 
ranging from minor to serious, such as damage to joints and muscles (for example, 
spraining an ankle). It is also possible that you could experience fatigue, soreness, 
and/or discomfort due to physical activity during this study. These are unlikely to be 
worse than what you would experience due to increased physical activity outside of 
the study. Some types of discomfort are normal responses to exercise and most 
discomfort will generally disappear within a matter of days. 
Having high blood pressure increases the risk of a cardiac event, like a heart attack or 
stroke. While acute exercise does further increase blood pressure temporarily, it is 
considered a treatment that over time can lower resting blood pressure. We will 
monitor your blood pressure closely and ask how you’re feeling at the exercise 
sessions for your safety. We will measure your resting blood pressure prior to each 
exercise session and prior to physical function tasks at clinic visits; if your blood 
pressure on the day of the exercise session or clinic visit is >200/110, we will not 
complete the exercise session or physical function tasks that day and we will ask you 
to follow-up with your primary care physician. 
Risks of blood pressure testing
The risks of placing a blood pressure cuff on a participant are that it may cause 
pinching, slight bruising, discomfort, or skin irritation from the cuff.
Risks of a blood draw
The risks of drawing blood from a vein include discomfort at the site of puncture; 
possible bruising and swelling around the puncture site; rarely an infection; and, 
uncommonly, faintness from the procedure.
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Questionnaires about your health and lifestyle
Some participants may feel uncomfortable with the number or detail of questions we 
ask about your health and lifestyle.  You are not required to answer any question. 
However, if we are unable to obtain sufficient information to assess enrollment criteria 
and satisfy our primary study objectives, then you might not be able to continue in the 
study.
This Research Study may also include risks that are unknown at this time.
Please note, participating in more than one research study or project may further 
increase the risks to you.  If you are already enrolled in a research study, please 
inform one of the Research Team members listed in question 3 of this form or the 
person reviewing this consent with you before enrolling in this or any other research 
study or project.
During the study, the Research Team will notify you of new information that may 
become available and might affect your decision to remain in the study. 
The University of Florida is required by law to protect your health information. Your 
health information will be stored in locked filing cabinets or on computer servers with 
secure passwords, or encrypted electronic storage devices, as required by University 
policy. However, there is a slight risk that information about you could be released 
inappropriately or accidentally. Depending on the type of information, a release could 
upset or embarrass you, or possibly affect your ability to get insurance or a job. 
If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the Research Team members listed in 
question 3 in this form.
13a. What are the potential benefits to you for taking part in this Research Study?
Benefits include information about your health and assessments of your 
cardiovascular status. You will be encouraged to communicate the results from the 
study to your primary care provider. Moreover, if you are randomly assigned to one of 
the exercise groups, you will receive supervised exercise training and instruction 
about how to maintain exercise habits at home. If you are randomly assigned to the 
NR alone group, you may experience potential benefits of the supplementation. 
Potential benefits of NR alone may be lowering systolic blood pressure and improving 
the flexibility of your arteries. The combination of NR and exercise may have better 
effects than exercise or NR alone on systolic blood pressure reduction and improving 
the flexibility of your arteries. 
13b. How could others possibly benefit from this Research Study?
Information gained from participation in this study may help to provide doctors with 
new information for recommending exercise treatments. The study may also provide 
scientists and physicians with new knowledge about the use of nicotinamide riboside 
and potential beneficial effects when combined with exercise.
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13c. How could the Research Team members benefit from this Research Study?
In general, presenting research results helps the career of a researcher. Therefore, 
the Research Team listed in question 3 of this form may benefit if the results of this 
Research Study are presented at scientific meetings or in scientific journals.
14.What other choices do you have if you do not want to be in this study? 
If you do not want to be in this study do not sign this form. If you have already signed 
this form, please notify the Principal Investigator listed in question 3 above. If you do 
not want to be in this study, the alternative choice is simply to not participate.
You may also refuse to authorize the use of your health information, but if you refuse, 
you may not be allowed to be in this research study or receive any research-related 
treatment that is only available in this research study. However, your decision not to 
sign this Authorization will not affect any other treatment you may be eligible to 
receive.
15a. Can you withdraw from this study?
You may withdraw your consent and stop participating in this Research Study at any 
time.  If you do withdraw your consent, there will be no penalty to you, and you will not 
lose any benefits to which you are otherwise entitled. 
If you decide to withdraw your consent to participate in this Research Study for any 
reason, please contact the Research Team listed in question 3 of this form. They will 
tell you how to safely stop your participation.
You can also change your mind and take back this Authorization at any time by 
sending a written notice to the Research Team listed in question 3 of this form to let 
them know your decision. If you take back this Authorization, the Research Team 
may only use and disclose your health information already collected for this research 
study. No additional health information about you will be collected or disclosed to the 
Research Team. However, if you take back this Authorization, you may not be able to 
continue in this study. Please discuss this with a member of the Research Team listed 
in question #3.
15b.Can the Principal Investigator withdraw you from this Research Study? 
You may be withdrawn from this Research Study without your consent for the following 
reasons:

