Clinical trial NCT03745898
Conditions: Heart Failure Central Sleep Apnea
Sponsor: Brigham and Women's Hospital
Start date: 2019-04-15; Completion date: 2022-06-17
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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).

Detailed description:

Arms: arm 1: Active nocturnal oxygen therapy arm 2: Sham nocturnal oxygen therapy (room air)
Interventions: intervention 1: Oxygen intervention 2: Room Air
Intervention descriptions: intervention 1: Active nocturnal oxygen concentrator intervention 2: Sham nocturnal oxygen concentrator (room air)

Protocol documents:
Prot_SAP_000.pdf: 
LOFT-HF Study 
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CLINICAL STUDY PROTOCOL NCT03745898 
 
 
 
LOFT-HF Study 
The Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Admissions and Mortality in Patients 
with 
Heart Failure and Central Sleep Apnea (LOFT-HF) 
 
 
 
Clinical Coordinating Center:  The Ohio State University College of Medicine 
 
 
 
Data Coordinating Center:  Brigham and Women’s Hospital / Harvard Medical School 
 
 
 
Study Sponsor / Funding:  National Heart, Lung, and Blood Institute 
 
 
 
 
 
 
 
 
 
 
 
 
Revision 
Description of Change 
Date 
A 
Draft Protocol 
12-February-2017 
B 
Revised Draft Protocol 
08-June-2018 
C 
Revised Draft Protocol 
13-Aug-2018 
D 
Revised Draft Protocol 
31-Oct-2018 
E 
Revised Draft Protocol – Statistical Plan 
26-Nov-2018 
F 
Revised Draft Protocol – Oximeter Model 
01-Mar-2019 
G 
Revised Draft Protocol – MOP Consistency 
09-Apr-2019 
H 
Revised Final Protocol – Procedural Changes 
18-Nov-2019 
I 
Revised Final Protocol – Procedural Changes 
08-Apr-2020 
J 
Revised Final Protocol – Procedural Changes 
17-JUL-2020 
K 
Revised Final Protocol – MOP Consistency 
15-May-2021 
L 
Revised Final Protocol –  
15-Sep-2021 


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Revision History 


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TABLE OF CONTENTS
1. 
PROTOCOL SUMMARY/SYNOPSIS ..................................................................................................... 11 
2. 
INTRODUCTION ....................................................................................................................................... 16 
2.1. 
BACKGROUND INFORMATION ................................................................................................... 16 
2.2. 
STUDY RATIONALE ................................................................................................................. 17 
3. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................. 18 
3.1. 
OBJECTIVES AND EFFICACY ENDPOINTS .................................................................................. 18 
 
Primary Endpoint ......................................................................................................................... 19 
 
Secondary Endpoints .................................................................................................................. 19 
3.2. 
SAFETY ASSESSMENTS ........................................................................................................... 20 
4. 
STUDY DESIGN ......................................................................................................................................... 20 
4.1. 
ENROLLMENT ......................................................................................................................... 20 
4.2. 
START-UP PHASE ................................................................................................................... 20 
4.3. 
STUDY DURATION ................................................................................................................... 21 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ............................................................................ 21 
5.1. 
INFORMED CONSENT .............................................................................................................. 21 
5.2. 
STUDY POPULATION ............................................................................................................... 21 
 
Number of Patients ...................................................................................................................... 22 
 
Patient Inclusion Criteria ............................................................................................................. 22 
 
Patient Exclusion Criteria ............................................................................................................ 22 
5.3. 
STOPPING AND DISCONTINUATION CRITERIA ............................................................................ 23 
 
Discontinuation Criteria Related to the Study .............................................................................. 23 
 
Discontinuation Criteria Related to the Patient ............................................................................ 23 
5.4. 
RANDOMIZATION ..................................................................................................................... 24 
6. 
INVESTIGATIONAL INTERVENTION ................................................................................................. 24 
6.1. 
GENERAL APPROACH ............................................................................................................. 24 
 
Nocturnal Oxygen Therapy (Treatment Group) ........................................................................... 25 
 
Sham Oxygen (Control Group) .................................................................................................... 25 
6.2. 
ADHERENCE MONITORING AND SUPPORT ................................................................................ 25 
6.3. 
REQUIRED TRAINING ............................................................................................................... 25 
6.4. 
CONCOMITANT THERAPY ........................................................................................................ 26 
7. 
ASSESSING AND REPORTING OF ADVERSE EVENTS ................................................................... 26 
7.1. 
ADVERSE EVENTS .................................................................................................................. 26 
 
Expected Adverse Events ........................................................................................................... 26 
 
Unanticipated Adverse Events .................................................................................................... 27 
 
Serious Adverse Events ................................................................ Error! Bookmark not defined. 
Death ............................................................................................................... Error! Bookmark not defined. 
Life-threatening ............................................................................................... Error! Bookmark not defined. 
Hospitalization ................................................................................................. Error! Bookmark not defined. 
7.2. 
RECORDING AND REPORTING ADVERSE EVENTS ...................................................................... 27 
8. 
STUDY SCHEDULE ................................................................................................................................... 28 
8.1. 
STUDY ENTRY ........................................................................................................................ 28 
8.2. 
FOLLOW UP AND PROCEDURES DURING THE STUDY VISITS/CALLS ............................................ 28 
8.3. 
DETAILED VISIT SCHEDULE ..................................................................................................... 29 
8.4. 
POLYSOMNOGRAPHY .............................................................................................................. 32 


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8.5. 
QUESTIONNAIRES ................................................................................................................... 33 
8.6. 
CLINICAL OUTCOMES .............................................................................................................. 34 
 
Death ........................................................................................................................................... 34 
 
Life-saving Cardiovascular Interventions .................................................................................... 34 
 
Hospitalization ............................................................................................................................. 34 
8.7. 
OVERVIEW OF VISITS .............................................................................................................. 35 
8.8. 
STUDY FLOW DIAGRAM ........................................................................................................... 36 
9. 
INVESTIGATIVE SITE INFORMATION .............................................................................................. 37 
9.1. 
INVESTIGATIVE SITE SELECTION .............................................................................................. 37 
9.2. 
SITE TRAINING ....................................................................................................................... 37 
10. 
RECRUITMENT AND RETENTION PLAN ...................................................................................... 37 
10.1. 
SITE SELECTION PROCESS ................................................................................................. 37 
10.2. 
OVERSIGHT OF ENROLLMENT PROGRESS ............................................................................ 38 
10.3. 
RECRUITMENT AND RETENTION PRACTICES ......................................................................... 39 
 
The 3E Approach ........................................................................................................................ 39 
 
Screening, Approaching, and Consenting ................................................................................... 40 
 
Recruitment of High-Risk Subgroup ............................................................................................ 41 
10.4. 
RECRUITMENT RATES, TIMELINES, AND MILESTONES ............................................................ 41 
 
Year 1:  Start-Up or UG3 Phase .................................................................................................. 41 
 
Years 2-5:  Completion of Enrolment or the UH3 Phase ............................................................. 41 
 
Recruitment Rate Contingencies ................................................................................................. 41 
10.5. 
RECRUITMENT AND RETENTION MONITORING ....................................................................... 42 
11. 
STATISTICS ........................................................................................................................................... 42 
11.1. 
DESCRIPTION OF STUDY ..................................................................................................... 42 
11.2. 
STATISTICAL ANALYSIS APPROACHES .................................................................................. 43 
 
Descriptive Comparisons between Treatment Groups at Baseline and Over Time .................... 43 
 
Statistical Approaches to Testing for Treatment Differences ...................................................... 43 
 
Secondary Analyses .................................................................................................................... 44 
 
Subgroup Analysis ...................................................................................................................... 44 
 
Interim Analyses .......................................................................................................................... 44 
11.3. 
SAMPLE SIZE CALCULATION ................................................................................................ 46 
12. 
ACCESS TO SOURCE DATA/DOCUMENTS ................................................................................... 47 
12.1. 
SOURCE DATA ................................................................................................................... 47 
12.2. 
SOURCE DOCUMENTS ......................................................................................................... 47 
12.3. 
DIRECT ACCESS ................................................................................................................. 48 
13. 
STUDY COORDINATION AND DATA MANAGEMENT .............................................................. 48 
13.1. 
QUALITY CONTROL ............................................................................................................. 50 
13.2. 
STUDY MONITORING ........................................................................................................... 51 
13.3. 
QUALITY ASSURANCE ......................................................................................................... 51 
13.4. 
INSPECTION ....................................................................................................................... 51 
13.5. 
AUDIT ................................................................................................................................ 51 
14. 
ETHICAL AND LEGAL CONSIDERATIONS .................................................................................. 51 
14.1. 
ETHICAL CONSIDERATIONS ................................................................................................. 52 
 
Central Institutional Review Board (IRB) ..................................................................................... 53 
 
Clinical Endpoints Committee (CEC) ........................................................................................... 54 
 
Data and Safety Monitoring Board (DSMB) ................................................................................ 54 


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14.2. 
MODIFICATION OF PROTOCOL ............................................................................................. 55 
14.3. 
PERSONAL DATA AND DATA PROTECTION ............................................................................ 55 
14.4. 
DATA HANDLING AND RECORD KEEPING .............................................................................. 56 
 
Completion of Case Report Forms .............................................................................................. 56 
 
Archiving ...................................................................................................................................... 56 
15. 
FINAL REPORT AND PUBLICATION POLICY ............................................................................. 56 
16. 
REFERENCES ........................................................................................................................................ 57 
17. 
SIGNATURES ......................................................................................................................................... 62 
 


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Responsibilities, Affiliations, and Key Contact Information 
 
Principal Investigators 
Clinical Coordinating Center (CCC) 
 
William T. Abraham, M.D. 
 
Professor of Medicine, Physiology, and Cell Biology 
 
College of Medicine Distinguished Professor 
 
Division of Cardiovascular Medicine 
 
The Ohio State University 
 
Phone: (614) 292-4967 
 
E-mail:  william.abraham@osumc.edu 
 
 
Data Coordinating Center (DCC) 
 
Susan Redline, M.D., M.P.H. 
 
Peter C. Farrell Professor of Sleep Medicine 
 
Harvard Medical School 
 
Professor of Epidemiology, 
 
Harvard T.H. Chan School of Public Health 
 
Director, Programs in Sleep Medicine Epidemiology and
 
Sleep and Cardiovascular Medicine 
 
Brigham and Women’s Hospital and Beth Israel 
 
Deaconess Medical School 
 
Phone: (617) 732-5859 
 
E-Mail:  sredline@partners.org 
 
Executive Committee 
William T. Abraham, M.D. (Co-Chair) 
 
The Ohio State University 
 
Susan Redline, M.D., M.P.H. (Co-Chair) 
 
Brigham and Women’s Hospital/Harvard Medical School 
 
Shahrokh Javaheri, M.D. (CCC Co-Investigator) 
 
Ohio State Medical School/ Bethesda North  
                                                                       Hospital/ University of Cincinnati 
 
Eldrin F. Lewis, M.D., M.P.H. (CEC Chair) 
 
Stanford University 
 
Rami Khayat, M.D. (CCC Co-Investigator) 
 
The Ohio State University/ University of California Irvine  
 
Rui Wang, Ph.D. (DCC Statistician) 
 
Harvard Medical School/Harvard School of Public Health 
 
George Sopko, M.D. (NIHLBI Program Officer) 
                                                                       Division of Cardiovascular Sciences 
Clinical Coordinating Center 
The Ohio State University 
 
Division of Cardiovascular Medicine 
Data Coordinating Center 
Brigham and Women’s Hospital 


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Program in Sleep and Cardiovascular Medicine 
 
 
Sites / Site Investigators 
See Site / Site Investigators Document 
Sponsor 
National Heart, Lung, and Blood Institute 
 
Bethesda, MD 
Statistician (and MPI DCC) 
Rui Wang, Ph.D. 
 
Associate Professor of Population Medicine  
 
Harvard Medical School  
 
Harvard Pilgrim Health Care Institute 
 
Assistant Professor in the Depart Biostatistics 
 
Harvard T.H. Chan School of Public Health 
 
Phone: (617) 867-4994 
 
E-mail:  rwang@hsph.harvard.edu 
Steering Committee 
William T. Abraham, M.D. (Co-Chair) 
 
The Ohio State University 
 
Susan Redline, M.D., M.P.H. (Co-Chair) 
 
Brigham and Women’s Hospital/Harvard Medical School 
 
Shahrokh Javaheri, M.D. 
 
Ohio State Medical School/ Bethesda North  
                                                                       Hospital/ University of Cincinnati 
 
Eldrin F. Lewis, M.D., M.P.H. 
 
Stanford University 
 
Rami Khayat, M.D. 
 
The Ohio State University/ University of California Irvine 
 
Rui Wang, Ph.D. 
 
Harvard Medical School/Harvard School of Public Health 
 
George Sopko, M.D. 
 
NHLBI Project Officer 
 Chair, Recruitment, Retention, and Operations 
Subcommittee (TBD) 
Chair, Quality Control Subcommittee (TBD) 
Chair, Publications and Presentations Subcommittee 
(TBD) 
Two at-large members from the LOFT-HF Investigator 
Team (TBD) 


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Clinical Events Committee (Chair) 
 Eldrin F. Lewis, M.D., M.P.H. 
 
Professor of Medicine 
 
Chief, Division of Cardiovascular Medicine  
 
Stanford University School of Medicine  
 
300 Pasteur Drive, Falk CVRB 
 
Palo Alto, CA 94304  
 
Phone: (650) 724-8773 
 
E-mail: eflewis1@stanford.edu 
                                                                            
Data & Safety Monitoring Board (Chair) 
Anne L. Taylor, M.D. 
 
 Senior Vice President for Faculty Affairs and Career 
 
Development 
 
Columbia University College of Physicians & Surgeons 
 
Phone (212) 305-4993 
 
E-mail: alt2127@mail.cumc.columbia.edu 
 
Scientific Advisory Board 
Andrew Coats, M.D., M.B.A. 
 
Monash and Warwick Universities 
 Martin Cowie, M.D. 
National Heart and Lung Institute 
Imperial College/Royal Brompton Hospital 
Akshay Desai, M.D. 
Brigham and Women’s Hospital/Harvard Medical School 
Daniel Gottlieb, M.D. 
Brigham and Women’s Hospital/Boston VA Health Care 
Center 
Andrew Kao, M.D. 
Saint Luke’s Mid America Heart Institute 
John Kimoff, M.D. 
McGill University 
Reena Mehra, M.D., M.S. 
Cleveland Clinic Foundation 
 
 
 
 
 
 


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Abbreviations and Definitions 
AASM 
American Academy of Sleep Medicine 
ACC/AHA 
American College of Cardiology/American Heart Association  
AE 
Adverse Event 
AHI 
Apnea/Hypopnea-Index 
ASV 
Adaptive Servo Ventilation 
ATS 
American Thoracic Society 
CCC 
Clinical Coordinating Center 
CEC 
Clinical Events Committee 
CPAP 
Continuous Positive Airway Pressure 
CRF 
Case Report Form 
CRT 
Cardiac Resynchronization Therapy 
CSA 
Central Sleep Apnea 
CSR 
Cheyne-Stokes Respiration 
CTMO 
Clinical Trials Management Office 
CV 
Cardiovascular 
CVA 
Cerebrovascular Accident 
DCC 
Data Coordinating Center 
DMS 
Data Management System 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EQ-5D 
EuroQol 5D 
ERF 
Event Review Form 
FEV 1 
Forced Expiratory Volume within one second 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
ICD 
Implantable Cardioverter Defibrillator 
IRB 
Institutional Review Board 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 


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kg 
Kilogram 
LVEF 
Left Ventricular Ejection Fraction 
L 
Liters 
MI 
Myocardial Infarction 
MICE 
Multiple Imputation through Chained Equations 
MLWHQ 
Minnesota Living with Heart Failure Questionnaire 
MOP 
Manual of Procedures  
NOXT 
Nocturnal Oxygen Therapy 
NYHA 
New York Heart Association 
ODI 
Oxygen Desaturation Index 
OSA 
Obstructive Sleep Apnea 
OSU 
Ohio State University 
P&P 
Policies and Procedures 
PAP 
Positive Airway Pressure 
PHQ-8 
Patient Health Questionnaire-8 
PCI 
Percutaneous coronary intervention 
PM 
Project Manager 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PSG 
Polysomnography 
QoL 
Quality of Life 
RROS 
Recruitment, Retention, and Operations Subcommittee 
SAE 
Serious Adverse Event 
SAC 
Scientific Advisory Committee 
SDB 
Sleep-Disordered Breathing 
SOP 
Standard Operating Procedure 
SRC 
Sleep Reading Center 
TBD 
To Be Determined 
Tsat90% 
Percent Time at oxygen saturation < 90% 


