Trial Outcomes & Findings for Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1 (NCT NCT03560323)

Last Updated: 2025-09-29

Results Overview

Within 2 weeks after the screening visit, subjects return to the Research Institute (RII) at 7:00AM for a cardiac MRI on 3.0T MRI System (TIM, Trio, Siemens Medical Solution, Malvern, PA). Cardiac output (CO) is measured using velocity encoded phase contrast MRI. The patient lies in the MRI scanner, and the imaging plane is positioned perpendicular to the ascending aorta where blood flow can be measured accurately. The MRI scan is synchronized with the patient's heartbeats using ECG gating. Two types of images are collected: magnitude images, which provide anatomical reference, phase images, which encode the speed and direction of blood flow. The system multiplies velocity by the cross-sectional area of the vessel to calculate the volume of blood passing through the vessel at each moment. Integrating the flow values over the entire cardiac cycle, the system calculates the stroke volume. Cardiac Output = Stroke Volume × Heart Rate

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

41 participants

Primary outcome timeframe

Baseline at 0 minute before B-OH-B infusion and 360 minutes after B-OH-B infusion for Group I & II. For Group III was baseline at 0 minute and 180 minutes after infusion

Results posted on

2025-09-29

Participant Flow

Participant milestones

Participant milestones
Measure	Group I Beta-Hydroxy-Butyrate Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end Beta-hydroxy-butyrate: Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end	Group II Beta-Hydroxy-Butyrate Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end Beta-hydroxy-butyrate: Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end	Group III Beta-Hydroxy-Butyrate Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end Beta-hydroxy-butyrate: Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end
Overall Study STARTED	13	14	13
Overall Study COMPLETED	12	12	12
Overall Study NOT COMPLETED	1	2	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group I Beta-Hydroxy-Butyrate n=13 Participants Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end Beta-hydroxy-butyrate: Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end	Group II Beta-Hydroxy-Butyrate n=14 Participants Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end Beta-hydroxy-butyrate: Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end	Group III Beta-Hydroxy-Butyrate n=13 Participants Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end Beta-hydroxy-butyrate: Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end	Total n=40 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	12 Participants n=5 Participants	11 Participants n=7 Participants	12 Participants n=5 Participants	35 Participants n=4 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Age, Continuous	57 years STANDARD_DEVIATION 2 • n=5 Participants	60 years STANDARD_DEVIATION 2 • n=7 Participants	57 years STANDARD_DEVIATION 3 • n=5 Participants	58 years STANDARD_DEVIATION 2 • n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	8 Participants n=4 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	11 Participants n=7 Participants	9 Participants n=5 Participants	32 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants n=5 Participants	10 Participants n=7 Participants	8 Participants n=5 Participants	28 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	12 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) White	13 Participants n=5 Participants	13 Participants n=7 Participants	10 Participants n=5 Participants	36 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	13 Participants n=5 Participants	14 Participants n=7 Participants	13 Participants n=5 Participants	40 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline at 0 minute before B-OH-B infusion and 360 minutes after B-OH-B infusion for Group I & II. For Group III was baseline at 0 minute and 180 minutes after infusion

Population: Patients with diabetes who met entry criteria were randomized (1:1:1 ratio) to receive one of three different infusion rates of b-OH-B ((prime dose was 0.4 mg/kg/min for 20 min followed by constant rate of infusion 0.2 mg/kg/min until study end). Group I and Group II received a 6-h b-OH-B infusion. Group III received a 3-h b-OH-B infusion

Outcome measures

Outcome measures
Measure	Group I Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end	Group II Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end	Group III Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end
Cardiac Output (CO) Baseline:before Beta-H-B infusion infusion	5.02 mL/min Standard Deviation 0.38	4.54 mL/min Standard Deviation 0.28	5.93 mL/min Standard Deviation 0.36
Cardiac Output (CO) After Beta-H-B infusion infusion	5.10 mL/min Standard Deviation 0.41	5.3 mL/min Standard Deviation 0.22	7.16 mL/min Standard Deviation 0.44

PRIMARY outcome

Timeframe: Baseline at 0 minute before infusion and 360 minutes after infusion for Group I & II. Group III was baseline at 0 minute of infusion and 180 minutes after infusion

Population: Below showed the difference before and after infusion. Patients were randomized (1:1:1 ratio) to receive one of three different infusion rates of b-OH-B ((prime dose was 0.4 mg/kg/min for 20 min followed by constant rate of infusion 0.2 mg/kg/min until study end). Group I and Group II received a 6-h b-OH-B infusion. Group III received a 3-h b-OH-B infusion

A measurement, expressed as a percentage, of how much blood the left ventricle pumps out with each heartbeat. It's a key indicator of heart function and can help diagnose and track heart failure. A normal EF typically falls between 55% and 70%. Values below 40% are often considered indicative of heart failure.

Outcome measures

Outcome measures
Measure	Group I Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end	Group II Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end	Group III Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end
Ejection Fraction (EF)	0.1 percentage(%) Standard Deviation 1.2	3.9 percentage(%) Standard Deviation 3.5	6.4 percentage(%) Standard Deviation 4.5

PRIMARY outcome

Timeframe: Baseline at 0 minute before infusion and 360 minutes after infusion for Group I & II. Group III was baseline at 0 minute of infusion and 180 minutes after infusion

Represents the amount of blood ejected from the heart's left ventricle with each heartbeat. It's a crucial indicator of cardiac function, reflecting how effectively the heart pumps blood to the body.

Outcome measures

Outcome measures
Measure	Group I Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end	Group II Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end	Group III Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end
Left Ventricular Stroke Volume (LVSV)	0.3 mL/m² Standard Error 1.3	9.7 mL/m² Standard Error 6.4	19.4 mL/m² Standard Error 6.0

SECONDARY outcome

Timeframe: MGU after B-OH-B or NaHCO3 infusion for 6 hours at minute 360 minutes

Population: Only participants in group II (12 subjects) underwent the cardiac PET with B-OH-B and NaHCO3 infusion , not in groups I and III

A sub-set of participants in group II also underwent a cardiac PET study to examine the effect of hyperketonemia on Myocardial Glucose Uptake (MGU) and Myocardial Blood Flow MBF). A 20-min transmission scan was performed after exposure to a retractable 68Ge ring source to correct emission data for tissue attenuation of g photons. Then, 15O-H2O (10.5 MBq/kg) was administered intravenously through the antecubital vein catheter over 20 s, and a PET scan was performed to measure MBF. Participants underwent a 6-h b-OH-B infusion (prime dose was 1.5 mg/kg/min for 20 min followed by constant rate of 0.75 mg/kg/min) or 6-h NaHCO3 infusion. At 280 min after the start of b-OH-B or NaHCO3 in- fusions, 15O-H2O was injected for repeated measurement of MBF. At 300 min, 18F-FDG ) was injected, followed by a dynamic PET scan for the measurement of MGU.

Outcome measures

Outcome measures
Measure	Group I Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end	Group II Beta-Hydroxy-Butyrate Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end	Group III Beta-Hydroxy-Butyrate Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end
Myocardial Energetics-Myocardial Glucose Uptake (MGU) Beta -H-B infusion	9.6 µmol/ (min x 100 g) Standard Deviation 1.01	—	—
Myocardial Energetics-Myocardial Glucose Uptake (MGU) NaHCO3 infusion	8.56 µmol/ (min x 100 g) Standard Deviation 0.74	—	—

SECONDARY outcome

Timeframe: MBF after B-OH-B or NaHCO3 infusion for 6 hours at 360 minutes (the results showed the difference betweenB-OH-B and NaHCO3 infusion for 6 hours)

Population: Only participants in group II (12 subjects) underwent the cardiac PET with B-OH-B and NaHCO3 infusion , not in groups I and III

Outcome measures

Outcome measures
Measure	Group I Beta-Hydroxy-Butyrate Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end	Group II Beta-Hydroxy-Butyrate n=12 Participants Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end	Group III Beta-Hydroxy-Butyrate Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end
Myocardial Energetics- Myocardic Blood Flow (MBF)	—	0.05 ml/min Standard Error 0.10	—

Adverse Events

Group I Beta-Hydroxy-Butyrate

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Group II Beta-Hydroxy-Butyrate

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Group III Beta-Hydroxy-Butyrate

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Yuejuan Qin, Assistant Professor

University of Texas Health -San Antonio

Phone: 210-358-7200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place