Clinical trial NCT03397966
Conditions: Obesity Cardiovascular Physiological Phenomena Metabolism
Keywords: obesity Cardiovascular Physiological Phenomena metabolism Energy Metabolism
Sponsor: VA Office of Research and Development
Start date: 2018-07-01; Completion date: 2019-05-01
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Accumulating evidence suggests that the natriuretic peptide (NP) hormonal system has important effects on metabolism. However, more information is needed to better understand the effects of NPs on metabolism in humans. Therefore, the investigators propose a study to determine the effects of b-type natriuretic peptide (BNP) on energy and fat metabolism in humans. The investigators' primary hypothesis is that the administration of BNP will increase energy expenditure in humans. The investigators' secondary hypothesis is that BNP administration will promote changes in gene expression in fat tissue suggestive of fat "beiging" in humans. Interventions that safely increase energy expenditure and promote fat "beiging" represent potential strategies for treating metabolic dysfunction due to obesity.

Detailed description:
Objective: The natriuretic peptide (NP) hormonal system is well-known for its important role in blood pressure regulation. However, accumulating evidence suggests that the NPs have significant effects on metabolism as well. For instance, administration of B-type natriuretic peptide (BNP) to wild-type mice leads to increased energy expenditure, changes in gene expression in fat tissue suggestive of fat "beiging" (which may be associated with cardiovascular and metabolic benefits), and reduced fat accumulation. Although recent studies in rodents suggest that NPs have important metabolic effects, there are few prospective data on the metabolic effects of NPs in humans.

Therefore, the investigators propose a physiologic, proof-of-concept study to determine the acute effects of b-type natriuretic peptide (BNP) on energy and fat metabolism in humans. The investigators' primary hypothesis is that the administration of BNP will increase energy expenditure in humans. The investigators' secondary hypothesis is that BNP administration will promote changes in gene expression in adipose tissue suggestive of a "beige" fat phenotype in humans.

Research Plan: The investigators propose the following research plan to address the investigators' specific aims:

Primary Aim: To investigate the acute effects of administration of BNP on energy expenditure in humans. The investigators propose a randomized, placebo-controlled, cross-over study in 50 adults (25 lean and 25 obese) without significant medical problems. Subjects will be randomized to intravenous infusion of recombinant human BNP(1-32) or normal saline (control), with assessment of energy expenditure and other physiologic measures. After a 7-day washout period, subjects will then undergo the other intervention.

Secondary Aim: To determine the acute effects of BNP on gene expression in white adipose tissue in humans. The investigators will assess markers suggestive of fat beiging in subcutaneous white adipose tissue biopsies after BNP infusion vs. control. This secondary aim will allow us to explore potential mechanisms underlying the hypothesized changes in energy expenditure.

Methods: In this cross-over study, each subject will receive BNP infusion at one visit and control at the other visit, in random order. The sequence of the treatments will be randomized. There will be a washout period (at least 14 days) between visits. Subjects will be stratified by BMI category (lean or obese). To address the Primary Aim, energy expenditure will be assessed via indirect calorimetry (metabolic cart). To address the Secondary Aim, subcutaneous fat biopsies will be performed, and tissue will be analyzed for gene expression of markers suggestive of fat beiging.

Clinical Relevance: This study will generate novel human data regarding the effects of the NPs on energy metabolism and adipose tissue. Interventions that safely increase energy expenditure and promote a beige fat phenotype represent potential strategies for treating obesity-associated metabolic dysfunction. The overarching scientific goals of this line of investigation are (1) to elucidate the role of the natriuretic peptide system in cardiometabolic health in humans, and (2) to investigate the potential for NP directed therapies in obesity-associated cardiometabolic dysfunction.

Update about Study Drug Supply Issues: The study started in 7/2018, and the last time participants were able to receive study drug was in May 2019, due to discontinuation of study drug by the drug manufacturer (nesiritide, Natrecor, Scios, LLC) after May 2019. Another potential source of drug supply was being sought out by the study team, and study recruitment was placed on hold during the search for new potential sources of study drug. A new viable source of study drug has not been identified, and funding is being closed. Thus, this study is being terminated. Results will be posted for the 5 participants who were able to complete the study procedures prior to the discontinuation of study drug.

Arms: arm 1: At Study Visit 1, subjects will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32), nesiritide) for 240 minutes. After a washout period of at least 2 weeks, subjects then present for Study Visit 2, where they will receive an IV infusion of placebo (control, normal saline) for 240 minutes. arm 2: At Study Visit 1, subjects will receive an IV infusion of placebo (control, normal saline) for 240 minutes. After a washout period of at least 2 weeks, subjects then present for Study Visit 2, where they will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32), nesiritide) for 240 minutes.
Interventions: intervention 1: recombinant human BNP(1-32) intervention 2: placebo (control, normal saline)
Intervention descriptions: intervention 1: Subjects will receive an IV infusion of recombinant human BNP(1-32) for 240 minutes at a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg. intervention 2: Subjects will receive an IV infusion of placebo (normal saline) at a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version #: 6 
 
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Protocol Date: 07/21/2023 
 
 
 
 
 
 
 
Metabolic Effects of Natriuretic Peptide Hormones 
 
 
Talat Alp Ikizler, M.D. FASN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Version #: 6 
 
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Protocol Date: 07/21/2023 
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
-Figure 1: Study Design Overview 
-Figure 2: Visit Time Line 
-Table 1: Time points for blood draws 
7.0 
Possible Side Effects  
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
13.0 Relevance to VA Mission 
14.0 References 
 
 
 
 


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1.0 
Background 
 
Obesity and obesity-related complications constitute serious public health problems. 
Obese individuals experience a markedly increased risk of cardiovascular and metabolic 
(“cardiometabolic”) diseases– including diabetes, hypertension, and coronary artery disease. 
The rising prevalence of these problems despite current therapies supports that obesity is a 
multifactorial disease, and highlights the need for novel approaches to treat obesity-related 
cardiometabolic dysfunction.  
 
A large body of evidence suggests that the natriuretic peptide (NP) hormonal 
system has important effects on metabolism, including increased energy 
expenditure and lipolysis. NPs are hormones produced by the heart in response to increased 
cardiac wall stress. NPs are well-known for their important role in blood pressure regulation. 
However, accumulating evidence suggests that the NPs have significant metabolic effects as 
well. For instance, administration of B-type natriuretic peptide (BNP) to wild-type mice leads to 
increased energy expenditure, increased thermogenic gene expression in brown as well as 
white adipose depots (a process referred to as “beiging” of white fat), and reduced fat 
accumulation.1  
 
Thus, the NP system may protect against cardiometabolic risk. NP-overexpressing mice 
are protected from obesity and insulin resistance induced by a high-fat diet.2 In humans, 
common genetic variants resulting in higher NP concentrations are associated with lower 
prevalence of hypertension, obesity, metabolic syndrome, and myocardial infarction, and a 
lower risk of developing Type 2 diabetes mellitus.3, 4  
 
NP levels are reduced in obesity. NP levels are reduced in obese individuals in large cohort 
studies.5 The low circulating NP levels appear to reflect a relative “NP deficiency,” which could 
contribute to the adverse cardiometabolic outcomes observed in obese individuals. Further, 
surgical weight loss, increased physical activity, and treatment with insulin-sensitizing 
medications are each associated with increased circulating NPs in obese individuals. 
 
 
2.0 
Rationale and Specific Aims 
 
Although recent studies in rodents suggest that NPs have important metabolic 
effects, there are few prospective data on the metabolic effects of NPs in humans. 
We propose a physiologic, proof-of-concept study to determine the acute effects of recombinant 
human B-type natriuretic peptide1-32 on energy expenditure and adipose tissue gene expression 
in humans. Our primary hypothesis is that the administration of BNP will increase energy 
expenditure in humans. Our secondary hypothesis is that BNP administration will promote 
changes in gene expression in adipose tissue suggestive of a “beige” fat phenotype in humans. 
Thus, we propose the following specific aims:  
 
Primary Aim: To investigate the acute effects of administration of BNP on energy 
expenditure in humans. We propose a randomized, placebo-controlled, cross-over study 
in 50 adults (25 lean and 25 obese) without significant medical problems. Subjects will be 
randomized to intravenous infusion of recombinant human BNP1-32 or normal saline 


Protocol Version #: 6 
 
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Protocol Date: 07/21/2023 
(control), with assessment of energy expenditure and other physiologic measures. After a 
minimum of a 14-day washout period, subjects will then undergo the other intervention.  
 
