Clinical trial NCT04252287
Conditions: Heart Failure
Sponsor: Janssen Research & Development, LLC
Start date: 2020-03-10; Completion date: 2021-11-09
Enrollment: 476 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the superiority of the effectiveness of canagliflozin 100 milligram (mg) daily versus placebo in participants with symptomatic heart failure (HF) in improving the overall Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS).

Detailed description:

Arms: arm 1: Participants will be administered 100 milligram (mg) immediate-release, over-encapsulated tablets (as a capsule) orally once daily for 12 weeks. arm 2: Participants will be administered matching placebo capsules orally once daily for 12 weeks.
Interventions: intervention 1: Canagliflozin 100 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 100 mg immediate-release, over-encapsulated tablets (as a capsule) orally once daily. intervention 2: Participants will receive matching placebo capsules orally once daily.

Protocol documents:
Prot_002.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 23 February 2021
Janssen Research & Development*
Clinical Protocol
Protocol Title
Canagliflozin: Impact on Health Status, Quality of Life, and Functional Status in Heart 
Failure
CHIEF-HF
Protocol 28431754HFA3002; Phase 3B
AMENDMENT 3
JNJ-28431754 (canagliflozin) (INVOKANA)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
Status:
Approved
Date:
23 February 2021
Prepared by:
Janssen Scientific Affairs
EDMS number:
EDMS-ERI-154820237, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04252287


JNJ-28431754 (canagliflozin) (INVOKANA)
Clinical Protocol 28431754HFA3002 Amendment 3
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Approved, Date: 23 February 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
23 February 2021
Amendment 2
02 June 2020
Amendment 1
07 February 2020
Original Protocol
07 November 2019
Amendment 3 (23 February 2021)
Overall Rationale for the Amendment: The overall rationale for the amendment is to clarify the adverse 
event (AE) reporting requirements and time frames for the study.
Section number
and Name
Description of Change
Brief Rationale
Synopsis (Adverse 
Event Data Collection, 
Adverse Event 
Evaluations, Adverse 
Event Analyses);
3. Objectives and
Endpoints (Adverse
Event Data
Collection);
8.3. Adverse Events
and Serious Adverse
Events and Special
Situations;
8.3.1. Time Period and
Frequency for
Collecting Adverse
Event and Serious
Adverse Event
Information;
9.4.3 Adverse Event
Analysis
The following text was modified:
“Due to the virtual method of data collection for 
this study, there will be 2 types of adverse event 
data collection, one will be done by participants 
instructed to self-report any adverse events from 
the study intervention to a call center, and the 
other by an analysis of medical claims data from 
the participant’s provider to their insurance 
system. Participant-reported adverse events to 
the call center will be captured from the time 
of informed consent until 30 days after the end 
of treatment (ie, the last dose of study 
intervention) and adverse events from medical 
claims data from the time of informed consent 
to the end of study. Adverse events will be 
captured from the time of informed consent 
through the end of treatment (Month 3) plus 30 
days. After the treatment period plus 30 days, 
serious adverse events will be identified solely 
through medical claims data. Adverse events 
that occur during the treatment period plus 30 
days identified from medical claims will be 
aggregated by treatment assignment when 
unblinding is available. In addition, for this 
time period, self-reported adverse events from 
the call center will be summarized in a listing. 
Serious adverse event data from medical 
claims for the 9-month study period will be 
aggregated by treatment assignment. Medical 
claims adverse event data will be reviewed and 
evaluated in aggregate at the end of the 3 month, 
double blind treatment period when the 
unblinded data are available.”
To clarify that 
1. Adverse events will be collected
from medical claims as well as
from the call center, from the time
of informed consent through the
end of treatment plus 30 days.
2. After the treatment period plus
30 days, serious adverse events
will be identified from medical
claims data.
3. Aggregated adverse events from
medical claims data will be
presented for the treatment period
plus 30 days. In addition, for the
same period, a listing will be
provided for the self-reported
adverse events from the call
center.
4. Serious adverse events from
medical claims will be
summarized at the end of the
9-month study period.
1.3 Schedule of 
Activities (SoA)
Reporting of adverse events is extended from end 
of treatment to end of study in SoA table.
Footnote ‘e’ revised to ‘Participant-reported 
adverse events to the call center occurs Lasts
from the time of informed consent until 30 days 
after the end of treatment (ie, the last dose of 
To clarify the duration of 
self-reported adverse events from
call center and adverse events
collected from medical claim data.


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Section number
and Name
Description of Change
Brief Rationale
study intervention). Adverse events from 
medical claims data occurs from the time of 
informed consent to the end of study.’
10.1 Appendix 1: 
Abbreviations
Abbreviation list updated for an ‘SAE’.
Minor errors were noted.
Throughout the 
protocol
Minor formatting and consistency changes were 
made.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
1.
PROTOCOL SUMMARY ..................................................................................................................... 6
1.1.
Synopsis........................................................................................................................................... 6
1.2.
Schema .......................................................................................................................................... 11
1.3.
Schedule of Activities (SoA)........................................................................................................... 12
2.
INTRODUCTION................................................................................................................................ 14
2.1.
Background and Study Rationale .................................................................................................. 18
2.2.
Benefit/Risk Assessment ............................................................................................................... 19
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 20
4.
STUDY DESIGN ................................................................................................................................ 22
4.1.
Overall Design................................................................................................................................ 22
4.2.
Scientific Rationale for Study Design............................................................................................. 24
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 26
4.3.
Justification for Dose...................................................................................................................... 26
4.4.
End of Study Definition................................................................................................................... 26
5.
STUDY POPULATION ...................................................................................................................... 27
5.1.
Inclusion Criteria ............................................................................................................................ 27
5.2.
Exclusion Criteria ........................................................................................................................... 28
5.3.
Prohibitions and Restrictions ......................................................................................................... 29
5.4.
Screen Failures .............................................................................................................................. 29
6.
STUDY INTERVENTION................................................................................................................... 30
6.1.
Study Interventions Administered .................................................................................................. 30
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 32
6.3.
Measures to Minimize Bias: Randomization and Blinding.............................................................32
6.4.
Study Intervention Compliance...................................................................................................... 33
6.5.
Prohibited Medications................................................................................................................... 33
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...............................................................................................33
7.1.
Discontinuation of Study Intervention ............................................................................................ 33
7.1.1.
Temporary Discontinuation of Study Intervention ......................................................................34
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 34
8.
STUDY ASSESSMENTS AND PROCEDURES ...............................................................................35
8.1.
Effectiveness Assessments ........................................................................................................... 35
8.1.1.
KCCQ Scores ............................................................................................................................. 35
8.1.2.
Actigraphy Measurements.......................................................................................................... 36
8.2.
Exploratory Assessments............................................................................................................... 36
8.2.1.
Patient Global Impression of Change (PGIC) Scores ................................................................36
8.2.2.
Patient Global Impression of Severity (PGI-S) Scores...............................................................36
8.2.3.
Participant Satisfaction Survey................................................................................................... 37
8.2.4.
Healthcare Resource Utilization and Health Economics............................................................ 37
8.3.
Adverse Events and Serious Adverse Events and Special Situations .......................................... 37
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 38
8.3.2.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 38
8.3.3.
Pregnancy................................................................................................................................... 38


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8.3.4.
Adverse Events of Interest.......................................................................................................... 38
9.
STATISTICAL CONSIDERATIONS..................................................................................................39
9.1.
Statistical Hypotheses.................................................................................................................... 39
9.2.
Sample Size Determination ........................................................................................................... 39
9.3.
Populations for Analyses................................................................................................................ 40
9.4.
Statistical Analyses ........................................................................................................................ 40
9.4.1.
Handling of Missing Data............................................................................................................ 40
9.4.2.
Effectiveness Analyses............................................................................................................... 40
9.4.2.1.
Primary and Secondary Effectiveness Analyses.....................................................................40
9.4.2.2.
Exploratory Analyses............................................................................................................... 41
9.4.3.
Adverse Events Analysis ............................................................................................................ 41
9.4.4.
Healthcare Resource Utilization and Health Economics Analyses ............................................ 42
9.5.
Interim Analysis.............................................................................................................................. 42
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 43
10.1
Appendix 1: Abbreviations ............................................................................................................. 43
10.2
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations......................................... 45
10.3
Appendix 3: Kansas City Cardiomyopathy Questionnaire (KCCQ) ............................................... 53
10.4
Appendix 4: Patient Global Impression of Change (PGIC)............................................................57
10.5
Appendix 5: Patient Global Impression of Severity (PGI-S) .......................................................... 58
10.6
Appendix 6: Participant Satisfaction Survey .................................................................................. 59
10.7
Appendix 7: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................... 60
10.8
Appendix 8: Protocol Amendment History .....................................................................................65
11.
REFERENCES................................................................................................................................... 72
INVESTIGATOR AGREEMENT ................................................................................................................. 74
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Effects of Sodium-glucose Cotransports-2 Inhibitors (SGLT-2is) on Heart Failure 
Outcomes.................................................................................................................................. 19
Table 2:
Description of Study Interventions ............................................................................................ 31
Table 3:
Analysis Populations................................................................................................................. 40
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 11


