Economic Impact of Reducing Hospital Admissions for Patients Presenting to the Emergency Department With Worsening Heart Failure: An Adaptive Clinical Trial of Furoscix Infusor
Phase: PHASE3
Conditions: Heart Failure
Sponsor: scPharmaceuticals, Inc.

 
 
 
Study Title:   
 
Economic Impact of Reducing Hospital Admissions for 
Patients Presenting to the Emergency Department with 
Worsening Heart Failure: An Adaptive Clinical Trial of 
Furoscix Infusor 
 
 
 
 
 
NCT Number: 
NCT03458325 
 
 
Amendment 6 Date: 
 
February 2, 2021 
 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 1 of 51 
 
 
 
Furoscix Real-World Evaluation for Decreasing Hospital 
Admissions in Heart Failure: FREEDOM-HF Trial Protocol 
 
 
Economic Impact of Reducing Hospital Admissions for Patients 
Presenting to the Emergency Department with Worsening Heart 
Failure: An Adaptive Clinical Trial of Furoscix Infusor 
 
 
IND Number: 
Sponsor: 
118919 
scPharmaceuticals, Inc. 
Protocol Number:  
scP-01-005 
Investigational Product:  
Furoscix On-Body Infusor  
Original Protocol Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date:  
Amendment 4 Date: 
Amendment 5 Date: 
February 5, 2018 
February 26, 2018 
March 28, 2018 
May 22, 2018  
March 27, 2020 
November 05, 2020 
Amendment 6 Date: 
 
February 2, 2021 
 
 
CONFIDENTIALITY STATEMENT 
 
The information contained in this document and all information provided to you related to 
Furoscix Infusor is the confidential and proprietary information of scPharmaceuticals, Inc. 
(Sponsor) and except as may be required by federal, state or local laws or regulations, may 
not be disclosed to others without prior written permission of the Sponsor. The Principal 
Investigator may, however, disclose such information to supervised individuals working on 
this protocol, provided such individuals agree to maintain the confidentiality of such 
information. 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 2 of 51 
PRINCIPAL INVESTIGATORS 
 
Dan Bensimhon, MD 
Medical Director, Advanced Heart Failure Clinic 
Moses Cone Hospital 
1200 N Elm St 
Greensboro, NC 27401 
 
 
 
W. Frank Peacock, MD, FACEP, FACC 
Associate Chair and Research Director 
Baylor College of Medicine 
1 Baylor Plaza 
Houston, TX 77030 
 
 
 
William S. Weintraub, MD, MACC, FAHA, FESC 
Director of Outcomes Research 
MedStar Heart & Vascular Institute, Suite 4B1 
MedStar Washington Hospital Center 
110 Irving Street NW 
Washington, DC 20010 
 
 
 
 
SPONSOR CONTACT INFORMATION 
 
John Mohr, PharmD, FIDP 
Sr. Vice President, Clinical Development and Medical Affairs 
2400 District Avenue, Suite 310 
Burlington, MA 01803 
 
 
 
 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 11 of 51 
PROTOCOL APPROVAL PAGE 
 
Protocol Title: 
Economic Impact of Reducing Hospital Admissions for Patients Presenting to the 
Emergency Department with Worsening Heart Failure: An Adaptive Clinical Trial 
of Furoscix Infusor 
Protocol Number: 
scP-01-005 
Original Protocol Date 
of Issue: 
February 5, 2018 
Amendment 1 Date: 
February 26, 2018 
Amendment 2 Date:  
March 28, 2018 
Amendment 3 Date:  
May 22, 2018 
Amendment 4 Date:  
March 27, 2020 
Amendment 5 Date: 
November 05, 2020 
Amendment 6 Date: 
February 2, 2021 
Sponsor Name and 
Address: 
 
scPharmaceuticals, Inc. 
2400 District Avenue, Suite 310 
Burlington, MA 01803 
 
I, the undersigned, have read and approve this protocol and agree on its content. It is confirmed that the 
information and guidance given in this protocol complies with scientific principles, the guidelines of Good Clinical 
Practices, the Declaration of Helsinki in the latest relevant version, and the applicable legal and regulatory 
requirements. 
 
Approval Section 
 
Name/Title 
Signature/Date 
Prepared by: 
 
scPharmaceuticals, Inc. 
Approvals obtained through MasterControl 
Prepared by: 
 
scPharmaceuticals, Inc 
Approvals obtained through MasterControl 
Reviewed and 
Approved by: 
 
  
scPharmaceuticals, Inc. 
Approvals obtained through MasterControl 
Reviewed and 
Approved by: 
 
 
scPharmaceuticals, Inc. 
Approvals obtained through MasterControl 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 12 of 51 
INVESTIGATOR PROTOCOL AGREEMENT 
 
Protocol Title: 
Economic Impact of Reducing Hospital Admissions for Patients Presenting to the 
Emergency Department with Worsening Heart Failure: An Adaptive Clinical Trial 
of Furoscix Infusor 
 
Protocol Number: 
scP-01-005 
Amendment 6  
 
By my signature, I  
 
a. agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make 
changes in a protocol after notifying the Sponsor, except when necessary to protect the safety, rights, or 
welfare of Subjects.  
b. agree to personally conduct or supervise the described investigation(s).  
c. 
agree to inform any patients, or any persons used as controls, that the study product is being used for 
investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 
CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.  
d. agree to report to the Sponsor adverse experiences that occur in the course of the investigation(s) in 
accordance with 21 CFR 312.64. I have read and understand the information in the Investigator’s brochure, 
including the potential risks and side effects of the study product.  
e. agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are 
informed about their obligations in meeting the above commitments.  
f. 
agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those 
records available for inspection in accordance with 21 CFR 312.68.  
g. 
will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial 
and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all 
changes in the research activity and all unanticipated problems involving risks to human subjects or others. 
Additionally, I will not make any changes in the research without IRB approval, except where necessary to 
eliminate apparent immediate hazards to human subjects.  
h. agree to comply with all other requirements regarding the obligations of clinical investigators and all other 
pertinent requirements in 21 CFR Part 312. 
 
 
 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
 
 
 
Print Name 
 
 
 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 13 of 51 
ABBREVIATIONS 
 
AE 
adverse event 
CRF 
case report form 
ED 
emergency department 
HF 
heart failure 
IFU 
instructions for use 
IV 
intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire  
NYHA 
New York Heart Association 
SAE 
serious adverse event 
TAU 
treatment as usual 
USA 
United States of America 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 14 of 51 
SYNOPSIS 
 
SHORT TITLE 
FREEDOM-HF 
PROTOCOL TITLE 
Economic Impact of Reducing Hospital Admissions for Patients Presenting to the 
Emergency Department with Worsening Heart Failure: An Adaptive Clinical Trial of 
Furoscix Infusor 
PROTOCOL NUMBER 
scP-01-005 
SPONSOR 
scPharmaceuticals, Inc. 
INVESTIGATIONAL 
PRODUCT 
Furoscix On-body Infusor drug-device combination product (hereinafter referred to as 
Furoscix Infusor) 
STUDY OBJECTIVES 
1. To evaluate differences in healthcare resource utilization costs for subjects treated 
with the Furoscix Infusor outside the hospital (“Furoscix arm”, “Furoscix cohort” or 
“Furoscix Infusor cohort”) compared to patients receiving intravenous furosemide 
for ≤ 72 hours in the hospital setting for 30 days post-discharge from the 
emergency department. 
2. To evaluate the safety of Furoscix administered outside the hospital.  
3. To evaluate and describe quality of life and patient satisfaction for patients who 
receive the Furoscix Infusor outside the hospital setting. 
STUDY DESIGN 
This adaptive clinical trial will include a prospective treatment arm (i.e., Furoscix 
administered via the Furoscix Infusor) administered outside the hospital that will be 
compared to a propensity-matched historical control arm of patients admitted to the 
hospital for ≤ 72 hours (i.e., Treatment As Usual (TAU)) that will be derived from 
administrative claims data. Eligible patients for the Furoscix arm will be patients with 
worsening HF due to congestion who initially present to the emergency department 
(ED) and who are expected to require parenteral diuresis.  
 
The control arm will be populated with claims data for patients  who presented to the 
emergency department with worsening HF and are admitted to the hospital for ≤ 72 
hours for the treatment of HF. The filter will be further strengthened by analyzing 
diagnostic codes and resource utilization during their hospital stay to remove patients 
with renal failure or those that c were in the hospital for other reasons. The eligibility 
of patients in the control arm will be determined based on a propensity-matched 
design according to the characteristics of the patients in the prospective Furoscix arm. 
 
Patients presenting to the emergency department with worsening HF and meeting all 
study eligibility criteria may be consented and enrolled in the study to receive diuresis 
outside of the hospital setting with Furoscix.  
 
Furoscix will be administered daily via the Furoscix Infusor whereby 80 mg is 
administered subcutaneously over 5 hours in a biphasic regimen (30 mg in the first 
hour, followed by 12.5 mg per hour for the subsequent 4 hours). Within a single 24-
hour period, the 80 mg dose can be repeated at the discretion of the investigator > 2 
hours after the completion of the first dose. Subjects should be transitioned back to 
their oral maintenance diuretic regimen when clinically indicated at the discretion of 
the investigator (approximately 4 doses). After Subjects have been transitioned to 
their oral maintenance diuretic regimen, additional doses of Furoscix can be 
prescribed during the 30-day study period as needed based on the presence of clinical 
triggers (dyspnea on exertion, edema, and/or excess weight gain) as determined by 
the investigator. No more than 7 doses of Furoscix is permitted during the 30-day 
study period. Additional doses beyond 7 requires approval by the medical monitor.   

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 15 of 51 
   
If subjects receiving Furoscix are hospitalized for heart failure during the treatment 
period, Furoscix should be discontinued and the subject treated with IV diuretics as 
clinically indicated.  
 
In addition to the scheduled phone and clinic visits,  the investigator can utilize 
unscheduled clinic or phone visits for additional assessments at any time. 
STUDY TREATMENTS 
Study Drug: Furoscix, (Furosemide Injection), 80 mg/10 mL is a proprietary furosemide 
formulation that is buffered to a neutral pH to enable subcutaneous administration 
and contained in a prefilled Crystal Zenith® (CZ) cartridge.  
 
Study Device: The Infusor is a compact, ethylene oxide (EtO) sterilized, single-use, 
electro-mechanical (battery powered, micro-processor controlled), on-body 
subcutaneous delivery system based on the SmartDose® Gen II 10 mL (West 
Pharmaceutical Services). 
 
The Furoscix Infusor is an investigational drug-device combination product. The Infusor 
is applied to the abdomen via a medical grade adhesive and delivers a subcutaneous 
infusion of Furoscix through a pre-programmed, biphasic delivery profile with 30 mg 
(3.75 mL) administered over the first hour, followed by 12.5 mg (1.56 mL) per hour for 
the subsequent 4 hours (Total dose is 80 mg (10 mL) over 5 hours).    
 
NUMBER OF 
SUBJECTS 
Based on an average hospital cost of a patient hospitalized for ≤ 72 hours with a 
primary diagnosis of HF (Diagnosis Related Group Code 291, 292 and 293) of $8,600 
(standard deviation: $3,045), 68 patients (34 in each group) are required to have an 
80% chance of detecting a decrease in hospital costs to $6,500 at a significance level of 
5%. The target sample size of the Furoscix cohort will initially be N=34 subjects. 
 
Given the anticipated overdispersion of the primary outcome (i.e., difference in total 
HF-attributable direct medical costs), we will employ adaptive trial design procedures 
for sample size re-estimation. This adaptive-total information criterion approach was 
taken due to the risk of incorrectly estimating the sample size due to misspecification 
of the cost outcome parameters. This will include re-assessment of the sample size at 
N=34 in the Furoscix cohort by using a group sequential design and testing to allow for 
stopping. It is not expected that the sample size for the Furoscix Infusor arm would 
exceed N=75, but the maximum value cannot be definitively stated until the analysis at 
N=34 is completed.  
 
The methodology by which the sample size will be re-estimated and stopping rules will 
be implemented will be detailed in the statistical analysis plan. 
NUMBER OF SITES 
Up to 20 sites 
COUNTRY 
United States of America (USA) 
SUBJECT 
POPULATION 
Male and female patients 18-80 years old with worsening HF presenting to the 
emergency department with evidence of congestion or fluid overload requiring 
parenteral diuresis in the judgment of the investigator, and who are receiving 40-160 
mg of oral furosemide equivalents daily (20-80 mg Torsemide or 1-4 mg Bumetanide).  
 
Subjects may be enrolled in the study only if all of the inclusion criteria and none of 
the exclusion criteria are met.  

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 16 of 51 
 
Inclusion Criteria 
 
1. Age 18-80 years 
2. NYHA Class II-III HF presenting to the ED for worsening HF at baseline 
3. On background therapy including 40-160 mg of oral furosemide equivalents daily 
(20-80 mg Torsemide or 1-4 mg Bumetanide) 
4. Signs of extracellular volume expansion, defined as one or more of the following:  
a. jugular venous distention 
b. pitting edema (≥ 1+) 
c. 
abdominal distension 
d. pulmonary congestion on chest x-ray 
e. pulmonary rales  
5. After initial emergency department evaluation and treatment (i.e., at the time of 
the care transition decision*), candidates for parenteral diuresis outside of the 
hospital, defined as all the following:  
a. Oxygen saturation ≥ 90% on exertion 
b. Respiratory Rate < 24 breaths per minute 
c. 
Resting Heart Rate < 100 beats per minute 
d. Systolic Blood Pressure > 100 mmHg 
6. Adequate environment for at-home administration of Furoscix 
 
*Decision point when the patient leaves the emergency department. 
 
Exclusion Criteria 
 
A Subject is not eligible for inclusion if any of the following criteria apply:  
 
1. Presence of a complicating condition, other than HF that requires immediate 
hospitalization or anticipated hospitalization in the next 30 days 
2. Evidence of acute renal failure as determined at the discretion of the investigator 
3. Known allergy to the active and inactive ingredients of the study medication or 
device adhesive 
4. Any local abdominal skin condition on the day of treatment i.e. sunburn, rash, 
eczema, etc. 
5. Currently participating in another interventional research study 
6. Women who are pregnant or who could become pregnant and are not willing to 
use an adequate form of contraception 
7. Estimated Creatinine Clearance < 30 mL per minute by Cockcroft-Gault equation 
CrCl (mL/min) =  (140 - age) x Lean Body Weight (kg)    (x 0.85 if female) 
                                   Serum Creatinine (mg/dL) x 72 
8. If baseline creatinine value is available: an increase of > 0.5 mg/dL in creatinine 
from baseline  
9. HF requiring immediate hospitalization 
 
STUDY 
ASSESSMENTS AND 
PROCEDURES 
Patients will be assessed in the emergency department by the investigator and/or 
study staff for signs and symptoms of worsening HF due to congestion or fluid 
overload. If it is determined by the investigator that the patient requires parenteral 
diuresis or continued diuresis outside of the ED care setting, and meets all study 
eligibility criteria, he/she may be consented and enrolled into the study.  

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 17 of 51 
 
The treatment comprises a 5-hour subcutaneous infusion of Furoscix via the Furoscix 
Infusor. Subjects will be instructed on the use of the Furoscix Infusor by the 
investigator and/or study staff in accordance with the instructions for use. The initial 
dose of the study product may be administered on the day of enrollment. Some 
subjects may not require their initial dose until the next day. Doses will be provided to 
the subject for self-administration or administration by a caregiver in the home setting 
as directed by the investigator or study staff. No more than 7 doses of Furoscix are 
permitted during the 30-day study period. If a subject uses the allotted 7 doses and 
additional doses are required to control signs and symptoms of congestion when oral 
diuretics are not effective, approval by the medical monitor is required. Subjects will 
receive scheduled at-home telephone calls from a HF nurse, or designee, on Days 1 
and 7, and one call between Days 14-21. Unscheduled calls can be conducted as 
needed. Planned in-clinic visits will be conducted between Day 2-4 and then Day 30+3 
days. Unscheduled at-home telephone calls by an HF nurse, or designee,  and 
unscheduled in-clinic visits may be performed if felt clinically indicated by the study 
team or the clinical provider.  
 
The study period will be up to 30 days after enrollment. All outcomes will be assessed 
up to 30 days after the initial discharge from the emergency department. 
STUDY ENDPOINTS 
Primary Endpoint 
 
The difference in overall and heart failure related healthcare costs  between subjects 
treated with the Furoscix Infusor 30 days post discharge from the emergency 
department compared to propensity score matched controls treated in the hospital for 
≤ 72 hours through 30 days post discharge.  
 
Secondary Endpoints 
 
To compare the measurements listed below between subjects treated with the 
Furoscix Infusor 30 days post discharge from the emergency department compared to 
propensity score matched controls treated in the hospital for ≤ 72 hours through 30 
days post discharge.  
 
1. Number of hospital admissions and duration with-in 30 days post discharge from 
the emergency department 
2. Number of HF-related hospital admissions and duration with-in 30 days post 
discharge from the emergency department 
3. Number of HF-related emergency department visits with-in 30 days post discharge 
from the emergency department 
4. Number of HF-related clinic visits with-in 30 days post discharge from the 
emergency department 
5. Description of health-related quality of life using the twelve-item Kansas City 
Cardiomyopathy Questionnaire (KCCQ-12, for Furoscix Infusor cohort only) 
6. Change in BNP or NT-proBNP (for Furoscix Infusor cohort only) 
7. Subject and/or caregiver satisfaction with Furoscix Infusor (for Furoscix Infusor 
cohort only) 
 
Safety Assessments 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 18 of 51 
The Furoscix Infusor cohort will be monitored for adverse events, and any adverse 
events will be recorded and reported according to Food and Drug Administration 
guidelines. Reactions at the infusion site and frequency of these reactions will be 
recorded as part of the safety assessments.  
 
STATISTICAL 
ANALYSIS 
Primary Endpoint 
 
Overall and heart failure related costs between subjects treated with the Furoscix 
Infusor 30 days post discharge from the emergency department for worsening heart 
failure due to fluid overload compared  to propensity score matched controls treated 
in the hospital for ≤ 72 hours through 30 days post discharge.  Comparison of these 
data between the matched (paired) cohorts will be conducted via a t-test or a 
Wilcoxon signed-rank test depending on the distribution of the data. 
 
Secondary Endpoints 
 
Outcomes for the endpoints related to healthcare utilization (i.e., Secondary Endpoints 
1-4) will be evaluated by appropriate statistical test dependent on the distribution of 
the outcome. Health-related quality of life outcomes will be evaluated for the Furoscix 
cohort only and will descriptively compare KCCQ-12 questionnaire responses at Day 0 
versus Day 30. Change in BNP or NT-proBNP will be evaluated for the Furoscix cohort 
only and will descriptively compare values obtained at Day 0 versus Day 30.  Subject 
and/or caregiver satisfaction with Furoscix Infusor will be descriptive.       
 
Safety Analysis 
 
There are no pre-planned analyses to compare Furoscix versus hospitalized cohort on 
the basis of safety. However, the safety of Furoscix will be monitored during the trial, 
and identified safety issues (including AEs, SAEs, and adverse reactions) will be 
summarized descriptively for the Furoscix cohort. The incidence (number and 
percentage of subjects) of adverse events will be presented overall and by MedDRA 
System Organ Class and Preferred Term for the Furoscix cohort.  Reactions at the 
infusion site and frequency of these reactions will be reported. This analysis will be 
repeated for serious adverse events, for treatment-related adverse events, and for 
adverse events leading to premature study withdrawal. 
 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
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CONFIDENTIAL |February 2, 2021 
 
Page 20 of 51 
CONTENTS 
PRINCIPAL INVESTIGATORS .............................................................................................. 2 
SPONSOR CONTACT INFORMATION .................................................................................. 2 
SUMMARY OF CHANGES ................................................................................................... 3 
PROTOCOL APPROVAL PAGE........................................................................................... 11 
INVESTIGATOR PROTOCOL AGREEMENT ......................................................................... 12 
ABBREVIATIONS ............................................................................................................. 13 
SYNOPSIS ....................................................................................................................... 14 
SCHEDULE OF ASSESSMENTS .......................................................................................... 19 
1. 
INTRODUCTION AND RATIONALE ............................................................................. 23 
 Risk: Benefit Evaluation ............................................................................................ 23 
1.1.1. 
Potential Benefits of Participating in the Study ...................................... 23 
1.1.2. 
Potential Risks of Participating in the Study ............................................ 23 
1.1.3. 
Risk Management .................................................................................... 24 
2. 
STUDY OBJECTIVES .................................................................................................. 24 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 24 
 Overall Study Design and Plan .................................................................................. 24 
 Furoscix Infusor ........................................................................................................ 25 
3.2.1. 
Primary Endpoint ..................................................................................... 27 
3.2.2. 
Secondary Endpoints ............................................................................... 27 
3.2.3. 
Safety Assessments .................................................................................. 28 
4. 
SELECTION OF STUDY POPULATION .......................................................................... 28 
 Inclusion Criteria ....................................................................................................... 28 
 Exclusion Criteria ...................................................................................................... 28 
 Removal of Subjects from Therapy and Premature Discontinuation ...................... 29 
5. 
TREATMENTS ........................................................................................................... 30 
 Treatments Administered ........................................................................................ 30 
 Identity of Investigational Product ........................................................................... 30 
5.2.1. 
Labeling .................................................................................................... 30 
5.2.2. 
Storage and Handling .............................................................................. 30 
 Method of Assigning Subjects to Treatment Groups ............................................... 30 
5.3.1. 
Treatment Assignment/Randomization .................................................. 30 
 Selection of Doses in the Study ................................................................................ 31 
 Selection and Timing of Dose for Each Subject ........................................................ 31 
 Procedures for Blinding ............................................................................................ 31 
 Prior and Concomitant Therapy ............................................................................... 31 
 Prohibited Medications ............................................................................................ 31 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
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CONFIDENTIAL |February 2, 2021 
 
Page 21 of 51 
 Other Restrictions ..................................................................................................... 31 
 Study Stopping Criteria .......................................................................................... 31 
 Study Drug-Device Combination Accountability .................................................... 32 
6. 
STUDY PROCEDURES ................................................................................................ 33 
 Study Measurements and Assessments ................................................................... 33 
6.1.1. 
Assessment of Primary Endpoint ............................................................. 33 
6.1.2. 
Assessment of Secondary Endpoints ....................................................... 33 
6.1.3. 
Safety Assessments .................................................................................. 33 
 Study Phases and Procedures .................................................................................. 33 
6.2.1. 
Screening Phase (Day 0) .......................................................................... 35 
6.2.2. 
Treatment Phase (Day 0 – Discretion of the investigator) ...................... 35 
6.2.3. 
Day 1 and 7 (Telephone Call Follow-Up) ................................................. 36 
6.2.4. 
Day 2-4 (In-Clinic visit) ............................................................................. 36 
6.2.5. 
Days 14 – 21 (Telephone Call Follow-Up) ................................................ 37 
6.2.6. 
Day 30 ± 3 days (In-Clinic Visit) ................................................................ 37 
6.2.7. 
Unscheduled Telephone Calls and Clinic Visits........................................ 38 
6.2.8. 
Cardiopulmonary Examinations .............................................................. 38 
6.2.9. 
BNP or NT-proBNP Assessments ............................................................. 39 
6.2.10. Clinical Laboratory Tests .......................................................................... 39 
6.2.11. Heart Failure Symptom Scoring ............................................................... 39 
6.2.12. Vital Signs ................................................................................................. 39 
6.2.13. Kansas City Cardiomyopathy Questionnaire – Short Form (KCCQ-12) ... 39 
6.2.14. Comfort of Wear Questionnaire .............................................................. 40 
6.2.15. Study Product Training ............................................................................ 40 
6.2.16. Skin Inspection ......................................................................................... 40 
7. 
ADVERSE EVENTS ..................................................................................................... 41 
 Definition of an Adverse Event ................................................................................. 41 
 Definition of an Adverse Reaction ............................................................................ 42 
 Definition of a Suspected Adverse Reaction ............................................................ 42 
 Definition of an Unexpected  Adverse Event ........................................................... 42 
 Definition of a Serious Adverse Event ...................................................................... 42 
 Severity of Adverse Events and Serious Adverse Events ......................................... 43 
 Outcome of Adverse Events and Serious Adverse Events ....................................... 43 
 Assessment of Relatedness to Study Product .......................................................... 43 
 Method, Frequency, and Time Period for Detecting Adverse Events and Serious 
Adverse Events ......................................................................................................... 44 
 Reporting Serious Adverse Events ......................................................................... 44 
7.10.1. Timeframes for Reporting Serious Adverse Events ................................. 44 

scPharmaceuticals Inc. 
 
 
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Protocol Number: scP-01-005 
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CONFIDENTIAL |February 2, 2021 
 
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7.10.2. Serious Adverse Event Information to Report ......................................... 44 
7.10.3. Other Assessments as Adverse Events and Serious Adverse Events....... 44 
7.10.4. Documenting Adverse Events and Serious Adverse Events .................... 44 
7.10.5. Regulatory and Ethics reporting requirement ......................................... 45 
7.10.6. Follow-up of Adverse Events and Serious Adverse Events ...................... 45 
8. 
STATISTICS ............................................................................................................... 46 
 Determination of Sample Size .................................................................................. 46 
 Baseline Characteristics and Subject Disposition ..................................................... 46 
 Endpoint Analyses .................................................................................................... 46 
8.3.1. 
Primary Endpoint ..................................................................................... 46 
8.3.2. 
Secondary Endpoints ............................................................................... 47 
 Safety Analyses ......................................................................................................... 47 
9. 
RESPONSIBILITIES .................................................................................................... 48 
 Investigator Responsibilities ..................................................................................... 48 
9.1.1. 
Good Clinical Practice .............................................................................. 48 
9.1.2. 
Institutional Review Board and Independent Ethics Committee Approval48 
9.1.3. 
Informed Consent .................................................................................... 48 
9.1.4. 
Confidentiality ......................................................................................... 48 
9.1.5. 
Compensation, Insurance, and Indemnity .............................................. 49 
9.1.6. 
Study Files and Retention of Records ...................................................... 49 
9.1.7. 
Case Report Forms ................................................................................... 49 
9.1.8. 
Protocol Deviations .................................................................................. 49 
9.1.9. 
Disclosure of Data .................................................................................... 49 
9.1.10. Financial Disclosure ................................................................................. 50 
9.1.11. Drug and Device Product Accountability ................................................. 50 
9.1.12. Inspections ............................................................................................... 50 
 Sponsor Responsibilities ........................................................................................... 50 
9.2.1. 
Study Materials and Instructions ............................................................. 50 
9.2.2. 
Protocol Modifications ............................................................................ 50 
 Joint Investigator and Sponsor Responsibilities ....................................................... 51 
9.3.1. 
Access to Information for Monitoring ..................................................... 51 
9.3.2. 
Study Discontinuation.............................................................................. 51 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
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CONFIDENTIAL |February 2, 2021 
 
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1.   
INTRODUCTION AND RATIONALE 
 
Heart failure (HF) affects 6.5 million adults in the United States, a figure that is expected to grow to 8 million by 
2030. In the United States, HF is implicated as the cause of at least 1-2 million hospitalizations and 700,000 
emergency department visits annually, and HF admissions generate the highest number of 30-day readmissions 
among Medicare enrollees. It is also estimated that 90% of patients presenting to the Emergency Department with 
worsening HF are admitted to the hospital and approximately 50% of hospital admissions for HF admitted from the 
emergency department could potentially be avoided. 
 
Intravenous furosemide is commonly indicated for the management edema which is commonly present in 
worsening HF as the absolute bioavailability of oral furosemide is low, highly variable and is exacerbated during an 
acute event. Recognizing this limitation of oral furosemide, national and international guidelines recommend that 
patients should be administered intravenous diuretics when significant signs and symptoms of volume overload 
are present. Thus, hospital admission or utilization of an observational unit is generally required. Admitting 
patients to the hospital, solely for the administration of intravenous furosemide, is expensive and increases risks of 
hospital-associated morbidity and mortality. Alternative treatment paradigms that shift HF management outside of 
the hospital are needed. 
 
Approximately 60% of hospital admissions in patients with HF are due to sodium retention and volume overload. 
While subcutaneous administration of furosemide would enable diuresis as an outpatient, avoiding a hospital 
admission, the current commercially available furosemide injectable products have an alkaline pH and poor 
solubility making them unsuitable for subcutaneous administration. A novel, pH neutral formulation of 
subcutaneous furosemide (Furoscix, Furosemide Injection 80 mg/10 mL for subcutaneous use)  has been 
developed to minimize burning and discomfort with subcutaneous administration and is delivered via the Furoscix 
Infusor: a wearable, pre-programmed on-body subcutaneous delivery system.  
 
Furoscix administered 80 mg subcutaneously via the Furoscix Infusor, with 30 mg administered over the first hour 
followed by 12.5 mg per hour over the subsequent four hours produced similar exposures of furosemide and 
equivalent diuresis and natriuresis compared to two bolus injections of furosemide 40 mg dosed over 2 minutes, 
two hours apart. 
 
The purpose of this study is to evaluate the economic impact of hospital avoidance and safety with management of 
worsening HF due to congestion with Furoscix administered via the Furoscix Infusor outside the hospital setting in 
patients initially presenting to the emergency department.  
 
 
Risk: Benefit Evaluation 
 
1.1.1.   
Potential Benefits of Participating in the Study 
 
The potential benefit to the participants beyond their contribution to the development and testing of this product 
is the potential avoidance of a hospital admission and administration of parental diuretics outside of the hospital 
setting.  
 
1.1.2.   
Potential Risks of Participating in the Study 
 
Furosemide has been extensively studied and used clinically for over 50 years. It is generally considered a safe and 
effective pharmaceutical product. Subjects may experience marked diuresis following the placement and 
activation of this drug-device combination product. Subjects should be instructed to have ready access to suitable 
toilet facilities. Marked diuresis may be accompanied by a drop in blood pressure including orthostatic 
hypotension and associated signs and symptoms.  

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1.1.3.   
Risk Management 
 
Subjects will be trained by the study staff on appropriate use of the Furoscix Infusor and will receive specific 
instructions and study materials created for the study (based on the Furoscix Infusor Instructions for Use) that 
include information regarding what to do in case of certain events during the drug delivery period. 
 
Subjects should be transitioned back to their oral maintenance diuretic regimen when clinically indicated at the 
discretion of the investigator (approximately 4 doses). After Subjects have been transitioned to their oral 
maintenance diuretic regimen, additional doses of Furoscix can be prescribed during the 30-day study period as 
needed based on the presence of clinical triggers (dyspnea on exertion, edema, and/or excess weight gain) as 
determined by the investigator. No more than 7 doses of Furoscix is permitted during the 30-day study period. 
Additional doses beyond 7 requires approval by the medical monitor.   
 
Subjects will receive scheduled at-home telephone calls from a HF nurse, or designee, on Days 1 and 7, and one 
call between Days 14-21. Unscheduled calls can be conducted as needed. The primary purpose of the calls will be 
to evaluate the safety and efficacy of diuresis and the need to adjust diuretic therapy. Two planned in-clinic visits 
will be conducted: the first occurring within Days 2-4 and the second occurring on Day 30 + 3 days. These visits will 
include laboratory testing of creatine and electrolytes. 
 
Unscheduled at-home telephone calls by an HF nurse, or designee, and unscheduled in-clinic visits may be 
performed if felt clinically indicated by the study team or the clinical provider. 
 
2.   
STUDY OBJECTIVES 
 
The objectives of this study are:  
 
1. To evaluate differences in healthcare resource utilization costs  for subjects treated with the Furoscix Infusor 
outside the hospital compared to patients receiving intravenous furosemide for ≤ 72 hours in the hospital 
setting for 30 days post-discharge from the emergency department. 
2. To evaluate the safety of Furoscix administered outside the hospital.  
3. To evaluate and describe quality of life and patient satisfaction for patients who receive the Furoscix Infusor 
outside the hospital setting. 
 
3.   
INVESTIGATIONAL PLAN 
 
 
Overall Study Design and Plan 
 
This adaptive clinical trial will include a prospective treatment arm (i.e., Furoscix administered via the Furoscix 
Infusor) administered outside the hospital that will be compared to a propensity-matched historical control arm 
consisting of patients admitted to the hospital for ≤ 72 hours (i.e., TAU). This healthcare cost data from the control 
arm will be generated from administrative claims data. Eligible patients for the Furoscix arm will be patients with 
worsening HF due to congestion who initially present to the emergency department and who are expected to 
require parenteral diuresis. The decision as to whether a patient will be enrolled in the study to receive Furoscix 
will be made collaboratively by an emergency medicine physician and a heart failure specialist or cardiologist. 
 
The control arm will be populated with claims data for patients who presented to the emergency department for 
worsening HF and are admitted to the hospital for ≤ 72 hours for the treatment of HF.. The filter will be further 
strengthened by analyzing diagnostic codes and resource utilization during their hospital stay to remove patients 
with renal failure or those that were in the hospital for other reasons. Furoscix-treated patients will be matched to 

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controls from an administrative claims database in ratios ranging from 1:1 to 4:1 using methods reported by Millar 
and Pasta 2010.1 The simulations will be used to find the matching ratio at which the level of precision is optimized 
without biasing the variance of the outcome measure. Additional methodological details are described in the 
prespecified statistical analysis plan. 
 
Patients presenting to the emergency department with worsening HF and meeting all study eligibility criteria may 
be consented and enrolled in the study to receive diuresis outside of the hospital setting with Furoscix. 
 
Furoscix will be administered daily via the Furoscix Infusor whereby 80 mg is administered subcutaneously over 5 
hours in a biphasic regimen (30 mg in the first hour, followed 12.5 mg per hour for the subsequent 4 hours). Within 
a single 24-hour period, the 80 mg dose can be repeated at the discretion of the investigator > 2 hours after the 
completion of the first dose. The total duration in days and total number of doses of the initial therapy will be 
determined by the investigator based on an estimated volume of diuresis desired to transition patient back to their 
oral diuretic maintenance therapy. The decision of when to discontinue Furoscix and switch to oral diuretics will be 
based on clinical judgement. If subjects receiving Furoscix are hospitalized for heart failure during the treatment 
period, Furoscix should be discontinued and the subject treated with IV diuretics as clinically indicated.  During the 
30-day study period, additional doses of Furoscix can be prescribed as needed due to clinical triggers (dyspnea on 
exertion, edema, and/or excess weight gain) as determined by the investigator.  In addition to the scheduled 
phone and clinic visits,  the investigator can utilize unscheduled clinic or phone visits for additional assessments at 
any time. 
 
 
Furoscix Infusor 
 
The Furoscix Infusor is a drug-device combination product consisting of Furoscix (Furosemide injection, 80 mg per 
10 mL), a novel, pH neutral furosemide formulation optimized for subcutaneous administration and contained in a 
prefilled, Crystal Zenith® (CZ) cartridge, and a proprietary wearable, pre-programmed on-body delivery system, the 
Infusor, based on the SmartDose® Gen II 10 mL (West Pharmaceutical Services). 
 
The Infusor is a compact, ethylene oxide (EtO) sterilized, single-use, electro-mechanical (battery powered, micro-
processor controlled), on-body delivery system that administers a fixed dose of drug product from a prefilled 
cartridge assembly into subcutaneous tissue of the abdomen. It is intended for use by patients, caregivers, or a 
health care professional (HCP) at home or in a clinic setting.  
 
The Furoscix Infusor is 117 mm x 62 mm x 30 mm (length x width x height) and weighs approximately 80 grams 
without the drug cartridge and 90 grams, with a filled drug cartridge inserted into the drug compartment. It has an 
integrated, adhesive patch which attaches the Infusor to the skin for dose administration. The device with 
adhesive is removed from the skin following completion of the dose and discarded.   
 
The system delivery parameters will be pre-programmed as part of the manufacturing process to deliver 80 mg (10 
mL) furosemide over 5 hours using a biphasic delivery profile of 30 mg furosemide (3.75 mL) over the first hour and 
12.5 mg furosemide (1.56 mL) per hour over the subsequent 4 hours. The device elements are shown in Figure 1. 
 
 
1 Millar SJ and Pasta DJ. 2010. The Last Shall Be First: Matching Patients by Choosing the Least Popular First. 
Accessed on July 16, 2018. https://www.lexjansen.com/wuss/2010/HOC/2940_2_HOR-Millar.pdf 

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Figure 1: Main Components of the Furoscix Infusor 
 
  
The Furoscix Infusor utilizes a primary container, which consists of the CZ cartridge (CZ barrel and elastomeric 
septum) and elastomeric piston. The primary container assembly is prefilled with the Furoscix as part of the fill-
finish process.   
 
Following removal of the Furoscix Infusor from the packaging, the drug compartment of the device is opened by 
the user, which turns the device on, and a built-in self-test is performed to verify the needle/button position, 
correct software parameters, the device was not operated prior to the current activation and the motor and 
batteries are functional. 
 
The user inserts the prefilled Cartridge into the drug compartment, closes the compartment, removes the adhesive 
liner and attaches the loaded Furoscix Infusor to the skin of the abdomen. Pressing the activation button 
automatically inserts the small, 27-guage, 6 mm needle into the subcutaneous tissue and drug administration is 
initiated. The needle is protected within the device and can only be deployed when the prefilled Cartridge is in 
place, the cartridge compartment is closed, the device is adhered to the patient, the safety latch is closed, and the 
activation button has been pressed. Dose administration stops automatically upon completion of drug delivery or 
opening of the safety latch upon the removal of the device from the abdomen.   
 
The Furoscix Infusor is designed to administer the entire dose without user intervention. The dose volume and 
dose administration time cannot be changed by the user. Both visual and auditory notifications provide feedback 
on the progress of drug administration. In the event of a drug delivery error, visual and auditory notification will 
alert the user. Once drug administration is complete, accompanied by visual and auditory notifications, the user 
removes the system with the administration needle by carefully peeling the adhesive from the skin which 
automatically opens the safety latch to conceal and protect the administration needle. The empty Cartridge cannot 
be removed from the system after administration of the drug product and the integrated Cartridge/Infusor are 
disposed of together. The device is battery-powered and enables removal of the battery by the user prior to 
disposal.  
 
The clinical study will include training the subject and/or caregiver in the preparation, placement, activation and 
removal of the Furoscix Infusor based on the Furoscix Infusor Instructions for Use (IFU). The steps include: 

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1. Wash hands, check expiration date on the carton and remove supplies from carton. 
2. Check the Infusor and prefilled cartridge for any damage. Check the liquid medicine in the prefilled cartridge.  
The liquid should be clear to slightly yellow. 
3. Clean the tip of the prefiled cartridge with an alcohol wipe. 
4. Load prefilled cartridge into the Infusor. 
5. Select a site on the stomach on either side of the belly button. Prepare application site. 
6. Apply the Furoscix Infusor by peeling away the adhesive liner and firmly pressing the Furoscix Infusor 
onto the skin.  
7. Start the infusion by firmly pressing and releasing the blue start button. 
8. Allow all the medicine to deliver for 5 hours.   
9. When the infusion is complete, remove the Furoscix Infusor from skin by holding the skin down and pulling 
on the blue tab.  
10. Check the infusion site. If there is any bleeding us a cotton ball or apply a small adhesive bandage.  
 
Training for study staff on the device operation and placement following the IFU and subject specific 
instructions will be conducted during an Investigator Meeting(s) and/or at the Site Initiation(s).  
 
Subjects will be instructed on the use of the Furoscix Infusor by the investigator and/or study staff in 
accordance with the IFU and subject specific instructions. The initial dose of the study product may be 
administered on the day of enrollment. Some subjects may not require their initial dose until the next day. 
Doses will be provided to the subject for self-administration or administration by a caregiver in the home 
setting as directed by the investigator or study staff.  
 
Study Subjects will be provided with instructions based on the IFU of the product. These include to not shower, 
bathe, swim or do activities that may cause sweat while wearing the Furoscix Infusor because it contains parts that 
should not get wet. Participants will be informed that marked diuresis may ensue after activation and that they 
should have access to bathroom facilities for up to 8 hours after starting the infusion.  
 
If the Subject experiences leakage or pain during the infusion period, they are instructed to call the study team at 
the clinical site as designated on the informed consent and subject specific instructions. If the infusion is 
interrupted for any reason (i.e. see visual and hear audio notifications) or the device becomes detached during the 
infusion period, subjects are instructed to call the study team at the clinical site.  
 
Following dosing and device removal, subjects should place the used Furoscix Infusor in the box and bring back to 
the clinic at their next scheduled study visit. Subjects will return all Furoscix Infusors by the Day 30 in-clinic visit. 
 
3.2.1.   
Primary Endpoint 
Overall and heart failure related healthcare costs between subjects treated with the Furoscix Infusor 30 days post 
discharge from the emergency department compared to propensity score matched controls treated in the hospital 
for ≤ 72 hours through 30 days post discharge.  
3.2.2.   
Secondary Endpoints 
 
To compare the measurements listed below between subjects treated with the Furoscix Infusor 30 days post 
discharge from the emergency department compared to propensity score matched controls treated in the hospital 
for ≤ 72 hours through 30 days post discharge.  
 
1. Number of hospital admissions and duration with-in 30 days post discharge from the emergency 
department  
2. Number of HF-related hospital admissions and duration with-in 30 days post discharge from the emergency 

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department  
3. Number of HF-related emergency department visits within 30 days post discharge from the emergency 
department 
4. Number of HF-related clinic visits with-in 30 days post discharge from the emergency department  
5. Description of health-related quality of life using the KCCQ-12 (for the Furoscix Infusor arm only) 
6. Change in BNP or NT-proBNP (for Furoscix Infusor arm only) 
7. Subject and/or caregiver satisfaction with Furoscix Infusor (for Furoscix Infusor cohort only) 
 
3.2.3.   
Safety Assessments  
 
The Furoscix Infusor cohort will be monitored for adverse events, and any adverse events will be recorded and 
reported according to the Food and Drug Administration guidelines. Reactions at the infusion site and frequency of 
these reactions will be recorded as part of the safety assessments.  
 
4.   
SELECTION OF STUDY POPULATION 
 
 
Inclusion Criteria 
 
Male and female patients 18-80 years old with NYHA Class II-III HF presenting to the emergency department with 
evidence of fluid overload requiring parenteral diuresis in the judgment of the investigator, and who are receiving 
40-160 mg of oral furosemide equivalents daily (20-80 mg Torsemide or 1-4 mg Bumetanide).  
 
Subjects may be enrolled in the study only if all of the inclusion criteria and none of the exclusion criteria are met.  
 
1. Age 18-80 years 
2. NYHA Class II-III HF presenting to the ED with worsening HF at baseline 
3. On background therapy includes those receiving 40-160 mg of oral furosemide equivalents daily (20-80 mg 
Torsemide or 1-4 mg Bumetanide). 
4. Signs of extracellular volume expansion, defined as one or more of the following:  
a. jugular venous distention 
b. pitting edema (≥1+),  
c. 
abdominal distension 
d. pulmonary congestion on chest x-ray 
e. pulmonary rales  
5. After initial emergency department evaluation and treatment (i.e., at the time of the care transition 
decision*), candidates for parenteral diuresis outside of the hospital, defined as all the following:  
a. Oxygen saturation ≥ 90% on exertion 
b. Respiratory Rate < 24 breaths per minute 
c. 
Resting Heart Rate < 100 beats per minute 
d. Systolic Blood Pressure > 100 mmHg 
6. Adequate environment for at-home administration of Furoscix 
 
*Decision point when the patient leaves the emergency department. 
 
 
Exclusion Criteria 
 
A Subject is not eligible for inclusion if any of the following criteria apply:  
 
1. Presence of a complicating condition, other than HF that requires immediate hospitalization or anticipated 
hospitalization in the next 30 days 

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2. Evidence of acute renal failure as determined at the discretion of the investigator 
3. Known allergy to the active and inactive ingredients of the study medication or device adhesive 
4. Any local abdominal skin condition on the day of treatment i.e. sunburn, rash, eczema, etc. 
5. Currently participating in another interventional research study 
6. Women who are pregnant or who could become pregnant and are not willing to use an adequate form of 
contraception 
7. Estimated Creatinine Clearance < 30 mL per minute by Cockcroft-Gault equation 
CrCl (mL/min)  =  (140 - age) x Lean Body Weight (kg)    (x 0.85 if female) 
                                    Serum Creatinine (mg/dL) x 72 
8. If baseline creatinine value is available: an increase of ≥ 0.5 mg/dL in creatinine from baseline 
9. HF requiring immediate hospitalization 
 
 
Removal of Subjects from Therapy and Premature Discontinuation 
 
Subjects may voluntarily withdraw at any time, but once treatment has occurred, every attempt will be made to 
continue assessments to ensure the safety of the subject. A Subject will be discontinued from the study for the 
following medical or administrative reasons: 
 
• 
Subject wishes to withdraw consent 
• 
Safety reasons 
• 
Subject non-compliance with study procedures specified in the protocol 
• 
Principal Investigator discretion 
 
The Investigator may discontinue individual Subjects from the study if anatomical or skin conditions prevent 
proper placement of the device. As far as possible, subjects who withdraw from the study after treatment, and 
before completion should be seen by the Principal Investigator or delegate and undergo the assessments and 
procedures scheduled for the follow-up visit.  

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5.   
TREATMENTS 
 
 
Treatments Administered  
 
Study drug will be administered by the subject or the subject’s caregiver in accordance with the procedures 
described in this protocol and in the Instructions for Use. 
 
 
Identity of Investigational Product 
 
Study Drug: Furoscix, (Furosemide Injection), 80 mg/10 mL is a proprietary furosemide formulation that is 
buffered to a neutral pH to enable subcutaneous administration and contained in a prefilled, Crystal Zenith® 
(CZ) cartridge. 
 
Furoscix (Furosemide Injection), 10 mL buffered furosemide solution (8 mg/mL), is manufactured by 
Swissfilllon AG, Rottenstrasse 7, CH-3930 Visp, Switzerland under good manufacturing practice conditions. 
Contains:  Tris Hydrochloride and may contain Sodium Chloride Hydrochloric Acid for pH adjustment:  pH 7.4 
(7.0 to 7.8).  
 
Study device: The Infusor is a compact, ethylene oxide (EtO) sterilized, single-use, electro-mechanical (battery 
powered, micro-processor controlled), on-body subcutaneous delivery system based on the SmartDose® Gen II 10 
mL (West Pharmaceutical Services). 
 
The Furoscix Infusor is an investigational drug-device combination product. The Infusor is applied to the abdomen 
via a medical grade adhesive and delivers a subcutaneous infusion of Furoscix through a pre-programmed, biphasic 
delivery profile with 30 mg (3.75 mL) administered over the first hour, followed by 12.5 mg (1.56 mL) per hour for 
the subsequent 4 hours (Total dose is 80 mg (10 mL) over 5 hours). 
 
5.2.1.   
Labeling 
 
Study drug (Furosemide Injection) and study device (Infusor) will bear labels that meet applicable laws for an 
investigational drug-device combination, which may include, but is not limited to, the following information: 
 
• 
Federal law statement limited to Investigational Use 
• 
Batch number  
• 
Storage information 
 
Subject specific instructions for the use and operation of the product will be available to the PI, study staff, and 
subjects. These materials will be based on the Furoscix Infusor Instructions for Use of the study product as it exists at 
the time of the study.  
 
5.2.2.   
Storage and Handling 
 
Store study drug at room temperature 15° to 30°C, (59° to 86°F). Protect from Light.  
 
 
Method of Assigning Subjects to Treatment Groups 
 
5.3.1.   
Treatment Assignment/Randomization 
 
Not applicable. 
 

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Selection of Doses in the Study 
 
The dose of 80 mg is the fixed dose of the study product. This was selected on the basis of clinical criteria and 
physician prescribing and is consistent with the approved labeling of furosemide injection, United States 
Pharmacopeia. Furoscix will be administered daily. Within a single 24-hour period, the 80 mg dose can be repeated 
at the discretion of the investigator > 2 hours after the completion of the first dose. The total duration in days and 
number of doses will be determined by the treating investigator based on an estimated volume of diuresis desired 
to transition patient back to their oral diuretic maintenance therapy. 
 
 
Selection and Timing of Dose for Each Subject  
 
Furoscix will be administered daily via the Furoscix Infusor whereby 80 mg is administered subcutaneously over 5 
hours in a biphasic regimen (30 mg in the first hour, followed 12.5 mg/hour for the subsequent 4 hours). Device 
removal will occur within 3 hours of completion of drug delivery. Within a single 24-hour period, the 80 mg dose 
can be repeated at the discretion of the investigator > 2 hours after the completion of the first dose. The total 
duration in days and the total number of doses will be determined by the investigator based on an estimated 
volume of diuresis desired to transition patient back to their oral diuretic maintenance therapy. 
 
Patients will be instructed on the use of the Furoscix Infusor by the investigator and/or study staff in accordance 
with the IFU and subject specific instructions. The initial dose of the study product may be administered on the day 
of enrollment. Some subjects may not require their initial dose until the next day. Doses will be provided to the 
patient for self-administration or administration by a caregiver in the home setting as directed by the investigator 
or study staff. 
 
 
Procedures for Blinding  
 
Not applicable. This is an unblinded study. 
 
 
Prior and Concomitant Therapy  
 
Prior and concomitant therapy will include all prescription medications and therapies 7 days prior to enrollment 
through Day 30. All information on prior and concomitant therapies will be recorded in the subject’s source and on 
the subject’s case report form (CRF). Requisite details will include the name of the therapy or drug and duration of 
the treatment (start and stop dates) including diuretics and electrolyte supplementation.  
 
 
Prohibited Medications 
 
Concomitant use of any drugs known to interact with furosemide, including aminoglycoside antibiotics, ethacrynic 
acid, high doses of salicylates, cisplatin, tubocurarine, succinylcholine, chloral hydrate, phenytoin, methotrexate, 
indomethacin and lithium is not permitted. 
 
 
Other Restrictions 
 
Subjects will be advised to not engage in strenuous physical activity or activities that could expose the device to 
moisture such as swimming, bathing, or showering. Subjects will be informed that marked diuresis may ensue after 
activation, and that they should avoid travel, operating a vehicle, or other situations without readily available 
access to toilet facilities.  
 
 
Study Stopping Criteria 
 

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The study may be stopped if the Investigator, Medical Monitor, Sponsor or IRB determines that subjects’ safety 
may be compromised by continuing in the study. 
 
To avoid biasing the outcomes by artificially restricting the variance, the study will be stopped once the fixed 
confidence interval width for the difference in the primary endpoint between the prospective arm (Furoscix 
Infusor) and the historical control (treatment as usual) is reached. This will include re-assessment of the sample 
size at N=34 in the Furoscix cohort by using a group sequential design and testing to allow for stopping. It is not 
expected that the sample size for the Furoscix Infusor arm would exceed N=75, but the maximum value cannot be 
definitively stated until the analysis at N=34 is completed. 
 
 
The methodology by which this stopping rule will be implemented is detailed in a separate statistical analysis plan. 
 
 
Study Drug-Device Combination Accountability 
 
The study drug-device combination product will be handled in accordance with the procedures of this protocol. 
Only subjects enrolled in the study may receive study drug-device combination product, in accordance with 
applicable regulatory requirements. 
  
Study staff authorized to handle and store the drug-device combination product must keep an accurate accounting 
of the receipt and disposition of the study products received from the sponsor. Drug-device combination product 
accountability will be assessed by the study monitor during periodic monitoring visits. 

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6.   
STUDY PROCEDURES 
 
 
Study Measurements and Assessments 
 
6.1.1.   
Assessment of Primary Endpoint 
 
The difference in the overall and heart failure related healthcare costs between subjects treated with the Furoscix 
Infusor through 30 days post discharge from the emergency department compared to propensity score matched 
controls treated in the hospital for ≤ 72 hours through 30 days post discharge. Overall and heart failure related 
healthcare costs comprised of all direct medical costs attributable to healthcare resource utilization incurred 
overall and for treatment of HF.  
6.1.2.   
Assessment of Secondary Endpoints 
 
The difference in the measurements listed below between subjects treated with the Furoscix Infusor 30 days post 
discharge from the emergency department compared to propensity score matched controls treated in the hospital 
for ≤ 72 hours through 30 days post discharge. 
 
1. Number of hospital admissions and duration with-in 30 days post discharge from the emergency department  
2. Number of HF-related hospital admissions and duration with-in 30 days post discharge from the emergency 
department 
3. Number of HF-related emergency department visits with-in 30 days post discharge from the emergency 
department 
4. Number of HF-related clinic visits with-in 30 days post discharge from the emergency department 
5. Description of health-related quality of life using the KCCQ-12 (for the Furoscix Infusor arm only) 
6. Change in BNP or NT-proBNP (for Furoscix Infusor cohort only) 
7. Subject and/or caregiver satisfaction with Furoscix Infusor (for Furoscix Infusor cohort only)  
 
6.1.3.   
Safety Assessments 
 
The Furoscix treatment cohort will be monitored for adverse events, and any adverse events will be recorded and 
reported according to guidelines specified by the United States Food and Drug Administration.  Reactions at the 
infusion site and frequency of these reactions will be recorded as part of the safety assessments.  
 
 
Study Phases and Procedures 
 
The Screening Phase will be conducted in the emergency department in a collaborative effort between the 
emergency physician and the cardiologist. All Subjects who sign the informed consent form and satisfy the 
inclusion/exclusion criteria will be enrolled into the trial on the same day as screening. Study drug administration 
can start on the day of screening and enrollment, and administration may commence either in the emergency 
department or at home.  
 
Furoscix will be administered daily via the Furoscix Infusor whereby 80 mg is administered subcutaneously over 5 
hours in a biphasic regimen (30 mg in the first hour, followed 12.5 mg/hour for the subsequent 4 hours). Within a 
single 24-hour period, the 80 mg dose can be repeated at the discretion of the investigator > 2 hours after the 
completion of the first dose. Subjects should be transitioned back to their oral maintenance diuretic regimen when 
clinically indicated at the discretion of the investigator (approximately 4 doses). After Subjects have been 
transitioned to their oral maintenance diuretic regimen, additional doses of Furoscix can be prescribed during the 
30-day study period as needed based on the presence of clinical triggers (dyspnea on exertion, edema, and/or 
excess weight gain) as determined by the investigator. No more than 7 doses of Furoscix is permitted during the 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
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30-day study period.  Additional doses beyond 7 requires approval by the medical monitor. If subjects receiving 
Furoscix are hospitalized for heart failure during the treatment period, Furoscix should be discontinued and the 
subject treated with IV diuretics as clinically indicated. In addition to the scheduled phone and clinic visits,  the 
investigator can utilize unscheduled clinic or phone visits for additional assessments at any time. 
 
Prior to leaving the emergency department on Day 0, the subject and/or caregiver will be trained by the study staff 
on how to prepare the study product and apply it to their abdomen and remove it once the infusion is completed. 
The initial dose of the study product may be administered on the day of enrollment. Some subjects may not 
require their initial dose until the next day. Doses will be provided to the patient for self-administration or 
administration by a caregiver in the home setting as directed by the investigator or study staff. No more than 7 
doses of Furoscix are permitted during the 30-day study period unless approved by the medical monitor.  Planned 
in-person follow-ups include a clinic visit occurring between Days 2-4 and a clinic visit on Day 30+3 days. Scheduled 
remote follow-ups conducted by telephone by a HF nurse, or designee, will occur on Days 1 and 7, and one call 
between Days 14-21. Unscheduled at-home telephone calls and unscheduled in-clinic visits may be performed if 
felt clinically indicated by the study team or the clinical provider. 
 
The Follow-Up Phase will occur on Day 30+3 days for a post treatment follow-up visit completing Subjects’ study 
participation.  
 
Refer to Figure 2 for an overview of study phases and procedures. Note that the depiction in Figure 2 of Furoscix 
administrations after Day 1 is for demonstration purposes. Again, the investigator can prescribe additional Furoscix 
dosing and administration at his/her discretion as long as this does not conflict with safe use practices as defined in 
this protocol and supplementary materials. 
 
 

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Figure 2: Study Phases and Procedures 
 
 
6.2.1.   Screening Phase (Day 0) 
 
The initial Screening assessment will be conducted the same day as the start of the Treatment Phase and will occur 
in the emergency department.  
 
The following procedures/assessments will be performed at Screening:  
 
• 
Informed consent (must be completed prior to any of the following procedures) 
• 
Eligibility review 
• 
Medical history and Subject demographics 
• 
Cardiopulmonary Exam including NYHA Classification 
• 
Weight and height obtained for body mass index (BMI)  
• 
Vital Signs 
• 
Venous blood for clinical chemistries, hematology, BNP or NT-proBNP 
• 
Urine pregnancy test on females of child bearing potential 
• 
Administer the KCCQ-12 (short form) 
• 
Perform site skin assessment where the study product will be placed 
• 
Record concomitant medications (all medications taken within 7 days prior to dosing) 
• 
Study product training with subject and/or caregiver 
• 
Assessments and laboratory tests done as usual care within 12 hours of study enrollment may be collected 
and entered into the eCRF for the study. 
 
6.2.2.   Treatment Phase (Day 0 – Discretion of the investigator) 
 
After the screening activities have been completed and eligibility confirmed, the subject may be enrolled into the 
Treatment Phase. 
 
The treatment includes a daily, preprogrammed bi-phasic 5 hour drug administration via the Furoscix Infusor. 
Eighty (80) mg is administered subcutaneously over 5 hours in a biphasic regimen (30 mg in the first hour, followed 
12.5 mg/hour for the subsequent 4 hours). Within a single 24-hour period, the 80 mg dose can be repeated at the 

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discretion of the investigator > 2 hours after the completion of the first dose. Subjects should be transitioned back 
to their oral maintenance diuretic regimen when clinically indicated at the discretion of the investigator 
(approximately 4 doses). After Subjects have been transitioned to their oral maintenance diuretic regimen, 
additional doses of Furoscix can be prescribed during the 30-day study period as needed based on the presence of 
clinical triggers (dyspnea on exertion, edema, and/or excess weight gain) as determined by the investigator. No 
more than 7 doses of Furoscix is permitted during the 30-day study period. Additional doses beyond 7 requires 
approval by the medical monitor.  
 
Prior to leaving the emergency department on Day 0, the subject and/or caregiver will be trained by the study staff 
on how to prepare the study product and apply it to their abdomen and remove it once the infusion is completed. 
The initial dose of the study product may be administered on the day of enrollment. Some subjects may not 
require their initial dose until the next day. Doses will be provided to the patient for self-administration or 
administration by a caregiver in the home setting as directed by the investigator or study staff. 
 
For all treatment days, these data will be recorded in the Subject Diary daily by the subject and reported to the 
study staff during phone contacts: 
• 
Infusor start and stop times for each dose 
• 
Diuretic use in addition to the study drug (name, route, dose) 
• 
Assessment for adverse events 
• 
Assessment for interval hospitalizations, emergency department visits, or unscheduled clinic visits 
 
The subject will be reminded to complete the Subject Diary daily for each dose, recording the start and end time 
for each dose and any issues preparing the dose.  
 
6.2.3.   
Day 1 and 7 (Telephone Call Follow-Up) 
 
Telephone call follow-ups will be conducted by an HF nurse, or designee, on Days 1 and 7 post discharge from the 
ED. The primary purpose of the follow-up telephone calls will be to evaluate the safety and efficacy of diuresis and 
the need to adjust diuretic therapy. The telephone follow-up will be guided by a suggested Telephone Script. 
Assessments during each phone call will include: 
 
• 
Suggested Telephone Script to review Subject Diary 
• 
Infusor start and stop time for each dose 
• 
Change in diuretic treatment since last point of contact (record on concomitant medication form) 
• 
Assessment for adverse events 
• 
Assessment for interval hospitalizations, emergency department visits, or unscheduled clinic visits 
o 
Been admitted to the hospital 
o 
Been admitted to the hospital for HF-related issues 
o 
Been seen at the emergency department for HF-related issues 
o 
Been seen in an outpatient clinic (including immediate care clinic) for HF-related issues 
o 
Sought any additional or new medical treatment for HF-related issues 
• 
Problems with drug or device use 
 
6.2.4.   
Day 2-4 (In-Clinic visit) 
 
The following procedures/assessments will be performed at the Day 2-4 in-clinic visit:  
 
• 
Interim medical history and medication review 
• 
Cardiopulmonary Exam, focused on signs and symptoms of congestion 
• 
NYHA Classification 

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• 
Weight obtained for BMI  
• 
Vital Signs 
• 
Venous blood for clinical chemistries, hematology, BNP or NT-proBNP  
• 
Change in diuretic treatment since last point of contact (record on concomitant medication form) 
• 
Assessment for selective electrolyte replacement (record on concomitant medication form) 
• 
Comfort of Wear Questionnaire 
• 
Abdominal skin assessment 
• 
Assessment for adverse events 
• 
Assess for interval hospitalizations, emergency department visits, or unscheduled clinic visits 
o 
Been admitted to the hospital 
o 
Been admitted to the hospital for HF-related issues 
o 
Been seen at the emergency department for HF-related issues 
o 
Been seen in an outpatient clinic (including immediate care clinic) for HF-related issues 
o 
Sought any additional or new medical treatment for HF-related issues 
• 
Problem with drug or device use 
• 
Review of Subject Diary for completeness 
• 
Return of all used study devices  
 
6.2.5.   
Days 14 – 21 (Telephone Call Follow-Up) 
 
Telephone call follow-ups will be conducted by an HF nurse, or designee, as deemed necessary by the investigator 
between Days 14-21. The primary purpose of these calls will be to assess whether the subject has experienced or is 
experiencing a study related adverse event, to assess status of change back to oral medication, and to assess 
congestion.  
 
The suggested script for conducting these telephone calls is the same that is described previously and will include: 
• 
Suggested Telephone Script  
• 
Additions or discontinuations of concomitant medications as per section 5.7 (record on 
concomitant medication form) 
• 
Assessment for adverse events 
• 
Assessment for interval hospitalizations, emergency department visits, or unscheduled clinic 
visits 
o 
Been admitted to the hospital 
o 
Been admitted to the hospital for HF-related issues 
o 
Been seen at the emergency department for HF-related issues 
o 
Been seen in an outpatient clinic (including immediate care clinic) for HF-related issues 
o 
Sought any additional or new medical treatment for HF-related issues 
• 
Device start and stop time for each dose (if received study drug after Day 2-4 clinic visit) 
• 
Problems with drug or device use (if received study drug after Day 2-4 clinic visit) 
 
6.2.6.   
Day 30 ± 3 days (In-Clinic Visit) 
 
The following procedures/assessments will be performed at the Day 30 in-clinic visit:  
 
• 
Directed medical history and medication review 
• 
Cardiopulmonary Exam focused on signs and symptoms of congestion 
• 
NYHA Classification 
• 
Weight for BMI  
• 
Vital Signs 

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• 
Venous blood for clinical chemistries, hematology, BNP or NT-proBNP  
• 
Administer the KCCQ-12 
• 
Abdominal skin assessment 
• 
Assessment of adverse events 
• 
Assessment of interval hospitalization, emergency department visits, or unscheduled clinic visits 
o 
Been admitted to the hospital 
o 
Been admitted to the hospital for HF-related issues 
o 
Been seen at the emergency department for HF-related issues 
o 
Been seen in an outpatient clinic (including immediate care clinic) for HF-related issues 
o 
Sought any additional or new medical treatment for HF-related issues 
 
Information regarding HF-related healthcare utilization collected before and at the 30-day in-clinic visit will be 
verified by the investigator through subjects’ medical records. 
 
6.2.7.   
Unscheduled Telephone Calls and Clinic Visits 
 
There are two forms of unscheduled follow-ups specified in this protocol: telephone call and clinic visit. These may 
be assigned at any time at the discretion of the investigator and may arise from a request by the subject or 
caregiver, a request by the HF nurse, or designee, conducting telephone follow-ups, or by the judgement of the 
investigator. Note that the investigator can pre-specify at any time the number and timing of unscheduled follow-
up visits.  
 
If subjects experience worsening signs and symptoms they can be seen in the clinic as an unscheduled visit. For 
subjects presenting for an unscheduled visit the following assessments will be performed:  
 
• 
Cardiopulmonary Exam including NYHA Classification  
• 
Vital Signs  
• 
Weight 
• 
Labs drawn at the discretion of the investigator (including BNP or NT-proBNP) 
• 
Assess for adverse events 
 
All subjects will have the option to receive unscheduled phone call by an HF nurse, or designee, at any time 
following the initial discharge from the emergency department. The primary purpose is to respond to issues 
affecting proper use and administration of the Furoscix Infusor. While these calls will follow according to the 
aforementioned script, the HF nurse, or designee, will address - per his or her best professional judgement - 
specific issues reported by the patient or caregiver. 
 
Additionally, the HF nurse, or designee, will ask (and document the responses) whether the subject has since the 
previous follow-up: 
 
• 
Been admitted to the hospital 
• 
Been admitted to the hospital for HF-related issues 
• 
Been seen at the emergency department for HF-related issues 
• 
Been seen in an outpatient clinic (including immediate care clinic) for HF-related issues 
• 
Sought any additional or new medical treatment for HF-related issues 
 
6.2.8.   Cardiopulmonary Examinations 
 
A cardiopulmonary examination will be performed consisting of assessments of the following: jugular venous 
distension, lungs/chest, heart, abdomen and edema. 

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6.2.9.   BNP or NT-proBNP Assessments 
 
BNP or NT-proBNP will be tested at all clinic visits (scheduled and unscheduled), sent to a local laboratory, and 
values recorded in the CRF. 
 
6.2.10.   Clinical Laboratory Tests 
 
All routine samples will be analyzed by a local licensed clinical laboratory. The clinical laboratory tests are as 
follows: 
• 
Blood clinical chemistry: Creatinine, blood urea nitrogen (BUN), sodium, potassium, chloride, bicarbonate, 
magnesium 
• 
Hematology: (CBC): Red blood cell count (RBC), Total white blood cell count (WBC), Differential WBC 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), Hemoglobin, Hematocrit (Hct), and Platelet 
count 
• 
Urine Pregnancy test: beta hCG test 
 
The investigator is responsible for determining if out-of-range laboratory values are clinically significant or not. All 
clinically significant values will be followed until stabilization, resolution or loss to follow up or until no further 
improvement is expected.  
6.2.11.   Heart Failure Symptom Scoring 
 
NYHA Functional classes will be used in this study. 
 
Class I 
- 
Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. 
 
 
Class II 
- 
Patients have cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal 
pain. 
 
 
Class III 
- 
Patients have cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea or 
anginal pain. 
 
 
Class IV 
- 
Patients have cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even 
at rest. If any physical activity is undertaken, discomfort is increased. 
 
6.2.12.   Vital Signs 
 
Vital signs will include respiratory rate (respirations per minute), blood pressure (mmHg) and heart rate (beats per 
minute). Blood pressure and heart rate will be obtained after the Subject has been resting in sitting position for 5 
minutes.  
 
Weight and height will be collected for BMI. Height collected Day 0 only. 
 
6.2.13.   
Kansas City Cardiomyopathy Questionnaire – Short Form (KCCQ-12)  
 

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The KCCQ-12 consists of 12 items pertaining to the impact of HF on quality of life. This self-administered 
instrument quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. 
 
6.2.14.   
Comfort of Wear Questionnaire 
 
Subjects will complete a comfort of wear questionnaire at the clinic visit. The questionnaire includes questions 
regarding the comfort of the device while performing activities as well as subject/caregiver satisfaction with the 
device/study product.  
 
6.2.15.   
Study Product Training 
 
Study staff will be trained on the use of the study product, subject/caregiver considerations, and methods for 
training subjects and/or their caregivers who are enrolled into the study. The study staff and enrolled subjects will 
be trained using the Furoscix Infusor IFU and a demonstration device. The trainer will have the subject/caregivers 
perform the steps following the IFU. Using the demo device, subjects and their caregivers will demonstrate their 
ability to properly prepare and place the device prior to leaving the ED. Additionally, subjects and caregivers will 
receive upon discharge the IFU and subject specific instructions and will have planned and on-demand phone calls 
with an HF nurse, or designee, to discuss any issues. 
 
6.2.16.   
Skin Inspection 
 
Study staff will inspect the skin on the subject’s abdomen during screening and subsequent in-clinic visits. Any 
anomalies will be recorded. Subjects and their caregivers will also be instructed to monitor for any skin reactions 
after dosing. 
 

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CONFIDENTIAL |February 2, 2021 
 
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7.   
ADVERSE EVENTS 
 
The Investigator is responsible for the detection and documentation of events meeting the definition of an adverse 
event (AE) or serious adverse event (SAE) as provided in this protocol. AEs will be assessed continuously through 
the last study visit unless the nature of the AE or SAE requires continued monitoring. All AEs are recorded as mild, 
moderate or severe, and as Not Related, Possibly Related, Probably Related, and Definitely Related to the 
investigational product. 
 
 
Definition of an Adverse Event 
 
An AE is any untoward medical occurrence associated with the use of an investigational product in humans, 
whether or not considered related to the investigational product. An adverse event (also referred to as an adverse 
experience) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, and does not imply any 
judgment about causality. An adverse event can arise with any use of the investigational product (e.g., off-label 
use, use in combination with another drug) and with any route of administration, formulation, or dose, including 
an overdose. 
 
A “pre-existing” condition is one that is present prior to administration of the investigational product and is 
reported as part of the Subject’s medical history. Pre-existing conditions should be reported as AEs only if the 
frequency, intensity, or character of the pre-existing condition worsens during the course of the study. 
 
Laboratory or functional test abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms or require medical intervention. A laboratory abnormality (e.g. a clinically significant 
change detected on clinical chemistry, hematology, urinalysis) or functional test abnormality (e.g. a clinically 
significant change detected on electrocardiogram, pulse oximetry, or spirometry) that is independent from a 
known underlying medical condition and that requires medical or surgical intervention, or leads to interruption or 
discontinuation of the investigational product, must be considered an AE. 
 
All AEs judged to be clinically significant, including clinically-significant laboratory, electrocardiogram and 
functional test abnormalities, will be followed until resolution or return to baseline or until no further 
improvement is expected. 
 
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 investigational product placement and/or 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: 
 
• 
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. 

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• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study is not 
considered an AE. 
 
 
Definition of an Adverse Reaction 
 
An adverse reaction means any AE caused by an investigational product. Adverse reactions are a subset of all 
suspected adverse reactions where there is reason to conclude that the investigational product caused the event. 
 
 
Definition of a Suspected Adverse Reaction 
 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that the 
investigational product caused the adverse event. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the investigational product and the AE. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction.  
 
 
Definition of an Unexpected  Adverse Event  
 
An adverse event or Suspected Adverse Reaction is considered “unexpected” if it is not listed in the investigator 
brochure, product labeling or is not listed at the specificity or severity that has been observed.  
 
 
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 
o 
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 
o 
NOTE: Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization, 
the event is an SAE. 
o 
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 
department. 
d. A disability/incapacity 
o 
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 
department or at home, blood dyscrasias or convulsions that do not result in Subject hospitalization, or the 
development of drug dependency or drug abuse. 
o 
NOTE: Medical and scientific judgment should be used in deciding whether prompt reporting is 
appropriate in this situation. 
 

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Severity of Adverse Events and Serious Adverse Events 
 
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. 
 
The severity (mild, moderate, or severe) of each AE or SAE must be assessed by the Investigator or designee.  
 
 
Outcome of Adverse Events and Serious Adverse Events 
 
Not Recovered / Not 
Resolved 
- 
One of the possible results of an AE outcome that indicates that the event has 
not improved or the patient recuperated. 
 
 
Recovered / Resolved 
- 
One of the possible results of an AE outcome that indicates that the event has 
improved or patient recuperated. 
 
 
Recovered / Resolved with 
Sequelae 
- 
One of the possible results of an AE outcome where the subject recuperated 
but retained pathological conditions resulting from the prior disease or injury. 
 
 
Recovering / Resolving 
- 
One of the possible results of an AE outcome that indicates that the event is 
improving. 
 
 
Unknown 
- 
Not known, not observed, not recorded, or refused. 
 
 
Fatal 
- 
The termination of life as a result of an AE. 
 
 
Assessment of Relatedness to Study Product  
 
The Investigator will assess each AE and SAE for causality based on their best medical judgment, the observed 
symptoms associated with the event, and the available information on investigational product. The relatedness 
guidance provided below can be used to assist in determining the relationship of the IP to the AE or SAE. However, 
it is ultimately the investigator’s responsibility to determine the relationship based on their best medical judgment, 
knowledge, and experience. 
 
Not Related - 
Based upon available information regarding subject history, disease process, relationship of AE 
to dosing and drug pharmacology, there is no reasonable relationship between the 
investigational product and the AE. 
 
 
Possibly 
Related 
- 
Relationship exists between the AE and IP, when the AE follows a reasonable sequence from the 
time of the investigational product administration, but could also have been produced by the 
subject’s clinical state or by other drugs administered to the subject. 
 
 
Probably 
Related 
- 
Relationship exists between the AE and the investigational product when the AE follows a 
reasonable sequence from the time of investigational product administration, follows a known 
response pattern of the drug class, is confirmed by improvement on stopping the investigational 
product and the investigational product is the most likely of all causes. 

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Definitely 
Related 
- 
Relationship exists between the AE and the investigational product when the AE follows a 
reasonable sequence from the time of the investigational product administration, follows a 
known response pattern of the drug class, is confirmed by improvement on stopping the 
investigational product and no other reasonable cause exists. 
 
 
Method, Frequency, and Time Period for Detecting Adverse Events and Serious Adverse Events 
 
AEs and SAEs will be assessed in the frequency and manner as described in Section 6.2 of this protocol. 
 
 
Reporting Serious Adverse Events  
7.10.1.   
Timeframes for Reporting Serious Adverse Events 
Prompt notification of the sponsor regarding SAEs is essential so that ethical and regulatory responsibilities and 
legal obligations can be satisfied. The Investigator must report SAEs according to the following time frames:  
  
• 
Initial notification of all SAEs based on the available information must be provided to the sponsor or designee 
within 24 hours of the investigational site learning of the event. (Initial notification within 24 hours of Death 
and life-threatening events is extremely important).  
• 
Follow-up information when available must be sent to the sponsor or designee within 48 hours of receipt of 
the information by the investigational site.  
 
7.10.2.   Serious Adverse Event Information to Report 
At a minimum, SAE reports must contain the Subject ID, the serious adverse event term, onset date, relationship to 
study product, and a brief narrative of the event. Please note that relationship to study product and causality is 
very important and must be included in the initial report as it may impact expedited regulatory reporting 
requirements for the event. 
 
There may be instances when copies of medical records for certain cases are requested. However, it is not 
acceptable for the Investigator to send photocopies of the Subject’s medical records in lieu of completion of the 
appropriate AE and SAE pages. If medical records are submitted, all Subject personal identifiers must be 
completely redacted prior to submission. 
 
7.10.3.   Other Assessments as Adverse Events and Serious Adverse Events 
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., electrocardiogram, 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 product administration or that are present before study 
product administration but worsen after study product administration should be assessed for AE criteria. 
 
7.10.4.   Documenting Adverse Events and Serious Adverse Events 
All AEs, including SAEs that occur after dosing of study product must be documented in the Subject's medical 
records and on the CRF. The Investigator should attempt to establish a diagnosis of the event based on signs, 

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CONFIDENTIAL |February 2, 2021 
 
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symptoms, and/or other clinical information. In such cases, the diagnosis should be documented as the AE and/or 
SAE term. 
 
7.10.5.   Regulatory and Ethics reporting requirement  
The Investigator will comply with the applicable local regulatory requirements related to the reporting of SAEs to 
the Institutional Review Board. 
 
7.10.6.   Follow-up of Adverse Events and Serious Adverse Events 
All AEs and SAEs documented at a previous visit/contact that are designated as ongoing will be reviewed at 
subsequent visits/contacts. AEs and SAEs will be followed until the last study visit unless the nature of the AE or 
SAE requires continued monitoring. If a Subject dies during participation in the study or during a recognized follow-
up period, a copy of any post-mortem findings, including histopathology, should be obtained, if available, and 
forwarded to scPharmaceuticals. New or updated information will be recorded on the originally completed SAE 
Report Form with all changes electronically signed/dated by the Investigator or designee.  

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8.   
STATISTICS  
 
 
Determination of Sample Size 
 
Based on an average hospital cost of a patient hospitalized for ≤ 72 hours with a primary diagnosis of HF (Diagnosis 
Related Group Code 291, 292 and 293) of $8,600 (standard deviation: $3,045), 68 patients (34 in each group) are 
required to have an 80% chance of detecting a decrease in hospital costs to $6,500 at a significance level of 5%. 
The target sample size of the Furoscix cohort will initially be N=34 subjects.  
 
Given the anticipated overdispersion of the primary outcome (i.e., difference in total HF-attributable direct 
medical costs), we will employ adaptive trial design procedures for sample size re-estimation.  This adaptive-total 
information criterion approach was taken due to the risk of incorrectly estimating the sample size due to 
misspecification of the cost outcome parameters. By using the adaptive sample size design, which includes no 
penalty for repeated interim analysis, the final sample size will be sufficient to provide adequate power to test the 
stated hypothesis.   
This will include re-assessment of the sample size at N=34 in the Furoscix cohort by using a group sequential design 
and testing to allow for stopping. It is not expected that the sample size for the Furoscix Infusor arm would exceed 
N=75, but the maximum value cannot be definitively stated until the analysis at N=34 is completed.  
 
 
We will explore ratios ranging from 1:1 to 4:1 for the number of historical controls to be matched to Furoscix-
treated patients using methods reported by Millar and Pasta 2010. The simulations will be used to find the 
matching ratio at which the level of precision is optimized without biasing the variance of the outcome measure. 
Additional methodological details are described in the prespecified statistical analysis plan. 
 
The methodology by which the sample size will be re-estimated and stopping rules will be implemented will be 
detailed in the statistical analysis plan. 
 
 
 
Baseline Characteristics and Subject Disposition 
 
Overall Baseline and demographic data will be summarized using descriptive statistics. Subject disposition (e.g., the 
number of Subjects enrolled, completed, and discontinued) will be summarized and medical history data will be 
listed.  
 
 
Endpoint Analyses 
 
Full descriptions of statistical assessments for primary and secondary endpoints are given in a separate statistical 
analysis plan. Included herein are brief descriptions. 
 
8.3.1.   
Primary Endpoint  
 
The primary endpoint analysis will compare the difference in the overall and heart failure related healthcare costs 
between subjects treated with the Furoscix Infusor 30 days post discharge from the emergency department for 
worsening heart failure due to fluid overload with propensity score matched controls treated in the hospital for ≤ 
72 hours through 30 days post discharge. Propensity scoring methods will be described in the statistical analysis 
plan. Comparison of these data between the matched (paired) cohorts will be conducted via a t-test or a Wilcoxon 
signed-rank test depending on distribution of data. 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
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8.3.2.   
Secondary Endpoints 
 
Outcomes for the endpoints related to healthcare resource utilization (i.e., Secondary Endpoints 1-4) will be 
evaluated by appropriate statistical test dependent on the distribution of the outcome. Health-related quality of 
life outcomes will be evaluated for the Furoscix cohort only and will descriptively compare KCCQ-12 questionnaire 
responses at Day 0 versus Day 30. Change in BNP or NT-proBNP will be evaluated for the Furoscix cohort only and 
will descriptively compare values obtained at Day 0 versus Day 30.  Subject and/or caregiver satisfaction with 
Furoscix Infusor will be descriptive.   
 
 
Safety Analyses 
 
There are no pre-planned analyses to compare Furoscix versus hospitalized cohort on the basis of safety. However, 
the safety of Furoscix will be monitored during the trial, and identified safety issues (including AEs, SAEs, and 
adverse reactions) will be summarized descriptively for the Furoscix cohort. 
 
The incidence (number and percentage of subjects) of adverse events will be presented overall and by MedDRA 
System Organ Class and Preferred Term for the Furoscix cohort. Reactions at the infusion site and frequency of 
these reactions will be reported. This analysis will be repeated for serious adverse events, for treatment-related 
adverse events, and for adverse events leading to premature study withdrawal. 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
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9.   
RESPONSIBILITIES 
 
 
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), International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use 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. For studies conducted under a United States investigational new drug application, 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. 
This study is also subject to and will be conducted in compliance with 21 CFR, part 320, 1993, “Retention of 
Bioavailability and Bioequivalence Testing Samples.” 
 
9.1.2.   
Institutional Review Board and Independent Ethics Committee 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 institutional review board or independent ethics committee. Approval from these bodies 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 will be submitted to these bodies 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 a 
consent form approved by the institutional review board for documenting written informed consent. Each 
completed 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 
 
All information about the nature of the proposed investigation provided by the Sponsor or study monitor to the 
Principal Investigator (with the exception of information required by law or regulations to be disclosed to the 
institutional review board, the Subject, or the appropriate regulatory authority) must be kept in confidence by the 
Principal Investigator. 
 
The Investigator will 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 institutional review board. The Investigator must keep a 
Subject log showing codes and, names, for all enrolled in the trial. 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
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9.1.5.   
Compensation, Insurance, and Indemnity 
 
Information regarding compensation, insurance, and indemnity is addressed in the Clinical Trial Research 
Agreement. 
 
9.1.6.   
Study Files and Retention of Records 
 
The Investigator will 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 including (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, approval by the 
institutional review board 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, 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 region (i.e., United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in the region(s); or, until two years 
after the investigational new drug 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. 
 
9.1.7.   
Case Report Forms 
 
For each subject who signs informed consent, a CRF must be completed and signed 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 AE, thorough efforts should be made 
to clearly document the outcome. 
 
9.1.8.   
Protocol Deviations 
 
If a situation requires a deviation from the Clinical Study Protocol, the Principal Investigator or other investigator in 
attendance will contact the Medical Monitor as soon as possible in order to discuss the situation and agree on an 
appropriate course of action. If possible, the Principal Investigator or designee will contact the Medical Monitor 
prior to making the deviation. Any departure from the Clinical Study Protocol together with the rationale for the 
deviation must be recorded on the CRF and source document. 
 
9.1.9.   
Disclosure of Data 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 50 of 51 
The Principal Investigator agrees by his/her participation that the results of this study may be used for submission 
to national and/or international registration and supervising authorities. If required, these authorities will be 
provided with the name of the Principal Investigator, their addresses, qualifications and extent of involvement. It is 
understood that the Principal Investigator is required to provide scPharmaceuticals with all study data, complete 
reports, and access to all study records.  
 
Data generated by this study must be available for inspection by the Food and Drug Administration, by 
scPharmaceuticals and its designees, and the institutional review board as appropriate. At a Subject’s request, 
medical information may be given to his or her personal physician or other appropriate medical personnel 
responsible for his or her welfare. Subject medical information obtained during the course of this study is 
confidential and disclosure to third parties other than those noted above is prohibited. 
 
9.1.10.   
Financial Disclosure 
 
The United States Food and Drug Administration Financial Disclosure by Clinical Investigators (21 CFR 54) 
regulations require Sponsors to obtain certain financial information from Investigators participating in covered 
clinical studies; each Principal Investigator and Sub-investigator is required to provide the required financial 
information and to promptly update scPharmaceuticals with any relevant changes to their financial information 
throughout the course of the clinical study and for up to 1 year after its completion. This rule applies to all Principal 
Investigators and Sub-investigators participating in covered clinical studies to be submitted to the Food and Drug 
Administration in support of an application for market approval. 
 
9.1.11.   
Drug and Device Product Accountability 
 
The Investigator or designee is responsible for ensuring adequate accountability of all used and unused study 
product. This includes acknowledgment of receipt of each shipment of study product (quantity and condition) and 
Subject dispensing records and returned 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 the end of the study, following final product reconciliation by the monitor, the study site will be instructed by 
the Sponsor to return all unused study product supplies. 
 
9.1.12.   
Inspections 
 
The Investigator will provide access to source documents and all study records for this trial to appropriately 
qualified personnel from scPharmaceuticals or its representatives, and to regulatory authority inspectors. 
 
 
Sponsor Responsibilities 
 
9.2.1.   
Study Materials and Instructions 
 
It is the Sponsor’s responsibility to ensure that the Investigator is provided with the documents and other study 
materials necessary to conduct the study. Examples of those materials include, but are not limited to: protocol, 
Investigator’s Brochure, study product, CRF, logs, etc. The Sponsor will also provide training and oversight through 
site and medical monitoring. 
 
9.2.2.   
Protocol Modifications 
 

scPharmaceuticals Inc. 
 
 
FREEDOM-HF 
Protocol Number: scP-01-005 
_____________________________________________________________________________________________ 
 
 
 
_____________________________________________________________________________________________ 
 
CONFIDENTIAL |February 2, 2021 
 
Page 51 of 51 
Protocol modifications, except those intended to reduce immediate risk to study Subjects, will be made by 
Sponsor-initiated amendment. Approval from an institutional review board must be obtained before changes can 
be implemented. 
 
Note that this provision does not apply to early stopping or sample size increases that are governed by the 
adaptive nature of the clinical trial design.  
 
 
Joint Investigator and Sponsor Responsibilities 
 
9.3.1.   
Access to Information for Monitoring 
 
In accordance with International Conference on Harmonization Good Clinical Practice guidelines, the study 
monitor must have direct access to the Investigator’s source documentation in order to verify the data recorded in 
the CRF for consistency. 
 
The monitor is responsible for routine review of the CRF at regular intervals throughout the study, to verify 
adherence to the protocol, and the completeness, consistency and accuracy of the data being entered. The 
monitor should have access to any Subject records needed to verify the entries on the CRF. The Investigator agrees 
to cooperate with the monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
 
9.3.2.   
Study Discontinuation 
 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. Should this be 
necessary, both parties will arrange discontinuation procedures and notify the appropriate regulatory authorities 
and institutional review board(s). In terminating the study, the Sponsor and the Investigator will assure that 
adequate consideration is given to the protection of the Subjects’ interests. 
 
Note that this provision does not apply to early stopping or sample size increases that are governed by the 
adaptive nature of the clinical trial design.