Secondary Aim: To determine the acute effects of BNP on gene expression in 
white adipose tissue in humans. We will assess markers suggestive of fat “beiging” in 
subcutaneous white adipose tissue biopsies after BNP infusion vs. control. This secondary 
aim will allow us to explore potential mechanisms underlying the hypothesized changes in 
energy expenditure. 
 
3.0 
Animal Studies and Previous Human Studies 
 
 
The natriuretic peptide (NP) system and metabolism 
 
The NP system is classically known for its role regulating of blood pressure and 
volume status. In response to increased cardiac wall stress, the heart secretes atrial 
natriuretic peptide (ANP) and BNP, which both cause natriuresis, vasodilation, and inhibition of 
the renin-angiotensin-aldosterone system.  
 
Recent studies have shown that NPs have important metabolic actions as well. 
Administration of NPs stimulate lipolysis in animals and humans.6-9 Transgenic mice that 
overexpress BNP are protected against weight gain, visceral fat accumulation, and insulin 
resistance induced by high-fat diets.2 Moreover, Bordiccia et al. demonstrated in wild-type mice 
that BNP administration over 7 days significantly increases energy expenditure and oxygen 
consumption.1 The increases in energy expenditure and oxygen consumption appear to be 
mediated by increased expression of thermogenic genes (including UCP1) in brown adipose 
tissue, as well as white adipose tissue (suggesting a “beiging” effect).1  
 
Whether many of the metabolic effects of NPs observed in animals also occur in 
humans is not well established.  Two small studies have examined the effects of ANP 
administration on energy expenditure in humans, but these lacked a control arm, and no data 
exist on the effects of BNP. In studies of 12 and 14 lean men, respectively, Birkenfeld et al. 
reported that systemic ANP infusion increased postprandial energy expenditure8 and caused a 
shift from carbohydrate oxidation to lipid oxidation.7 There are also no data on the effects of 
NPs on beige fat markers.  
 
Epidemiologic and genetic evidence linking the NP system with cardiometabolic 
health 
 
Data from population genetic studies suggest that the NP system may protect 
against cardiometabolic risk. In humans, a common genetic variant resulting in ~10-20% 
higher NP concentrations (still within the physiologic range) is associated with lower prevalence 
of hypertension (by 15%),4 obesity (by 46%), and metabolic syndrome (by 42%), and a lower 
risk of developing Type 2 diabetes (by 12%).3, 10 Moreover, this genetic variant that causes 
higher NP levels is associated with favorable cardiovascular biomarkers and a lower prevalence 
of myocardial infarction.3  
Circulating NP levels are inversely associated with presence of metabolic syndrome 
components, insulin resistance, and risk of developing Type 2 diabetes. In a large 
cohort study, BNP levels were 24-29% lower in individuals who met ≥3 criteria for the metabolic 


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syndrome, even after adjustment for BMI.11 Moreover, higher NP levels are associated with lower 
levels of insulin resistance (as measured by homeostatic model assessment of insulin resistance, 
HOMA-IR) as well as lower risk of future Type 2 diabetes in large cohort studies.12, 13  
 
Obese individuals have low circulating NP levels,5 which appears to reflect a relative 
“NP deficiency.” Obese individuals have lower NP levels than lean individuals in large cohort 
studies.5 Obese individuals have a propensity toward hypertension and hypervolemia, which 
would be expected to cause higher circulating NP concentrations. Thus, the lower NP 
concentrations in obese individuals are physiologically inappropriate and may reflect a relative 
NP deficiency in obesity. Whether the low NP levels in obesity are due to decreased NP 
production, increased NP clearance, or both is unknown.  Obese individuals have higher 
expression of the NP clearance receptor in adipose tissue compared with lean individuals,14 
which could conceivably lead to greater clearance of circulating NPs in obese individuals. As the 
NP axis appears to protect against cardiometabolic risk, a relative NP deficiency could contribute 
to the adverse cardiometabolic outcomes observed in obesity.  
 
  
4.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria:  
• 
Men and women ages 18-40 years  
• 
Body Mass Index (BMI): 18.5≤BMI<25 kg/m2 (lean)  
or BMI ≥30 kg/m2 (obese) 
 
Exclusion Criteria:  
• 
Significant cardiovascular disease (including heart failure and atrial fibrillation)  
• 
Significant pulmonary, liver, or renal disease 
• 
Diabetes Mellitus  
• 
Significant hypertension (systolic blood pressure ≥ 170 mmHg and/or diastolic blood 
pressure ≥ 110 mmHg) 
• 
Hypotension  
• 
Thyroid dysfunction 
• 
Active malignancy 
• 
Current or recent use of glucocorticoids 
• 
Current use of antihypertensive medications, including diuretics 
• 
Current use of medications affecting glucose metabolism, including metformin 
• 
Current use of amphetamines or other medications known to affect energy 
homeostasis 
• 
Currently pregnant or breastfeeding, or unwilling to avoid becoming pregnant or 
breastfeeding during study duration 
• 
Significant claustrophobia that would prevent the use of the metabolic cart as part of 
the study protocol 


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• 
Currently abnormal serum or plasma sodium or potassium level 
• 
Known hypersensitivity to recombinant human b-type natriuretic peptide, BNP(1-32) 
(nesiritide) 
• 
Hemoglobin A1c (HbA1c) ≥6.5% 
• 
Liver Function Tests (LFTs) elevated >2x upper limit of normal 
• 
Estimated Glomerular Filtration Rate (eGFR) <60 ml/min 
• 
Currently abnormal thyroid stimulating hormone (TSH) 
 
 
5.0 
Enrollment/Randomization 
 
Recruitment will take place at Tennessee Valley Healthcare System outpatient clinics, 
community-based outpatient clinics, veteran centers, veteran service organizations, and 
Vanderbilt University Medical Center (VUMC).  All patients coming for outpatient services at 
TVHS may be considered. We will place IRB approved flyers and brochures in target clinics, 
veteran centers, and community boards (electronic and physical) with basic study information 
and study team contact information for potential subjects to signal potential interest. Working 
with the VA Public Affairs office, we will utilize their advertisement services such as waiting 
lobby TV advertisements, VA web homepage announcements, and newspaper. A link may also 
be posted on My HealtheVet. We will also screen medical records in CPRS system.  VA subjects, 
once identified through the CPRS system, will be sent recruitment letters about participation in 
the study.  The recruitment letters may be followed by a phone call to the participant.  Study 
personnel may also approach possible study participants in clinic once permission is received by 
that subject’s provider. Subjects may also be recruited using My HealthEVet and the VINCI 
system. Subjects may also be recruited via the Vanderbilt Broadcast email system 
(research.notifications@vanderbilt.edu). ResearchMatch.org may be utilized as a recruitment 
tool for this protocol.  ResearchMatch.org is a national electronic, web-based recruitment tool 
that was created through the Clinical & Translational Science Awards Consortium in 2009 and is 
maintained at Vanderbilt University as an IRB-approved data repository.  
Subjects will be randomized in a 1:1 ratio to each treatment sequence (BNP followed by control; 
or control followed by BNP) with the use of stratified permuted block randomization (blocks of 
size 4). Subjects will be stratified by BMI category (lean vs. obese). Randomization occurs after 
the screening visit to determine eligibility. Prior to study initiation, block size and randomization 
schemes will be determined by a biostatistician. 
 