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Canagliflozin: Impact on Health Status, Quality of Life, and Functional Status in Heart Failure
Canagliflozin (JNJ-28431754) is an inhibitor of sodium-glucose co-transporter 2 (SGLT2) that has been 
developed as an oral antihyperglycemic agent (AHA) for the treatment of patients with type 2 diabetes 
mellitus (T2DM). The full chemical name for canagliflozin is (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-
2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate.
Canagliflozin therapy has been shown to improve clinical outcomes including hospitalizations for heart 
failure (HHF) in patients with T2DM and HF based on results from the CANVAS program (CANVAS 
[DIA3008]/CANVAS-Renal [DIA4003]) and CREDENCE [DNE3001] study. An improvement in 
patient’s symptoms of HF would be an important advance in the clinical management of HF. This 
randomized study is designed to assess whether canagliflozin therapy improves HF symptoms as assessed 
by the Total Symptom Score (TSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) 
patient-reported outcome (PRO) scale in participants with HF and with or without T2DM in a real-world 
setting.
OBJECTIVES AND ENDPOINTS
Primary Objective
The primary objective is:
!
to determine the superiority of the effectiveness of canagliflozin 100 mg daily versus placebo in
participants with symptomatic HF in improving the overall KCCQ TSS.
Secondary Objectives
The first key secondary objective is:
!
to determine the superiority of the effectiveness of canagliflozin 100 mg daily versus placebo in 
improving the total daily step count.
The second key secondary objective is:
!
to determine the superiority of the effectiveness of canagliflozin 100 mg daily versus placebo in 
improving the KCCQ individual domain scores (physical limitation, quality of life, clinical summary, 
and overall).
Exploratory Objectives
The exploratory objectives are to assess the effectiveness of canagliflozin 100 mg daily in participants with 
symptomatic HF by:
!
responses on the Patient Global Impression of Change (PGIC) and the Patient Global Impression of 
Severity (PGI-S)
!
healthcare resource utilization (HRU) and health economics data
!
associations (correlations and/or categorical association measures) between digital markers (step count
and floors climbed), and clinical events such as need for outpatient intravenous therapies, emergency 
department (ED) visits, and hospitalizations
!
daily floors climbed


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!
time to first hospitalization/readmission for heart failure
!
time to first hospitalization/readmission for other events
!
time to death
!
the participant’s satisfaction with their experience with the virtual design at the end of the study.
Endpoints
The primary effectiveness endpoint is the change in KCCQ TSS from baseline to Month 3.
The key secondary effectiveness endpoints are 1) change in total daily step count from baseline to Month 
3, and 2) changes in KCCQ individual domain scores (physical limitation, quality of life, clinical summary, 
and overall) from baseline to Month 3.
The exploratory endpoints are the following:
!
mean PGIC scores over time
!
changes in PGI-S scores from baseline to Month 3
!
change in number of daily floors climbed
!
change in HRU and health economics data
!
number of outpatient intravenous therapies, ED visits, and hospitalizations
!
time to first hospitalization/readmission for heart failure
!
time to first hospitalization/readmission for other events
!
time to death
Adverse Event Data Collection
Due to the virtual method of data collection for this study, there will be 2 types of adverse event data 
collection, one by participants instructed to self-report any adverse events to a call center, and the other by 
an analysis of medical claims data from the participant’s provider to their insurance system. Participant-
reported adverse events to the call center will be captured from the time of informed consent until 30 days 
after the end of treatment (ie, the last dose of study intervention) and adverse events from medical claims 
data from the time of informed consent to the end of study. After the treatment period plus 30 days, serious 
adverse events will be identified solely through medical claims data. Adverse events that occur during the 
treatment period plus 30 days identified from medical claims will be aggregated by treatment assignment 
when unblinding is available. In addition, for this time period, self-reported adverse events from the call 
center will be summarized in a listing. Serious adverse event data from medical claims for the 9-month 
study period will be aggregated by treatment assignment.
Hypotheses
The primary hypothesis is that canagliflozin is superior to placebo as assessed by improvement in the TSS 
on the KCCQ scale during the 3-month, double-blind treatment period.
OVERALL DESIGN
This is a randomized, double-blind, placebo-controlled, decentralized, virtual, interventional, superiority 
study conducted in the United States (US) in participants with symptomatic HF (stratified by heart failure 
with reduced ejection fraction [HFrEF] and heart failure with preserved ejection fraction [HFpEF]) to 
examine the improvement in the KCCQ TSS after 3 months of treatment with canagliflozin 100 mg or 


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placebo. The study will continue for an additional 6 months without any study intervention to collect 
participant follow-up in a real-world setting.
The study will enroll participants from large, integrated, health networks and large physician practices in 
the US with the participants conducting the majority of their study-related activities through an app on a 
smartphone and actigraphy data from a Fitbit device. There will be no in-person clinic visits required by 
the study.
The study consists of a screening period and a 3-month, double-blind treatment period. Approximately 
1,900 participants will be randomized into the study in a 1:1 ratio to canagliflozin 100 mg daily or placebo 
groups (950 in each study intervention group). After Month 3 (the end of the double-blind treatment period), 
the study will continue for an additional 6 months when study intervention will no longer be provided. Data 
collection from medical claims, smartphone, Fitbit device, and selected PROs will continue until Month 9 
for the purpose of secondary and further exploratory endpoints analyses. In addition, the KCCQ, PGIC, and 
PGI-S data will be collected at 6 and 9 months. An optional participant satisfaction survey about the virtual 
nature of the study will be provided to the participant at end of the study.
Participants will be of any gender, 18 years of age or older, and have clinically stable, symptomatic HF 
with or without T2DM with a KCCQ baseline overall summary score of ≤80 prior to randomization.
Study assessments include the KCCQ, Fitbit device data (step count and floors climbed), PGIC, PGI-S,
participant satisfaction survey, medical and pharmacy claims data (including up to 36 months history for 
eligibility confirmation), HRU and health economics (including hospitalization/readmission due to HF or 
other reason, ED visits, the duration of stay at each hospitalization/readmission), review of medical claims 
for prohibited medications and new diagnoses that may require discontinuation, dates of deaths, and adverse 
events.
NUMBER OF PARTICIPANTS
Approximately 1,900 participants will be randomized in the study in a 1:1 ratio to canagliflozin 100 mg 
daily or placebo. Randomization of participants into the study will be stratified by the type of ejection 
fraction (ie, HFrEF or HFpEF) at study entry as recorded in the participant’s electronic health record (EHR).
INTERVENTION GROUPS AND DURATION
The total duration of study participation for each participant is approximately 9 months. Participants will 
be randomly assigned to receive canagliflozin 100 mg daily immediate-release over-encapsulated tablets 
(capsules) taken orally or placebo capsules for the duration of the 3-month, double-blind treatment period, 
followed by a 6-month, no treatment period during which data will continue to be collected.
Description of Interventions
The study intervention, JNJ-28431754 (canagliflozin), will be provided as immediate-release, 
over-encapsulated tablets (as a capsule) or a placebo capsule taken orally once daily for the duration of the 
3-month, double-blind treatment period.
Participant Unblinding
After each randomized participant completes the 3-month, double-blind treatment period of the study, they 
will be provided with their treatment allocation, whether they had been randomized to canagliflozin or 
placebo.
EFFECTIVENESS EVALUATIONS
Effectiveness evaluations include the KCCQ and daily step count.


