Conditions: Acute Heart Failure
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
The Pilot study is designed to evaluate the overall safety and feasibility of a strategy based on subcutaneous delivery of furosemide. It will be used to inform the subsequent evaluation phase of the study (separate protocol). The primary objective of the study is to determine if a strategy of a novel subcutaneous delivery of furosemide is safe and feasible in patients with acute heart failure.

Detailed description:
Multi-center, open-label, pilot study conducted in 2 phases. Each phase will enroll 20 subjects that will be used to inform the study design of the SUBQ-HF Study (approximately 300 evaluable patients randomized to either usual inpatient care or early discharge with home subcutaneous furosemide for 1-7 days).

Inpatient Pilot Phase:

Eligible in-patients will be approached for participation. Subjects who consent for participation will be treated with subcutaneous furosemide for 48 hours, during which they will remain in the hospital. This will be primarily a safety and feasibility assessment. There will be no formal hypothesis tested, and statistical analysis will be descriptive in nature.

Outpatient Pilot Phase:

Eligible in-patients who are nearing discharge will be approached for participation. Subjects who consent for participation will be instructed on use of device, discharged to home and treated at home with subcutaneous furosemide for 1-7 days. This will be primarily a safety and feasibility assessment. There will be no formal hypothesis tested, and statistical analysis will be descriptive in nature.

Arms:
arm 1: All subjects in the pilot study will receive the subcutaneous pump to administer a special formulation of furosemide to be delivered subcutaneously.

Interventions: intervention 1: Furosemide
Intervention descriptions: intervention 1: subcutaneous furosemide delivered via subcutaneous pump

Protocol document:
Prot_SAP_000.pdf: 
May 15, 2017 
 
 
 
1
 
 
 
 
 
Protocol for the Heart Failure Clinical Research 
Network 
 
Subcutaneous Furosemide in Acute Decompensated Heart 
Failure 
The SUBQ-HF Pilot Study 
 
 
Compiled by: 
The Heart Failure Network Research Group 
 
 
3.0 
 
IND#: 129562 
 
 
Distributed by: 
Heart Failure Network Coordinating Center 
Duke Clinical Research Institute 
Duke University 
P.O. Box 17969 
Durham, NC   27715 
 


May 15, 2017 
 
 
 
2
Study Funding: 
 
 
 
National Heart, Lung, and Blood Institute 
 
 
 
 
 
 
 
National Institutes of Health 
 
Project Officer: 
 
 
 
Patrice Desvigne-Nickens, MD 
 
 
 
 
 
 
 
 
Network Chair: 
 
 
 
Eugene Braunwald, MD 
 
Protocol Principal Investigator: Michael Felker, MD (Duke University) 
 
 
 
 
 
 
 
 
  
Sponsor/ 
Coordinating Center:  
 
Adrian Hernandez, MD 
Kevin Anstrom, PhD 
 
 
 
 
 
 
 
Duke Clinical Research Institute 
Durham, NC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


May 15, 2017 
 
 
 
3
Table of Contents 
1.0 List of Abbreviations ...................................................................................................................... 6 
2.0 EXECUTIVE SUMMARY ................................................................................................................... 7 
3.0  INTRODUCTION ............................................................................................................................ 9 
3.1 Background and Significance .................................................................................................................. 9 
3.2 Preliminary Data ..................................................................................................................................... 9 
4.0  OBJECTIVES ................................................................................................................................ 11 
4.1 Primary Objectives ................................................................................................................................ 11 
5.0 BASIC STUDY DESIGN ................................................................................................................... 12 
5.1 
Inpatient Pilot.............................................................................................................................. 12 
5.2 Outpatient Pilot ..................................................................................................................................... 12 
6.0 STUDY FLOW DIAGRAM ............................................................................................................... 13 
7.0 STUDY POPULATION AND ELIGIBILITY CRITERIA ........................................................................... 14 
7.1 Inclusion Criteria ................................................................................................................................... 14 
7.2 Exclusion Criteria ................................................................................................................................... 14 
8.0  TREATMENT INTERVENTIONS ..................................................................................................... 15 
8.1 Inpatient Pilot ....................................................................................................................................... 15 
8.2 Outpatient Pilot ..................................................................................................................................... 15 
8.2.1 Subcutaneous furosemide outpatient strategy: ........................................................................ 15 
8.3 Diuretic Dose Adjustments ................................................................................................................... 16 
8.4 Electrolyte Repletion ............................................................................................................................. 16 
8.5 Concomitant Medications ..................................................................................................................... 16 
9.0 RECRUITMENT PROCEDURES ........................................................................................................ 16 
10.0 STUDY SCHEDULE ....................................................................................................................... 17 
10.1 Baseline Evaluation: Inpatient Pilot .................................................................................................... 17 
10.1.1 Study Days 1‐2.......................................................................................................................... 17 
10.1.2 Study Day 9 .............................................................................................................................. 17 
10.2 Baseline Evaluation: Outpatient Pilot ................................................................................................. 18 
10.2.1 Study Days 1 through 7 ............................................................................................................ 18 
10.2.2 D1, D3 & D5 Phone Call ............................................................................................................ 18 
10.2.3 D2 Lab Visit............................................................................................................................... 19 


May 15, 2017 
 
 
 
4
10.2.4 D7 Clinic Visit ............................................................................................................................ 19 
10.2.5 D14 Phone Call ......................................................................................................................... 19 
11.0 PARTICIPANT SAFETY AND ADVERSE EVENTS ............................................................................. 19 
11.1 Definitions ........................................................................................................................................... 19 
11.1.1 Adverse Events ......................................................................................................................... 19 
11.1.2 
Suspected Adverse Reaction ............................................................................................... 20 
11.1.3 
Serious Adverse Events ....................................................................................................... 20 
11.1.4 
Laboratory Test Abnormalities............................................................................................ 20 
11.1.5 
Assessment of Severity ....................................................................................................... 20 
11.1.6 
Assessment of Causal Relationship ..................................................................................... 21 
11.1.7 
Expectedness ...................................................................................................................... 21 
11.2 
Suspected Unexpected Serious Adverse Reaction...................................................................... 21 
11.2.1 
Day Zero ...................................................................................................................................... 21 
11.2.2 
Pregnancy ............................................................................................................................ 21 
11.3 
Recording and Reporting of Adverse Events .............................................................................. 22 
11.4 
Follow‐up .................................................................................................................................... 22 
11.5 
Anticipated Disease Related Adverse Events .............................................................................. 22 
11.6 Summary of the Risks .......................................................................................................................... 23 
11.6.1 Drug Adverse Reactions ........................................................................................................... 23 
11.6.2 Information for Patients .......................................................................................................... 24 
11.6.3 Device Adverse Reactions ........................................................................................................ 25 
12.0 STATISTICAL CONSIDERATIONS AND DATA MANAGEMENT PROCEDURES .................................. 25 
12.1 
Overview ..................................................................................................................................... 25 
12.2 
Analysis of Safety Data and Statistical Monitoring Plan ............................................................. 26 
12.3 
Overview of Data Management .................................................................................................. 26 
12.3.1 Data Management Process ...................................................................................................... 26 
12.3.2 Data Quality Control ................................................................................................................ 26 
12.4 
Data Security ............................................................................................................................... 27 
12.5 
Publication Policy ........................................................................................................................ 27 
13 
STUDY ADMINISTRATION ........................................................................................................... 27 
13.1 Data and Safety Monitoring Board (DSMB) ........................................................................................ 27 
13.2 
Coordinating Center .................................................................................................................... 27 


May 15, 2017 
 
 
 
5
14.0 ETHICAL AND REGULATORY CONSIDERATIONS ........................................................................... 28 
14.1 Ethics and Good Clinical Practice ........................................................................................................ 28 
14.2 
Institutional Review Board/Independent Ethics Committee ...................................................... 28 
14.3 
Informed Consent ....................................................................................................................... 28 
14.4 Confidentiality and HIPAA Requirements ................................................................................... 28 
15.0 MONITORING ............................................................................................................................. 29 
16.0 REFERENCES ............................................................................................................................... 30 
17.0 APPENDICES ............................................................................................................................... 32 
17.1 Appendix A. Schedule of Assessments ................................................................................................ 32 
17.2 
Appendix B. Numerical Rating Scale for Breathlessness ............................................................. 34 
17.3 
Appendix C.  Guidelines for Remote Adjustment of Diuretics during outpatient Subcutaneous 
treatment .................................................................................................................................................... 35 
 