 
 
 
 
 
 
 
 
 
 
 


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6.0 
Study Procedure 
 
 
 
 
 
 
Screening Visit 
After informed consent has been obtained, the subject’s medical history and medications will be 
discussed and documented. A physical exam, including measurement of height, weight, and 
vital signs, will be performed.  Blood will be collected for a comprehensive metabolic panel, 
complete blood count (CBC), Hemoglobin A1c, thyroid stimulating hormone (TSH) test, and free 
T4. A urine or serum pregnancy test will be completed on female subjects of child-bearing 
potential. Whenever possible, we will combine these research screening tasks and procedures 
with standard of care tasks and procedures to decrease the burden placed on the patient. This 
information will be acceptable from standard of care visits as far back as 6 months prior to the 
day the patient is identified as a possible candidate. Even if the patient has had these 
assessments completed during a standard of care visit, it is up to the discretion of the Principle 
Investigator to use them or require an updated set of assessments. Inclusion/exclusion criteria 
will be reviewed to confirm that the subject meets study eligibility requirements. Subjects will 
be given instruction on how to perform 24-hour urine collections, which will be collected at two 
study time points (immediately prior to study visits 1 and 2). 
 
Study Visits 1 and 2 
 
After the Screening Visit, eligible subjects who wish to participate in the study will be scheduled 
for two additional outpatient visits at the Vanderbilt CRC (Clinical Research Center): Study Visits 
1 and 2. The two visits will be scheduled ≥14 days apart. For women, Study Visits 1 and 2 will 
be scheduled to coincide with the follicular phase of the menstrual cycle to minimize the impact 
of hormonal changes on energy expenditure (EE) and on measurements of renin-angiotensin-
aldosterone (RAAS) system.  In the 24 hours prior to each study visit, subjects will collect urine 
for quantification of urine sodium, urine creatinine, and other metabolic endpoints. Each subject 
will receive a BNP infusion at one study visit and a control (saline) infusion at the other visit 
(Figure 1). Other than the drug received, the study procedures and timeline are identical for 
both study visits (Figure 2).  
 
 


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Protocol Date: 07/21/2023 
 
 
Subjects will arrive at the Vanderbilt CRC after having fasted for at least 8 hours. Upon arrival, 
subjects will return the 24 hour urine collection, two peripheral intravenous (IV) lines will be 
placed and subjects will lie supine. Women of childbearing potential will undergo a pregnancy 
test. Subjects will need to remain supine during the entire study visit, with exceptions for urine 
collection timepoints, as some of the hormone measurements are affected by body position. 
Baseline resting energy expenditure will be assessed using indirect calorimetry (metabolic cart, 
described below) after approximately 30 minutes of lying supine (t= -30 to 0 minutes, Figure 
2). A baseline blood draw, including measurements of NPs and measurements of the RAAS 
system (renin and aldosterone), will occur after subjects have been supine for approximately 60 
minutes. Next, subjects will undergo IV infusion of either BNP1-32 (nesiritide) or control (normal 
saline) for 240 minutes. The IV infusion rate (whether BNP infusion or control infusion) will be 
the same (a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg). 
In addition, during each visit (both BNP visit and control visit), subjects will receive a small 
amount of normal saline through the IV lines to maintain the integrity of the IV lines and to 
provide hydration. During the infusion the subjects will undergo hemodynamic monitoring, as 
described below. Energy expenditure will be measured during the infusion again from t=90-120 
minutes, t=150-180 minutes, and t=210-240 minutes with the metabolic cart. At the completion 
of the infusion, the subjects will then undergo the subcutaneous adipose tissue biopsy 
procedure, as described below. The subjects will undergo a dual-energy x-ray absorptiometry 
(DXA) scan at one of the study visits.  At the end of Study Visit 1, subjects will be given another 
24 hour urine collection kit, to be turned in upon arrival for Study Visit 2. 
 
Other study procedures 
 
Phlebotomy: Blood draws will occur at Minutes 0, 60, 120, 180, 240 (Table 1).  
 
 
Table 1: Time points for blood draws 
 
Endpoints
Timepoints
NP system markers (ANP, BNP, and their propepties)
Min 0, 240
RAAS system markers (direct renin, aldosterone)
Min 0, 240
Plasma catecholamines
Min 0, 60, 120, 180, 240
Glucose metabolism (glucose, insulin)
Min 0, 60, 120, 180, 240
Lipolysis (glycerol, free fatty acids)
Min 0, 60, 120, 180, 240


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In addition, renal function will be checked at the end of Study Visits 1 and 2. 
 
Urine collection: All urine during the visit will be collected. All subjects will utilize a bedside 
commode to collect urine.  CRC staff will be available to assist the subject from the bed to the 
bedside commode to ensure the subject’s safety. Urine will be collected at baseline and at 
Minutes 120, and 240, and urine volume will be measured at each timepoint. Ideally urine will 
be collected at these exact timepoints. If subject is unable to void at this exact timepoint, urine 
should be collected as close as possible to the exact timepoint and the time documented. Urine 
will be tested for urine sodium, urine creatinine, and other metabolic endpoints.   
 
Ins/Outs: Strict Ins/Outs will be recorded throughout the study visit, and total ins/outs will be 
recorded.  
 
Hemodynamic monitoring: During both Study Visits 1 and 2, blood pressure will be measured 
frequently via sphygmomanometer and/or volume clamp method (finger 
photoplethysmography). Heart rate and rhythm will be monitored throughout infusions using 
cardiac telemetry. Temperature will be monitored using a thermometer.  
 
Indirect Calorimetry (Metabolic Cart): At each visit, resting energy expenditure will be 
determined by indirect calorimetry, using a metabolic cart. We will measure energy expenditure 
(EE) four times during the infusion (Figure 2): baseline (30 minutes leading up to start of 
infusion), EE2 (Minute 90-120), EE3 (Minute 150-180), and EE4 (Minute 210-240). For each 
energy expenditure assessment, we will measure energy expenditure over the course of 30 
minutes.  
 
Substrate oxidation (lipid oxidation and carbohydrate oxidation): Respiratory exchange ratio will 
be determined using VO2 and VCO2 measurements, which is determined via indirect 
calorimetry, and collected at the same time points as energy expenditure.  
 
Subcutaneous adipose tissue biopsy: Participants will undergo percutaneous subcutaneous 
adipose tissue biopsies on the abdomen (peri-umbilical region) after the BNP infusion and after 
the control infusion. This procedure will be performed by a trained study physician. After the 
completion of the 4-hour infusion (of either BNP or saline, as described above), the subject will 
remain supine, and an approximately 10cm diameter area will be cleaned with a chlorhexidine 
swab lateral to the umbilicus. A fenestrated sterile drape will be placed to establish the sterile 
field. Approximately 20 ml of 1% lidocaine will be applied to anesthetize the skin. A small 
(approximately 0.5 cm) incision is made through the skin with a scalpel, a few centimeters 
lateral to the umbilicus. A TULIP 2.7mm liposuction cannula with a syringe attached is inserted 
and moved parallel to the skin at a rate of approximately 1 Hz without breaking suction and 
with a twisting motion. The sampling continues until approximately 10 ml of tissue 
(approximately 9.5 g) is collected. The syringe is then removed, antibiotic ointment applied, a 
steri-strip is placed, and the incision is covered with an adhesive bandage. The tissue will be 
washed in physiologic serum and then placed immediately in liquid nitrogen and stored at -80 
degrees Celsius until analysis. The bandages will be removed after 24 hours, and steri-strips 
are left in place until they fall off. 
 
Biomarkers 


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Blood, urine, and tissue samples will be coded for subject confidentiality.  Additional samples 
will be frozen and stored for possible future investigation. 
 
 
7.0 
Possible Side Effects 
 
Fasting: Inconvenience and hypovolemia. To minimize risks of hypovolemia, subjects will be 
instructed to drink plenty of fluids the day before the visits, and we will measure subjects’ blood 
pressure and heart rate upon arrival for their study visits and frequently throughout the study 
visits. Also, there is a potential risk of hypoglycemia while fasting. However, the risk of 
hypoglycemia in healthy individuals while fasting for this amount of time is low. Subjects will be 
monitored for signs and symptoms of hypoglycemia throughout the study visits. 
 
