Ketone Pharmacokinetic Study in Heart Failure With Reduced Ejection Fraction
Phase: PHASE1
Conditions: Heart Failure With Reduced Ejection Fraction
Sponsor: Duke University

Version Date: 7.24.23, version 1.8 
 
 
 
 
 
 
 
 
 
 
Ketone pharmacokinetic study in HFrEF 
 
 
Senthil Selvaraj, MD, MS, MA 
Duke University School of Medicine 
NCT05757193 
 
 

Ketone Ester in Heart Failure 
 
Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
2 
 
1 
CLINICAL SIGNIFICANCE 
Despite advances in the treatment of patients with heart failure (HF), there remains substantial residual 
morbidity and mortality. Even with insights into diverse mechanisms of myocardial dysfunction, virtually all 
current medical treatment is focused on modulating the “neurohormonal axis”. Our project extends these 
principles to an emerging frontier, the ketone “metabolic axis”, as a means of ameliorating symptoms through 
exogenous delivery of a ketone ester. In this pharmacokinetic study, we first seek to find the optimal dose of a 
ketone ester product. We will subsequently use this information to inform dosing for a randomized trial of 
ketone therapy in HF.  
 
2 
SPECIFIC AIMS  
HF is a major public health problem: it affects 6.2 million people in the U.S.1 The lifetime risk for developing HF 
after the age of 40 years approaches 20%,2 and five-year survival after HF hospitalization is a dismal 35%.3 
These statistics highlight the urgent need to identify novel therapies to reduce the substantial morbidity and 
mortality of the disease process. Current HF therapies focus on ameliorating pathophysiologic adaptations, 
including antagonism of the activated renin-angiotensin-aldosterone and sympathetic nervous systems, 
reducing excess vasoconstriction, and mitigating fluid retention. At its most basic level, however, HF is a 
metabolic imbalance - an inability of the heart to generate sufficient energy to adequately supply blood to the 
body, or only to do so at elevated filling pressures. The heart is a very metabolically demanding organ, which 
requires nearly 12 times its own body weight in ATP daily.4 Abnormal myocardial energetics have been 
described in both HFrEF.5 Targeting the metabolic axis in HF therefore may hold great therapeutic promise.  
 
Under physiologic conditions, fatty acids are the predominant energetic substrate for the heart, providing 50-
70% of the ATP need. Glucose serves as a secondary source, necessary for flexibility and adaptive fuel 
utilization shifts during embryologic development and during a diverse array of nutritional and physiologic 
conditions.6, 7 However, two important studies lead by our team have demonstrated that free fatty acid 
oxidation is impaired in advanced HF due to mitochondrial substrate reprogramming, and the hypertrophied 
and failing heart utilizes ketone bodies as a metabolic substrate, in both animals and humans.4, 8 It was 
previously unknown whether this shift was adaptive or maladaptive, but recent small and large animal data 
demonstrates that ketone body oxidation is an adaptive feature of the failing heart. Importantly, delivery of 
exogenous ketones improves pathologic cardiac remodeling and dysfunction while enhancing mitochondrial 
bioenergetics.7  
 
We now have a unique opportunity to study a ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate 
(commercially known as “DeltaG”), that provides systemic ketosis in a deep phenotyping study of HF patients.9 
Initial studies of DeltaG demonstrated significant improvement in exercise capacity among endurance 
athletes.10 In this first study, we attempt to find the optimal dose of the ketone product. As patients may be 
taking minimally ketogenic medications (SGLT2 inhibitors), we will study the pharmacokinetic effects of ketone 
ester with patients on, and not on, these medications.  
 
Our Specific Aims are as follows: 
 
Aim 1. To assess the pharmacokinetics and safety of ketone ester in patients on, and not on, SGLT2 
inhibitors. We will perform serial peripheral blood sampling to understand the effects of acute ketone ester on 
pH, glucose, systolic blood pressure, and ketone levels to find an optimal dose of the product. 

