Clinical trial NCT02797184
Conditions: Heart Failure
Sponsor: Washington University School of Medicine
Start date: 2017-10-31; Completion date: 2021-12-15
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to do the work that is necessary and sufficient for setting up an appropriate multi-center, randomized clinical trial (RCT) of a new therapy for heart failure: inorganic nitrate. The investigators will first determine the effects and palatability of \~12.8mmol KNO3 (an oral pill) as compared to the roughly equivalent amount of nitrate in 2 beetroot juice (BRJ) Sports Shots (by James White Drinks). Next, the investigators will determine the effects of inorganic nitrate (KNO3 in an oral pill format) on blood pressure, blood nitrate levels, breath nitric oxide (NO) levels, and exercise performance in a dose-response study. Third, the investigators will perform a small phase II chronic treatment study that will allow them to determine the best primary endpoint and the numbers of patients the investigators will need to study in the large, multi-center RCT to follow this project. In the small study and in the RCT to follow, the investigators will determine whether inorganic nitrate can improve aerobic exercise capacity, muscle power, and speed of muscle contraction, and lessen the effort of breathing during exercise.

Detailed description:
1. Subjects will be patients with Heart Failure (HF).
2. All subjects will be consented.
3. All subjects will give permission for the investigators to review their medical records.
4. After consenting to participate, subjects will be instructed to refrain from spitting or the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum during the morning of each clinic visit.
5. Subjects will have a physical examination.
6. Subjects will undergo transthoracic echocardiographic imaging at rest (unless they had this performed within the past 6 months).
7. Subjects will be asked to undergo a mouth swab for bacterial DNA analyses.
8. Subjects will be asked to answer questionnaires regarding their medical health (basic health questionnaire, Minnesota living with heart failure questionnaire, a combined fatigue questionnaire.
9. Dose visit 1: Subjects will receive 2 capsules containing either 10 or 20 mmol of potassium nitrate (KNO3).
10. Before and at 3 hourly time points after receiving the KNO3, subjects will undergo phlebotomy for plasma nitrite levels, will have their blood pressure measured, and will blow into a small machine to assess the amount of nitric oxide in their breath.
11. Exercise Test 1: Subjects will complete measurements of leg muscle power by doing knee extension exercises on a dynamometer (a device that measures voluntary muscle force production while controlling the speed of movement).
12. Exercise Test 2: Subjects complete a measurement of peak aerobic capacity (VO2peak) while walking on a treadmill and breathing into a mouthpiece. Blood pressure, heart rate and heart rhythm will be monitored during this test.
13. Subjects will undergo a 7 d washout period.
14. Dose visit 2: Subjects will receive 2 capsules containing either 10 or 20 mmol of KNO3 (whichever dose they did not receive at dose visit 1). They will repeat the same assessments listed above in 10, 11, and 12.

Arms: arm 1: Intervention: Subjects with heart failure will receive a single oral dose of potassium nitrate (10 or 20 mmol KNO3) in 2 gelatin capsules during dose visit 1 and the other dose (10 or 20 mmol KNO3) during dose visit 2. The dose order will be randomized. arm 2: Intervention: Subjects with heart failure will receive a single oral dose of potassium nitrate (10 or 20 mmol KNO3) in 2 gelatin capsules during dose visit 1 and the other dose (10 or 20 mmol KNO3) during dose visit 2. The dose order will be randomized.
Interventions: intervention 1: KNO3, potassium nitrate
Intervention descriptions: intervention 1: Potassium nitrate (KNO3) will be given orally in 2 gelatin capsules, which will be compounded by the Barnes-Jewish Hospital Pharmacy. The doses are 10 mmol and 20 mmol KNO3.

Protocol documents:
Prot_SAP_000.pdf: 
The Inorganic Nitrate for Exercise in Heart Failure (iNIX-HF) Trial 
 
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Protocol #1 
Protocol version #14 
Date: 01/07/2020  
ClinicalTrials.gov: NCT02797184 
 
Principal Investigators: Linda R. Peterson, MD and Andrew R. Coggan, PhD 
 
Background: 
Heart Failure (HF) is a major public health problem when considering the incidence, prevalence, 
mortality rate, and costs to the patient and the health care system. According to the American 
Heart Association (AHA), it is estimated that there are over 5.1 million people in the United 
States (US) and 23 million people worldwide affected by HF.1, 2 One in nine deaths is due to 
heart failure, and 50 percent of people who have heart failure will die within the first 5 years of 
diagnosis. HF costs the healthcare system in the US $32 billion dollars annually in missed 
workdays, medications, and heath care services.1 A contributing factor to this cost is that 
surviving patients with heart failure have a higher burden due to the debility HF causes 
compared to those without heart failure. The debility is so profound that the New York Heart 
Association classification system of HF is based on the severity of the patient’s inability to 
exercise and perform activities of daily living. Given the disabling nature of HF and its impact on 
both the patient as well as the healthcare system, any improvement in exercise capacity or 
tolerance would be of benefit. 
 
There is emerging data from our group and others that dietary nitrate, particularly in nitrate-
rich foods such as beetroot juice (BRJ), increases plasma NO3- levels, plasma NO2- levels, and 
breath NO levels.3-5 This increase in NO improves exercise performance even in patients with 
HF.3  This improvement in performance is due to several physiologic effects of NO. It is a 
vasodilator and helps improve muscle perfusion.  NO also increases muscle power and speed of 
contraction through its actions on cGMP.6 Thus, dietary INORGANIC nitrate in beetroot juice 
appears to be a novel treatment with which to attack the disabling effects of heart failure.  
 
Unfortunately, BRJ has potential unwanted side effects, which might limit its use on a large 
scale.  First, the taste is bitter, earthy, and salty. One reviewer of a grant even remarked that it 
was “unfit for human consumption”.  Second, the juice can cause beeturia and red-colored 
stools, which may make patients think they are bleeding or may mask true internal bleeding.  
Next, beetroot juice is high in oxalate; thus, its chronic consumption may increase kidney stone 
formation. Lastly, it is administered as 2/3 of a cup of liquid, so it is by nature less portable. 
Thus, there is a clear need for a new form of delivery for inorganic nitrate for patients with HF. 
 
Therefore, potassium nitrate (KNO3) is an intriguing alternative for delivery of inorganic nitrate 
to subjects with HF.  Dietary inorganic nitrate in KNO3 as a source of NO has several advantages 
over the classical nitric oxide synthase production pathway (L-arginine), current pharmacologic 
ORGANIC nitrates, sildenafil, and beetroot juice (see Table 1. below). Ten mmol of pharmacy-
grade KNO3 can be put into a single gelatin capsule (gelcap) by the Barnes-Jewish compounding 


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pharmacy.  This is roughly the equivalent of two-thirds of a cup of beetroot juice.  The gelcap 
would be devoid of taste, is portable, does not contain oxalate, and would not cause beeturia 
or red stools. We also believe that these advantages of KNO3 will increase medication 
compliance.  
 
Table 1. KNO3 versus other possible approaches for increasing NO 
Current Approaches 
Advantages of KNO3 
L-arginine 
• Not dependent on NO synthase (NOS) 
• Functions well in acidic tissues 
• Functions well in ischemic tissues 
Organic, pharmacologic 
nitrates (e.g., 
nitroglycerin) 
• Does not cause tolerance 
• Does not increase reactive oxygen species (ROS) in 
mitochondria 
• May be less likely to cause hypotension 
• May be less likely to cause headaches 
Sildenafil 
• Inadvertent inhibition of PDE6 is thought to be responsible 
for retinal dysfunction and vision changes 
• May be less likely to cause hypotension 
• May be less likely to cause flushing or headache 
Beetroot juice 
• Does not contain oxalate (decreased risk of kidney stones) 
• No allergies 
• No bitter taste 
• Easier to control exact nitrate content 
• More portable 
• No beeturia to be confused with/mask renal/urinary tract 
disease 
• No red stool to be confused with/mask gastrointestinal 
disease 
 
Study Aims: 
Aim 1: To determine the optimum dose of inorganic nitrate to improve exercise performance 
(i.e., aerobic capacity and muscle power) in patients with heart failure and reduced ejection 
fraction (HFrEF). Aerobic capacity will be assessed by peak oxygen consumption (V̇O2peak) and 
muscle power will be assessed as maximal knee extensor power using a Biodex machine. This is 
a double-blind, cross-over study aim in which each participant will receive single doses of 
potassium nitrate (10 or 20 mmol KNO3) administered in gelatin capsules in random order one 
week apart.  
Aim 1 Sub-Study: Pharmacokinetics. To determine the time course of effects of a single 10 
mmol dose of KNO3 on plasma nitrate and nitrite concentrations, breath nitric oxide 
concentration, blood pressure, and heart rate at rest. Blood samples will be drawn before 
dosing, every hour for 3 hours after KNO3 ingestion, and at 4.5, 6, 12, 18 (optional), and 24 
hours post-dose. Plasma levels of nitrate and nitrite will be quantified using HPLC.   


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Aim 2: To determine the effects of 2 weeks of inorganic nitrate therapy vs. placebo on aerobic 
capacity and muscle power in patients with HFrEF. The dose for this aim will be 10 mmol of 
KNO3 daily in a single gelatin capsule taken in the morning. This dosing regimen is based on the 
results of Aim 1, which revealed that the beneficial effects on exercise performance were not 
statistically different for the 10 and 20 mmol doses taken on one occasion in the morning, 
whereas tolerability was lower with the 20 mmol dose. The rationale for taking the 10 mmol 
dose once daily is based on the half-life of KNO3. 
Aim 3: To determine the effects of 6 weeks of inorganic nitrate therapy vs. placebo on aerobic 
capacity and muscle power in patients with HFrEF. The dose for this aim will be 10 mmol of 
KNO3 daily in a single gelatin capsule taken in the morning. This dosing regimen is based on the 
results of Aim 1, which revealed that the beneficial effects on exercise performance were not 
statistically different for the 10 and 20 mmol doses taken on one occasion in the morning, 
whereas tolerability was lower with the 20 mmol dose. The rationale for taking the 10 mmol 
dose once daily is based on the half-life of KNO3. 
 
Participants: 
Inclusion: Subjects included in this study will be patients ≥18 years of age with documented 
stable, NYHA class II-IV, non-ischemic heart failure with an ejection fraction <45%. Participants 
must be on a stable medical regimen that is considered standard of care for HF (e.g., a beta-
blocker and ACE-inhibitor/angiotensin receptor blocker) for at least 60 days prior to study. This 
is required to exclude any patients with reversible causes of cardiac dysfunction. All subjects 
must be free of any significant orthopedic limitations or other contraindications to strenuous 
exercise. 
Exclusion: Vulnerable populations as defined by the U.S. Department of Health and Human 
Services, including prisoners and children, will be excluded from this study, as will be women 
who are pregnant. Those taking pharmacologic (organic) nitrates during the last 3 mo will be 
excluded, as will be those taking phosphodiesterase inhibitors (e.g., Viagra), as these can 
potentiate NO effects. Those taking proton pump inhibitors, antacids, or xanthine oxidase 
inhibitors will be asked to hold these medications for the duration of the study, if approved by 
his/her physician. These drugs will also be held for at least 5 half-lives before any study-related 
activity. Otherwise patients taking these drugs will be excluded as these can affect reduction of 
NO3- and NO2-. Subjects having active angina/ischemia from epicardial coronary disease, 
requiring supplemental O2 at rest or for exercise, will be excluded. Similarly, subjects with 
systolic blood pressure <95 or >180 mmHg or diastolic blood pressure <40 or >95 mmHg at 
consent, a plasma K+ level 5mEq/L, or an estimated glomerular filtration rate of <45 mL/min 
based on most recent clinical laboratories will be excluded. Subjects with primary hypertrophic 
cardiomyopathy, infiltrative cardiomyopathy (e.g., amyloid), active myocarditis, complex 
congenital heart disease, active collagen vascular disease, more than mild mitral or aortic 
stenosis, valvular heart disease with severe regurgitation of any valve, or who have undergone 
percutaneous coronary intervention, new bi-ventricular pacing, or coronary bypass grafting in 
the last 3 mo will be excluded. Subjects with acute or chronic severe liver disease as evidenced 


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by encephalopathy, INR>1.7 without anticoagulant therapy, or variceal bleeding will be 
excluded. Subjects with a terminal disease other than HF with expected survival <1 y will be 
excluded. Finally, subjects with any major orthopedic, psychiatric, neurological, or other 
condition that would impair performance of the exercise studies will be excluded. 
 
Methods: 
Aim 1:  Dose Response of Potassium Nitrate (KNO3) 
The effects of a two different, single doses of KNO3 on V̇O2peak and maximal muscle power 
in patients with HFrEF will be evaluated during 2 study visits. The screening visit may be 
conducted as a separate visit or combined with the first dose visit. 
Screening Visit. 
1) Consent: All study procedures will be reviewed with the participant before he/she 
provides written informed consent. Consent includes giving permission for the 
investigators to review their medical records. 
2) Blood Sample: A blood sample will be drawn for basic screening laboratories, including 
glucose and creatinine (for estimation of glomerular filtration rate).  
3) Physical Exam: Subjects will have a brief history and physical examination. These will not 
be done with participants who have had a physical exam within the past 6 months. 
4) Resting Echocardiogram: A resting echocardiogram will be performed to enable 
assessment of cardiac blood flow. An intravenous contrast agent may used to obtain a 
clearer assessment of cardiac blood flow, if needed. The echocardiogram may not be 
necessary if the participant had an echocardiogram within the past 12 months. 
5) Questionnaires: Subjects will be asked to complete two questionnaires: Basic Health 
Questionnaire and the Minnesota Living with Heart Failure Questionnaire.  
6) Instructions for KNO3 dose visits: Subjects will be instructed to refrain from using 
mouthwash, antacids, proton pump inhibitors, or chewing gum before each KNO3 dose 
visit. 
 
KNO3 Dose Visit 1 
1) Subjects will report to the Clinical Translational Research Unit (CTRU) at Washington 
University.  
2) KNO3 Gelcaps: Subjects will receive 10 or 20 mmol of KNO3 in the form of a gelcap. 
3) Blood Samples: Subjects will have blood drawn (20mL or about 1.5 tbsp).  An 
intravenous catheter will be placed to facilitate blood sampling 5 times during the visit. 
The first blood sample will be obtained before ingestion of the cap and the others will be 
obtained once each hour for 4 hours after ingestion of the gelcap. The blood will be used 
to determine blood levels of nitrate and nitrite.  A sample also will be obtained for 
measurement of blood lipids. 
4) Blood Pressure and Heart Rate: Blood pressure and heart rate will be measured once 
before the gelcap is consumed and once each hour for 4 hours after the gelcap is 
consumed. 


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5) Breath Nitric Oxide: Subjects will exhale into a tube attached to a portable 
electrochemical analyzer (NIOX VERO, Aerocrine Inc., Morrisville, NC) following the 
American Thoracic Society/European Respiratory Society guidelines before and 4 times 
after ingestion of the gelcap. Breath nitric oxide concentration provides a surrogate 
biomarker of whole-body NO production. 
6) Saliva Sample: A sample of saliva will be obtained to determine the different types of 
oral bacteria residing in the mouth, based on bacterial DNA analyses. Some types of 
bacteria can convert nitrate to nitrite. This will be done only once. 
7) Exercise Test – Maximal Muscle Power: 2 hours after ingesting the gelcap, subjects will 
complete the following series of tests to assess leg muscle power. A Biodex 4 isokinetic 
dynamometer (Biodex Medical Systems, Shirley, NY) will be used to measure maximal 
voluntary force and power during knee extension exercise performed with the dominant 
leg at angular velocities of (in order) 0, 1.57, 3.14, 4.71, and 6.28 rad/second, which 
equate to 0, 90, 180, 270, and 360 °/second. The chair back-chair seat angle will be set 
to 85° and the dynamometer adjusted to place the axis of rotation of the lever arm 
adjacent to the lateral femoral epicondyle. To minimize other movement, straps will be 
placed across the torso, hips, and thigh, and subjects will not be allowed to use the 
handholds. Range of motion will be determined. Next, the subject will perform 3-4 knee 
extensions at each velocity, with the isometric testing conducted at an angle of 1.22 rad 
(70°). Two minutes of rest will be allowed after each group of contractions. Strong verbal 
encouragement will be provided throughout all portions of the isokinetic testing. 
8) Exercise Test – Aerobic Capacity: After 10 min of recovery from the muscle power 
testing, peak oxygen consumption (V̇O2peak) will be determined with an incremental 
treadmill exercise test to volitional fatigue using the modified Naughton protocol. 
Subjects will walk on a treadmill and breathe into a mouthpiece while wearing a nose 
clip (to prevent airflow through the nose). Subjects will be asked to give their maximal 
effort. Blood pressure and heart rhythm will be monitored. A ParvoMedics TrueOne 
metabolic cart will be used to measure ventilation (Ve), oxygen consumption (V̇O2), and 
carbon dioxide production (V̇CO2) throughout exercise. Data from this test will be used 
to quantify Ve/V̇O2, Ve/V̇CO2, ventilatory threshold (defined using the V-slope method), 
oxygen uptake efficiency slope (OUES), and V̇O2peak. Subjects will also be asked to give a 
rating of perceived exertion (RPE) on the Borg scale (6-20) and their perceived dyspnea 
on a five-point visual-analog scale. 
 
KNO3 Dose Visit 2 
At least 7 days after KNO3 Dose Visit 1, subjects will receive a different gelcap than they 
received during Dose Visit 1 (i.e., 10 or 20 mmol KNO3) and then complete all of the 
assessments listed under KNO3 Dose Visit 1 except the saliva sample. 
 
Aim 1 Sub-Study: Pharmacokinetics 
To determine the time course of effects of a single 10 mmol dose of KNO3 on plasma nitrate 
and nitrite concentrations, breath nitric oxide (NO) concentration, blood pressure, and 
heart rate at rest. Blood samples will be drawn and breath NO will be sampled before 


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dosing, every hour for 3 hours after KNO3 ingestion, and at 4.5, 6, 12, 18 (optional), and 24 
hours post-dose.   
 
Screening Visit  
1) Consent: All study procedures will be reviewed with the participant before he/she 
provides written informed consent. Consent includes giving permission for the 
investigators to review their medical records. 
2) Blood Sample: A blood sample will be drawn for basic screening laboratories, including 
glucose, K+, and creatinine (for estimation of glomerular filtration rate).  
3) Physical Exam: Subjects will have a brief history and physical examination. These will 
not be done with participants who have had a physical exam within the past 6 months. 
4) Resting Echocardiogram: A resting echocardiogram will be performed to enable 
assessment of cardiac blood flow. An intravenous contrast agent may used to obtain a 
clearer assessment of cardiac blood flow, if needed. The echocardiogram may not be 
necessary if the participant had an echocardiogram within the past 12 months. 
5) Questionnaire: Subjects will be asked to complete a Health Questionnaire.  
6) Instructions to participants: Subjects will be instructed to refrain from using 
mouthwash, antacids, proton pump inhibitors, or chewing gum before the KNO3 dose 
visit. 
 