Intravenous Lines: Risks related to the placement of peripheral intravenous lines are minimal. 
Risks include pain, hematoma formation, bruising, rarely fainting, and phlebitis 
 
Phlebotomy: Volume depletion and anemia are possible risks of phlebotomy. The risks 
associated with phlebotomy in healthy individuals are minimal. Risks will be minimized by 
excluding subjects with anemia or history of hypotension. Subjects will be advised to drink 
plenty of the fluids the night before the study visit, and after the study visit.  
 
Hemodynamic monitoring (blood pressure monitoring using sphygmomanometer and finger 
photoplethysmography, and heart rate monitoring by cardiac telemetry): A non-invasive 
technique with no symptoms aside from possible minimal discomfort. 
 
Study Medications: *Of note, Dr. Bachmann (Principal Investigator) has obtained an 
IND exemption for all drugs in the proposed protocol from the Food and Drug 
Administration (FDA). VUMC Investigational Drug Services (IDS) Pharmacy will provide the 
intravenous medications for this study because IDS Pharmacy is co-located at the VUMC Clinical 
Research Center (CRC) where all the study visits will take place. The study medications 
provided by IDS Pharmacy are intravenous medications that need to be prepared locally due to 
drug stability requirements and study timeline procedures. 
 
• 
BNP(1-32) (nesiritide): The main potential side effect of nesiritide is hypotension. However, in 
healthy controls, BNP administered at doses and durations similar to what we will administer 
has been shown to be safe and well-tolerated, without significant hypotension or other 
significant adverse events.15, 16 Other symptoms reported by subjects with heart failure who 
received nesiritide in prior trials include headache (8%), nausea (4%), and angina (2%). 
Furthermore, in the proposed study, hypotension is extremely unlikely as trained study 
personnel will remain at bedside and closely monitor blood pressure during the entire 
infusion.  Because of the very low risk of hypotension, firm stopping rules for the BNP 
infusion will be implemented:  The BNP infusion will be stopped if systolic blood pressure 
decreases by 30 mmHg or greater from baseline, if absolute systolic blood pressure drops 
below 80 mmHg, or if the subject demonstrates symptomatic hypotension as clinically 
assessed by the investigator.  If these unlikely cases occur, any changes in blood pressure 
should resolve extremely quickly (within a few minutes) because the half-life of BNP is very 
short.  If the infusion is stopped, remaining study procedures (e.g. blood and urine 
collections, energy expenditures, and fat biopsy procedure) may be resumed with the 
permission of the subject and at the discretion of the study team. Finally, as with any drug, 


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Protocol Date: 07/21/2023 
there is a potential risk of hypersensitivity. We will not enroll any subject with history of 
hypersensitivity to BNP, and subjects will be closely monitored during the infusions. 
 
Percutaneous subcutaneous adipose tissue biopsy: The biopsy procedure will be performed by 
the study physician. The percutaneous subcutaneous adipose tissue biopsy procedure is 
associated with low risk. Possible risks of the biopsy procedure include pain, local skin irritation, 
bleeding, bruising, and hematoma at the site. There is potential risk for local or systemic 
infection, more severe bleeding, or a small scar; however, the risk of these events is extremely 
low.  
Lidocaine: May cause local discomfort during injection, or a rash, redness or soreness at the 
injection site. In rare cases, lidocaine could potentially cause hypersensitivity reactions, 
confusion, or induce a transient alteration in heart rhythm; to reduce this risk, suction will be 
applied to the syringe prior to injection to ensure the lidocaine is not being injected into a 
vessel. 
Dual Energy X-ray Absorptiometry (DXA): Radiation risk is very minimal. DXA uses very low 
dose radiation, and the expected total exposure for each participant is in the range of 7 
millirem, which is equivalent to approximately 9 days of background radiation.  
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
Participants should and will be instructed to notify study personnel regarding any adverse 
events or unanticipated problems. Adverse events will be reported to the IRB per IRB policy. 
Also, all serious and unanticipated adverse events or problems involving risks to subjects that 
may possibly be or are known to be related to the research activity will be reported promptly to 
the IRB office per IRB policy.  
 
Any adverse event associated with the use of drug that is serious, unexpected and possibly or 
definitely study-related will be reported promptly to the IRB per IRB policy. 
 
The Data Monitoring Committee (DMC) of the U.S. Department of Veteran Affairs’ Office of 
Research and Development will monitor the study, per instruction by the administrators with 
Clinical Science Research and Development (CSR&D). The DMC will provide ongoing evaluation 
of studies’ progress including patient accrual and retention, monitoring of adverse events, and 
the adequacy and efficiency of the analysis plan to discern outcomes that might require study 
modifications, or result in early cessation of the study due its benefits or harms. Reports will be 
submitted to the DMC for review approximately every 4 months. 
 
9.0 
Study Withdrawal/Discontinuation 
 
Subjects may withdraw from the study at any time and should notify study personnel if they 
wish to withdraw from the study. Subjects may request their biological samples to be destroyed 
at any time. However, any data or biological samples that have already been used for research 
cannot be destroyed.  
 


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Subjects may be discontinued from the study at the discretion of the investigators’ (possible 
reasons listed below).  
 
Possible reasons for withdrawal/discontinuation from study include, but are not limited to: 
• 
Noncompliance with treatment or procedures 
• 
Decision by participant/participant withdraws consent 
• 
Lost to follow-up 
• 
Change in patient’s health status that makes them no longer eligible for study. 
• 
Development of a significant medical condition specified in the exclusion criteria 
• 
In female subjects, becoming pregnant during study 
• 
Significant adverse event deemed by investigator to preclude continued participation 
 
 
10.0 Statistical Considerations 
 
The primary endpoint will be change in resting energy expenditure, calculated as final resting 
energy expenditure adjusted for baseline level, using linear regression. Secondary endpoints 
include adipose tissue gene expression and protein levels. We will test the effect of treatment 
(BNP vs. control) on the primary endpoint and secondary endpoints (all are continuous variables 
that are repeated and correlated) in a similar fashion. We will use mixed effects modeling, 
adjusting for treatment sequence, to assess the effect of treatment on each endpoint. The null 
hypothesis is that there will be no significant effect of treatment on each endpoint. In addition, 
we will assess for a period effect and a treatment-period interaction effect; the null hypothesis 
is that there will be no period effect and no interaction effect. We will adhere to intention-to-
treat principles. No interim analysis is planned. In a secondary analysis, we will examine 
whether treatment effects differ between lean and obese individuals. We will perform 
exploratory analyses to investigate whether treatment effects differ by sex or race (white vs. 
non-white). To address missing data, we will apply multiple imputation methods. 
 
 
11.0 Privacy/Confidentiality Issues 
 
Strict confidentiality will be maintained to the fullest extent possible by the research team, 
including keeping all data in a secure location. All specimens will be de-identified and coded 
after they are obtained and the code key kept in a secure location. Only study personnel will 
access to the data and specimens. Samples may be shared with third parties outside of the VA 
and Vanderbilt for future testing but will remain anonymous to the recipient.  Subjects may 
contact the principal investigator at any time to request that samples be destroyed.  However, 
any data or biological samples that have already been used for research cannot be destroyed. 
 
The Research Electronic Data Capture (REDCap) database is a secure web application housed 
on the TVHS VA secured computer network and is password protected. REDCap offers secure 
institutional data hosting and includes full audit-trails in compliance with HIPAA security 
requirements. Only members of the study team will have access to this database.   
 


Protocol Version #: 6 
 
13 
Protocol Date: 07/21/2023 
Adverse event reports and annual summaries will not include subject-identifiable material but 
only the assigned study identification numbers. 
 
 
12.0 Follow-up and Record Retention 
 
Anticipated study duration is 60 months. Research data will be maintained by the PI after study 
closure. After study closure, research data will be maintained for a minimum of 6 years and 
possibly indefinitely. Data will be stored on a secure computer network in a password-protected 
database. Only members of the study team will have access. Pertinent paper documentation will 
be kept in a locked office and only study personnel will have access. Only personnel directly 
involved with the study will have access to source data and the electronic database. 
 