Ketone Ester in Heart Failure 
 
Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
3 
 
Aim 2. To assess the effects of KE on metabolomics, proteomics, and systemic biomarkers (pending 
sufficient funding). 
 
 
3 
BACKGROUND AND SIGNIFICANCE 
HF affects 6.2 million Americans and is associated with substantial morbidity and mortality in the contemporary 
era.1 By 2030, the burden of HF is anticipated to surpass 8 million with an associated economic toll of a 
staggering $69.8 billion.1 The cardinal clinical feature of patients with HF is reduced exercise capacity, which is 
associated with a substantial reduction in quality of life.11 Despite significant advancements in therapy for 
patients with HF, particularly among those with reduced ejection fraction (EF), many still suffer from limitations 
in exercise capacity and a poor prognosis. As such, exploring other avenues to reduce morbidity from HF is of 
vital interest from societal, economic, clinical, and patient-centered perspectives.  
Recently, several alterations in the cardiac metabolism of patients with HF have been described, setting the 
stage for randomized trials of novel therapies that modulate energy fuel metabolism.4, 7, 8 Among healthy 
individuals, the heart, a very metabolically active organ, uses a combination of free fatty acids and glucose (to 
a lesser extent) as the primary sources of adenosine triphosphate (ATP) production. However, free fatty acid 
oxidation is impaired in the failing heart, and the heart increases its use of ketone bodies for fuel.7  
Ketone bodies (acetoacetate, β-hydroxybutyrate [BHB], and acetone) are water-soluble molecules produced 
from acetyl-CoA following breakdown of fatty acids (and amino acids) mainly in hepatic cells. Ketone bodies 
are typically absent from the circulation during the normal fed state, but are produced continuously during 
metabolic stress conditions and/or periods of carbohydrate deprivation such as acute medical stress, 
prolonged exercise, or starvation, and become a key source of energy to vital organs including the brain and 
heart under these circumstances.12 Ketone production has long been teleologically considered as a means to 
provide the brain with an efficient, alternative fuel source during starvation, sparing carbohydrate and protein 
stores, since the brain cannot effectively metabolize free fatty acids (which represent 99% of the body’s energy 
stores).12, 13 When completely oxidized in the citric acid cycle, ketones have a respiratory quotient similar to 
glucose (acetoacetate = 1.0, BHB = 0.89) and produce greater amounts of ATP, releasing approximately 30% 
more energy per molecule than pyruvate.14, 15 The liver produces ketone bodies from mobilized fat stores that 
then can be utilized by neural tissue to produce ATP. It is therefore not surprising that several neurologic 
diseases have been treated, or are under study, with ketone therapy, such as epilepsy, Parkinson’s disease, 
and Alzheimer’s disease.16  
Macronutrient resources (low glucose, high free fatty acids) and hormonal signaling (low insulin, high glucagon, 
high cortisol) are the primary methods of regulating ketone production, and thus dietary modification has been 
studied extensively to treat these conditions (the “ketogenic diet”). Adherence to this diet, however, can be 
challenging, and may also be accompanied by dyslipidemia (due to increased flux of free fatty acids), impaired 
cardiac metabolism, or gastro-intestinal upset, leading to interest in alternative exogenous modes of delivery.17, 
18 Exogenous delivery of ketones holds several advantages over dietary modification such as increased 
compliance, lack of alteration on other fuel stores (such as intramuscular glycogen), and its unique effect of 
lowering both glucose and free fatty acids due to negative feedback on lipolysis.19  
Different formulations of oral ketone therapy have been studied, including ketone salts and KE. Oral ketone 
salts result in a high amount of salt intake (which may be problematic for patients with HF) and results in half 
the plasma concentration of D-betahydroxybutyrate (D-BHB).17 A novel KE compound, I-3-hydroxybutI(R)-3-
hydroxybutyrate (DeltaG), has been extensively studied for the purposes of therapeutic exogenous ketosis and 
is approved as a nutraceutical by the Food and Drug Administration (FDA).9, 10, 17, 20-23 Advantages of DeltaG 
consumption include a rapid rise of blood levels of BHB in humans to ~3 mmol/L within 60 minutes of 
consumption with moderate doses of KE, equivalent to a week of fasting, which is markedly increased from the 
levels of detectable ketones in normal populations (<0.5 mmol/L).9, 17, 21 By way of comparison, a carbohydrate-

Ketone Ester in Heart Failure 
 
Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
4 
 
restricted (high-fat) diet typically results in mild hyperketonemia, with BHB levels of  0.5 mmol/L, which is 
currently considered as an accepted definition of ketosis.24  
 
Benefits of KE therapy among athletes have already been demonstrated. In a blinded, crossover study of 
endurance athletes, DeltaG increased exercise distance by an average of 411 meters over 30 minutes cycling 
duration, demonstrating that ketone therapy improves exercise capacity among highly trained athletes.10 
Importantly, it has been suggested that pathologic conditions that cause metabolic dysregulation, and where 
incremental improvements in energy transduction may translate to significant increases in exercise capacity, 
may afford the greatest clinical benefit, such as in HF.10  
 
Further data has emerged regarding potential benefits of intravenous infusions of sodium-3-hydroxybutyrate.25 
In a crossover study of 16 patients with HF and reduced EF (HFrEF) randomized to 6 hours of ketone infusion 
vs. isotonic saline (placebo arm), infusion of the ketone increased cardiac output by 2 L/min with an absolute 
improvement in left ventricular EF of 8%. Notably, the hemodynamic effects of ketones were dose-dependent 
and detectable even in the physiological concentration range. While important, this trial was limited by use of 
an intravenous infusion (impractical for the outpatient management) and concerns related to salt infusion, such 
as pH disturbances and sodium loading. In addition, this trial did not assess patient-centered metrics, such as 
exercise capacity, which is an important determinant of quality of life in HF.26 However, the fact that 
intravenous ketone therapy increased cardiac output to this extent supports the hypothesis that there is a 
fundamental limitation of fuel utilization in HF that can be therapeutically targeted. In addition, recent data 
shows important improvements in cardiac output and function without significant safety concerns in patients 
with cardiogenic shock at 500 mg/kg of the KE.27 
 
In this first study, we seek to determine whether the optimal dose of a liquid ketone ester drink in patients on, 
and not on, SGLT2 inhibitors.  
 
4 
Published Data on Ketone Ester 
DeltaG is a ketone ester (KE) that undergoes complete enzymatic hydrolysis to form BHB (and R-1,3-
butanediol) by carboxylesterases expressed widely, including within the gastrointestinal tract, liver, and blood. 
R-1,3-butanediol, itself, is further metabolized in the liver by first-pass metabolism and blood to produce BHB 
by alcohol dehydrogenase and aldehydye dehydrogenase. BHB undergoes further metabolism to acetoacetate 
and acetone, though only BHB and acetoacetate are taken up by extra hepatic tissues as energy sources.  
 
KE is eliminated through at least first order kinetics and capacity limited elimination. Elimination is 
accomplished via 3 predominant means, including (1) conversion to acetone and lung exhalation, (2) renal 
elimination (of BHB and acetoacetate, though this contribution is negligible particularly during exercise), and 
(3) uptake by tissues using monocarboxylate transporters for conversion to ATP.10, 21  
 
Concentrations of the KE compound of roughly 3-5 mmol/L are reached within 60 minutes at doses 
comparable to what is studied here.9, 10 The half-life of the compound is 0.8-3.1 hours.9 The KE compound has 
a very favorable safety profile with adverse effects limited to dose-dependent, gastrointestinal distress that 
typically occur only at the highest levels of administration (714 mg/kg).9, 28  
 