If the Principal Investigator or study physician decide that your participation in

the study could be harmful to you

If you develop a medical condition or need treatment not allowed in the study

If you do not follow study instructions

If the study is cancelled

Other various administrative reasons
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WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE?
16. If you choose to take part in this Research Study, will it cost you anything?
Study Services
The Sponsor will pay for or provide all study services/activities required as part of 
your participation in this study. There will be no cost to you other than incidental costs 
associated with traveling to the study site (e.g., cost of gas) or purchasing food before 
or after your visit.  If you receive a medical bill related to this study, please contact 
Robert Mankowski, PhD 352-294-5055 or Study Coordinator 352-273-9212. 
Items/Services Not Paid for by the Sponsor 
Any medical services you receive would have been provided to you even if you were 
not in this study. These services will be billed to you or your insurance company in the 
usual manner. You will be responsible for paying any deductible, co-insurance, co-
payments, for those services, and for any non-covered or out-of-network services. 
17.Will you be paid for taking part in this Research Study?
Yes, you will be compensated up to $380 in the form of gift cards. A gift card in the 
amount of $75 will be given at the completion of the baseline assessment visit and the 
6-week closeout visit. You will be given a $50 gift card at the completion of the 3-
week follow-up visit. You will be compensated at a rate of $10 per class attended for 
attending the study exercise classes.  You will receive compensation for attending the 
study exercise classes at the 3-week and 6-week closeout visit.  You will not be 
compensated for the screening visit.
If you are paid more than $199 for taking part in this study, your name and social 
security number will be reported to the appropriate University employees for purposes 
of making and recording the payment as required by law. You are responsible for 
paying income taxes on any payments provided by the study. Payments to 
nonresident aliens must be processed through the University of Florida Payroll and 
Tax Services department. If the payments total $600 or more in a calendar year, the 
University must report the amount you received to the Internal Revenue Service 
(IRS). The IRS is not provided with the study name or its purpose. If you have 
questions about the collection and use of your Social Security Number, please visit: 
http://privacy.ufl.edu/SSNPrivacy.html.
Your payment for participation in this research study is handled through the University 
of Florida’s Human Subject Payment (HSP) Program.  Your information which will 
include your name, address, date of birth, and SSN (depending on amount of money 
you are paid) is protected.  Access to the (HSP) Program site is limited to certain staff 
with the assigned security role.  You will be randomly assigned a specific identification 
(ID) number to protect your identity.
If you have any problems regarding your payment contact the study coordinator.
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18.What if you are injured while in this Research Study?
If you are injured as a direct result of your participation in this study, only the
Professional services that you receive from any University of Florida Health Science
Center healthcare provider will be provided without charge. These healthcare
providers include physicians, physician assistants, nurse practitioners, dentists or
psychologists. Any other expenses, including Shands hospital expenses, will be billed
to you or your insurance provider.
You will be responsible for any deductible, co-insurance, or co-payments. Some
insurance companies may not cover costs associated with research studies or
research-related injuries. Please contact your insurance company for additional
information.
The Principal Investigator will determine whether your injury is related to your
participation in this study.
No additional compensation is routinely offered. The Principal Investigator and others
involved in this study may be University of Florida employees. As employees of the
University, they are protected under state law, which limits financial recovery for
negligence.
Please contact the study physician at (412) 607-3914 if you experience an injury or 
have questions about any discomforts that you experience while participating in this 
study. 
 
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SIGNATURES
As an investigator or the investigator’s representative, I have explained to the participant 
the purpose, the procedures, the possible benefits, and the risks of this Research Study; 
the alternative to being in the study; and how the participant’s protected health information 
will be collected, used, and shared with others: 
Signature of Person Obtaining Consent and Authorization
Date
You have been informed about this study’s purpose, procedures, possible benefits, and 
risks; the alternatives to being in the study; and how your protected health information will 
be collected, used and shared with others. You have received a copy of this Form. You 
have been given the opportunity to ask questions before you sign, and you have been told 
that you can ask questions at any time.  
You voluntarily agree to participate in this study. You hereby authorize the collection, use 
and sharing of your protected health information as described above. By signing this form, 
you are not waiving any of your legal rights.
Signature of Person Consenting and Authorizing
Date
Study ID:IRB201900746   Date Approved: 3/2/2023