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SECONDARY AND EXPLORATORY EVALUATIONS
Secondary and exploratory evaluations include KCCQ individual domains, PGIC, PGI-S, participant 
satisfaction survey, the HRU and health economics data collected in this study, time to death, and
associations (correlations and/or categorical association measures) between digital markers (step count and 
floors climbed) and clinical events such as need for outpatient intravenous therapies, ED visits, and
hospitalizations.
ADVERSE EVENT EVALUATIONS
Adverse events will be captured through medical claims (from the time of informed consent to the end of 
study) and by the call center (from the time of informed consent until 30 days after the end of treatment).
After the treatment period plus 30 days, serious adverse events will be identified solely through medical 
claims data. Adverse events that occur during the treatment period plus 30 days identified from medical 
claims will be aggregated by treatment assignment when unblinding is available. In addition, for this time 
period, self-reported adverse events from the call center will be summarized in a listing. Serious adverse 
event data from medical claims for the 9-month study period will be aggregated by treatment assignment.
STATISTICAL METHODS
Sample Size Determination
The primary effectiveness endpoint is the change from baseline in the KCCQ TSS at the end of the 3-month,
double-blind treatment period. Although a 5-point improvement in the KCCQ TSS is generally viewed as 
clinically meaningful, recent studies have shown that improvements in the range of 3 to 5 points on the 
KCCQ TSS are equally meaningful in the overall HF-related health status measured by the KCCQ over a
12-week time period. Based on the evidence from these studies, the current study is powered to detect a 
mean change from baseline of 3 points in the KCCQ TSS between canagliflozin 100 mg and placebo groups 
at 12 weeks. Assuming a significance level of 5% and a standard deviation of 18 points for mean change in 
KCCQ TSS, a total of 1,900 participants will be randomized in this study providing approximately 95% 
power. This sample size is adequate to account for a potential 5% dropout rate.
Effectiveness Analyses
Primary and Secondary Effectiveness Analysis
The primary and key secondary effectiveness analyses will be based on the intent-to-treat (ITT) analysis 
population (using all randomized participants).
As the KCCQ TSS is measured repeatedly over time (ie, at baseline, Weeks 4, 6, and 12 respectively), the 
primary effectiveness endpoint (change in KCCQ TSS from baseline to Month 3) will be analyzed by a 
mixed effect model repeated measures (MMRM) method simultaneously adjusting for study intervention
group, stratification factor (HFrEF versus HFpEF), time, time by study intervention group, and baseline 
KCCQ TSS value as covariates. An unstructured covariance structure will be assumed across study 
intervention groups to model the within-participant errors. The primary comparison will be based on the 
difference in least squares means between treatments at Month 3. The treatment difference in the 
least-squares means and their 2-sided 95% confidence interval (CI) will be provided. An MMRM model 
accounts for data missing at random.
A responder analysis will also be performed when comparing proportions of participants with a 5- (or 10-) 
point improvement in KCCQ TSS from baseline between the groups. This will be based on a two-sample 
difference in proportions test along with a 95% confidence interval for the difference in 2 proportions. 
Additionally, empirical cumulative distribution functions of the KCCQ TSS and other domain scores will 
be presented.


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Subgroups defined by age, gender, race and baseline disease/demographic characteristics will be 
pre-specified in the Statistical Analysis Plan (SAP) for the primary effectiveness analysis. Details about the 
imputation of any missing data will be provided in the SAP. Each subgroup will be analyzed following a 
similar MMRM model used in the analysis of the primary effectiveness endpoint (change in KCCQ TSS 
from baseline to Month 3). The treatment difference in the least-squares means and their 2-sided 95% CI 
will be provided from each subgroup analysis. Quantitative and/or qualitative interactions will be identified. 
Qualitative interactions will be investigated further by the Gail and Simon test and interpreted accordingly.
The first key secondary endpoint of daily step count will be tested once the primary endpoint is shown to 
be significant at the 5% significance level using a two-sided t-test. This approach will control for the overall 
Type I error rate at 5%.
For the second key effectiveness endpoint, an MMRM model (like that used in the analysis of the primary 
endpoint) will be employed to summarize changes in KCCQ individual domain scores (physical limitation, 
quality of life, clinical summary, and overall) from baseline to Month 3. This hypothesis will be 
independently tested at 5% without any control for overall Type I error rate.
Exploratory Analyses
Exploratory analyses include the following:
!
summary statistics of PGIC and PGI-S scores
!
associations (correlations and/or categorical association measures) between digital markers (step count
and floors climbed) and clinical events such as need for outpatient intravenous therapies, ED visits, 
and hospitalizations
!
tabulation and comparison of total HRU and health economics data across groups
!
descriptive statistics (eg, mean, median, and standard deviation) of daily floors climbed
!
association between the KCCQ change from baseline to Month 3 and the PGIC at Month 3 will be 
examined and summarized
!
time to death
!
descriptive statistics of the participant's satisfaction with his/her experience with the virtual design at 
the end of the study.
Adverse Event Analyses
Adverse events reported to the call center will be assessed by Janssen Global Medical Safety (GMS) for 
causality and meeting suspected unexpected serious adverse reaction (SUSAR) reporting requirements. 
Self-reported adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be reported by preferred term by T2DM and non-T2DM. Adverse events collected 
from medical claims will be categorized by diagnosis code and reported by T2DM and non-T2DM. 
Discontinuations will be summarized based on any available data. Self-reported adverse events from the 
call center will be summarized in a listing.
Healthcare Resource Utilization (HRU) and Health Economics
Healthcare Resource Utilization and health economics data will be descriptively summarized by study 
intervention group.


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1.2.
Schema
Figure 1:
Schematic Overview of the Study






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2.
INTRODUCTION
Canagliflozin (JNJ-28431754) is an inhibitor of sodium-glucose co-transporter 2 (SGLT2) that has 
been developed as an oral antihyperglycemic agent (AHA) for the treatment of patients with type 
2 diabetes mellitus (T2DM). The full chemical name for JNJ-28431754 is (1S)-1,5-anhydro-1-[3-
[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate.
The development program for canagliflozin has investigated the compound's efficacy and safety 
profile both as a monotherapy and in combination with other AHAs as adjunctive treatment to diet 
and exercise to improve glycemic control in the treatment of adult participants with T2DM. Three 
of the Phase 3 and Phase 4 studies evaluated canagliflozin in special populations, including older 
adults with T2DM and participants with T2DM who had moderate renal impairment. Recently 
completed cardiovascular (CV) safety studies have evaluated canagliflozin as a treatment to reduce 
the risk of major adverse CV events (MACE - CV death, nonfatal myocardial infarction (MI), and 
nonfatal stroke) in adults with T2DM who have established cardiovascular disease (CVD) or at 
least 2 risk factors for CVD. Canagliflozin therapy has been shown to be associated with improved 
clinical outcomes in patients with T2DM and heart failure (HF) based on results from the 
CANVAS program (CANVAS [DIA3008] /CANVAS-Renal [DIA4003]) and CREDENCE 
[DNE3001] studies.
Proposed mechanisms of action of sodium-glucose co-transporter 2 inhibitors (SGLT2is) and 
recent information from the DAPA-HF and DEFINE-HF studies16,21 suggest that the effects of the 
SGLT2i class of medicines in patients with HF may extend to HF patients with or without T2DM.
This randomized study is designed to assess whether canagliflozin therapy improves HF symptoms 
as assessed by the Total Symptom Score (TSS) of the Kansas City Cardiomyopathy Questionnaire 
(KCCQ) patient-reported outcome (PRO) scale in participants with HF and with or without T2DM
in a real-world setting.
CANVAS Heart Failure Data
Approximately 14.4% of all participants in the CANVAS Program had a prior history of HF. While 
the CANVAS Program met its primary endpoint,15 the principal secondary endpoint (superiority 
of canagliflozin with respect to reducing all-cause mortality) did not meet statistical significance, 
hence the results of the subsequent analyses examining endpoints including hospitalization for HF
(HHF) must be viewed as exploratory. The hazard ratio (HR) for HHF in the combined 
canagliflozin group versus placebo was 0.67 (95% CI: 0.52, 0.87), with similar effects seen in the 
canagliflozin 100 mg and 300 mg groups in the CANVAS study.26 These HR results resulted in 
choosing the lower dose of canagliflozin 100 mg for this study.
Canagliflozin lowered the risk of HHF in both patient groups: primary (participants with only risk 
factors for CV disease) (HR: 0.64; 95% CI: 0.35 to 1.15) and secondary (participants with a history 
of CV disease) (HR: 0.68; 95% CI: 0.51 to 0.90) with no evidence of statistical heterogeneity
(p=0.91).