13.0 Relevance to VA Mission 
 
Obesity represents a serious public health burden in our veteran population and in the general 
population. Over 30% of veterans are obese. Obese individuals experience increased risk of 
cardiovascular and metabolic (“cardiometabolic”) diseases, including insulin diabetes, 
resistance, hypertension, and dyslipidemia, which markedly increase morbidity and mortality. 
Obesity is a major problem that spans across a wide age range, all race/ethnic groups, and 
both sexes.  There are multiple approaches for tackling the problem of obesity at the 
VA:  system-level factors, provider-level factors, and patient-level factors. All of these 
approaches are valuable. This particular study focuses on patient-level factors. Specifically, we 
are interested in improving the understanding of the pathogenesis of cardiometabolic risk, in 
order to identify novel therapeutic approaches. 
 
Obesity and obesity-associated cardiometabolic dysfunction are significant contributors to 
morbidity and mortality in veterans. This indicates that obesity and cardiometabolic dysfunction 
are complex and multifactorial, and suggests that there are additional factors that contribute to 
the pathogenesis of obesity and its associated cardiometabolic risk that have not been 
discovered. Moreover, some of the pharmacologic therapies for obesity can have adverse 
cardiovascular effects (like phentermine, which can cause hypertension). Conversely, some of 
the treatments for cardiovascular disease can have adverse metabolic effects (like beta 
blockers, which can lead to weight gain). Thus, it is crucial to improve our understanding of the 
multiple pathways contributing to the pathogenesis of obesity and obesity-associated 
cardiometabolic risk, including the identification of novel relevant pathways, in order to develop 
more effective treatments for these diseases. Characterizing the metabolic effects of the 
natriuretic peptides in the present study has the potential to inform future studies aimed at 
assessing the natriuretic peptide system as a target for the treatment of obesity and obesity-
associated metabolic dysfunction, a field of paramount importance to veterans. 
 
 
 
 
 
14.0 References 
 


Protocol Version #: 6 
 
14 
Protocol Date: 07/21/2023 
1. 
Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessi-Fulgheri P, Zhang C, Takahashi N, 
Sarzani R and Collins S. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat 
thermogenic program in mouse and human adipocytes. J Clin Invest. 2012;122:1022-36. 
2. 
Miyashita K, Itoh H, Tsujimoto H, Tamura N, Fukunaga Y, Sone M, Yamahara K, Taura 
D, Inuzuka M, Sonoyama T and Nakao K. Natriuretic peptides/cGMP/cGMP-dependent protein 
kinase cascades promote muscle mitochondrial biogenesis and prevent obesity. Diabetes. 
2009;58:2880-92. 
3. 
Cannone V, Boerrigter G, Cataliotti A, Costello-Boerrigter LC, Olson TM, McKie PM, 
Heublein DM, Lahr BD, Bailey KR, Averna M, Redfield MM, Rodeheffer RJ and Burnett JC, Jr. 
A genetic variant of the atrial natriuretic peptide gene is associated with cardiometabolic 
protection in the general community. Journal of the American College of Cardiology. 
2011;58:629-36. 
4. 
Newton-Cheh C, Larson MG, Vasan RS, Levy D, Bloch KD, Surti A, Guiducci C, 
Kathiresan S, Benjamin EJ, Struck J, Morgenthaler NG, Bergmann A, Blankenberg S, Kee F, 
Nilsson P, Yin X, Peltonen L, Vartiainen E, Salomaa V, Hirschhorn JN, Melander O and Wang 
TJ. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and 
blood pressure. Nat Genet. 2009;41:348-53. 
5. 
Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW and Vasan RS. 
Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004;109:594-600. 
6. 
Polak J, Kotrc M, Wedellova Z, Jabor A, Malek I, Kautzner J, Kazdova L and 
Melenovsky V. Lipolytic effects of B-type natriuretic peptide 1-32 in adipose tissue of heart 
failure patients compared with healthy controls. Journal of the American College of Cardiology. 
2011;58:1119-25. 
7. 
Birkenfeld AL, Boschmann M, Moro C, Adams F, Heusser K, Franke G, Berlan M, Luft 
FC, Lafontan M and Jordan J. Lipid mobilization with physiological atrial natriuretic peptide 
concentrations in humans. JClinEndocrinolMetab. 2005;90:3622-3628. 
8. 
Birkenfeld AL, Budziarek P, Boschmann M, Moro C, Adams F, Franke G, Berlan M, 
Marques MA, Sweep FC, Luft FC, Lafontan M and Jordan J. Atrial natriuretic peptide induces 
postprandial lipid oxidation in humans. Diabetes. 2008;57:3199-204. 
9. 
Sengenes C, Zakaroff-Girard A, Moulin A, Berlan M, Bouloumie A, Lafontan M and 
Galitzky J. Natriuretic peptide-dependent lipolysis in fat cells is a primate specificity. Am J 
Physiol Regul Integr Comp Physiol. 2002;283:R257-65. 
10. 
Jujic A, Nilsson PM, Engstrom G, Hedblad B, Melander O and Magnusson M. Atrial 
natriuretic peptide and type 2 diabetes development--biomarker and genotype association study. 
PLoS One. 2014;9:e89201. 
11. 
Wang TJ, Larson MG, Keyes MJ, Levy D, Benjamin EJ and Vasan RS. Association of 
plasma natriuretic peptide levels with metabolic risk factors in ambulatory individuals. 
Circulation. 2007;115:1345-1353. 
12. 
Khan AM, Cheng S, Magnusson M, Larson MG, Newton-Cheh C, McCabe EL, Coviello 
AD, Florez JC, Fox CS, Levy D, Robins SJ, Arora P, Bhasin S, Lam CS, Vasan RS, Melander O 
and Wang TJ. Cardiac natriuretic peptides, obesity, and insulin resistance: evidence from two 
community-based studies. J Clin Endocrinol Metab. 2011;96:3242-9. 
13. 
Magnusson M, Jujic A, Hedblad B, Engstrom G, Persson M, Struck J, Morgenthaler NG, 
Nilsson P, Newton-Cheh C, Wang TJ and Melander O. Low plasma level of atrial natriuretic 
peptide predicts development of diabetes: the prospective Malmo Diet and Cancer study. J Clin 
Endocrinol Metab. 2012;97:638-45. 


Protocol Version #: 6 
 
15 
Protocol Date: 07/21/2023 
14. 
Kovacova Z, Tharp WG, Liu D, Wei W, Xie H, Collins S and Pratley RE. Adipose tissue 
natriuretic peptide receptor expression is related to insulin sensitivity in obesity and diabetes. 
Obesity (Silver Spring). 2016;24:820-8. 
15. 
Heinisch BB, Vila G, Resl M, Riedl M, Dieplinger B, Mueller T, Luger A, Pacini G and 
Clodi M. B-type natriuretic peptide (BNP) affects the initial response to intravenous glucose: a 
randomised placebo-controlled cross-over study in healthy men. Diabetologia. 2012;55:1400-5. 
16. 
Vila G, Grimm G, Resl M, Heinisch B, Einwallner E, Esterbauer H, Dieplinger B, 
Mueller T, Luger A and Clodi M. B-type natriuretic peptide modulates ghrelin, hunger, and 
satiety in healthy men. Diabetes. 2012;61:2592-6. 
17. 
Gamboa A, Okamoto LE, Raj SR, Diedrich A, Shibao CA, Robertson D and Biaggioni I. 
Nitric oxide and regulation of heart rate in patients with postural tachycardia syndrome and 
healthy subjects. Hypertension. 2013;61:376-81. 
18. 
Gamboa A, Shibao C, Diedrich A, Paranjape SY, Farley G, Christman B, Raj SR, 
Robertson D and Biaggioni I. Excessive nitric oxide function and blood pressure regulation in 
patients with autonomic failure. Hypertension. 2008;51:1531-6. 
 