 
 


May 15, 2017 
 
 
 
6
1.0 List of Abbreviations 
Abbreviation 
Definition 
AHF 
Acute Heart Failure 
AE 
Adverse Event 
BID 
Twice daily 
BMP 
Basic Metabolic Panel 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
CC 
 
CPET 
Coordinating Center 
Cardiopulmonary Exercise Test 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DCRI 
Duke Clinical Research Institute 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
EE 
Expedited Event 
EF 
Ejection fraction 
eGFR 
Estimated Glomerular Filtration Rate 
ER 
Emergency Room 
FDA 
Food and Drug Administration 
GFR 
glomerular filtration rate 
HF 
Heart Failure 
HFCRN 
Heart Failure Clinical Research Network 
HFN  
Heart Failure Network 
HFpEF 
Heart Failure with preserved Ejection Fraction 
HFrEF 
Heart Failure with reduced Ejection Fraction 
ICF 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intention To Treat 
IV 
 
Intravenous 
JVP 
Jugular Venous Pressure 
NHLBI 
National Heart, Lung and Blood Institute 
NRS 
Numerical Rating Score 
NT-proBNP 
N terminal pro-B-type natriuretic peptide 
NYHA 
New York Heart Association 
PO 
By mouth 
QD 
Once daily 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SQ 
Subcutaneous 
 
 
 
 


May 15, 2017 
 
 
 
7
2.0 EXECUTIVE SUMMARY 
 
Title 
SUBQ-HF Pilot: Subcutaneous Furosemide in Acute Decompensated 
Heart Failure 
Indication 
Patients hospitalized with acute decompensated heart failure. 
Location 
Approximately 3-5 clinical centers in the United States 
Brief Rationale 
 
 
 
 
Most Acute Heart Failure (AHF) hospitalizations are related to congestion, 
and the primary inpatient treatment modality is parenteral loop diuretics. 
The average length of stay for an AHF hospitalization in the US is 5.5 days. 
After initial stabilization, many patients remain in the hospital for several 
days with a primary goal of additional decongestion with IV loop diuretics. A 
novel subcutaneous furosemide pump has been developed that allows 
patients to self-administer the equivalent of 80 mg of IV furosemide over a 
5-hour period outside of the hospital setting. Existing data suggest that this 
approach provides bioavailability similar to that of IV furosemide injection. 
The clinical utility of this approach in a real world AHF population has not 
been evaluated.   
 
Primary Objective 
The Pilot study is designed to evaluate the overall safety and feasibility of a 
strategy based on subcutaneous delivery of furosemide.  It will be used to 
inform the subsequent evaluation phase of the study (separate protocol).  
 
Patient Population 
 
Patients hospitalized for AHF who have had at least 24 hours of inpatient 
therapy and are hemodynamically stable, but still have objective signs and 
symptoms of congestion necessitating ongoing parenteral diuretic therapy. 
Study Design 
 
Multi-center, open-label, pilot study conducted in 2 phases.  Each phase 
will enroll 20 subjects that will be used to inform the study design of the 
SUBQ-HF Study (approximately 300 evaluable patients randomized to 
either usual inpatient care or early discharge with home subcutaneous 
furosemide for 2-7 days). 
 
Inpatient Pilot Phase: 
Eligible in-patients will be approached for participation.  Subjects who 
consent for participation will be treated with subcutaneous furosemide for 
48 hours, during which they will remain in the hospital. This will be primarily 
a safety and feasibility assessment. There will be no formal hypothesis 
tested, and statistical analysis will be descriptive in nature.  
 
Outpatient Pilot Phase: 
Eligible in-patients will be approached for participation.  Subjects who 


May 15, 2017 
 
 
 
8
consent for participation will be instructed on use of device, discharged to 
home and treated at home with subcutaneous furosemide for 1-7 days. 
This will be primarily a safety and feasibility assessment. There will be no 
formal hypothesis tested, and statistical analysis will be descriptive in 
nature.  
 
Intervention 
Inpatient pilot: A strategy of subcutaneous furosemide for 48 hours 
inpatient. 
Outpatient pilot: A strategy of subcutaneous furosemide for 1-7 days post 
discharge  


May 15, 2017 
 
 
 
9
3.0 
INTRODUCTION 
3.1 Background and Significance 
 
Hospitalization for acute heart failure (AHF) is a major clinical event in the natural history of heart 
failure, associated with a high morbidity and mortality over the subsequent months, high health 
care utilization, and costs1. AHF is the most common cause of hospital admission in patients over 
age 65, accounting for 1,000,000 admissions, over 6 million hospital days, and $12 billion in costs 
annually2. The prognosis of patients admitted with AHF is dismal, with a 20-30% readmission rate 
and a 20-30% mortality rate within six months after admission. Approximately 75% of heath care 
spending on heart failure is driven by the costs of inpatient care, and costs of heart failure care 
are projected to more than double by 20303.  Given these facts, AHF has become a major focus 
of health care reform and public policy. Most AHF hospitalizations are for signs and symptoms of 
congestion, and successful decongestion is a central therapeutic goal of a heart failure 
hospitalization. The vast majority (> 90%) of AHF patients are still treated with loop diuretics as 
the primary therapy, and the need for ongoing parenteral diuretics is a primary determinant of 
length of stay4. 
 
Despite the utility of loop diuretics in relieving congestion in most AHF patients, data suggest that 
many AHF patients have persistent congestion at the time of hospital discharge, whether overt 
(symptoms and signs) or hemodynamic (elevated filling pressures). Persistent congestion has 
been shown in multiple studies to contribute to high readmission rates5, 6. However, the average 
length of stay for an AHF hospitalization in the United States is approximately 6 days, and even 
longer hospitalizations are observed in Europe and Asia7. Data from the ASCEND-HF study 
suggest that higher length of stays are associated with lower risks of readmission, even after 
adjustment for differing periods of time at risk for rehospitalization8.  While prolonged use of 
parenteral diuretics may improve decongestion and decrease risk of rehospitalization, but this 
strategy is limited by patient factors as well as cost to the health care system (typical cost heart 
failure hospitalization is ~ $2500/day in the United States). An alternative system of parenteral 
loop diuretic delivery via a subcutaneous  furosemide pump may allow parenteral loop diuretic 
use outside the hospital system in selected patients. Patients undergoing parenteral diuresis at 
home rather than in hospital may experience greater overall activity, improved sleep, and better 
overall well- being compared to being hospitalized. Outpatient parenteral diuresis may allow for 
more complete decongestion which could decrease readmission rates. Overall, the treatment 
strategy could potentially result in fewer hospital days, lower costs, lower rates of readmission, 
greater patient satisfaction and substantial public health impact.  
 
3.2 Preliminary Data 
Furosemide is traditionally administered orally or via intravenous injection. Variability in oral 
bioavailability of furosemide, particularly in volume overload states, is a known limitation of oral 
administration and contributes to the well-described clinical phenomenon of decreasing 


May 15, 2017 
 
 
 
10
effectiveness of oral furosemide in the days leading up to AHF hospitalization. Intravenous 
furosemide is effective at initiating diuresis in most patients but is limited to use in hospital or in 
specialized clinics. From a pharmacokinetic standpoint, furosemide infusion has theoretical 
advantages over IV bolus infusion, although the DOSE trial did not suggest a clinically important 
difference between these two strategies as initial therapy in AHF patients9. The device to be tested 
in this trial, the SC2Wear pump (subcutaneous pump) utilizes a reformulated neutral pH 
formulation of furosemide for subcutaneous delivery. The subcutaneoupump is designed to 
deliver a total of 80mg of parenteral furosemide over a period of 5 hours via subcutaneous 
injection (30 mg in hour 1, then 12.5 mg/hour over the next 4 hours) utilizing a reusable, 
subcutaneous delivery system (Figure 1). 
 
Figure 1. SC2Wear furosemide pump.  
 
