Ketones for Pulmonary Hypertension - Effects on Hemodynamics

Phase 2

Completed

• Conditions: Ketonemia; Pulmonary Hypertension
• Interventions: Dietary Supplement: Hyperketonemia - use of ketone (3-OHB) infusion; Dietary Supplement: Placebo - use of saline infusion

• Registration Number: NCT04615754
• Lead Sponsor: University of Aarhus

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Status Verified: 2020-07
• Study First Submitted: 2020-08-10
• Study Start: 2020-08-18
• Study First Submitted QC: 2020-11-03
• Study First Posted: 2020-11-04
• Primary Completion: 2021-05-01
• Study Completion: 2021-11-29
• Last Update Submitted: 2021-12-01
• Last Update Posted: 2021-12-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

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

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Exclusion Criteria

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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
3-OHB vs Saline	Placebo - use of saline infusion	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
3-OHB vs Saline	Hyperketonemia - use of ketone (3-OHB) infusion	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
Saline vs 3-OHB	Hyperketonemia - use of ketone (3-OHB) infusion	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
Saline vs 3-OHB	Placebo - use of saline infusion	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

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Dept. of cardiology, Aarhus University hospital Skejby,; 🇩🇰 Aarhus, Region Midjylland, Denmark