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An analysis of CANVAS26 program demonstrated that canagliflozin decreased the risk of HHF in 
those with pre-existing history of HF (HR: 0.51; 95% CI: 0.33 to 0.78), and in those without a 
history of HF (HR: 0.79; 95% CI: 0.57 to 1.09) with no evidence of statistical heterogeneity
(p = 0.47). This effect of reducing the risk of HHF in those with or without a history of HF was 
consistent irrespective of established treatments for the prevention or management of HF 
(ie, inhibitors of the renin-angiotensin-aldosterone system, beta-blockers, and diuretics).
Therefore, a study to demonstrate that canagliflozin improves patient symptoms of HF would be 
an important advance in the clinical management of HF patients and would offer an important and 
valuable therapeutic option.
CREDENCE Study
The CREDENCE study (NDA 204042 S-032, approved 27 September 2019, was a large, 
international, randomized, double-blind, event-driven study undertaken to formally test whether 
canagliflozin 100 mg, administered once daily, reduces the risk of kidney failure and CV events 
in participants with Stage 2 or 3 chronic kidney disease (eGFR ≥30 to <90 mL/min/1.73 m2) and 
macroalbuminuria (urinary ACR >300 to ≤5,000 mg/g) and T2DM who were receiving Standard 
of Care (SoC) therapy. SoC was defined in the National Kidney Foundation Kidney Disease 
Outcomes Quality Initiative consensus guidelines22 and included a maximum tolerated labeled 
daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker 
(ARB). This study was conducted between 21 February 2014 and 30 October 2018.
The renal protective effect of canagliflozin relative to placebo in a population with established 
CKD and T2DM was measured using a composite endpoint of doubling of serum creatinine, 
progression to end-stage kidney disease (ESKD) (defined as dialysis, renal transplantation, or 
sustained eGFR <15 L/min/1.73 m2), and renal or CV death. The study also assessed the effects of 
canagliflozin on several adverse CV outcomes (CV death, HHF, nonfatal MI, nonfatal stroke, and 
hospitalization for unstable angina), and all-cause mortality. The results demonstrated clinical 
benefit of the 100 mg dose of canagliflozin in reducing important cardiovascular and renal clinical 
endpoints in patients with T2DM and impaired renal function.14 Specifically, HHF (which was a 
secondary endpoint) was significantly decreased in the canagliflozin versus placebo group 
(HR=0.61 [0.47-0.80]). Additionally, the rate of amputation was not shown to be statistically 
significantly increased with canagliflozin treatment in the CREDENCE study in the overall 
population (HR=1.11 [0.79-1.37]).
Recently, INVOKANA® was approved as the only diabetes medicine indicated to reduce the risk 
of ESKD, worsening of kidney function, cardiovascular death, and HHF in adults with type 2 
diabetes and diabetic kidney disease (nephropathy) with a certain amount of protein in the urine.
Use of SGLT2is in Heart Failure With or Without T2DM
A mechanistic basis has been proposed for the SGLT2i class of medicines to exert beneficial 
effects in HF irrespective of the diabetic state and effects on glycemic control or osmotic diuresis.25
Inhibition of sodium-hydrogen (Na/H) exchange in the kidney by SGLT2 inhibitors may reduce 
diuretic and endogenous natriuretic peptide resistance, and similar inhibition in the myocardium 


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may lead to a reduction in cardiac injury, hypertrophy, fibrosis, remodeling, and systolic 
dysfunction. Furthermore, the major pathophysiological derangements of HF and a preserved 
ejection fraction may be mitigated by the actions of SGLT2 inhibitors to reduce blood pressure, 
body weight, and fluid retention as well as to improve renal function.25
The use of canagliflozin in patients without T2DM has been studied in approximately 1,200 
healthy subjects in multiple Phase 1 studies. A thorough QT/QTc study in healthy subjects (study 
DIA1010 NDA 204042 Sequence 0000 Module 5.3.4.1) demonstrated that canagliflozin at single 
therapeutic (300 mg) or supra-therapeutic (1,200 mg) doses does not lead to QT/QTc prolongation. 
At the 1,200 mg dose, canagliflozin Cmax was approximately 1.4 times that for steady-state Cmax at 
a 300 mg QD dose in T2DM subjects. This is important in light of the proarrhythmic myocardial 
substrate present in HF, in particular HFrEF, which is more prevalent in the non-type 2 diabetes 
population than in the type 2 diabetes population who experiences a higher incidence of HFpEF. 
For this study, the proposed dose of canagliflozin is 100 mg daily.
Additional evidence for the safety of canagliflozin in patients with HF comes from sub-group 
analyses of patients with T2DM in the CANVAS Program and in the CREDENCE study, in which 
there was no signal of increased arrhythmic death, or hyperkalemia – the latter of which is 
reassuring since many HF patients are on medications that are potassium-sparing, such as ACEis, 
ARBs, or mineralocorticoid receptor antagonists (MRAs), and diabetics are more predisposed to 
hyperkalemia with these agents than non-diabetics. CREDENCE in particular, which studied a 
population with a greater prevalence of kidney disease and a higher likelihood of hyperkalemia 
than the population in the CANVAS Program, demonstrated no increased incidence of 
hyperkalemia with canagliflozin versus placebo. In addition, in the CANVAS Program, there was 
no evidence of proportional differences in the risk of volume depletion, fracture, amputation, 
osmotic diuresis, acute kidney injury events, adverse events leading to discontinuation, and all 
serious adverse events (SAEs) between patients with or without HF at baseline (p interaction 
>0.160).26
A growing body of evidence is being generated for use of the SGLT2i class in HF. A randomized 
clinical study, DAPA-HF, in 4,774 HFrEF patients with (42%) and without (58%) T2DM
demonstrated safety consistent with the known profile of dapagliflozin.16 Ninety-four percent of 
patients were on ACEis or ARBs, and the mean eGFR was 66 mL/min/1.73m2. In the study, 
dapagliflozin met the primary composite endpoint with a statistically significant and clinically
meaningful reduction of cardiovascular death or the worsening of HF (defined as hospitalization 
or an urgent HF visit), compared to placebo. Based on these data, dapagliflozin was recently 
approved by the Food and Drug Administration (FDA) to reduce the risk of CV death and 
hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced 
ejection fraction with or without T2DM. This further supports more evaluations of this class of 
drugs in additional clinical trials in HFrEF and HFpEF, including measurement of symptomatic 
and functional improvement with tools such as the KCCQ.
Another recent randomized clinical study with dapagliflozin, DEFINE-HF in HFrEF, was 
completed in 510 patients with (62%) and without (36%) T2DM.21 Results were consistent among 


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patients with or without T2DM, including safety analyses. Mean eGFR was 69 mL/min/1.73m2. 
In the study, patients treated with dapagliflozin vs. placebo had clinically meaningful improvement 
in health status (KCCQ Overall Summary score &5 points).
Finally, there are multiple ongoing randomized studies with SGLT2 inhibitors in HF with or 
without T2DM (see below). As such, there is ample precedent to justify starting another study in 
HF patients irrespective of a diagnosis of T2DM.
Dapagliflozin:
!
DEFINE-HF: biomarkers, symptoms, health status and quality of life in HFrEF patients (listed 
in clinicaltrials.gov March 2016)
!
DELIVER: Outcomes study in HFpEF patients (listed in clinicaltrials.gov Aug. 2018)
!
DETERMINE-REDUCED: Exercise capacity study in HFrEF patients (listed in 
clinicaltrials.gov March 2019)
!
DETERMINE-PRESERVED: Exercise capacity study in HFpEF patients (listed in 
clinicaltrials.gov March 2019)
Empagliflozin:
!
EMPEROR-Reduced: Outcomes study in HFrEF patients (listed in clinicaltrials.gov 
Feb. 2017)
!
EMPEROR-Preserved: Outcomes study in HFpEF patients (listed in clinicaltrials.gov 
Feb. 2017)
!
EMPERIAL-Reduced: Exercise capacity study in HFrEF patients (listed in clinicaltrials.gov 
Feb. 2018)
!
EMPERIAL-Preserved: Exercise capacity study in HFpEF patients (listed in clinicaltrials.gov 
Feb. 2018)
Safety
The safety profile of canagliflozin is well established having been broadly evaluated for safety in 
several well-designed, randomized, clinical studies. The broader Phase 3/4 canagliflozin program 
was conducted in 22,645 patients, including 13,278 patients treated with canagliflozin and 
9,367 patients treated with a comparator, in 15 double-blind, controlled, clinical studies; among 
them, more than 1,100 patients reported a history of HF at baseline. In addition, there is an 
extensive, real-world base of adverse event reporting based on approximately 1,475,000,000 
person days treated worldwide. The SGLT2 inhibitor, dapagliflozin, was studied in HFrEF patients 
both with and without diabetes in the DAPA-HF and the DEFINE-HF studies16,21 (those with 
HFrEF and type 2 diabetes). In those studies, the side effect profile was not different between those 
with or without T2DM or HF. Taken together, the evidence indicates that the safety profile of 
SGLT2 inhibitors, of which canagliflozin is a member, is well described and broadly understood 
in the study population included in this study.


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For the most comprehensive nonclinical and clinical information regarding canagliflozin, refer to 
the latest version of the Investigator's Brochure11 and Addenda for JNJ-28431754 (canagliflozin).
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
The term “study intervention” refers to canagliflozin or placebo.
2.1.
Background and Study Rationale
Outcomes in studies of antidiabetic agents improving HF outcomes include canagliflozin, 
empagliflozin, and dapagliflozin CV that have shown a strong signal for improvement in HF 
endpoints with SGLT2i, but further studies are needed to validate these findings. However, very 
recently, the FDA approved dapagliflozin to reduce the risk of HHF in adults with T2DM and 
established CV disease or multiple CV risk factors. Based on results of the DECLARE-TIMI 58,
the possible role that SGTL2i may play in HF has been hypothesized but evaluation of the various 
pathways has not been performed.30
Heart failure contributes to one in nine deaths and is a leading cause of hospitalization in the US, 
yet there are limited treatment options for people living with this debilitating disease. It is highly 
prevalent and despite best available therapy, is associated with poor patient outcomes.23,24 The 
CANVAS Program demonstrated that canagliflozin treatment in patients at cardiovascular (CV) 
risk was associated with improved clinical outcomes, including a reduction in the composite of 
CV death and HHF. A similar finding was observed with empagliflozin in the EMPA-REG
cardiovascular outcomes study and dapagliflozin in DECLARE-TIMI 58.19
A meta-analysis of EMPA-REG OUTCOME, CANVAS PROGRAM, and DECLARE-TIMI 58 
looked at a total of 20,060 T2DM patients and the CV outcomes of SGLT2i therapies. Enrolling 
3,891 HF patients at baseline, this meta-analysis demonstrated similar significant reduction in 
HHF, regardless of the patient’s baseline HF status (HR 0.68 vs HR 0.71) for those with or without 
HF. The benefit for these groups was affected only by renal function, with greater benefit observed 
in patients with lower estimated glomerular filtration rate (eGFR).18
In addition, the OBSERVE-4D real-world meta-analysis is the largest retrospective observational 
study of effects of SGLT2i in this patient population. It compared the experience of over 140,000 
new canagliflozin patients to over 100,000 empagliflozin and dapagliflozin new users, as well as 
460,000 new users of non-SGLT2i. Patients treated with canagliflozin showed comparable HHF 
reduction to other SGLT2is on the market, and greater reduced risk for HHF and below knee lower 
extremity amputations when compared to non-SGLT2is. This held true even when comparing 
patients with established CV disease to the overall study population. While limitations exist in 
OBSERVE-4D pertaining to the length of treatment duration with canagliflozin, this may not be 
entirely comparable to the randomized clinical study data discussed above. However, findings in 
the OBSERVE-4D meta-analysis suggest similarity to reductions observed in randomized clinical 
studies and provide added confidence in the results of this meta-analysis.27


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This meta-analysis (Table 1), as well as real-world data from CVD-REAL studies and the United 
States (US) Department of Defense Military Health System, support the effect of an SGLT2i on 
reducing HF-related hospitalizations; however, they did not seek to differentiate or provide any 
insight on the effect of these therapies specifically on HF with reduced ejection fraction (HFrEF) 
and HFpEF phenotypes, defining the need for further investigation.20
Table 1: 
Effects of Sodium-glucose Cotransports-2 Inhibitors (SGLT-2is) on Heart Failure Outcomes
Nassif ME, Kosiborod M. Effects of sodium-glucose co-transporter type 2 inhibitors in heart failure. Diabetes Obes Metab. 
2019;21(Suppl. 2):19-23.
HFpEF is well recognized as the predominant type of HF in patients with T2DM and is possibly 
related to insulin resistance and obesity. Such predisposing factors are thought to be at the crux of 
ineffectiveness of traditional HF therapies in treating HFpEF patients, making the need for 
impactful therapies in this patient population even more urgent.2,6 While more studies are 
underway, some encouraging data comes from the Canagliflozin for Japanese Patients with 
Chronic Heart Failure and Type II Diabetes (CANOSSA) study,28 which assessed the effect of 
canagliflozin on Japanese patients with T2DM and stable HF. The study enrolled 35 patients, of 
which 33 had HFpEF, and focused on canagliflozin’s effect of weight and adipose tissue reduction 
on these patients. Beyond reduction in glycated hemoglobin (HbA1c) and fat volumes, the study 
demonstrated reduction in oxidative stress, improved diastolic disfunction, and decrease in left 
ventricular mass, potentially linking canagliflozin use to an improved HFpEF condition.
In addition to showing an improvement in HHF, improvement in clinical symptoms, physical 
functioning and quality of life would be a highly important clinical outcome for patients with HF.
It is believed that canagliflozin, through its diuretic, blood pressure, and body weight reduction 
effects would have a clinically meaningful impact on these outcomes in these patients and 
represent an advance in the clinical management of these patients. This study is designed to assess 
whether canagliflozin can impact these important patient-centric outcomes not only in HFrEF 
patients but also in HFpEF patients for which there is no approved SGLT2i for treatment.
2.2.
Benefit/Risk Assessment
Before randomization and throughout the study, the participant’s physician(s) will continue to 
manage the participant’s background medications to achieve goals for controlling the participant’s 
HF and T2DM (if present). Participants enrolled in this study will be managed based on the 
standards of care for HF and T2DM (if applicable) according to established local and regional 
guidelines. An Independent Scientific Advisory Committee comprised of experts in the 
management of patients with HF and sponsor representatives will be commissioned for this study. 
Other medications in the SGLT2i class of medicines are being studied in patients with HF with or 


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without T2DM as outlined in Section 2, Introduction; however, none of these agents are currently 
indicated for the clinical improvement in HF symptoms or for use in patients with HFpEF.
The risks of participation in the study include exposure to study intervention, with the potential for 
side effects. Participant safety will be assured throughout the study by providing participants and 
their physicians access to a call center to ask questions and to report adverse events. In addition, 
the adverse effect profile of canagliflozin has been well described and will be outlined in the 
informed consent form (ICF). In addition, participant prescribing information with a listing of 
potential adverse events will be sent to the participant in their welcome kit.
This study was designed based in general accordance with the FDA7 and European Medicines 
Agency (EMA) guidance6 on the development of medications and clinical investigations for the 
use of canagliflozin for the reduction of HF symptoms of HF and in consultation with Health 
Authorities. In addition, the design was also based on the FDA’s draft guidance to industry on drug 
development in HF which supports measures of patients’ symptoms and physical function as 
endpoints.8 This study will be conducted under FDA Investigational New Drug (IND) regulations.
More detailed information about the known and expected benefits and risks of JNJ-28431754 
(canagliflozin) may be found in the Investigator’s Brochure, Canagliflozin.11
3.
OBJECTIVES AND ENDPOINTS
OBJECTIVES
Primary Objective
The primary objective is:
!
to determine the superiority of the effectiveness of canagliflozin 100 mg daily versus placebo 
in participants with symptomatic HF in improving the overall KCCQ TSS.
Secondary Objectives
The first key secondary objective is:
!
to determine the superiority of the effectiveness of canagliflozin 100 mg daily versus placebo 
in improving the total daily step count.
The second key secondary objective is:
!
to determine the superiority of the effectiveness of canagliflozin 100 mg daily versus placebo 
in improving the KCCQ individual domain scores (physical limitation, quality of life, clinical 
summary, and overall).
Exploratory Objectives
The exploratory objectives are to assess the effectiveness of canagliflozin 100 mg daily in 
participants with symptomatic HF by:


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!
responses on the Patient Global Impression of Change (PGIC) and the Patient Global 
Impression of Severity (PGI-S)
!
healthcare resource utilization (HRU) and health economics data
!
associations (correlations and/or categorical association measures) between digital markers 
(step count and floors climbed), and clinical events such as need for outpatient intravenous 
therapies, emergency department (ED) visits, and hospitalizations
!
daily floors climbed
!
time to first hospitalization/readmission for heart failure
!
time to first hospitalization/readmission for other events
!
time to death
!
the participant's satisfaction with their experience with the virtual design at the end of the 
study.
ENDPOINTS
The primary effectiveness endpoint is the change in KCCQ TSS from baseline to Month 3.
The key secondary effectiveness endpoints are 1) change in the daily step count from baseline to 
Month 3, and 2) changes in KCCQ individual domain scores (physical limitation, quality of life, 
clinical summary, and overall) from baseline to Month 3.
The exploratory endpoints are the following:
!
mean PGIC scores over time
!
changes in PGI-S scores from baseline to Month 3
!
change in number of daily floors climbed
!
change in HRU and health economics data
!
number of outpatient intravenous therapies, ED visits, and hospitalizations
!
time to first hospitalization/readmission for heart failure
!
time to first hospitalization/readmission for other events
!
time to death
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
Adverse Event Data Collection
Due to the virtual method of data collection for this study, there will be 2 types of adverse event 
data collection, one by participants instructed to self-report any adverse events to a call center, and 
the other by an analysis of medical claims data from the participant’s provider to their insurance 
system. Participant-reported adverse events to the call center will be captured from the time of 
informed consent until 30 days after the end of treatment (ie, the last dose of study intervention) 
and adverse events from medical claims data from the time of informed consent to the end of study.