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1. Protocol Summary/Synopsis 
Title 
The Impact of Low Flow Nocturnal Oxygen Therapy on Hospital 
Admissions and Mortality in Patients with Heart Failure and Central 
Sleep Apnea (LOFT-HF) 
Objective 
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 Design 
LOFT-HF is a Phase 3, multi-center, randomized, double-blind, sham-
controlled outcomes trial with parallel group design, with patients 
randomized to either control (optimal GDMT plus sham NOXT) or 
active treatment (optimal GDMT plus NOXT) in a 1:1 ratio.  
Intervention to be Tested 
Supplemental oxygen delivered via nasal cannula. 
Number of Sites 
Approximately 30 to 50 centers in the United States (U.S.) and 
Canada 
Number of Patients 
858 patients will be randomized to one of the two study groups. 
Patient Selection Criteria 
 
Inclusion criteria:  
• 
Age ≥ 21 years 
• 
History of chronic, stable HFrEF with a 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: 
            a. ≥ 1 hospitalization for HF in the last 24 months  
            b. a BMI corrected BNP ≥ 300 pg/ml or a corrected NT-proBNP   
                ≥ 1500 pg/ml  
            c. an ED visit for HF exacerbation where the patient has  
                received an IV diuretic within 12 months of enrollment 
• 
Treatment with stable, optimized 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 GDMT 
must be documented) 
• 
In the investigator’s opinion, willing and able to comply with all 
study requirements 


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• 
Able to fully understand study information and sign an IRB-
approved informed consent (including HIPAA authorization in the 
U.S.) 
Exclusion Criteria 
• 
Current positive airway pressure (PAP) use or diagnosis of 
obstructive sleep apnea (OSA) 
• 
Oxygen saturation < 90% at rest during the day 
• 
Chronic daytime or nighttime use of supplemental oxygen 
• 
Nocturnal oxygen saturation <88% for > 5 minutes 
unaccompanied by apneas or hypopneas 
• 
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 COPD with FEV1 < 50% 
• 
Cardiac surgery, percutaneous coronary intervention, myocardial 
infarction or unstable angina within the previous 3 months 
• 
Cardiac resynchronization therapy implantation scheduled or 
performed within 3 months prior to randomization 
• 
Transient ischemic attack or stroke within the previous 3 months 
• 
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) 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 


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Primary Endpoint 
First occurrence (time-to-first event analysis) of either mortality due to 
any cause, a life-saving cardiovascular (CV) intervention, or 
unplanned hospitalization for worsening HF measured over the 
duration of the trial. 
Life-saving CV interventions will be identified using criteria that are 
considered as being equivalent to HF-related death (i.e., progressive 
pump dysfunction or sudden [arrhythmic] cardiac death), including 
cardiac transplantation, long-term ventricular assist device 
implantation, resuscitation of sudden cardiac arrest, or shock from an 
implantable cardioverter-defibrillator (ICD) associated with sudden 
loss of consciousness associated with ventricular tachycardia or 
ventricular fibrillation. 
Unplanned hospitalizations for HF will be identified when a patient is 
admitted to a hospital inpatient bed, observation unit, or emergency 
department for worsening signs and/or symptoms of HF requiring 
treatment with IV diuretics and/or IV vasoactive medications for HF. 
Worsening of HF will require evidence of two or more of the following:  
pulmonary edema; elevated jugular venous pressure; worsening 
dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, 
peripheral edema, or fatigue; decreasing exercise tolerance; 
worsening renal function; radiological signs of congestive HF; or 
elevated BNP or NTproBNP level. 
A Clinical Endpoints Committee (CEC) will be responsible for 
finalizing event definitions in a CEC Manual of Operations and 
adjudicating each of these primary endpoint events, blinded to study 
assignment. 
Secondary Endpoints 
Morbidity and Mortality 
• 
All-cause mortality, CV interventions, or hospitalization for 
worsening HF (recurrent event analyses) 
• 
CV death, life-saving CV interventions, or hospitalization for 
worsening HF (time-to-first event and recurrent event analysis) 
• 
All-cause mortality or life-saving CV interventions (time-to-first 
event analysis) 
• 
CV mortality or life-saving CV interventions (time-to-first event 
analysis) 
• 
All-cause mortality (time-to-event analysis) 
• 
CV Mortality (time-to-event analysis) 
• 
Rate of hospitalization for worsening HF (recurrent event 
analysis) 
 
 


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Quality of Life and Symptoms 
• 
Change in HF disease-specific quality of life, assessed by 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
Change in generic-quality of life, assessed by the EQ-5D 
• 
Change in depressive symptoms assessed by the PHQ-8 
• 
Change in sleep symptoms and sleep related daytime 
impairment (including fatigue), assessed by the PROMIS Sleep 
Disturbance and Sleep Related Impairment Questionnaires 
Functional Status 
• 
Change in NYHA Functional Class Ranking 
Secondary morbidity and mortality endpoints will be measured over 
the full duration of study follow up. Quality of life, symptoms, and 
functional status endpoints will be measured at baseline and at 6 and 
12 months follow up. 
Safety Assessments 
Continuous assessment of study-related adverse events (AEs) will be 
collected. 
Scheduled follow up 
Patients will be followed up on average for a period of about 2.5 
years.  All patients will be followed, until the last patient randomized 
completes 6 months of follow up. Thus, minimum follow up time will 
be 6 months, and maximum follow up is anticipated to be about 4.5 
years, assuming that the enrolment accrual pattern is uniform across 
and completed over 3.5 years. 
In-clinic or remote study visits will occur at Screening/Consent, 
Baseline, 6 months, and 12 months. Telephone follow-up will occur at 
1 month, 3 months, 9 months, 18 months, and then every 6 months 
after that, until the last participant completes the study. There will be 
a telephone assessment for each patient at the end of the study, for 
final ascertainment of mortal and morbid events. 
Prior the De-briefing Visit, a follow-up in home sleep study will be 
performed. At the De-briefing Visit the coordinator will review the 
baseline and follow-up sleep study results, reveal the participant’s 
treatment arm and provide letters for continuity of care. 
Independent Committees 
An independent CEC will adjudicate all outcomes associated with the 
primary and secondary mortality and morbidity endpoints. 
An Independent Data and Safety Monitoring Board (DSMB) will 
monitor all efficacy and safety outcomes (including study-related 
AEs), but will be able to recommend early termination of the trial only 
for significant excess mortality in the treatment group or for 
overwhelming evidence of patient benefit or harm. 


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Statistical 
Considerations/Sample 
Size 
We hypothesize a treatment effect resulting in a 20% annual 
reduction in the primary endpoint (all-cause death, life-saving CV 
interventions, or hospitalization for worsening HF). This treatment 
effect is comparable to established therapies for the treatment of HF, 
such as renin-angiotensin system inhibitors, beta-blockers, and 
mineralocorticoid receptor antagonists. A total sample of 858 subjects 
(429 in each arm) achieves 90% power at a 5% significance level to 
detect a hazard ratio (HR) of 0.755, when the annual event rate in the 
control group is 40%, using a two-sided logrank test. 


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2. Introduction 
2.1. Background information 
As reported in the 2017 American Heart Association (AHA) Statistical Update (1), an estimated 
6.5 million American adults have heart failure (HF). Projections show that the prevalence of HF 
will increase 46% from 2012 to 2030, resulting in greater than 8 million Americans with HF (2). 
Heart failure is associated with substantial morbidity, mortality, and economic costs. One in 8 
U.S. deaths have HF mentioned on the death certificate (3). In 2014, HF “any-mention” mortality 
was 308,976 (3). Hospitalization for HF represents a major public health concern. Hospital 
discharges for HF in the U.S. have remained unchanged for more than a decade, numbering 
more than 1 million annually (1), and HF is the number one cause of hospital readmission in 
Medicare beneficiaries (4). In 2012, the total cost of HF in the U.S. was estimated at $30.7 
billion, with 68% attributable to direct medical costs (2). One projection places the total cost of 
HF in the U.S. at nearly $70 billion, by 2030 (2). Worldwide, these figures may be multiplied 4-
fold given the global prevalence of HF of 26 million (5). 
Beyond the high rates of morbidity and mortality and the staggering economic cost, HF 
produces substantial patient disability, impairing quality of life, functional status, and exercise 
capacity, despite currently available guideline-directed medical therapies (GDMT). For example, 
advanced HF patients (those categorized in New York Heart Association [NYHA] Class III or IV) 
comprise about 30% to 40% of the HF population and cannot perform many or any activities of 
daily living. Thus, beyond GDMT, additional interventions that improve quality of life and 
exercise capacity and reduce hospital admissions and mortality in HF are needed. One target 
for intervention that, if successfully treated, has the potential to improve both patient-centered 
and clinical outcomes is co-morbid sleep disordered breathing (SDB). 
Sleep disordered breathing is very common in HF patients, particularly in those with HF and a 
reduced (left ventricular) ejection fraction (HFrEF), with a reported prevalence rate of 50% to 
75% (6-12). Two types of abnormal breathing predominate; obstructive sleep apnea (OSA) and 
central sleep apnea (CSA) including Cheyne-Stokes Respiration (CSR). Obstructive sleep 
apnea is seen in 20% to 45% of chronic HFrEF patients (6-12), a rate that is considerably higher 
than the general population (13), while CSA is also common and reported in 25% to 40% of 
chronic HFrEF patients (6-12). Importantly, SDB has been associated with high rates of 
morbidity and mortality in HFrEF patients. In such patients, multiple studies have shown that 
SDB is a strong and independent risk factor for excess and recurrent HF hospitalizations and for 
excess mortality (14-19). 
There are several mechanisms by which SDB may be detrimental in the setting of HFrEF. 
These include tissue hypoxia and repetitive arousals from sleep with increased sympathetic 
nervous system activity (20,21). In patients with OSA, apneas and hypopneas can be directly 
treated with continuous positive airway pressure (CPAP), which operates as a pneumatic stent 
to stabilize the collapsible upper airway characteristic of this disorder. While CPAP is a well-
accepted treatment for patients with OSA, there is no consensus on how to treat CSA, 
especially in the setting of HFrEF where instability of the respiratory control system is the major 
pathophysiological mechanism. Several approaches to the treatment of CSA in HF, including 
CPAP and other positive airway pressure (PAP) therapies, have been evaluated; none have 
been yet proven to be safe and effective while some have proven to be potentially harmful. 
The largest trial of CPAP in heart failure patients, the Canadian Positive Airway Pressure 
(CANPAP) study, was terminated early after 200 patients were followed for at least 6 months 


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(22). After a pre-specified interim analysis, the Data and Safety Monitoring Board (DSMB) 
recommended the termination of the study because of an early divergence of cardiac 
transplantation-free survival (the primary endpoint) favoring the control group. Despite this early 
trend, the overall study outcome was neutral in demonstrating no statistically significant 
improvement or worsening of cardiac transplantation-free mortality. The authors and others (23) 
concluded that their data did not support the use of CPAP to extend life in patients who have 
CSA and HF; however, the door was left open to the study of other PAP therapies in this setting. 
Following CANPAP, it was hypothesized that a more efficient PAP way of treating CSA, namely 
adaptive servo ventilation (ASV), might prove useful in the treatment of HFrEF patients (24). 
Adaptive servo ventilation automatically adjusts pressure support to stabilize and reduce the 
ventilation of patients with CSA and has been shown to significantly lower the apnea hypopnea 
index (AHI), in such patients (25,26). However, a large randomized controlled outcomes study 
of ASV in HFrEF patients with CSA not only failed to meet its primary endpoint of reducing the 
combined outcome of death from any cause, life-saving cardiovascular (CV) intervention, or 
unplanned hospitalization for worsening HF due to futility, it also demonstrated significant 
increases in all-cause and CV mortality, by 28% and 34%, respectively (27). The results of this 
study, the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by 
Adaptive Servo Ventilation in Patients with Heart Failure trial (SERVE-HF), have resulted in a 
contraindication for the use of ASV for the treatment of CSA in HFrEF patients, following an 
urgent safety warning released in May 2015 (28). The SERVE-HF investigators hypothesized 
one of the reasons accounting for the treatment-associated increase in mortality was the 
increased intrathoracic pressure associated with the PAP therapy adversely affecting cardiac 
physiology (27,29). Although a second large trial evaluating ASV in heart failure (Effect of 
Adaptive Servo Ventilation on Survival and Hospital Admissions in Heart Failure [ADVENT-HF]; 
www.clinicaltrials.gov; NCT01128816) is underway, that study is enrolling patients with both 
OSA and CSA and is not powered to specifically address the role of treatment of CSA in HFrEF. 
Thus, the outcome of SERVE-HF left few options and none proven for the treatment of patients 
suffering from CSA and HFrEF, highlighting the need to rigorously test alternative treatments. 
This study protocol is a response to the imperative to identify and rigorously evaluate alternative 
treatments for patients with HFrEF and CSA, a group with particularly high morbidity and 
mortality. One such treatment is low flow nocturnal oxygen therapy (NOXT), which provides a 
physiologically sound approach for blunting hypoxemia-associated physiological stresses and 
sympathetic activation, as well as a means for stabilizing the ventilatory control abnormalities 
characteristic of CSA, that is postulated to improve patient-centered and clinical outcomes in 
HFrEF. To date, no adequately powered randomized controlled outcomes trial of NOXT for the 
treatment of CSA in HFrEF has been performed. 
2.2. Study Rationale 
In the current study, the role of nocturnal oxygen as a physiologically-sound option for treating 
patients with CSA and HFrEF will be evaluated. The pathogenesis of CSA (and CSR) in HFrEF 
relates to an increased gain of the respiratory control system to hypoxia and sensitivity to 
hypocapnia, which together trigger recurrent cycles of hyperventilation and central apneas 
(21,30). Hypoxia amplifies the controller gain for changes in PaCO2 and reduces intrapulmonary 
gas stores of oxygen (causing “under-damping”). Accordingly, use of low flow oxygen can 
stabilize the breathing pattern by reducing the hyperventilation phase of CSA and the 
subsequent hypocapnia that leads to apneas. Oxygen supplementation also attenuates the 
individual’s overall exposure to hypoxia, a known contributor to sympathetic over-activity, 


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ischemia, pulmonary hypertension, and vascular dysfunction (21,30). The adverse effect of 
hypoxemia was highlighted in the results of a recent large observational study in patients with 
HFrEF that reported that overnight hypoxemia predicted mortality more strongly than AHI (31). 
Specifically, this study demonstrated that it was the time below a saturation of 90%, and not the 
AHI, that predicted excess mortality in a dose dependent manner. This association between 
nocturnal hypoxemia as a more potent predictor of mortality than the AHI in HFrEF patients has 
been observed by others. 
The impact of supplemental oxygen on clinical and physiological outcomes in patients with 
HFrEF and CSA was recently summarized in a systematic review (32). Several small short-term 
studies in patients with HF have shown that low flow oxygen virtually eliminates overnight 
hypoxemia and improves the number of central apneas, as well as decreases arousal frequency 
and sleep fragmentation (33-39). In one of the first systematic studies of NOXT, 36 HFrEF 
patients with CSA and an AHI of 15 or greater were treated with nasal oxygen during a full night 
polysomnography (36). Oxygen therapy significantly decreased the percent of total sleep time 
with an oxygen saturation below 90% from 23 ± 21% to 0.8 ± 2.3%. The AHI was decreased by 
nearly 50% (from a baseline average of 49 to 28 on therapy). Two AHI response groups were 
identified, those with a major reduction (averaging > 80%) and those with a more modest 
reduction (averaging < 25%); however, oxygen desaturation was virtually eliminated in both 
groups. Based on the aforementioned strong association between oxygen desaturation and 
mortality, NOXT has the potential to improve outcomes in both groups of patients. The potential 
beneficial effects of nocturnal oxygen in patients with HF are also supported by evidence that 
oxygen can positively impact important predictors of survival in HF, in particular, sympathetic 
activity (34,35), peak exercise oxygen consumption (35-38), and left ventricular ejection fraction 
(35,39).  From a patient’s perspective, oxygen use in HF also has been shown to improve 
exercise capacity (35), subjective sleep quality (37), and quality of life (35,39,40). 
Despite these promising short-term studies, there have been no long-term studies that have 
evaluated nocturnal oxygen use in patients with HFrEF and CSA. In fact, the longest prior trial 
that evaluated nocturnal oxygen in patients with CSA was conducted in Japan and followed 
participants for a maximum period of only 6 months (39,40). With a sample of only 51 patients, 
this study was under-powered to detect changes in clinical event rates although demonstrated 
significant improvements in EF, NYHA functional class, and exercise capacity.  Several LOFT-
HF investigators completed a study showing that 3 months of oxygen use was safe in patients 
with cardiovascular disease and OSA, improved overnight hypoxemia (41), and improved 
measures of physical functioning measured by the SF-36 (42). Long term nocturnal oxygen also 
has been shown to have favorable effects in patients with severe COPD (43). Thus, low flow 
nocturnal oxygen is a physiologically sound intervention, has been shown to improve 
physiological targets, is considered to be minimally burdensome and attractive to patients and 
clinicians, and appears to be safe. The lack of high level evidence to guide treatment of co-
morbid CSA with HFrEF, the considerable morbidity and mortality of this condition, and 
promising short term efficacy and safety data for use of low flow oxygen, provide compelling 
reasons to rigorously evaluate the long-term role of NOXT on clinically important outcomes. 
3. Study Objectives and Endpoints 
3.1. Objectives and Efficacy Endpoints 
The primary purpose of this trial is to evaluate the long-term effects of NOXT on the mortality 
and morbidity of patients with stable HFrEF, already receiving optimal GDMT, who have CSA. 


