TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure
Phase: PHASE3
Conditions: Heart Failure
Sponsor: Duke University

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Study Protocol 
 
ToRsemide compArisoN with furoSemide FOR Management of Heart Failure 
SHORT TITLE:  TRANSFORM-HF 
 
 
ClinicalTrials.gov Identifier: 
NCT03296813 
NATIONAL, HEART, LUNG AND BLOOD INSTITUTE 
NATIONAL INSTITUTES OF HEALTH 
 
Compiled by: 
Yale University and Duke Clinical Research Institute 
Version 2.0 / October 23, 2018 
 
 
 
Distributed by: 
 
Eric Velazquez, MD 
Robert Mentz, MD 
Yale University 
Duke Clinical Research Institute 
PO Box 20817 
Duke University 
New Haven, CT  06520 
P.O. Box 17969 
 
Durham, NC  27715 

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Study Funding: 
 
 
National Heart, Lung, and Blood Institute 
 
 
 
 
 
National Institutes of Health 
 
 
Project Officer: 
 
 
Patrice Desvigne-Nickens, MD (NHLBI) 
Study Chair:  
 
 
Bertram Pitt, MD 
Protocol Development Team:  
Clinical Coordinating Center 
Eric 
Velazquez, 
MD 
(Principal 
Investigator, 
Yale 
University) 
Robert Mentz, MD (Co-Principal Investigator, DCRI)  
Stephen Greene, MD (Fellow, DCRI) 
 
Data Coordinating Center 
 
 
 
 
 
Kevin Anstrom, PhD (Co-Principal Investigator, DCRI)  
Eric Eisenstein, DBA (Co-Principal Investigator, DCRI) 
 
 
 
 
 
 
 
 
 

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PROTOCOL APPROVAL PAGE 
 
PROTOCOL VERSION AND AMENDMENT TRACKING 
Version Number/Amendment 
Date 
Version 1.0 
February 28, 2018 
Version 2.0 
October 23, 2018 
 
 
 
 
 

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TABLE OF CONTENTS 
Protocol Version and Amendment Tracking ...................................................................................... 3 
1.EXECUTIVE SUMMARY ................................................................................................................ 6 
2.HYPOTHESES AND OBJECTIVES ............................................................................................... 7 
2.1 
Primary Objectives and Hypothesis ................................................................................... 7 
2.2 
Secondary Objectives ........................................................................................................ 7 
3.BACKGROUND AND RATIONALE ................................................................................................ 8 
4.BASIC STUDY DESIGN ................................................................................................................. 9 
5.STUDY POPULATION AND ELIGIBILITY CRITERIA ................................................................. 10 
5.1 
Overview ........................................................................................................................... 10 
5.2 
Inclusion Criteria ............................................................................................................... 10 
5.3 
Exclusion Criteria ............................................................................................................. 10 
6.TREATMENT INTERVENTIONS ................................................................................................. 11 
6.1 
Overview of Treatment Interventions ............................................................................... 11 
6.2 
Blinding ............................................................................................................................. 11 
6.3 
Patient Safety and Concomitant Therapies ..................................................................... 11 
7.RECRUITMENT AND SCREENING PROCEDURES ................................................................. 11 
7.1 
Common Recruitment/Screening Procedures ................................................................. 11 
7.2 
Estimated Enrollment Period ........................................................................................... 12 
8.INITIAL STUDY EVALUATIONS AND RANDOMIZATION ......................................................... 12 
8.1 
Screening/ Patient Enrollment ......................................................................................... 12 
8.2 
Randomization/ Study Baseline ....................................................................................... 12 
9.FOLLOW-UP EVALUATIONS ...................................................................................................... 12 
9.1 
30 days ............................................................................................................................. 13 
9.2 
6 months ........................................................................................................................... 13 
9.3 
12 months ......................................................................................................................... 13 
9.4 
National Death Index ........................................................................................................ 13 
10. MEDICATION ADHERENCE ..................................................................................................... 13 
11. COST CONSIDERATIONS ....................................................................................................... 14 
12. OUTCOME DETERMINATIONS ............................................................................................... 14 
12.1 
Primary Endpoint .............................................................................................................. 14 
12.2 
Secondary Endpoints ....................................................................................................... 14 
13. PARTICIPANT SAFETY AND ADVERSE EVENTS ................................................................. 15 
13.1 
Institutional Review Boards .............................................................................................. 15 
13.2 
Informed Consent ............................................................................................................. 15 
13.3 
Voluntary Withdrawal from the Study .............................................................................. 15 
13.4 
Adherence Assessments and Discontinuation of Study Medications ............................. 15 
13.5 
Summary of the Risks and Benefits ................................................................................. 16 