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After the treatment period plus 30 days, serious adverse events will be identified solely through 
medical claims data. Adverse events that occur during the treatment period plus 30 days identified 
from medical claims will be aggregated by treatment assignment when unblinding is available. In 
addition, for this time period, self-reported adverse events from the call center will be summarized 
in a listing. Serious adverse event data from medical claims for the 9-month study period will be 
aggregated by treatment assignment.
HYPOTHESIS
The primary hypothesis is that canagliflozin is superior to placebo as assessed by improvement in 
the TSS on the KCCQ scale during the 3-month, double-blind treatment period.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, double-blind, placebo-controlled, decentralized, virtual, interventional, 
superiority study conducted in the US in participants with symptomatic HF (stratified by HFrEF 
and HFpEF) to examine the improvement in the KCCQ TSS after 3 months of treatment with 
canagliflozin 100 mg or placebo. The study will continue for an additional 6 months without any 
study intervention to collect participant follow-up in a real-world setting.
The study will enroll participants from large, integrated, health networks and large physician 
practices in the US with the participants conducting the majority of their study-related activities 
through an app on a smartphone and actigraphy data from a Fitbit device. There will be no 
in-person clinic visits required by the study.
The study consists of a screening period and a 3-month, double-blind treatment period. 
Approximately 1,900 participants will be randomized into the study in a 1:1 ratio to canagliflozin 
100 mg daily or placebo groups (950 in each study intervention group). After Month 3 (the end of 
the double-blind treatment period), the study will continue for an additional 6 months when study 
intervention will no longer be provided. Data collection from medical claims, smartphone, Fitbit 
device, and selected PROs will continue until Month 9 for the purpose of secondary and further 
exploratory endpoints analyses. In addition, the KCCQ, PGIC, and PGI-S data will be collected at 
6 and 9-months. An optional participant satisfaction survey about the virtual nature of the study 
will be provided to the participant at the end of the study.
Participants will be of any gender, 18 years of age or older, and have clinically stable, symptomatic 
HF (HFrEF or HFpEF) with or without T2DM with a KCCQ baseline overall summary score of
≤80 prior to randomization.
Participants should be receiving guideline recommended HF medications as prescribed by their 
treating physician(s) (such as ACEi, ARB, beta-adrenergic blocking agent or beta blocker 
[β-blocker], oral diuretics, MRA, angiotensin receptor-neprilysin inhibitor).
Study assessments include the KCCQ, Fitbit device data (step count and floors climbed), PGIC, 
PGI-S, participant satisfaction survey, medical and pharmacy claims data (including up to 


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36 months history for eligibility confirmation), HRU and health economics (including 
hospitalization/readmission due to HF or other reason, ED visits, the duration of stay at each 
hospitalization/readmission), review of medical claims for prohibited medications and new 
diagnoses that may require discontinuation, dates of deaths, and adverse events.
The total duration of study participation for each participant is approximately 9 months. 
Participants will be randomly assigned to receive canagliflozin 100 mg daily immediate-release 
over-encapsulated tablets (capsules) taken orally or placebo capsules for the duration of the 
3-month, double-blind treatment period, followed by a 6-month, no treatment period during which 
data will continue to be collected.
Participants will be enrolled from large, integrated, health networks or large physician practices 
who have electronic health records (EHR) to identify participants. The primary and secondary 
endpoint data collection will be done via an app for a smartphone (being developed specifically 
for the study) as well as data from the Fitbit device.
Data integrity will be assured by automatic data collection directly from data sources (Fitbit device, 
Fitbit app on smartphone, structured electronic PROs on smartphone via the study app, and 
medical claims data from or to payers) without manual entry. Significant changes in actigraphy 
mid-study will be used to confirm that a Fitbit device remains associated with the participant to 
whom it is assigned. The Fitbit app on the participant’s phone will collect all data from the Fitbit 
device, and significant latencies between wearable sensor data uploads via the app will be used to 
identify any smartphone and Fitbit device dissociation. In addition, the participant will be informed 
during the consenting process that the study Fitbit device must only be paired to the participant’s 
smartphone and is to be used only by the participant.
There will be virtual study coordinating center support for initial participant onboarding to answer 
any study-related questions, assist with proper set up and use of the study app with the participant’s 
smartphone and Fitbit device/app as data collection tools, confirming drug receipt and compliance, 
and to collect participant-reported adverse events and report them to the sponsor. The virtual study 
coordinating center will help participants appropriately set up their devices for the purposes of the 
study. In this particular instance, the main requirement for the Fitbit device is maximal wear time, 
as all of the sensor data will be collected passively. The blinded study intervention will be hand 
delivered directly to the participants from a drug distribution vendor. No formal on-site monitoring 
of the study will be performed as this is a decentralized clinical study, however, the sponsors’ 
designee will centrally monitor participant medical claims, study app data, and Fitbit device data 
monthly for compliance with the study. For example, monitoring will include detecting non-use 
of the study app or Fitbit device. Medical claims data will also be monitored for 
inclusion/exclusion criteria, adverse events, prohibited medications, HRU, relevant concomitant 
medications, and new diagnoses that would require discontinuation. In addition, the study app will 
send reminders to participants of study items to complete assessments (KCCQ, PGI-S, PGIC), and 
will collect weekly study drug compliance. If lack of participation is detected by any of the 
monitoring, the virtual study coordinating center will contact the participants for follow-up 
information.


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Participant Unblinding
After each randomized participant completes the 3-month, double-blind treatment period of the 
study, they will be provided with their treatment allocation, whether they had been randomized to 
canagliflozin or placebo.
A diagram of the study design is provided in Section 1.2, Schema.
4.2.
Scientific Rationale for Study Design
Study Population
The study population selected represents participants with HF (HFrEF and HFpEF), with or 
without T2DM, who would potentially benefit from a drug intervention that could offer 
improvement in health status outcomes, such as clinical symptoms (eg, dyspnea and fatigue 
commonly experienced by these participants) and impaired quality of life (eg, physical limitations 
and emotional dysfunction such as depression and anxiety). Participants who meet the inclusion 
criteria for these conditions include adults of any gender 18 years of age and older, representing 
the demographic group in which these conditions are prevalent, and mortality and hospitalization 
rates are high, despite the recommendations of existing clinical practice guidelines.
Length of Study Periods
The screening period of 28 days allows for an appropriate length of time for screening procedures 
to determine study eligibility (with EHR reviews, app set-up, completion of the KCCQ, and 
consenting). The baseline period of 7 days begins upon randomization and allows for shipment of 
the study drug and Fitbit device to the participant. The 3-month, double-blind treatment period 
provides sufficient timepoints for effectiveness assessments to demonstrate treatment differences 
between canagliflozin and placebo.
Placebo Control, Randomization, Blinding, Intervention Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints that may occur in the absence of active intervention. Randomization will be used to 
minimize bias in the assignment of participants to intervention groups, to increase the likelihood 
that known and unknown participant attributes (eg, demographic and baseline characteristics) are 
evenly balanced across intervention groups, and to enhance the validity of statistical comparisons 
across intervention group. Blinded intervention will be used to reduce potential bias during data
collection and evaluation of clinical endpoints.
Dose and Dosage Administration Regimen
In the CANVAS program, canagliflozin reduced the relative risk of the composite of CV death or 
HHF compared with placebo, with a HR of canagliflozin versus placebo of 0.78 (95% CI: 0.67, 
0.91). The HRs were similar in the canagliflozin 100 and 300 mg groups. The HR for HHF in the 
combined canagliflozin group versus placebo was 0.67 (95% CI: 0.52, 0.87), with similar effects 
results seen in the canagliflozin 100 and 300 mg groups. These HR results resulted in choosing the 
lower dose of canagliflozin 100 mg daily for this study. In addition, because few participants


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required titration to 300 mg/d in the CANVAS-R (DIA4003) study, and the treatment period in 
this study is relatively short, titration to the 300 mg/d dose is not necessary.
Kansas City Cardiomyopathy Questionnaire (KCCQ)
Patient-reported outcomes (PROs) are a measurement tool for the symptom burden and functional 
limitations in patients with HF and have demonstrated greater reproducibility than other clinical 
study measures like ejection fraction (EF) valve gradients,13 6-minute walk test, and a biomarker 
(B-type natriuretic peptide [BNP]).29 The KCCQ (Section 10.3, Appendix 3) is a well-established 
PRO for use in patients with HF, with published validity and reliability. This instrument was 
developed and validated by Dr. John Spertus, the Lauer/Missouri Endowed Chair and Tenured 
Professor at the University of Missouri – Kansas City and the Clinical Director of Outcomes 
Research at Saint Luke’s Mid America Heart Institute. After reviewing its extensive psychometric 
profile, the KCCQ has been endorsed by the Center for Devices and Radiological Health as a 
Certified Outcome Assessment through its Medical Device Development Tools Program.17 In 
addition, the KCCQ was recently qualified by the Center for Drug Evaluation and Research as a 
PRO instrument for use in clinical investigations in heart failure.4
The KCCQ is a 23-item, self-administered questionnaire and requires, on average, 4 to 6 minutes
to complete, with a resulting score of 0 to 100, and higher scores indicating better health. It was 
developed to measure the patient’s perception of their health status, including their HF symptoms, 
impact on physical and social function and how their HF impacts the quality of life. The KCCQ 
has been repeatedly used as a clinically meaningful outcome measure in CV research, patient 
management, and quality assessment. It has been extensively tested for its validity, reliability, and 
responsiveness improvement in participants with HF, and is well suited as the primary endpoint 
for this study. In addition, the intent of the study is to enroll participants with New York Heart 
Association (NYHA) class II to IV. As it would be difficult to verify NYHA class with medical 
claims and EHR data, the sponsor will use a KCCQ overall summary score at baseline of ≤80, 
which is highly correlated to class II to IV in HFrEF and HFpEF based on the research published 
by Joseph, et al.12
Actigraphy Measurements
Total step count and total floors climbed will be collected continuously from the Fitbit device from 
each participant for the entire duration of the study. These actigraphy measures will be used to 
assess patient activity as it relates to treatment effect on the participant’s daily activity.
Patient Global Impression of Change (PGIC)
The PGIC (Section 10.4, Appendix 4) is a commonly accepted, validated outcome measure used 
in clinical studies to assess the overall change in the participant’s status as it relates to the 
participant’s HF symptoms since starting the study as rated by the participant.


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Patient Global Impression of Severity (PGI-S)
The PGI-S (Section 10.5, Appendix 5) is a commonly accepted, validated outcome measure used 
in clinical studies to assess the change in the severity of the participant’s HF symptoms since 
starting the study as rated by the participant.
Health Resource Utilization and Health Economics Data Collection
Treatment of patients with symptomatic HF with JNJ-28431754 (canagliflozin) versus placebo
may result in lower utilization of any incident of hospitalization/readmission due to HF or other 
reason, ED visits, the duration of stay at each hospitalization/readmission, and discharge 
destination; therefore, comparison will be done across study intervention groups.
Participant Satisfaction Survey
Participants will be provided with an optional participant satisfaction survey at the end of the study 
to provide feedback on this virtual study and the use of the Fitbit device and smartphone to collect 
their information. This feedback may be important to consider when designing studies that use 
technology and devices.
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation, including availability of an approved medicine for HF in the same SGLT2i class of 
medicines as canagliflozin, which now includes the recent approval of dapagliflozin for HFrEF. 
They will be told that their consent to participate in the study is voluntary and may be withdrawn at 
any time with no reason given and without penalty or loss of benefits to which they would otherwise 
be entitled. Only participants who are fully able to understand the risks, benefits, and potential 
adverse events of the study, and provide their consent voluntarily will be enrolled.
4.3.
Justification for Dose
Canagliflozin 100 mg daily taken orally is the dose selected based on data from a similar study 
population in the CANVAS program that demonstrated a significant treatment effect, with no 
differences observed between the 100 and 300 mg doses. In addition, there are fewer 
dose-dependent adverse events such as volume-related adverse events associated with this dose. 
Refer to Section 4.2, Study Design Rationale for further details.
4.4.
End of Study Definition
A participant will be considered to have ended the treatment period of the study (at 3 months), 
regardless of whether the participant has completed the study intervention, if he or she has 
completed assessments at Month 3 of the double-blind treatment period, withdrew earlier from the 
treatment, or died prior to the Month 3 assessment.
The end of study (at 9 months) is considered as the last visit shown in the Schedule of Activities 
for the last participant in the study. The final data from the study clinical research organization


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partner will be sent to the sponsor (or designee) after completion of the collection of the study data 
from the Fitbit device and the claims in the time frame specified in the Trial Agreement.
5.
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before randomization into the 
study.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the participant or designee must consult with the call center 
to resolve any issues before enrolling in the study.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
Sample Size Determination.
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study at 
enrollment (consent date):
1.
any gender
2.
18 (or the legal age of consent in the jurisdiction in which the study is taking place)
years of age or older
3.
Criterion modified per Amendment 2
3.1. have clinically stable symptomatic HF (HFrEF or HFpEF)
For HFrEF:
a) EF ≤40% AND
b) a primary diagnosis of HF OR 2 medical visits (including virtual) with a HF diagnosis 
code in any position in the past 18 months.
For HFpEF:
a) EF >40% AND
b) a primary diagnosis of HF OR 2 medical visits (including virtual) with a HF diagnosis 
code in any position in the past 18 months, AND
c) on a loop diuretic or spironolactone or eplerenone (mineralocorticoid receptor
antagonists)1,3 in the past 18 months.
4.
Criterion modified per Amendment 2


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4.1. have a KCCQ baseline overall summary score of ≤80 prior to randomization
5.
be able to read and understand English
6,
possess and have sole use (eg, not shared with other users) of smartphone compatible 
with the Fitbit device
7.
willing/able to wear the Fitbit device on a regular basis for the 9-month study period
8.
must sign an electronic informed consent form (eICF) indicating that he or she 
understands the purpose of, and procedures required for, the study and is willing to 
participate in the study, including follow-up.
5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria prior to enrollment (consent date) 
will be excluded from participating in the study:
1.
Criterion modified per Amendment 2
1.1. currently taking an SGLT2i or within the last 3 months
2.
history of diabetic ketoacidosis or have type 1 diabetes mellitus (T1DM)
3.
Criterion modified per Amendment 2
3.1. have acute decompensated HF (exacerbation of symptomatic HF) requiring 
intravenous diuretics, inotropes, or vasodilators within the last 4 weeks
4.
Criterion modified per Amendment 2
4.1. have stage 4 or 5 Chronic Kidney Disease (ie, eGFR <30ml/min on dialysis) from 
the most recent assessment
5.
Criterion modified per Amendment 2
5.1. have a history of atraumatic amputation within past 12 months of screening, or an 
active skin ulcer, osteomyelitis, gangrene, or critical ischemia of the lower extremity 
within 6 months
6.
Criterion modified per Amendment 2
6.1. have a diagnosis of hypotension within 30 days
7.
Criterion modified per Amendment 2


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7.1. had major surgery within 3 months or have any surgery, ie, cardiac surgery, planned 
during the 3-month treatment (except for minor surgery, ie, outpatient surgery under 
local anesthesia)
8.
Criterion modified per Amendment 2
8.1. any condition for which, in the opinion of the investigator, participation would not
be in the best interest of the participant (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments or have a life expectancy
of ∋6 months or current immobility
9.
have known allergies, hypersensitivity, or intolerance to JNJ-28431754 (canagliflozin)
or its excipients (refer to Investigator's Brochure, Canagliflozin5)
10.
be a woman participant who is pregnant, or breastfeeding, or planning to become
pregnant while enrolled in this study
11.
are legally incompetent
12.
Criterion modified per Amendment 2
12.1. currently enrolled in an investigational study receiving an investigational study
medication
13.
has a left ventricular assist device
14.
patient identity or association with enrolling network cannot be verified
NOTE: The required source documentation to support meeting the enrollment criteria are noted 
in Section 10.2, Appendix 2: Regulatory, Ethical, and Study Oversight Considerations.
5.3.
Prohibitions and Restrictions
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1.
Refer to details in Section 6.5, Prohibited Medications.
2.
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria.
5.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study may be rescreened. 
Generally, a participant may only be rescreened once, but an additional screening may be allowed 
with concurrence by the sponsor.