ICF_001.pdf: 
 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
               
                          Version Date:  12/27/2018
Title of Study:     
ID#:   
Metabolic Effects of Natriuretic Peptide Hormones 
 
Principal Investigator:    
Katherine N. Bachmann, M.D. 
VAMC: 
(626) 
Tennessee Valley 
Healthcare System (VA TVHS) 
Participant Name: 
 
Date: 
 
 
                                       IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                            Page 1 of 11  
 
PURPOSE OF THE STUDY 
You are being asked to take part in a research study at the VA Tennessee Valley Healthcare 
System Medical Center because you are a healthy volunteer without significant medical 
problems, and you have a body mass index (BMI) either in the normal range (18.5-25 kg/m2) or 
in the obese range (greater than 30 kg/m2).  We intend to recruit a total of 50 subjects for this 
study (25 lean and 25 obese). This study is sponsored by the VA.  
The purpose of this study is to learn about the effects of natriuretic peptide hormones on 
metabolism, specifically on energy and fat metabolism.   
 
Natriuretic peptides (NPs) are hormones produced by the heart to maintain its structure and 
function. NPs are well-known for their important role in blood pressure regulation. In addition, 
in recent years, findings from scientific studies suggest that the NPs may also have effects on 
metabolism.  Studies in animals have suggested that natriuretic peptide hormones may protect 
against fat accumulation, and may affect energy and fat metabolism.  However, much more 
information must be learned about the effects of natriuretic peptide hormones on energy and 
fat metabolism in humans.  
 
In this study, we will study the effects of recombinant human b-type natriuretic peptide 
hormone (BNP (1-32)) on metabolism, specifically on energy and fat metabolism.  The goal of 
this study is to provide important information about the role of the NP system on metabolism in 
humans.  
 
The study will consist of 3 visits: Screening Visit, Study Visit 1, and Study Visit 2.  
 Screening Visit: Approximately 60 minutes duration 
 Study Visit 1: (Approximately 0.5-2 weeks after Screening Visit); Approximately 7 hour 
duration 
 Study Visit 2: (At least two weeks after Study Visit 1); Approximately 6 hour duration 
 
DESCRIPTION OF THE PROCEDURES AND APPROXIMATE DURATION OF THE STUDY 
 
If you agree to participate in this research study, it will take you approximately 1-2 months to 
complete the study. During this time we will ask you to come in for a screening visit to 
determine eligibility. If eligible, you will complete two additional visits. There will be at least two 
weeks in between the 2 main study visits. 
 


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 2 of 11   
 
 
 
 
Research investigational procedures being performed at Vanderbilt University Medical 
Center (VUMC):  
 
Some or all aspects of the screening visit (as detailed below) may occur at Vanderbilt 
University Medical Center (VUMC).  If you are deemed eligible for the study, the subsequent 
main study visits (Study Visits 1 and 2) will occur at the VUMC Clinical Research Center 
(CRC), located at the Vanderbilt University Medical Center main campus. Details for each 
study visit are outlined below.  Also, VUMC is permitting access to your medical records to the 
research study team.  This will allow the study team to have access to information that may be 
relevant to your study participation.   
 
 
Screening Visit 
 
This visit will be approximately 60 minutes in length. During this visit, we will tell you about the 
study and review the consent form in detail, have you sign the consent form, and perform tests 
and procedures to see if you qualify to take part in this research study. The study doctor will 
review the results of these tests. If you do not qualify, the study staff will tell you why. 
 
At this visit, we will: 
 Ask about your medical history.  
 Give you a physical exam, including measurement of height, weight and vital signs (e.g. 
blood pressure and heart rate). 
 Test your blood or urine for pregnancy if you are a woman able to become pregnant. 
(Women who are pregnant or breastfeeding cannot take part in this research study). 
 Collect a blood draw of about 7.5 ml (1/2 tbsp) to check your thyroid function, blood 
counts, electrolyte and fluid balance, kidney function, liver function, and glucose levels. 
 
Whenever possible, we will combine the research screening tasks and procedures with 
standard-of-care tasks and procedures that you receive from your usual clinical providers.  If 
the study team can determine your eligibility based on your information gathered from your 
standard-of-care tasks and procedures, you may not need to come in for a specific screening 
visit. This will be at the discretion of the study team.  
 
 
Study Visits 1 and 2 
 
We will ask you to collect your urine for 24 hours before your study visits.  You will need to 
bring the urine collection with you to your visits. 
 
During each of the two study visits, you will receive an intravenous (IV) infusion.  During one 
visit, you will receive the infusion of BNP.  During the other visit, you will receive an infusion of 
saline (salt water).  Which infusion you receive at which visit will be determined randomly. 
Using a procedure like the flip of a coin, you will have a one in two chance of receiving the 


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 3 of 11   
 
 
BNP infusion at the first visit and the saline infusion at the second visit, and a one in two 
chance of receiving the saline infusion at the first visit and the BNP infusion at the second visit.  
 
For each of these two visits, you will arrive fasting.  This means that you cannot eat or drink 
anything (other than water) for at least 8 hours before your visit. Each visit will take 
approximately 6-7 hours to complete.  Upon your arrival to the research facility, two 
peripheral intravenous (IV) lines, a blood pressure cuff on your arm and/or finger, and chest 
leads to monitor your heart will be placed.  You will then be asked to lay supine (flat on 
your back) for the remainder of the study visit with breaks for urine specimen collection 
timepoints.  While you are still supine, a non-restrictive clear hood will be placed over your 
head that has a tube which allows air (oxygen) in and air (carbon dioxide) out. The use of 
this machine (called a metabolic cart) will allow us to measure your resting energy 
expenditure.  You will wear this hood for 30 minutes.  Afterwards, we will begin the infusion 
of either BNP or saline.  Blood will be drawn from an IV every hour starting right before the 
infusion begins.  Energy expenditure will be measured 3 additional times during the day (for 
30 minutes each time).  At each study visit you will receive a total of 5 blood draws and 4 
energy expenditure measurements.  A total of approximately 140 ml (~9.5 tbsp) of blood 
will be drawn during each study visit.  You will receive some fluids for hydration during the 
visit.  Also, we will collect all your urine during your visits. Because body positioning is 
crucial for stable and reliable evaluation of our hormone measurements, you will need to 
remain supine (flat on your back) during the entire visit, except while urinating. Thus, while 
urinating, you will be instructed to use a bedside commode with the assistance of medical 
personnel. We will also monitor your blood pressure and heart rate throughout the 
infusions.  
 
At the end of the infusion, you will undergo a biopsy of your subcutaneous fat tissue 
(under-the-skin fat tissue) on your abdomen, a few centimeters away from your belly 
button. This procedure will be performed by a trained study physician using sterile 
technique. A local anesthetic (lidocaine) will be used to numb the site of biopsy. A small 
incision (approximately 0.5 cm (1/5 inch)) will be made.  Then a small liposuction cannula, 
with a syringe attached, is inserted and moved parallel to the skin until a small sample of 
tissue (less than the weight of a dime) is collected. After the biopsy is complete, antibiotic 
ointment will be applied followed by a steri-strip and adhesive bandage.  
 
You will receive a Dual Energy X-Ray Absorptiometry (DXA) scan during the study. A DXA 
scan uses x-ray technology to measure bone thickness. During this test, X-ray pictures of 
your body will assess the amount of bone, fat, and muscle in your body.  You will lie flat on 
a table and a machine will take pictures of different areas of your body.  This test will last 
about 15 minutes. 
 
 
 
 
 
 
 


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 4 of 11   
 
 
 
Research procedures being performed at VA TVHS:  
 
Some or all aspects of the screening visit (as detailed above) may occur at the VA depending 
on scheduling and availability.  Also, the VA is permitting access to your medical records to the 
research study team.  This will allow the study team to have access to information that may be 
relevant to your study participation.  
 
  Table Of Events:  
Procedure
Screening Visit
Study Visit 1
Study Visit 2
Informed Consent
X
Medical History & 
Physical exam
X 
 
 
Vital Signs, height, 
weight
X 
X 
X 
Pregnancy test
X
X
X
Clinical Laboratory 
sample collection
X 
X 
X 
24 hr urine collection
X
X
IV Infusion (Saline or 
BNP)
 
X 
X 
DXA scan
X
Metabolic Cart
X
X
Fat Biopsy 
X
X
Blood pressure, heart 
rate, and temperature 
monitoring
 
X 
X 
 
The table above and the description of study procedures above reflect the intended 
schedule of events.  However, due to scheduling and logistical issues, there may be minor 
differences in the occurrence/sequence of events.  
 