Dose Visit   
1)  Subjects will report to the Clinical Translational Research Unit (CTRU) at Washington 
University for either two outpatient visits or a single inpatient (overnight) visit, based on 
their preferences.  
2) KNO3 Gelcaps: Subjects will receive a single KNO3 gelcap containing 10 mmol of 
inorganic nitrate. 
3) Blood Samples: An intravenous catheter will be placed to facilitate blood sampling 
throughout the visit. The total amount of blood drawn will be ~30 mL (2.0 Tbsp). The 
first blood sample will be obtained before ingestion of the KNO3 gelcap and the others 
will be obtained once each hour for 3 hours after ingestion of the gelcap and at 4.5, 6, 
12, 18 (optional), and 24 hours post-dose. If this sub-study is completed as two 
outpatient visits, then the 18h blood sample is optional and the 24h blood sample will 
be drawn at the second visit. For inpatient visits, all blood samples will be drawn during 
this dose visit. 
4)  Breath Nitric Oxide: Subjects will exhale into a tube attached to a portable 
electrochemical analyzer (NIOX VERO, Aerocrine Inc., Morrisville, NC) following the 
American Thoracic Society/European Respiratory Society guidelines before and several 
times after ingestion of the gelcap, on the same schedule as the post-dose blood 
samples. Breath nitric oxide concentration provides a surrogate biomarker of whole-
body NO production. 
5) Blood Pressure and Heart Rate: Blood pressure and heart rate will be measured once 
before the gelcap is consumed and several times after ingestion of the gelcap, on the 


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same schedule as the post-dose blood samples. 
 
Visit 2 (only needed if the dose visit was an outpatient visit)   
1)  Subjects will report to the Clinical Translational Research Unit (CTRU) at Washington 
University approximately 23.5 hours after they received the KNO3 gelcap.  
2) 24h Assessments: The 24h blood sample will be drawn, breath nitric oxide will be 
assessed, and blood pressure and heart rate will be measured.  
 
Aim 2.  Randomized Controlled Trial of Potassium Nitrate (KNO3) Therapy for 2 Weeks 
The effects of KNO3 therapy on V̇O2peak and maximal muscle power in patients with HFrEF 
will be evaluated in a randomized, placebo-controlled trial. The KNO3 dose used in this aim 
will be 10 mmol daily. The treatment (or placebo) period will be 2 weeks, with 
measurements of V̇O2peak and maximal muscle power completed before and at the end of 
the intervention using the same methodology as in Aim 1.  
 
Screening Visit. 
The screening visit procedures will be the same as for Aim 1 above. If a subject participated 
in Aim 1, then he/she will not have to repeat the screening procedures for Aim 2. 
 
Exercise Testing Visit 1.  
1) Subjects will report to the Clinical Translational Research Unit (CTRU) at Washington 
University.  
2) Blood Samples: Subjects will have blood drawn (20mL or about 1.5 tbsp) to determine 
blood levels of nitrate and nitrite using HPLC. A sample also will be obtained for 
measurement of potassium and blood lipids. 
3) Blood Pressure and Heart Rate: Blood pressure and heart rate will be measured once 
before the gelcap is consumed and once each hour for 4 hours after the gelcap is 
consumed. 
4) Breath Nitric Oxide: Subjects will exhale into a tube attached to a portable 
electrochemical analyzer (NIOX VERO, Aerocrine Inc., Morrisville, NC) following the 
American Thoracic Society/European Respiratory Society guidelines.  
5) Saliva Sample: A sample of saliva will be obtained to determine the different types of 
oral bacteria residing in the mouth, based on bacterial DNA analyses. Some types of 
bacteria can convert nitrate to nitrite. This will not be done if the subject participated in 
Aim 1. 
6) Exercise Test – Maximal Muscle Power: Subjects will complete the following series of 
tests to assess leg muscle power. A Biodex 4 isokinetic dynamometer (Biodex Medical 
Systems, Shirley, NY) will be used to measure maximal voluntary force and power during 
knee extension exercise performed with the dominant leg at angular velocities of (in 
order) 0, 1.57, 3.14, 4.71, and 6.28 rad/second, which equate to 0, 90, 180, 270, and 
360 °/second. The chair back-chair seat angle will be set to 85° and the dynamometer 
adjusted to place the axis of rotation of the lever arm adjacent to the lateral femoral 


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epicondyle. To minimize other movement, straps will be placed across the torso, hips, 
and thigh, and subjects will not be allowed to use the handholds. Range of motion will 
be determined. Next, the subject will perform 3-4 knee extensions at each velocity, with 
the isometric testing conducted at an angle of 1.22 rad (70°). Two minutes of rest will be 
allowed after each group of contractions. Strong verbal encouragement will be provided 
throughout all portions of the isokinetic testing. 
7) Exercise Test – Aerobic Capacity: After 10 min of recovery from the muscle power 
testing, peak oxygen consumption (V̇O2peak) will be determined with an incremental 
treadmill exercise test to volitional fatigue using the modified Naughton protocol. 
Subjects will walk on a treadmill and breathe into a mouthpiece while wearing a nose 
clip (to prevent airflow through the nose). Subjects will be asked to give their maximal 
effort. Blood pressure and heart rhythm will be monitored. A ParvoMedics TrueOne 
metabolic cart will be used to measure ventilation (Ve), oxygen consumption (V̇O2), and 
carbon dioxide production (V̇CO2) throughout exercise. Data from this test will be used 
to quantify Ve/V̇O2, Ve/V̇CO2, ventilatory threshold (defined using the V-slope method), 
oxygen uptake efficiency slope (OUES), and V̇O2peak. Subjects will also be asked to give a 
rating of perceived exertion (RPE) on the Borg scale (6-20) and their perceived dyspnea 
on a five-point visual-analog scale. 
8) KNO3 Gelcaps: Subjects will receive a 2-week supply of KNO3 gelcaps or placebo gelcaps 
in a double-blinded manner (i.e., neither the subject nor the investigators will know 
which gelcap the subject receives).  
 
Exercise Testing Visit 2. 
Two weeks after Exercise Testing Visit 1, subjects will report to the Clinical Research Unit 
(CRU) at Washington University after an overnight fast and repeat all of the procedures that 
were performed during Exercise Testing Visit 1 (except the saliva sample). 
 
 
Safety Monitoring:  
We will make every effort to minimize risks by observing and monitoring participants during 
testing and throughout the 2-week and 6-week treatment periods. Emergency equipment and 
trained personnel are available to deal with an emergency that may arise during assessments in 
the clinical research unit. The risk of bruising or infection at an IV site will be minimized by 
having experienced personnel trained in the appropriate sterile techniques place the 
IVs. Possible risks associated with the echocardiogram procedures include an allergic reaction 
to the contrast agent, an allergic skin reaction to the electrode gel, and mild discomfort due to 
the light pressure of the ultrasound probe. The risk of an allergic reaction to the contrast agent 
will be minimized by not using contrast in anyone with a known allergy, not using contrast 
unless necessary for adequate image analysis, and monitoring subjects closely after the 
contrast agent is administered.  
If any particular question on a questionnaire makes the subject uncomfortable, he/she may 
discuss its importance and the need to answer it with the research team member. They may 


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choose not to answer any question. If a subject has an incidental finding on his/her 
echocardiogram, blood work, or physical exam that is noted and is clinically important, he/she 
will be made aware of it through an incidental finding letter. He/she will be advised to share the 
information with his/her physician. 
The data will be reviewed by the PI at least every 6 months. Dr. Edward Geltman will also 
review the relevant data (events, complaints, and the results of all the study endpoints) at least 
once each year. The safety monitoring panel is comprised of Edward Geltman, MD; Janet 
McGill, MD; and Mae Gordon, PhD. 
 
Data Analysis: 
Aim 1: Data comparing the 2 doses of KNO3 on exercise performance, plasma NO3-, plasma NO2-
, and breath NO will be analyzed using two-way (i.e., treatment x time) analysis of variance 
(ANOVA) for repeated measures using an alpha set at 0.05. In addition, the changes in 
measured variables will be analyzed using univariable regression methods. 
Aim 1 Sub-Study: Pharmacokinetics data from the blood samples will be used to determine the 
time course and peak plasma concentrations of nitrate and nitrite in response to a single dose 
(10 mmol) of KNO3.  
Aim 2: Data from the randomized, controlled trial of 2 weeks of KNO3 treatment will be 
analyzed using analyses of covariance in which the post-treatment value of the outcome 
measure will be the dependent variable and the pre-treatment value and the study group will 
be the independent variables. Additional analyses will adjust for sex as a covariate. The mean 
and standard deviation of the pre- to post-treatment change in the two outcome measures 
(i.e., V̇O2peak and maximal muscle power) will serve as a guide for power calculations in the 
subsequent RCT for which this application is a prelude. In all analyses of covariance, regression 
residuals will be evaluated so we can assess the fit of the model. If the model fit is poor, we will 
explore data transformations that improve the fit and, if such transformations cannot be found, 
it is possible that we will analyze the data using semi parametric methods based on the ranks of 
the data. Since experience suggests that both outcome measures tend to be normally 
distributed, it is unlikely that these alternative approaches will prove necessary. 
 
 
Sample Size Estimation: 
Aim 1: Sample sizes were estimated using data from our previous beetroot juice (BRJ) study, in 
which the BRJ beverage contained 11.2 mmol of nitrate. Based on average breath NO measured 
1 hour, 2 hours, and 3 hours after consuming the BRJ, breath NO increased 12 +/- 11 ppb in 
response to 11.2 mmol nitrate, for an effect size of 1.1. If we assume a comparable increase 
with a KNO3 capsule relative to placebo, then approximately 6 subjects would be sufficient to 
provide a power of more than 0.9 at alpha=0.05. However, a larger sample size will be needed 
to determine the effects of different doses of the KNO3 capsule on exercise performance, 
plasma NO3-, and plasma NO2-, as these have not been studied previously. To be conservative 


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and based on what we know about variability in exercise tolerance among HF patients, we will 
enroll 25 subjects, with the goal of obtaining complete data on 20 subjects. Power calculations 
were performed using G*Power 3.1.9.2. 
Aim 1 Sub-Study: The sample size will be approximately 10 participants.  
Aim 2: While this aim is not designed to reach statistical significance with adequate power, we 
have performed power computations to estimate the magnitude of the improvement in the 
two outcomes (i.e., V̇O2peak and maximal muscle power) that could be detected with 10 
subjects in each group. Those computations are based on two-sided tests at the 0.05 level of 
significance. Our preliminary aerobic capacity data indicate that HFrEF patients will have a 
baseline V̇O2peak value of 22.5±5.5 mL/kg/min. Given these data, the power to detect an 
increase in V̇O2peak of 32.4% will be 0.8; the power to detect an increase in V̇O2peak of 37.8% 
will be 0.9. Our preliminary muscle power data suggest that HFrEF patients will have a mean 
baseline maximal knee extensor power of 4.2±1.1 W/kg. Using these data and 10 subjects per 
group, the power will be 0.8 if the magnitude of the increase in knee extensor power is 35.7%; 
the power will be 0.9 if the increase in knee extensor power is 40.5%. 
 
References: 
1. Go AS, Mozaffarian D, Roger VL et al. Heart disease and stroke statistics--2014 update: a 
report from the American Heart Association. Circulation. 2014;129:e28–e292. 
2. McMurray JJ, Petrie MC, Murdoch DR, Davie AP. Clinical epidemiology of heart failure: 
public and private health burden. Eur Heart J. 1998;19 Suppl P:P9–16. 
3. Coggan AR, Leibowitz JL, Spearie CA et al. Acute Dietary Nitrate Intake Improves Muscle 
Contractile Function in Patients With Heart Failure: A Double-Blind, Placebo-Controlled, 
Randomized Trial. Circ Heart Fail. 2015;8:914–20. 
4. Coggan AR, Leibowitz JL, Kadkhodayan A et al. Effect of acute dietary nitrate intake on 
maximal knee extensor speed and power in healthy men and women. Nitric Oxide. 
2015;48:16–21. 
5. Kapil V, Webb AJ, Ahluwalia A. Inorganic nitrate and the cardiovascular system. Heart. 
2010;96:1703–9. 
6. Coggan AR, Peterson LR. Dietary Nitrate and Skeletal Muscle Contractile Function in Heart 
Failure. Curr Heart Fail Rep. 2016 
7. Coggan AR, Mahmood K, Mikhalkova D et al. Dietary nitrate reduces ventilatory demands 
and increases VO2peak in patients with systolic heart failure. Med Sci Sports Exerc. 
2016;48:S198. 
 

ICF_001.pdf: 
 
FOR IRB USE ONLY 
IRB ID #: 201708212 
APPROVAL DATE: 02/15/18 
RELEASED DATE: 02/15/18 
EXPIRATION DATE: 09/26/18 
 
February 09, 2018 
 
Page 1 of 11 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
The Inorganic Nitrate for Exercise in Heart Failure (iNIX-HF) Trial 
 
(Aim 1: Dose Response) 
 
Principal Investigators: 
Linda R. Peterson, MD  
 
Research Team Contact:  
Dakkota Thies, RMA  
(314) 747-3839 
Susan B. Racette, PhD 
(314) 286-1424 
 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights and responsibilities as a research participant. By signing this 
form, you are agreeing to participate in this study. 
• You should read and understand the information in this document including the procedures, risks 
and potential benefits.  
• If you have questions about anything in this form, you should ask the research team for more 
information before you agree to participate.   
• You may also wish to talk to your family or friends about your participation in this study. 
• Do not agree to participate in this study unless the research team has answered your questions and 
you decide that you want to be part of this study. 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study.  We invite you to participate in this research study because you have a history of 
heart failure.   
 
The purpose of this research study is to determine the optimum dose of inorganic nitrate to improve 
exercise performance in patients with heart failure. We believe that increasing the body’s nitrate levels 
will improve exercise tolerance. We will compare two doses of potassium nitrate (KNO3), also known 
as saltpeter, on blood nitrate (NO3-), blood nitrite (NO2-), and breath nitric oxide (NO) levels and on 
exercise performance. You will receive 10 or 20 mmol of KNO3 in gel capsules during 2 study visits. 
There will be a 7-day wash-out period (a time when you are not given KNO3) in between these visits. 
 
Heart failure is a condition in which the heart cannot pump enough blood throughout the body.  Heart 
failure often limits a person’s ability to exercise because he or she becomes short of breath with exertion. 
 
We know relatively little about the effect of diet / nutrition on heart failure, but there is evidence that 
dietary nitrates may improve exercise capacity in patients with heart failure. Nitrates are naturally-
occurring substances that have a nitrogen atom and are found in foods and water. Nitrates also can be 
administered in a capsule in the form of KNO3.  
 
Although KNO3 is available for purchase in grocery stores, for the purposes of this study it is considered 
investigational, which means that the U.S. Food and Drug Administration has not approved it as a 
medical therapy.   


 
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February 09, 2018 
 
Page 2 of 11 
WHAT WILL HAPPEN DURING THIS STUDY? 
 For this study, you are asked to give permission for the research team to access your medical record 
so they may verify your medical history.  If you have recently (within one year) had some of the 
physical exams or tests described in this project, the investigators may elect not to repeat these 
exams. 
 For the duration of the study, you will be asked to refrain from using mouthwash, antacids, Viagra, 
Cialis, or medicines like them (i.e., phosphodiesterase inhibitors).   
 The study includes 2 or 3 visits. There will be a screening visit and 2 KNO3 dose visits, but we may 
combine the screening visit with the first KNO3 dose visit. At the screening visit you will complete a 
series of screening tests, including a medical history, physical exam, blood draw, and resting 
echocardiogram. For both of the KNO3 dose visits, you will be given a gelcap containing either 10 or 
20 mmol of KNO3 (in random order; you will not know which dose you are receiving at each visit), 
have blood drawn, and complete a series of exercise tests. 
 
Screening Visit.  
1) Physical Exam and Echocardiogram: You will be asked to undergo a brief physical examination, 
have a blood sample drawn for a metabolic panel, and have a resting echocardiogram. An 
echocardiogram uses sound waves to make pictures of your heart, which helps show how well your 
heart pumps blood. A contrast agent may be administered intravenously to provide a clearer picture 
of blood flow in your heart during the echocardiogram. If you had these screening blood tests or 
echocardiogram done recently, then we may not repeat them. 
2) Questionnaires: You will be asked to fill out questionnaires about your health. This should take 
about 15 minutes.  A member of the study team will be available to answer questions. You are free to 
skip any questions that you prefer not to answer. 
 
KNO3 Dose Visit 1. 
1) KNO3 gelcap: You will receive 10 or 20 mmol of KNO3 in the form of a gelcap. 
2) Blood Samples: You will have blood drawn (20mL or about 1.5 tbsp).  An intravenous (IV) catheter 
(flexible tube) will be placed in your arm to facilitate blood sampling 5 times during your visit. The 
first blood sample will be obtained before you ingest the gelcap and the others will be obtained once 
each hour for 4 hours after you ingest the gelcap. The blood will be used to determine the levels of 
nitrate and nitrite in your blood, and to measure blood lipids. A small sample of blood also may be 
saved for genetic analyses (this is optional).  
3) Blood Pressure and Heart Rate: You will have your blood pressure and heart rate checked 5 times: 
once before you take the gelcap and once each hour for 4 hours after you take the gelcap.  
4) Breath Nitric Oxide: You will be asked to exhale into a tube attached to a small machine 5 times: 
once before and 4 times after you take the gelcap. This machine will measure the amount of nitric 
oxide in your breath. 
5) Saliva Sample: You will also be asked to provide a saliva sample to determine the different types of 
oral bacteria. Some types of bacteria can convert nitrate to nitrite. This will be done only once. 
6) Leg Muscle Power Test: 2 hours after ingesting the gelcap, we will measure the power of your leg 
muscles using an isokinetic dynamometer (a machine that measures voluntary muscle force 
production while controlling the speed of movement). 


 
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7) Aerobic Capacity Treadmill Test: This is an endurance exercise test that will enable us to 
determine your peak oxygen consumption (V̇ O2peak). You will walk on a treadmill and breathe into 
a mouthpiece while wearing a nose clip (to prevent you from breathing through your nose). You will 
be asked to give your maximal effort as the speed or grade of the treadmill increases. Your blood 
pressure and heart rhythm will be monitored.  
 
Washout period 1.  You will be asked to refrain from eating foods high in nitrates for the next 7 days.  
A dietitian will instruct you as to which foods are high in nitrates. 
 
KNO3 Dose Visit 2. 
At least 7 days after Dose Visit 1, you will receive a different KNO3 gelcap than you received during 
Visit 1 (i.e., 10 or 20 mmol KNO3) and then complete all of the assessments under KNO3 Dose Visit 1 
(except the saliva sample).  
 
