Back to results

The Effect of Inflammation in Heart Failure

Primary Purpose

Myocardial Dysfunction, Heart Failure, Inflammation

Status

Withdrawn

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Dapagliflozin

MRI scan

CMR imaging

About this trial

This is an interventional basic science trial for Myocardial Dysfunction focused on measuring Dapagliflozin, Hfpef, Cardiac MRI, NLRP3 Inflammasome, Perfusion

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Experimental

Arm Label

Control

Subjects with HFpEF

Arm Description

Healthy volunteers who are age and sex matched

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.

Outcomes

Primary Outcome Measures

IL-1 beta levels

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

Secondary Outcome Measures

Change in CMR, ECHO in affected vs healthy individuals

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

Immunological profiles in affected vs healthy individuals

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

Full Information

NCT ID

NCT05330013

First Posted

April 14, 2022

Last Updated

June 23, 2022

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT05330013

Brief Title

The Effect of Inflammation in Heart Failure

Official Title

Pilot Study to Evaluate the Effect of Inflammation in Heart Failure

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Withdrawn

Why Stopped

PI left NIH

Study Start Date

June 23, 2022 (Actual)

Primary Completion Date

June 23, 2022 (Actual)

Study Completion Date

June 23, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

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. ...

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myocardial Dysfunction, Heart Failure, Inflammation

Keywords

Dapagliflozin, Hfpef, Cardiac MRI, NLRP3 Inflammasome, Perfusion

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Control

Arm Type

Other

Arm Description

Healthy volunteers who are age and sex matched

Arm Title

Subjects with HFpEF

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Dapagliflozin

Intervention Description

Subjects will be instructed to take dapagliflozin 10 mg once daily for 6 months (with or without food).

Intervention Type

Device

Intervention Name(s)

MRI scan

Intervention Description

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).

Intervention Type

Device

Intervention Name(s)

CMR imaging

Intervention Description

Enrolled subjects will undergo stress vasodilator and rest perfusion CMR

Primary Outcome Measure Information:

Title

IL-1 beta levels

Description

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

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Change in CMR, ECHO in affected vs healthy individuals

Description

Time Frame

2.5 years

Title

Immunological profiles in affected vs healthy individuals

Description

Time Frame

2.5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Wunan Y Zhou, M.D.

Organizational Affiliation

National Heart, Lung, and Blood Institute (NHLBI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

32358544

Citation

Kim SR, Lee SG, Kim SH, Kim JH, Choi E, Cho W, Rim JH, Hwang I, Lee CJ, Lee M, Oh CM, Jeon JY, Gee HY, Kim JH, Lee BW, Kang ES, Cha BS, Lee MS, Yu JW, Cho JW, Kim JS, Lee YH. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020 May 1;11(1):2127. doi: 10.1038/s41467-020-15983-6.

Results Reference

background

PubMed Identifier

32578850

Citation

Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial. Eur Heart J. 2020 Sep 21;41(36):3421-3432. doi: 10.1093/eurheartj/ehaa419.

Results Reference

background

PubMed Identifier

34449189

Citation

Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Pina IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27.

Results Reference

background

Links:

URL

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_000710-H.html

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

The Effect of Inflammation in Heart Failure

We'll reach out to this number within 24 hrs