DESCRIPTION OF STUDY RELATED COSTS  
 
If you agree to take part in this research study, you and/or your insurance will not have to pay 
for the tests and treatments that are being done only for research. 
 
However, you are still responsible for paying for the usual care you would normally receive for 
the treatment of any illness. This includes treatments and tests you would need even if you 
were not in this study. These costs will be billed to you and/or your insurance. 


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 5 of 11   
 
 
 
PAYMENT FOR PARTICIPATION 
 
You will receive compensation to help cover the cost of time and inconvenience. The amount 
that you are reimbursed is commensurate with the time and inconvenience incurred that you 
otherwise would not have incurred. You will receive $100 for completing Visit 1, and you will 
receive $400 for completing Visit 2, for a total of $500 for completing the entire study. You will 
receive the payment in the mail after you have completed your participation in the study.  We 
ask that you join the study only if you intend on completing all study visits, as we need 
complete information in order to address the scientific question. You must agree to the release 
of personally identifying information such as your name, address and social security number to 
the VA Tennessee Valley Healthcare System so that you may receive your money.  Your 
payment will be issued from the Austin Financial Service Center which will generate the IRS 
Form 1099 regardless of the amount of your participation compensation. 
MEDICAL TREATMENT FOR RESEARCH-RELATED INJURY  
 
Every reasonable safety measure will be used to protect your well-being.  The VA has the 
authority to provide medical treatment to participants injured by participation in a VA project.   
VA medical facilities will provide necessary medical treatment to you as a research participant 
if you are injured as a result of your participation in this study.   
 
Compensation may or may not be available to you under applicable state and federal law in 
the event that you suffer physical injury or illness arising from this study.  By agreeing to 
participate in this study you are not waiving or giving up your legal rights to seek 
compensation.  If you have questions you may contact the VA TVHS Institutional Review 
Board office at 615-873-6076 or the Research and Development Service office at 615-873-
8694. 
COMPENSATION FOR RESEARCH-RELATED INJURY  
If you want to make a legal claim against the VA or anyone who works for the VA, special 
laws may apply. The Federal Tort Claims Act (28 U.S.C. 1346(b), 2671-2680) is a federal law 
that controls when and how a person can bring a claim against the U.S. Government. If you 
sign this document you are not giving up your right to make a legal claim against the United 
States.   
If it is determined by the Investigator that an injury occurred as a direct result of the tests or 
treatments that are done for research, then you and/or your insurance will not have to pay for 
the cost of immediate medical care provided at the Nashville VA to treat the injury, if you 
have VA benefits. 
If you do not have VA benefits, if it is determined by the investigator that an injury occurred as 
a direct result of the tests or treatments that are done for research, then you and/or your 
insurance will not have to pay for the cost of immediate medical care provided at Vanderbilt 


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 6 of 11   
 
 
Medical Center to treat the injury. There are no plans for Vanderbilt to pay for the costs of any 
additional care. There are no plans for Vanderbilt to give you money for the injury.  
DESCRIPTION OF THE DISCOMFORTS, INCONVENIENCES, AND/OR RISKS  
Fasting: Inconvenience and low fluid status in the body. To minimize this risk, please drink 
plenty of fluids the day before the visits. Also, there is a potential risk of hypoglycemia (low 
blood sugar) while fasting. However, the risk of hypoglycemia in healthy individuals while 
fasting for this amount of time is low. Signs of hypoglycemia include dizziness, 
lightheadedness, extreme sweating, and extreme hunger; please let us know if you experience 
any of these symptoms. 
Intravenous Lines: Risks related to the placement of peripheral intravenous lines are minimal. 
Risks include pain, hematoma formation, bruising, inflammation, and rarely fainting and 
infection. 
Phlebotomy: The risks associated with phlebotomy in healthy individuals are minimal. Risks 
include pain, bruising, inflammation, and rarely fainting and infection. Other possible risks 
include low fluid status in the body and anemia (low blood counts). 
Hemodynamic monitoring (blood pressure monitoring using sphygmomanometer and/or finger 
photoplethysmography, and heart rate monitoring by cardiac telemetry): A non-invasive 
technique with no symptoms aside from minimal discomfort. 
BNP(1-32) (nesiritide): The main potential side effect of nesiritide is hypotension (low blood 
pressure). However, in healthy controls, BNP administered at doses and durations similar to 
what we will administer has been shown to be safe and well-tolerated, without significant 
hypotension or other significant adverse events. Other symptoms reported by subjects with 
heart failure who received nesiritide in prior trials include headache (8%), nausea (4%), and 
angina.  Low blood pressure is extremely unlikely in this study, because your blood pressure 
will be closely monitored by trained medical personnel, and if your systolic blood pressure 
drops by ≥ 30 mmHg or your systolic blood pressure goes below 80 mmHg or you have 
symptoms due to low blood pressure as clinically assessed by trained medical personnel, the 
BNP infusion will be stopped.  Because BNP is cleared quickly from the body, any blood 
pressure changes due to BNP would go away quickly after stopping the infusion.  Finally, as 
with any drug, there is risk of allergic reaction; you will be closely monitored during the 
infusions, but please let us know if you develop any signs or symptoms of allergic reaction (like 
shortness of breath, swelling, or rash).  
 
Subcutaneous adipose tissue biopsy: Possible risks of the biopsy procedure include pain, local 
skin irritation, bleeding, bruising, and hematoma at the site. There is potential risk for local or 
systemic infection, more severe bleeding, or a small scar; however, the risk of these events is 
extremely low. 
Lidocaine: May cause local discomfort during injection, or a rash, redness or soreness at the 
injection site. In rare cases, lidocaine could potentially cause hypersensitivity reactions, 
confusion, or induce a transient alteration in heart rhythm.  


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 7 of 11   
 
 
Dual Energy X-ray Absorptiometry (DXA): You will be exposed to some radiation because DXA 
is an x-ray. The amount of radiation from the one DXA scan is equal to the amount of radiation 
in the natural environment if you were to walk around outside for 9 days. 
 
 
ANTICIPATED BENEFITS RESULTING FROM STUDY PARTICIPATION 
Taking part in this study may not personally help you, but your participation may lead to 
knowledge that will help others. Your participation may benefit science and humankind through 
the results of this study. It is possible that we may learn information that will help to improve 
prevention and/or therapy for diseases like obesity and obesity-associated complications, like 
insulin resistance and cardiovascular disease. The results may help patients in the future. 
 
ALTERNATIVE PROCEDURES/OTHER TREATMENT AVAILABLE 
You are not required to take part in this research study. This is not a treatment study.  Your 
participation is entirely voluntary.  You can refuse to participate now, or you can withdraw from 
this study at any time after giving your consent without affecting your healthcare/services or 
other rights.  This will not interfere with your regular medical treatment if you are a patient. 
 
The investigator(s) may stop your participation in this study without your consent for reasons 
such as:  it will be in your best interest; you do not follow the study plan; or you experience a 
study-related illness or injury. You may be withdrawn from the study if laboratory tests suggest 
that it is not safe for you to continue. 
 
GENETIC RESEARCH  
 
Samples and information about you may be shared with others to use for research; however, 
we will not release your name. Because certain genetic information may be unique to an 
individual, it is possible that your genetic information could link research information to you.  
 
It is possible that a commercial product, test or findings will be developed as part of this 
research. These may have value and may be developed and owned by the study staff, and/or 
others.  If this happens, there are no plans to provide money to you.  
 
What we learn about you from this sample will not be put in your health record. Your test 
results will not be shared with you or your doctor. No one else (like a relative, boss, or 
insurance company) will be given your test results.  Health insurance companies and group 
health plans may not request your genetic information that comes from this research. 
 
A new federal law, the Genetic Information Nondiscrimination Act (GINA), makes it illegal for 
health insurance companies, group health plans, and most employers to discriminate against 
you based on your genetic information.  This law generally will protect you in the following 
ways: 


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 8 of 11   
 
 
 Health insurance companies and group health plans may not request your genetic 
information obtained from this research. 
 Health insurance companies and group health plans may not use your genetic 
information obtained from this research when making decisions regarding your eligibility 
or premiums. 
 Employers with 15 or more employees may not use your genetic information obtained 
from this research when making a decision to hire, promote, or fire you or when setting 
the terms of your employment. 
 All health insurance companies and group health plans must follow this law by May 21, 
2010.  All employers with 15 or more employees must follow this law as of November 
21, 2009. 
 