 
Small preliminary studies examined the pharmacokinetics and pharmacodynamics of the 
furosemide delivery via a subcutaneous pump compared to oral furosemide or IV furosemide.  
In a preliminary study of 10 
stable (NYHA class II heart 
failure patients), 80mg 
subcutaneous furosemide 
dose achieved similar peak 
furosemide level (Cmax), 
longer half-life (t1/2), and 
greater total exposure 
(AUC) compared to a single 
80mg oral dose (Figure 2).  
 
Figure 2. Plasma 
furosemide levels for oral 
furosemide and 
subcutaneous furosemide.  
 
 


May 15, 2017 
 
 
 
11
 
 
In a pharmacodynamic study of 80mg IV furosemide given as two 40mg IV pushes 2 hours apart 
(the FDA label dosing for IV furosemide) vs. 80mg subcutaneous furosemide produced similar 
diuretic effect over 8 hours (Figure 3). These data support the concept that subcutaneous delivery 
of furosemide can achieve results comparable to intravenous administration. The clinical utility of 
this approach has not been tested in AHF population. The goal of the SUBQ-AHF study is to test 
the ability of a treatment strategy utilizing the subcutaneous pump in selected AHF patients to 
improve the total days alive and out of the hospital within the 30 days after randomization, as well 
as lower overall costs of care.  
 
Figure 3. Pharmacokinetics and diuresis from 80 mg furosemide via subcutaneous pump 
vs 80mg IV furosemide given as two 40mg boluses separated by 2 hours 
 
 
 
4.0 
OBJECTIVES 
4.1 Primary Objectives 
To determine if a strategy of a novel subcutaneous delivery of furosemide is safe and feasible in 
patients with AHF. 
 
OUTCOME DETERMINATIONS 
The analysis of data from the Pilot Phase will be primarily descriptive in nature and there will be 


May 15, 2017 
 
 
 
12
no formal hypothesis testing. 
5.0 BASIC STUDY DESIGN 
SUBQ-HF Pilot is a multicenter clinical trial of selected AHF patients with persistent congestion 
after initial stabilization. Broadly speaking, the pilot phase is designed to evaluate the overall 
safety and feasibility of a strategy based on subcutaneous delivery of furosemide. The pilot 
phase will consist of an inpatient and outpatient pilot occurring as described below and will be 
followed by review of data by the HF Network Steering Committee and Data Safety Monitoring 
Board.  The same inclusion and exclusion criteria will be used for both phases of the pilot. 
5.1 
Inpatient Pilot  
For the inpatient pilot, 20 patients will be enrolled. The inpatient pilot will be a non-randomized 
feasibility assessment of subcutaneous furosemide in the target study population. After 
stabilized in the hospital for at least 24 hours of IV diuretic therapy. Subjects in the inpatient pilot 
will receive subcutaneous furosemide for 48 hours, during which they will remain in hospital. 
This will be primarily a safety and feasibility assessment. There will be no formal hypothesis 
tested, and statistical analysis will be descriptive in nature. The specific goals of the inpatient 
pilot will be to: 
 
Test patient tolerability of subcutaneous delivery of furosemide in AHF population  
 
Develop and refine screening and recruitment strategies to identify the target study 
population. 
5.2 Outpatient Pilot 
For the outpatient pilot, an additional 20 patients will be enrolled. The outpatient phase will be 
a non-randomized feasibility assessment that will mirror the planned outpatient subcutaneous 
strategy planned for the larger trial. Eligible patients will be discharged home on either 80mg 
subcutaneous daily or BID (based on their anticipated diuretic requirements at the time of 
enrollment). Subcutaneous device therapy will continue for 1-7 days and dose (QD vs. BID) will 
be directed by the treating physician. Subjects in the outpatient pilot phase will have contact 
with the study site by telephone on D1, D3 and 5 days post enrollment.  They will have a lab 
visit on D2 (+2d) post enrollment. They will have a clinic visit on D7 (+2d) post enrollment to 
assess the ability to utilize the subcutaneous device at home, the adequacy of diuresis, and 
resolution of signs and symptoms related to congestion. Subjects will have a D14 phone call to 
assess for adverse events.  More frequent clinic contacts or laboratory monitoring may be 
performed as clinically indicated. A set of guidelines based on weight, symptoms, and subject-
reported qualitative diuresis (see details in Appendix C) will be utilized in deciding when to 
transition from subcutaneous device therapy to oral diuretic therapy by the treating physician.  
Outpatients may not continue subcutaneous therapy beyond day 7.  
 
The specific goals of the outpatient pilot will be to: 


May 15, 2017 
 
 
 
13
 
Assess the feasibility of subcutaneous furosemide delivery in the target population in the 
outpatient setting, as measured by qualitative assessment of subject compliance and 
successful use of the device and related aspects of self-care (daily weights, blood 
pressure, etc.).  
 
Assess subject tolerability and safety of subcutaneous furosemide 
 
Assess and refine the planned guidelines for monitoring clinical response and 
adjustment of subcutaneous diuretics and transitioning to oral diuretics shown in 
Appendix C 
 
Assess and refine the frequency and nature of site interactions (phone calls, clinic visits, 
lab visits) that will be utilized in the Evaluation phase 
At the completion of the pilot phase, the results will be reviewed by the HF Network Steering 
Committee and the Data and Safety Monitoring Board. The main SUBQ-HF study protocol will 
be amended, if needed, based on the analysis of the results from the pilot phase experience. If 
there are no substantive concerns about safety or feasibility, the SUBQ-HF study will proceed 
as designed.  
6.0 STUDY FLOW DIAGRAM  
Figure 6A. Inpatient Pilot Flow Diagram  
 
 
 
Figure 6B. Outpatient Pilot Phase Flow Diagram 
 
  


May 15, 2017 
 
 
 
14
7.0 STUDY POPULATION AND ELIGIBILITY CRITERIA 
The study population for both the Inpatient and Outpatient Pilots will be identical. Patients 
hospitalized with acute heart failure (AHF) will be screened for participation in the study using 
the inclusion and exclusion criteria listed below.   
7.1 Inclusion Criteria 
1. Age >18 years 
2. Willingness and ability to provide informed consent 
3. Hospitalization for AHF with at least 1 symptom (dyspnea, orthopnea, or edema) AND 1 sign 
(rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest 
radiography, BNP > 250 ng/mL or NTproBNP > 1000 ng/mL) of congestion 
4. Persistent congestion despite at least 18 hours of IV therapy, defined by the presence of at 
least 2 or more of the following at the time of consent: 
a. Peripheral edema 
b. Rales 
c. Elevated JVP 
d. Ascites 
e. BNP > 250 ng/mL or NTproBNP > 1000 ng/mL  
5. Total anticipated daily IV furosemide dose (at time of screening) >80-200 mg (or 
equivalent)/day 
6. Anticipated need for at least 24 more hours of parenteral diuretic therapy 
7.2 Exclusion Criteria 
1. Severe renal dysfunction (eGFR< 30 ml/min/1.73m2)  
2. Requirement for inotropes (other than digoxin) or mechanical support during hospitalization 
3. Clinically significant electrical instability during hospitalization 
4. Ongoing need for other intravenous therapies beyond diuretics (vasodilators, antibiotics, etc.) 
5. Anticipated need for ongoing parenteral electrolyte repletion  
6. Planned discharge to location other than home (e.g, hospice, skilled nursing facility, etc.) 
7. Anticipated cardiac transplantation or left ventricular assist device within the next 30 days 
8. Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis, 
constrictive pericarditis or tamponade 
9. Known or anticipated pregnancy in the next 30 days 
10. Prior use of subcutaneous furosemide pump or current use of any subcutaneous pump, on-
body infusion devices or patients who give regimented injections at the intended site of the 
furosemide infusion device 
11. Other psychosocial or physical barriers to following the protocol and using a subcutaneous 
pump device outside the hospital setting 
12. Unable to accurately measure urine output 
13. Known allergy to furosemide 
14. Known sensitivity or allergy to medical adhesive tape 


May 15, 2017 
 
 
 
15
8.0 
TREATMENT INTERVENTIONS 
8.1 Inpatient Pilot  
Eligible patients who are in the hospital for AHF will receive subcutaneous furosemide, with 
planned treatment for 48 hours. Subject’s last dose must start prior to 48-hour time period and 
will have a maximum of 4 doses.  They will be treated with 5-hour 80 mg subcutaneous 
furosemide injection either once or twice daily, based on clinical assessment of diuretic 
requirements. Assessment of renal function and electrolytes will be performed as clinically 
indicated consistent with standard of care for inpatient treatment of AHF.  The subjects will be 
instructed on the pump and have it applied for the first dose.  The subjects will be encouraged to 
apply the pump while supervised at their next dosing.  Subjects will be phoned at day 9 to 
collect safety data. 
8.2 Outpatient Pilot  
Eligible patients who are in the hospital for AHF will receive subcutaneous furosemide at 
hospital discharge, with planned treatment for 1-7 days in the outpatient setting. They will be 
treated with 80 mg subcutaneous furosemide injection over 5 hours either once or twice daily, 
based on clinical assessment of diuretic requirements. Prior to discharge the subjects will be 
instructed on the pump and the subject will apply it, while supervised.  It is anticipated that the 
subject will then be discharged and they will self-administer pump at home for remainder of 
usage.  In subjects whose hospitalization extends beyond the anticipated period, the protocol 
driven assessments should occur during the inpatient stay when possible.   
 
8.2.1 Subcutaneous furosemide outpatient strategy:  
Subjects will receive device training and study materials (subcutaneous pump device and 7-day 
supply of subcutaneous furosemide vials) on the day of planned hospital discharge (study day 
0). It is assumed the subject will be discharged within 24 hours. If they are not discharged within 
24 hours the subject will remain on the pump as ordered by the treating physician. Training will 
include instruction on daily weights and dyspnea numerical rating for symptoms. Scales will be 
provided to all subjects. Subjects will be discharged with a planned treatment with 80 mg 5-hour 
subcutaneous furosemide injection either QD or BID depending on anticipated diuretic 
requirements. If there are unanticipated delays in discharge after enrollment, subjects will 
continue with their assigned therapy and assessments in the hospital. Discharged subjects will 
receive a phone contact from study team on D1, D3, and D5 in order to assess adequacy of 
diuresis, persistence of congestion, and planned duration and dose of ongoing subcutaneous 
therapy (see Appendix C for guidelines on adjusting therapy). Additional clinical contact 
(additional phone contacts or clinical visits) may be performed if felt clinically indicated by the 
study team or clinical provider. All subjects will have a clinic visit at Day 7 (+2) and a safety 
follow up phone call at Day 14. Subjects will have assessment of electrolytes and renal function 
by protocol at 48 hours from discharge.  Day 2 (+2) labs can be done at the study site or via 
home laboratory testing that is set up by study site prior to discharge if assurances are made 
that results will be sent to the study team in a timely manner (<24 hours). More frequent 
electrolyte monitoring can be performed at the discretion of the study team or clinical provider 
as clinically indicated. Subjects receiving the subcutaneous pump for outpatient use should be 


May 15, 2017 
 
 
 
16
prescribed a supplementation regimen based on electrolyte supplementation needs in the 
hospital with IV therapy.  The duration of subcutaneous therapy will be planned from 1-7 days 
depending on clinical response. Dose and frequency of oral diuretics once subcutaneous 
therapy is completed will be per the discretion of the treating physician. 
8.3 Diuretic Dose Adjustments 
Diuretic therapy will be adjusted as needed based on clinical assessment of signs and 
symptoms of congestion, vital signs, laboratory values, and diuretic response by their attending 
provider. All study participants will be on 80mg subcutaneous by subcutaneous pump either 
once or twice daily.  Outpatient pilot subjects will be prescribed either 80mg subcutaneous by 
subcutaneous pump either once or twice daily at hospital discharge depending on the provider 
assessment of their degree of congestion and diuretic responsiveness. For inadequate diuretic 
response, providers may either increase to 80mg subcutaneous BID (if initially treated with 
80mg subcutaneous QD) or add additional open label oral diuretics, or other adjunctive 
treatments (such as metolazone, based on clinical judgment). The timing and dosage of the 
decision to discontinue subcutaneous therapy and switch to oral diuretics will be based on 
clinical judgment. Outpatients may not continue subcutaneous therapy beyond day 7. If subjects 
are readmitted for heart failure during the treatment period, subcutaneous therapy should be 
discontinued and the patient treated with IV diuretics as clinically indicated. 
8.4 Electrolyte Repletion 
Repletion of electrolytes will be based on clinical assessment of potassium and/or magnesium 
balance and subject’s prior need for supplementation. The extent of ongoing electrolyte 
monitoring will be based on clinical judgment. 
8.5 Concomitant Medications 
Other than SUBQ pump diuretic therapy, all subjects will be treated with standard of care heart 
failure therapy as directed by treating providers. Information on cardiovascular medications, 
diuretics and electrolytes will be collected.  
9.0 RECRUITMENT PROCEDURES 
All patients admitted to the participating Heart Failure Clinical Research Network centers with a 
diagnosis of AHF will be screened for possible participation in the study. Given that the protocol 
requires patients to be stabilized for at least 18 hours of IV therapy prior to enrollment, this will 
allow for identifying and following potential patients for eligibility. Patients meeting eligibility 
criteria will be approached regarding participation in this study. Patients who agree to participate 
will be enrolled. There is no screening period in this study.   


May 15, 2017 
 
 
 
17
10.0 STUDY SCHEDULE  
A complete schedule of assessments throughout the pilot study is provided in Appendix A. 
10.1 Baseline Evaluation: Inpatient Pilot 
At the time of enrollment, all study subjects will undergo: 
 
 
Directed history and physical examination, focused on signs and symptoms of 
congestion 
 
Vital signs (including weight) 
 
NYHA Classification prior to decompensation 
 
Input and Output measurement starts at enrollment (time of consent) 
 
Review of concomitant cardiovascular medications, diuretics and electrolyte 
supplementation 
 
Baseline NTpro-BNP or BNP, creatinine, BUN, and electrolytes (local laboratory), 
pregnancy test (if female and if not done during hospitalization) 
 
Numerical rating score (0-10 point NRS) for symptoms (see Appendix B) 
Assessments and labs done as usual care within 4 hours of enrollment may be collected 
and entered into the eCRF for the study. 
 
Once the baseline data points have been collected, a member of the study team will teach the 
subject about the subcutaneous pump and the infusion will be started. 
10.1.1 Study Days 1-2  
For study days 1-2 the following will be collected daily: 
 
 
Physical examination focused on signs and symptoms of congestion 
 
Daily AM weight post void 
 
Numerical rating score (0-10 point NRS) for symptoms  
 
Total inputs and outputs (i.e. fluid balance) 
 
Daily furosemide dose plus any rescue therapy (i.e. need for additional diuretics) 
 
Need for electrolyte supplementation and dose 
 
Lab values for basic metabolic panel (only if done per standard of care) 
 
Assessment for adverse events 
 
 
10.1.2 Study Day 9 
There will be a phone visit for all subjects 9 days (+2 days to allow for arranging the call on a 
weekday) post enrollment.  
 
Assessments during this phone call will include: 
 
 
Assessment for adverse events 
Assessment for interval hospitalizations, ED visits, or unscheduled clinic visits 


May 15, 2017 
 
 
 
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10.2 Baseline Evaluation: Outpatient Pilot 
At the time of enrollment, all study subjects will undergo: 
 
 
Directed history and physical examination, focused on signs and symptoms of 
congestion 
 
Vital signs (including weight)  
 
NYHA Classification prior to decompensation 
 
Concomitant cardiovascular medications, diuretics and electrolyte supplementation  
 
Baseline creatinine, BUN, NT-proBNP or BNP, and electrolytes (local laboratory, 
standard of care), pregnancy test (if female of child bearing potential and not done 
during hospitalization) 
 
Numerical rating score (0-10 point NRS) for symptoms (see Appendix B) 
 
Assessment for adverse events 
Assessments and labs done as usual care within 12 hours prior to enrollment may be 
collected and entered into the eCRF for the study. 
 
 
Once the baseline data points have been collected, and prior to discharge, a member of the 
study team will teach the subject on the use of the subcutaneous pump and the subject will 
apply it for their first dose while supervised.   
10.2.1 Study Days 1 through 7  
For study days 1-7, the following will be collected daily. These data will be recorded daily by the 
subject and reported to the study site during phone contacts: 
 
 
Daily AM weight (from chart if subject in hospital, self weigh if home). Subjects will be 
instructed to collect an AM post-void weight and record this information. 
 
Numerical rating score (0-10 point NRS) for symptoms (subject recorded) 
 
Total diuretic dose 
 
Electrolyte supplementation (type and dose) 
 
Assessment for adverse events 
 
Assessment for interval hospitalizations, ED visits, or unscheduled clinic visits 
10.2.2 D1, D3 & D5 Phone Call 
There will be a phone visit for all subjects 1, 3, and 5 days post enrollment.  
 
Assessments during each phone call will include: 
 
 
Weight (patient reported) 
 
Numerical rating score (0-10 point NRS) for symptoms (patient reported) 
 
Changes in diuretic dose 
 
Electrolyte supplementation 
 
Assessment for adverse events 
 
Assessment for interval hospitalizations, ED visits, or unscheduled clinic visits 
 
Any problems with the pump use or drug  


May 15, 2017 
 
 
 
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10.2.3 D2 Lab Visit  
On study day 2 (window: + 2 days), subjects will undergo laboratory testing of BUN, creatinine, 
and electrolytes. Labs can be done at the study site or via home laboratory testing that is set up 
by study site prior to discharge if assurances are made that results will be sent to the study 
team in a timely manner (<24 hours).  
10.2.4 D7 Clinic Visit  
There will be a protocol specified clinic visit for all subjects who have been discharged.  This will 
occur on day 7 (+ 2 days to allow for arranging clinic visit on a weekday) post enrollment.  Out-
patient subjects may not continue subcutaneous therapy beyond day 7. 
 
Assessments will include: 
 
Directed history and physical examination, focused on signs and symptoms of 
congestion. 
 
Vital signs (including weight) 
 
Numerical rating score (0-10 point NRS) for symptoms 
 
Creatinine, BUN, and electrolytes 
 
Changes in cardiovascular medications 
 
Assessment for adverse events 
 
Assessment for interval hospitalizations, ED visits, or unscheduled clinic visits 
 
Blood sample for BNP or NT-proBNP (local) 
 
Total diuretic dose 
 
Electrolyte supplementation (type and dose) 
 
Any problems with the pump use or drug 
 
Return pump and all used and unused vials, cartridges and diary 
 
10.2.5 D14 Phone Call 
There will be a phone visit for all subjects 14 days (+2 days to allow for arranging the call on a 
weekday) post enrollment.  
 
Assessments during this phone call will include: 
 
Assessment for adverse events 
Assessment for interval hospitalizations, ED visits, or unscheduled clinic visits 
11.0 PARTICIPANT SAFETY AND ADVERSE EVENTS 
11.1 Definitions 
11.1.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
a subject whether or not considered drug or biologic related. An AE can therefore be any 
unfavorable and unintended sign, symptom or disease temporally associated with the use of a 
pharmaceutical product or biologic. 


May 15, 2017 
 
 
 
20
11.1.2 Suspected Adverse Reaction 
A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the drug caused the event. “Reasonable possibility” suggests there is a causal 
relationship between the drug and the adverse event. “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse 
event caused by a drug.  
 
11.1.3 Serious Adverse Events 
An AE or SAR is considered serious if the Investigator or sponsor believes any of the following 
outcomes may occur: 
 
Death 
 
Life-threatening AE: Places the subject at immediate risk of death at the time of the 
event as it occurred. It does not include an AE that, had it occurred in a more severe 
form, might have caused death. 
 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 
Inpatient hospitalization or prolongation of hospitalization.  
 
Congenital anomaly or birth defect.  
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition above. 
 
This determination is based on the opinion of either the investigator or sponsor (e.g., if either 
believes it is serious, it must be considered serious). 
 
11.1.4 Laboratory Test Abnormalities 
 
For laboratory test abnormalities that meet the definition of a serious adverse event (SAE), 
which required the subject to have the investigational product discontinued or interrupted, or 
required the subject to received specific corrective therapy, the clinical diagnosis rather than the 
laboratory term will be used by the reporting investigator (e.g., anemia versus low hemoglobin 
value). 
11.1.5 Assessment of Severity 
The determination of adverse event severity rests on medical judgment of a medically qualified 
investigator.  The intensity of AEs will be graded using the following definitions: 
 
Mild: awareness of sign, symptom, or event but easily tolerated. 
Moderate: discomfort enough to cause interference with usual activity and may warrant 
intervention. 
Severe: incapacitating with inability to do usual activities or significantly affects clinical 
status, and warrants intervention. 


May 15, 2017 
 
 
 
21
11.1.6 Assessment of Causal Relationship 
A medically-qualified investigator must assess the relationship of any AE to the use of study 
drug, based on available information, using the following guidelines:  
 
Not related: There is not a reasonable causal relationship to the investigational product 
and the adverse event.  
 
Unlikely related: No temporal association or the cause of the event has been identified, 
or the drug or biologic cannot be implicated. 
 
Possibly related: There is reasonable evidence to suggest a causal relationship between 
the drug and adverse event. 
 
Related: There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
 
The Investigator reports causality, but the sponsor retains the final decision on causality when 
filing to the FDA. 
11.1.7 Expectedness 
The expectedness of an AE or SAR shall be determined according to the specified reference 
document containing safety information (e.g., most current product label). Any AE that is not 
identified in nature, severity, or specificity in the current study drug reference document(s) is 
considered unexpected. Events that are mentioned in the product label as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the drug, but not specifically 
mentioned as occurring with the particular drug under investigation are considered unexpected. 
11.2 
Suspected Unexpected Serious Adverse Reaction 
AEs that meet the criteria of serious, related to study drug, and unexpected per investigator 
brochure, qualify for expedited reporting to the regulatory authorities. The sponsor or their 
designee will notify the FDA and all participating investigators in a written IND safety report of 
an SAR that is serious and is unexpected, as determined by the sponsor. The reporting will 
occur as soon as possible, but not later than 15 calendar days after sponsor determines that it 
qualifies for expedited reporting. The sponsor will identify all safety reports concerning a similar 
SAR, and will analyze the significance of the SAR in light of the previous, similar reports. 
Follow-up reports will be sent to investigators to inform and update them about an important 
suspected adverse reaction if it significantly affects the care of the participants or conduct of the 
study. 
11.2.1 Day Zero 
Day zero (0) is the calendar day that the sponsor is first notified of an event. Day zero can also 
be the date the event qualified for expedited reporting as determined by the sponsor. 
11.2.2 Pregnancy 
Pregnancy occurring during a clinical investigation, although not considered a serious adverse 
event, must be reported to DCRI within the same timelines as a serious adverse event.  The 
pregnancy will be recorded on the appropriate paper pregnancy tracking form.  The pregnancy 
will be followed until final outcome.  Any associated AEs or SAEs that occur to the mother or 


May 15, 2017 
 
 
 
22
fetus will be recorded in the AE/SAE eCRF, within the study database.  
11.3 
Recording and Reporting of Adverse Events 
The Site Investigator is responsible for monitoring the safety of participants enrolled into the 
study at the study sites. Non-serious AEs that occur from the time of informed consent and up to 
7 days post last product use will be collected in the study database.  These events should be 
documented in the source documents and followed until clinically resolved.  
 
SAEs, except for those anticipated AEs listed above, occurring from signed informed consent to 
the 7 days post last product use will be captured on the SAE form. Unless exempted as 
described above, all SAEs, whether or not deemed drug-related or expected, must be reported 
to the sponsor (or designee) by the investigator or qualified designee within 24 hours of first 
becoming aware of the event. The investigator or qualified designee will enter the required 
information regarding the SAE into the appropriate module of the study database, which will 
automatically result in distribution of the information to the sponsor or their designee (e.g. DCRI 
Safety Surveillance). If the study database system is temporarily unavailable, the event, 
including the investigator-determined causality to study drug should be reported via the back-up 
paper SAE form to the sponsor or their designee. Upon return of the availability of the electronic 
data capture (EDC) system, the SAE information must be entered into the study database. 
11.4 
Follow-up 
When additional relevant information becomes available, the Investigator will record follow-up 
information according to the same process used for reporting the initial event as described 
above. The Investigator will follow all reportable events until resolution, stabilization or the event 
is otherwise explained.  
 
The sponsor or their designee will follow all SAEs until resolution, stabilization, until otherwise 
explained or until the subject completes the final follow-up, whichever occurs first.  
 
Investigators are also responsible for promptly reporting AEs and SAEs to their reviewing 
IRB/EC in accordance with local requirements.  
 
The DSMB will review detailed safety data approximately every 6 months throughout the study.  
 
11.5 
Anticipated Disease Related Adverse Events  
The following AEs are anticipated, disease-related events in patients admitted with AHF: 
 
Arrhythmias: This refers to both atrial and ventricular arrhythmias.  
 
Sudden Cardiac Death:  This refers to witnessed cardiac arrests and sudden 
deaths without an otherwise apparent cause such as trauma or malignancy. 


May 15, 2017 
 
 
 
23
 
Acute Coronary Syndrome: This refers to unstable angina, non ST segment 
elevation myocardial infarction (NSTEMI), and ST segment elevation myocardial 
(STEMI). 
 
Cerebrovascular Event:  This refers to cerebrovascular accidents (stroke) of any 
cause (hemorrhagic, ischemic, or embolic) and transient ischemic attack (TIA). 
 
Venous Thromboembolism: This includes both deep venous thrombosis and 
pulmonary embolus. 
 
Lightheadedness, Presyncope, or Syncope: This includes dizziness, 
lightheadedness, or fainting from any cause. 
 
Acute kidney injury as defined by KDOQI guidelines:  Acute kidney injury, 
typically defined as a rise in creatinine > 0.3 mg/dL over 48 hours, or progressive 
loss of renal function over time. 
 
Worsening HF: Worsening of symptoms and signs of heart failure requiring 
intensification of IV therapy or initiation of mechanical therapy. 
 
Hypokalemia (K+ <3.5 mmol/L) 
 
Hypomagnesemia (Mg <1.0 mEq/L or <0.70 mmol/L)  
 
All anticipated disease related events, will not be captured as AEs/SAEs during the study, but 
will be entered on the appropriate eCRF module. 
11.6 Summary of the Risks 
Experience with subcutaneous furosemide injection has been limited.  Although preclinical 
studies did not suggest any local irritation or reaction from administration of the study drug, local 
discomfort or irritation following administration of the study drug cannot be excluded. 
The subcutaneous administration of furosemide is expected to be associated with the same 
systemic adverse experience profile as the intravenous and intramuscular administration.  The 
systemic adverse experience profile for intravenous and intramuscular furosemide is listed 
below. 
11.6.1 Drug Adverse Reactions 
General 
Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse 
and possibly vascular thrombosis and embolism, particularly in elderly patients. As with any 
effective diuretic, electrolyte depletion may occur during furosemide therapy, especially in 
patients receiving higher doses and a restricted salt intake. Hypokalemia may develop with 
furosemide, especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is 
present, or during concomitant use of corticosteroids, ACTH, licorice in large amounts, or 
prolonged use of laxatives may exaggerate metabolic effects of hypokalemia, especially 
myocardial effects. 
 
All patients receiving furosemide therapy should be observed for these signs or symptoms of 
fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia, 
hypomagnesemia, or hypocalcemia): dryness of mouth, thirst, weakness, lethargy, drowsiness, 
restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, 
arrhythmia, or gastrointestinal disturbances such as nausea and vomiting. Increases in blood 
glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2-hour 
postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus has been 
reported. In patients with severe symptoms of urinary retention (because of bladder emptying 


May 15, 2017 
 
 
 
24
disorders, prostatic hyperplasia, urethral narrowing), the administration of furosemide can cause 
acute urinary retention related to increased production and retention of urine. Thus, these 
patients require careful monitoring, especially during the initial stages of treatment. In patients at 
high risk for radiocontrast nephropathy, furosemide can lead to a higher incidence of 
deterioration in renal function after receiving radiocontrast compared to high-risk patients who 
received only intravenous hydration prior to receiving radiocontrast. In patients with 
hypoproteinemia (e.g., associated with nephrotic syndrome) the effect of furosemide may be 
weakened and its ototoxicity potentiated. Asymptomatic hyperuricemia can occur and gout may 
rarely be precipitated. Patients allergic to sulfonamides may also be allergic to furosemide. The 
possibility exists of exacerbation or activation of systemic lupus erythematosus. As with many 
other drugs, patients should be observed regularly for the possible occurrence of blood 
dyscrasias, liver or kidney damage, or other idiosyncratic reactions. 
11.6.2 Information for Patients 
Patients receiving furosemide should be advised that they may experience symptoms from 
excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can 
usually be managed by getting up slowly. Potassium supplements and/or dietary measures may 
be needed to control or avoid hypokalemia. 
 
Patients with diabetes mellitus should be told that furosemide may increase blood glucose 
levels and thereby affect urine glucose tests. The skin of some patients may be more sensitive 
to the effects of sunlight while taking furosemide. 
Hypertensive patients should avoid medications that may increase blood pressure, including 
over-the counter products for appetite suppression and cold symptoms. 
 
Adverse Reactions 
 
Adverse reactions are categorized below by organ system and listed by decreasing severity. 
 
Gastrointestinal System Reactions 
(1) Hepatic encephalopathy in patients with hepatocellular insufficiency (2) Pancreatitis (3) 
jaundice (intrahepatic cholestatic jaundice) (4) increased liver enzymes (5) anorexia (6) oral and 
gastric irritation (7) cramping (8) diarrhea (9) constipation (10) nausea (11) vomiting. 
 
Systemic Hypersensitivity Reactions 
(1) Severe anaphylactic or anaphylactoid reactions (e.g., with shock) (2) Systemic vasculitis (3) 
interstitial nephritis (4) necrotizing angiitis. 
 
Central Nervous System Reactions 
(1) Tinnitus and hearing loss (2) paresthesias (3) vertigo (4) dizziness (5) headache (6) blurred 
vision (7) xanthopsia. 
 
Hematologic Reactions 
(1) Aplastic anemia (2) thrombocytopenia (3) agranulocytosis (4) hemolytic anemia (5) 
leukopenia (6) anemia (7) eosinophilia. 
 
Dermatologic-Hypersensitivity Reactions 
(1) Exfoliative dermatitis (2) bullous pemphigoid (3) erythema multiforme (4) purpura (5) 
photosensitivity (6) urticaria (7) rash (8) pruritus (9) Stevens-Johnson Syndrome (10) toxic 
epidermal necrolysis. 


May 15, 2017 
 
 
 
25
 
Cardiovascular Reaction 
(1) Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics,  
(2) Increase in cholesterol and triglyceride serum levels. 
 
Other Reactions 
(1) Hyperglycemia (2) glycosuria (3) hyperuricemia (4) muscle spasm (5) weakness (6) 
restlessness (7) urinary bladder spasm (8) thrombophlebitis (9) transient injection site pain (10) 
fever. 
11.6.3 Device Adverse Reactions  
 
SC2Wear System 
Mild skin irritation such as redness, itching and edema or skin trauma and abrasion may occur 
during exposure or removal of the adhesive. Removal of the device may be uncomfortable or 
painful. Rarely, allergic reactions to the adhesive may occur. If the subject knows they are 
sensitive or allergic to medical adhesive tape, they should not participate in the study. 
 
The needle used to inject the drug into the subcutaneous tissue is automatically inserted at the 
beginning of the infusion cycle, and automatically retracted at the end. The needle is 27 gauge 
and 8.5 mm. Common risks with needle injection include pain or discomfort upon needle 
injection, or minor bruising from needle movement.  Injection site reactions were minimal and 
limited to very slight edema and very slight to definite erythema.  An accidental needle stick 
injury may occur if (a) the needle appears before the Pump is placed on the body or (b) the 
Pump falls off the body while it is pumping. If either of the above happens, the Pump should be 
handled carefully.  
 
As with all devices that use medical adhesives for adherence the usual risks are: it is possible 
that there may be instances of complete or near complete dislodgement of the device from the 
abdominal skin.  In a previous study designed to look at adhesive effectiveness in combination 
with the sc2Wear device, 2 out of 132 device applications (1.5%) became completely detached 
from the skin.   In the same study 6 subjects (4.5%) had evidence of medical adhesive-related 
skin injury (MARSI).   The finding of rare cases of dislodgement and rare cases of MARSI 
indicate that the objective to find an adhesive with the optimal balance between adhesive 
strength and skin tolerability has been achieved.  Using more aggressive adhesive would 
increase the risk of MARSI which carries a risk of infection and may reduce the patient 
acceptance of this treatment.  Should dislodgement occur, there would be minimal risk to the 
patient, as it would be obvious and clearly discoverable by the patient being treated.  In such 
instances, the patients will be instructed to call their healthcare provider. In this study, patients 
are instructed to contact the study team in cased of complete dislodgement or if leakage is 
detected.   
12.0 STATISTICAL CONSIDERATIONS AND DATA MANAGEMENT 
PROCEDURES 
12.1 Overview 
There will be no formal hypothesis tested, and statistical analysis will be descriptive in nature.  


May 15, 2017 
 
 
 
26
12.2 Analysis of Safety Data and Statistical Monitoring Plan 
Interim data analysis for efficacy and futility will not be conducted due to relatively small size 
and short duration of this clinical trial. Safety data will be assessed at the completion of the pilot 
study by the NHLBI-appointed DSMB. The safety analyses will be based on the entire ITT 
population. Safety will be evaluated by comparing the rates of occurrence and severity of AEs of 
the study population to expected rates of occurrences.  
12.3 Overview of Data Management 
The CC will have primary responsibility for data management, including the development of data 
collection systems, data monitoring processes, and data storage and back up. State-of-the-art 
technology will be used for the management of the network’s data.  
 
The CC team will develop modules necessary for this study. Common fields and data elements 
will be used across the HFN trials to promote data standardization and facilitate cross-network 
analyses. Study components may include an enrollment and demographics form; forms for 
recording relevant history, HF symptoms, physical exam results, laboratory results, baseline 
biomarker levels, and other baseline presenting characteristics; follow-up forms for use during 
regular follow-up visits; forms to track the participant’s clinical course over time; and event forms 
for recording the circumstances and details surrounding the occurrence of a death or 
hospitalization.  
 
The data will be collected in a validated, 21 CFR Part 11-compliant EDC system. The DCRI has 
an internal team of skilled data managers and programmers that will design and produce a tailored 
network system that provides operational efficiency and meaningful reporting of metrics.  
12.3.1 Data Management Process 
The EDC system will be used for data entry and may be used for simple reports. All data will be 
entered into the eCRF by personnel at the clinical sites. The system allows for both automatic 
and manual queries.  
 
The CC may create reports to identify trends in the data that may require additional clarification 
and training. The CC may perform internal database quality-control checks during the study to 
identify systematic deviations requiring corrections.  
12.3.2 Data Quality Control  
A two-step approach to data quality control will be implemented. 
 
1. Training: Prior to the start of enrollment, the Investigators and Study Coordinators will be 
trained on the clinical protocol and data collection procedures. Recent site surveys 
indicate that most Coordinators are very familiar with the EDC system, so training is 
typically targeted to a specific protocol. For Coordinators new to the InForm database, 
the CC will be available to provide training with hands-on database interaction and  
demonstration of key EDC system functionality as needed. Personnel at the clinical sites 


May 15, 2017 
 
 
 
27
will enter the data mandated by the protocol into the eCRFs. The data will be extracted 
from the participant’s medical charts and other source documents. The CC will conduct 
follow-up training and training for new study personnel as needed. 
2. Monitoring: A CC monitor will visit sites during the enrollment period to ensure that data 
collection is being handled properly, to provide in-service training, and to address 
questions from site investigators and coordinators. Additional details will be outlined in 
the Clinical Monitoring Plan.  
12.4 Data Security 
Access to databases will be controlled centrally by the CC through user passwords linked to 
appropriate privileges. This protects the data from unauthorized changes and inadvertent loss or 
damage. Database and web servers will be secured by a firewall and through controlled 
physical access. Database back-up will be performed daily using standard procedures in place 
at the CC. All disk drives that provide network services, and all user computers, will be 
protected using virus-scanning software. 
12.5 Publication Policy 
Dissemination of preliminary information can adversely affect the objectivity of study data. For 
this reason, Investigators will be prohibited from performing subset analyses at any point prior to 
the conclusion of the study, and any data, other than safety data, cannot be used for publication 
or reporting outside of this study until the study is completed or discontinued by the DSMB or 
HFN Steering Committee.  
13 
STUDY ADMINISTRATION 
13.1 Data and Safety Monitoring Board (DSMB) 
A DSMB has been appointed by the NHLBI for the HFN. This committee consists of a group of 
highly experienced individuals with extensive pertinent expertise in HF and clinical trials. The 
DSMB will advise the HFN Steering Committee regarding the continuing safety of current 
participants and those yet to be recruited, as well as the continuing validity and scientific merit of 
the trial. Safety data, summarized at the treatment level, will be assessed approximately every 6 
months by the DSMB. The safety analyses will be based on the entire ITT population. During the 
evaluation phase, safety will be evaluated by comparing the occurrence of AEs and changes in 
laboratory values between study strategies. 
13.2 Coordinating Center 
The Duke Clinical Research Institute will function as the CC for this trial as specified by the 
National Institute of Health and NHLBI HFN grant. 


May 15, 2017 
 
 
 
28
14.0 ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and applicable national and local 
regulations. This will ensure adherence to Good Clinical Practice, as described in the following 
documents: 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 312 (IND 
regulations), 54 (financial disclosure), 50 (informed consent), 56 (IRB regulations). 
Participating investigators agree to adhere to the instructions and procedures described in the 
protocol and thereby to adhere to the principles of Good Clinical Practice to which it conforms. 
 
14.2 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC must be provided to the CC before 
study initiation. Any amendments to the protocol, other than administrative ones, must be 
approved by this committee. 
14.3 
Informed Consent 
The investigator or designee must explain to each participant (or legally authorized 
representative) the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved and any discomfort it may entail. Each 
participant must be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
 
The informed consent form(s) must be submitted by the investigator for IRB/IEC approval. The 
Coordinating Center will supply template informed consent forms, which comply with regulatory 
requirements, and are appropriate for the study. Any changes to the template consent form 
suggested by the Investigator must be agreed to by the Coordinating Center before submission 
to the IRB/IEC, and a copy of the approved version must be provided to the Coordinating Center 
after IRB/IEC approval. 
 
14.4 Confidentiality and HIPAA Requirements 
All information collected on study participants will be stored in a confidential manner using the 
procedures in place at each participating center. Only approved study personnel will have access 
to data collected as part of the study. Study participants will be identified by a participant ID 
number on all study documents. Data will be transmitted to the CC in a secure manner, and 
stored securely at the CC using standard Duke Clinical Research Institute operating procedures. 


May 15, 2017 
 
 
 
29
15.0 MONITORING 
The study will be monitored remotely by representatives of the Duke Clinical Research Institute or 
its designee according to the prospective clinical monitoring plan for the following purposes: 
 
To enable real-time monitoring of compliance with study protocol inclusion and exclusion 
criteria; this will be enabled via triggers and range checks programmed in the InForm 
database.  
 
To assist site personnel who will verify data identified within query reports against source 
documents through frequent telephone and email contact. 
 
To verify that written informed consent was obtained before initiation of any screening 
procedures that are performed solely for determining eligibility for the clinical study and/or 
prior to any tests or procedures. 
 
 


May 15, 2017 
 
 
 
30
16.0 REFERENCES 
 
1. 
Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol. 
2009;53:557-573 
2. 
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, 
Després J-P, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland 
DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler 
ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, 
Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani 
SS, Willey JZ, Woo D, Yeh RW, Turner MB. Heart disease and stroke statistics—2015 
update: A report from the american heart association. Circulation. 2015;131:e29-e322 
3. 
Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, Ikonomidis 
JS, Khavjou O, Konstam MA, Maddox TM, Nichol G, Pham M, Pina IL, Trogdon JG, 
American Heart Association Advocacy Coordinating C, Council on Arteriosclerosis T, 
Vascular B, Council on Cardiovascular R, Intervention, Council on Clinical C, Council on 
E, Prevention, Stroke C. Forecasting the impact of heart failure in the united states: A 
policy statement from the american heart association. Circ Heart Fail. 2013;6:606-619 
4. 
Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW. Temporal trends in 
clinical characteristics, treatments, and outcomes for heart failure hospitalizations, 2002 
to 2004: Findings from acute decompensated heart failure national registry (adhere). Am 
Heart J. 2007;153:1021-1028 
5. 
Gheorghiade M, Follath F, Ponikowski P, Barsuk JH, Blair JE, Cleland JG, Dickstein K, 
Drazner MH, Fonarow GC, Jaarsma T, Jondeau G, Sendon JL, Mebazaa A, Metra M, 
Nieminen M, Pang PS, Seferovic P, Stevenson LW, van Veldhuisen DJ, Zannad F, 
Anker SD, Rhodes A, McMurray JJ, Filippatos G. Assessing and grading congestion in 
acute heart failure: A scientific statement from the acute heart failure committee of the 
heart failure association of the european society of cardiology and endorsed by the 
european society of intensive care medicine. Eur J Heart Fail. 2010;12:423-433 
6. 
Logeart D, Thabut G, Jourdain P, Chavelas C, Beyne P, Beauvais F, Bouvier E, Solal 
AC. Predischarge b-type natriuretic peptide assay for identifying patients at high risk of 
re-admission after decompensated heart failure. J Am Coll Cardiol. 2004;43:635-641 
7. 
Bueno H, Ross JS, Wang Y, Chen J, Vidan MT, Normand SL, Curtis JP, Drye EE, 
Lichtman JH, Keenan PS, Kosiborod M, Krumholz HM. Trends in length of stay and 
short-term outcomes among medicare patients hospitalized for heart failure, 1993-2006. 
Jama. 2010;303:2141-2147 
8. 
Eapen ZJ, Reed SD, Li Y, Kociol RD, Armstrong PW, Starling RC, McMurray JJ, Massie 
BM, Swedberg K, Ezekowitz JA, Fonarow GC, Teerlink JR, Metra M, Whellan DJ, 
O’Connor CM, Califf RM, Hernandez AF. Do countries or hospitals with longer hospital 


May 15, 2017 
 
 
 
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stays for acute heart failure have lower readmission rates?: Findings from ascend-hf. 
Circulation: Heart Failure. 2013;6:727-732 
9. 
Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, 
Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez 
EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald 
E, O'Connor CM. Diuretic strategies in patients with acute decompensated heart failure. 
N Engl J Med. 2011;364:797-805 
 
 
 
 


May 15, 2017 
 
 
 
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17.0 APPENDICES 
17.1 Appendix A. Schedule of Assessments  
 
Inpatient Pilot 
 
D0 
D1 
D2 
D9  
(+2d)
Inpatient 
x 
x 
x 
 
Phone Call 
 
 
 
x 
Vitals 
x 
x 
x 
 
Weight 
x 
x 
x 
 
I/O 
x 
x 
x 
 
Diuretic dose and electrolyte 
supplementation1 
x 
x 
x 
 
Medical History 
x 
 
 
 
PE/Congestions Assessment 
x 
x 
x 
 
Symptom Rating (NRS) 
x 
x 
x 
 
AEs/SAEs 
x 
x 
x 
x 
Electrolytes2 & Renal 
Function 
x 
x 
x 
 
BNP or NTproBNP 
x 
 
 
 
Pregnancy test  
(females only) 
x 
 
 
 
1Potassium and magnesium supplementation changes from pre-hospitalization. 
2For the basic metabolic panel, all available lab values performed as standard of care will be 
collected.  However, the protocol driven lab values are: sodium, potassium, chloride, BUN, 
creatinine, calcium, glucose, and magnesium. 
 
 
 


May 15, 2017 
 
 
 
33
 
Outpatient Pilot 
 
D0 
D1  
D2 
(+2d) 
D3 
D4 
D5 
D6 
D7  
(+2d) 
D14 
(+2d) 
Inpatient 
x 
 
 
 
 
 
 
 
 
Clinic Visit 
 
 
 
 
 
 
 
x 
 
Phone Call 
 
x 
 
x 
 
x 
 
 
x 
Vital Signs(includes 
weight) 
x 
 
 
 
 
 
 
x 
 
Weight  
 
x3 
x3 
x3 
x3 
x3 
x3 
 
 
Diuretic dose and 
electrolyte 
supplementation1 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
x 
 
Medical History 
x 
 
 
 
 
 
 
 
 
Physical 
Exam/Congestion 
Assessment 
x 
 
 
 
 
 
 
x 
 
Symptom Rating (NRS) 
x 
x3 
x3 
x3 
x3 
x3 
x3 
x 
 
AEs/SAEs 
x 
x 
 
x 
 
x 
 
x 
 
Electrolytes2 & Renal 
Function 
x 
 
x 
 
 
 
 
x 
 
BNP or NT-Pro BNP 
x 
 
 
 
 
 
 
x 
 
Pregnancy Test  
(females only) 
x 
 
 
 
 
 
 
 
 
1Potassium and magnesium supplementation changes from pre-hospitalization. 
2For the basic metabolic panel, all available lab values that were performed for standard of care 
will be collected.  However, the protocol driven lab values are: sodium, potassium, chloride, 
BUN, creatinine, calcium, glucose, and magnesium. 
3Subject to record daily and report to coordinator on call and return diary at Day 7 visit. 
 
 


May 15, 2017 
 
 
 
34
17.2 Appendix B. Numerical Rating Scale for 
Breathlessness 
 
 
 
 


May 15, 2017 
 
 
 
35
17.3 Appendix C.  Guidelines for Remote Adjustment of 
Diuretics during outpatient Subcutaneous treatment 
This document provides a framework for remote decision-making (I.e., assessing and adjusting 
therapy in the absence of a face-to-face encounter with the patient) to guide the use and 
adjustment of outpatient diuretics during outpatient treatment with subcutaneous diuretics 
therapy. It is intended to provide general guidance rather than specific instructions, and the 
guidelines herein will have to interpreted and applied in the context of good clinical judgment. 
Data from laboratory testing (renal function, electrolytes, etc.) will also inform decision-making. 
 
Assessments will generally include consideration of the following variables: 
 
Patient reported weight/change in weight relative to best “dry weight” as determined at 
time of study enrollment 
 
Blood pressure and heart rate (patient reported) 
 
Presence and/or change in-patient reported symptoms and/or signs related to 
congestion (dyspnea, orthopnea, edema, abdominal distension).  
 
Presence and/or change in symptoms related to intravascular volume depletion 
(dizziness, lightheadedness, pre-syncope, syncope etc.) 
 
Patients subjective report of adequacy of diuresis 
 
Recommend continue current strategy without change: 
Persistent signs/symptoms of congestion 
Weight still >=5 lbs. above dry weight 
Blood pressure and heart rate within acceptable range (will vary by patient) 
No signs of suggestive of intravascular volume depletion 
Subjectively adequate diuresis 
 
Recommend increase diuretic regimen or clinic visit 
Persistent or worsening signs symptoms of congestion 
Weight still >=5 lbs above dry weight or increasing 
Blood pressure and heart rate within acceptable range (will vary by patient) 
No signs of suggestive of intravascular volume depletion 
Subjectively inadequate diuresis 
 
Recommend transition to oral diuretics 
Signs or symptoms of congestion at or near baseline 
Weight within 3 lbs. of dry weight 
Blood pressure and heart rate within acceptable range (will vary by patient) 
No signs of suggestive of intravascular volume depletion 
Subjectively adequate diuresis 
 
Recommend clinic visit 
Clinically important changes in blood pressure or heart rate (will vary by patient) 
Signs or symptoms of intravascular depletion 
Any other evidence of clinical instability