The Effect of Inflammation in Heart Failure

June 23, 2022 updated by: National Heart, Lung, and Blood Institute (NHLBI)

Pilot Study to Evaluate the Effect of Inflammation in Heart Failure

Background:

Heart failure is a serious health condition. Researchers believe inflammation plays a role. They want to see if adding an additional heart drug to a person s treatment can help treat heart failure with preserved ejection fraction (HFpEF).

Objective:

To learn if chronic inflammation is high in heart failure and if taking dapagliflozin along with the standard of care medicines for 6 months will reduce inflammation and improve heart function in people with HFpEF.

Eligibility:

People aged 18 and older who have heart failure and qualify for dapagliflozin therapy. Healthy adult volunteers are also needed.

Design:

  • Participants will be screened with:

    • Medical history
    • Physical exam
    • Heart function tests
    • X-ray scans of the heart and blood vessels. They may receive medicines to slow their heart rate or make their heart blood vessels bigger. An intravenous (IV) catheter will be placed in their arm to inject contrast.
    • Blood and urine tests
  • Participants will have up to 3 study visits. Some screening tests will be repeated.

Participants will take one tablet of the study drug daily for 6 months.

-Participants will have an imaging scan of their heart and blood vessels. They will receive a contrast and stress medicine through an IV to view blood supply.

Participants will have a stress test that measures exercise ability. They will wear sticky pads on their chest, a blood pressure cuff, and a mask. They will also have a 6-Minute Walk Test.

Participants will complete questionnaires about their symptoms and their health.

Participants may be on the study for up to 6 months. They will have a follow-up phone call 1 month after treatment ends.

...

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Study Description:

Heart failure (HF) remains a significant public health burden. Unlike heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF) currently does not have any effective therapies, suggesting incomplete understanding of the underlying mechanisms of the syndrome. Chronic inflammation has been postulated to be one of the central mechanisms in HFpEF pathogenesis. In this pilot study to be conducted at the NIH Clinical Center, we propose to examine the role of the NLRP3 inflammasome- IL-1 pathway in HFpEF and evaluate whether treatment using the sodium glucose co-transport 2 (SGLT2) inhibitor dapagliflozin can attenuate NLRP3 inflammasome activation.

Objectives:

  • To test the hypothesis that macrophage NLRP3 inflammasomeactivation is upregulated in subjects with HFpEF compared to healthy controls and that NLRP3 inflammasome activation will be attenuated by dapagliflozin therapy
  • To test the hypothesis that pro-inflammatory signatures in peripheral blood mononuclear cells (PBMCs) will be increased in HFpEF compared to healthy controls and that they will be attenuated by dapagliflozin therapy
  • To test the hypothesis that macrophage NLRP3 inflammasome activation associates with perturbances in myocardial perfusion, structure, and function and that attenuation of NLRP3 inflammasome activation with dapagliflozin therapy will associate with improvement in myocardial perfusion, myocardial structure, and function
  • To test the hypothesis that NLRP3 inflammasome activation is inversely associated with maximum oxygen consumption (VO2max), exercise functional status, and symptoms in HFpEF and that attenuation of NLRP3 inflammasome activation with dapagliflozin therapy will associate with improvement in VO2max, exercise functional status, and symptoms.

Endpoints:

Primary outcome will be:

-IL-1 beta, a measure of NLRP3 inflammasome activation, from macrophages in subjects with HFpEF compared to healthy controls.

Secondary outcomes will be:

  • Delineation of the differences in PBMC gene expression profiles measured by RNA sequencing and in immunophenotyping signatures measured by flow cytometry in subjects with HFpEF compared to healthy controls. The effect of dapagliflozin on these immunological profiles will also be determined in the HFpEF study subjects.
  • Myocardial perfusion (on CMR), left ventricular mass (on CMR), diastolic function (on echocardiogram), myocardial mechanics (on echocardiogram and CMR), myocardial edema and inflammation, and interstitial fibrosis (on CMR) in subjects with HFpEF compared to healthy controls and in response to dapagliflozin therapy.

Exploratory outcomes will be:

- VO2max, symptoms and exercise functional status in HFpEF compared to healthy controls and in response to dapagliflozin therapy.

Study Type

Interventional

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA

Subjects of both genders will be considered for inclusion in this study. There will be no racial, ethnic, or gender discrimination.

Affected Subjects:

  • 18years of age or older
  • Diagnosed with HFpEF clinically confirmed by licensed physician or advanced practitioner
  • Signs and symptoms of HFpEF
  • LVEF >= 50% on echocardiography from screening visit
  • Left ventricular hypertrophy (interventricular septal thickness (Bullet) 1cm) or enlarged left atrial volume ( (Bullet)34ml/m2) on echocardiography from screening visit
  • NT-proBNP > 300pg/mL

Healthy Controls:

Females and males 18 years of age or older

EXCLUSION CRITERIA:

Affected Subjects:

  • Pregnant or lactating women
  • Acute coronary syndrome, cardiac surgery or percutaneous coronary intervention within past 6 months
  • Atrial fibrillation
  • Coronary artery disease with >= 50% stenosis in the left main, left anterior descending artery, left circumflex artery, or right coronary artery on CCTA from screening visit

  • Infiltrative cardiomyopathy by diagnosis or imaging

    -> Moderate valvular stenosis on screening echocardiography

  • Diagnosis of an inflammatory disease (including psoriasis, psoriatic arthritis, rheumatoid arthritis, lupus, inflammatory bowel disease, HIV)
  • Currently taking an SGLT2 inhibitor
  • Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m^2 body surface area according to the Modification of Diet in Renal Disease criteria
  • Subjects with a contraindication to MRI scanning will not receive the CMR assessment.

These contraindications include subjects with the following devices:

i. Central nervous system aneurysm clips

ii. Implanted neural stimulator

iii. Implanted cardiac pacemaker or defibrillator

iv. Cochlear implant

v. Ocular foreign body (e.g. metal shavings)

vi. Implanted Insulin pump

vii. Metal shrapnel or bullet

  • History of seizures or taking anti-epileptic medications
  • History of serious hypersensitivity to dapagliflozin
  • History of diabetic ketoacidosis
  • Inability to provide informed consent

Healthy Controls:

  • History of HF
  • Acute coronary syndrome, cardiac surgery or percutaneous coronary intervention within past 6 months
  • Coronary artery disease with >= 50% stenosis in the left main, left anterior descending artery, left circumflex artery, or right coronary artery on CCTA
  • Diagnosis of an inflammatory disease (including psoriasis, psoriatic arthritis, rheumatoid arthritis, lupus, inflammatory bowel disease, HIV)
  • Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m^2 body surface area according to the Modification of Diet in Renal Disease criteria
  • Pregnant women and lactating women
  • Subjects with a contraindication to MRI scanning will not receive the CMR assessment.

These contraindications include subjects with the following devices:

viii. Central nervous system aneurysm clips

ix. Implanted neural stimulator

x. Implanted cardiac pacemaker or defibrillator

xi. Cochlear implant

xii. Ocular foreign body (e.g. metal shavings)

xiii. Implanted Insulin pump

xiv. Metal shrapnel or bullet

  • History of seizures or taking anti-epileptic medications
  • Inability to provide informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: Control
Healthy volunteers who are age and sex matched
Device: MRI scan
For subjects, depending on the subject's heart rate, base, mild, or apex short-axis slices will be acquired during the first pass of the contract (60 measurements).
Device: CMR imaging
Enrolled subjects will undergo stress vasodilator and rest perfusion CMR
EXPERIMENTAL: Subjects with HFpEF
Subjects are defined as patients with a diagnosis of HFpEF clinically confirmed by a licensed physician or advanced practitioner who meet the inclusion and exclusion criteria and are able to provide informed consent.
Device: MRI scan
For subjects, depending on the subject's heart rate, base, mild, or apex short-axis slices will be acquired during the first pass of the contract (60 measurements).
Device: CMR imaging
Enrolled subjects will undergo stress vasodilator and rest perfusion CMR
Drug: Dapagliflozin
Subjects will be instructed to take dapagliflozin 10 mg once daily for 6 months (with or without food).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
IL-1 beta levels
Time Frame: 6 months
IL-1 beta, a measure of NLRP3 inflammasome activation, from macrophages in subjects with HFpEF compared to healthy controls
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in CMR, ECHO in affected vs healthy individuals
Time Frame: 2.5 years
1. Myocardial perfusion(CMR), 2. Left ventricular mass(CMR), 3. Diastolic function (ECHO), 4. Myocardial mechanics (ECHO, CMR), 5. Myocardial edema and inflammation, and interstitial fibrosis(CMR) Compared to both group and in response to dapagliflozin therapy
2.5 years
Immunological profiles in affected vs healthy individuals
Time Frame: 2.5 years
Delineation of the differences in PBMC gene expression profiles measured by RNA sequencing and in immunophenotyping signatures measured by flow cytometry in subjects with HFpEF compared to healthy controls. The effect of dapagliflozin on these immunological profiles will also be determined in the HFpEF study subjects
2.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Wunan Y Zhou, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 23, 2022

Primary Completion (ACTUAL)

June 23, 2022

Study Completion (ACTUAL)

June 23, 2022

Study Registration Dates

First Submitted

April 14, 2022

First Submitted That Met QC Criteria

April 14, 2022

First Posted (ACTUAL)

April 15, 2022

Study Record Updates

Last Update Posted (ACTUAL)

June 27, 2022

Last Update Submitted That Met QC Criteria

June 23, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 10000710
  • 000710-H

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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