Ketone Ester in Heart Failure 
 
Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
5 
 
Request for IND exemption: We believe this study qualifies under the criteria for IND exemption. DeltaG has 
been granted GRAS status through the FDA as a food, and the GRAS documentation will be separately 
submitted. We believe this study is exempt from the IND requirements because it meets the conditions of FDA 
guidance (sections VI.D.1 & VI.D.2). Specifically, DeltaG, as used in this study, is not intended for use “in the 
diagnosis, cure, mitigation, treatment, or prevention of disease”. As DeltaG is only received on one study date 
as an acute study, and endpoints assessed here are for safety, we believe the use of DeltaG fulfills these 
critiera here. Participants will be notified in the ICF specifically that they will not benefit as a result of 
participating in the study. The intent of the study is to describe the acute effect of DeltaG (a food) on venous 
pH, glucose, and blood pressure as a safety mechanism. In addition, the results of this study are not intended 
to affect the marketing or labeling of DeltaG. 
We have previously performed research with this compound at another institution in patients with heart failure, 
who have given IND exemption for the use of ketone ester. This letter has also been submitted. 
 
5 
Research Design and Methods 
Overview: We first begin with a pharmacokinetic study to establish dosing among 20 HF participants.  
 
5.1 
Study population  
Study population (Inclusion criteria) 
Participants aged at least 18 years of age with a diagnosis of HFrEF and with systolic blood pressure >90 
mmHg will be included for this study. We will recruit 20 HFrEF (LVEF <=45%) participants. Participants will be 
stratified by use of prescribed SGLT2i (taken as part of their clinical care and not provided through this 
research study). Participants will be recruited from within the Duke Health System.  
 
 
Exclusion Criteria  
1. Intentional ketogenic (high fat, low carbohydrate) diet (must be off ketogenic diet for >7 days prior to 
visit) 
2. Significant liver disease (cirrhosis) or alcohol abuse disorder (>14 drinks/week)  
3. Unique cardiomyopathies: infiltrative/hypertrophic cardiomyopathy, pericardial disease, or other 
unique cardiomyopathies that in the opinion of the investigator would be less likely to respond to 
ketone therapy 
4. Estimated glomerular filtration rate<25 mL/min/1.73 m2 as the most recent value in the last year. 
5. Type 1 diabetes mellitus  
6. Use of ventricular assist device, history of heart transplant, or use of continuous inotropes 
7. Pregnant women. Due to unknown affects of nutritional ketosis in pregnant women, pregnancy will 
be an exclusion.  Accordingly, women of childbearing age with a menstrual cycle within the past year 
will be asked to submit a urine specimen for pregnancy testing. 
 
5.2 
Participant clinical data collection 
We will assess the following clinical data parameters on study intake, which may include but are not limited to:  
1. Age, date of birth, gender, race   
2. New York Heart Association class 
3. Smoking status, alcohol status. 
4. Comorbidities (supplemented by chart view of the problem list): previous HF hospitalization in last 6 
months, myocardial infarction, stroke, coronary artery bypass graft surgery, percutaneous coronary 
intervention, chronic obstructive pulmonary disorder, asthma, hypertension, peripheral artery disease, 

Ketone Ester in Heart Failure 
 
Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
6 
 
atrial fibrillation or flutter, dyslipidemia, implanted cardioverter-defibrillator, pacemaker, and diabetes 
mellitus, and others. 
5. Vital signs: height, weight, heart rate, systolic blood pressure, diastolic blood pressure, oxygen 
saturation, and others 
6. Medications will be obtained from the medical chart and confirmed with the participant.  
 
 
5.3 
Pharmacokinetic study:  
SGLT2i are standard-of-care ketogenic medications in HFrEF that minimally raise ketone levels though 
still well within normal limits (0.10mM to 0.13mM, normal <~0.5mM) through reducing insulin:glucagon 
ratio.29, 30 Since exogenous ketones increase this ratio as shown in our previous work31 and reduce 
endogenous ketosis, the combination of exogenous ketones and SGLT2i is not expected to perpetuate 
ketoacidosis risk by SGLT2i (which has not been a significant concern in clinical trials of HFrEF).32 
Further, recent work has supported the safety of ketogenic interventions in patients taking SGLT2 
inhibitors.33 Additionally, pH changes with robust ketosis by KE are noted (1 study showed a pH 
decrease of 0.10 to an arterial pH of 7.31 after the ketone drink as an expected change).17 
Nevertheless, we will first perform a dose-finding study in 10 HFrEF participants on SGLT2i and 10 not 
on SGLT2i to assess safety (Table 1). We will measure venous pH, glucose, blood pressure, and BHB 
every 60 minutes for 4 hours. After a standardized meal containing carbohydrate (to limit endogenous 
ketosis), we will assess 5 participants in each stratum using 250 mg/kg to initially target BHB levels ~1-
2 mmol/L, and then dose escalate to 500 mg/kg for 5 participants27 which is predicted to achieve BHB 
levels ~3 mmol/L (safely achieved in HF patients previously with KE34 without inducing significant side 
effects including mild acidosis).9, 28, 35, 36 This is also the dose used in a recent trial in cardiogenic shock 
without significant safety concerns but with significant efficacy.27 We will not escalate past 500 mg/kg 
given increasing risk for gastrointestinal symptoms.9, 37  
 
Table 1. Pharmacokinetic Study Details and Dose Escalation/De-escalation Plan 
Strata 
Dose 
Timepoints 
assessed 
Endpoints assessed  
SGLT2i arm 
and no SGLT2i 
arm 
250 mg/kg KE for 5 
participants, then 500 
mg/kg for 5 participants 
Every 60 minutes 
for 4 hours 
Venous pH, systolic blood 
pressure, glucose 
Food may be provided to participants if they have hypoglycemia (glucose <55 mg/dl) but otherwise we 
will ask participants to refrain from consuming food after the ketone drink is administered until the 4 
hour blood draw. 
 
Prior to the ketone drink, we will collect blood –twice - in the fasted status (>8 hours of fasting) and then 
after a light breakfast. We will collect blood 6 times after ketone drink. There will be at most 8 blood 
draws as below.  
Blood draw 
number 
Approximate time of blood 
draw 
Blood draw for endpoint 
assessment 
Blood draw for 
storage 
1 
Fasting, prior to ketone drink 
 
x 
2 
After light meal, prior to 
ketone drink 
 
x 
3 
30 minutes after ketone drink 
 
x 
4 
60 minutes after ketone drink 
x 
x 

Ketone Ester in Heart Failure 
 
Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
7 
 
5 
90 minutes after ketone drink 
 
x 
6 
120 minutes after ketone 
drink 
x 
x 
7 
180 minutes after ketone 
drink 
x 
x 
8 
240 minutes after ketone 
drink 
x 
x 
Timepoints delinated here are approximate. We aim to draw blood as close to the timeline outlined 
here, but +/- 15 minutes from the timepoint is considered acceptable without deviation. Likewise, lack of 
blood draws at times not used for endpoint assessment will not be considered a deviation. 
 
We preferentially enroll unique patients in this study (i.e. 20 different patients). However, in the event of 
difficult enrollment in the “no SGLT2i arm”, participants currently taking an SGLT2i may enroll and hold 
the SGLT2i for at least 4 days (with the permission of their treating physician). This amount of time is 
similar to what is advised prior to some procedures (i.e. surgery). Therefore, participants could enroll 
twice in this study (in each arm). 
 
A total of ~100 mL of blood will be obtained at this visit. 
Blood samples will be stored (either within the Duke Heart Center or the Duke Molecular Physiology Institute) 
at -80C for later analysis. We may perform routine blood testing (metabolic panels, blood counts), 
comprehensive metabolomic/proteomic profiling from this peripheral blood, as well as other biomarkers, in 
addition to other testing, pending sufficient funding.  
 
6 
Risks and Safety Assessment 
Ketone Ester: This proposal includes a ketone ester which is commercially available and has been granted 
“Generally Regarded as Safe” (GRAS) status from the FDA. This KE undergoes complete enzymatic 
hydrolysis to form BHB (and R-1,3-butanediol) by carboxylesterases expressed widely, including the 
gastrointestinal tract, liver and blood. R-1,3-butanediol, itself, is further metabolized in the liver and blood to 
produce BHB. The TMax ranges from ~1-3 hours. Elimination is accomplished via conversion to acetone and 
lung exhalation, renal elimination, and uptake by tissues using for conversion to ATP (including the brain, 
heart, kidney, and skeletal muscles).10, 21 We exclude participants both with a history of significant renal 
impairment (eGFR <25 ml/min/m2) or hepatic impairment (history of cirrhosis, alcohol abuse). Peak 
concentrations of KE are reached around 60 minutes at doses anticipated to be administered here.9, 10 The 
half-life of BHB from the compound is 0.8-3.1 hours.9 Adverse effects are infrequent and dose-dependent; 
gastrointestinal distress occurs at the highest levels of administration (714 mg/kg), consistent with our own 
experience.9, 28 No clinically significant changes in vital signs, lipid levels, blood counts, renal function, and 
urinalysis parameters were observed at doses similar to those studied here. Participants may be on SGLT2i 
which are minimally ketogenic medications in themselves with minimal risk for ketoacidosis in HF.32 As outlined 
in this section, it is not anticipated that the KE will amplify risk of ketoacidosis with SGLT2i given the differing 
biologies of endogenous versus exogenous ketosis. However, this potential risk will be outlined to participants 
who enroll in this study. Dose: In this proposal, we will perform a pharmacokinetic study to determine optimal 
dose without significant safety concerns which will be explored in our pharmacokinetic study.  Our product is 
purchased commercially as “DeltaG” (TdeltaS, Orlando, FL). We have administered these doses proposed 
here to 15 HFpEF patients in an ongoing study without significant adverse events related to the nutraceutical. 
We will monitor for any adverse events throughout the study visit. The compound half-life is short as indicated 
above. To aid intolerability, participants are served a light meal. In addition, water (which may be naturally 
flavored and/or carbonated) is freely permitted.  

Ketone Ester in Heart Failure 
 
Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
8 
 
 
Phlebotomy and blood draws: We leverage healthcare professionals who have experience in blood draws 
and maintaining venous catheters in our study. Risks from the peripheral (e.g. antecubital fossa) venous 
catheterization include minor discomfort, minor bruising, bleeding, hematoma and/or fainting associated with 
the drawing of blood. There is also a very small chance (less than 1%) of infection at the blood draw site. The 
amount of blood to be drawn during each study is modest (100 mL). 
 
7 
Statistical analysis plan 
Primary outcomes 
1. Venous pH at 1 hour 
2. Systolic blood pressure at 1 hour  
3. Glucose at 1 hour  
4. Beta-hydroxybutyrate level at 1 hour  
 
Participant characteristics will first be summarized using means (standard deviations), medians (interquartile 
range), and counts (percentages) as appropriate for the type of variable and its distribution. We will plot summary 
estimates of venous pH, glucose, ketone levels, and systolic blood pressure over time, overall and stratified by 
SGLT2i use and ketone ester dose. We will compare whether achieved venous pH, glucose, ketone levels, and 
systolic blood pressure vary by background SGLT2i use, accounting for related baseline measurements. Sensitivity 
analysis will adjust for age, sex, ketone ester dose, eGFR, and hemoglobin a1c (if available). Repeated measures 
techniques (accounting for clustering at the level of the participants) may be used to assess overall changes in pH, 
ketone levels, systolic blood pressure, and glucose. We will describe peak ketone concentrations achieved by arm. 
Similarly, we will assess the relationship between peak ketone levels (dependent variable) and dose of KE 
(independent variable). P<0.05 will be used to indicate statistical significance. 
 
 
  
 

Ketone Ester in Heart Failure 
 
Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
9 
 
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Senthil Selvaraj, MD 
 
 
 
Duke University 
 
 
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