Flow Regulation by Opening the SepTum in Patients With Heart Failure; a Prospective, Randomized, Sham-controlled, Double-blind, Global Multicenter Study

Heart Failure With Preserved Ejection Fraction (HFpEF) Clinical Trial

— FROST-HF  

Official title:

Flow Regulation by Opening the SepTum in Patients With Heart Failure; a Prospective, Randomized, Sham-controlled, Double-blind, Global Multicenter Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05136820
• Other study ID #: G210281
• Status: Active, not recruiting
• Phase: N/A
• Start date: March 9, 2023
• Est. completion date: February 2029

Study information

• Verified date: October 2023
• Source: Occlutech International AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this clinical study is to assess the safety and effectiveness of the Atrial Flow Regulator in the treatment of subjects, 18 years of age or older, who have symptomatic heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) while on stable guideline directed medical therapy (GDMT) as outlined in the Guidelines for the Management of Heart Failure.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 698
• Est. completion date: February 2029
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

General Inclusion Criteria:

• Aged =18 years
• Presence of chronic symptomatic HF (NYHA =class 2) and at least one of the following:

1. Previous heart failure hospitalization within 6 months of informed consent or

2. Elevated NT-proBNP (or BNP):

1. If in Sinus Rhythm, must have a corrected elevated Brain Natriuretic Peptide (BNP) level of at least 300 pg/mL or an N-terminal pro-BNP (NT-proBNP) level of at least 900 pg/mL, according to local measurement, within 2 months of the Screening Visit during a clinically stable period*.

2. If in Atrial Fibrillation or Atrial Flutter, must have a corrected elevated BNP level of at least 400 pg/mL or an NT-proBNP level of at least 1200 pg/mL within 2 months of the Screening Visit during a clinically stable period*.

• If LVEF documented at screening is >55%, then must have one of either:

1. Left atrial enlargement (LA diameter >2.3 cm/m2 or LA volume index >28 mL/m2), or

2. PCWP = 15 mmHg at rest within previous 12 months, or

3. LVEDP =15 mmHg at rest within previous 12 months

• 6 MWT distance 100-450 meters
• Treated with maximally tolerated doses of class I GDMT and class electrical therapies (CRT and ICD) according to latest applicable guidelines (e.g., AHA or ESC) for at least 2 months prior to informed consent, and a stable dose diuretic for at least 1 month prior to informed consent.

General Exclusion Criteria:

• Myocardial infarction and/or revascularization with percutaneous intervention (PCI) or coronary artery bypass grafting (CABG) within 3 months prior to informed consent
• Surgical or transcatheter valve (aortic, mitral, or tricuspid) repair or replacement within 2 months prior to informed consent
• Automated implantable cardioverter defibrillator (AICD) placement within 2 months prior to informed consent
• Resynchronization therapy started within 3 months prior to informed consent
• Major surgery within 3 months prior to informed consent
• History of stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT), or pulmonary emboli within 6 months prior to informed consent, or any prior stroke with persistent neurologic deficit, or any prior intracranial bleed, or known intracerebral aneurysm, AV malformation or other intracranial pathology increasing the risk of bleeding
• Uncontrolled atrial fibrillation with resting heart rate >110 beats per minute despite medical therapy
• Documented history of non-dilated cardiomyopathy (obstructive hypertrophic, restrictive, infiltrative) or pericardial disease
• Clinically significant valvular heart disease:

1. regurgitation grade =3+ or

2. severe stenosis of mitral or tricuspid valves, or

3. moderate or greater stenosis of aortic valves

• Prior diagnosis of pulmonary hypertension with current treatment with one or more pulmonary hypertension specific drugs (e.g. endothelin receptor antagonists (ERAs), phosphodiesterase inhibitors (PDE 5 Inhibitors) or prostacyclin analogues)
• Uncontrolled hypertension, Systolic Blood Pressure (SBP) =160 or Diastolic Blood Pressure (DBP) =100 mmHg despite medical therapy at the time of screening visit
• Previous interventional or surgical atrial septal defect (ASD) or patent foramen ovale (PFO) closure
• Inadequate vascular access for implantation of shunt, e.g., suboptimal femoral venous access for transseptal catheterization or inferior vena cava (IVC) is not patent
• Chronic kidney disease currently requiring dialysis
• Allergy or contraindication to aspirin, or clopidogrel and prasugrel and ticagrelor, or heparin and bivalirudin
• Bleeding disorders (international normalized ratio [INR] >2.0, platelet count <100,000 x 109/L, hemoglobin <10.0 g/dL)
• Known clinically significant untreated carotid artery stenosis likely to require intervention, at discretion of investigator
• Current untreated coronary artery disease with indication for revascularization
• Significant Right Ventricular dysfunction demonstrated by:

1. Tricuspid Annular Plane Systolic Excursion (TAPSE) <16mm or

2. Right Ventricular Fractional Area Change (RVFAC) =30%

• Right Atrial Volume Index (RAVI) > 31ml/m2
• Left Ventricular End-Diastolic Diameter (LVEDD) > 8.0 cm as assessed by echocardiography
• Severe COPD requiring oral steroid therapy or daytime oxygen
• Echocardiographic evidence of intra-cardiac mass, thrombus, or vegetation
• On current immunosuppression or systemic oral steroid treatment
• Any condition that limits exercise tolerance other than heart failure (e.g., peripheral vascular disease, orthopedic issues, angina, other), at the discretion of the Investigator

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction (HFpEF)
• Heart Failure With Reduced Ejection Fraction (HFrEF)

Intervention

Device:
• Atrial Flow Regulator
Subjects will be randomized 1:1:1 where subjects will either receive the 6mm AFR device, 8mm AFR device or Sham procedure.
• Sham Comparator
Subjects will be randomized 1:1:1 where subjects will either receive the 6mm AFR device, 8mm AFR device or Sham procedure.

Locations

Country	Name	City	State
United States	Ascension St. Vincent's	Birmingham	Alabama
United States	Erlanger Institute for Clinical Research	Chattanooga	Tennessee
United States	Kootenai Health	Coeur d'Alene	Idaho
United States	University of Colorado Health Memorial Hospital	Colorado Springs	Colorado
United States	Prisma Health	Columbia	South Carolina
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Northside Hospital Cardiovascular Institute	Dahlonega	Georgia
United States	Essentia Health	Duluth	Minnesota
United States	Hackensack Meridian Health JFK University Medical Center	Edison	New Jersey
United States	The University Health Science Center at Houston	Houston	Texas
United States	University of Texas Health Science Center at Houston	Houston	Texas
United States	Community Health Network, Inc	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Baptist Health Research Institute	Jacksonville	Florida
United States	Colorado Heart & Vascular	Lakewood	Colorado
United States	Memorial Heart Institute Long Beach	Long Beach	California
United States	University of Louisville	Louisville	Kentucky
United States	North Shore Northwell University Hospital Lenox Hill	New York	New York
United States	ChristianaCare Christiana Hospital	Newark	Delaware
United States	Oklahoma Heart Hospital	Oklahoma City	Oklahoma
United States	Arizona Heart Rhythm Center	Phoenix	Arizona
United States	The University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Stony Brook Medicine	Stony Brook	New York
United States	University of Arizona College of Medicine	Tucson	Arizona
United States	MedStar Washington Hospital Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Occlutech International AB

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary Safety Endpoint for Major Adverse Cardiovascular and Neurologic Events (MACNE) within 12 months	The Primary Safety Endpoint is defined as Major Adverse Cardiovascular and Neurologic Events (MACNE) within 12 months of randomization. MACNE includes all-cause mortality, stroke, systemic thromboembolism, open cardiac surgery or major endovascular repair, and major bleeding (BARC 3-5).	Baseline through 12 months
Primary	Composite Primary Efficacy Endpoint - Frequency of Cardiovascular Mortality	Incidence of and time to cardiovascular mortality through 12-24 months	Baseline through 12 - 24 months depending on rate of enrollment. The final primary endpoint analysis will occur when the last subject enrolled reaches their 12-month follow-up.
Primary	Composite Primary Efficacy Endpoint - Frequency of heart transplant or Left Ventricular Assist Device (LVAD)	Incidence of and time to heart transplant or LVAD	Baseline through 12 - 24 months depending on rate of enrollment. The final primary endpoint analysis will occur when the last subject enrolled reaches their 12-month follow-up.
Primary	Composite Primary Efficacy Endpoint - Total rate of Heart Failure Hospitalizations	Total rate (first plus recurrent) per patient year of heart failure hospitalization admissions and time to first heart failure hospitalizations through 12-24 months	Baseline through 12 - 24 months depending on rate of enrollment. The final primary endpoint analysis will occur when the last subject enrolled reaches their 12-month follow-up.
Primary	Composite Primary Efficacy Endpoint - Total rate of Heart Failure Treatment Intensification	Total rate (first plus recurrent) per patient year of heart failure treatment intensification event and time-to-first heart failure treatment intensification event through 12-24 months	Baseline through 12 - 24 months depending on rate of enrollment. The final primary endpoint analysis will occur when the last subject enrolled reaches their 12-month follow-up.
Primary	Composite Primary Efficacy Endpoint - KCCQ Score	Change in baseline KCCQ total summary score at 6-months	Baseline through 6 months. The final primary endpoint analysis will occur when the last subject enrolled reaches their 12-month follow-up.
Secondary	Clinical performance - change from baseline in NYHA Classification	Clinical performance assessed by the change from baseline in NYHA Classification	Baseline through end of study, approximately 5 years
Secondary	Clinical performance - change from baseline using KCCQ	Clinical performance assessed by the change from baseline using KCCQ	Baseline through end of study, approximately 5 years
Secondary	Clinical performance - change from baseline using EQ-5D	Clinical performance assessed by the change from baseline using EQ-5D	Baseline through end of study, approximately 5 years
Secondary	Clinical performance - change from baseline using the 6 Minute Walk Test (MWT)	Clinical performance assessed by the change from baseline using the 6 Minute Walk Test (MWT)	Baseline through end of study, approximately 5 years
Secondary	Components of the primary efficacy endpoint (cardiovascular mortality, heart failure hospitalization rate, heart transplant or LVAD placement).	Analysis on components of the primary efficacy endpoint (cardiovascular mortality, heart failure hospitalization rate, heart transplant or LVAD placement).	Baseline through 24 Months
Secondary	Components of Device Performance- Device placed in-situ as assessed by Investigator	Analysis on components of device performance (Device placed in-situ as assessed by Investigator)	Implant through end of study, approximately 5 years
Secondary	Components of Device Performance - Patency: Evidence of left to right shunt through AFR device	Analysis on components of device performance- Patency: Evidence of left to right shunt through AFR device as assessed by core lab	Implant through end of study, approximately 5 years
Secondary	Components of Device Performance- Implant embolization and clinically significant device migration	Analysis on components of device performance- Implant embolization and clinically significant device migration (i.e. SAEs probably related to device).	Implant through end of study, approximately 5 years