Oxford - Fibrates in Aortic Stenosis

NCT05256758 | Unknown DMC

• 1 other identifier: OxFAST
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 1

Brief Summary

Aortic stenosis (AS) is characterised by left ventricular (LV) hypertrophy and altered myocardial substrate metabolism. Peroxisome proliferator-activated receptor (PPARα), a regulator of lipid metabolism is deactivated in pressure overload hypertrophy such as in AS and can lead to dysregulation of fatty acid oxidation, myocardial triglyceride accumulation (steatosis) and lipotoxicity. The investigators propose a proof-of-concept study to investigate the effect of altering myocardial triglyceride (MTG) using a PPARα agonist, fenofibrate on cardiac physiology in patients with asymptomatic moderate-severe AS. The primary endpoint is a change in MTG assessed by magnetic resonance spectroscopy at baseline and after 6 months of treatment. Exploratory endpoints are changes in cardiac physiology including myocardial deformation (strain) as assessed by cardiac magnetic resonance imaging. The investigators hypothesise that pharmacological reduction of MTG with a PPARα agonist will result in steatosis regression and changes in cardiac physiology.

Conditions

Aortic Valve Stenosis

Outcome Measures

Primary Outcomes (1)

• Change in myocardial triglyceride (MTG) content as assessed by cardiac magnetic resonance (CMR) spectroscopy

  All participants will undergo blood tests (full blood count, renal and liver function, lipid profile, free fatty acids and NT- proBNP), CMR cine imaging for assessment of cardiac volumes, function including strain (myocardial tagging), aortic valve imaging and late gadolinium enhancement will be undertaken. MTG will be assessed using cardiac 1H-MRS (proton spectroscopy), which utilises the abundant hydrogen (1H) protons. For 1H-MRS, data are typically acquired at breath hold during diastole from a single voxel (14-16mL) localised in the myocardial septum and take 10-15 minutes to acquire. Myocardial lipid content is calculated as myocardial lipid/water ratio and expressed as percentage. It is hypothesised that Fenofibrate, PPAR alpha agonist will shift the cardiac metabolism back to mainly using free fatty acids and hence the investigators may see a reduction in myocardial lipid content.

  6 months

Secondary Outcomes (2)

• Change in myocardial energetics (PCr/ATP ratio) as assessed by Phosphorous magnetic resonance spectroscopy

  6 months

• Change in left ventricular function measured using CMR imaging

  6 months

Study Arms (2)

OxFAST Fibrate group

EXPERIMENTAL

49 patients randomised to receive fenofibrate 200mg capsules.

Drug: Fenofibrate Capsules

OxFAST placebo group

PLACEBO COMPARATOR

13 patients randomised to receive placebo will act as controls.

Drug: Placental Lactogen

Interventions

Fenofibrate Capsules DRUG

49 patients randomised to receive fenofibrate for 6 months.

Also known as: Fenofibrate

OxFAST Fibrate group

Placental Lactogen DRUG

13 patients randomised to receive placebo for 6 months.

OxFAST placebo group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Asymptomatic moderate to severe AS (with at least two of the following: aortic valve area \<1.5 cm2, peak pressure gradient \>36 mmHg or mean pressure gradient \>25 mmHg)
• Not planned aortic valve replacement or transcatheter aortic valve implantation (TAVI)
• Age \>18
• No other significant valvular pathology
• No contraindication to magnetic resonance imaging.

You may not qualify if:

• Known coronary artery disease, history of angina, myocardial infarction or presence of regional wall motion abnormalities
• Other underlying cardiomyopathy
• Left ventricular ejection fraction\<50%
• Uncontrolled hypertension
• Diabetes Mellitus
• Liver impairment
• Pregnancy and lactation
• Body mass index \>35 kg/m2
• Renal impairment (eGFR\<30 ml/min)
• Intolerance to or concurrent use of fibrates or PPARα agonists.

Sponsors & Collaborators

• University of Oxford: lead
• British Heart Foundation: collaborator

Study Sites (1)

OUH NHS trust

Oxford, OX3 9DU, United Kingdom

Location

MeSH Terms

Conditions

Aortic Valve Stenosis

Interventions

Fenofibrate; Placental Lactogen

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction

Intervention Hierarchy (Ancestors)

Fibric Acids; Isobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Phenyl Ethers; Ethers; Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols; Ketones; Placental Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Pregnancy Proteins; Proteins

Study Officials

• Mahmod

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Randomised double-blind placebo controlled study
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised double-blind placebo controlled study

Study Record Dates

• First Submitted: January 20, 2022
• First Posted: February 25, 2022
• Study Start: May 29, 2019
• Primary Completion: March 31, 2022
• Study Completion: March 31, 2022
• Last Updated: February 25, 2022

Record last verified: 2022-01

Locations

GB (1)