Will you save my samples or research data to use in future research studies? 
As part of this study, we are obtaining blood samples as well as research data from you, which will 
become the property of Washington University.  We would like to use this blood and data for studies 
going on right now as well as studies that are conducted in the future. These studies may provide 
additional information that will be helpful in understanding heart and vascular function, or other 
diseases or conditions, including research to develop investigational tests, treatment, drugs or devices 
that are not yet approved by the U.S. Food and Drug Administration.  It is unlikely that what we learn 
from these studies will have a direct benefit to you. There are no plans to provide financial 
compensation to you should this occur.   By allowing us to use your blood samples and research data, 
you give up any property rights you may have in the blood samples and research data. 
 
We also request permission to draw and store 1 tablespoon of your blood for a period of up to 10 years 
to be used in future studies for screening for differences in genes related to nitric oxide metabolism 
(including, but not limited to, genes known as eNOS Glu298Asp and ACTN3 R577X). Genes are a 
unique combination of molecules (called DNA) that we inherit from our parents.  There are millions of 
tiny differences in our genes that determine things like our height or the color of our eyes.  Some of 
these differences may make some people more or less likely to develop certain diseases or conditions or 
to have certain characteristics. This test would be solely for research purposes. You will not hear from us 
regarding these results. We may share your blood sample or results with other investigators doing 
research in similar fields.  
 
We will share your blood and data with other researchers. They may be doing research in areas similar to 
this research or in other unrelated areas.  These researchers may be at Washington University, at other 
research centers and institutions, or industry sponsors of research.  We may also share your research data 
with large data repositories (a repository is a database of information) for broad sharing with the 
research community.  If your individual research data is placed in one of these repositories, only 
qualified researchers who have received prior approval from individuals that monitor the use of the data 
will be able to look at your information.   
 
If you change your mind and do not want us to store and use your blood or data for future research you 
should contact the research team member identified at the top of this document. The blood and data will 
no longer be used for research purposes. However, if some research with your blood or data has already 


 
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RELEASED DATE: 02/15/18 
EXPIRATION DATE: 09/26/18 
 
February 09, 2018 
 
Page 4 of 11 
been completed, the information from that research may still be used. Also, if the blood or data has been 
shared with other researchers, it might not be possible to withdraw the blood or data to the extent it has 
been shared. 
 
Please place your initials in the blank next to Yes or No for each of the questions below: 
 
My blood and data may be stored and used for future research as described above. 
 
_____ Yes 
_____ No 
Initials  
Initials 
 
My blood and data may be shared with other researchers and used by these researchers for the 
future research as described above. 
 
_____ Yes  
_____ No 
Initials  
Initials 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 25 people will take part in this aim of the study conducted by investigators at 
Washington University.   
 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last for approximately 3 weeks. 
The total number of visits is 3. The screening visit will last about 2 hours; the KNO3 dose visits will last 
approximately 4½ to 5 hours. 
 
WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study. 
 
Likely / Common:  
Mild: 
 The insertion of an intravenous tube for blood drawing or administration of the echocardiography 
contrast agent is associated with a small amount of discomfort while it is being placed. This 
should be brief. 
 You may feel short of breath at the end of the treadmill exercise tests.  
 
 
Less Likely / Less Common: 
Mild: 
 You may experience muscle pain or joint pain during or after the exercise tests. 
 You may experience emotional discomfort when answering some questions in the health 
questionnaires.  If any question makes you uncomfortable, you may discuss its importance and 
the need to answer it with us.  You may choose not to answer any question that makes you feel 


 
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February 09, 2018 
 
Page 5 of 11 
uncomfortable. 
 You may experience temporary discomfort during blood pressure readings due to the pressure of 
the cuff on your arm. 
 
Rare: 
Life Threatening: 
• Very rarely, a treadmill exercise test may be associated with serious complications including, but 
not limited to: fainting, erratic heart beat (too fast or too slow, which may require 
hospitalization), heart attack, stroke, or death. We will take every precaution to minimize these 
rare risks by closely monitoring you and your vital signs during the exercise tests. Emergency 
equipment and trained personnel are available during these tests to deal with an emergency.  
Serious: 
 There is a potential risk of an allergic reaction to the echocardiogram contrast material. 
 There is a theoretical increased risk of upper gastrointestinal cancers associated with a compound 
called “nitrosamine” that is made from nitrates by the body.  However, in large studies of many 
people followed for many years, a diet rich in fruits and vegetables (and very high in dietary 
nitrates) was not associated with an increase in cancer or mortality. The 2003 Joint Food and 
Agricultural Organization/World Health Organization Expert committee concluded that there was 
no evidence that nitrates are carcinogenic to humans. 
Mild: 
 You may experience abdominal pain, nausea, vomiting, headache, a decrease in blood pressure, or 
diarrhea after ingesting KNO3. If you develop a headache, you will be offered Tylenol.  If you 
experience a symptomatic decrease in blood pressure, you will be treated by the 
cardiologist/study team member in attendance, initially with IV fluids. 
 The insertion of an intravenous tube for blood drawing or administration of the echocardiography 
contrast agent is associated with a small risk of bleeding or infection.   
 Possible risks associated with the echocardiogram procedures include an allergic skin reaction to 
the electrode gel and mild discomfort due to the light pressure of the ultrasound probe. 
 
There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this 
law makes it illegal for health insurance companies, group health plans and employers with greater than 
15 employees to discriminate against you based on your genetic information. However, it does not 
protect you against discrimination by companies that sell life insurance, disability insurance or long 
term-care insurance.  
 
Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
You may or may not benefit from being in this study.  
 
However, we hope that in the future other people might benefit from this study because if KNO3 


 
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EXPIRATION DATE: 09/26/18 
 
February 09, 2018 
 
Page 6 of 11 
improves exercise tolerance in patients with heart failure, it may be used as a treatment even in places of 
the world where pharmaceutical agents for heart failure are difficult to obtain.  Also, we will have an 
improved knowledge of what to tell patients with heart failure in regards to their nutritional needs.  We 
will also improve our understanding of how KNO3 may improve muscle energy and exercise tolerance.  
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
You will not have any costs for being in this research study. 
 
You and/or your medical/hospital insurance provider will remain responsible for your regular medical 
care expenses. 
 
WILL I BE PAID FOR PARTICIPATING? 
You will be paid for being in this research study.  You will be paid $180 for completing the 2 KNO3 dose 
visits. You will need to provide your social security number (SSN) for us to compensate you with a 
check. You may choose to participate without being paid if you do not wish to provide your social 
security number (SSN) for this purpose.  You may also need to provide your address if a check will be 
mailed to you. It should take about 2 weeks to receive the check. If you do not receive it by 2 weeks, 
please contact the research coordinator Dakkota Thies at 314-747-3839. If your social security number is 
obtained for payment purposes only, it will not be retained for research purposes.    
 
