Ketones for Pulmonary Hypertension - Effects on Hemodynamics (KEPAH)

Ketone Administration in Patients With Pulmonary Hypertension - Effects on Hemodynamics

In the present study, patients with idiopathic pulmonary hypertension (IPAH) and chronic thromboembolic pulmonary hypertenion will be investigated in a randomized cross-over design with ketone infusions and placebo. Invasive and non-invasive hemodynamics will be evaluated

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension; Ketonemia
• Intervention / Treatment: Dietary supplement: Hyperketonemia - use of ketone (3-OHB) infusion; Dietary supplement: Placebo - use of saline infusion

Detailed Description

Pulmonary hypertension (PH) is a debilitating disease that affects both the pulmonary vasculature and the heart. It is associated with increased mortality and hospitalization and impairs daily life for the affected patients. Despite substantial advances in treatment within the past decade the prognosis remains poor with an 1-year mortality of more than 10%.1 The pathophysiology of PH is multifactorial and can be caused by left sided cardiac disease, pulmonary pathophysiological changes in the pulmonary vessels, respiratory diseases and pulmonary embolism.The treatment is targeted at the underlying cause. Hence, left sided heart disease is treated with anticongestive medications4 and respiratory disease by pulmonary medications. However, pulmonary vascular diseases such as chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (IPAH) are treated with pulmonary endarterectomy and vasodilators targeting the pulmonary vasculature, respectively. However, not all patients have an optimal pulmonary hemodynamic response on treatment. If patients are left with persistent pulmonary hypertension the disease may progress further and cause right heart failure which worsens the prognosis.

Data from a recent study conducted at the investigator's institution demonstrated 40% increase in cardiac output during infusion of the ketone body 3-hydroxybutyrate (3-OHB). Intriguingly, this was associated with an increase in RV function and a decrease in the pulmonary vascular resistance of approximately 20%.

In the present study, 10 patients with IPAH and 10 patients with CETPH will be subjected to placebo and 3-OHB infusion in a randomized cross-over design. Each of the infusions will be given for 2.5 hours and cross-over will be carried out on the same day. Echocardiography and right sided heart catheterization will be applied and blood will be sampled.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Region Midjylland
    • Aarhus, Region Midjylland, Denmark, 8200
      • Dept. of cardiology, Aarhus University hospital Skejby,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Persistent pulmonary hypertension (defined as PVR > 3 WU, pulmonary capillary wedge pressure (PCWP) < 15 mmHG, mean pulmonary arterial pressure (mPAP) ≥25 mmHg) on the most resent right heart catheterization.
• Preserved left ventricular ejection fraction (<50%) on most recent echocardiography
• Able to give informed consent

Exclusion Criteria:

• Other Significant pulmonary, mitral or aortic valve disease
• Other disease or treatment making subject unsuitable for study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 3-OHB vs Saline; 3-OHB will be infused for 2.5 hours in IPAH (n=5) and CETPH (n=5) patients- 6 in each group is recruited for taking drop-out into account	Dietary supplement: Hyperketonemia - use of ketone (3-OHB) infusion; The effect of intravenous ketone supplement; Dietary supplement: Placebo - use of saline infusion; Saline is infused as an comparator
Experimental: Saline vs 3-OHB; Saline will be infused for 2.5 hours in IPAH (n=5) and CETPH (n=5) patients- 6 in each group is recruited for taking drop-out into account	Dietary supplement: Hyperketonemia - use of ketone (3-OHB) infusion; The effect of intravenous ketone supplement; Dietary supplement: Placebo - use of saline infusion; Saline is infused as an comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac output (L/min	Measured by Swan-Ganz monitoring	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mixed venous saturation (%)	Hemodynamics - Swan Ganz monitoring	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
systemic blood pressure (mmHg)	Hemodynamics - non-invasive blood pressure measurement	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
pulmonary capillary pressure (mmHg)	Hemodynamics - Swan Ganz monitoring	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
Pulmonary pressure (mmHg)	Hemodynamics - Swan Ganz monitoring	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
TAPSE (mm)	Echocardiography	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
RV strain (%)	Echocardiography	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
LV strain (%)	Echocardiography	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
systolic tricuspid plane velocity (cm/sec)	Echocardiography	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
Left ventricular ejection fraction (%)	Echocardiography	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
Changes in Prostaglandines (pmol/L)	Blood samples	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
pH	Blood samples	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
sodium (mM)	Blood samples	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
potassium (mM)	Blood samples	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion
lactate (mM)	Blood samples	changes during the infusion for 2.5 hours compared to 2.5 hours of Saline infusion

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Danish Heart Foundation
• Investigators: Principal Investigator: Roni R Nielsen, MD PhD, Dept. of Cardiology, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2020
• Primary Completion (Actual): May 1, 2021
• Study Completion (Actual): November 29, 2021

Study Registration Dates

• First Submitted: August 10, 2020
• First Submitted That Met QC Criteria: November 3, 2020
• First Posted (Actual): November 4, 2020

Study Record Updates

• Last Update Posted (Actual): December 2, 2021
• Last Update Submitted That Met QC Criteria: December 1, 2021
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Echocardiography; Hemodynamics; Right sided heart catheterization
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Respiratory Tract Diseases; Lung Diseases; Acid-Base Imbalance; Acidosis; Hypertension; Hypertension, Pulmonary; Ketosis
• Other Study ID Numbers: 1-10-72-232-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No