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13.6 
Adverse Events ................................................................................................................ 16 
14. STATISTICAL CONSIDERATIONS .......................................................................................... 16 
14.1 
Overview ........................................................................................................................... 16 
14.2 
Analysis of Primary Endpoint ........................................................................................... 16 
14.3 
Sample Size Justification ................................................................................................. 17 
14.4 
Analysis of Secondary Endpoints .................................................................................... 18 
14.5 
Analyses of Patient Subgroups ........................................................................................ 19 
14.6 
Statistical Monitoring Plan ................................................................................................ 19 
15. STUDY ADMINISTRATION ....................................................................................................... 20 
15.1 
Executive and Steering Committees ................................................................................ 20 
15.2 
DSMB ............................................................................................................................... 20 
16. ETHICS AND GOOD CLINICAL PRACTICE ............................................................................ 20 
17. REFERENCES ........................................................................................................................... 21 
18. APPENDICES ............................................................................................................................ 23 
18.1 
Appendix A. Schedule of Assessments* ......................................................................... 23 
 
 

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1. 
EXECUTIVE SUMMARY 
 
Title: 
ToRsemide compArisoN with furoSemide FOR Management of 
Heart Failure (TRANSFORM-HF) 
Location: 
Approximately 50 clinical sites in the United States 
Objectives: 
To compare torsemide versus furosemide on long-term clinical 
outcomes among patients hospitalized for heart failure.  
Study Design: 
An approximately 6000-patient, randomized, unblinded, two-arm, 
multicenter clinical trial comparing torsemide with furosemide among 
patients hospitalized for heart failure.  
Treatment 
Regimens: 
1:1 randomization to either oral torsemide OR oral furosemide 
(dosing at discretion of local provider with dose equivalency guidance 
provided)  
 
Primary 
Endpoint: 
All-cause mortality  
Secondary 
Endpoints: 
• All-cause mortality or all-cause hospitalization over 12 months 
• Total hospitalizations over 12 months  
• All-cause mortality or all-cause hospitalization over 30 days 
• Health-related quality of life over 12 months 
• Symptoms of depression over 12 months 

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Study Flow Chart 
 
2. 
HYPOTHESES AND OBJECTIVES 
2.1 
Primary Objectives and Hypothesis 
The primary objective of the TRANSFORM-HF study is to compare the treatment 
strategy of torsemide versus furosemide on long-term clinical outcomes among 
patients hospitalized for heart failure. All patients will be followed for a minimum of 12 
months. 
Our primary hypothesis is that torsemide will reduce all-cause mortality by a relative 
20% (i.e. a hazard ratio of 0.80) compared to furosemide. This is an event-driven trial 
that will require at least 721 primary endpoint events to have ≥ 85% power. 
2.2 
Secondary Objectives 
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 12 months 
• Total hospitalizations over 12 months  
• All-cause mortality or all-cause hospitalization over 30 days 

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• Health-related quality of life, as measured by the Kansas City Cardiomyopathy 
Questionnaire (KCCQ), over 12 months 
• Symptoms of depression, as measured by the Patient Health Questionnaire-2 (PHQ-
2), over 12 months 
3. 
BACKGROUND AND RATIONALE 
Heart failure is a major and growing public health problem in the United States, affecting 
over 5 million Americans, causing over 1 million hospitalizations, and accounting for 
over $30 billion in total costs per annum.1 Reduced cardiac output in heart failure 
patients activates the renin-angiotensin-aldosterone system (RAAS) which increases 
water and sodium retention with resultant edema and shortness of breath.2 Loop 
diuretics including furosemide and torsemide (both of which are available as generic 
formulations) are commonly prescribed for the symptomatic treatment of heart failure—
with use in >70% of patients.3 
Furosemide is the most commonly used loop diuretic (approximately 90% use).4 
However, preclinical and clinical data support the benefits of torsemide over furosemide. 
Compared with furosemide, torsemide has increased bioavailability and a longer half-life 
with maintained absorption in the setting of oral intake (Table 1).5 Torsemide also has 
beneficial effects on myocardial fibrosis, aldosterone production, sympathetic activation, 
ventricular remodeling and natriuretic peptide levels.6-10 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 (Figure 1).4,11-13 
Table 1. Pharmacokinetic properties of loop diuretics. 
 
Furosemide 
Torsemide 
Bumetanide 
Relative potency 
1x 
2-4x 
40x 
Bioavailability, % 
10-100 (avg 50) 
80-100 
80-100 
Affected by food 
Yes 
No 
Yes 
Half-life, h 
 
 
 
     Normal 
1.5-2 
3-4 
1 
     Heart Failure 
2.7 
6 
1.3 
     Renal Dysfunction 
2.8 
4-5 
1.6 
     Liver Dysfunction 
2.5 
8 
2.3 
Average effect, h 
6-8 
6-8 
4-6 
Most Common Dosing Schedule 
Once or Twice Daily 
Once Daily 
Once Daily 
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.1 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. Given this unmet 
clinical need, the TRANSFORM-HF trial was designed to be a prospective, 
randomized, comparative-effectiveness study to definitively compare torsemide 
with furosemide in heart failure patients. 

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Figure 1. Mortality With Torsemide Compared With Furosemide. Modified from Bikdeli B, et al. J 
Am Coll Cardiol 2013. 
 
4. BASIC STUDY DESIGN 
This study will be a randomized, unblinded, two-arm, multi-center clinical trial of patients 
hospitalized for heart failure. Approximately 6,000 patients will be enrolled in the trial.  
Patients will be randomized 1:1 to either oral torsemide OR oral furosemide prior to 
hospital discharge. 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 20 mg or furosemide 40-80 mg. Providers will be asked to document their 
planned initial dose and dosing frequency of torsemide and furosemide prior to patient 
randomization to assess the exact conversion factor being utilized. 
Randomization can occur at any time before hospital discharge at the discretion of the 
healthcare provider. If patients receive intravenous diuretic therapy during the index 
hospitalization, it is expected that randomization will occur near the time of transition to 
oral loop diuretic therapy or after the patient has successfully transitioned to oral loop 
diuretic therapy. Following randomization, the study medication is expected to constitute 
the oral diuretic therapy for the remainder of the hospitalization, with the expectation for 
patients to receive at least 1 dose of study medication prior to discharge. Patients will 
be prescribed the randomized study medication at time of index hospital discharge. 
Post-discharge 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. 
The primary endpoint will be all-cause mortality over the follow-up period.  
Patients will receive follow-up per standard care without any additional study-specific 
visits.  
All patients will have 30-day, 6-month, and 12-month post-randomization phone 
contacts performed by the Duke Clinical Research Institute (DCRI) Call Center for 
X 

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assessment of vital status, interval hospitalizations, concomitant HF medications, 
adherence, quality of life, and symptoms of depression. As an additional mechanism to 
safeguard against hospitalization under-reporting, the DCRI Call Center will initiate a 
medical record query 12 months after patient randomization to screen for 
hospitalizations at the enrolling center and potential treating hospitals identified by the 
patient. The National Death Index (NDI) will be searched during follow-up and prior to 
study close-out.  
5. 
STUDY POPULATION AND ELIGIBILITY CRITERIA 
5.1 
Overview 
The population will exclusively enroll patients while they are hospitalized. Eligible 
patients will have been hospitalized for worsening of chronic heart failure or hospitalized 
for management of a new diagnosis of heart failure. The diagnosis of heart failure 
utilized will be the responsibility of the treating clinician, with the exception that all 
patients must meet the ejection fraction and/or natriuretic peptide criteria outlined below. 
The selection criteria below were designed to be inclusive and representative of the 
broad heart failure population in routine clinical practice, including appropriate 
representation of women and minorities. 
5.2 
Inclusion Criteria 
1) Patient hospitalized (≥ 24 hours or over a change in calendar date) with 
worsening of chronic heart failure, or new diagnosis of heart failure AND 
meets 1 of the following criteria: 
a. Has a left ventricular ejection fraction (EF) ≤40% within 24 months 
prior to and including index hospitalization by any method (with most 
recent value used to determine eligibility) 
b. Has an elevated natriuretic peptide level (either NT-pro-B-type 
natriuretic peptide or B-type natriuretic peptide) during index 
hospitalization as measured by local laboratory  
2) Plan for a daily outpatient oral loop diuretic regimen upon hospital discharge 
with anticipated need for long-term loop diuretic use 
3) ≥ 18 years of age 
4) Signed informed consent 
5.3 
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 

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6. 
TREATMENT INTERVENTIONS 
6.1 
Overview of Treatment Interventions 
This will be an unblinded, two-arm randomized clinical trial comparing: 
• Oral torsemide  
 
• Oral furosemide 
 
Prior studies have suggested oral torsemide has a relative potency 2-4 fold greater than 
oral furosemide per mg.11,12,14-16 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 during the remainder of their hospitalization with continuation of the 
randomized therapy post-discharge. Post-discharge 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. 
6.2 
Blinding 
As this is a pragmatic trial with an objective primary endpoint, this study will be 
unblinded for patients, managing clinicians, and the study team.  
6.3 
Patient Safety and Concomitant Therapies 
This study will evaluate and compare treatment strategies of loop diuretics in patients 
with heart failure. Although investigators are encouraged to follow the assigned 
treatment strategy until the end of the study (≥12 months for all patients), in all cases 
the patient’s safety based on the clinical judgment of the treating physician will take 
priority over the specific treatment assignment.   
7. 
RECRUITMENT AND SCREENING PROCEDURES 
7.1 
Common Recruitment/Screening Procedures 
All patients with a diagnosis of heart failure admitted to participating centers will be 
screened by study staff at the local sites. Patients meeting eligibility criteria will be 
approached regarding participation in this study.  