Payment will be pro-rated, with $50 allocated for dose visit 1 and $130 for dose visit 2. 
 
WHO IS FUNDING THIS STUDY? 
The National Institute of Health (NIH) is funding this research study.  This means that Washington 
University is receiving payments from NIH to support the activities that are required to conduct the 
study.  No one on the research team will receive a direct payment or increase in salary from NIH for 
conducting this study. 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the principal 
investigator Dr. Peterson 314-362-4577, her secretary Ava Ysaguirre 314-362-1297, or the Human 
Research Protection Office at 1-800-438-0445. 
 
Decisions about whether payment for medical treatment for injuries relating to your participation in 
research will be made by Washington University. If you need to seek medical care for a research-related 
injury, please notify the investigator as soon as possible. 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
Other people such as those indicated below may become aware of your participation in this study and 
may inspect and copy records pertaining to this research.  Some of these records could contain 
information that personally identifies you. We will keep your participation in this research study 
confidential to the extent permitted by law.   
• Government representatives (including the Office for Human Research Protections), to complete 
federal or state responsibilities. 
• The U.S. Food and Drug Administration. 
• The Washington University granting agencies: Mentors in Medicine and Center for Clinical Imaging 


 
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February 09, 2018 
 
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Research (CCIR). 
• Your primary care physician if a medical condition that needs urgent attention is discovered. 
• Hospital or University representatives to complete Hospital or University responsibilities. 
• Information about your participation in this study may be documented in your health care records 
and be available to your health care providers who are not part of the research team.  
• The last four digits of your social security number may be used in hospital or University systems to 
track billing information for research procedures 
• Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The Institutional 
Review Board has reviewed and approved this study. 
• A data safety monitoring board. 
  
To help protect your confidentiality, we will enroll you in the study in a private setting.  You will be able 
to ask questions of the study team member in a private setting. 
 
Interventions will generally occur with only you and research study team members in the room. Some 
research rooms are semi-private, but curtains may be pulled to provide the privacy necessary for you to 
have their blood pressure checked, have an IV placed, or to have blood drawn in a manner respecting 
your privacy. 
 
The information collected during the study is necessary to make sure you qualify for the study and so we 
can answer the scientific questions being posed. We will ask your permission to access your personal 
medical records.  If you do not agree, you will not be enrolled in the study. Your PHI will not be made 
available to anyone outside the study team.  All data collected will be stored on password-protected 
computers in locked rooms.  You will be assigned unique identifiers that will be used to label blood 
tubes, other study samples, and study data.  The key to the identifiers will only be available to the 
members of the study team and will be under double-lock.   
 
All hardcopy charts will be stored in a locked cabinet in a locked room. Any report or article that we 
write will not include information that can directly identify you.  The journals that publish these reports 
or articles require that we share your information that was collected for this study with others. Sharing 
this information will allow others to make sure the results of this study are correct and help develop new 
ideas for research. Your information will be shared in a way that cannot directly identify you. 
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. 
 
Are there additional protections for my health information? 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?” 
 


 
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Page 8 of 11 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   
 
The research team will only use and share your information as talked about in this form or as permitted 
or required by law.  When possible, the research team will make sure information cannot be linked to 
you (de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact the University’s Privacy Officer at 866-747-4975. 
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
• your treatment or the care given by your health provider. 
• your insurance payment or enrollment in any health plans.   
• any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
• You authorize the use of your PHI for this research 
• This authorization does not expire. 
• You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
• To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
http://hrpo.wustl.edu/participants//withdrawing-from-a-study/ or you may request that the 
investigator send you a copy of the letter.    
 
 
 
o If you revoke your authorization: 
▪ The research team may only use and share information already collected for 
the study. 
▪ Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons. 
▪ You will not be allowed to continue to participate in the study. 
 
 
Can we contact you by email? 
We would like to contact you by email for the purposes listed below.  Some of these emails may contain 
health information that identifies you. 
• We may contact you to schedule your study visits or to send reminders of study visits. 
 
Only the research team will have access to your email communications.  We will only communicate by 
email to send you the information listed above.  If you have any questions or need to contact us for an 
urgent or emergent situation, please contact the research team member identified at the top of this 
document. 


 
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Page 9 of 11 
 
You should be aware that there are risks associated with sending your health information via email.   
• There is always a risk that the message could be intercepted or sent to the wrong email 
address.  To avoid sending messages to the wrong email address, the first email we send you 
will be a test message to ensure we have the correct email address. 
• When using any computer you should be careful to protect your username and password.  
Make sure you log-out before getting up from the computer.   
• If you share a home computer with other family members, and do not want them to know you 
are participating in this study make sure you provide an email address that only you can 
access.  
• Your employer will have access to any email communications sent or received on any 
electronic devices used for work or through a work server. 
  
Do you agree to allow us to send your health information via email?   
 
_____ Yes  
_____ No 
Initials  
Initials 
 
 
IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time. Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed.   
 
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify.   
 
What if I decide to withdraw from the study? 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
http://hrpo.wustl.edu/participants/ under Withdrawing from a Research Study. 
 
Will I receive new information about the study while participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
Under certain circumstances, the investigator might decide to end your participation in this research 
study earlier than planned.  This might happen for no reason or because it would not be safe for you to 
continue, because your condition has become worse, because you are or became pregnant, or because 
funding for the research study has ended. 
 
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Dakkota Thies, research coordinator at 314-747-3839 or Linda Peterson, MD at 314-362-4577.   


 
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February 09, 2018 
 
Page 10 of 11 
If you experience a research-related injury, please contact: Dakkota Thies at 314-747-3839 or Linda 
Peterson, MD at 314-362-4577.  
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office at 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, 1-(800)-438-0445, or email hrpo@wustl.edu.   General information about being a research 
participant can be found on the Human Research Protection Office web site, http://hrpo.wustl.edu.  To 
offer input about your experiences as a research participant or to speak to someone other than the 
research staff, call the Human Research Protection Office at the number above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study. 
As a participant you have rights and responsibilities as described in this document and including: 
• To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
• To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
• To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
• To give the research team accurate and complete information. 
• To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
 
Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 09/26/18. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that he or she understands 
the risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed)