The Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Admissions and Mortality in Patients With Heart Failure and Central Sleep Apnea

The Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Admissions and Mortality in Patients With Heart Failure and Central Sleep Apnea (LOFT-HF)

The purpose of this trial is to evaluate the long-term effects of Nocturnal Oxygen Therapy (NOXT) on the mortality and morbidity of patients with stable heart failure and a reduced ejection fraction (HFrEF), already receiving optimal guideline-directed medical therapy (GDMT), who have central sleep apnea (CSA).

Study Overview

• Status: Terminated
• Conditions: Heart Failure; Central Sleep Apnea
• Intervention / Treatment: Drug: Oxygen; Other: Room Air

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85721
      • University of Arizona
  • California
    • Stanford, California, United States, 94305
      • Stanford University
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale School of Medicine
  • Florida
    • Coral Gables, Florida, United States, 33124
      • University of Miami
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Kansas
    • Kansas City, Kansas, United States, 64111
      • Saint Luke's Mid America Health Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48217
      • Wayne State University
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University in St. Louis
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico School of Medicine
  • New York
    • New York, New York, United States, 11029
      • ICAHN School of Medicine at Mount Sinai
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43202
      • Ohio State University
    • Highland Hills, Ohio, United States, 44122
      • University Hospitals
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh Medical Center
    • Wynnewood, Pennsylvania, United States, 19096
      • Main Line Health
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22904
      • University of Virginia
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington
  • Wisconsin
    • Madison, Wisconsin, United States, 53706
      • University of Wisconsin-Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged ≥ 21 years at the date of consent.
• History of chronic, stable heart failure with reduced ejection fraction with left ventricular ejection fraction (LVEF) ≤ 50% determined by echocardiography, radionuclide angiography, left ventriculography, or cardiac magnetic resonance imaging, within the year prior to enrollment.
• Central sleep apnea, defined using as an apnea-hypopnea index (AHI) > 15/h with ≥ 50% central events (apnea and hypopneas).

• New York Heart Association (NYHA) Class III or IV, or NYHA Class II with any of the following:

  1. at least one hospitalization for heart failure within the 24 months prior to enrollment or;
  2. a BMI corrected BNP ≥ 300 pg/ml or a corrected NT-proBNP ≥ 1500 pg/ml or;
  3. an ED visit for HF exacerbation where the patient has received an IV diuretic within 12 months of enrollment.
• Treatment with stable, optimized guideline-directed medical therapies (GDMT) according to applicable guidelines in the U.S. and Canada, where stable is defined as the addition of no new class of disease-modifying drug for ≥ 30 days prior to randomization (reasons for intolerance to GDNT must be documented).
• In the investigator's opinion, willing and able to comply with all study requirements.
• Able to fully understand study information and sign an Institutional Review Board (IRB) approved informed consent (including HIPAA authorization in the U.S.).

Exclusion Criteria:

• Current positive airway pressure use or predominantly obstructive rather than central sleep apnea.
• Oxygen saturation < 90% at rest during the day.
• Nocturnal oxygen saturation < 88% for > 5 continuous minutes unaccompanied by apneas or hypopneas.
• Chronic daytime or nighttime use of supplemental oxygen.
• Participants and their bed-partners who currently smoke in the bedroom.
• Severe pulmonary disease requiring continuous home oxygen therapy or the continuous or frequent intermittent use of oral steroids or documented severe chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second (FEV1) < 50%.
• Cardiac surgery, percutaneous coronary intervention, myocardial infarction or unstable angina within the previous 3 months.
• Transient ischemic attack or stroke within the previous 3 months.
• Cardiac resynchronization therapy implantation scheduled or performed within 3 months prior to randomization.
• Primary hemodynamically-significant uncorrected valvular heart disease (obstructive or regurgitant) or any valvular disease expected to require surgery during the trial.
• Acute myocarditis/pericarditis or other cause of potentially reversible cardiomyopathy (e.g., post-partum cardiomyopathy, tachycardia-induced cardiomyopathy), within the previous 6 months.
• End-stage (Stage D) heart failure (HF) requiring continuous outpatient intravenous (IV) inotropic therapy, placement of ventricular assist device, listing for cardiac transplantation, or end-of-life care (e.g. hospice care).
• Pregnancy or of child bearing potential without a negative pregnancy test within 10 days prior to enrollment.
• Life expectancy < 1 year for diseases unrelated to chronic HF.
• Enrolled or planning to enroll in another study that may conflict with protocol requirements or confound subject results in this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nocturnal Oxygen Therapy; Active nocturnal oxygen therapy	Drug: Oxygen; Active nocturnal oxygen concentrator
Sham Comparator: Sham Nocturnal Oxygen Therapy; Sham nocturnal oxygen therapy (room air)	Other: Room Air; Sham nocturnal oxygen concentrator (room air); Other Names: Sham Oxygen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First Occurrence of Mortality Due to Any Cause or an Unplanned Hospitalization for Worsening Heart Failure or a Life-saving Cardiovascular (CV) Intervention	This is a composite primary outcome	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrent Event Analyses of Mortality and Morbidity	Count of occurrences of mortality due to any cause or an unplanned hospitalization for worsening heart failure or a Life-saving Cardiovascular (CV) Intervention. (Death, Hospitalization HF / Outpatient HF, Myocardial Infarction / Unstable Angina, Resuscitated Cardiac Arrest, Stroke)	From enrollment to study termination, attrition or death. Min = 41 days, Max = 626 Days
Quality of Life and Symptoms - HF Disease-specific Quality of Life	HF disease-specific quality of life will be assessed by the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ). The KCCQ quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life for those who have heart failure. An overall summary score is derived from the physical function, symptom (frequency and severity), social function and quality of life domains. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	Baseline, 6 month follow up
Quality of Life and Symptoms - Generic-quality of Life	Generic-quality of life will be assessed by the change in the Euroqol - 5 Dimensions (EQ-5D) questionnaire. The questionnaire comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. A total score in calculated using a US-specific weighted algorithm with a possible range [-0.109,1], where 1 represents the best outcome with 'no problems' selected for every item on the scale.	Baseline, 6 month follow up
Quality of Life and Symptoms - Depressive Symptoms	Depressive symptoms will be assessed by the change in the Patient Health Questionnaire - 8 items (PHQ-8). A scores ranges from 0 to 24. A score greater than 10 is considered major depression and a score 20 or more is considered severe major depression.	Baseline, 6 month follow up
Quality of Life and Symptoms - Sleep Symptoms and Sleep Related Daytime Impairment	Sleep symptoms and sleep related daytime impairment will be assessed by the change in the Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance (SD) Questionnaire and Sleep Related Impairment (SRI) Questionnaire. The final score for each is represented by the T-score, a standardized score with a population mean of 50 and a standard deviation (SD) of 10, where a higher score indicates a worse score. For SRI a T-score >= 60 implies high levels of sleep related impairment, and for PROMIS SD a T-score >= 60 implies high levels of sleep disturbance.	Baseline, 6 month follow up
Functional Status	Functional status will be assessed by the change in New York Heart Association (NYHA) Functional Class Ranking, where higher classes indicate decreased function (worse outcome). Possible Classes are I-IV, which indicate a score of 1-4. Class I indicates No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or shortness of breath. ; Class II indicates Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, shortness of breath or chest pain. ; Class III indicates Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, shortness of breath or chest pain. ; and Class IV indicates Symptoms of heart failure at rest. Any physical activity causes further discomfort.	Baseline, 6 month follow up

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Ohio State University

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2019
• Primary Completion (Actual): June 17, 2022
• Study Completion (Actual): June 17, 2022

Study Registration Dates

• First Submitted: November 9, 2018
• First Submitted That Met QC Criteria: November 16, 2018
• First Posted (Actual): November 19, 2018

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 10, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Heart Failure; Sleep Apnea Syndromes; Apnea; Sleep Apnea, Central
• Other Study ID Numbers: U24HL140412-01_UG3; U24HL140412-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All relevant deidentified data will be deposited in Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) and the National Sleep Research Resource (NSRR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes