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Effects of Sacubitril/Valsartan on Subclinical Heart Failure in HIV (The ENCHANTMENT HIV Study)

Primary Purpose

HIV/AIDS, Heart Failure With Preserved Ejection Fraction

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Sacubitril-Valsartan 49-51Mg Oral Tablet

Placebo oral tablet

About this trial

This is an interventional treatment trial for HIV/AIDS focused on measuring HIV, Sacubitril/valsartan, Heart Failure with Preserved Ejection Fraction, Aldosterone, Natriuretic Peptides, Myocardial Dysfunction, Cardiovascular Disease

Eligibility Criteria

40 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Antiretroviral therapy use for >12 months
HIV Viral Load <200 copies/mL
Increased waist circumference based on International Diabetes Federation criteria with ethnicity specific values (male≥94cm and female≥80cm, or male≥90cm and female≥80cm for Asian and Ethnic South and Central Americans) or increased waist to hip ratio based on WHO criteria (male>0.95 and female>0.80)
Left Ventricular Ejection Fraction>50%
Demonstration of one or more criteria for myocardial dysfunction on cardiac transthoracic echocardiogram, relevant to the progression of heart failure with preserved ejection fraction:
- Left Atrial Volume Index > 28 mL/m2
- Global Longitudinal Strain <18%
- Left Ventricular Mass Index > 95g/m2 (female), 115 g/m2 (male)

Exclusion Criteria:

Known history of congestive heart failure or valvular disease
Recent cardiac event or stroke within 3 months
Current medication use acting along the RAAS pathway (ACEi, ARB, MR blockade, direct renin inhibitor), potassium (K) supplementation or diuretic
Angioedema to ACEi or ARB
SBP<100 mmHg
Medication suspected to have contraindication with active study drug
Steroid use within last 3 months
Uncontrolled diabetes requiring insulin and/or HbA1c > 7.5%
Creatinine (Cr)>1.5 mg/dL and estimated GFR<60 mL/min/1.73m2
K>5.5 mEq/L
Hemoglobin <10.0 g/dL
Known liver disease or ALT>3x upper limit normal
Pregnant, actively seeking pregnancy or breastfeeding
Estrogen, progestin derivative, or other sex steroid use within 3 months. Stable physiologic testosterone replacement (> 3 months) is acceptable
Current bacterial or other infection
Active substance abuse
Known reaction to gadolinium

Sites / Locations

Massachusetts General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sacubitril/Valsartan

Placebo

Arm Description

Sacubitril/Valsartan 49-51mg twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 6 months

Placebo twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 6 months

Outcomes

Primary Outcome Measures

Myocardial Inflammation/Fibrosis

Myocardial Inflammation/Fibrosis measured by extracellular volume fraction via cardiac magnetic resonance imaging

Left Atrial Volume Index

Left Atrial Volume Index measured by cardiac transthoracic echocardiography

Secondary Outcome Measures

Indices of Myocardial Dysfunction

Alterations in other cardiac structure and function as measured by cardiac magnetic resonance imaging or cardiac transthoracic echocardiogram

Markers of Myocardial Inflammation and Fibrosis

Circulating biomarkers of myocardial inflammation and fibrosis: Gal3, ST2, GDF15, hs-cTnT

Cardiac Natriuretic Peptides

Circulating cardiac natriuretic peptides: ANP, BNP, NT-proBNP

Full Information

NCT ID

NCT04153136

First Posted

October 30, 2019

Last Updated

June 28, 2023

Sponsor

Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04153136

Brief Title

Effects of Sacubitril/Valsartan on Subclinical Heart Failure in HIV (The ENCHANTMENT HIV Study)

Official Title

Ending Subclinical Heart Failure Using an Aldosterone and Natriuretic Peptide Targeted Treatment in HIV--The ENCHANTMENT HIV Study

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 11, 2020 (Actual)

Primary Completion Date

June 30, 2024 (Anticipated)

Study Completion Date

December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Persons with HIV, even those well-treated, are at increased risk for heart disease when compared to the general population. Two hormones called aldosterone and brain natriuretic peptide (BNP), which have been shown to be abnormal in HIV, may be associated with inflammation as well as early changes in structure and function of the heart. This study is being conducted to evaluate whether therapies to block aldosterone and increase BNP levels may reduce the burden and progression of heart failure to improve cardiovascular health.

Detailed Description

This is a 6-month study enrolling persons with HIV with no known history of heart disease. Participants will be screened for early signs of heart failure using cardiac ultrasound (cardiac transthoracic echocardiography or cardiac TTE). Those participants who have early changes in the structure and function of the heart and may be at future risk for heart failure will be enrolled into the study. Additional imaging of the heart will occur using cardiac magnetic resonance imaging (cardiac MRI). Following baseline studies, participants will either receive a medication called sacubitril/valsartan or placebo for 6 months. Sacubitril/valsartan in an FDA approved medication currently being used for heart failure with reduced ejection fraction in the general population, and we are evaluating whether this medication could be useful to reduce HIV-related heart failure with preserved ejection fraction. Sacubitril/valsartan is an oral medication taken twice daily that may block aldosterone hormone and increase natriuretic peptide hormone. Overall, this study aims to investigate the effect of sacubitril/valsartan on measures of heart disease related to inflammation, structure and function of the heart muscle in HIV using cardiac TTE and cardiac MRI imaging as well as blood markers of heart failure and inflammation.

6. Conditions and Keywords

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

HIV/AIDS, Heart Failure With Preserved Ejection Fraction

Keywords

HIV, Sacubitril/valsartan, Heart Failure with Preserved Ejection Fraction, Aldosterone, Natriuretic Peptides, Myocardial Dysfunction, Cardiovascular Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sacubitril/Valsartan

Arm Type

Experimental

Arm Description

Sacubitril/Valsartan 49-51mg twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 6 months

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 6 months

Intervention Type

Drug

Intervention Name(s)

Sacubitril-Valsartan 49-51Mg Oral Tablet

Other Intervention Name(s)

Entresto

Intervention Description

By mouth twice daily

Intervention Type

Drug

Intervention Name(s)

Placebo oral tablet

Intervention Description

Placebo oral tablet By mouth twice daily

Primary Outcome Measure Information:

Title

Myocardial Inflammation/Fibrosis

Description

Myocardial Inflammation/Fibrosis measured by extracellular volume fraction via cardiac magnetic resonance imaging

Time Frame

6 months

Title

Left Atrial Volume Index

Description

Left Atrial Volume Index measured by cardiac transthoracic echocardiography

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Indices of Myocardial Dysfunction

Description

Alterations in other cardiac structure and function as measured by cardiac magnetic resonance imaging or cardiac transthoracic echocardiogram

Time Frame

6 months

Title

Markers of Myocardial Inflammation and Fibrosis

Description

Circulating biomarkers of myocardial inflammation and fibrosis: Gal3, ST2, GDF15, hs-cTnT

Time Frame

6 months

Title

Cardiac Natriuretic Peptides

Description

Circulating cardiac natriuretic peptides: ANP, BNP, NT-proBNP

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Antiretroviral therapy use for >12 months HIV Viral Load <200 copies/mL Increased waist circumference based on International Diabetes Federation criteria with ethnicity specific values (male≥94cm and female≥80cm, or male≥90cm and female≥80cm for Asian and Ethnic South and Central Americans) or increased waist to hip ratio based on WHO criteria (male>0.95 and female>0.80) Left Ventricular Ejection Fraction>50% Demonstration of one or more criteria for myocardial dysfunction on cardiac transthoracic echocardiogram, relevant to the progression of heart failure with preserved ejection fraction: Left Atrial Volume Index > 28 mL/m2 Global Longitudinal Strain <18% Left Ventricular Mass Index > 95g/m2 (female), 115 g/m2 (male) Exclusion Criteria: Known history of congestive heart failure or valvular disease Recent cardiac event or stroke within 3 months Current medication use acting along the RAAS pathway (ACEi, ARB, MR blockade, direct renin inhibitor), potassium (K) supplementation or diuretic Angioedema to ACEi or ARB SBP<100 mmHg Medication suspected to have contraindication with active study drug Steroid use within last 3 months Uncontrolled diabetes requiring insulin and/or HbA1c > 7.5% Creatinine (Cr)>1.5 mg/dL and estimated GFR<60 mL/min/1.73m2 K>5.5 mEq/L Hemoglobin <10.0 g/dL Known liver disease or ALT>3x upper limit normal Pregnant, actively seeking pregnancy or breastfeeding Estrogen, progestin derivative, or other sex steroid use within 3 months. Stable physiologic testosterone replacement (> 3 months) is acceptable Current bacterial or other infection Active substance abuse Known reaction to gadolinium

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Suman Srinivasa, MD, MS

Phone

6177269109

ssrinivasa@mgh.harvard.edu

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Suman Srinivasa, MD

Phone

617-726-1585

ssrinivasa@mgh.harvard.edu

First Name & Middle Initial & Last Name & Degree

Allie Walpert, MSN

Phone

617-726-1696

awalpert@mgh.harvard.edu

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

26086328

Citation

Srinivasa S, Fitch KV, Wong K, Torriani M, Mayhew C, Stanley T, Lo J, Adler GK, Grinspoon SK. RAAS Activation Is Associated With Visceral Adiposity and Insulin Resistance Among HIV-infected Patients. J Clin Endocrinol Metab. 2015 Aug;100(8):2873-82. doi: 10.1210/jc.2015-1461. Epub 2015 Jun 18.

Results Reference

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PubMed Identifier

29408981

Citation

Murphy CA, Fitch KV, Feldpausch M, Maehler P, Wong K, Torriani M, Adler GK, Grinspoon SK, Srinivasa S. Excessive Adiposity and Metabolic Dysfunction Relate to Reduced Natriuretic Peptide During RAAS Activation in HIV. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1558-1565. doi: 10.1210/jc.2017-02198.

Results Reference

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PubMed Identifier

29659888

Citation

Srinivasa S, Fitch KV, Wong K, O'Malley TK, Maehler P, Branch KL, Looby SE, Burdo TH, Martinez-Salazar EL, Torriani M, Lyons SH, Weiss J, Feldpausch M, Stanley TL, Adler GK, Grinspoon SK. Randomized, Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Metabolic and Inflammatory Indices in HIV. J Clin Endocrinol Metab. 2018 Jun 1;103(6):2376-2384. doi: 10.1210/jc.2018-00330.

Results Reference

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Effects of Sacubitril/Valsartan on Subclinical Heart Failure in HIV (The ENCHANTMENT HIV Study)

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