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7.2 
Estimated Enrollment Period 
This study will enroll approximately 6000 patients at approximately 50 U.S. study sites. 
The projected timeline for enrollment is approximately 36 months. 
8. 
INITIAL STUDY EVALUATIONS AND RANDOMIZATION 
A complete schedule of assessments throughout the study is given in Appendix A. 
8.1 
Screening/ Patient Enrollment 
Potential trial patients believed to meet study selection criteria will be approached and 
willing patients will be consented for trial participation. After providing informed consent 
and signing the informed consent form (ICF), trial eligibility criteria will be formally 
confirmed. Patient contact information will be obtained for the post-randomization DCRI 
Call Center contacts. Patients will also designate and provide contact information for a 
person familiar with their medical care whom the DCRI Call Center may contact should 
the patient be unavailable. 
8.2 
Randomization/ Study Baseline 
Among those meeting eligibility criteria, once the patient is on an oral loop diuretic 
regimen or the patient is near the time of transition from intravenous to oral loop diuretic 
therapy, patients will be randomized in a 1:1 fashion to one of two treatment groups 
prior to hospital discharge. Anticipated initial daily dosing regimens for oral torsemide 
and oral furosemide will be recorded by site investigators 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. Baseline KCCQ and 
PHQ-2 data should be obtained and recorded on the same day of but prior to 
randomization.  
Following randomization, site study staff will identify the treatment assignment and 
confirm inpatient oral loop diuretic use and outpatient loop diuretic prescription and 
accessibility. Patients will be provided medication adherence and educational materials 
to support adherence (see Adherence Section, 10). After this initial contact, no further 
study-specific patient contact will be required at the site level. 
9. 
FOLLOW-UP EVALUATIONS 
There will be no scheduled study-specific visits. All study patients will be followed on a 
usual care basis.  

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9.1 
30 days 
Patients will be contacted by the DCRI Call Center to document vital status, medication 
adherence, concomitant HF medications, KCCQ and PHQ-2 questionnaires, and to 
capture hospitalization information. The Call Center will obtain discharge summaries 
from hospitalizations as appropriate.  
9.2 
6 months 
Patients will be contacted by the DCRI Call Center to document vital status, medication 
adherence, concomitant HF medications, KCCQ and PHQ-2 questionnaires, and to 
capture hospitalization information. The Call Center will obtain discharge summaries 
from hospitalizations as appropriate.  
9.3 
12 months  
Patients will be contacted by the DCRI Call Center to document vital status, medication 
adherence, concomitant HF medications, KCCQ and PHQ-2 questionnaires, and to 
capture hospitalization information. The Call Center will obtain discharge summaries 
from hospitalizations as appropriate. As an additional mechanism to safeguard against 
hospitalization under-reporting, the DCRI Call Center will initiate a medical record query 
12 months after patient randomization to screen for hospitalizations at the enrolling 
center and potential treating hospitals identified by the patient. 
9.4 
National Death Index 
NDI searches will be performed during follow-up and prior to study close-out. The DCRI 
will coordinate the NDI searches. 
10.       MEDICATION ADHERENCE 
To adequately test the study’s primary hypothesis, patient adherence with the 
randomized diuretic treatment is paramount. The approach to maintain study drug 
adherence in TRANSFORM-HF will involve study identification cards for patients, 
patient education materials, and validated adherence-assessment metrics. Since 
patients may receive care (including medication changes) from providers outside the 
enrolling institution, patients will be provided with a medication card for their wallet that 
identifies them as a trial patient randomized to a specific loop diuretic therapy. Patients 
will be asked to present this card to all care providers, including those who attempt to 
adjust their diuretic regimen. Patients will also receive educational information at 
baseline related to medication adherence. Recognizing that patients could mistake 
changes in medication dosage or appearance (e.g., pill color, size) with a change to the 
alternate study therapy, DCRI Call Center personnel will ask patients to specify the 
exact name of the therapy they are receiving and will encourage patient confirmation 
with pill bottles whenever a question. 
The study will also utilize the Voils Medication Adherence Scale.17 This simple 
questionnaire will be administered by the DCRI Call Center during phone contacts at 30 

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days, 6 months, and 12 months post-randomization, which will capture patient-reported 
adherence to the randomized study therapy.  
11. COST CONSIDERATIONS 
Furosemide is currently the most commonly used loop diuretic; however, torsemide 
represents a relatively inexpensive alternative therapy. Both furosemide and torsemide 
are generic medications. At the present time, costs vary modestly by region and 
pharmacy for these medications (e.g., medication tiers), but on average, the patient cost 
for a 30-day supply of torsemide is less than $3 more than furosemide and there is no 
difference for many patients. Clinicians currently prescribe these medications 
interchangeably in the context of routine HF management, and both are recommended 
by current ACC/AHA HF guidelines. Furthermore, this cost differential is less than that 
seen with other guideline-recommended and routinely used HF medications. 
12. OUTCOME DETERMINATIONS 
12.1 
Primary Endpoint 
The primary endpoint of this study will be all-cause mortality. Patients will receive a call 
from the DCRI Call Center at 30 days, 6 months, and 12 months post-randomization to 
document vital status. Subsets of patients enrolled early in the study will receive 
additional phone calls from the DCRI Call Center at 6 month intervals to document vital 
status. The NDI will be queried during follow-up and prior to study close-out. All patients 
will be followed for a minimum of 12 months. 
12.2 
Secondary Endpoints 
• All-cause mortality or all-cause hospitalization over 12 months 
o Hospitalization data will be acquired via the DCRI Call Center with 
acquisition of hospital discharge summaries. The DCRI Call Center will 
initiate a medical record query 12 months after patient randomization to 
screen for hospitalizations at the enrolling center and potential treating 
hospitals identified by the patient. 
• Total hospitalizations over 12 months  
o Hospitalization data will be acquired via the DCRI Call Center with 
acquisition of hospital discharge summaries. The DCRI Call Center will 
initiate a medical record query 12 months after patient randomization to 
screen for hospitalizations at the enrolling center and potential treating 
hospitals identified by the patient. 
• All-cause mortality or all-cause hospitalization over 30 days 
o Hospitalization data will be acquired via the DCRI Call Center with 
acquisition of hospital discharge summaries. 
• Health-related quality of life over 12 months  
o KCCQ 
• Symptoms of depression over 12 months  

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o PHQ-2 
13. 
PARTICIPANT SAFETY AND ADVERSE EVENTS 
13.1 
Institutional Review Boards 
All sites will submit the study protocol, informed consent form, and other relevant study 
documents to their Institutional Review Board (IRB) or the central IRB for approval. 
13.2 
Informed Consent 
A signed ICF is a requirement for patient inclusion in the study. All patients will have the 
purpose of the study, the study interventions and evaluations, and the potential risks 
and benefits of participation explained to them and their questions answered.  If patients 
consent to participation in this study, they will review and sign the ICF. The ICF will be 
administered by study staff at the enrolling site during the index hospitalization. At the 
time of ICF discussion, patients will receive study informational materials and the 
contact information for the site study staff at the enrolling site.  
13.3 
Voluntary Withdrawal from the Study 
Patients may withdraw at any time during the study without giving reasons and will not 
suffer disadvantage as a result. In cases of study withdrawal, patient care will continue 
per the discretion of healthcare providers. 
At the time of ICF discussion and signature, patients will have received the contact 
information for the study staff at the enrolling site and the DCRI Call Center. For 
patients electing to withdraw from the study prior to index hospitalization discharge, 
patients will alert site study staff at their enrolling site so that the site may notify the 
DCRI Call Center. For patients electing to withdraw from the study after index 
hospitalization discharge, patients may contact either study staff from the enrolling site 
or the DCRI Call Center.  
Since both study therapies are standard of care and because the only study-specific 
patient follow-up requirement is participation in pre-specified DCRI Call Center calls, the 
impact of study withdrawal on patient activities will be cessation of study related phone 
calls. In cases of study withdrawal, individual patient care will continue per the discretion 
of local care providers.  
13.4 
Adherence Assessments and Discontinuation of Study Medications 
The ongoing prescription of and adherence to randomized therapy during follow-up will 
be documented by the DCRI Call Center, as specified above. Since both study 
therapies are standard of care and because the only study-specific patient follow-up 
requirement is participation in pre-specified DCRI Call Center calls, the impact of study 
withdrawal on patient activities will be cessation of study related phone calls. 

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13.5 
Summary of the Risks and Benefits 
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. Potential benefits to study participants include the 
possibility of improvements in clinical congestion and associated symptoms and 
outcomes. Some patients may feel a sense of well-being due to their contribution to 
help their fellow heart failure patient by participating in this scientific research. In 
addition, there are several potential societal benefits to this study since determining the 
optimal loop diuretic care could impact the care of millions of patients with heart failure.  
13.6 
Adverse Events 
Given that this is a study of 2 standard of care therapies, there will be no additional 
adverse event reporting beyond that of standard care.  
14. 
STATISTICAL CONSIDERATIONS 
14.1 
Overview 
Means, standard deviations, medians, 25th and 75th percentiles will be presented for 
continuous variables; the number and frequency of patients in each category will be 
presented for nominal variables. For the primary analysis, a two-sided p-value <0.05 will 
be considered statistically significant. For all other analyses, including secondary 
analyses and subgroup analyses, a p-value <0.005 will be considered statistically 
significant.18 Analyses will be performed using SAS version 9.4 or higher software (SAS 
Institute, Inc., Cary, NC). 
14.2 
Analysis of Primary Endpoint 
Detailed description of the plan for statistical analysis of each endpoint will be detailed 
in a Statistical Analysis Plan.  
The primary analysis will be based on intention-to-treat. The data used for the primary 
analysis will be based on the DCRI Call Center data supplemented with the NDI search 
results. 
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 

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treatment, age, sex, ejection fraction category, and loop diuretic treatment prior to index 
hospital admission. 
14.3 
Sample Size Justification 
The planned study population for TRANSFORM-HF is broader than most prior HF 
clinical trials. As such, it is difficult to anticipate the expected event rates at 12 months. 
Additionally the planned statistical power is dependent on adherence to the assigned 
treatments. Table 2 shows the required number of primary endpoint events (i.e. all-
cause mortality) to obtain power ranging from 80% to 90% with hazard ratios ranging 
from 0.75 to 0.85. Ideally, the TRANSFORM-HF protocol will have 85+% power to 
detect a hazard ratio 0.80 for the primary endpoint. Therefore, TRANSFORM-HF will 
continue until at least 721 primary endpoint events have been observed. These power 
estimates are based on the following assumptions: 1:1 randomization, two-sided Type I 
error of 0.05, and a test statistic based on the log-rank test.  
Table 2. Required number of primary endpoint events (two-sided Type I error of 0.05) 
Power 
HR= 
0.75 
HR= 
0.76 
HR= 
0.77 
HR= 
0.78 
HR= 
0.79 
HR= 
0.80 
HR= 
0.81 
HR= 
0.82 
HR= 
0.83 
HR= 
0.84 
HR= 
0.85 
80% 
379 
417 
460 
509 
565 
631 
707 
797 
909 
1033 
1189 
85% 
434 
477 
526 
582 
646 
721 
809 
912 
1034 
1181 
1360 
90% 
508 
558 
615 
681 
756 
844 
947 
1067 
1211 
1383 
1591 
HR – hazard ratio 
In Table 3, the required number of events for the secondary time-to-event endpoints is 
provided to have power of 80% to 90%. The sample size assumptions are based on the 
log-rank test with a more conservative Type I error rate of 0.005. 
Table 3. Required number of events for secondary endpoints (2-sided α=0.005) 
Power 
HR= 
0.75 
HR= 
0.76 
HR= 
0.77 
HR= 
0.78 
HR= 
0.79 
HR= 
0.80 
HR= 
0.81 
HR= 
0.82 
HR= 
0.83 
HR= 
0.84 
HR= 
0.85 
80% 
643 
707 
780 
863 
958 
1069 
1199 
1352 
1534 
1752 
2016 
85% 
714 
785 
865 
957 
1063 
1187 
1331 
1500 
1702 
1944 
2237 
90% 
808 
888 
979 
1083 
1203 
1343 
1506 
1698 
1926 
2200 
2532 
HR – hazard ratio 
Table 4 shows the sample sizes required to provide 80-90% power for key continuous 
endpoints, such as QOL. Differences are provided in terms of standardized differences. 
These calculations are based on the two-sample t-test and assume 1:1 randomization 
with a two-sided Type I error rate of 0.005. The planned sample size of approximately 
6000 patients should provide >80% power to detect differences larger than 0.10 
standard deviations. For the KCCQ overall summary and clinical summary scores that 
value equated to a treatment group difference of between 1.5 and 2.0 points. Generally, 

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a clinically meaningful difference, on a patient-level, is considered to be a 5 point 
difference.19  
Table 4. Required Sample Sizes for Continuous Endpoints 
Power 
Std diff = 
0.10 
Std diff = 
0.15 
Std diff = 
0.20 
Std diff = 
0.25 
Std diff = 
0.30 
80% 
5400 
2400 
1340 
860 
600 
85% 
6000 
2700 
1500 
1000 
700 
90% 
6700 
3000 
1700 
1100 
780 
*values shown have been rounded up to the 10’s digit. The total sample sizes shown do not allow for any 
missing data. 
All enrolled patients will have DCRI Call Center interviews at 30 days, 6 months, and 12 
months. We anticipate that the first cohort of 500 patients will have additional follow-up 
telephone calls at months 18, 24, and 30. Similarly, the second cohort of 500 patients 
will have two additional phone calls at months 18 and 24, and a third cohort of 500 
patients will have a follow-up interview at 18 months. These data will be used to provide 
estimates on long-term treatment adherence data and to determine whether the study 
will provide the anticipated number of primary endpoint events. Table 5 shows the 
expected half-width (i.e. distance from the point estimate to the confidence limit) for the 
95% confidence interval for the pooled event rate. 
Table 5. Expected Half-Width of 95% Confidence Intervals for Pooled Event Rates 
Expected 
proportion 
N=500 
N=1000 
N=1500 
0.10 
0.026* 
0.019 
0.015 
0.12 
0.028 
0.020 
0.016 
0.14 
0.030 
0.022 
0.018 
0.16 
0.032 
0.023 
0.019 
0.18 
0.034 
0.024 
0.019 
0.20 
0.035 
0.025 
0.020 
*Distance from the observed proportion to the 95% confidence interval limit based on a large-sample 
approximation. 
14.4 
Analysis of Secondary Endpoints 
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. 
Analyses of the longitudinal quality-of-life (QOL) data will be conducted using linear 
mixed models. A secondary analysis of the QOL data will apply the worst-rank approach 
of Lachin et al. to account for missing data related to deaths, and the test statistic will be 
based on a two-sample nonparametric test.20 The total hospitalization endpoint will be 

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analyzed using the method of Bang and Tsiatis with partitions set at the planned 
interview dates.21 The analyses of the remaining secondary endpoints will be detailed in 
the Statistical Analysis Plan. 
14.5 
Analyses of Patient Subgroups 
Subgroup analyses will be conducted with the purpose of assessing consistency of 
treatment effects over subgroups. Subgroup analyses will be performed on the primary 
and secondary endpoints. Further details will be included in the Statistical Analysis 
Plan. The following pre-specified subgroup analyses are planned, with subgroups 
defined using data collected at study baseline (i.e., randomization): 
- 
Age groups (<65, ≥65;  <75, ≥75 years) 
- 
Sex 
- 
Race (Caucasian, Black, Asian, Other) 
- 
Ejection Fraction (≤ 40%, 41-49%, ≥50%) 
- 
Loop diuretic treatment prior to index hospitalization (furosemide, torsemide, 
bumetanide/ethacrynic acid, none) 
- 
New York Heart Association class at randomization (I/II vs III/IV) 
- 
Systolic blood pressure (</≥ median) 
- 
eGFR categories (<30, ≥30 to <60, ≥60 mL/min/1.73m2) 
- 
Diabetes mellitus (yes/no, based on medical history) 
- 
Mineralocorticoid receptor antagonist use at randomization (yes/no) 
- 
Enrolling center an academic/teaching hospital (yes/no) 
- 
Duration of heart failure prior to index hospitalization (worsening chronic heart 
failure, newly diagnosed heart failure during index hospitalization) 
14.6 
Statistical Monitoring Plan 
Interim data analysis for efficacy will be conducted due to the large sample size. The 
DSMB will meet approximately every 6 months to review study progress. The data 
presented at these meetings will include information regarding clinical outcomes, 
enrollment, patient characteristics, and trial processes. All-cause mortality is primary 
endpoint in the TRANSFORM-HF study. The study investigators are suggesting that the 
DSMB use a Haybittle-Peto-type boundary using p=0.005 as a guideline for stopping 
the study due to differences in all-cause mortality. Given the importance of this 
endpoint, the investigators recommend that the guideline is applied in a two-sided 
symmetric fashion.  
Additionally, the DCRI Coordinating Center will monitor treatment adherence by 
enrolling site using one-sided 90% confidence intervals based on the exact binomial 
distribution. Enrolling sites with poor adherence (e.g. <90%) will review their study 
practices with the DCRI study monitors and the TRANSFORM-HF coordinating center. 
Crossovers will be tracked by the DCRI Call Center at 30 days, 6 months, and 12 
months post-randomization. A set of sensitivity analyses will be conducted on the 

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subset of patients with documented adherence to the assigned therapy at 30-days. 
Details of the planned DSMB reviews will be described in the DSMB Charter. 
15. 
STUDY ADMINISTRATION 
15.1 
Executive and Steering Committees 
An Executive Committee comprised of NHLBI representatives, the CCC and DCC 
investigators and the Study Chair will be the primary decision making body of the study 
and is responsible for its successful completion. A Steering Committee will meet 
regularly (no less than once, yearly) and will include site investigators and other 
investigators with specific expertise in heart failure and clinical trials to advise the 
Executive Committee on the operational conduct of the trial and with primary 
responsibility to approve and amend the protocol. 
15.2 
DSMB 
A DSMB will be appointed by the NHLBI for the TRANSFORM-HF trial, which will 
include individuals with pertinent expertise in heart failure, clinical trials, research ethics, 
and biostatistics. The DSMB will make recommendations to the Steering Committee 
and NHLBI regarding the continuing safety of current participants and those yet to be 
recruited.  
16.        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 Human 
Subjects 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. 

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17. REFERENCES 
1. 
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the 
management of heart failure: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. 
Journal of the American College of Cardiology 2013;62:e147-239. 
2. 
Braunwald E. Heart failure. JACC: Heart Failure 2013;1:1-20. 
3. 
Adams KF, Jr., Fonarow GC, Emerman CL, et al. Characteristics and outcomes 
of patients hospitalized for heart failure in the United States: rationale, design, 
and preliminary observations from the first 100,000 cases in the Acute 
Decompensated Heart Failure National Registry (ADHERE). American heart 
journal 2005;149:209-16. 
4. 
Bikdeli B, Strait KM, Dharmarajan K, et al. Dominance of furosemide for loop 
diuretic therapy in heart failure: time to revisit the alternatives? Journal of the 
American College of Cardiology 2013;61:1549-50. 
5. 
Felker GM, Mentz RJ. Diuretics and ultrafiltration in acute decompensated heart 
failure. Journal of the American College of Cardiology 2012;59:2145-53. 
6. 
Uchida T, Yamanaga K, Nishikawa M, Ohtaki Y, Kido H, Watanabe M. Anti-
aldosteronergic effect of torasemide. European journal of pharmacology 
1991;205:145-50. 
7. 
Goodfriend TL, Ball DL, Oelkers W, Bahr V. Torsemide inhibits aldosterone 
secretion in vitro. Life sciences 1998;63:PL45-50. 
8. 
Harada K, Izawa H, Nishizawa T, et al. Beneficial effects of torasemide on 
systolic wall stress and sympathetic nervous activity in asymptomatic or mildly 
symptomatic patients with heart failure: comparison with azosemide. Journal of 
cardiovascular pharmacology 2009;53:468-73. 
9. 
Lopez B, Querejeta R, Gonzalez A, Sanchez E, Larman M, Diez J. Effects of 
loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart 
failure. Journal of the American College of Cardiology 2004;43:2028-35. 
10. 
Kasama S, Toyama T, Hatori T, et al. Effects of torasemide on cardiac 
sympathetic nerve activity and left ventricular remodelling in patients with 
congestive heart failure. Heart (British Cardiac Society) 2006;92:1434-40. 
11. 
Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial of 
torsemide compared with furosemide therapy for patients with heart failure. The 
American journal of medicine 2001;111:513-20. 
12. 
Cosin J, Diez J. Torasemide in chronic heart failure: results of the TORIC study. 
European journal of heart failure 2002;4:507-13. 
13. 
DiNicolantonio JJ. Should torsemide be the loop diuretic of choice in systolic 
heart failure? Future cardiology 2012;8:707-28. 
14. 
Brater DC, Leinfelder J, Anderson SA. Clinical pharmacology of torasemide, a 
new loop diuretic. Clin Pharmacol Ther 1987;42:187-92. 
15. 
Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. 
Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and 
furosemide in patients with congestive heart failure. Clin Pharmacol Ther 
1995;57:601-9. 

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16. 
Muller K, Gamba G, Jaquet F, Hess B. Torasemide vs. furosemide in primary 
care patients with chronic heart failure NYHA II to IV--efficacy and quality of life. 
European journal of heart failure 2003;5:793-801. 
17. 
Voils CI, Maciejewski ML, Hoyle RH, et al. Initial validation of a self-report 
measure of the extent of and reasons for medication nonadherence. Med Care 
2012;50:1013-9. 
18. 
Benjamin DJ, Berger JO, Johannesson M, et al. Redefine statistical significance. 
Nat Hum Behav 2017 September 1 [E-pub ahead of print] doi: 10.1038/s41562-
017-0189-z. 
19. 
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation 
of the Kansas City Cardiomyopathy Questionnaire: a new health status measure 
for heart failure. Journal of the American College of Cardiology 2000;35:1245-55. 
20.   Lachin JM. Worst-rank score analysis with informatively missing observations in    
clinical trials. Control Clin Trials 1999;20:408-22. 
21. Bang H, Tsiatis AA. Estimating medical costs with censored data. Biometrika 
2000;87:329-43. 
 

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18. APPENDICES 
18.1 
Appendix A. Schedule of Assessments* 
 
Screening/ 
Enrollment 
Randomization/ 
 Baseline 
30 days 
6 
months 
12 
months 
18 
months^ 
24 
months^ 
30 
months^ 
Informed Consent 
(Site study staff) 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria confirmed 
X 
X 
 
 
 
 
 
 
Age, sex, race, 
ethnicity, most recent 
ejection fraction by 
any modality, past 
medical history, 
routine vital signs/ 
laboratories, and 
randomized study 
therapy 
 
X 
 
 
 
 
 
 
Anticipated initial 
dosing regimen for 
oral torsemide and 
oral furosemide 
 
X (completed 
prior to 
randomization 
on the same 
day) 
 
 
 
 
 
 
Concomitant heart 
failure medications 
 
X 
X 
X 
X 
X 
X 
X 

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* NDI queries will be conducted by the DCRI Call Center during follow-up and prior to study close-out.  
^The first cohort of 500 patients enrolled will have additional follow-up telephone calls at 18, 24, and 30 months. The 
second cohort of 500 patients will have additional follow-up telephone calls at 18 and 24 months. The third cohort of 500 
patients will have an additional follow-up telephone call at 18 months. 
 
Adherence wallet 
card and education 
materials 
 
X 
 
 
 
 
 
 
Vital status 
 
 
X  
X  
X  
X 
X 
X 
Interval 
rehospitalizations 
 
 
X 
X 
X 
 
 
 
KCCQ and PHQ-2 
Assessment 
 
X (completed 
prior to 
randomization 
on the same 
day) 
X 
X 
X 
 
 
 
Medication 
Adherence  
 
 
X  
X 
X 
X 
X 
X