RESEARCH RESULTS 
 
In the event new information becomes available that may affect the risks and/or benefits 
associated with this study or your willingness to participate in it, you and your physician will be 
notified so you can make a decision whether or not to continue your participation in this study. 
 
Your study records and data will be stored in a secure database. The database will reside in a 
password protected secure website supported by the TVHS VA. Information in the database 
will only be available to study personnel. Your biological samples will be stored with a study ID 
label in a locked freezer. This label will not include any identifying information. Only key study 
staff will have access to your identifying information. All key study personnel involved in the 
design or conduct of this study will receive the required education on the protection of human 
participants. 
 
If results of this study are reported in medical journals or at meetings, you will not be identified 
by name, by recognizable photograph, or by any other means without your specific consent. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law.  This website will not include information that can identify you.  At most, the website 
will include a summary of the results.  You can search this website at any time. 
DISPOSITION OF RESEARCH DATA AND/OR SPECIMENS 
 
This research study is anticipated to last 5 years.  This study involves access of PHI 
data/limited data set for research as listed: Name, SSN for screening candidates (necessary 
for reimbursement), date(s) of lab tests and x-rays, and phone number for follow-up phone 
calls.  
 
The research data will be stored in a RedCap database which is a password protected, secure 
web-based application maintained by the TVHS VA and retained in your research record in 
accordance with Veterans Health Administration (VHA) and Federal Records Control Schedule 
policies after the study is completed.  Research data will be used/shared outside TVHS at the 
PI’s office at Vanderbilt University Medical Center. 
 


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 9 of 11   
 
 
 Sensitive Research data (hard-copy data such as signed consent form, case reports 
forms): 
o PI’s work space in VA TVHS 
o PI’s office at VUMC 
o Research coordinators’ office at VUMC 
 Electronic sensitive research data  
o PI’s folder on VA TVHS Server 
o PI’s folder on VUMC Server  
 The code linking your name with your ID number will be stored electronically on the 
VA’s secure computer network. 
 Data collected (per the HIPAA Authorization page 1) will be stored in the REDCap 
database on the TVHS computer server. A copy of this data collected will also be stored 
on the PI’s TVHS Research Folder. 
The research specimens will be stored at Dr. Bachmann’s freezer in TVHS in Nashville.  
Specimens may also be stored in the Cardiovascular Core Lab at Vanderbilt University 
Medical Center before they are processed. Research samples will be retained indefinitely for 
future use, as applicable to this protocol, and may also be used in future research. 
 
We may look at information collected in your medical record prior to the study and continue to 
view information in your records collected after the completion of the study. This is so we may 
view your medical chart before and after you complete the study.  
Your samples and information about you may be made available to others to use for research. 
To protect your privacy, we will not release your name. You will not receive any benefit as a 
result of the tests done on your samples. These tests may help us learn more about the 
causes, risks, treatments, or how to prevent this and other health problems.  
Your samples may be used to make new products or tests. These may have value and may be 
developed and owned by the study staff, TVHS, Vanderbilt University Medical Center, and/or 
others. If this happens, there are no plans to provide money to you. 
 
Should you qualify for future studies, we ask that you give us permission to contact you to 
discuss your interest and eligibility. 
 
 
        Yes, I give my permission to be contacted in the future regarding other research projects I 
may qualify for. 
 
 
         No, I do not give my permission to be contacted in the future regarding other research 
projects I may qualify for. 
 
ADDITIONAL STUDY OPTION:  


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 10 of 11   
 
 
 
You may choose to opt into another study in which an additional 10ml of blood will be drawn at 
each of your two study visits.  The blood will be used to study BNP levels using a different 
technique than is used in the main study.  
 
         Yes, I wish to participate in the additional study and have an additional 10 ml of blood 
         drawn at each study visit. 
 
          No, I do not wish to participate in the additional study and have an additional 10 ml of  
          blood drawn at each study visit. 
 
CONTACT INFORMATION 
If you have questions about this study, wish to express concerns or complaints about the 
research, or to report a research-related injury, you can contact: 
 Study Coordinator: Grace Henderson (615) 936-5356 
 Clinical Trials Manager: Cassandra Reynolds (615) 875-9854 
 Principal Investigator (PI), Dr. Katherine Bachmann: (615) 875-9520 
For 24-hour availability: (615)-835-8267, the automated voice will prompt you to enter your 
phone number in order for Dr. Bachmann to return your call. Once you have entered your 
phone number, please hang up. 
 
If you have general questions about giving consent or your rights as a participant in this study 
or wish to discuss problems or concerns, offer input, or you want to make sure this is a valid 
VA study, or request information you can call the VA Tennessee Valley Healthcare System 
(VATVHS) Institutional Review Board Office at (615) 873-6076 or the Research and 
Development Service Office at (615) 873-6940.You may also contact the VATVHS Patient 
Advocate at 1-800-228-4973, extension 67225 or 1-800-876-7093 extension 22560, or (615) 
873-7225 to discuss problems or concerns and ask questions not related to the consent 
process, offer input, or request information.   
 
CONFIDENTIALITY AND PRIVACY 
 
Your rights of privacy will be maintained in the following manner.  Your medical records will be 
maintained according to this medical center’s requirements and the Privacy Act of 1974.  All 
information obtained about you during the research study will be kept as confidential as legally 
possible and will be accessible only to the investigators and members of the research team, 
the sponsor (when applicable), and any appropriate government agency.  Research records, 
like any other hospital records, may be inspected by federal regulatory authorities, including 
the VA Office of Research Oversight, the VA TVHS Research Compliance Officer, the Food 
and Drug Administration (FDA), state regulatory authorities, and legally authorized parties.     
 
Your permission to allow access to your medical information and a description of your rights 
under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) is addressed in 
a separate HIPAA Authorization document.   By signing the separate HIPAA Authorization 


 
Department of Veterans Affairs 
VA RESEARCH CONSENT FORM 
 
                                IRB Form 020 -  Research Consent Form Template  - Version (2.2) Date: 10-25-2016                                         Page 11 of 11   
 
 
form you agree to allow access, use and disclosure of your personal health information as 
described in the HIPAA Authorization form. By signing the consent form, you are voluntarily 
choosing to participate in the study as described below in this consent form. 
STATEMENT & SIGNATURE OF PERSON AGREEING TO PARTICIPATE IN THIS 
RESEARCH STUDY: 
Signatures.  I agree to participate in this research project as described in this consent form. I 
will be given a signed copy of this consent form for my records.  I have read or have had this 
consent form read to me.  
 This study has been explained to me and all of my questions have been answered by 
the person obtaining consent. I have been told of the risks or discomforts and possible 
benefits of the study. I have been told of other choices of treatment available to me.  If I 
have questions later, I understand I can contact the researcher or a member of the 
research team. 
 If I do not take part in this study, my refusal to participate will involve no penalty or loss 
of rights to which I am entitled. I may withdraw from this study at any time without 
penalty or loss of VA or other benefits to which I am entitled. 
 I have been told my rights as a research subject, and I voluntarily consent to participate 
in this study. I have been told what the study is about and how and why it is being 
done.  All my questions have been answered. 
 I will receive a copy of this consent form and a copy will be forwarded to the VA 
Tennessee Valley Healthcare System Research Compliance Office.   
 
SIGNATURES:  (Note: ALL signatures and dates of signature below are required for 
legally effective research consent and HIPAA authorization.)  
 
 
__________________________   
Study Participant’s SSN – full SSN required
 
 
__________________________ 
Study Participant Name (Print) 
______________________________ 
Study Participant Signature 
_____________ 
Date 
 
__________________________ 
Name of person (Print) obtaining 
authorization and consent
 
______________________________ 
Signature of person obtaining 
authorization and consent
____________ 
Date