Torsemide Comparison With Furosemide for Management of Patients With Stable Heart Failure
Phase: PHASE3
Conditions: Heart Failure
Sponsor: Yale University

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CLINICAL STUDY PROTOCOL
Interventional Drug or Biologic
 
Torsemide comparison with Furosemide 
for management of patients with stable 
heart failure
 Protocol Number 
HIC 2000029589
Protocol Version 
06/02/2021
Version 4
PRINCIPAL INVESTIGATOR:
Name: Jeffrey Testani, MD. MTR.
Department: Internal Medicine - Cardiology
Telephone Number: (203)-737-6226
Email Address: Jeffrey.testani@yale.edu
IND Number: N/A
IND Holder: N/A 
NCT Number: Study 
Phase 0
Confidentiality Statement:
REVISION HISTORY:
Revision #
Version Date
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APPROVED BY THE YALE UNIVERSITY IRB 6/11/2021APPROVED BY THE YALE UNIVERSITY 
IRB 4/21/2021
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Synopsis
Primary Objective
The primary objective of this study is to compare the effects of two standard of care loop 
diuretics (furosemide versus torsemide) on clinical outcomes among patients currently on a 
stable dose of loop diuretics. All patients will be followed for one year.
Our primary hypothesis is that torsemide will improve clinical outcomes when compared to 
furosemide. 
Secondary Objective (if applicable)
Secondary objectives of this protocol will be to examine the effect of torsemide versus 
furosemide for the following endpoints:
All-cause mortality or all-cause hospitalization over one year
Total hospitalizations over one year
Change in weight over one year
Study Duration 
Subject enrollment is planned to last 4 years. Completion of enrollment, statistical analysis, and 
publication is planned to be complete within 6 years.
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Study Design
This study will be a randomized, unblinded, two-arm, multi-center clinical trial of patients receiving 
loop diuretics for treatment of heart failure in an outpatient clinic. This study will serve as 
additional enrollment for Cardio-Renal Effects of Torsemide vs. Furosemide: A TRANSFORMHF 
Mechanistic Sub-Study (HIC 2000025867) which is currently only enrolling patients admitted to 
the hospital for worsening heart failure. Thus allowing for expanded enrollment into HIC 
2000025867 with a more diverse group of heart failure patients. Participants will be co-enrolled 
into this study and HIC 2000025867. 
Patients will be randomized 1:1 to either oral torsemide OR oral furosemide (dosing at discretion 
of local provider with dose equivalency guidance provided). This study will include stable 
subjects seen at the outpatient setting. The initial and follow-up dosing of torsemide and 
furosemide will be at healthcare provider discretion, with the following conversion provided as a 
guide: 1 mg torsemide to 2-4 mg oral furosemide. For instance, a patient would receive 
torsemide 20mg or furosemide 40-80 mg. Providers will be asked to document their planned 
initial dose and dosing frequency of torsemide and furosemide
Randomization will occur within thirty days  after the consent process and at the discretion of the 
healthcare provider and research team. Following randomization, the study medication is 
expected to constitute the oral diuretic therapy for one year. Patients will be prescribed the 
randomized study medication on the day of randomization.
Dose adjustments will be at the discretion of the treating healthcare provider(s) with strategies in 
place to maintain prescription of and adherence to the randomized medication. All patients will 
have 30-day, and 12-month post-randomization phone contacts for assessment of vital status, 
interval hospitalizations, concomitant HF medications, adherence, and weight.
To achieve these goals, we propose a multi-center 125-patient study that will also co-enroll into 
Transform Ancillary (HIC 2000025867) a mechanistic sub-study of this study and 
TRANSFORMHF. 
Number of Study Sites
 Three
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Study Population
The population will enroll participants that are being treated in YNHH outpatient clinics for heart 
failure. Eligible patients will be under the care of Yale cardiologists or heart failure clinicians at 
an outpatient clinic. The diagnosis of heart failure utilized will be the responsibility of the treating 
clinician.
Number of Participants
The overall enrollment goal for all sites is 125 participants.  The enrollment goal for the 
University of Utah is 25 participants.  The enrollment goal for Yale University is 100 participants. 
Primary Outcome Variables
All-cause mortality 
Secondary and Exploratory Outcome Variables (if applicable)
All-cause mortality or all-cause hospitalization over one year
Total hospitalizations over one year
Change in weight 
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Contents
Synopsis ..................................................................................................................................3
1
Introduction.......................................................................................................................8
1.1
Introductory 
Statement....................................................................................................8
2
Background.......................................................................................................................8
2.1.1
Preclinical Experience........................................................................................8
2.1.2
Clinical Experience.............................................................................................8
3
Rationale/Significance ....................................................................................................9
3.1
Problem 
Statement....................................................................................................... 9
3.2
Purpose of Study/Potential 
Impact................................................................................ 9
3.2.1
Potential 
Risks..................................................................................................9
3.2.3
Alternatives.......................................................................................................11
3.2.4
Payments for Participation (Economic Considerations)...................................11
3.2.5
In Case of Injury...............................................................................................11
4
Study Objectives.............................................................................................................12
4.1
Hypothesis........................................................................................................... 
..........12
4.2
Primary 
Objective....................................................................................................12 
Secondary Objectives (if 
applicable)..............................................................................................................12
4.3
Exploratory Objectives (if 
applicable)...........................................................................12
N/A.....................................................................................................................................12
5
Study Design .................................................................................................................13
5.1
General Design 
Description..........................................................................................13
5.1.1
Study Date Range and 
Duration......................................................................13
5.1.2
Number of Study 
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Sites.....................................................................................13
5.2
Outcome 
Variables........................................................................................................13
5.2.1
Primary Outcome 
Variables.............................................................................13
5.2.2
Secondary Outcome Variables (if 
applicable)..................................................13
5.3
Study Population 
..........................................................................................................14
6
Methods..........................................................................................................................15
6.1
Treatment............................................................................................................
..........15
6.1.1
Identity of Investigational 
Product....................................................................15
6.1.2
Dosage, Administration, 
Schedule...................................................................15
6.1.3
Method of 
Assignment/Randomization.............................................................15
6.1.4
Blinding and Procedures for 
Unblinding...........................................................16
6.1.5
Packaging/Labelling............................................................................. 
............16
6.1.6
Storage 
Conditions...........................................................................................
16
6.1.7
Concomitant 
therapy........................................................................................16
6.1.8
Restrictions........................................................................................... 
............16
6.2
Assessments.......................................................................................................
..........16
6.2.1
Efficacy................................................................................................. 
............16
6.2.2
Safety and Pregnancy-related 
policy................................................................16
6.2.3
Adverse Events Definition and 
Reporting.........................................................16
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6.2.4
Pharmacokinetics (if 
applicable).......................................................................19
6.2.5
Biomarkers (if 
applicable).................................................................................19
6.3
Study 
Procedures..........................................................................................................
19
6.3.1
Study 
Schedule..............................................................................................
..19
6.3.2
Informed 
Consent.............................................................................................2
0
6.3.3
Screening............................................................................................. 
............20
6.3.4
Enrollment   
............................................................................................................
21
6.3.5
On Study 
Visits.................................................................................................21
6.3.6
End of Study and Follow-
up.............................................................................21
6.3.7
Removal of 
subjects.........................................................................................22
6.4
Statistical 
Method..........................................................................................................22
6.4.1
Sample Size 
Considerations............................................................................22
6.5
Planned 
Analyses.........................................................................................................23
6.5.1
Primary Objective 
Analysis...............................................................................23
6.5.2
Secondary Objectives 
Analyses.......................................................................23
6.5.3
Exploratory Objectives Analyses (if 
applicable)...............................................24
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6.5.4
Safety................................................................................................... 
............24
6.5.5
Analysis of Subject 
Characteristics..................................................................24
6.5.6
Interim Analysis (if 
applicable)..........................................................................24
6.5.7
Health economic 
evaluation.............................................................................24
6.5.8
Other.................................................................................................... 
............24
6.5.9
Subsets and 
Covariates...................................................................................24
6.5.10
Handling of Missing 
Data.................................................................................24
7
Trial Administration.........................................................................................................25
7.1
Ethical Considerations: Informed Consent/Assent and HIPAA 
Authorization...............25
7.2
Institutional Review Board (IRB) 
Review......................................................................26
7.3
Subject 
Confidentiality..................................................................................................26
7.4
Deviations/Unanticipated 
Problems.............................................................................26
7.5
Data 
Collection.............................................................................................................
26
7.6
Data Quality 
Assurance................................................................................................27
7.7
Study 
Records..............................................................................................................
27
7.8
Access to Source 
Documents......................................................................................27
7.9
Data or Specimen 
Storage/Security.............................................................................27
7.10
Retention of 
Records...................................................................................................28
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7.11
Study 
Monitoring..........................................................................................................2
8 
Data Safety Monitoring Plan .......................................................................................28
7.12
............................................................................................................................. 
....... 28
7.13
Study 
Modification........................................................................................................2
9
7.14
Study 
Discontinuation..................................................................................................2
9
7.15
Study 
Completion.........................................................................................................2
9
7.16
Conflict of Interest 
Policy..............................................................................................29
7.17
Funding 
Source............................................................................................................29
7.18
Publication 
Plan............................................................................................................30
8
Appendices.....................................................................................................................32
9
List of Tables ..................................................................................................................33
1 Introduction
1.1
Introductory Statement
This document is a protocol for a human research study. The purpose of this protocol is to 
ensure that this study is to be conducted according to (International Conference on 
Harmonisation-Good Clinical Practice) ICH GCP guidelines, and according to CFR 21 Part 
312, other applicable government regulations and Institutional research policies and 
procedures.
2 Background
2.1.1
Preclinical Experience
Preclinical and clinical data support the benefits of torsemide over furosemide. Compared 
with furosemide, torsemide has increased bioavailability and a longer half-life with 
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maintained absorption in the setting of oral intake.1 Torsemide also has beneficial effects on 
myocardial fibrosis, aldosterone production, sympathetic activation, ventricular remodeling 
and natriuretic peptide levels.2-6 Several small studies of torsemide vs. furosemide and two 
recent meta-analyses suggest a substantial decrease in heart failure morbidity and 
potentially mortality with torsemide compared to furosemide 7,8-10.
2.1.2
Clinical Experience
Background/prevalence of research topic 
Nearly 7 million Americans are affected with heart failure (HF), and its prevalence is 
expected to increase to nearly 10 million by 2030.11 At age 40, an American’s lifetime risk of 
developing HF is 1 in 5.11 HF causes tremendous morbidity and mortality, with over 1 million 
hospitalizations in the U.S. each year and with HF listed on 1 in 9 death certificates 
respectively.11 While HF is generally regarded as the inability of the heart to pump sufficient 
blood, on a population level,  congestion is the primary driver of symptoms leading to 
hospitalization.12-15
Strategies to treat and prevent fluid/sodium retention have not changed significantly since 
the 1960’s with the introduction of loop diuretics. Despite the fact that loop diuretics are 
central to our therapy in HF, they are paradoxically one of the least well-studied classes of 
HF medications.
Torsemide has theoretical pharmacokinetic (PK) advantages to furosemide: Furosemide is 
currently the mostly commonly prescribed loop diuretic but it has erratic absorption, with 
bioavailability reported to range from 10%.  to 100%.16,17 Additionally, even if total 
absorption is constant, the peak serum concentration can vary widely based on the prandial 
and clinical status of the patient18,19 Since, loop diuretics require a minimal threshold 
concentration to induce natriuresis, even with identical bioavailability, slow absorption can 
limit the time above the renal threshold and result in minimal natriuresis. Importantly, the 
variability in absorption occurs both on an inter- and intra-patient level. For instance, factors 
such as a large meal (i.e., sodium load) or bowel edema (i.e., progressive volume retention) 
can adversely alter furosemide PK parameters, when it is most important the diuretic is 
effective. Unlike furosemide, torsemide has consistent bioavailability of >80% and absorption 
kinetics are reproducible and typically approximate that of an intravenous 
diuretic.18,19Torsemide also has a significantly longer half-life in HF (~6 hours) compared to 
furosemide (~2.7 hours).17 The major reason that once daily furosemide is not effective as 
an antihypertensive is due to post diuretic sodium retention. When a short half-life diuretic 
(i.e., furosemide) wears off, the kidney is left unchecked to reabsorb sodium, and the 
quantity of excreted sodium during diuresis equals the quantity of sodium reabsorbed after 
the diuretic is cleared, resulting in no net loss of sodium. Given that torsemide has 
predictable bioavailability, absorption kinetics, and a relatively long half-life, the hypothesis 
follows that it could offer more consistent and superior control of volume status, thus 
improving outcomes such as death and rehospitalization.
The American College of Cardiology (ACC) and the American Heart Association (AHA) 
guidelines indicate that the optimal use of diuretics is the cornerstone of any successful 
approach to the treatment of heart failure.20 However, in light of the lack of an adequately 
powered study, there is insufficient evidence to conclude that torsemide should be 
recommended over furosemide in the management of heart failure.
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3 Rationale/Significance
3.1
Problem Statement
As heart failure cases continue to grow exponentially, patients are routinely placed on 
furosemide as a first line therapy, potentially delaying treatment with a more effective 
medication (Torsemide) to relieve their fluid congestion and help prevent further sequela of 
heart failure.
3.2
Purpose of Study/Potential Impact
This study is designed to be a prospective, randomized, comparative-effectiveness study to 
definitively compare torsemide with furosemide in heart failure patients. It is meant to serve 
as additional enrollment in Cardio-Renal Effects of Torsemide vs. Furosemide: A 
TRANSFORM-HF Mechanistic Sub-Study (HIC 2000025867) to broaden the heart failure 
population to include those that are more stable in their treatment. Patients will be coenrolled 
into this study and HIC 2000025867.
3.2.1
Potential Risks
This study will evaluate oral torsemide versus oral furosemide in patients with heart failure. 
Both torsemide and furosemide are currently used in routine clinical practice and are 
recommended by the current ACC/AHA heart failure guidelines. We therefore do not 
anticipate that participation in this study will be associated with increased risks beyond that 
of standard heart failure therapy. 
Furosemide: Risks include hepatic encephalopathy, oral and gastric irritation, cramping, 
pancreatitis, diarrhea/constipation, jaundice, increased liver enzymes, nausea, vomiting, 
anorexia, systemic vasculitis, tinnitus and hearing loss, leukopenia, thrombocytopenia, 
anemia, photosensitivity, drug rash, orthostatic hypotension, increase in cholesterol and 
triglyceride serum levels, hyperglycemia, restlessness, glycosuria, urinary bladder spasm, 
hyperuricemia, thrombophlebitis, severe anaphylaxis, interstitial nephritis, pruritis, 
paresthesias, headache, dizziness, vertigo, blurred vision, muscle spasm, fever, weakness. 
Torsemide: Risks include headache, excessive urination, dizziness, rhinitis, asthenia, 
diarrhea, ECG abnormality, cough Increase, constipation, nausea, leucopenia, 
thrombocytopenia, anemia, increase in liver transaminases, thiamine (B1) deficiency, 
hypotension, hypokalemia, hypomagnesemia, Hypocalcemia Hyperchloremic alkalosis, 
Hyperglycemia, Hyperuricemia Hyponatremia, Arthralgia, Dyspepsia Sore Throat, Myalgia 
Chest Pain, Insomnia Edema, Nervousness, Pancreatitis, Abdominal pain, Paresthesia, 
Confusion, Visual impairment, Loss of appetite, Stephens- Johnsons Syndrome), 
Photosensitivity (sensitivity to light), Pruritis(itchy), Acute urinary retention (urine in your 
bladder that you have not been able to pass), Tinnitus (ringing in your ears), Hearing loss, 
Severe renal impairment (loss of kidneys full ability to filter wastes and excess fluids from 
your blood, which are then excreted in your urine).
Data collection: We anticipate minimal risk related to collection of data from the clinical 
record, including paper charts, EMR, physical exams, and blood and urine samples. We also 
anticipate minimal risk associated with data entry into the electronic database, which is 
password-protected and stored on a secure server. 
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Urine collection for pregnancy test: There are virtually no risks to the patient related to 
urine collection. 
Minimizing Risks
Furosemide and Torsemide: Both diuretics are currently used in routine clinical practice 
and are recommended by the current ACC/AHA heart failure guidelines. We therefore do not 
anticipate that participation in this study will be associated with increased risks beyond that 
of standard heart failure therapy. 
Data collection: Identifying data will be available only to the study PI and study coordinator, 
and will be used only to facilitate medical record review, and prevent duplicate screenings of 
patients while looking for subjects to enroll in the study. All data sheets, electronic data 
entries, and laboratory samples will be labeled with a unique identifier code. These numbers 
will be unique to the patient and will be the common link between specimens and the data. 
No identifying data will be reported to the public or in any publications that may result from 
this research.
Urine collection for pregnancy testing: There is virtually no risk to the patient related to 
urine collection.
3.2.2 Potential Benefits
The drugs in this study are already used to treat heart failure and clinicians can prescribe 
either of these medications outside of this study. Therefore, this study will not directly benefit 
our subjects. However, it may help researchers learn about which diuretic is better at treating 
heart failure. The results of this study may benefit heart failure patients in the future.
3.2.3
Alternatives
Subjects can choose not to participate and continue receiving standard care from their 
treatment team.
3.2.4
Payments for Participation (Economic Considerations)
Subjects will be compensated 25 dollars for the first study visit and randomization. For each 
of the phone calls they will be compensated 10 dollars each, for a total study compensation 
of 45 dollars.
Payment will be in the form of a Bank of America prepaid card. No additional compensation 
will be given for transportation or parking.
3.2.5
In Case of Injury
a. Will medical treatment be available if research-related injury occurs? Yes. 
b. Where and from whom may treatment be obtained? Patient’s medical provider.
c. Are there any limits to the treatment being provided? Unknown. 
d. Who will pay for this treatment? Patient’s own insurance. 
e. How will the medical treatment be accessed by subjects? Through standard contact with 
their health care provider.
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4 Study Objectives
4.1
Hypothesis
Our primary hypothesis is that torsemide will improve clinical outcomes when compared to 
furosemide in a nonacute heart failure patient population.  
4.2
Primary Objective
The primary objective of this study is to compare the treatment strategy of torsemide versus 
furosemide on clinical outcomes after one year, among a more stable heart failure 
population. All patients will be followed for a up to one year. Outcomes will be collected at 
thirty (+2/-2) days and one year (+2/-2 days).
Secondary Objectives (if applicable)
Other secondary objectives of this protocol will be to examine the effect of torsemide versus 
furosemide for the following endpoints:
•
All-cause mortality or all-cause hospitalization over one year
•
Total hospitalizations over one year
•
Change in weight over one year
4.3
Exploratory Objectives (if applicable) N/A
5 Study Design
5.1
General Design Description
Study Design
This study will be a randomized, unblinded, two-arm, multi- center clinical trial of patients 
receiving loop diuretics for treatment of heart failure in an outpatient clinic. This study will serve 
as additional enrollment for Cardio-Renal Effects of Torsemide vs. Furosemide: A 
TRANSFORM-HF Mechanistic Sub-Study (HIC 2000025867) which is currently only enrolling 
patients admitted to the hospital for worsening heart failure. Thus allowing for expanded 
enrollment into HIC 2000025867 with a more diverse group of heart failure patients. 
Participants will be co-enrolled into this study and HIC 2000025867. 
Patients will be randomized 1:1 to either oral torsemide OR oral furosemide (dosing at 
discretion of local provider with dose equivalency guidance provided). This study will include 
stable subjects seen at the outpatient setting. The initial and follow-up dosing of torsemide 
and furosemide will be at healthcare provider discretion, with the following conversion 
provided as a guide: 1 mg torsemide to 2-4 mg oral furosemide. For instance, a patient 
would receive torsemide 20mg or furosemide 40-80 mg. Providers will be asked to document 
their planned initial dose and dosing frequency of torsemide and furosemide Randomization 
will occur within thirty days after the consent process and at the discretion of the healthcare 
provider and research team. Following randomization, the study medication is expected to 
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constitute the oral diuretic therapy for one year. Patients will be prescribed the randomized 
study medication on the day of randomization.
Dose adjustments will be at the discretion of the treating healthcare provider(s) with 
strategies in place to maintain prescription of and adherence to the randomized medication. 
All patients will have 30-day and 12-month post-randomization phone contacts for 
assessment of vital status, interval hospitalizations, concomitant HF medications, adherence, 
quality of life, and symptoms of depression.
5.1.1
Study Date Range and Duration
Participants will be enrolled for a period of one year and enrollment is planned to last 4 
years.  Completion of enrollment, statistical analysis, and publication is planned to be 
complete within 6 years.
5.1.2
Number of Study Sites
Three 
5.2
Outcome Variables
5.2.1
Primary Outcome Variables
All-cause mortality at one-year. This will be assessed at 30 days, and one year.
5.2.2
Secondary Outcome Variables (if applicable)
•
All-cause mortality or all-cause hospitalization over 12 months
•
Total hospitalizations over 12 months 
•
Change in weight 
5.3
Study Population
The study will be enrolling participants from YNHH outpatient clinics, or the Yale Transitional 
Care Clinic.  Eligible patients will have a diagnosis of heart failure and have a continued 
need for diuretic treatment as an outpatient.  The diagnosis of heart failure utilized will be the 
responsibility of the treating clinician.  Patients will be approached by study personnel as 
listed in the IRB which can include doctors, cardiac surgeons, residents, fellows, nurse 
practitioners, physician assistants, research assistants and registered nurses. All patients 
approached will be 18 years or older and capable of providing written, informed consent. The 
selection criteria below were designed to be inclusive and representative of the broad heart 
failure population in routine clinical practice
Recruitment Methods
5.3.0
Number of Participants
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The target enrollment for this study will be 125 participants across all sites.
Inclusion/ Exclusion Criteria
Inclusion
1) Patients with a diagnosis of heart failure and who have been on a stable dose of a 
diuretic for at least 30 days.
2) Plan for a daily outpatient oral loop diuretic regimen with anticipated need for long 
term loop diuretic use
3) ≥ 18 years of age
4) Signed informed consent
 Exclusion Criteria
1) End-stage renal disease requiring dialysis therapy
2) Inability or unwillingness to comply with the study requirements
3) History of heart transplant or actively listed for heart transplant
4) Implanted left ventricular assist device or implant anticipated <3 months
5) Pregnant or nursing women or women who are trying to conceive
6) Malignancy or other non-cardiac condition limiting life expectancy to <12 months
7) Known hypersensitivity to furosemide, torsemide, or related agents
6 Methods
6.1
Treatment 
This will be an unblinded, two-arm randomized outpatient clinical trial comparing oral 
torsemide and oral furosemide.
Prior studies have suggested oral torsemide has a relative potency 2-4 fold greater than oral 
furosemide per mg. The initial and follow-up dosing of torsemide and furosemide will be at 
healthcare provider discretion, with the following conversions provided as a guide: 1 mg oral 
torsemide = 2- 4 mg oral furosemide 1 mg oral or intravenous bumetanide = 40 mg oral 
furosemide. 
         
Prior to randomization, the starting dose of furosemide and torsemide will be documented by 
healthcare providers, with the intent that providers will initially order this dose of study 
medication after randomization. Patients will receive the randomized medication to be started 
the day of randomization (if they have not yet taken their current loop diuretic) or the 
following day. The randomized study medication dose adjustments will be at the discretion of 
the treating healthcare provider(s) with strategies in place to maintain adherence (if possible) 
to the randomized medication.
6.1.1
Identity of Investigational Product
FDA Approved oral Furosemide (Lasix) 
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FDA approved oral Torsemide (Demadex)
6.1.2
Dosage, Administration, Schedule 
The participant’s treating healthcare provider is responsible for dosage and the medication 
schedule. 
6.1.3
Method of Assignment/Randomization 
Among those meeting eligibility criteria, and after they are consented; the participants will be 
randomized in a 1:1 fashion to one of two treatment groups. Anticipated initial daily dosing 
regimens for oral torsemide and oral furosemide will be recorded by the study team for each 
patient prior to randomization. Patient treatment assignment will be generated using a simple 
randomization scheme (i.e. no stratification) given the open-label nature of the intervention to 
limit the potential bias due to predictable treatment assignment.
At the time of randomization, the following baseline characteristics should be documented: 
age, sex, race, ethnicity, ejection fraction (most recent by any modality), concomitant HF 
medications and other key baseline variables. Following randomization, study team will 
identify the treatment assignment and confirm with the patient and the treatment team the 
outpatient loop diuretic prescription and accessibility. 
6.1.4
Blinding and Procedures for Unblinding 
As this is a pragmatic trial with an objective primary endpoint, this study will be unblinded for 
patients, managing clinicians, and the study team.
6.1.5
Packaging/Labelling
After randomization, the participants will receive a prescription for the randomized 
medication through their treating healthcare provider. This prescription can be filled though 
the participants standard of care pharmacy. 
6.1.6
Storage Conditions
N/A
6.1.7
Concomitant therapy
There are no restrictions for concomitant therapy.
6.1.8
Restrictions
If after consent, the treating healthcare provider deems that the patient should not be 
randomized, at that time the patient would be considered a screen failure. If after 
randomization the participant’s randomized study medication is changed for any reason, the 
participant will be asked to continue with the follow up phone calls at thirty (+2/-2) days and 
one year (+2/-2) days.
6.2
Assessments
Participants of this trial will be called at the end of thirty (+2/-2) days and at one year (+2/-2 
days) to obtain subjective and objective data including how they are feeling, compliance to 
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their randomized study medication, if they have had any recent hospitalizations, and what 
their current weight is.  
6.2.1
Efficacy
Participants of this trial will be called at the end of thirty (+2/-2) days and at one year (+2/-2 
days).  During the two phone calls they will be asked how are they feeling, if they are still 
taking their randomized medication, if not why was it changed, and what their current weight 
is. If the participant is not able to be reached after three attempts, this information will be 
recorded from their EMR. 
6.2.2
Safety and Pregnancy-related policy
For participants under the age of 65 years old that have not had a documented 
hysterectomy, a point of care urine test will be performed prior to randomization. If the 
participant tests positive for pregnancy, they will be withdrawn from the study. 
6.2.3
Adverse Events Definition and Reporting
Data Safety Monitoring Plan: We believe this study presents greater than minimal risks to 
participants, as furosemide and torsemide used routinely are standard of care therapy.  
•
The principal investigator is responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency quarterly. 
During the review process the principal investigator will evaluate whether the study 
should continue unchanged, require modification/amendment, or close to enrollment.
•
The principal investigator and the Institutional Review Board (IRB) have the authority 
to stop or suspend the study or require modifications.
•
This protocol presents greater than minimal risks to the subjects and Unanticipated 
Problems Involving Risks to Subjects or Others (UPIRSOs), including adverse 
events, are not anticipated but may occur. In the unlikely event that such events 
occur, Reportable Events [which are events that are serious or life-threatening and 
unanticipated (or anticipated but occurring with a greater frequency than expected) 
and possibly, probably, or definitely related] or Unanticipated Problems Involving 
Risks to Subjects or Others that may require a temporary or permanent interruption 
of study activities will be reported immediately (if possible), followed by a written 
report within 5 calendar days of the Principal Investigator becoming aware of the 
event to the IRB (using the appropriate forms from the website) and any appropriate 
funding and regulatory agencies. The investigator will apprise fellow investigators 
and study personnel of all UPIRSOs and adverse events that occur during the 
conduct of this research project via email as they are reviewed by the principal 
investigator.
•
If children are involved, what is the investigator’s assessment of the overall risk level 
for the children participating in this study? N/A
•
For multi-site studies for which the Yale PI serves as the lead investigator: 
o
How will adverse events and unanticipated problems involving risks to 
subjects or others be reported, reviewed and managed? 
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Adverse events and unanticipated problems will be recorded 
and reported in accordance with local institutional and IRB 
policies.
o
What provisions are in place for management of interim results?
Given the observational nature of this study, no interim data 
analysis is planned.
o
What will the multi-site process be for protocol modifications? 
Modifications will be assessed for relevancy to the clinical site and 
for their impacts on the study design. When necessary, protocol 
modifications will be submitted in accordance with local IRB 
policy.
Definitions
Adverse event (AE) means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
An AE or suspected adverse reaction is considered “serious” (SAE) if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 
•
death, 
•
a life-threatening adverse event, 
•
inpatient hospitalization or prolongation of existing hospitalization, 
•
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
•
a congenital anomaly/birth defect, or
•
An important medical event that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse.
Severity
Adverse events will be graded according to [name grading scale, e.g. CTCAE v5.0]. For AEs 
not included in the protocol defined grading system, the following guidelines will be used to 
describe severity. 
•
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially 
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lifethreatening or incapacitating.  Of note, the term “severe” does not necessarily 
equate to “serious”.]
Relationship to Investigational Product
All AEs must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. 
In a clinical trial, the study product must always be suspect.
•
Definitely Related – There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including an 
abnormal laboratory test result, occurs in a plausible time relationship to study 
intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if 
necessary.
•
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.
•
Potentially Related – There is some evidence to suggest a causal relationship (e.g., 
the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as 
appropriate.
•
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments).
•
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There 
must be an alternative, definitive etiology documented by the clinician.
Expectedness
The Principal Investigator will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study 
intervention.
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Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs), including adverse 
events, are not anticipated but may occur. In the unlikely event that such events occur, 
Reportable Events [which are events that are serious or life-threatening and unanticipated 
(or anticipated but occurring with a greater frequency than expected) and possibly, probably, 
or definitely related] or Unanticipated Problems Involving Risks to Subjects or Others that 
may require a temporary or permanent interruption of study activities will be reported 
immediately (if possible), followed by a written report within 5 calendar days of the Principal 
Investigator becoming aware of the event to the IRB (using the appropriate forms from the 
website) and any appropriate funding and regulatory agencies. The investigator will apprise 
fellow investigators and study personnel of all UPIRSOs and adverse events that occur 
during the conduct of this research project via email as they are reviewed by the principal 
investigator.
6.2.4
Pharmacokinetics (if applicable)
N/A
6.2.5
Biomarkers (if applicable)
N/A
6.3
Study Procedures
1.
Enrollment: Patients that meet inclusion/exclusion criteria will be approached during 
their visit at YNHH outpatient clinics or in the TCC.  If they agree to participate, the 
patient will sign an Informed Consent form prior to any study procedures taking 
place.  
2.
Prior to randomization and small urine sample will be collected from any female 
participant who is under the age of 65 and has not had a hysterectomy.  A point of 
care urine test will be performed. 
3.
After consenting and the point of care urine test the participant will be randomized to 
one of the two loop diuretic treatment groups.
4.
The study team will work with the treating healthcare provider to ensure that the 
participant receives a prescription for their randomized therapy. 
6.3.1
Study Schedule
Once the participant is consented and after a negative point of care urine pregnancy test (as 
explained in 6.3), they will be randomized to one of the two treatment groups. Assessments 
of primary and secondary outcomes will occur as follows:
•
30 (±2) days: Patients will be contacted to document vital status, medication 
adherence, concomitant HF medications, weight change, and to capture 
hospitalization information. 
•
12 months (±2 days): Patients will be contacted to document vital status, medication 
adherence, concomitant HF medications, weight change, and to capture 
hospitalization information.
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6.3.2
Informed Consent
Proper written, informed consent and HIPAA authorization will be obtained prior to patient 
participation in this trial. The overall protocol (including objectives, procedures and duration), 
potential risks and benefits, voluntary nature and ability to withdraw will be discussed with 
each patient. The patient will be given a copy of the IRB-approved ICF to review and will 
have all questions answered before being asked to sign the informed consent form (ICF). 
Verification of comprehension of the consent will be obtained by asking the subject to 
describe in their words the purpose and risks of the study. The patient will be instructed that 
his or her care will not be affected by his or her decision to participate, or not. If the patient 
voluntarily agrees to participate in the trial, he or she will be asked to sign the ICF. The 
original ICF will be kept with the study documents and a copy will be made for the patient’s 
chart. The subject will be given a signed copy of the ICF and HIPAA authorization form. All 
study subjects will be 18 years or older, with the capacity and ability to provide informed 
consent, thus making parental or surrogate permission not applicable. 
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Based on treating 
clinicians’ recommendations regarding appropriate patients who have agreed to be 
approached about a potential research study will be screened within EPIC for study eligibility, 
including mental status and ability to provide informed consent. Study coordinators will 
confirm with the patient’s provider that the patient has the requisite ability and capacity to 
give informed consent prior to approaching the patient regarding the study. If at any time 
during the study there is concern regarding a patient’s mental status, study staff will both 
notify the patient’s RN and provider, and reevaluate whether the patient is still appropriate for 
participation in the study. After the study objectives and procedures are explained to the 
subject, they will be asked to describe in their words what the purpose and risks of the study. 
are. 
6.3.3
Screening
Potential subjects will be identified by study coordinators in conjunction with treating 
clinicians by screening the EMR of patients with a clinical diagnosis of HF receiving 
outpatient loop diuretics. Patients whose providers feel they are appropriate for the study will 
be approached. Pursuant to HIPAA regulations, a log of disclosures of protected health 
information for recruitment/screening purposes will be kept.
Any participant that has a positive point of care urine pregnancy test will be withdrawn from 
the study. Any participant that becomes pregnant during the study will be withdrawn from the 
study. Any participant that has their randomized study medication changed over the course 
of the year will be asked to continue with their study participation. 
Participants will have the option to select whether they are interested in hearing about future 
heart failure studies. Locating stable heart failure patients who are on a stable dose of loop 
diuretics can be difficult, and the inclusion/ exclusion criteria aligns with the majority of our 
ongoing and future research projects.
6.3.4
Enrollment 
The PI or study coordinators will first approach the treating clinician (e.g. physician, nurse 
practitioner, or physician’s assistant) regarding possible involvement in the study. If the 
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provider feels the patient is appropriate for the study, the participant will be approached and 
then asked if they would like to participate.  The study team always asks permission from the 
treating healthcare provider to enroll and randomize a participant. 
Participants who meet all eligibility for enrollment will be approached by trained study 
coordinators either in-person during a clinic visit or by phone / SMS / E-mail.  Study 
coordinators will provide a brief description of the study and confirm eligibility.  
Eligible patients who have been missed during an in-clinic visit will be contacted by one of 
the study coordinators by phone.  This may be via a phone call or, if unable to reach the 
patient, via text messaging and/or via e-email through a MyChart message.  The following 
text messaging script will be sent to an eligible patient:
“You have been selected by your Yale physician to participate in our Yale Heart 
Failure ‘TRANFORM’ Study.  If eligible, you will be:

Compensated for your time

Helping us determine the most beneficial diuretic treatment to offer 
HF patients
We need your help!  A study team member will be reaching out shortly to provide 
you with more information.  If you have any questions, you can also respond to this 
text.”
The following MyChart message will be sent:
“If you attend one of Yale’s Congestive Heart Failure Clinics and are at least 18 
years of age with heart failure and taking a loop diuretic such as Furosemide or 
Torsemide, you may be eligible to participate in a free and confidential research 
study investigating the use of loop diuretics in heart failure.  If you enroll, you will be 
compensated up to $850 for your time and participation.  To learn more or see if 
you are eligible to participate, click on “I am interested” or call the Yale Heart Failure 
Study line at 203-737-6226.  
No action by you is required.  You may ignore this message or click “not interested.”  
Thank you very much for considering being a part of research at Yale. 
To learn more about future research opportunities, you may also create a volunteer 
profile through the “Research Tab” in MyChart.
To opt-out of all future research communications, please call the Yale Clinical Trials 
Office at 1-877-978-8343 and select option 3.”  
During an enrollment phone call, the coordinator will discuss the study and instruct the 
patient through the enrollment process outlined above.  The patient will access our study 
website through a link that will be sent to them via email, text message, or other electronic 
means acceptable to the potential enrollee, 
Informational issued flyers will also distributed to Yale Cardiology clinics. Patients who are 
interested in participating in the research study will be able to contact the research team with 
the number provided to receive more information. 
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Enrollment and randomization will take place after a patient has been seen by their 
healthcare provider in the outpatient setting. Thus, the patient’s healthcare provider will have 
assessed the patient’s clinical status and will be able to determine their eligibility and 
suitability for study participation with consideration of the previously defined enrollment 
criteria (see section 5.3.0). The study team will contact the providers of potential patients 
who have been identified via screening of the electronic medical record either in advance of 
the patient’s scheduled clinic visit or in the clinic at the time of the patient’s visit. The details 
of the study and enrollment criteria will be discussed with the provider in order for the 
provider to make an informed decision of the patient’s suitability for the study. Patients 
whose provider feels they are not appropriate for the study will not be approached for 
enrollment into the study. 
6.3.5
On Study Visits
Randomization
•
Prior to randomization any female participant that is 65 years old or younger, who 
has not had a hysterectomy, will be asked to produce a small urine sample that will 
only be used for a point of care pregnancy test. 
•
After confirmation from the treating healthcare provider that the participant is safe to 
randomize, the potential doses for furosemide and torsemide will be collected.
•
The participant will be randomized in a secure database (Yale REDCap).  After 
randomization, the treating healthcare provider and the participant will be notified of 
the treatment assignment. 
•
The treating healthcare provider will be asked to place an order for the assigned 
treatment therapy.
•
The study team will ensure that the randomized study medication has been 
prescribed and that the participant has been able to attain the medication from their 
pharmacy.
6.3.6
End of Study and Follow-up
The participant will be called at 30 days (+2/ -2 days) to assess for any adverse events, to 
see how they are feeling, their current weight, if they are still taking the randomized study 
medication, and any hospitalizations during the study period.  If the participant is unable to 
be reached by phone (after three attempts) the study team will conduct a medical record 
review to assess for the participant’s health status and obtain the required data.
The final phone call will take place one year from randomization (+2/-2 days) to assess for 
any adverse events, to see how they are feeling, their current weight, if they are still taking 
the randomized study medication, and any hospitalizations during the study period. If the 
participant is unable to be reached by phone (after three attempts) the study team will 
conduct a medical record review to assess for the participant’s health status and obtain the 
required data. 
6.3.7
Removal of subjects
Participants will be withdrawn from the study if:
•
Tests positive for pregnancy prior to randomization. 
•
Becomes pregnant while on study. 
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•
Significant study intervention non-compliance is observed. 
•
Any clinical adverse event, laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the 
best interest of the participant. 
•
Disease progression which requires discontinuation of the study intervention occurs. 
•
The participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation
Continuation of Drug Therapy After Study Closure: Both possible randomized treatments are 
standard of care therapy. While the participant will no longer be required to take the study 
medication as part of the study, it will be at the discretion of their treating healthcare provider 
whether to continue the patient on the randomized treatment.   
6.4
Statistical Method 
Statistical Design
This will be a randomized, parallel-arm, controlled trial. Randomization will occur at the 
patient level with no blocks of stratification. Treatment factor will include two levels: 
furosemide vs torsemide. 
This study will serve as additional enrollment for the “Cardio-Renal Effects of Torsemide vs. 
Furosemide: A TRANSFORM-HF Mechanistic Sub-Study” (HIC 2000025867), which is 
currently only enrolling patients admitted to the hospital for worsening heart failure. Thus, the 
present study will allow for expanded enrollment into HIC 2000025867 with a more diverse 
group of heart failure patients. Therefore, sections 6.4.1. to 6.5.10 were based on the 
“CardioRenal Effects of Torsemide vs. Furosemide: A TRANSFORM-HF Mechanistic 
SubStudy” (HIC 2000025867). 
6.4.1
Sample Size Considerations
The present study is thought to potentially be part of the “ToRsemide compArisoN with 
furoSemide FOR Management of Heart Failure” (TRANSFORM-HF, NCT03296813). For that 
study, sample size was estimated as 721 events (approximately 6000 patients) assuming a 
hazard ratio of 0.80 and a power of 85%. Given that it is unlikely that the present study will 
enroll so many patients, and patients enrolled in the present study will also be coenrolled in 
the “Cardio-Renal Effects of Torsemide vs. Furosemide: A TRANSFORM-HF Mechanistic 
Sub-Study (HIC 2000025867)”, we calculated sample size based on the later study (see 
below).    
In the “Cardio-Renal Effects of Torsemide vs. Furosemide: A TRANSFORM-HF Mechanistic 
Sub-Study (HIC 2000025867)” , the endpoint change in plasma volume has the largest 
number of causal inputs and thus will be expected to drive the sample size requirement. The 
change in plasma volume in real world hospitalized patients undergoing several days of IV 
diuresis was reported by Miller and Mullan to be on average -0.5L, with a standard deviation 
of 0.8L.41 Notably, the vast majority of those patients were discharged with a substantially 
expanded blood volume, leaving room for additional improvement in TRANSFORM-HF.41 
The correlation between pre and post treatment blood volumes was high at r=0.87 (personal 
communication with Dr. Miller). A clinically relevant difference in the current proposed study 
would be a ≥300cc change in plasma volume. Of note, this small magnitude of change is 
similar  to that observed in patients that hemoconcentrate, a finding associated with 
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improved survival.42-47 The test related coefficient of variation of plasma volume 
determined by I-131 albumin is small (~2%) and the within subject correlation of serial 
plasma volume measures before and after treatment is high (i.e., r>0.9 is expected in this 
study).48 Given that the present study will include stable outpatients, we expect the standard 
deviation in blood volume from randomization to 30 days will be significantly less than the 
0.8L seen in the acute hospitalized setting where a much greater degree of treatment 
heterogeneity exists. As such, with a sample size of 125 patients (62 per group) we will have 
>80% power to detect a difference in mean changes between groups of >26.5% between 
groups. (Calculated using PASS version 15.0.5 using Tests for Two Groups of PrePost 
Scores with an assumed correlation of r=0.9 within subject, an alpha of 0.05 using a 
twosided, two sample t-test). 
6.5
Planned Analyses
6.5.1
Primary Objective Analysis
The statistical comparison of the two randomized arms with respect to the primary endpoint 
will be a time-to-event analysis, and therefore will be based on the time from randomization 
to mortality. The Cox proportional hazards regression model will be the primary tool to 
analyze and assess outcome differences between the two treatment arms. A hazard ratio 
and 95% confidence interval for summarizing the difference in outcomes between the two 
treatment arms will be computed using the Cox proportional hazards regression model. 
Covariates in the primary model will include the randomized treatment, age, sex, ejection 
fraction category, and loop diuretic treatment prior to index hospital admission.
6.5.2
Secondary Objectives Analyses
The analyses for the time-to-event secondary endpoints will be similar to those outlined for 
the primary endpoint using the time from randomization through the first occurrence of any 
component of a specific secondary endpoint (or censoring) as the response variable, and 
assessing group differences using the Cox proportional hazards model.
With regards to the “Cardio-Renal Effects of Torsemide vs. Furosemide: A TRANSFORM-HF 
Mechanistic Sub-Study” (HIC 2000025867), treatment factor will include two levels: 
Furosemide vs Torsemide, and time will be included also as a main factor with two levels: 
baseline vs end of the intervention. Primary outcome variables (such as plasma volume) will 
be measured at baseline and at day 30. Repeated measures or “change” parameters will be 
analyzed via a linear mixed model (LMM)  (e.g., to estimate the changes in randomization to 
day 30 in plasma volume). 
6.5.3
Exploratory Objectives Analyses (if applicable)
N/A
6.5.4
Safety 
Participants enrolled in this study will receive one of two standard of care therapies for heart 
failure: furosemide or torsemide. The participant’s treating healthcare provider will be 
adjusting the dosing based on the participant’s presenting symptoms at their regularly 
scheduled visits.  At any point in time, the treating healthcare provider may stop the 
randomized therapy for the participant’s well-being if they deem it necessary. We will only be 
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monitoring their loop diuretic treatment through phone calls and chart reviews at 30 days and 
one year. 
6.5.5
Analysis of Subject Characteristics
Data that will be collected is: age, race, ethnicity, weight, height, ejection fraction, baseline 
medications, and past medical history.  
Continuous variables will be presented as mean ± standard deviation or median (interquartile 
range) according to the observed distribution. Between randomized group comparisons of 
continuous parameters will be analyzed using a student’s t test with appropriate 
transformation if required, or with Man-Whitney U test. Categorical variables will be 
presented with n (%), and they will be analyzed with the chi squared test or Fisher exact test 
as appropriate. 
6.5.6
Interim Analysis (if applicable)
N/A
6.5.7
Health economic evaluation
N/A
6.5.8
Other
N/A
6.5.9
Subsets and Covariates
N/A
6.5.10 Handling of Missing Data
Analysis of survival data as time-to-event allows to include all available information. If a 
patient is lost, his survival will be censored to the last time the patient was contacted.
 
7 Trial Administration
7.1
 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
Proper written, informed consent and HIPAA authorization will be obtained prior to patient 
participation in this trial. The overall protocol (including objectives, procedures and duration), 
potential risks and benefits, voluntary nature and ability to withdraw will be discussed with 
each patient. The patient will be given a copy of the IRB-approved ICF to review and will 
have all questions answered before being asked to sign the informed consent form (ICF). 
Verification of comprehension of the consent will be obtained by asking the subject to 
describe in their words the purpose and risks of the study. The patient will be instructed that 
his or her care will not be affected by his or her decision to participate, or not. If the patient 
voluntarily agrees to participate in the trial, he or she will be asked to sign the ICF. The 
original ICF will be kept with the study documents and a copy will be made for the patient’s 
chart. The subject will be given a signed copy of the ICF and HIPAA authorization form. All 
study subjects will be 18 years or older, with the capacity and ability to provide informed 
consent, thus making parental or surrogate permission not applicable.
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Based on 
treating clinicians’ recommendations regarding appropriate patients who have agreed to be 
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approached about a potential research study will be screened within EPIC for study eligibility, 
including mental status and ability to provide informed consent. Study coordinators will 
confirm with the patient’s provider that the patient has the requisite ability and capacity to 
give informed consent prior to approaching the patient regarding the study. If at any time 
during the study there is concern regarding a patient’s mental status, study staff will both 
notify the patient’s RN and provider, and reevaluate whether the patient is still appropriate for 
participation in the study. After the study objectives and procedures are explained to the 
subject, they will be asked to describe in their words what the purpose and risks of the study 
are.
ETHICS AND GOOD CLINICAL PRACTICE
This study must be carried out in compliance with the protocol. These procedures are 
designed to ensure adherence to Good Clinical Practice, as described in the following 
documents:
1) ICH Harmonized Tripartite Guidelines for Good Clinical Practice (ICH E6) 1996.
2) US 21 Code of Federal Regulations Title 45 Part 46 Protection of HumanSubjects dealing 
with clinical studies (including parts 50 and 56 concerning informed consent and IRB 
regulations).
Participating investigators agree to adhere to the instructions and procedures described in 
the protocol. This protocol was designed to conform to principles of Good Clinical Practice 
and investigators agree to adhere to these principles.
Non-English Speaking Subjects: N/A. Only English-speaking participants will be enrolled.
Patients will be compensated for completion of the study visit and phone calls. Patients 
completing all required visit and phone calls will receive a total of up to $45 for completion.
7.2
Institutional Review Board (IRB) Review
The protocol will be submitted to the IRB for review and approval. Approval of the protocol 
must be obtained before initiating any research activity. Any change to the protocol or study 
team will require an approved IRB amendment before implementation.  The IRB will 
determine whether informed consent and HIPAA authorization are required.  
The IRB will conduct continuing review at intervals appropriate to the degree of risk, but not 
less than once per year.
A study closure report will be submitted to the IRB after all research activities have been 
completed.   
Other study events (e.g. data breaches, protocol deviations) will be submitted per [insert 
institution's] IRB's policies.
7.3
Subject Confidentiality
Subject confidentiality is held in strict trust by the research team. Subject medical record 
review will be limited to just the elements needed to complete the study. Only authorized 
HIPAA and GCP trained study team members will be allowed to extract research data from 
medical records and enter it into REDCap and OnCore data bases.  No direct subject 
identifiers will be entered into REDCap data base.  
Each subject will be assigned a unique study number. A master list linking the unique study 
number to the human subject will be maintained in a secure database. 
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7.4
Deviations/Unanticipated Problems
If the study team becomes aware of an anticipated problem (e.g. data breach, protocol 
deviation), the event will be reported to the IRB by the PI in accordance with the policy and 
procedures in place for reporting.
7.5
Data Collection
Name, address, telephone number, MRN, medical history, date of birth, age, sex, allergies, 
current and past medications or therapies, family medical history, information from a physical 
examination (ex: BP, heart rate, respiratory rate and temperature), results of blood and urine 
tests, pathology tests (biopsies), results of imaging tests (ex: x-rays, CT scans, MRI scans, 
or ultrasound) will be collected.
Data will be collected from the EMR, and the participant themselves. Data will be recorded in 
electronic databases (REDCap & OnCore), stored in password-protected software on a 
secure server. Each subject’s samples will be given a unique study ID number and cryovials 
will be labeled with barcodes. There will be no PHI or information directly linking the patient 
to these samples. Subjects’ clinical data will be stored on password-protected software 
maintained on a secure server. A “linker file” with PHI will be maintained on a separate, 
password-protected system, which only the study PI and study coordinator will have access 
to.
After study enrollment is complete continued analysis of data will be undertaken, and thus 
destruction of identified data is not planned until completion of all analyses. 
7.6
Data Quality Assurance
All study team members are trained and certified in GCP and HIPPA regulations and are 
required to annual renew their trainings. Systematic data verification is in place within the 
study team to ensure accurate data collection. Standard operating procedures (SOP)’s are 
routinely used for each protocol and throughout the laboratory to ensure accurate processing 
and collection. 
7.7
Study Records 7.8
Access to Source Documents
The source documents that will be collected during this study include: A patient contact form, 
phone call follow-up at thirty-day CRF and phone call follow-up at one year CRF. All source 
documents will be stored in a locked file cabinet within a locked facility that is only accessed 
by the study staff. Information from source documents will be collected and stored on secure 
data base REDCap. This information will be assigned a study code before it is shared with 
study collaborators. 
7.9
Data or Specimen Storage/Security
Name, address, telephone number, medical record number (MRN), medical history and 
allergies, current and past medications and therapies, information from a physical 
examination (ex: BP, heart rate, respiratory rate and temperature), family medical history, 
results of blood, urine and imaging tests (ex: x-rays, CT scans, MRIs, or ultrasound) and 
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pathology tests (biopsies), DNA, RNA, tissue and blood. The patients’ entire medical record 
will be reviewed.
Digital data will be stored in a secured server.
Data collected by the PI and other study personnel listed in this protocol will be distributed for 
secondary research purposes only after the recipient investigator has obtained HIC approval 
for the proposed research objective, received an exemption or determination by the HIC the 
study is not considered human subject research. Data will be distributed for research 
projects of the same nature and similar purpose specified in this protocol, as agreed to by 
the subjects by signing the compound informed consent and HIPAA authorization form upon 
enrollment to the study. The PI is responsible for receiving appropriate attestation by 
recipient investigators prior to permitting access to the database for activities considered 
preparatory to research.
Data collected during the research study will be shared with other investigators for research 
projects of the same nature and similar purpose specified in this protocol, as described 
above. Researchers may still use the data that was collected before the subject withdrew 
permission/authorization in order to complete the research that has already commenced. All 
data retained and not yet used for research purposes will be destroyed upon receiving notice 
of a subject’s withdrawal of permission for continued use of their data. 
The PI will ensure participants’ anonymity is maintained. Each participant is assigned a 
unique study identification number and is tracked through this number. Participants’ clinical 
data will be entered into password-protected software and stored on a secure server. A log 
of participants’ names, participant ID numbers and pertinent registration information (ex: 
address, phone number and emergency contact information) is maintained on a password 
protected computer, to allow re-identification of participants when necessary. This will be 
maintained by the PI and will not be shared.
7.10 Retention of Records
After study enrollment is complete continued analysis of data will be undertaken, and thus 
destruction of identified data is not planned until completion of all analyses. 
7.11 Study Monitoring
The principal investigator is responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency quarterly. During 
the review process the principal investigator will evaluate whether the study should continue 
unchanged, require modification/amendment, or close to enrollment. The principal 
investigator and the Institutional Review Board (IRB) have the authority to stop or suspend 
the study or require modifications.
7.12 Data Safety Monitoring Plan
Greater than Minimal Risk Data and Safety Monitoring Plan (DSMP) Personnel 
responsible for the safety review and its frequency: The PI will be responsible for 
monitoring the data, assuring protocol compliance, and conducting the safety reviews at the 
specified frequency which must be conducted at a minimum of every 6 months (including 
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when re-approval of the protocol is sought). During the review process, the PI will evaluate 
whether the study should continue unchanged, require modification &/or amendment, or 
close to enrollment. Either the PI or the IRB, have the authority to stop or suspend the study 
or require modifications.
The overall risk associated with the proposed study is deemed greater than minimal 
for the following reasons: We believe this study presents greater than minimal risk with the 
randomization of furosemide or torsemide because although both medications are standard 
of care treatments for heart failure, the potential exists for anticipated and/or unanticipated 
adverse events, serious or otherwise, to occur since it is not possible to predict with certainty 
the absolute risk in any given individual or in advance of firsthand experience with the 
proposed study methods. The study poses minimal risk from the data collection, as all data 
will be collected and stored in password protected data bases and all research personnel 
have been trained in appropriate data collection and storage.  
7.13 Study Modification
Consistent review of the protocol and study procedures will be conducted on a frequent 
basis, depending on the need of the study team or if new information has been obtained. 
Based on this the protocol will be modified on an as needed basis. 
7.14 Study Discontinuation
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met Determination of futility
7.15 Study Completion
Once enrollment has been completed or at the end of the four-year planned enrollment the 
study team will notify the IRB of their plans to close enrollment. Upon completion of data 
analysis the study team will again notify the IRB of its plans to close the study.
7.16 Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership in conjunction with the appropriate conflict of interest review 
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committee has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.
All investigators will follow the applicable conflict of interest policies.
7.17 Funding Source
Departmental
7.18 Publication Plan
Subject enrollment is planned to last 4 years. Data analysis will occur after study completion. 
Completion of enrollment, statistical analysis, and publication is planned to be complete 
within 6 years
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Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela 
BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, 
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Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D and Turner MB. 
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Executive summary: heart disease and stroke statistics--2012 update: a report from the 
American Heart Association. Circulation. 2012;125:188-97. 
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Drazner MH, Fonarow GC, Jaarsma T, Jondeau G, Sendon JL, Mebazaa A, Metra M, 
Nieminen M, Pang PS, Seferovic P, Stevenson LW, van Veldhuisen DJ, Zannad F, Anker 
SD, Rhodes A, McMurray JJ and Filippatos G. Assessing and grading congestion in acute 
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Heart Failure: Problems and Perspectives. J Am Coll Cardiol. 2012.
16. Brater DC. Diuretic therapy. N Engl J Med. 1998;339:387-95.
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2017;377:1964-1975.
18. Brenner BM and Rector FC. Brenner & Rector's the kidney. Philadelphia: Saunders 
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19. Gottlieb SS, Khatta M, Wentworth D, Roffman D, Fisher ML and Kramer WG. The effects 
of diuresis on the pharmacokinetics of the loop diuretics furosemide and torsemide in 
patients with heart failure. Am J Med. 1998;104:533-8.
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8 Appendices
Appendix #
Title
Section
Topic
No appendices are included 
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9 List of Tables
No tables are included in this version
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