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

• ClinicalTrials.gov Identifier: NCT05136820
• Recruitment Status: Active, not recruiting
• First Posted: November 29, 2021
• Last Update Posted: October 26, 2023
• Sponsor: Occlutech International AB
• Information provided by (Responsible Party): Occlutech International AB

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Heart Failure With Preserved Ejection Fraction (HFpEF); Heart Failure With Reduced Ejection Fraction (HFrEF)	Device: Atrial Flow Regulator; Device: Sham Comparator	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 698 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Patients will be identified from the investigator's pool of heart failure patients who are symptomatic on stable guideline directed medical therapy. An electronic randomization scheme in the EDC system will be used to minimize risk of bias in the investigation
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The Interventional cardiologist will be unblinded and the Heart failure cardiologist and participants will be blinded. There will also be an unblinded study coordinator and a blinded study coordinator.
• Primary Purpose: Treatment
• Official Title: Flow Regulation by Opening the SepTum in Patients With Heart Failure; a Prospective, Randomized, Sham-controlled, Double-blind, Global Multicenter Study
• Actual Study Start Date: March 9, 2023
• Estimated Primary Completion Date: February 2026
• Estimated Study Completion Date: February 2029

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Randomization to 6mm AFR device; AFR Device 6mm vs Sham procedure	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.; Other Name: AFR
Active Comparator: Randomization to 8mm AFR device; AFR device 8mm vs Sham procedure	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.; Other Name: AFR
Sham Comparator: Randomization to sham procedure; Sham procedure to AFR device (6mm or 8mm)	Device: Sham Comparator; Subjects will be randomized 1:1:1 where subjects will either receive the 6mm AFR device, 8mm AFR device or Sham procedure.
Roll-in Arm; Patients in the Roll-in Arm will receive the AFR device	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.; Other Name: AFR

Outcome Measures

Primary Outcome Measures :

1. Primary Safety Endpoint for Major Adverse Cardiovascular and Neurologic Events (MACNE) within 12 months [ Time Frame: Baseline through 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).
2. Composite Primary Efficacy Endpoint - Frequency of Cardiovascular Mortality [ Time Frame: 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. ]
   Incidence of and time to cardiovascular mortality through 12-24 months
3. Composite Primary Efficacy Endpoint - Frequency of heart transplant or Left Ventricular Assist Device (LVAD) [ Time Frame: 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. ]
   Incidence of and time to heart transplant or LVAD
4. Composite Primary Efficacy Endpoint - Total rate of Heart Failure Hospitalizations [ Time Frame: 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. ]
   Total rate (first plus recurrent) per patient year of heart failure hospitalization admissions and time to first heart failure hospitalizations through 12-24 months
5. Composite Primary Efficacy Endpoint - Total rate of Heart Failure Treatment Intensification [ Time Frame: 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. ]
   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
6. Composite Primary Efficacy Endpoint - KCCQ Score [ Time Frame: Baseline through 6 months. The final primary endpoint analysis will occur when the last subject enrolled reaches their 12-month follow-up. ]
   Change in baseline KCCQ total summary score at 6-months

Secondary Outcome Measures :

1. Clinical performance - change from baseline in NYHA Classification [ Time Frame: Baseline through end of study, approximately 5 years ]
   Clinical performance assessed by the change from baseline in NYHA Classification
2. Clinical performance - change from baseline using KCCQ [ Time Frame: Baseline through end of study, approximately 5 years ]
   Clinical performance assessed by the change from baseline using KCCQ
3. Clinical performance - change from baseline using EQ-5D [ Time Frame: Baseline through end of study, approximately 5 years ]
   Clinical performance assessed by the change from baseline using EQ-5D
4. Clinical performance - change from baseline using the 6 Minute Walk Test (MWT) [ Time Frame: Baseline through end of study, approximately 5 years ]
   Clinical performance assessed by the change from baseline using the 6 Minute Walk Test (MWT)
5. Components of the primary efficacy endpoint (cardiovascular mortality, heart failure hospitalization rate, heart transplant or LVAD placement). [ Time Frame: Baseline through 24 Months ]
   Analysis on components of the primary efficacy endpoint (cardiovascular mortality, heart failure hospitalization rate, heart transplant or LVAD placement).
6. Components of Device Performance- Device placed in-situ as assessed by Investigator [ Time Frame: Implant through end of study, approximately 5 years ]
   Analysis on components of device performance (Device placed in-situ as assessed by Investigator)
7. Components of Device Performance - Patency: Evidence of left to right shunt through AFR device [ Time Frame: Implant through end of study, approximately 5 years ]
   Analysis on components of device performance- Patency: Evidence of left to right shunt through AFR device as assessed by core lab
8. Components of Device Performance- Implant embolization and clinically significant device migration [ Time Frame: Implant through end of study, approximately 5 years ]
   Analysis on components of device performance- Implant embolization and clinically significant device migration (i.e. SAEs probably related to device).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Alabama

Ascension St. Vincent's

Birmingham, Alabama, United States, 35205

United States, Arizona

Arizona Heart Rhythm Center

Phoenix, Arizona, United States, 85016

University of Arizona College of Medicine

Tucson, Arizona, United States, 85719

United States, California

Memorial Heart Institute Long Beach

Long Beach, California, United States, 90806

United States, Colorado

University of Colorado Health Memorial Hospital

Colorado Springs, Colorado, United States, 80909

Colorado Heart & Vascular

Lakewood, Colorado, United States, 80210

United States, Delaware

ChristianaCare Christiana Hospital

Newark, Delaware, United States, 19718

United States, District of Columbia

MedStar Washington Hospital Center

Washington, District of Columbia, United States, 20010

United States, Florida

Baptist Health Research Institute

Jacksonville, Florida, United States, 32207

United States, Georgia

Northside Hospital Cardiovascular Institute

Dahlonega, Georgia, United States, 30533

United States, Idaho

Kootenai Health

Coeur d'Alene, Idaho, United States, 83814

United States, Indiana

Community Health Network, Inc

Indianapolis, Indiana, United States, 46256

United States, Kentucky

University of Louisville

Louisville, Kentucky, United States, 40202

United States, Minnesota

Essentia Health

Duluth, Minnesota, United States, 55805

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, New Jersey

Hackensack Meridian Health JFK University Medical Center

Edison, New Jersey, United States, 08820

United States, New York

North Shore Northwell University Hospital Lenox Hill

New York, New York, United States, 10075

Stony Brook Medicine

Stony Brook, New York, United States, 11794

United States, Ohio

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Oklahoma

Oklahoma Heart Hospital

Oklahoma City, Oklahoma, United States, 73120

United States, South Carolina

Prisma Health

Columbia, South Carolina, United States, 29203

United States, Tennessee

Erlanger Institute for Clinical Research

Chattanooga, Tennessee, United States, 37403

United States, Texas

The University Health Science Center at Houston

Houston, Texas, United States, 77030

University of Texas Health Science Center at Houston

Houston, Texas, United States, 77030

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

Occlutech International AB

Investigators

• Principal Investigator: Megan Coylewright, MD, MPH, FSCAI, FACC; Erlanger Health System
• Principal Investigator: Muthiah Vaduganathan, MD, MPH; Brigham and Women's Hospital Heart and Vascular Center

More Information

• Responsible Party: Occlutech International AB
• ClinicalTrials.gov Identifier: NCT05136820
• Other Study ID Numbers: G210281
• First Posted: November 29, 2021
• Last Update Posted: October 26, 2023
• Last Verified: October 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Keywords provided by Occlutech International AB:

Heart Failure; Preserved Ejection Fraction; Reduced Ejection Fraction; HFpEF; HFrEF

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases