Prospective, Randomized, Parallel-Group Pilot Study Comparing IV Furosemide to Subcutaneous Furosemide in Acute Decompensated Heart Failure Patients
Phase: PHASE2
Conditions: Congestive Heart Failure
Sponsor: Johns Hopkins University

 
 
John Hopkins Heart Failure Bridge Clinic (HFBC) 
 
 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
Prospective, Randomized, Parallel-Group Pilot Study Comparing 
IV Furosemide to Subcutaneous Furosemide in Decompensated 
Heart Failure Patients 
 
 
 
Protocol Number:  
2015 - 1 
Protocol Date: 
05 August 2015 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
SYNOPSIS 
PROTOCOL TITLE 
Prospective, Randomized, Parallel-Group Pilot Study Comparing IV 
Furosemide to Subcutaneous Furosemide in Decompensated Heart 
Failure Patients 
PROTOCOL NUMBER 
 
SPONSOR 
Johns Hopkins Heart Failure Bridge Clinic (HFBC) 
INVESTIGATIONAL 
PRODUCT 
Furosemide Injection Solution, (SCP-101) 8 mg/mL  manufactured by 
Cook Pharmica for scPharmaceuticals, Inc. (test treatment) and 
Furosemide Injection, USP 10 mg/mL  (reference treatment) 
STUDY OBJECTIVES 
The objectives of this study are:  
Primary objective:  To determine the clinical efficacy of subcutaneously 
administered Furosemide Injection Solution (SCP -101) versus 
intravenous administration of Furosemide Injection, USP in adult patients 
at the HFBC presenting with decompensated heart failure. 
Secondary objective:  To determine the adverse effects and patient 
satisfaction with subcutaneously administered Furosemide Injection 
solution (SCP-101) versus intravenous administration of furosemide in 
adult patients at the HFBC presenting with decompensated heart failure. 
STUDY DESIGN & 
DURATION 
This clinical trial is a prospective, randomized, parallel-group pilot study 
comparing the intravenous administration of Furosemide Injection, USP, 
to subcutaneous administration of a buffered furosemide formulation - 
Furosemide Injection Solution (SCP-101), in patients presenting to the 
Johns Hopkins Hospital Heart Failure Bridge Clinic (HFBC) with 
decompensated heart failure.  Patients presenting to the HFBC will be 
assessed to determine whether they need IV diuretics.  If they do, they 
will be screened for eligibility.  If they are eligible, written informed 
consent will be obtained.  Patients will then be randomized to receive 
Furosemide Injection, USP intravenously or Furosemide Injection 
Solution (SCP-101) delivered subcutaneously.  The IV patients will get 
the usual care of the HFBC, which includes having an IV placed and 
delivery of a one-time dose of IV furosemide with the dose determined by 
the providers (maximum dose 160mg IV). The subcutaneous patients will 
receive 80mg of Furosemide Injection Solution (SCP-101) administered 
subcutaneously over 5 hours (30mg in first hour and 12.5mg/hour for 4 
hours).  Administration will take place with the B Braun Perfusor® Space 
Infusion Pump System and a standard commercial infusion set.  Both 
groups of patients will be observed for 6 hours to assess diuresis.  The 
goal will be to enroll a total of 40 patients, 20 in the IV furosemide group, 
and another 20 in the subcutaneous furosemide group.  Vital signs and 
urine output will be monitored closely for 6 hours. Patients will be asked 
to fill out a survey about their symptom improvement (Kansas City 
Cardiomyopathy questionnaire) and overall satisfaction related to the 
treatment experience.  They will also be monitored for side effects 
including ototoxicity and discomfort at the access site (burning, itching, 
and pain). Electrolytes and renal function will be checked once after the 
patients receive diuretic therapy.  Study participants will be on fluid 

 
 
 
restriction during the study, with no more than 100ml of fluid consumed 
during the 6 hours. 
Study Drug: 
 
 
Furosemide Injection, USP:  Furosemide Injection, Solution, 
single dose determined by Investigator (maximum dose 160mg) 
administered intravenously by IV bolus over approximately 2 
minutes (reference treatment) 
 
Furosemide Injection Solution (SCP-101), 8 mg/mL: 80 mg dose 
administered subcutaneously as 30 mg over the first hour and 
then as 12.5 mg per hour over the subsequent 4 hours (test 
treatment) 
Since the HFBC gives IV diuretics about 15 times per month, HFBC 
plans to enroll 40 patients within three to four months. The study requires 
only one clinical visit – a visit that would have already been scheduled for 
the patient. 
NUMBER OF  
SUBJECTS 
The number of subjects in this prospective study is 40.  20 in the IV 
furosemide group and another 20 in the subcutaneous furosemide group.   
NUMBER OF SITES 
1 
PARTICIPATING 
COUNTRIES 
US 
SUBJECT 
POPULATION 
Female and male subjects may be enrolled in the study only if all of the 
inclusion criteria and none of the exclusion criteria are met. 
Inclusion Criteria (low risk, intermediate risk):   
 
An Institutional Review Board (IRB) approved informed 
consent is signed and dated prior to any study-related activities. 
 
Male and female subjects > 18 years of age 
 
History of at least 3 months treated heart failure (NYHA class 
II/III/IV), or recent hospitalization for heart failure; presenting to 
HFBC with decompensated heart failure symptoms including 
elevated jugular venous pressure, dyspnea and peripheral edema 
where the decision is made to give IV diuretics 
 
Able to participate in the study in the opinion of the investigator 
 
Has the ability to understand the requirements of the study and 
is willing to comply with all study procedures 
  
Exclusion Criteria (high risk):  
A subject is not eligible for inclusion if any of the following criteria 
apply: 
 
Presenting with symptoms where it is anticipated that there is a 
high chance of hospitalization such as ischemia, uncontrolled 
arrhythmia, infection, hemodynamic instability (elevated or low 
blood pressure), respiratory compromise, or electrolyte 

 
 
 
abnormalities (>25% increase in creatinine from baseline, 
potassium, hyponatremia). 
 
On experimental medication or currently participating in a 
cardiovascular research study. 
 
Presence or need for urinary catheterization, urinary tract 
abnormality or disorder interfering with urination 
 
Any surgical or medical condition which in the opinion of the 
investigator may interfere with participation in the study or which 
may affect the outcome of the study 
 
Inability to comply with study requirements 
ENDPOINTS 
Primary Endpoints:  
1) Total volume of voids over a 6-hour period 
2) Total natriuresis over a 6-hour period 
 
Secondary endpoints: 
1) Volume of voids between 0-2 hours, 2-4 hours and 4-6 hours post 
initiation of treatment. 
2) Heart Failure Symptom Scoring/Symptom Improvement- (Kansas 
City Cardiomyopathy questionnaire) 
3) Overall Satisfaction with Treatment- (Treatment Satisfaction 
Survey) 
 
Safety endpoints:  
1) Patient reported Pain  
2) Increases in serum creatinine of 0.5 mg/dL or greater 
3) Local skin reactions including hematoma, induration, infection, 
thrombosis, necrosis etc. 
4) Occurrence of treatment-emergent Adverse Events (AEs) or 
Serious Adverse Events (SAEs) 
 
STATISTICAL 
ANALYSIS 
Determination of Sample Size:  For this pilot study, the determination of 
sample size was primarily based on clinical consideration; with the aim to 
yield meaningful preliminary data.  
Statistical Analysis Plan: A full statistical analysis plan will be developed.  
All data will be analyzed as intention-to-treat. Continuous variables will 
be presented as mean ± standard deviation and will be compared using 
the Students t-test (2-tailed), unpaired. Differences between treatment 
groups for the categorical variables will be analyzed using the chi-square 
test. For the purposes of this study, P values ≤.05 will be considered 
significant.  
Early Stopping Rules:  The study will be stopped early if there is a 
significant difference in number of patients with intolerable side effects: 
Ototoxicity, severe discomfort, burning and stinging at the access site, 
itching, and/or pain. 

 
 
 
Table 1. 
Time and Events Schedule 
Time and Events 
Table 
Screening 
Phase 
 
Pre-Dose 
Start of 
Dosing 
Dosing  
6 hours post Start of 
Dosing 
Informed Consent 
X 
 
 
 
 
 
Confirmation of 
Eligibility 
X 
 
 
 
 
 
Co-morbidity 
X 
 
 
 
 
 
Cardio-Pulmonary 
Examination 
X 
 
 
 
 
 
Serum Creatinine 
X 
 
 
 
 
X 
Weight and Height 
X 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
12-lead EKG 
X 
 
 
 
 
 
Collection and 
Measurement of Urine 
Voids 
 
 
 
X 
X 
X 
Urine Sodium 
 
 
X 
 
 
X 
Clinical Chemistry 
X 
 
 
 
 
X 
BNP/NT ProBNP 
 
 
X 
 
 
X 
Study Drug 
Administration 
 
 
 
X 
 
X 
Injection Site Pain 
Assessment  
 
 
 
 
 
X 
Injection Site 
Inspection  
 
 
X 
 
 
X 
Randomization to 
Treatment Sequence 
X 
 
 
 
 
 
Kansas City 
Cardiomyopathy 
questionnaire 
 
 
X 
 
 
X 
Treatment Satisfaction 
Survey 
 
 
 
 
 
X 
Treatment Emergent 
Serious Adverse Events 
 
 
 
X 
X 
X 
 
 

 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................9 
1.1. Rationale for the Current Study ...................................................................................9 
2. 
STUDY OBJECTIVES ..................................................................................................11 
3. 
INVESTIGATIONAL PLAN ........................................................................................11 
3.1. Overall Study Design and Plan ..................................................................................11 
3.1.1. 
Endpoints ..................................................................................................12 
3.1.2. 
Safety Endpoints .......................................................................................12 
4. 
SELECTION OF STUDY POPULATION ..................................................................12 
4.1. Inclusion Criteria .......................................................................................................12 
4.2. Exclusion Criteria ......................................................................................................13 
4.3. Enrollment .................................................................................................................13 
4.4. Removal of Subjects from Therapy/Premature Discontinuation ...............................13 
5. 
TREATMENTS ..............................................................................................................14 
5.1. Treatments Administered ..........................................................................................14 
5.2. Identity of Investigational Product(s) ........................................................................14 
5.2.1. 
Labeling ....................................................................................................14 
5.2.2. 
Storage and Handling ...............................................................................14 
5.3. Method of Assigning Subjects to Treatment Groups ................................................14 
5.3.1. 
Treatment Assignment/Randomization ....................................................14 
5.4. Selection of Doses in the Study .................................................................................14 
5.5. Procedures for Blinding .............................................................................................15 
5.6. Prior and Concomitant Therapy ................................................................................15 
5.7. Contraindications .......................................................................................................15 
5.8. Treatment Compliance ..............................................................................................15 
5.9. Study Drug Accountability ........................................................................................15 
6. 
STUDY PROCEDURES ................................................................................................15 
6.1. Study Measurements and Assessments .....................................................................15 
6.1.1. 
Assessment of Efficacy .............................................................................15 
6.1.2. 
Assessment of Safety ................................................................................16 
6.1.3. 
Clinical Laboratory Tests .........................................................................16 
6.1.4. 
Physical Examinations ..............................................................................16 
6.1.5. 
Heart Failure Symptom Scoring ...............................................................16 
6.1.6. 
Vital Signs ................................................................................................16 
6.1.7. 
12-Lead ECG ............................................................................................17 
6.1.8. 
Pain Assessment .......................................................................................17 
6.1.9. 
Injection Site Inspection ...........................................................................17 
6.1.10. Meals and Dietary Restrictions .................................................................17 
7. 
ADVERSE EVENTS ......................................................................................................17 

 
 
 
7.1. Definition of an Adverse Event .................................................................................17 
7.2. Definition of a Serious Adverse Event ......................................................................18 
7.3. Severity of AEs/SAEs ...............................................................................................19 
7.4. Assessment of Relatedness to Study Drug ................................................................19 
7.5. Method, Frequency, and Time Period for Detecting Adverse Events and Serious 
Adverse Events ..........................................................................................................19 
7.6. Reporting SAEs .........................................................................................................20 
7.6.1. 
Timeframes for Reporting SAEs ..............................................................20 
7.6.2. 
SAE Information to Report .......................................................................20 
7.6.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as AEs and SAEs ......................................................................................20 
7.6.4. 
Documenting AEs and SAEs ....................................................................20 
7.6.5. 
Regulatory/Ethics reporting requirement .................................................21 
8. 
STATISTICS ...................................................................................................................21 
8.1. Determination of Sample Size ...................................................................................21 
8.2. Statistical Analysis Plan ............................................................................................21 
8.3. Safety Analyses .........................................................................................................21 
9. 
RESPONSIBILITIES .....................................................................................................21 
9.1. Investigator Responsibilities .....................................................................................21 
9.1.1. 
Good Clinical Practice ..............................................................................21 
9.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval .........................................................................................21 
9.1.3. 
Informed Consent .....................................................................................22 
9.1.4. 
Confidentiality ..........................................................................................22 
9.1.5. 
Study Files and Retention of Records ......................................................22 
9.1.6. 
Case Report Forms ...................................................................................23 
9.1.7. 
Drug Accountability .................................................................................23 
9.1.8. 
Inspections ................................................................................................23 
9.1.9. 
Access to Information for Monitoring ......................................................23 
10. REFERENCES ...............................................................................................................24 
 
 

 
 
 
ABBREVIATIONS 
AE 
adverse event 
BNP/NTProBNP 
B-type natriuretic peptide/N-terminal prohormone of brain natriuretic 
peptide 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
Cmax 
peak plasma concentration, observed 
CRF/eCRF 
case report form / electronic case report form 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
EP 
European Pharmacopoeia 
GCP 
good clinical practice 
HFBC 
Johns Hopkins Heart Failure Bridge Clinic 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IV 
Intravenous 
IRB/EC 
Institutional Review Board/Ethics Committee 
mmHg 
millimeters of mercury 
p.o. 
by mouth, orally 
SAE 
serious adverse event 
SC 
subcutaneous 
USP 
United States Pharmacopeia 
 
 

 
 
 
1.   
INTRODUCTION 
The prevalence of chronic heart failure is increasing, and it is the most common diagnosis in 
hospital patients age 65 years and older.  Despite advances in the treatment of chronic heart 
failure, in-hospital mortality and readmission are high.  Heart failure costs the US about 32 
billion per year, and a large percentage of the costs are due to hospitalizations.  The Heart 
Failure Society of America guidelines for the management of decompensated heart failure 
offer recommendations for clinical circumstances that should prompt hospital admission.  
Most clinicians would agree that patients with decompensated heart failure presenting with 
hypotension, worsening renal function and altered mental status should be hospitalized.  
However, there is a subset of patients presenting with dyspnea and edema due to volume 
overload that necessitate rapid symptom improvement but are hemodynamically stable.  Oral 
diuretics would likely be ineffective but admission for IV diuretics seems excessive.  
The Johns Hopkins Heart Failure Bridge Clinic (HFBC) was designed as a clinic to reduce 
heart failure hospital admissions.  Patients with chronic heart failure are primarily seen either 
in the early post discharge period or if they are referred for an infusion of IV diuretic.  The 
HFBC sees about 160 patients each month and administers on average 15 infusions of 
Intravenous (IV) diuretics.  The average visit duration is 220 minutes, with mean IV 
furosemide dose 100mg resulting in average urine output 1460 ± 730 ml, and weight loss of 
2.3 ± 1.8 kg.  
The HFBC has been successful at preventing hospital admissions by treating patients with IV 
diuretics.  However, it requires patients to come to the clinic for treatment and close 
monitoring.  Subcutaneous diuretics present a potential alternative to IV diuretics and offer 
patients an opportunity to receive treatment outside of the hospital setting.  Very few studies 
have evaluated the efficacy and safety of subcutaneous furosemide in chronic heart failure 
patients presenting with symptoms of volume overload.   
1.1.   Rationale for the Current Study 
The research hypothesis is that subcutaneously administered furosemide will be an effective 
alternative to IV furosemide for hemodynamically stable chronic heart failure patients 
presenting with volume overload in the ambulatory setting.  The significance of this research 
is finding a potential intervention that could help decrease heart failure hospitalizations and 
improve the quality of life for patients with chronic heart failure. In addition, we can 
decrease the costs associated with heart failure. 
There is very little experience with subcutaneous administration of furosemide EP/USP 
(current form of commercially available furosemide injection solution). There are a few 
studies that show the delivery of subcutaneous furosemide by electric infusion pump in 
terminally ill patients is effective for weight loss and symptom improvement (1,2). A group 
in Spain was successfully able to resolve 41 episodes of decompensated heart failure in 24 
elderly patients using continuous subcutaneous furosemide administered by elastomeric 
infusion pumps (2). They found that the elastomeric infusion pumps provided safe outpatient 
treatment without the need for daily monitoring. In addition, it helped prevent hospital 
admissions and decreased costs due to the low price of the devices. It was also a good 
alternative for patients with venipuncture failure and the inability to transition from 
intravenous to oral diuretics.  

 
 
 
Furosemide USP has a pH of 8.3 -9.0 and may cause irritation and discomfort upon 
administration.  A novel buffered formulation with a physiologic pH (7.4) is currently under 
development in support of a NDA submission later in 2015.  The product is to be marketed 
with a wearable patch pump for a slow 5-hour administration to optimize 8-hour diuresis. 
scPharmaceuticals, Inc. (Lexington, MA), the developer of the novel furosemide formulation 
and its drug delivery device, provided the following information.  The pivotal clinical study 
with the buffered furosemide solution (Furosemide Injection Solution (SCP-101)) started in 
Q2 of 2015 in support of the NDA.  This study is conducted in the United States in stable HF 
patients under IND 118,919.     
The company has previously conducted a Phase I pilot study (NCT02350725) to investigate 
the pharmacodynamics and pharmacokinetic parameters of Furosemide Injection Solution 
(SCP-101) administered subcutaneously as compared to oral furosemide.  The study was a 
randomized open-label cross-over study in patients with stable HF.  Patients were mildly 
symptomatic with NT-proBNP of >300 pg/mL.  Treatments were separated by a 14 +/- 3 day 
interval.  Subcutaneous administration of Furosemide Injection Solution (SCP-101) 
(8mg/mL; 80 mg total), was delivered using a B Braun Perfusor® Space Infusion Pump 
System as 30 mg over the first hour followed by 12.5 mg per hour over the subsequent 4 
hours. Reference treatment consisted of 80mg p.o. furosemide. 
Ten subjects were enrolled (80% males) with a mean age of 69.9 years and mean plasma 
NTproBNP of 1638 ng/mL.  All patients were on standard medication including ACE 
inhibitors and beta blockers. Main daily dose of oral furosemide was 40 mg/day. 
Subcutaneous administration of the novel formulation was well-tolerated.  All participants 
achieved therapeutic plasma furosemide levels of over 1000ng/mL within one hour of start of 
subcutaneous infusion. Therapeutic plasma levels were maintained for a minimum of 5 hours 
(Figure 1).    
 
 

 
 
 
Figure 1: Mean Plasma Furosemide Levels after SC or Oral Administration 
  
Figure 1.  Plasma furosemide levels were measured just prior to dosing (Time 0) and at 30, 
60, 120, 240, 300, 360 and 480 minutes post dosing. Mean plasma levels + 2 SE across the 
10 subjects are shown for each treatment period. 
Plasma furosemide levels in the plateau phase (60-300 minutes post start of infusion) were 
maintained in a narrow range (67%-93%) from the Cmax when compared to oral (11% - 
40%).  P.o. furosemide administration resulted in highly variable plasma levels: 90% of the 
participants achieved levels of 1000ng/mL at some point following administration; but only 
one participant (10%) maintained plasma levels over 1000 ng/mL for 5 hours.  The mean 
total furosemide exposure (expressed by area under the curve, AUC) was 66% higher after 
subcutaneous administration when compared to oral (p< 0.0001).   
2.   
STUDY OBJECTIVES 
The objectives of this study are:  
(1) Primary objective:  To determine the clinical efficacy of subcutaneously 
administered Furosemide Injection Solution (SCP-101) versus intravenous 
administration of Furosemide Injection, USP in adult patients at the HFBC presenting 
with decompensated heart failure. 
(2) Secondary objective:  To determine the adverse effects and patient satisfaction 
with subcutaneously administered SCP-101 versus intravenous furosemide in adult 
patients at the HFBC presenting with decompensated heart failure. 
3.   
INVESTIGATIONAL PLAN 
3.1.   Overall Study Design and Plan 
This clinical trial is a prospective, randomized, parallel-group pilot study comparing the 
intravenous administration of Furosemide Injection, USP, to subcutaneous administration of 
a buffered furosemide formulation – Furosemide Injection Solution (SCP-101), in patients 
presenting to the Johns Hopkins Hospital Heart Failure Bridge Clinic with decompensated 
heart failure.  Patients presenting to the HFBC will be assessed to determine whether they 
need IV diuretics. If they need it, they will be screened for eligibility.  If they are eligible, 
written informed consent will be provided.  Patients will then be randomized to receive 
Furosemide Injection, USP intravenously, or SCP-101 delivered subcutaneously. The IV 
patients will get the usual care of the Heart Failure Bridge Clinic, which includes having an 
IV placed and delivery of  a one-time dose of IV furosemide with the dose determined by the 
providers (maximum dose 160mg IV). The subcutaneous patients will receive 80mg of 
Furosemide Injection Solution, 8 mg/mL, administered subcutaneously over 5 hours (30mg 
in first hour and 12.5mg/hour for 4 hours).   
Administration will take place with the BBraun Perfusor® Space Infusion Pump System and 
a standard commercial infusion set.  Both groups of patients will be observed for 6 hours to 
assess diuresis.  The goal will be to enroll a total of 40 patients, 20 in the IV furosemide 
group, and another 20 in the subcutaneous furosemide group.  Vital signs and urine output 

 
 
 
will be monitored closely for 6 hours. Patients will be asked to fill out a survey about their 
symptom improvement (Kansas City Cardiomyopathy questionnaire) and overall satisfaction 
related to the treatment experience. They will also be monitored for side effects including 
ototoxicity and discomfort at the access site (burning, itching, and pain). Electrolytes and 
renal function will be checked once after the patients receive diuretic therapy.  Study 
participants will be on fluid restriction during the study, with no more than 100 ml of fluid 
consumed during the 6 hours.  
Study Drug: 
 Furosemide Injection, USP:  Furosemide Injection, Solution, single dose determined 
by Investigator (maximum dose 160mg) administered intravenously by IV bolus over 
approximately 2 minutes (reference treatment). 
 Furosemide Injection Solution, 8 mg/mL (SCP-101):  80 mg dose administered 
subcutaneously as 30 mg over the first hour and then as 12.5 mg per hour over the 
subsequent 4 hours (test treatment) 
3.1.1.   
Endpoints 
Primary Endpoints:  
1) Total volume of voids over a 6-hour period 
2) Total natriuresis over a 6-hour period 
 
Secondary endpoints: 
1) Volume of voids between 0-2 hours, 2-4 hours and 4-6 hours post initiation of 
treatment. 
2) Heart Failure Symptom Scoring/Symptom Improvement- (Kansas City 
Cardiomyopathy questionnaire) 
3) Overall Satisfaction with Treatment- (Treatment Satisfaction Survey) 
 
3.1.2.   
Safety Endpoints 
1) Patient reported Pain  
2) Increases in serum creatinine of 0.5 mg/dL or greater 
3) Local skin reactions including hematoma, induration, infection, thrombosis, necrosis 
etc. 
4) Occurrence of treatment-emergent Adverse Events (AEs) or Serious Adverse Events 
(SAEs) 
4.   
SELECTION OF STUDY POPULATION 
4.1.   Inclusion Criteria 
Female and male subjects are eligible for inclusion only if all of the following criteria are 
met: 
Inclusion Criteria (low risk, intermediate risk):   

 
 
 
 An Institutional Review Board (IRB) approved informed consent is signed and dated 
prior to any study-related activities 
 Male and female subjects > 18 years of age 
 History of at least 3 months treated heart failure (NYHA class II/III/IV), or recent 
hospitalization for heart failure; presenting to HFBC with decompensated heart 
failure symptoms including elevated jugular venous pressure, dyspnea and peripheral 
edema where the decision is made to give IV diuretics 
 Able to participate in the study in the opinion of the investigator 
 Has the ability to understand the requirements of the study and is willing to comply 
with all study procedures 
  
4.2.   Exclusion Criteria  
A Subject is not eligible for inclusion if any of the following criteria apply 
 Presenting with symptoms where it is anticipated that there is a high chance of 
hospitalization such as ischemia, uncontrolled arrhythmia, infection, hemodynamic 
instability (elevated or low blood pressure), respiratory compromise, or electrolyte 
abnormalities (>25% increase in creatinine from baseline, potassium, hyponatremia) 
 On experimental medication or currently participating in a cardiovascular research 
study. 
 Presence or need for urinary catheterization, urinary tract abnormality or disorder 
interfering with urination 
 Any surgical or medical condition which in the opinion of the investigator may 
interfere with participation in the study or which may affect the outcome of the study 
 Inability to comply with study requirements 
 
4.3.   Enrollment 
It is anticipated that enrollment of 40 participants will take approximately 3 to 4 months 
based on HFBC current estimate of providing IV diuretics 15 times a month. 
4.4.   Removal of Subjects from Therapy/Premature Discontinuation 
Participants may discontinue participation at any time without penalty or loss of benefits to 
which the subject is otherwise entitled.    
The subject's participation may be terminated by the investigator for safety reasons or if, in 
the opinion of the investigator, continued participation may interfere with clinical 
management.   
The study will be stopped early if there is a significant difference in number of patients with 
intolerable side effects: Ototoxicity, severe discomfort, burning and stinging at the access 
site, itching, and/or pain. 

 
 
 
5.   
TREATMENTS 
5.1.   Treatments Administered  
Study drug will be administered by qualified study staff only in accordance with the 
procedures described in this protocol. 
5.2.   Identity of Investigational Product(s) 
Furosemide Injection Solution, 8mg/mL (SCP-101): 80 mg undiluted buffered 
furosemide solution, manufactured by Cook Pharmica, Bloomington, IN, USA for 
scPharmaceuticals, Inc. under GMP conditions (test treatment). 
 
Contains Tris Hydrochloride, Sodium Chloride and may contain Sodium Hydroxide and 
Hydrochloric acid for pH adjustment: pH 7.4 (7.0 - 7.8).  Furosemide Injection Solution 
(SCP-101) will be provided by scPharmaceuticals to the investigational site. 
 
Furosemide Injection, USP: Furosemide Injection, Solution, single dose determined by 
Investigator (maximum dose 160mg) by intravenous bolus administration. (reference 
treatment) 
   
5.2.1.   
Labeling 
Study test drug (Furosemide Injection Solution (SCP-101)) will bear a label that meets 
applicable laws for an investigational drug, which may include, but is not limited to, the 
following information: 
 Federal law statement 
 Batch number  
 Storage information 
Furosemide Injection, USP for intravenous administration will be obtained from local 
pharmacy commercial stock with commercial labeling.   
5.2.2.   
Storage and Handling 
Store at 20° - 25°C, (68° - 77°F), excursions permitted between 15°C and 30°C, (between 59°F 
and 86°F).  Protect from Light. 
 
5.3.   Method of Assigning Subjects to Treatment Groups 
5.3.1.   
Treatment Assignment/Randomization 
Randomization will be performed in blocks of 4.   Treatment assignment will be performed by 
means of numbered envelopes, which will identify the treatment group. 
5.4.   Selection of Doses in the Study 
The attending physician will decide the IV furosemide dose to be administered (max 160mg).   
IV furosemide is to be administered by single IV bolus over approximately 2 minutes. 

 
 
 
The subcutaneous furosemide dose is predefined at 80mg total – 30mg of which is 
administered over the first hour followed by 12.5mg/hour for 4 hours. 
5.5.   Procedures for Blinding  
Not Applicable - This is an open label study. 
5.6.   Prior and Concomitant Therapy  
Heart failure patients are generally on multiple medications used in the management of heart 
failure.   Additionally the majority of patients are on prescription or over-the-counter 
medications for one or more co-morbidities.   The clinic staff will evaluate these medications 
on a case by case basis and decide what medications may be used on the day of 
administration.   This determination will be made prior to randomization.        
5.7.   Contraindications 
Subcutaneous administration of Furosemide Injection Solution is not intended for use is 
emergency situations such as acute decompensated heart failure or in patients with 
pulmonary edema. 
5.8.   Treatment Compliance 
All study medication will be administered by study personnel and all information regarding 
study drug administration will be documented.   
5.9.   Study Drug Accountability 
Study drug will be administered in accordance with the procedures of this protocol.  Only 
authorized site personnel may supply or administer study drug and only subjects enrolled in 
the study may receive study drug, in accordance with applicable regulatory requirements. 
  
6.   
STUDY PROCEDURES 
6.1.   Study Measurements and Assessments 
6.1.1.   
Assessment of Efficacy 
Diuresis: 
Urine will be collected from start of treatment through 6 hours post initiation of treatment.  
Individual voids will be measured and then pooled over the 6 hour time period, and the 
volume of the pool will be recorded.  Time of voids and volume of each void will be 
recorded.   
 
Natriuresis: 
Participants will not be given any fluid by mouth during the 6-hour observation period, 
except when required for taking oral medication, in which case fluid intake will be 
limited to 100mL over the 6 hour period. 
  
A 5mL aliquot of the first void, and a 5 mL aliquot of the total 6 hour pool will be 
obtained by the study staff for determination of sodium.      

 
 
 
 
Symptomatic Improvement 
Symptom scoring using the Kansas City Cardiomyopathy questionnaire will be performed 
prior to drug administration and at the end of the 6 hour observation period.  A treatment 
satisfaction survey will be conducted at 6 hours.  
 
6.1.2.   
Assessment of Safety 
Evidence in Kidney Injury  
Serum creatinine will be obtained just before administration and at the end of the 6 hour 
observation period. 
Adverse Events 
Incidence of Treatment-Emergent adverse events (AEs) or serious adverse events (SAEs) 
will be assessed. Treatment associated pain and any local skin reaction including hematoma, 
induration, infection, thrombosis, necrosis etc. will be assessed.  
 
6.1.3.   Clinical Laboratory Tests 
All routine samples will be analyzed by a licensed clinical laboratory.  The clinical 
laboratory tests are as follows: 
 Blood Clinical Chemistry:  blood urea nitrogen (BUN), creatinine, sodium, potassium, 
calcium, chloride, magnesium and bicarbonate.  
 BNP/NTproBNP 
 Urinalysis: A 5 ml aliquot from the first void post start of treatment and a 5 ml aliquot 
from the pooled urine voids over the 6 hour observation period will be analyzed for 
sodium.  
 
6.1.4.   
Physical Examinations 
A cardiopulmonary examination will be conducted and consist of assessments of the 
following: heart sounds, murmur, chest sounds, pedal edema and peripheral pulses.   
6.1.5.   Heart Failure Symptom Scoring 
The Kansas City Cardiomyopathy questionnaire will be used in this study to assess subjects 
and monitor overall response to treatment. 
6.1.6.   Vital Signs 
Vital signs will include respiration rate (breaths per minute), oral temperature, and supine 
blood pressure (mmHg) and heart rate (beats per minute [bpm]). Blood pressure and heart 
rate will be obtained after the subject has been resting in supine position for 5 minutes.   

 
 
 
6.1.7.   
12-Lead ECG 
12-lead ECGs will be performed after the subject has rested quietly for at least 5 minutes in a 
supine position.   
6.1.8.   
Pain Assessment 
Pain assessment will be conducted at the end of the 6 hour observation period.  Subjects will 
be asked to verbally rate the intensity of any discomfort using numeric rating scale of 0 to 10 
with zero equivalent to no pain and 10 being the worst possible pain.  (Appendix 2) 
6.1.9.   
Injection Site Inspection 
Study staff will inspect the injection site for erythema and edema using the Draize Scale 
which includes a 5-point scale for erythema and a 5-point scale for edema. (Appendix 3) 
In addition to the Draize scale scoring, the investigator will assess the injection site area for 
other local reactions, including hematomas, thrombosis, induration, infection, necrosis, etc. 
The Investigator will rate the reactions as mild, moderate or severe and make an assessment 
as to causality. 
6.1.10.   
Meals and Dietary Restrictions 
Participants will not be given any fluid by mouth during the 6-hour observation period, 
except when required for taking oral medication, in which case fluid intake will be 
limited to 100mL over the 6 hour observation period.     
 
7.   
ADVERSE EVENTS 
The Investigator is responsible for the detection and documentation of events meeting the 
definition of an AE or SAE as provided in this protocol.  Only treatment-emergent AEs and 
SAEs (occurring after the first dose of study drug through the appropriate follow-up period) 
will be recorded in this study. Treatment Emergent AEs, will be assessed continuously after 
administration of study drug through discharge.  
 
7.1.   Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product which does not necessarily have a causal relationship 
with this treatment.  
An AE can therefore be any unfavorable and unintended sign (that could include a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
An AE does include any: 
 Exacerbation of a pre-existing illness. 
 Increase in frequency or intensity of a pre-existing episodic event or condition. 

 
 
 
 Condition detected or diagnosed after study drug administration even though it may have 
been present prior to the start of the study. 
 Continuous persistent disease or symptoms present at baseline that worsen following the 
start of the study. 
An AE does not include a/an: 
 Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an AE. 
 Pre-existing diseases or conditions present or detected at the start of the study that do not 
worsen. 
 Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for cosmetic elective surgery, social and/or convenience admissions). 
 Overdose of either study drug or concurrent medication without any signs or symptoms. 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen during 
the study is not considered an AE. 
 
7.2.   Definition of a Serious Adverse Event 
An SAE is any AE occurring at any dose that results in any of the following outcomes: 
a. Death. 
b. A life-threatening AE. 
 NOTE: Life-threatening means that the subject was, in the view of the 
Investigator, at immediate risk of death from the event as it occurred.  This 
definition does not include an event that, had it occurred in a more severe 
form, might have caused death. 
c. Inpatient hospitalization or prolongation of existing hospitalization. 
 NOTE: Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization, the event is an SAE. 
 NOTE: “Inpatient” hospitalization means the subject has been formally 
admitted to a hospital for medical reasons.  This may or may not be overnight.  
It does not include presentation at a casualty or emergency room. 
d. A disability/incapacity. 
 NOTE: The term disability means a substantial disruption of a person’s 
ability to conduct normal life functions.  This definition is not intended to 
include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, accidental 
trauma (i.e., sprained ankle) that may interfere or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. A congenital anomaly in the offspring of a subject who received drug. 

 
 
 
f. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE 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.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
subject hospitalization, or the development of drug dependency or drug abuse. 
 Medical and scientific judgment should be used in deciding whether prompt 
reporting is appropriate in this situation. 
 
7.3.   Severity of AEs/SAEs 
The severity (mild, moderate, or severe) of each AE/SAE must be assessed by the 
Investigator or designee.  The following criteria should be considered when assessing 
severity:  
 Mild 
The symptom is barely noticeable to the subject and does not 
influence performance or functioning.   
 Moderate The symptom is of sufficient severity to make the subject 
uncomfortable, and performance of daily activities is influenced.  
Treatment for the symptom may be needed. 
 Severe 
The symptom causes severe discomfort.  Treatment for the 
symptom may be necessary. 
 
7.4.   Assessment of Relatedness to Study Drug  
The Investigator will assess each AE and SAE for causality based on their medical judgment 
and the observed symptoms associated with the event.  Each AE and SAE will be assessed as 
related or unrelated to study drug based on the following criteria: 
 Unrelated 
This category applies to those AEs that the Investigator 
determines are most likely due to extraneous causes (disease, 
environment, etc.) 
 Related 
This category applies to those AEs that the Investigator 
determines are most likely due to test drug.   
 
7.5.   Method, Frequency, and Time Period for Detecting Adverse Events and 
Serious Adverse Events 
Patients will be evaluated for AEs and SAEs at the end of the 6 hour observation.  After the 
subject has had an opportunity to spontaneously mention any problems, the Investigator 
should inquire about AEs by asking a non-leading question such as “How are you feeling?” 
 

 
 
 
7.6.   Reporting SAEs  
7.6.1.   
Timeframes for Reporting SAEs 
The Investigator must report SAEs according to the following time frames:      
 Death or Life-Threatening Event: 
o Initial notification must be provided to the sponsor or designee within 24 
hours of the Investigational site learning of the death or life-threatening event 
(regardless of causality).   
o Complete SAE information (i.e., all SAE pages) must be sent to the 
manufacturer or designee within 48 hours  
o Follow-up information must be sent to the sponsor or designee within 48 
hours of receipt of the information by the Investigational site.  
 All other SAEs 
 
o Complete SAE information (i.e., all SAE pages) must be sent to the sponsor or 
designee within 24 hours 
o Follow-up information must be sent to the sponsor or designee within 48 
hours of receipt of the information by the Investigational site.  
7.6.2.   
SAE Information to Report 
At a minimum, SAE reports must contain the subject ID, the serious adverse event term, onset 
date, relationship to study drug, and a brief narrative of the event.   
7.6.3.   
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
AEs and SAEs 
The Investigator should exercise his or her medical and scientific judgment in deciding whether 
an abnormal laboratory finding or other abnormal assessment is clinically significant. 
Abnormal laboratory findings (e.g., clinical chemistry, hematology, and urinalysis) or other 
abnormal assessments (e.g., ECGs, vital signs) that are judged by the Investigator as 
clinically significant must be recorded as AEs or SAEs if they meet the definition of an 
adverse event.  Clinically significant abnormal laboratory findings or other abnormal 
assessments that are detected after study drug administration or that are present before study 
drug administration but worsen after study drug administration should be assessed for AE 
criteria. 
7.6.4.   
Documenting AEs and SAEs 
All adverse events, including SAEs, which occur after the first dose of study drug must be 
documented in the subject's medical records and on the CRF.   
A separate set of SAE pages should be used for each SAE.  However, if at the time of initial 
reporting, multiple SAEs are present that are temporally and/or clinically related, they may 
be reported on the same SAE page. 
The Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and/or SAE term. 

 
 
 
7.6.5.   
Regulatory/Ethics reporting requirement  
The Investigator must comply with the applicable local regulatory requirements related to the 
reporting of SAEs to the IRB. 
The sponsor of the IND must report SAEs and AEs to the FDA in accordance with 
21CFR312.32. 
 
8.   
STATISTICS  
8.1.   Determination of Sample Size 
For this pilot study, the determination of sample size was primarily based on clinical consideration; 
with the aim to yield meaningful preliminary data.  
8.2.   Statistical Analysis Plan 
A full statistical analysis plan will be developed.  All data will be analyzed as intention-to-
treat. Continuous variables will be presented as mean ± standard deviation and will be 
compared using the Students t-test (2-tailed), unpaired. Differences between treatment groups 
for the categorical variables will be analyzed using the chi-square test. For the purposes of 
this study, P values ≤.05 will be considered significant. 
8.3.   Safety Analyses 
Extent of Exposure, Adverse Events, Clinical Laboratory Assessments and Vital Signs will 
be summarized with descriptive statistics.  
Pain assessments and local injection site reactions will be tabulated and assessed using 
descriptive statistical analysis. 
9.   
RESPONSIBILITIES 
9.1.   Investigator Responsibilities 
9.1.1.   
Good Clinical Practice 
The Investigator will ensure that this study is conducted in full compliance with the 
principles of the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong 
Kong, and South Africa), ICH guidelines, or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the study 
Subject. The Investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 
CFR, part 50, 1998, and 21 CFR, part 56, 1998, are adhered to.  
9.1.2.   
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval 
This protocol and any accompanying material to be provided to the Subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted, by the Investigator, to an IRB.  Approval from the IRB 

 
 
 
must be obtained before starting the study and should be documented in a letter to the 
Investigator specifying the protocol number, protocol version, documents reviewed, and date 
on which the committee met and granted the approval. 
Any modifications or amendment to the protocol must also be submitted to the IRB for 
approval prior to implementation. 
9.1.3.   
Informed Consent 
It is the responsibility of the Investigator or designee to obtain written informed consent from 
each individual participating in this study after adequate explanation of the aims, methods, 
objectives, and potential hazards of the study and prior to undertaking any study-related 
procedures.  The Investigator or designee must utilize an IRB-approved consent form for 
documenting written informed consent.  Each informed consent will be appropriately signed 
and dated by the subject and the person obtaining consent.  A copy of the signed consent 
form will be provided to the subject. 
9.1.4.   
Confidentiality 
The Investigator must assure that Subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only Subject initials and an 
identification code (i.e., not names) should be recorded on any form submitted to the sponsor 
and IRB.  The Investigator must keep a subject log showing codes and, names, for all 
enrolled in the trial. 
9.1.5.   
Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into 2 separate categories (although not limited to) the 
following:  (1) Investigator’s study file, and (2) Subject clinical source documents. 
The Investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB approval with correspondence, informed consent, drug records, staff curriculum vitae 
and authorization forms, and other appropriate documents and correspondence. 
Subject clinical source documents  would include (although is not limited to) the following: 
subject hospital/clinic records, physician’s and nurse’s notes, appointment book, original 
laboratory reports, electrocardiogram (ECG), electroencephalogram (EEG), X-ray, pathology 
and special assessment reports, consultant letters, screening and enrollment log, etc.   
All clinical study documents must be retained by the Investigator until at least two years after 
the last approval of a marketing application in an International Conference on Harmonization 
(ICH) region (i.e., United States, Europe, or Japan) and until there are no pending or 
contemplated marketing applications in an ICH region; or, until two years after the IND is 
discontinued and regulatory authorities have been notified. The Investigator must notify 
scPharmaceuticals prior to destroying any clinical study records. 
Should the Investigator wish to move study records to another location, arrangements must 
be made to store these in sealed containers so that they can be returned sealed to the 
Investigator in case of a regulatory audit.  Where source documents are required for the 

 
 
 
continued care of the Subject, appropriate copies should be made for storage outside of the 
site. 
9.1.6.   
Case Report Forms 
For each Subject who signs informed consent, a CRF must be completed and signed (or 
electronically signed if eCRF) by the principal Investigator or sub-Investigator within a 
reasonable time period after data collection.  This also applies to records for those Subjects 
who fail to complete the study.  If a Subject withdraws from the study, the reason must be 
noted on the CRF.  If a Subject is withdrawn from the study because of a treatment-limiting 
adverse event, thorough efforts should be made to clearly document the outcome. 
9.1.7.   
Drug Accountability 
The Investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgment of receipt of 
each shipment of study product (quantity and condition) and Subject dispensing records and 
returned or destroyed study product. Dispensing records will document quantities received 
and quantities dispensed to Subjects, including lot number, date dispensed, Subject identifier 
number, Subject initials, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction in order to ensure that it complies with study requirements.  At the 
end of the study, following final drug reconciliation by the monitor, the study site will be 
instructed by the Sponsor to return or destroy all unused study drug supplies, including 
empty containers. 
9.1.8.   
Inspections 
9.1.9.   
Access to Information for Monitoring 
scPharmaceuticals, Inc. (Lexington, MA) is the manufacturer of the test product.   The 
manufacturer may monitor the study in accordance with industry practices.  

 
 
 
10.   REFERENCES 
1. Goenaga, MA, Millet M, Sanchez E, Garde, C, Carera JA, Arzelius E, Subcutaneous 
furosemide. Ann Pharmacother., 2004. 38(10):1751 
2. Garcia-Gonzalex, P, Cozar-Santiago, P, Fabregat-Andres, O., Sanchez-Jurado, R., 
Estornell-Erill, J., Ridocci-Soriano, F., Subcutaneous Infusion of Furosemide 
Administered by Elastomeric Pumps for Decompensated Heart Failure Treatment: 
Initial Experience. Scientific letters/Rev Exp Cardiol., 2013 66(12):999 
 
 

 
 
 
Appendix 1: Time and Events Schedule 
 
 
Time and Events 
Table 
Screening 
Phase 
 
Pre-Dose 
Start of 
Dosing 
Dosing  
6 hours post Start of 
Dosing 
Informed Consent 
X 
 
 
 
 
 
Confirmation of 
Eligibility 
X 
 
 
 
 
 
Co-morbidity 
X 
 
 
 
 
 
Cardio-Pulmonary 
Examination 
X 
 
 
 
 
 
Serum Creatinine 
X 
 
 
 
 
X 
Weight and Height 
X 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
12-lead EKG 
X 
 
 
 
 
 
Collection and 
Measurement of Urine 
Voids 
 
 
 
X 
X 
X 
Urine Sodium 
 
 
X 
 
 
X 
Clinical Chemistry 
X 
 
 
 
 
X 
BNP/NT ProBNP 
 
 
X 
 
 
X 
Study Drug 
Administration 
 
 
 
X 
 
X 
Injection Site Pain 
Assessment  
 
 
 
 
 
X 
Injection Site 
Inspection  
 
 
X 
 
 
X 
Randomization to 
Treatment Sequence 
X 
 
 
 
 
 
Kansas City 
Cardiomyopathy 
questionnaire 
 
 
X 
 
 
X 
Treatment Satisfaction 
Survey 
 
 
 
 
 
X 
Treatment Emergent 
Serious Adverse Events 
 
 
 
X 
X 
X 
 
 
 
 

 
 
 
Appendix 2    Numeric Pain Scale 
 
 
 
 
 
 
 
 
 
0
1
2
3
4
5
6
7
8
9
10
Verbally indicate the number on the Numeric Rating Scale that best represents the 
intensity of pain at or around the injection site NOW, with 0 being no pain and 
10 being the worst possible pain.
None
Mild
Moderate
Severe

 
 
 
Appendix 3   The Draize Scale for Erythema and Edema Scoring 
 
 
 
 
Erythema formation 
 
 
 
 
 
 
Edema formation 
Description 
 
 
 
 
Score  
 
Description 
 
 
 
 
Score 
No erythema 
 
 
 
 
0 
 
 
No edema 
 
 
 
 
0 
Very slight erythema (barely perceptible) 
1 
 
 
Very slight edema (barely perceptible)  
1 
Well defined erythema  
 
 
2 
 
 
Well defined edema 
 
 
 
2 
Moderate erythema 
 
 
 
3 
 
 
Moderate edema (raise approx. 1 mm)  
3 
Severe erythema (beet redness) to slight 
4 
 
 
Severe Edema (raised more than 1 mm and  
4 
eschar formation 
 
 
 
 
 
 
beyond exposure area)