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The secondary objectives are to evaluate the effects of NOXT on disease-specific mortality; 
cardiovascular events; patient-reported outcomes (disease-specific and generic quality of life); 
and functional status. Finally, subgroup analyses are planned to identify which patients treated 
with NOXT benefit most, examining potential predictors that include baseline assessment of 
CSR, severity of left ventricular systolic dysfunction assessed by left ventricular ejection fraction 
(LVEF), levels of hypoxemia, apnea hypopnea index (AHI), circulatory time, loop gain, arousal 
threshold, as well as important demographic factors including gender. 
 
Primary Endpoint 
First occurrence (time-to-first event analysis) of either mortality due to any cause, a life-saving 
CV intervention, or unplanned hospitalization for worsening HF measured over the duration of 
the trial. 
Life-saving CV interventions will be identified using criteria that are considered as being 
equivalent to HF-related death (i.e., progressive pump dysfunction or sudden [arrhythmic] 
cardiac death), including cardiac transplantation, long-term ventricular assist device 
implantation, resuscitation of sudden cardiac arrest, or shock from an implantable cardioverter-
defibrillator (ICD) associated with sudden loss of consciousness associated with ventricular 
tachycardia or ventricular fibrillation. 
Unplanned hospitalizations for HF will be identified when a patient is admitted to a hospital 
inpatient bed, observation unit, or emergency department for worsening signs and/or symptoms 
of HF requiring treatment with intravenous (IV) diuretics and/or IV vasoactive medications for 
HF. Worsening of HF will require evidence of two or more of the following:  pulmonary edema; 
elevated jugular venous pressure; worsening dyspnea on exertion, orthopnea, paroxysmal 
nocturnal dyspnea, peripheral edema, or fatigue; decreasing exercise tolerance; worsening 
renal function; radiological signs of congestive HF; or elevated BNP or NTproBNP level. 
The primary endpoint components will be measured over the full duration of study follow up. 
A Clinical Endpoints Committee (CEC) will be responsible for finalizing event definitions in a 
CEC Manual of Operations and adjudicating each of these primary endpoint events, blinded to 
study assignment. 
 
Secondary Endpoints 
Morbidity and Mortality 
• 
All-cause mortality, CV interventions, or hospitalization for worsening HF (recurrent event 
analyses) 
• 
CV death, life-saving CV interventions, or hospitalization for worsening HF (time-to-first 
event and recurrent event analysis) 
• 
All-cause mortality or life-saving CV interventions (time-to-first event analysis) 
• 
CV mortality or life-saving CV interventions (time-to-first event analysis) 
• 
All-cause mortality (time-to-event analysis) 
• 
CV Mortality (time-to-event analysis) 
• 
Rate of hospitalization for worsening HF (recurrent event analysis) 
 
 


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Quality of Life and Symptoms 
• 
Change in HF disease-specific quality of life, assessed by Kansas City Cardiomyopathy 
Questionnaire (KCCQ) 
• 
Change in generic-quality of life, assessed by the EQ-5D 
• 
Change in depressive symptoms assessed by the PHQ-8 
• 
Change in sleep symptoms and sleep related daytime impairment (including fatigue), 
assessed by the PROMIS Sleep Disturbance and Sleep Related Impairment 
Questionnaires 
Functional Status 
• 
Change in NYHA Functional Class Ranking 
Secondary morbidity and mortality endpoints will be measured over the full duration of study 
follow up. Quality of life, symptom, and functional status endpoints will be measured at baseline 
and at 6 and 12 months follow up. 
3.2. Safety Assessments 
Continuous assessment of study-related adverse events (AEs) will be collected. An 
independent Data and Safety Monitoring Board (DSMB) will review events. 
4. Study Design 
LOFT-HF is a Phase 3, multi-center, randomized, double-blind, sham-controlled outcomes trial 
with parallel group design, with patients randomized to either control (optimal GDMT plus sham 
NOXT) or active treatment (optimal GDMT plus NOXT) in a 1:1 ratio. 
4.1. Enrollment 
Participants will be recruited from outpatient clinics and inpatient clinical settings (see Section 
10 for Recruitment Plan). To enrich the study population for morbid and mortal events, we will 
enroll at least 30% of patients with poor prognostic markers, such as HF hospitalization within 
the prior year and/or elevated outpatient BNP or NTproBNP level. Those screened from 
inpatient settings for decompensated HF and without a previous clinical sleep study within the 
past 12 months can be screened prior to hospital discharge, when in a stable, optimized health, 
using the research PSG device. Baseline morbidity measurements will be continuously 
monitored to ensure that the study enrolls a high morbidity group (recruitment strategies will be 
changed if departures from expectation are observed.) 
Patients will be screened for SDB, as detailed in Section 8.2. Screening will be documented in a 
screening log. Based on the assumptions detailed in the sample size calculation (see Section 
11.2 for Sample Size Calculation), including a 35% screen positive rate by sleep study, a total of 
2,450 patients will need to be screened with sleep studies to randomize a total of 858 patients 
(429 per arm) eligible patients. 
Written informed consent must be obtained prior to any study related procedure. Before final 
enrolment, all eligibility criteria must be checked by filling in the inclusion/exclusion criteria case 
report form (CRF) and entered and verified into a secure study web portal.  
4.2. Start-Up Phase 
There will be a 3-month start-up phase with a limited number of 10 centers participating to 


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randomize the first 20 patients. At the end of the start-up phase there will be a feasibility-check 
performed by the Steering Committee and the study sponsor, the National Heart, Lung, and 
Blood Institute (NHLBI). The Steering Committee, with input from the NHLBI, will decide on the 
need for changes of study procedures and the need for amendments of the study protocol, if 
required. 
4.3. Study duration 
Following the start-up phase, the total study duration is expected to be 4.5 years. Patients will 
be followed up on average for a period of about 2.49 years. All patients will be followed, until the 
last patient randomized completes 6 months of follow up. Thus, minimum follow up time will be 
6 months, and maximum follow up is anticipated to be about 4.5 years. With a randomization 
rate of 0.35 patients per center per month, 838 patients will be randomized over approximately 
54 months of enrollment (although this period may be extended based on COVID-19 pandemic-
related enrollment delays).  Enrollment contingencies are planned, should the actual 
randomization rate be higher or lower than that assumed (see Section 10.4.3). 
5. Selection and withdrawal of patients 
5.1. Informed Consent 
Signed written informed consent forms, written in accordance with country-specific applicable 
data privacy acts, the Declaration of Helsinki, and the responsible central IRB, will be obtained 
from all patients prior to any study-related procedure.  
The investigator or responsible staff will explain the nature, purpose and risks of the study and 
provide the patient with a copy of the patient informed consent form. The patient will be given 
sufficient time to consider the study's implications before deciding whether to participate. 
Completion of the informed consent process can occur in-person and/or through remote 
encounters. Acceptable remote methods of consent include mailing, emailing, and/or faxing of 
consent documents and telephone or video contact with potential research subjects. REDCap 
and other 21CFR Part 11 capable and HIPAA compliant electronic data capture systems can be 
used for documentation of the informed consent process. Regardless of the method used, the 
informed consent process needs to ensure that all elements of informed consent are adhered 
to. The manner in which the informed consent process is completed should be fully documented 
and stored in study files. 
Should there be any amendments to the protocol, such that would directly affect the patient’s 
participation in the study (e.g. a change in any procedure), the informed consent form will be 
amended to incorporate this modification and the patient must agree to sign this amended form 
indicating that they re-consent to participate in the modified study. 
A signed copy of the patient’s informed consent form must be maintained in the study files. The 
patient’s permanent medical records should indicate that the patient has been included in the 
study. 
5.2. Study Population 
The intended population for this study is patients with HFrEF and predominant CSA. Eligible 
subjects meeting inclusion/exclusion criteria will be considered for the study. Patients will be 
recruited from investigators’ cardiology and sleep practices and from the institution’s broad 
referral network. 


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Number of Patients 
The hypothesized treatment effect is a 20% annual reduction in the primary endpoint (all-cause 
death, life-saving CV interventions, or hospitalization for worsening HF). This treatment effect is 
comparable to established therapies for the treatment of HF, such as renin-angiotensin system 
inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. A total sample of 858 
subjects (429 in each arm) achieves 90% power at a 5% significance level to detect a hazard 
ratio (HR) of 0.755, when the annual event rate in the control group is 40%, using a two-sided 
logrank test, assuming a 10% lost to follow-up rate and a 5% cross-over rate. (see Section 11.4 
for Sample Size Calculation) 
 
Patient Inclusion Criteria 
• 
Age ≥ 21 years 
• 
History of chronic, stable HFrEF with a left ventricular ejection fraction (LVEF) ≤ 50%, 
determined by echocardiography, radionuclide angiography, left ventriculography, or 
cardiac magnetic resonance imaging, 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: 
a.  at least 1 hospitalization for HF within the 24 months prior to enrollment or 
b.  a BMI corrected BNP ≥ 300 pg/ml or a corrected NT-proBNP ≥ 1500 pg/ml or 
c.  an ED visit for HF exacerbation where the patient has received an IV diuretic within 12 
months of enrollment 
• 
Treatment with stable, optimized GDMT or best tolerated 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 
GDMT 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 IRB-approved informed consent 
(including HIPAA authorization in the U.S.) 
 
Patient Exclusion Criteria 
• 
Current positive airway pressure use or predominantly obstructive rather than central 
sleep apnea 
• 
Oxygen saturation < 90% at rest during the day 
• 
Chronic daytime or nighttime use of supplemental oxygen 
• 
Nocturnal oxygen saturation < 88% for > 5 minutes unaccompanied by apneas or 
hypopneas 
• 
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 COPD with FEV1 < 
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• 
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) 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 
5.3. Stopping and Discontinuation Criteria 
When the study is terminated, the nature of termination will be documented (scheduled end or 
early discontinuation with justification). Discontinuation of the study will be communicated in 
writing and will be a decision of the Steering Committee, with input from the NHLBI. 
 
Discontinuation Criteria Related to the Study 
Discontinuation of the study may be decided due to efficacy criteria or adverse events in either 
study group at the discretion of the Steering Committee and the Data and Safety Monitoring 
Board (DSMB), with input from the NHLBI. The DSMB may recommend early termination of the 
trial for overwhelming evidence of patient benefit or harm, associated with the intervention. 
Discontinuation of the study can also be decided if patients cannot be recruited in sufficient 
numbers within a certain time period (i.e., if enrollment milestones are not substantively met).  
 
Discontinuation Criteria Related to the Patient 
The patients will be advised in the informed consent form that they have the right to withdraw 
from the study at any time without prejudice. In the event that a patient drops out of the study, a 
study stop form will be completed. In the study stop form, the investigator will record the date 
and the reason of the individual study termination. The patient will be informed that, in addition 
to their withdrawal, they can request that none of their data should be analyzed. Otherwise, their 
data remains in the intention-to-treat group. 
Reasonable effort will be made to contact any patient lost to follow up during the course of the 
study, unless they have withdrawn consent and request that no additional contact be made, in 
order to complete assessments and retrieve any outstanding data and study supplies. 
Once randomized, the patient stays within their group regardless of changes in NOXT 
treatment, and will be followed to the end of the study. An exception is women who become 
pregnant during the study, who will be discontinued from the study once pregnancy is identified. 


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Follow-up will also be stopped (data censured) in patients who reach the endpoints of cardiac 
transplantation or LVAD implantation. Those patients in whom protocol deviation or violation is 
noticed will remain in the intention-to-treat group and will be followed according to protocol. If a 
patient from the control group gets NOXT, they will also remain in the study and will be followed 
according to protocol. 
Patients other than those who experience pregnancy, cardiac transplantation or LVAD implants 
will be followed according to the study protocol, regardless of whether they experience a 
primary endpoint. This will allow for recurrent event analyses. 
Study therapy may be stopped in several circumstances: a) by participant request; b) if the 
participant’s clinical situation changes and his provider prescribes oxygen therapy indefinitely or 
other therapy that precludes use of oxygen; or c) the participants become pregnant, undergoes 
cardiac transplantation or LVAD implant. All attempts will be made to continue outcomes 
assessments on these patients. 
5.4. Randomization 
Patients meeting all of the inclusion and none of the exclusion criteria will be randomized to one 
of two groups, a control group receiving optimal GDMT and sham NOXT and a treatment group 
receiving optimal GDMT and active NOXT. 
Patients will be randomly assigned to one of the two study groups in a 1:1 ratio using a 
permuted block design, stratified by the presence or absence of high-risk markers 
(hospitalization for HF in the last 12 months and/or an elevated outpatient BNP or NTproBNP 
level), within sites. Eligible participants will be randomized via a web-based randomization 
module, initiated by the research coordinator at the participating clinical center. The data 
management system will confirm all eligibility criteria, and will deliver a randomization identifier 
(e.g., A or B). Randomization codes also will be linked to identifiers of each oxygen 
concentrator, providing the ability to assign a participant a concentrator without unblinding local 
staff. The randomization distributions and system will be re-assessed on a quarterly basis to 
ensure that it is working as expected. To minimize problems with connectivity, staff will be asked 
to confirm Internet connectivity at the beginning of the baseline visit to avoid any problems with 
entry of the randomization case report form. If problems arise with connectivity during a given 
baseline visit, site staff will be asked to immediately contact the Data Coordinating Center to 
resolve these; a manually generated randomization assignment would then be generated based 
upon the subject stratification factor. 
6. Investigational Intervention 
6.1. General Approach 
All patients (treatment and control) will receive standardized sleep education addressing 
sleep hygiene recommendations that provide guidance on regular bed and wake times; 
avoidance of alcohol, caffeine, and excessive fluid and food consumption before bedtime; 
sleeping in dark, cool, and quiet quarters; use of the bed for sleep and intimacy only; 
avoidance of excessive napping; and avoidance of TV or light exposure before bedtime. 
At the end of the baseline visit, after randomization, arrangements will be made to provide each 
participant a Philips-Respironics Everflo stationary unit concentrator (active or sham) for in-
home use, with optional humidification. This may be through a DME or other local resources. 
Each unit will contain Bluetooth central monitoring capacity, providing ongoing real-time use 


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monitoring (indications of flow rates and flow rate changes). The sham model delivers 
pressurized room air, providing the same sounds and appearances as the active device. 
Inventories for each device (serial numbers, sham versus active) will be monitored at SRC, and 
the SRC will instruct the local staff/DME provider as to which specific concentrator (serial 
number to use). 
 
Nocturnal Oxygen Therapy (Treatment Group) 
In the treatment group, supplemental oxygen will be delivered via nasal cannula at a flow rate of 
3L/min. If the patient cannot tolerate this flow rate despite efforts to add humidification, the flow 
may be reduced. 
 
Sham Oxygen (Control Group) 
In the control arm, sham oxygen (pressurized room air) will be delivered via nasal cannula at a 
flow rate of 3L/min. If the patient cannot tolerate this flow rate despite efforts to add 
humidification, the flow may be reduced. 
6.2. Adherence Monitoring and Support 
Each oxygen concentrator (sham and active) will be equipped with sensors for monitoring the 
duration of “on” use and for recording each time an oxygen flow delivery change is made. 
These data, collected using Bluetooth and cloud-based computer technology, will be 
monitored by the SRC at weekly intervals for each participant throughout the duration of the 
study. Sleep Reading Center personnel will be responsible for identifying participants with 
average oxygen or sham use of < 4 hours/night and relaying this information to the relevant 
site for follow-up. Clinical site research staff will query participants on hours of use of oxygen 
(and hours per night of sleep), during each scheduled study call and visit. Clinical site 
research staff will respond to reports of low adherence by contacting participants by phone to 
identify possible barriers, concerns, or side-effects that may influence treatment adherence. 
Following a protocolized telephone-based adherence intervention modeled after ones that 
have been developed for CPAP (44), they will engage in problem solving, implementing 
recommend changes such as the addition of humidification (for dryness or nasal discomfort) 
or changes to address noise. The SRC will centrally train site personnel on techniques of 
motivational enhancement therapy (MET), a client-centered counseling style designed to 
increase intrinsic motivation and resolve ambivalence about health behavior change (45,46). 
Sleep Reading Center personnel recently demonstrated a 1.7 hours/night increase in average 
adherence to CPAP resulting from a simple MET program (44). With the participant’s 
permission, a behavioral sleep therapist may join selected calls with the participant and site 
staff to reinforce MET techniques. The participant and coordinator will be asked not to use 
any identifying language in order to avoid sharing any PHI the behavioral sleep therapist. Site 
staff will contact the SRC should problems related to side effects or resistance to treatment be 
identified that cannot be resolved using the study protocol, and to discuss any interruptions in 
therapy (due to intercurrent illnesses or other issues). Staff will identify if alternative 
approaches are needed, consulting with study investigators as needed. All interactions 
related to adherence (and potential adverse events) will be recorded on Clinical Report 
Forms.  
6.3. Required Training 
Site staff and/or the DME provider will instruct patients on usage of the device. The SRC is 
responsible for site staff training and certification. 


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6.4. Concomitant Therapy 
All participants will be recruited from centers with expertise in managing HF and will be 
managed with optimal GDMT for HF, according to applicable guidelines in the U.S. (47,48) 
and Canada (49), including subsequent guideline updates, 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 GDMT will be documented, as will post-randomization changes in 
GDMT. 
7. 
Assessing and Reporting of Adverse Events 
7.1. Adverse Events 
Generally, an Adverse Event (AE) is any untoward clinical occurrence in a study patient. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease. Some AEs may meet the definition of Serious Adverse Event 
(SAE). Adverse events are either expected or unexpected. Adverse events may also be 
Unanticipated Problems.  
 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward occurrence or effect that: 
• 
Results in death 
• 
Is life threatening 
• 
Requires inpatient unplanned hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
More than one of the criteria above can be applicable to one event. 
Death 
Death is defined as either irreversible cessation of circulatory and respiratory functions, or 
irreversible cessation of all functions of the entire brain, including the brain stem. A 
determination of death must be made in accordance with accepted medical standards. Thereby 
the condition leading to death is absolutely circumstantial, whether it occurs as outcome of 
disease or unnatural causes such as accidents. Efforts will be made to avoid double 
documentation of death as an outcome of other SAEs and as a dedicated SAE itself. 
Life-threatening 
The definition of a SAE refers to an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event that hypothetically might have caused death, if it was 
more severe. 
Hospitalization 
Is defined as inpatient care of more than one calendar day (overnight admission). Admission for 
ambulatory diagnostic procedures, overnight observation visits, or ambulatory visits to an 
emergency ward are not considered hospitalizations for the purpose of SAE reporting, unless 
any of the other criteria for serious is met. 
 
Expected Adverse Events 
An Expected AE is an AE for which the nature, severity, or degree of incidence is known and 
identified in the product labeling, published literature, or study protocol or follows the natural 


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progression of or results from routine treatment of any underlying disease, disorder, or 
condition of the participant experience the AE. Expected AEs associated with 
polysomnography, the delivery of NOXT using nasal cannula and an oxygen concentrator, 
and study participation include: skin irritation (e.g., nose or nares, upper lip, face, area 
above/behind ears); nasal irritation, inflammation, or dryness; nosebleeds; rhinitis; sinusitis; 
potential increased incidence of other upper respiratory infection; headache; noise irritation: 
disrupted sleep; anxiety; falls (tripping over tubing or concentrator); fire hazard; oxygen 
toxicity. The risk of nosebleeds may be increased in a subset of the study population 
prescribed an oral anticoagulant or those on antiplatelet (especially dual antiplatelet) 
therapy. This risk will be mitigated through the provision of humidification to any patient 
complaining of nasal dryness or discomfort. Excluding patients and/or patients with a bed 
partner who smokes in bed will mitigate the risk of fire. Patients will also be instructed to 
avoid the use of (flammable) petroleum-based lotions or creams, like Vaseline, on their face, 
neck, or upper chest. Patients will be warned about the fall-risk associated with oxygen 
tubing and the concentrator and instructed on how to avoid tripping, especially when 
awakening at night to use the bathroom or first thing in the morning, through awareness and 
through optimal positioning of the concentrator and tubing. Investigators must report any 
suspected Exemplar Expected AEs above thresholds outlined in the Manual of Procedures 
(MOP) to the DCC, as soon as possible and within the timeframe specified in the MOP 
following discovery of the event. 
 
 
 Unanticipated Problems 
An unanticipated problem includes any incident, experience, or outcome that meets all of the 
following criteria: 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
• 
related or possibly related to participation in the research as defined in the MOP; and 
• 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2. Recording and Reporting Adverse Events 
At each evaluation, the investigator or research coordinator will determine whether any 
adverse events (AEs) have occurred. In this trial, all AEs that occur between enrollment and 
subject exit will be documented in a timely manner and reported to the Data Coordinating 
Center (DCC). Investigators must report any serious adverse events (SAEs) that are also 
Unanticipated Problems (events that are unexpected, related or possibly related to the 
research, and suggest a greater risk of harm to participants or others. to the DCC as soon as 
possible but no later than 7 days following discovery of the event. The investigator at the site 
should follow subjects with AEs until the AE has resolved, the condition has stabilized, or the 
subject exits the trial, and report such follow-up information to the DCC. AEs will be recorded 
in detail on an AE electronic Case Report Form (eCRF). A description of the event, its 
severity, and its relatedness to the study intervention will be documented, as well as the 
resolution of the event. The investigator at the site will adjudicate AEs and assure patient 


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safety, the DSMB chairperson will receive real-time reports of all USAEs, and the DSMB will 
periodically review aggregated AE data. 
8. 
Study Schedule 
8.1. Study Entry 
A patient meets eligibility criteria of the study if the following characteristics are present and 
documented:  all of the inclusion criteria (see Section 6.2.2.) are met and none of the exclusion 
criteria (see Section 6.2.3.) are met. 
8.2. Follow Up and Procedures during the Study Visits/Calls 
In-clinic study or remote visits will occur at Screening/Consent, Baseline, 6 months, and 12 
months. Telephone follow-up will occur at 1 month, 3 months, 9 months, and 18 months, and 
then every 6 months after that, until the last participant completes the study. There will be a 
telephone assessment for each patient at the end of the study, for final ascertainment of mortal 
and morbid events. Patients potentially meeting eligibility criteria will be consented for further 
screening. There are two pathways for determination of CSA eligibility for the LOFT-HF trial: a 
clinical sleep study, polysomnography or home sleep apnea test within 12 months prior to 
randomization; or a research polysomnogram obtained at home or prior to hospital discharge, 
when the participant is considered at a baseline, stable condition. The research PSG device is 
designed for unattended sleep monitoring and contains high quality sensors for quantifying 
ventilation and oxygenation, and has the ability to measure EEG using self-applied sensors. 
Participants will be instructed on how to apply several simple electrodes at home before bed, 
and return the devices by courier, mail, or direct pick up or drop off. For studies done in the in- 
patient setting, sensors will be applied by research personnel. 
After the results of the clinically-obtained or research PSG are obtained and centrally scored by 
the SRC, patients meeting sleep eligibility criteria will be invited to participate in a brief baseline 
examination (remote or in-person) which will include administration of questionnaires (patient-
reported outcomes). At the end of the visit, patients will be randomized (stratified by center and 
the presence or absence of high-risk markers) to sham oxygen (control group) or to NOXT 
(treatment group). All participants will receive standardized sleep education. A Philips- 
Respironics EverFlo stationary concentrator for in-home use will be provided to each participant. 
Devices will be delivered and installed and patients educated on their use by study staff and/or 
vendors with established agreements with the study (through a DME company, similar to the 
INOX trial [https://clinicaltrials.gov; NCT01044628]). 
Participants will be contacted by telephone (at 1 month, 3 months, 9 months, and 18 months, 
and then every 6 months after that, until the last participant completes the study) for adverse 
event and clinical outcomes surveillance. Adverse events and the primary endpoints will be 
followed until the last subject has undergone a 6-month exam. At 6 and 12 months, subjects will 
be asked to complete the patient-reported outcomes questionnaires. At study end, each patient 
and their physician will be provided a copy of relevant clinical information and be offered 
facilitated referral to a sleep specialist to determine appropriate management of their sleep 
disorder. Patient-reported outcomes will be collected via validated questionnaires, including the 
Kansas City Cardiomyopathy Questionnaire (KCCQ), the EuroQol 5D (EQ-5D), the Patient 
Health Questionnaire-8 (PHQ-8), and the Patient-Reported Outcomes Measurement 
Information System (PROMIS) Sleep Disturbance and Sleep-Related Impairment 
Questionnaires. Site personnel will administer these questionnaires, using standard scripted 


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instructions to patients. 
In general, reasonable effort will be undertaken and documented to obtain complete follow up. 
All follow up visits and calls should be performed within visit windows detailed in Section 8.3, 
calculated from the date of randomization. 
During each study visit and call, the medication taken by the patient as well as the dosage will 
be recorded. Also, patients will be asked if they take their medication regularly. 
Authorized study personnel will document all data requested carefully in the eCRFs, as soon as 
possible. 
8.3. Follow-up Sleep Study and De-briefing Visit 
Before the De-briefing Visit, participants will undergo a repeat in-home sleep assessment to 
serve two purposes: a) provide critical clinical data for use in transitioning to routine clinic care; 
and b) to maximize the scientific impact of the LOFT-HF study. Participants will be contacted by 
phone, mail, and/or in-person (coordinating with regularly scheduled clinic or research visits) 
and offered the opportunity to undergo a repeat in-home research sleep study. The equipment 
and procedures are the same as described for the research sleep screening visit other than 
participants will be asked to use their assigned LOFT-HF study treatment during the study and 
not use the nasal pressure cannula. (The two cannot easily be used together). Devices and 
equipment will be distributed and returned in-person, by courier, or mail. Study data will be 
analysed by the BWH SRC, and reports generated with summary data from the overnight sleep 
study. 
 
At the time of the De-briefing Visit, held on or after Dec 15 2021, when study follow-up will stop, 
the coordinator will complete assessments for study intervention (sham/NOXT) adherence; 
collect any pending research data not previously collected (e.g., missing questionnaires);  
assess for new AEs that occurred up until the final study follow-up date; determine if any 
medication changes have occurred since last contact thought Dec 15 2021; determine if any 
clinical outcomes events have occurred through Dec 15 2021;  and complete a general rating of 
improvement/satisfaction survey. After these data are collected, Participants will be provided 
with a letter that informs the participant of which arm they were randomized to and the results of 
the baseline and follow-up sleep studies. Participants will be encouraged to discuss further 
clinical management with their physicians; if needed, the participant  will be provided a list of 
local sleep specialists to access for further clinical follow-up.  The coordinator will arrange for 
return of the oxygen concentrator for final equipment disposition, and if requested, provide a 
letter to the PCP for continuity of care. 
8.4. Detailed Visit Schedule 
Screening/Consent 
1. Obtain signed written consent 
2. Document patient demographics (Health Questionnaire CRF) 
3. Perform medical history (Health Questionnaire CRF) and medication review. 
Completion of a physical examination is optional.  Results of a recently completed 
physical examination during a clinical encounter may be recorded.  The site may 
perform a physical examination at the discretion of the PI either in-person or via 
telehealth. 


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4. Evaluate NYHA classification 
5. Document that all of the inclusion criteria (except for the sleep eligibility criteria) and 
none of the exclusion criteria are met (this defines a potentially eligible study 
patient) 
6. Submit de-identified clinical sleep studies to the SRC or administer in-home PSG (if 
sleep eligibility criteria are met, this defines an eligible patient) 
Baseline Visit (to occur within 2 weeks of final eligibility [sleep eligibility] screening) 
1. If interim clinical change, repeat medical history and medication review, and 
reassess NYHA classification. A physical examination is optional. 
2. Administer KCCQ, EQ-5D, PHQ-8, and PROMIS questionnaires 
3. Provide standard sleep education 
4. Randomize patient (within 48 hours of Baseline Visit) 
5. Arrange for immediate delivery of oxygen concentrator, by contracted DME 
provider or staff, for in-home use  
(Note: measures that were not completed during the screening visit and not 
required to determine eligibility, may be collected at the Baseline Visit.) 
1-Month Follow Up Call (± 1 week) 
1. Assess for study intervention (sham/NOXT) adherence (Phone contact CRF) 
2. Assess for AEs (Phone contact CRF) 
3. Determine if any medication changes have occurred since last contact (Phone 
contact CRF) 
4. Determine if any clinical outcomes events have occurred since last contact (Phone 
contact CRF) 
3-Month Follow Up Call (± 10 days) 
1. Assess for study intervention (sham/NOXT) adherence (Phone contact CRF) 
2. Assess for AEs (Phone contact CRF) 
3. Determine if any medication changes have occurred since last contact (Phone 
contact CRF) 
4. Determine if any clinical outcomes events have occurred since last contact (Phone 
contact CRF) 
6-Month In-Clinic or Remote Follow Up Visit (± 2 weeks) 
1. Assess for study intervention (sham/NOXT) adherence (Phone contact CRF) 
2. Assess for AEs (Phone contact CRF) 
3. Determine if any medication changes have occurred since last contact (Phone 
contact CRF) 
4. Determine if any clinical outcomes events have occurred since last contact (Phone 
contact CRF) 
5. Perform medical history (Health Questionnaire CRF) and medication review. A 


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physical examination is optional. 
6. Evaluate NYHA classification 
7. Administer KCCQ, EQ-5D, PHQ-8, and PROMIS questionnaires 
9-Month Follow Up Call (± 2 weeks) 
1. Assess for study intervention (sham/NOXT) adherence (Phone contact CRF) 
2. Assess for AEs (Phone contact CRF) 
3. Determine if any medication changes have occurred since last contact (Phone 
contact CRF) 
4. Determine if any clinical outcomes events have occurred since last contact (Phone 
contact CRF) 
12-Month In-Clinic or Remote Follow Up Visit (± 2 weeks) 
1. Assess for study intervention (sham/NOXT) adherence (Phone contact CRF) 
2. Assess for AEs (Phone contact CRF) 
3. Determine if any medication changes have occurred since last contact (Phone 
contact CRF) 
4. Determine if any clinical outcomes events have occurred since last contact (Phone 
contact CRF) 
5. Perform medical history (Health Questionnaire CRF) and medication review. A 
physical examination is optional. 
6. Evaluate NYHA classification 
7. Administer KCCQ, EQ-5D, PHQ-8, and PROMIS questionnaires 
18-Month and Every 6 Months Thereafter Follow Up Calls (± 4 weeks) 
1. Assess for study intervention (sham/NOXT) adherence (Phone contact CRF) 
2. Assess for AEs (Phone contact CRF) 
3. Determine if any medication changes have occurred since last contact (Phone 
contact CRF) 
4. Determine if any clinical outcomes events have occurred since last contact (Phone 
contact CRF) 
Follow-up Sleep Study (within 8 weeks of De-briefing Visit) 
1. Obtain signed written consent 
2. Administer in-home PSG 
De-briefing Visit: (within 6 weeks of the final randomized participant’s 6 month visit) 
1. Assess for study intervention (sham/NOXT) adherence (Phone contact CRF) 
2. Assess for AEs (Phone contact CRF) 
3. Determine if any medication changes have occurred since last contact (Phone 
contact CRF) 
4. Determine if any clinical outcomes events have occurred since last contact (Phone 


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contact CRF) 
5. Administer Satisfaction SurveyReview Feedback Letter 
6. Arrange for return of oxygen concentrator and referral for further clinical care 
8.5. Screening Polysomnography 
For participants without qualifying clinical sleep studies and not studied during an in- patient 
stay, in-home polysomnography will be performed using an approach that has low participant 
and site burden, high accuracy, and is amenable to high levels of standardization. 
Participants will be evaluated in their homes using a lightweight (4.6 oz), state-of-the art, PSG 
data collection system (Nox A1 PSG; Nox Medical, Reykjavik, IC), with all data centrally 
scored by research technicians blinded to all other data. The monitoring device is fully 
compliant with American Academy of Sleep Medicine (AASM) standards, with capacity for 
acquiring high resolution signal quality through 32-bit signal processing and 256 kHz sampling 
on all channels, providing advanced noise reduction and anti-aliasing. The system uses one 
AA battery that supplies power for up to 12 hours and has 1 GB of data collection capacity per 
study. The key respiratory data recommended for identifying apneas and hypopneas will be 
collected: airflow (via a nasal pressure cannula, DC-coupled for linearization), respiratory 
effort (high resolution thoracic and abdominal inductance plethysmography bands), and pulse 
oximetry. Heart rate will be measured by ECG sensors. A simplified self-applied frontal EEG 
system applied near the hairline will provide information to estimate sleep-wake time and 
identify arousals. Participant burden will be minimized by the use of the Bluetooth enabled 
oximeter, eliminating the need for cables connecting the finger to a recorder, and through use 
of self-adhesive electrode pads that are yoked to a single cable. 
The PSG devices will be dispensed at the screening visit by staff who will be trained and 
certified to configure, dispense, download data, and maintain the device. (If this visit is done 
remotely, the device will be mailed to the participant, along with an instructional video, with 
follow-up phone/video-based instructions). An operations manual specific to the LOFT-HF 
sleep study procedure will document each step and that provide site research staff specific 
instructions on the sleep study process, including the purpose of each sensor. At the end of 
the screening visit, participants (and their partners when available) will be provided simple 
instruction brochures with pictures that show the placement of each sensor and videos via a 
CD or web app. The brochure will provide information on who to contact should any questions 
or problems arise after the clinic visit, and will detail how to remove the sensors and return the 
device to the clinic. Participants undergoing the in-home PSG will be asked to practice using 
the device at the study clinic visit and will be provided ample time to ask any questions about 
the home sleep study process. When the devices are returned (by courier, staff pick up, or 
mail, according to site preference), the sleep data containing a participant and site ID and 
date but no other identifying data will be transmitted electronically to the SRC. The SRC will 
provide consistent and accurate scoring of all data, blinded to participant information, for 
evaluating subject eligibility, identifying urgent alerts (see Human Subjects), and for 
quantifying quantitative metrics for use for predictive modeling. Within two business days, 
sites will receive electronic reports indicating eligibility status (based on PSG criteria), urgent 
referrals, and quality grades for each study. Studies that do not meet minimal criteria for 
acceptability (> 2 hours of artifact free data during the sleep period on respiratory bands, 
airflow, and oximetry) will be repeated. 


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Patients recruited during an in-patient hospitalization may undergo a bedside research 
polysomnography study prior to discharge, when their providers determine their clinical status 
is near or at baseline. In that circumstance, after research personnel obtain consent, they will 
directly attach the research polysomnography sensors using the same protocol as provided to 
patients for self-application for home studies. 
Clinical sleep studies performed within 12 months of enrollment will be transferred 
electronically to the SRC where they will be scored using approaches as similar as possible to 
the research studies. Studies will be considered for eligibility are those that include at least 4 
hours of overnight monitoring, were collected using AASM approved guidelines, and 
performed within 12months of the baseline visit and at a time when clinically stable (i.e., not in 
acute decompensation). The sleep study will need to be exported as an EDF file, removing 
name, MRN, and other identifying information other than date of study. Studies will be 
transferred via a secure process to the DCC for scoring to evaluate eligibility. 
8.6. Questionnaires 
Study staff will instruct participants on questionnaire completion using standardized scripts. 
Questionnaire responses will be directly obtained from participants using electronic tablets 
configured with a streamlined user interface, with appropriate font sizes for an older 
(frequently Medicare-aged) population. An integrated web application allows progress in 
completion to be tracked with a parallel display on a second device, enabling staff to assist 
with questionnaire completion as needed. Forms require all items to be completed before 
each is closed. Staff will undergo centralized training in use of the electronic data capture 
system and submit a test sample of data, as part of certification procedures. Each form will 
have a “Q by Q” guide (specifying responses to sample questions participants may have for 
each question/item) for staff to refer to if participants raise questions during form completion, 
supporting consistency. 
• 
Kansas City Cardiomyopathy Questionnaire:  The KCCQ is a validated 23-item instrument 
that quantifies physical function, symptoms (frequency, severity, and recent change), 
social function, self-efficacy and knowledge, and quality of life in patients with HF (52). It is 
considered to be a clinically meaningful outcome relevant for research, patient 
management, and quality assessment (52). A change of 5 points is considered to be 
clinically significant. 
• 
EuroQol 5D:  The EQ-5D assesses preference-based health-related quality of life. It is 
comprised of a descriptive profile and a single-index visual analogue scale (VAS) (52). It 
has excellent psychometric properties in patients with HF and cardiac diseases (53,54). 
The descriptive profile assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Responses can be mapped to previously derived 
utility weights, reflecting society’s ratings of the desirability of a given health state. The 
VAS records the patient’s personal perspective of their current health status (55,56). 
• 
Patient Health Questionnaire-8:  The PHQ-8 provides a psychometrically valid measure of 
depression, a common concern in patients with sleep apnea and HF. The PHQ-8 is an 8-
item depression questionnaire with scores categorized as 0-4 (no/minimal depressive 
symptoms), 5-9 (mild depressive symptoms), 10-14 (moderate depressive symptoms), 15-
19 (moderate-severe depressive symptoms), and 20-26 (severe depressive symptoms) 
(57). A PHQ score ≥ 10 has been shown to have a specificity of 90%, sensitivity of 54%, 
and a negative predictive value of 88% for detecting depression (58,59).  It has been used 
in heart failure populations to characterize depression (60,61). 


LOFT-HF Study 
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34 
 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep 
Disturbance and Sleep-Related Impairment item banks:  These two 8-item questionnaires 
assess self-perceived sleep quality, sleep depth, and sleep restoration. They are designed 
using item response theory to gauge the severity of sleep-wake problems on a continuum, 
applicable across a range of conditions and have high measurement reliability and 
precision (62). 
8.7. Clinical Outcomes 
A CEC will be responsible for finalizing event definitions in a CEC Manual of Operations and 
adjudicating each of the primary endpoint events, blinded to study assignment. Brief 
definitions of endpoint events follow, to provide guidance to the CEC development of event 
definitions. 
 
Death 
Death is defined as either irreversible cessation of circulatory and respiratory functions, or 
irreversible cessation of all functions of the entire brain, including the brain stem. A 
determination of death must be made in accordance with accepted medical standards. The 
CEC will adjudicate the cause of death. While all-cause mortality is a component of the 
primary endpoint, important secondary endpoints evaluate cause-specific mortality particularly 
CV death. Deaths will be considered cardiovascular unless a specific non-cardiovascular 
cause is identified. Deaths classified as “Unknown” will be considered cardiovascular. 
Cardiovascular death will include such occurrences as death due to sudden cardiac death, 
heart failure, myocardial infarction (MI), cerebrovascular accident (CVA), CV procedure death, 
other cardiac death (e.g., death from valvular heart disease), and other vascular death (e.g., 
death from pulmonary embolism, aortic dissection, or aortic rupture). 
 
Life-saving Cardiovascular Interventions 
Life-saving CV interventions will be identified using criteria that are considered as being 
equivalent to HF-related death (i.e., progressive pump dysfunction or sudden [arrhythmic] 
cardiac death), including cardiac transplantation, long-term ventricular assist device 
implantation, resuscitation of sudden cardiac arrest, or shock from an implantable 
cardioverter-defibrillator (ICD) associated with sudden loss of consciousness associated with 
ventricular tachycardia or ventricular fibrillation. 
 
Hospitalization 
Hospitalization will be defined as a non-elective hospital stay (inpatient, observation, or 
emergency department [ED] stay) for medical or surgical therapy. Observation and ED stays 
are included in this definition, given growing financial incentives to hospitals to treat patients 
in these settings, rather than in the setting of a true Medicare-qualifying inpatient admission. 
This is especially true in an era of heightened efforts to avoid HF hospitalizations, to avoid 
Medicare reimbursement penalties. A hospitalization classification will be based on the 
primary reason for which the subject was admitted, not on the development of new events 
that occur during the hospitalization or if the subject had additional conditions at the time of 
admission that were not the primary reason for the admission. The CEC will develop 
definitions to describe hospitalization for HF, other CV causes (e.g., acute MI, cardiac arrest, 
CVA, TIA, or pulmonary thromboembolism), and non-cardiovascular causes. 
 


LOFT-HF Study 
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35 
 
8.8. Overview of Visits 
 
Screening/ 
Consent 
(in clinic****) 
Baseline 
(in clinic****) 
1 Month 
(by phone) 
3 Months 
(by phone) 
6 Months 
(in 
clinic****) 
9 Months 
(by phone) 
12 Months 
(in clinic****) 
18 Months then 
every 6 Months 
(by phone) 
Follow-up 
Sleep 
Study 
De-briefing 
Visit  (by 
phone) 
Consent patient (*) 
✔ 
 
 
 
 
 
 
 
✔ 
 
Patient demographics (Health Questionnaire 
CRF) 
✔ 
 
 
 
 
 
 
 
 
 
Medical history (Health 
Questionnaire CRF) and optional 
physical  examination 
✔ 
(**) 
 
 
✔ 
 
✔ 
 
 
 
Medication review 
✔ 
(**) 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
Assess NYHA Class 
✔ 
(**) 
 
 
✔ 
 
✔ 
 
 
 
Document inclusion/exclusion criteria 
✔ 
 
 
 
 
 
 
 
 
 
Administer research PSG 
✔ £ 
 
 
 
 
 
 
 
✔ 
 
Randomization 
 
✔ 
 
 
 
 
 
 
 
 
Provide sleep education 
 
✔ 
 
 
 
 
 
 
 
 
KCCQ, EQ-5D, PHQ-8, PROMIS 
 
✔ 
 
 
✔ 
 
✔ 
 
 
 
Home study therapy concentrator 
delivery (***) 
 
✔ 
 
 
 
 
 
 
 
 
Adherence assessment (Phone contact CRF) 
 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
Clinical outcomes assessment (Phone contact 
CRF) 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
Adverse events monitoring (Phone contact 
CRF) 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
Return of home study therapy concentrator 
 
 
 
 
 
 
 
 
 
✔ 
Satisfaction Survey 
 
 
 
 
 
 
 
 
 
✔ 
Review sleep study reports 
 
 
 
 
 
 
 
 
 
✔ 
Review treatment arm and referral for further 
care 
 
 
 
 
 
 
 
 
 
✔ 
(*) Patients will be re-consented following any protocol amendments requiring changes in the written informed consent form. 
(**) Assessments will be repeated if there has been a change in the patient’s clinical status since screening/consent. 
(***) Arrange for immediate delivery by contracted home DME provider.  
(****) Could occur remotely as needed. 
£ For patients without a clinical qualifying sleep study within the prior 12 months


LOFT-HF Study 
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36 
 
Study Flow Diagram 
 
CSA, central sleep apnea; NOXT, nocturnal oxygen therapy; GDMT, guideline-directed medical therapy; AE, adverse event; 
NYHA, New York Heart Association  
 
 
Active NOXT + GDMT 
Baseline Assessment / Randomization 1:1 
Initial Inclusion / Exclusion Criteria Met 
Sham NOXT + GDMT 
Follow up 6 months (in-person or remote):  Medical history and optional physical 
examination, clinical outcomes assessment, AE monitoring, medication history, 
adherence assessment, NHYA Class assessment, Questionnaires 
Follow up 9 months (by phone): Clinical outcomes assessment, AE monitoring, 
medication history, adherence assessment 
Follow up 3 months (by phone): Clinical outcomes assessment, AE monitoring, 
medication history, adherence assessment 
Follow up 18 months and every 6 months thereafter (by phone): Clinical outcomes 
assessment, AE monitoring, medication history, adherence assessment, assessment of 
study therapy  
Follow up 1 month (by phone): Clinical outcomes assessment, AE monitoring, 
medication history, adherence assessment, assessment of study therapy 
Follow up 12 months (in-person or remote):  Medical history and physical 
examination, clinical outcomes assessment, AE monitoring, medication history, 
adherence assessment, NHYA Class assessment, Questionnaires 
De-briefing Visit: Clinical outcomes assessment, AE monitoring, medication history, 
adherence assessment, satisfaction survey, review sleep studies and treatment arm, 
arrange for return of study therapy concentrator and referral for further clinical care 
Until the last patient 
randomized reaches 6 
months of follow up 
Follow-up sleep study: Consent participant, administer research psg 


LOFT-HF Study 
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37 
 
9. 
Investigative Site Information 
9.1. Investigative Site Selection 
Sites will be selected for participation based on the following criteria: 
• 
A sleep medicine specialist (investigator) with experience and knowledge of SDB 
• 
A cardiologist/HF specialist (investigator) with experience and knowledge of HF 
• 
A large patient population to identify potential candidates for study participation within 
the given study timeframe 
• 
Sufficient resources within the site to conduct the screening, enrollment, data collection, 
and follow-up requirements of all subjects 
• 
Willingness and interest in conducting the study 
Sites will have demonstrated interest and accomplishment in the field of SDB in HF and have 
conducted and/or participated in prior studies in this arena. It is expected that there will be 
coordination between the sleep medicine specialist and cardiologist/HF specialist. The primary 
investigator (PI) is responsible for the overall conduct of the study. The PI may train and 
designate person(s) to conduct study-related activities but must retain overall responsibility for 
the trial. All training and delegation of tasks will be documented. While a single site PI will be 
identified for regulatory (IRB) purposes, the LOFT-HF study will consider the lead sleep 
medicine and the lead cardiologist/HF specialist as Co-PIs, thus promoting close collaboration 
between the two disciplines. These Co-PIs, along with site Co-Investigators and research 
coordinators and the LOFT-HF leadership team, will be referred to as the LOFT-HF Study 
Group.) 
9.2. Site Training 
Protocol-specific training and education customized to the specific roles of all investigational site 
personnel will take place during a central training session, during site visits, and throughout the 
study as needed. All training will be documented and staff will be required to be certified for 
study specific procedures. All study personnel, including new study personnel added during the 
course of the study, must be trained and delegated prior to performing any study-related 
activities. 
10. Recruitment and Retention Plan 
10.1. Site Selection Process 
One of the most important precursors of effective recruitment and retention throughout the 
duration of the LOFT-HF trial is the selection of key clinical research sites with proven 
historical records of strong performance in HF and sleep medicine research trials. To address 
this fundamental base, we have chosen prospective sites using rigorous standards such as 
requiring evidence of investigator trial experiences; sufficient patient population; and detailed 
descriptions of research infrastructure including accreditation, number of experienced 
research personnel, and volume of active trials. Every site chosen by the CCC and DCC has 
established local infrastructures for the performance of clinical studies and proven track 
records of accomplishment in HF and SDB clinical trials which has been documented in 
administered site surveys. Site surveys solicited the following information from each potential 
LOFT-HF site: contact information; estimate of site specific HF and CSA populations including 
volume and demographics; current practices for treatment of CSA in patients with HF at each 


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site; defined referral base; presence of SDB screening in HF program; HF and SDB clinical 
research trial portfolios including site performance metrics; history and findings of FDA audits; 
agreement to Central IRB use; and anticipated timeline for execution of clinical trial 
agreement. In addition, we will require commitment of both a sleep medicine and cardiology 
physician to serve as Co-Principal Investigators in order to ensure symbiotic collaboration in 
identification of at-risk patients and subsequent clinical management. Strategic site selection 
by the CCC and DCC is one of many critical steps in the process of securing target 
enrollment in a timely fashion. 
To complement the process above, we planned on utilizing the Trial Innovation Network (TIN) 
services to identify strategic collaborators in an effort to identify secondary and tertiary sites. 
This TIN collaboration takes place during the UG3 phase. Our aim is to identify a minimum of 
10 sites that would be activated if suboptimal recruitment rates are observed. 
LOFT-HF sites should have expertise in sleep medicine and cardiology in order to ensure 
symbiotic collaboration in identification of at-risk patients and subsequent clinical 
management. 
In addition, as of August 2019, the CCC established a new partnership with the Heart Failure 
Society of America (HFSA) Research Network. This partnership is a novel process that will 
take advantage of an established organization with excellent track records in supporting heart 
failure trials. The new relationship will be on an ongoing process that will continue throughout 
the duration of the trial. The arrangement will allow LOFT-HF to access a vast network of 
vetted research sites to add to or replace non-performing site on ongoing basis. A revised low 
burden-low cost site activation approach, along with vigilant site monitoring plan, combined 
with the TIN and HFSA research network partnership will ensure robust enrollment and 
achievement of accrual targets. 
Another aspect to the partnership with TIN is the relation with an assigned Trial Innovation 
Center (TIC) to develop customized electronic medical record (EMR) feasibility queries to be 
distributed to the Clinical Translational Science Award (CTSA) consortium. 
10.2. Oversight of Enrollment Progress 
The LOFT-HF Executive committee will diligently oversee study progress through regular 
meetings and sophisticated project management tools such as the internet-based software 
application, Slice, that will be used to track enrollment, stratification factors (e.g., proportions 
with high morbidity risk factors) and screen failure rates in real-time. Committee members will 
be responsible for analyzing progress reports, interpreting barriers to enrollment, and 
deploying the appropriate risk mitigation practice (i.e. site-specific additional training, issuing 
broad guidance’s, or protocol amendments). We will use Pareto analysis to capture and 
analyze incidences of screen failures and protocol deviations as one of many tools to identify 
trends in protocol compliance so that preemptive actions can be implemented to avert 
potential endemic complications. 
A Recruitment, Retention, and Operations Subcommittee (RROS) will be established which 
will include Research Coordinators from representative clinical sites, the CCC Project 
Manager, and two site PIs. The committee will design recruitment brochures, oversee the 
development of newsletters, and provide input into developing the community-facing web 
portal. Recruitment and retention statistics will be posted in real-time on a study web site, 
including graphs that show deviations from projections. Sites, which fail to meet projections 
for 2 consecutive months, will be asked to provide a report with an analysis and action plan to 
the Steering Committee. If continued lags are observed, the study PIs (Williams; Redline), in 


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consultation with the DSMB and NHLBI, will determine further actions, which may include 
replacement of the site. 
10.3. Recruitment and Retention Practices 
 The 3E Approach 
The CCC will work closely with the DCC to development training and certification 
requirements during the UG3 phase that is aimed at successful recruitment and retention. We 
plan to use a trident approach to recruitment and retention training that is focused on 
education, empathy, and engagement, the 3E Approach, coined by the OSU Clinical Trials 
Management Organization (CTMO). In our experiences in leading multidisciplinary multi-site 
trials, we believe education is the most powerful tool in the recruitment and retention practices 
toolbox. Extensive training of research personnel will focus on equipping study coordinators 
and study nurses with sufficient knowledge of heart failure and sleep disordered breathing. 
Although we have chosen experienced sites that have performed well in either heart failure or 
sleep medicine research trials, we understand that each site may be organized in disease-
specific groups and as a result, are most well versed in single disease trials. Thus, we will 
need to thoroughly provide all research personnel with information related to the mechanism 
of CSA, the consequences of maintaining a hypoxic state and activated sympathetic nervous 
system in the context of heart failure, the negative relationship between heart failure with 
untreated SDB and mortality and hospital readmissions, and the importance of a 
simultaneous treatment approach. We know that if research personnel understand the 
physiology and scientific basis for the trial, their knowledge may translate into more 
confidence in describing the objectives of trial to at-risk patients which will increase the 
likelihood their message is well-received. Proper education of site research personnel is 
essential for countering misconceptions with evidence-based facts and statistics. The CCC 
and DCC will be responsible for designing and implementing training; however, we will 
encourage site Co-PIs to provide supplemental education to their study coordinators and 
study nurses on a regular basis. 
Drawing from the successes of the OSU Sleep Heart Program, training will encompass the 
importance of empathy in recruiting at-risk patients. Our philosophy has been to “meet people 
where they are” by acknowledging the fears and concerns of patients with heart failure, 
making a genuine effort in understanding their challenges, and exhibiting patience as the 
majority of patients with heart failure are elderly. The training modules will address common 
rationales of prospective patients that research personnel may have to confront and ways of 
handling these situations. We will encourage research personnel that may be arranged on 
disease-specific teams at each site to share experiences with each other and the broader 
community of research personnel across sites via posting comments on the study website. 
The generated discussion should result in the proactive suggestions that will translate into 
better recruitment and retention of participants in the LOFT-HF trial. 
Multi-faceted engagement practices will be stressed in all training initiatives for recruitment 
and retention. Research personnel will be encouraged to form genuine bonds with 
prospective patients and enrolled patients. The training will address the relationship between 
rates of retention of enrolled patients with the formation of good relationships between 
research personnel and patients. In addition to these primary relationships, the training will be 
applicable to the broader heart failure and sleep medicine clinician community at each site. It 
is important to realize that the LOFT-HF trial will not occur in a vacuum; other clinicians must 
be engaged as they will interface with prospective and enrolled patients, delivering care and 


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may be a potential source of referrals. Therefore, training in-services for various clinical teams 
including palliative medicine, patient advocacy groups, and social workers, will be provided at 
the request of each academic site and recruitment materials will be provided to the clinical 
community as a buy-in measure to generate awareness and support of the LOFT-HF trial. 
Training and recruitment materials will explicitly address the relevance of the LOFT-HF trial in 
the context of current international clinical practice post SERVE-HF, thereby presenting a 
compelling argument in favor of the prioritization of LOFT-HF trial in the setting of other 
overlapping clinical trials. OSU CTMO routinely puts this comprehensive approach to 
community engagement into practice during implementation of multi-site research trials. 
Each site also will receive nearly real-time feedback on recruitment activities through the 
study web portal, which displays recruitment graphs by time and site, and includes actual 
versus projected numbers. This provides positive feedback, allows each site actual data to 
examine and use for planning and trouble-shooting, and helps to quickly identify sites (and 
best practices) that can inform study-wide procedures. 
 Screening, Approaching, and Consenting 
The LOFT-HF protocol will be inclusive of multifaceted recruitment practices such as in- 
person recruitment from both HF and sleep clinics and during hospitalization for acute HF, as 
well as mailed SDB screening questionnaires. Study coordinators and nurses will identify 
patients by daily screening of hospital admission rosters for patients diagnosed with acute HF 
and patients scheduled for routine follow-up in outpatient HF clinics. In addition, potential 
research patients will be identified by the Co-PIs, sleep medicine and cardiology providers, as 
well as referrals from patient advocacy groups and the broader clinical community including 
social workers, patient care resource managers, and palliative care specialists. Study 
coordinators and nurses will confirm eligibility thorough review of the medical record, approval 
of site investigators, and approval from the CCC as needed. After initial eligibility criteria are 
confirmed, patients will be asked to undergo an in-home sleep study (PSG) to evaluate SDB if 
needed. Those screened from inpatient settings after admission for decompensated HF and 
without a previous clinical sleep study within the past 12 months can be screened prior to 
hospital discharge, when in a stable optimized health, using the research PSG device. All 
sites will be provided with screening tip cards including inclusion and exclusion criteria and an 
eligibility flowchart. Notably, patients under the age of 21 are ineligible for the trial and will not 
be approached. Women of childbearing potential may be approached and will be eligible for 
the trial once a negative pregnancy test is confirmed. Once Good Clinical Practice (GCP) and 
protocol training has been completed and research personnel have received study 
certifications, those with the delegated authority to consent patients for the LOFT-HF trial, 
primarily study coordinators and nurses, will be responsible for approaching prospective 
patients and initiating and completing the informed consent process. The consenting 
coordinators and nurses will be experienced clinical research professionals as determined 
prior to site activation. Patients will sign an informed consent to authorize participation in the 
study prior to undergoing the sleep study screening procedure or submission of a clinically 
obtained sleep study to the SRC. Patients with confirmed diagnosis of CSA, and otherwise 
eligible, will be eligible to be randomized. Study personnel will record inclusion and exclusion 
criteria in an eCRF. Before final enrollment, these criteria will be entered and verified into a 
secure study web portal. 
The primary PI will be responsible for the overall conduct of the study. The PI may train and 
designate person(s) to conduct study-related activities but must retain overall responsibility for 
the trial. All training and delegation of tasks will be documented. 


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 Recruitment of High-Risk Subgroup 
Participants will be recruited from outpatient clinics and inpatient clinical settings. To study a 
high-risk group we will prioritize recruitment strategies that target patients based on poor 
prognostic markers, including hospitalization within the prior year and/or an elevated BNP or 
NTproBNP level, to meet the goal of recruiting at least 30% of the sample with high-risk 
markers. Moreover, the requirement for CSA alone identifies a population with high event 
rates. We will not use a run-in design that would select samples with better prognosis. Based 
on the assumptions detailed in our power calculation, including a 35% screen positive rate by 
sleep study, we will need to screen a total of 2,450 patients with sleep studies to randomize a 
total of 858 patients (429 per arm). We will stratify randomization based on the presence of 
high-risk markers. We will monitor total event rates by recruitment sources and the presence 
of high-risk markers and adjust recruitment strategies, if needed, to ensure our actual event 
rates are comparable to the estimated event rates. 
10.4. Recruitment Rates, Timelines, and Milestones 
 Year 1:  Start-Up or UG3 Phase 
During the third quarter of Year 1, we will attempt to activate10 clinical sites will be activated. 
The first enrollments will then occur in the last quarter of Year 1, which is anticipated to be in 
May 2019. A total of 20 patients will be targeted for randomization during the last quarter of 
this phase. Before the end of Year 1, an additional 20 sites will be activated to begin 
enrolment at the beginning of Year 2 (the UH3 Phase), bringing the total number of active 
sites to 30. Approximately 10 additional sites will be identified to serve as potential 
replacement sites. During the first quarter of Year 1, we will submit a request for TIN services 
in site identification and we anticipate to meet our target number of secondary and tertiary 
sites by fourth quarter of Year 1. 
 Years 2-5:  Completion of Enrolment or the UH3 Phase 
Assuming the accrual pattern is constant across time (after a slower ramp up in the first year 
for site activation) at 0.35 patients per center per month, the following milestones will be 
reached within 54 months: 25% of target enrollment (n=215) in Jan 2021, 50% of target 
enrollment (n=429) in Jan 2022 75% of target enrollment (n=644) in Jan 2023, and 100% 
enrollment (n=858) in January 2024. 
 Recruitment Rate Contingencies 
Based on prior experience and on a survey of proposed investigational sites, the expected 
rate of randomization is 0.25 patients per center per month. The possible range of assumed 
randomization rates is 0.25-0.5 patients per center per month (or a screening/consent rate of 
about 1.5 to 3 patients per center per month). The revised site number is 50 as discussed 
previously. The decision to open additional sites will be made early based on the monitored 
monthly accrual target. Given the per patient reimbursement to sites, there is little additional 
cost to opening new sites. The updated budget and revised site activation process will ensure 
low cost and burden of adding additional sites. The CCC is committed to cover any cost 
overruns in site initiation fees (estimated to be $40,000 or less) via its own contingency funds, 
if an expansion of sites becomes necessary. Alternatively, the period for patient enrollment 
and randomization could be extended, within the current budget limits. However, this is a less 
preferable contingency, as completion of enrollment and randomization on schedule is 
essential to providing a timely assessment of the central hypothesis of LOFT-HF. 


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10.5. Recruitment and Retention Monitoring 
Successful recruitment and retention are critical for the success of any clinical trial and are 
often more challenging in operation than anticipated during planning. Extensive experience 
with strategies for optimizing recruitment and retention, including careful selection of 
participating sites, ongoing monitoring and real-time feedback, capitating payments, providing 
patient stipends, and sharing expertise across sites in “what works”, will be utilized. Each 
clinical center has experience in sleep and CV trials and has direct access to large numbers 
of patients with HF. Sites have Co-Is with good working relationships and expertise in both 
sleep medicine and cardiology, promoting multi-disciplinary collaboration. A Recruitment, 
Retention and Operations Subcommittee (RROS) will be established that will include 
coordinators from representative clinical sites, the CCC Project Manager, and two site PIs. 
The committee will design recruitment brochures, oversee the development of newsletters, 
and provide input into developing the community-facing web portal. Patient representatives 
from a sleep apnea patient network will provide input into recruitment materials to ensure 
patient-centeredness. The importance of recruitment of women and minorities will be stressed 
during training, and we will work with site personnel to use various recruitment materials in 
ways that that promote recruitment of these populations (i.e. placing materials in women’s 
health clinics and on community accessible websites affiliated with the site). We have 
selected sites from across the U.S. and Canada as another strategy for increasing 
demographic diversity. In addition, the LOFT-HF study will utilize diverse recruitment 
practices including IRB-approved print and electronic versions of recruitment posters, 
pamphlets, letters, and other study promotional advertisements that can be disseminated in 
research and clinical offices and other applicable public spaces and via mail, email, website, 
patient medical record applications, TV and/or radio. 
In addition to patient engagement training, we will offer a participation stipend in order to 
enhance retention. The study will require four in-person or remote study visits including the 
initial screening visit in which patients elect to complete an overnight sleep test if needed and 
three 1-hour in-person or remote visits at baseline, 6 month, and 12 month, as well as 
multiple phone follow ups. Participants can receive check-in by telephone, email and/or text 
messaging in order to maximize retention. Text messaging will only be utilized with 
participants who agree to receive text messages. We will offer a participation stipend. 
Patients will receive research participation stipends at various visit milestones: $50 for each 
in-person visit or remote data collection visit and $20 for phone follow-up. The average total 
stipend of $340 is justifiable reimbursement to compensate patients and for an average of 15 
hours of study time, as well as associated travel times in the region. We anticipate this will 
increase enrollment without introducing selection bias and will improve retention in the study. 
Recruitment and retention statistics will be posted in real-time on a study web site, including 
graphs that show deviations from projections. Sites that fail to meet projections for 2 
consecutive months will be asked to provide a report with an analysis and action plan to the 
Steering Committee. If continued lags are observed, Drs. Williams and Redline, in 
consultation with the Steering Committee and DSMB/NHLBI, will determine further actions, 
which may include replacement of the site. 
11. Statistics 
11.1. Description of Study 
LOFT-HF is a Phase 3, multicenter, randomized, double-blind, sham-controlled outcomes trial 
with parallel group design, with patients randomized to either control (optimal guideline based 
medical treatment [GDMT] plus sham NOXT) or active treatment (optimal GDMT plus NOXT) 


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in a 1:1 ratio. The primary objective is to evaluate the long-term effects of NOXT on the 
mortality and morbidity of patients with stable heart failure with reduced ejection fraction 
(HFrEF), already receiving optimal GDMT who have central sleep apnea (CSA). The 
secondary objectives are to evaluate patient-reported outcomes (disease-specific and generic 
quality of life); disease-specific mortality; and cardiovascular events. Subgroup analyses are 
planned to identify which patients treated with NOXT benefit most based on physiological 
endotypic traits. Adults, ages 21 years and older, with HFrEF and CSA who meet study 
eligibility criteria, will be recruited from approximately 50 well-established cardiovascular 
medicine/sleep centers, and further evaluated with sleep studies to identify the presence of 
CSA. It is anticipated, based on the literature and our experience conducting similar 
screening, that about 35% of participants will be eligible after PSG. Approximately 2,450 
patients will be recruited to undergo PSGs to randomize a total of 858 patients (429 per arm). 
Participants will undergo standardized assessments including anthropometry, blood pressure, 
and questionnaires at baseline and at 6 and 12 month follow-up in-person or remote visits. 
Telephone calls will be conducted at months 1, 3, 9, and every 6 months after the 12 month 
visit until the last participant has completed his 12-month visit. Adverse events, 
hospitalizations and vital status will be collected over the entire intervention period. Given a 
3.5 accrual period, mean follow-up time is estimated at 2.5 years (max 4.5 years). 
11.2. Statistical Analysis Approaches 
Primary analyses will follow the “intention-to-treat” principle; that is, individuals will be 
analyzed according to their assigned treatment group, whether or not they receive the study 
treatment as assigned. Every effort will be made to obtain follow-up data on all randomized 
subjects, whether or not they follow their assigned treatment. Preliminary Analyses 
Our approach will involve close collaboration between clinical experts (on the Steering 
Committee and Scientific Advisory Committee) and biostatisticians, while ensuring 
appropriate blinding. Interim analyses of baseline variables (aggregated across intervention 
groups) will be conducted early in the study to ensure that the collected and derived data 
follow the assumed distributions, and that appropriate methods for identifying outliers and for 
computing clinical scores are implemented. Reports will provide a full description of the 
distributions of each study variable, along with indices of associated data quality, and include 
graphical displays. The amount and patterns of missing data, if any, will be characterized. 
Measures that are not normally distributed may be transformed to meet model assumptions. 
Before conducting final analyses, descriptive statistics will be generated using the total data 
set, ensuring that outliers or potential discrepancies in the data are resolved. 
 Descriptive Comparisons between Treatment Groups at Baseline and Over 
Time 
Descriptive analyses will be performed to characterize the treatment groups, and to confirm 
that the randomization resulted in no important group differences at baseline. Study 
endpoints, dropout rates, cross-over rates, and patterns of missing data will be described. 
Graphical methods such as stem-and-leaf diagrams, boxplots, and scatter plots will be used 
to examine distributions, and guide the choice of transformations.  
 Statistical Approaches to Testing for Treatment Differences 
The primary analysis is in the intention-to-treat population that consists of all patients 
randomized. The primary study endpoint is the time to first event (all-cause death, HF-related 
hospitalization, life-saving CV procedure), as assessed by the CEC. The primary analysis will 


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use a Cox proportional hazard model relating the primary outcome and treatment indicator, 
adjusting for the stratification factor. 
The null hypothesis (H0) is:  The distribution of time to first event in the intervention group is 
identical to that in the control group. The alternative hypothesis (H1) is: 
The distribution of time to first event in the intervention group differs from time to first event in 
the control group.  
 Secondary Analyses 
While our primary analysis focus on time to first event, we will collect data on all events 
occurring during follow-up and conduct recurrent event analyses.  
In secondary analyses, we also will compare the effect of sham NOXT vs. NOXT on 
secondary endpoints including patient-reported outcomes; exercise capacity; disease-specific 
causes of re-hospitalization and death; and cardiovascular events.  
Secondary analyses are considered exploratory and will be tested at significance level of 0.05 
without adjusting for multiple comparison. Secondary endpoints will be analyzed according to 
type of scale. Time-to-event endpoints will be analyzed analogously to the primary endpoint. 
To assess the treatment effect on time to first HF-related hospitalization and CV mortality, 
mortality from other causes will be treated as a competing risk. Cause-specific cumulative 
incidence functions, instead of the standard Kaplan-Meier method, will be used to describe 
the probability of event occurring over time. Treatment effect will be quantified by cause-
specific hazard ratios, obtained from Cox regression models, and care will be taken in 
interpreting the resulting HRs as among those who did not yet experience the event of 
interest or a competing event. Categorical variables will be analyzed using Fisher’s exact 
tests or chi-square tests. Continuous endpoints will be compared using Wilcoxon rank-sum 
tests. Generalized linear models will be fit to assess the treatment effect on various endpoints 
adjusting for covariates for continuous, dichotomous or count data. Cox proportional hazard 
models will be used for time-to-event endpoints. 
 Subgroup Analysis  
We will identify factors that moderate study outcomes in response to NOXT.  The potential 
effect modifiers we will test and analysis methods are pre-specified in the Statistical Analysis 
Plan. 
 Interim Analyses 
The study will be monitored routinely for issues of data quality, study conduct (including 
recruitment and follow-up rates), and adverse events. Monthly reports addressing these 
issues will be provided to the Executive Committee (aggregate [blinded] data). Reports will be 
provided to the DSMB and NIH every six months or more frequent as requested. We will 
monitor our primary outcome in planned interim analyses of safety, efficacy and futility. 
We plan to perform two interim looks when roughly 30% and 60% of events have occurred. 
With the proposed design, a total of 520 events are expected and the first interim review for 
efficacy and futility would be scheduled to occur after approximately 156 primary endpoint 
events have been observed. It is estimated that this will occur approximately 24 months after 
enrollment starts, at which time, about 57% of subjects have been enrolled into the study with 
average follow-up time about 12 months. The second interim review would be scheduled after 
approximately 312 primary endpoint events have been observed. It is anticipated that the 
second interim look will occur around 36 months since the initiation of enrollment. 


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For futility monitoring, we will apply the inefficacy monitoring rule of Freidlin, Korn and Gray 
(Clinical Trials 2010; 7: 197-208) with a conservative boundary LIB0. For both interim reviews, 
the LIB0 conservative boundary would suggest stopping the trial for inefficacy if the oxygen 
arm had a hazard ratio >1.0 compared to the control arm. The Freidlin, Korn, and Gray 
approach will result in a trivial loss of power and requires no sample size adjustment. 
For interim efficacy analyses, we will use the method of Haybittle and Peto. To create a formal 
framework for assessment of interim results, we will use the Haybittle-Peto boundary. That is, 
interim results for comparisons of the mortality and HF-related hospitalization rates between 
treatment groups will be considered sufficient to consider early termination only if the 
between-group differences are statistically significant at significance level of 0.001. The 
Haybittle-Peto stopping rule allows the final analysis to be evaluated at a 5% level of 
significance. As we do not anticipate that the interim analysis will yield efficacy data 
sufficiently compelling to require early termination, the Haybittle-Peto boundary is particularly 
suited for this situation. 
Interim reports (open and closed) will be generated every 6 months (or more often as 
requested) including information on recruitment, baseline characteristics, data quality and 
availability, protocol deviations, and adverse events. Expected and actual number of 
randomized subjects and cumulative number of events will be reports and reviewed to ensure 
that recruitment is on target and the observed event rate is consistent with the assumed event 
rate. 
At 18 months following randomization (or when approximately 43% of enrollment goal will be 
met), we will conduct a blinded sample size re-estimation using accumulating aggregate data 
to re-estimate nuisance parameters that have an impact on the power calculation of the trial. 
A comprehensive simulation study will be conducted to determine the impact of increasing the 
sample size and/or follow-up time on study power and overall type I error. The simulation 
study will be designed to mimic the LOFT trial as closely as possible and make use of the 
observed rate of early termination from the study and the overall event rates for all study 
participants, but will be blinded to the observed treatment arm-specific event rates and the 
difference between them. The overall observed event rate and its 95% confidence interval will 
provide a range of event rates that might be expected for the duration of the trial. The 
treatment arm specific event rate will be calculated based on the planned 20% reduction in 
12-month event rate and the observed overall event rate. We will consider the following 
various scenarios including: 1) the originally planned study design; 2) additional year of 
follow- up after 858 participants are accrued. Additional scenarios may be included if deemed 
necessary upon discussion of the investigation team, the DSMB and the funding agency. The 
estimated power for different scenarios will inform the decisions on whether or not additional 
participants and/or follow-up time will be needed. 
Interim comparative data will be considered confidential and will be available only to the 
DSMB members and to the DCC statistician/unblinded DCC staff analyzing the interim data 
and preparing the DSMB report. Concurrence with the monitoring plan by the Steering 
Committee, the DSMB, and the NIH will be required prior to implementation of the plan. 
We hypothesize a 20% reduction in the 1-year composite event rate, which is high enough to 
change practice. This effect is within the range of that observed across intervention studies 
(ranging from 35% for cardiac resynchronization therapy and beta blockers to 15% to 25% for 
other medications). We anticipate a 1-year event rate of 40% in the control group based on 
the HF literature showing that patients with advanced HF will experience annual morbidity and 


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mortality event rates of approximately 40% or greater, especially in the setting of co- morbid 
CSA. 
A total sample of 858 subjects (429 in each arm) achieves 87.9% power at a 5% significance 
level to detect a hazard ratio (HR) of 0.755 when the 1-year event rate in the control group is 
40%, using a two-sided logrank test. We assume a 5% cross-over throughout the study and 
10% loss to follow-up throughout the study, and a Cox model with exponential distribution 
(assuming constant hazard rate), and a 2.49 average length of follow-up. 
 
Original and Revised LOFT-HF Patient Accrual 
 
 
Original* 
Revised$ 
Accrual end date 
Jan 31, 2023 
 
Jan 31, 2024 
 
Additional Follow- 
up Period 
12 months 
6 months 
9 months 
12 months 
Average length of 
follow-up 
2.75 years 
2.49 years 
2.74 years 
2.98 years 
Power 
90.2% 
87.9% 
89.8% 
90.4% 
 
 
*: Corresponds to calculations provided in the original study protocol. Assumes the 
accrual pattern is uniform over 3.5 years. 
$: Based on the revised projected accrual pattern allowing a slower accrual during 
site activation. 
 
11.3. Sample Size Calculation 
We hypothesize a 20% reduction in the 1-year composite event rate, which is high enough to 
change practice. This effect is within the range of that observed across intervention studies 
(ranging from 35% for cardiac resynchronization therapy and beta blockers to 15% to 25% for 
other medications [47,48]). We anticipate a 1-year event rate of 40% in the control group 
based on the HF literature showing that patients with advanced HF will experience annual 
morbidity and mortality event rates of approximately 40% or greater (71,72), especially in the 
setting of co-morbid CSA (18,19). As described in the CCC application and Protocol Draft, 
several design strategies will be employed to enrich the risk of the enrolled patients. We will 
not use a run-in design that would select samples with better prognosis. 
A total sample of 858 subjects (429 in each arm) achieves 88% power at a 5% significance 
level to detect a hazard ratio (HR) of 0.755 when the 1-year event rate in the control group is 
40%, using a two-sided logrank test. We assume that an accrual period of 4.5 years with a 
slow ramp up until the end of May 2020, then uniform across the remaining recruitment period 
until the end of January 2024, and that the study will last until the last enrolled subject 
completes six-month follow-up. We further assume that the drop-out rate and cross-over rate 
during the study period are 10% and 5% respectively for both treatment groups. 
Conservatively assuming that 35% will screen positive will require screening a total of 2,450 
subjects. 
We performed sensitivity analyses for power analysis based on varying assumptions of effect 
sizes (HR=0.72, 0.755, and 0.78) and 1-year event rates in the control group (30%, 35%, and 


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40%), assuming the same rates of losses to follow-up and cross-over. As shown in the Figure, 
the proposed sample size achieves over 80% power for most of these settings. 
 
 
 
Power for varying effect sizes and 1-yearcontrolevent rate (1-Survival).  
AT=Accrual Time (in Months); T=Total Time (in months). 
 
Our sample size also provides adequate power for key secondary endpoints. Using two-sided 
tests at 5% significance level, a sample size of 858 provides 80% power to detect 0.2 SD 
difference in means for a continuous endpoint using a two-sample t-test; to detect a 35%, 
23%, and 16% reduction in risks when the risk in the control group is 20%, 40% and 60% for 
a binary outcome using a Z-test with pooled variance. 
12. Access to source data/documents 
The investigator will permit study-related monitoring, audits, IRB/IEC (Independent Ethics 
Committee) review and regulatory inspections, providing direct access to primary patient data 
(i.e. source data) which supports the data in the eCRFs for the study, i.e. general practice 
charts, hospital notes, appointment books, original laboratory records etc. Because this enters 
into the realm of patient confidentiality, this fact must be included in the Informed Consent Form 
to be signed by the patient.  
12.1. Source Data 
Source data are defined as all information in original records and certified copies of original 
records of clinical findings, observations or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are contained in source documents 
(original records or certified copies). 
12.2. Source Documents 
Source documents are defined as original documents, data and records (e.g. hospital records, 
clinical and office charts, electronic patient records, laboratory notes, memoranda, patient 
diaries or evaluation check lists, sleep study records, pharmacy dispensing records, recorded 
data from automated instruments, copies or manuscripts certified after verification as being 


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accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
patient files, records kept at pharmacy, at the laboratories and at medico technical departments) 
involved in this clinical study. In case of data that are collected while speaking to the patient and 
not documented as part of normal clinical routine, the e-CRF is the source document, if the 
patients answer is documented there without prior documentation on paper. 
12.3. Direct Access 
Direct access is defined as the permission to examine, analyze, verify and reproduce any 
records and reports that are important to evaluation of a clinical study. Any party (e.g. domestic 
and foreign regulatory authorities, the Sponsor and/or authorized representatives of the Sponsor 
such as monitors and auditors) with direct access should take all reasonable precautions within 
the constraints of the applicable regulatory requirements to maintain the confidentiality of patient 
identities and Sponsor proprietary information. 
13. Study Coordination and Data Management 
The CCC will be based at OSU. It will be responsible for finalizing the informed consent 
templates (along with input from the DCC and overall study leadership and SAC), navigating 
central IRB approval (including reliance agreements across entities), working with the DCC to 
design and implement the eCRFs, coordinating the clinical activities of each of the clinical 
sites, providing key input into medical safety monitoring and central adjudication of treatment 
failures and adverse events, and monitoring and driving enrolment. The CCC leadership and 
the CCC Program Manager will interact regularly with site personnel to promote enrolment, 
using the many techniques described in Section 10.3, and leverage the RROS in meeting the 
enrolment milestones of the trial. CCC project management will directly support the needs of 
scientific study leadership (Executive Committee and Steering Committee) to identify barriers, 
make timely responses, and optimize the allocation of limited resources to meet the pre-
defined study objectives. 
The DCC will be based at the Brigham’s and Women’s Hospital Program in Sleep Medicine 
Epidemiology and Harvard Medical School. Its responsibilities include data management, 
study coordination, communications, statistical oversight, report generation, and data archival 
and dissemination. The DCC will be responsible developing and maintaining the database 
and study web portal; monitoring data quality and conducting data audits; supporting quality 
control; generating all case report forms; supporting study communications; designing; 
conducting the statistical analyses and preparing Steering Committee and DSMB reports; and 
creating final archives of study data for data dissemination. In collaboration with the CCC and 
other study investigators, the DCC will be responsible for preparing and maintaining key study 
documents (including training manuals and Manuals of Procedures [MOP]); and coordinate 
central training sessions and site visits. 
A central Sleep Reading Center (SRC), based at Brigham and Women’s Hospital, will provide 
centralized PSG support for the trial. It will develop all sleep training manuals, oversee the 
training and certification of site personnel on the use/administration of the portable sleep 
monitors, oversee sleep data quality, score the sleep studies, provide timely reports (within 2 
business days) of parameters used to determine eligibility (central apnea hypopnea indices, 
obstructive apnea index, and CSR), identify urgent referrals from the sleep studies and report 
these to the clinical sites, and generate metrics of ventilation/airway function for use in 
predictive analyses. It will produce archives of the raw and scored data from data 
dissemination. The SRC also will be ensuring a protocol is in place to deliver, set-up, and 
educate participants on use of home oxygen; developing the final protocol for home 


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oxygen/sham oxygen use; will provide real-time monitoring of oxygen flow use; and 
communicate with the local clinical teams any need to reinforce adherence to oxygen. A 
central oxygen use adherence expert will support local staff in messaging and actions to help 
reinforce treatment adherence. 
The Clinical Endpoints Committee (CEC) will be based in the Department of Cardiology, 
Brigham and Women’s Hospital, Harvard Medical School. The CEC is responsible for 
unbiased and consistent endpoint review and adjudication of all investigator-reported and 
CEC-identified study endpoints, according to pre-specified endpoint criteria. The CEC will 
develop a manual of operations that defines the CEC process and expands on endpoint 
definitions, for use in the adjudication process. The Executive Committee will review and 
approve of the CEC manual of operations, prior to initiating the study. 
The final version of this study protocol and corresponding MOP will specify the study design 
in sufficient detail to assure that the trial is conducted in a consistent and rigorous manner, 
including details such as procedures for:  electronic data capture system and responding to 
queries, collecting and transmitting various types of data; adverse event ascertainment and 
reporting, reporting protocol deviations; and scripts/instructions for recruitment. The DCC will 
ensure that any study amendments, protocol updates, and versions are clearly labeled, and 
that revised information is distributed in a timely fashion to the CCC and each site. 
The Data Management System (DMS), housed within a dynamic secure, HIPAA compliant, 
study web portal (Slice, built on Ruby-on-Rails), will provide data entry, integration, 
processing, and reporting services. Data will be captured through a variety of ways, including 
patient and staff direct entry of data into electronic tablets that present e-CRFs using a 
streamlined user interface. Data also will be received as electronic files (e.g., sleep studies, 
oxygen use records) and as pdfs (certain source documents). The backend relational 
database is PostgreSQL. In addition to on-line e-CRFs, the system will provide functionality 
for: tracking CRFs, data validation, query generation and tracking, and reporting. Data access 
is defined and tightly controlled according to each person’s roles (blinded, unblinded). 
Advanced data filtering functions will ensure that staff have access to appropriate data while 
reducing likelihood of unblinding. The DMS will provide functionality for displaying a variety of 
real-time reports, graphs, and study documents required by key personnel and stakeholders 
to quickly view the status of the study and access procedure manuals and study materials 
directly.  
A Central IRB based at Vanderbilt University will be used. 
The Executive Committee will ensure that the study operations and milestones are congruent 
with the approved proposal. It will meet bi-weekly or monthly to review current and planned 
activities, relating these to milestones and operational plans, identifying study operations and 
communications that may require changes. It will identify areas for Steering Committee of 
Data Safety and Monitoring Board input.  
The Steering Committee will provide overall study leadership, including overseeing all 
scientific and administrative aspects of the study, monitoring study progress and milestones, 
review the work of the subcommittees and provide input to their work and approve 
publications, presentations and ancillary studies. The Steering Committee will be responsible 
for all key study decisions with decisions made by majority vote. It will review the reports and 
work of all subcommittees, be responsible for responding to input from the DSMB and NHLBI, 
and ensure that all study decisions and study updates are communicated to the larger LOFT-
HF Study Group through emails, portal newsletters, and direct contact as needed. The 


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Steering Committee will be co-led and co-managed the CCC and DCC PIs. It will also include 
representation of key Subcommittee Chairs and study site representatives.  
The RROS will consist of diverse representatives from the clinical sites, including study 
coordinators. It will meet monthly to discuss strategies for optimizing recruitment and retention 
and oversee overall flow of the clinic examinations, data collection, and participant 
interactions.  
13.1. 
Quality Control 
Quality Control is defined as the operational techniques and activities, such as monitoring, 
undertaken within the quality assurance system to verify that the requirements for quality of the 
study related activities have been fulfilled. 
Quality Control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
A data quality control process will be implemented that addresses all stages of data handling, 
from data capture to analysis. First, all procedures will be specified in the Final Protocol and 
MOP to allow for unambiguous use in the study. A central training session and subsequent site 
visits will be held to ensure that personnel understand the study’s goals and objectives, data 
collection process, adverse event collection, database software, and all applicable standard 
operating procedures.  Key procedures (e.g., survey administration, adverse event identification, 
distribution of oxygen concentrators, data entry and transfer, sleep apnea testing, and blood 
pressure measurement) will require certification of staff prior to their use with study participants. 
Requirements differ per procedure, but may include documentation of successful performance 
during central training, completion of a written exam, and submission of successfully completed 
pilot studies. After initial certification, each research staff’s performance will be monitored on an 
ongoing basis. If submitted studies fall below threshold levels for quality, the site PI will be 
notified and procedures for remediation will be implemented (e.g., re-training, or removal from 
the study). 
Second, a subject registration procedure will be used that checks eligibility criteria prior to 
assigning a randomization code, minimizing the likelihood that ineligible participants are 
randomized.  
Third, data accuracy and completeness is optimized through easy to use electronic interfaces 
that provide dynamic feedback during data entry or survey (e-CRF) completion regarding 
implausible values or skipped fields. Forms require all items to be completed before each is 
closed. A sample of data will be entered a second time using a web-interface that requires on-
line resolution of conflicts between data values being entered for the second time and first data 
entry values. Each conflict will be documented in an audit report that will provide feedback for 
summarizing and tracking the accuracy of data entry. Furthermore, all incoming data will be 
checked to assess the accuracy and the completeness of electronic reports. Data are validated 
through checks on variable formatting, range-checking (minimum/maximum values), and logic 
checks (skip patterns, etc.). Queries will be made of the full spectrum of study data: those 
directly entered and those electronically transmitted, including those from the Sleep Reading 
Center and CEC. Queries will be run on a weekly schedule. For key variables, or those prone to 
coding or collection errors, additional data checks will be established, such as the creation of 
graphs showing relationships between variables (e.g., height vs weight). The DMS will send 
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13.2. Study Monitoring 
Clear benchmarks for ensuring compliance with the study protocol, including adherence to 
regulatory and privacy requirements; recruitment and retention milestones; and targets for data 
completeness and data integrity will be established and monitored over the course of the study. 
If given sites or staff member exceed thresholds, appropriate retraining or remediation will be 
initiated. 
13.3. Quality Assurance 
Quality Assurance is defined as the planned and systematic actions that are established to 
ensure that the study is performed and the data are generated, documented (recorded) and 
reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory 
requirements. 
Using study milestones, the Executive and Steering Committees will regularly review graphic 
and tabular displays of randomized individuals by site and week, as well as breakdowns of 
screened, consented, eligible, and randomized subjects along with key demographic data. 
Pareto event graphs and other quality assurance tools will be deployed to provide feedback 
and assist with analysis. 
13.4. Inspection 
An Inspection is defined as the act by a regulatory authority of conducting an official review of 
documents, facilities, records and any other resources that are deemed by the authorities to 
be related to the clinical study and that may be located at the site of the study, or at the 
Sponsors and/or clinical research organization facilities or at any other establishments 
deemed appropriate by the regulatory authorities. 
13.5. Audit 
An audit is a systematic and independent review of study related activities and documents to 
determine whether the validated study related activities were conducted and the data were 
recorded, analyzed and accurately reported according to the protocol, designated Standard 
Operating Procedure (SOPs), Good Clinical Practice (GCP) and the applicable regulatory 
requirements. An independent audit at the study site will take place within 3 months after 
recruitment is begun. Additional audits may take place at any time during or after the study. 
Audit results will be shared with the Steering Committee, relevant QA committees and other 
study personnel, and the DSMB. If data quality or procedures do not meet pre-specified 
thresholds, remediation, including additional training, or changes in procedures will be 
implemented. 
All data operations and modifications will be recorded to a Data Audit Trail which will specify 
detailed information related to the types of data operations performed, by whom these 
operations were performed, date and time of operations, and data values modified.  
14. Ethical and Legal Considerations 
The respect for the rights of the patients will be guaranteed in each phase of the study in 
accordance with the Declaration of Helsinki and its current revision. The trial will be conducted 
in accordance with International Conference on Harmonization-Good Clinical Practice (ICH-
GCP), Investigational Device Exemption (US federal regulations, CFR Title 21, part 812) 
regulations and requirements and ISO 14155. 


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14.1. Ethical Considerations 
Trained research personnel who have completed necessary certification for human subject 
research will screen the targeted clinics (medical records) to identify and recruit potentially 
eligible patients, contact referring physicians to ascertain study eligibility and assure that HIPPA 
requirement are met, obtain informed consent, and confirm further eligibility criteria at clinic 
encounters and by telephone.  Study PIs will perform a history and may elect to complete a 
physical examination to further assess eligibility.  
Consent from the participant will be obtained at the time of study entry by trained study 
coordinators or a study investigator. All aspects of the study will be explained in detail.  Before 
being entered into the study, each patient will sign an informed consent form that has been 
approved by the central Institutional Review Board. They will be informed of the nature of this 
research, its potential benefits and possible risks. They will be informed that they are free to 
refuse participation or to withdraw from the study and that this will not affect any future medical 
care. 
The general procedures to be followed are: 
• 
Participant who are potentially eligible (i.e., by diagnosis, echocardiography findings, 
hospitalization history, lack of comorbidities) will be identified by electronic records or 
review of medical charts. 
• 
Prior to the scheduled screening visit, referring physicians will be contacted to confirm 
appropriateness of study participation for each potential participant and to agree to 
allow study personnel to contact the family. 
• 
Potential participants will be contacted by telephone, mail or in-person (before hospital 
discharge, while at a clinic appointment), with arrangements made for a subsequent full 
screening visit, or for a follow-up interview if needed. The study will be described and 
written informed consent obtained. 
• 
At a screening visit, an interview will be administered to assess eligibility criteria. A 
physical examination may be performed at the discretion of the PI to further assess 
eligibility criteria. 
• 
Potentially eligible participants (after initial screening) will be provided with a home 
sleep monitor to use for one night unless a recent clinical sleep study is unavailable. If 
the sleep monitor shows that criteria for CSA are met, the participant will be invited to a 
full baseline visit and then will be randomized. If a clinical sleep study is available, that 
study will be transferred to the SRC for centralized scoring and eligibility assessment. 
More specific approaches to the consent process: At the time of enrollment, discussion of the 
protocol and written consent for the research will be obtained by trained research coordinators 
or study investigators (who have been ethics committee certified). Consent forms explain in a 
lay persons' terms the nature of all procedures.  It is stressed that participation is voluntary.  The 
research assistant and PI are available to answer questions. The study PI (or his/her designee) 
will also meet and examines each participant at the time of the screening or baseline visit. The 
investigators will also be available to answer questions about the study at other times. 
Across sites, common elements of the consent forms will include: 
• 
Introduction/purpose that briefly explains what the research is studying and what the 
potential participant is being asked to participate 


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• 
Study procedures – what the participants will experience in their participation, what is 
standard care and what is added because of research participation, duration of the 
study and number of visits involved. 
o 
Screening procedures to determine if the subject can participate 
o 
Randomization/Study Intervention (full discussion of oxygen; health education) 
o 
Duration and number of visits using subheading for each visit type 
o 
Procedures performed at each visit 
o 
Follow-up procedures (phone calls) and procedures; what will occur and time 
involved 
o 
Description of procedures for discontinuation, including the participant’s right to 
withdraw 
o 
Risks 
o 
Benefits 
o 
Alternatives to participation 
o 
Financial information 
o 
Confidentiality 
o 
Research related injury 
o 
Termination of participation 
o 
Summary of rights as a participant in a research study 
o 
Disclosure of study records 
o 
Contact information 
Published data will not include patient identifiers.  
 Central Institutional Review Board (IRB) 
Regulatory oversight of the LOFT-HF study will be administered by a Central Institutional 
Review Board (IRB) through one of three Trial Innovation Centers (TICs), a component of the 
Trial Innovation Network (TIN), (Duke University / Vanderbilt University). We intend to leverage 
these institutions' collective, extensive experience in the facilitation of quality and efficient 
regulatory oversight. The OSU CCC will submit an application to the TIN during the UG3 phase 
soliciting one of the TICs to serve as the IRB of record for participating clinical sites. TICs utilize 
the SMART IRB platform. The CCC has an existing SMART IRB reliance agreement and will 
partner with the TIC IRB to secure IRB authorization agreements with all sites using the SMART 
IRB platform. As the IRB of record, the TIC IRB will be responsible for conducting the review of 
the LOFT-HF protocol in accordance to 21 CFR Parts 50, 56, 312, and 812, 45 CFR 46 and  
applicable international and local regulations and laws with respect to the initial review, 
continuing reviews, and any potential modifications to the protocol. The TIC IRB will review 
reported adverse events, unanticipated problems involving risks to subjects, and any incident of 
serious noncompliance in accordance to the IRB’s defined policies and procedures. All research 
–related documents will require TIC IRB review and approval prior to use. The TIC IRB will 
operate in a transparent manner, readily providing IRB meeting minutes to sites per requests 
and investigators and sites will be notified in writing of all IRB decisions. 


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The OSU CCC Project Manager (PM) will be responsible for communication across sites and 
ensuring each site is provided with IRB-approved versions of study documents. Other CCC PM 
duties will include notification of site research teams of TIC IRB determinations and 
communications, maintaining records of education and human subjects research training of 
investigators and research teams, and obtaining information related to potential variations in 
study conduct for purposes of evaluation of the local context by the LOFT-HF Executive 
Committee. The OSU CCC will work with the TIC IRB to release study records if needed for an 
audit by the relying sites’ institutions or other regulatory agencies. 
 Clinical Endpoints Committee (CEC) 
The CEC will be responsible for unbiased and consistent endpoint review and adjudication of all 
investigator-reported and CEC-identified study endpoints, according to pre-specified criteria, 
blinded to treatment assignment. Event review and adjudication will be performed in compliance 
with all Institutional guidelines as well as all other applicable FDA regulations and ICH E6 
guidelines concerning the conduct of human subject research. In addition to the study-specific 
MOP, the CEC uses center-wide CEC Policies and Procedures (P&Ps) that serve as the 
backbone to all key components, processes and functions of the CEC.  
The general approach for CEC adjudication entails:  a) Each event will be independently 
reviewed by two physician reviewers with expertise in adjudication of CV events in clinical trials; 
b) The CEC project management staff will be responsible for assigning and distributing events 
to physician reviewers and scheduling adjudication committee meetings with the CEC Chair. c) 
The Committee will receive and adjudicate endpoints via Committee on a regular, consistent 
basis (i.e. daily and weekly activity) to avoid back logs in events receipt and adjudication.   
The specific procedures entail:  The CEC will adjudicate all potential primary and secondary 
endpoints (see Protocol and CCC Application). It will be responsible for providing clear, concise, 
and thorough internal documentation of the key event details and rationale for event 
adjudication. The CEC will receive electronic source documents from sites for each potential 
event via an on-line portal.  Project management staff will assign the electronic dossiers to 2 
physician reviewers, maintain a database to track these assignments, and will be responsible 
for CEC-generated queries, resolving them with the site, and forwarding appropriate responses 
back to the physician reviewers. Relevant information will be documented on the Event Review 
Form (ERF) completed by each physician assigned to the event. There will be one final 
adjudication form completed and signed by both physician reviewers assigned to the event and 
an administrative staff person responsible for ensuring that the form has been completed in a 
clear and thorough manner. Once an event has been reviewed in Committee and an 
adjudication has been reached, the ERF will be finalized and signed, with the final adjudication 
entered by the chairman into the electronic database system.  
 Data and Safety Monitoring Board (DSMB) 
The NHLBI will establish an external DSMB according to NHLBI policies. The members will 
include experts in heart failure, sleep medicine, biostatistics, clinical trials, and ethics (some 
overlapping). The DSMB will convene to review the final protocol and DSMB Charter before 
study initiation and then periodically, and not less frequently than annually. The DSMB Chair 
will receive all reports of unanticipated serious adverse events in real time. The DSMB will 
receive interim reports every 6 months for the DSMB call/meeting. At each meeting they will 
determine whether study progress, data integrity and safety monitoring warrant continuation 
of the study and will recommend the study to continue or be terminated, accordingly. They 


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also approve the data safety plan before the study is begins. Duties of the chairperson:  The 
chair will lead the scheduled board meeting and review the prepared board meeting minutes. 
DSMB Meetings and Recommendations:  Meetings will require a quorum. All members will be 
responsible to read the submitted DSMB reports. The chairperson will lead the discussion. 
Duties of the board will include evaluation of the progress of the trial, including assessment of 
data quality and timeliness, participant recruitment, accrual and retention, participant risk 
versus benefit, and other factors that can affect study outcome.  Monitoring will also consider 
factors external to the study when interpreting the data, such as scientific or therapeutic 
developments that may have an impact on the safety of the participants or the ethics of the 
study. 
Potential motions of the board meeting include recommendations for either of the following: 
a. Study continuation; no change required 
b. Study continuation with stipulation to be formally addressed and approved by the 
DSMB chair 
c. Study suspension with stipulation to be formally addressed and approved by the 
DSMB prior to resumption 
d. Study termination 
The DSMB’s summary report will be reviewed and finalized by the chairperson. The report will 
then be communicated to the NHLBI who will communicate recommendations to the DCC and 
CCC. DSMB recommendations will be communicated to the IRB in the context of the 
continuing review process. It is the responsibility of the PI to ensure that the IRB is notified by 
motions requiring termination or suspension of the trial. 
DSMB Report and format:  An interim report will be prepared for each meeting by the BWH 
DCC, supervised by the study statistician, Dr. Wang. The DCC will propose a draft report 
format to be finalized at the first DSMB meeting. Adverse event reports will follow NIH 
recommendations (http://www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm). 
14.2. Modification of Protocol 
The Steering Committee, DSMB and NHLBI will be required to approve any changes to the 
protocol. Changes will be clearly documented, including dates of the change. All materials will 
be maintained using version controlled identifiers, minimizing likelihood of using outdated 
materials. 
14.3. Personal Data and Data Protection 
All staff will have completed certification in The Collaborative IRB Training Initiative (CITI) 
program.  
All information will be kept strictly confidential and used for research purposes only. Records will 
be identified by a subject id and visit number rather than the subjects' name, and will be secured 
in locked files. Attempts will be made to minimize the possibility of linking such data to personal 
identification information by restricting access to personal identification information to the study 
coordinator, with such information (names, addresses and identification numbers) stored 
separately from other data in locked files, and computers secured appropriately. Data will be 
transmitted electronically as encrypted files via secure FTP protocols. The DCC will not receive 
identifying data nor PHI other than dates of events, except in cases where participants need to 


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receive timely shipments of study therapy supplies.  The DCC may receive PHI (name, mailing 
address, phone number) so replacement therapy supplies (cannulas, tubing, etc.) may be 
shipped directly to study participants. As soon as the shipment is placed, the 
address/identification information will be destroyed securely (and this information will not be 
stored physically or electronically). Study-wide data will be stored at the Brigham and Women’s 
Hospital DCC computers that are located in a restricted access research suite; computer 
information is protected by use of passwords and a firewall. All DCC web and database servers 
are secured within the Partners Corporate Datacenter and behind the Partners Information 
Security firewall. They comply with all Partners Healthcare Information Security policies, 
developed and maintained by the Partners Chief Information Security Officer, for authenticated, 
secure and minimum access. All systems are patched, monitored and scanned routinely for 
vulnerabilities and intrusions by the systems administrator and PHS Information Security. Data 
is encrypted, where applicable, in compliance with state and federal government standards, 
regulations, and in accordance with Partners Security and Privacy policies. All configuration 
changes that could affect accessibility or security are approved by management. 
14.4. Data Handling and Record Keeping 
All NHLBI requirements related to study close-out will be followed. At a predetermined 
termination date, all computerized, non-database files and, minimally, a complete database 
table transfer to CSV files will be archived to a suitable media format. The format of the archive 
media will be a standard format to ensure reliable restoration of any project file(s). All non-
computerized project data will be packaged and documented to ensure that the project package 
and related archived media will be available for future queries about the project. The DCC will 
coordinate retention and transfer of documents with the PIs and the sponsors, and also will 
disseminate data through BioLINCC and the National Sleep Research Resource, as described 
in the Resource Sharing Plan.  
 Completion of Case Report Forms 
All medical data in this trial are to be recorded directly in the eCRFs. The investigator must 
ensure the accuracy, completeness, legibility and timeliness of data. Built in features will provide 
checks for completeness as well as logic and range checks. 
 Archiving 
Reports will be created and posted on secure areas of the study portal to provide ongoing 
feedback to the Steering Committee, DSMB, NIH, and each site regarding outstanding tasks 
and the quality of data already entered (i.e. counts, completeness, missing data). 
15. 
Final Report and Publication Policy 
To be finalized by Publications and Presentations Subcommittee and approved by the 
Executive Committee and Steering Committee. 
 


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17. Signatures 
The undersigned have read this protocol and agreed to conduct this study in accordance with all 
stipulations of the protocol and in accordance with the Declaration of Helsinki. 
 
 
 
Date 
Signature 
 
 
 
 
 
 
 
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