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Participant Identification
All potential participants who opt in to participate in the study on the website will receive a unique 
identifier in the study database held by a third-party representative. All data entered and collected 
via the study app with the participant’s smartphone and Fitbit device are time and date stamped 
for completeness. Those participants who electronically sign the remote e-consent but do not enroll 
in the study can be tracked up to the point that they no longer interact with the app. Reports will 
be available to permit a detailed listing of each participant from remote e-consent through the
study.
6.
STUDY INTERVENTION
6.1.
Study Interventions Administered
The study intervention, JNJ-28431754 (canagliflozin), will be provided as immediate-release,
over-encapsulated tablets (capsules) or placebo capsules taken orally once daily before the first 
meal of the day for the duration of the 3-month, double-blind treatment period. The capsules should 
be swallowed intact and participants should not attempt to dissolve them in water. The following 
table provides a description of the study interventions.


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Table 2:
Description of Study Interventions
Group Name
Group 1
Group 2
Study Intervention Name
canagliflozin
placebo
Type
drug
placebo
Dose Formulation
over-encapsulated tablets (capsules)
capsule
Unit Dose Strength
100 mg
0 mg
Dosage Level
100 mg
0 mg
Route of Administration
oral
oral
Use
experimental
placebo-comparator
Sourcing
Provided centrally by the sponsor
Provided centrally by the sponsor
Packaging and Labeling
Individual participant bottles
Individual participant bottles
Child resistant
Child resistant
Brand Name
INVOKANA®
Not applicable


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JNJ-28431754 (canagliflozin) will be manufactured and provided under the responsibility of the 
sponsor. Refer to the Investigator's Brochure, Canigliflozin11 for a list of excipients.
6.2.
Preparation/Handling/Storage/Accountability
All study intervention must be stored at controlled temperatures ranging from 20°C to 25°C (68°F 
to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) and kept out of the reach of 
children.
The drug depot can refer to the pharmacy manual investigational product and procedures manual for 
additional guidance on study intervention preparation, handling, and storage.
The drug depot is responsible for ensuring that all study intervention received at the depot is 
inventoried and accounted for throughout the study. The dispensing of study intervention to the 
participant must be documented at the drug depot.
Study intervention must be handled in strict accordance with the protocol and the container label 
and must be stored at the drug depot in a secure area under appropriate environmental conditions.
Study intervention will be delivered to the participant by a qualified member of the drug 
depot/vendor. Study intervention will be supplied only to participants participating in the study. 
Participants will be instructed on how to store study intervention and how to destroy any unused 
study intervention at the end of the 3-month, double-blind treatment period.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 study intervention groups based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor before initiation of the study.
Randomization will be balanced by using randomly permuted blocks and will be stratified by EF 
(HFrEF or HFpEF) at study entry as recorded in the participant’s EHR.
The interactive web response system (IxR) will generate a randomization code, participant 
randomization number, and kit numbers once consent is completed and the participant is confirmed
eligible by the virtual principal investigator. The kit number will dictate the study intervention 
assignment and the matching study intervention bottle(s) to be shipped to the participant directly 
from the drug distribution vendor.


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Blinding
The IxR will provide the kit number of the study intervention bottle(s) to be dispensed for each 
randomly assigned participant to begin dosing on Day 1 of the double-blind treatment period. 
Based on these randomization codes, study intervention will be packaged and labeled in a manner 
that maintains the double-blinded nature of the study.
The drug depot will not be provided with randomization codes. The codes will be maintained 
within the IxR, which has the functionality to allow the virtual principal investigator or designee
to break the blind for an individual participant.
Under normal circumstances, the blind should not be broken until participants have completed the 
3-month, double-blind treatment period. The Study Responsible Physician or other sponsor 
physician designee may in an emergency determine the identity of the study intervention by 
contacting the IxR. Telephone contact with the sponsor or its designee will be available 7 days per 
week. The date and reason for the unblinding must be documented in the study database. The 
documentation received from the IxR indicating the code break must be retained. All 
randomization codes will be released after completion of the study. The translation of 
randomization codes into treatment and control groups will be disclosed only to those authorized.
Participants who have had their intervention assignment unblinded should continue to perform 
their scheduled evaluations.
6.4.
Study Intervention Compliance
Participants will be instructed and notified by the study app weekly to confirm the number of study 
intervention capsules that they took that week. Study intervention compliance data will be 
monitored bi-weekly and if compliance is not >80%, the participant will be contacted by the call 
center who will re-educate the participant on the importance of diary completion and taking study 
intervention daily.
6.5.
Prohibited Medications
Prohibited medications include other SGLT2i medications (including commercially available 
canagliflozin); participants must not take any other investigational agents during the study.
Medications will be reviewed monthly through medical claims data by the sponsor or designee.
The sponsor must be notified as soon as possible of any instances in which prohibited therapies 
are administered.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant's study intervention must be discontinued during the 3-month, double-blind treatment 
period if:
!
the participant has started another SGLT2i
!
the participant has been diagnosed with T1DM


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!
for safety reasons or tolerability reasons (eg, adverse event), it is in the best interest of the 
participant to discontinue study intervention
!
the participant develops severe renal impairment or End Stage Renal Disease, or is on dialysis
!
the participant becomes pregnant
!
the participant develops diabetic ketoacidosis
!
the participant develops a new active skin ulcer, osteomyelitis, gangrene, or critical ischemia 
of the lower extremity or has an amputation.
The participant may choose to discontinue the study intervention only and remain in the study. In 
this case, the participant will continue to perform assessments (KCCQ, PGI-S, PGIC) and allow 
continued passive data collection from the app, Fitbit, and medical claims. If contacted during the 
study, the call center or designee will inform the participant of the importance to the study and 
results to have ongoing ascertainment of assessments and vital status.
Additional information on informed consent for collection of vital status can be found in 
Section 10.2, Appendix 2: Regulatory, Ethical, and Study Oversight Considerations.
7.1.1.
Temporary Discontinuation of Study Intervention
Study intervention may be temporarily discontinued; however, these interruptions should be kept 
to a minimum. Study intervention can be resumed when the participant, the virtual principal 
investigator, or the participant’s physician deems it is appropriate to do so.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
!
lost to follow-up
!
withdrawal of consent
!
death
In the event a participant withdraws consent and does not agree to any kind of follow-up and 
specifically refuses any further contact with the call center or designee, this must be documented 
in the study database. If a participant is lost to follow-up, vital status will still be attempted for 
collection at study end through the participant’s physician, medical claims, or public information 
according to local guidelines and as allowed by local regulations.
If a participant is lost to follow-up, every reasonable effort must be made by the call center or 
designee to contact the participant to determine vital status (eg, alive or dead) and the reason for 
discontinuation/withdrawal. This should include repeated telephone calls, certified letters, email 
requests, etc. The study screeners and app will obtain primary telephone contact number (eg, 
smartphone numbers), as well as other contact information (eg, email addresses) from participants
before randomization. In addition, the call center should emphasize the importance of follow-up 
information to the participant before randomization. Follow-up can also be done with the help of 
the study site personnel. The measures taken to obtain follow-up information must be documented.


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Unless consent is specifically withdrawn, participants are expected to be followed up through 1 of 
the alternative follow-up mechanisms described above.
Before withdrawing from the study, participants who request to withdraw from the study should 
be asked if they agree to be contacted to obtain follow-up information.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (SoA) summarizes the frequency and timing of effectiveness, medical 
resource utilization, health economic, and safety measurements applicable to this study.
Study-Specific Materials
The participants will be provided with the following supplies prior to starting the study:
!
study intervention supply
!
Fitbit device
!
instruction manual(s) and patient drug information handouts.
8.1.
Effectiveness Assessments
The primary effectiveness endpoint (KCCQ TSS) will be assessed at baseline and Weeks 2, 4, 6, 
and 12 during the double-blind treatment period (first 3 months) and afterwards at 6 and 9 months 
when no study intervention is administered. The following sensor data will be obtained from the 
Fitbit: step count and floors climbed.
8.1.1.
KCCQ Scores
The KCCQ is a 23-item, self-administered questionnaire on the study app and requires, on average, 
4 to 6 minutes to complete. It was developed to measure the patient’s perception of their health 
status, including their HF symptoms, impact on physical and social function and how their HF 
impacts the quality of life. It scored by assigning a number for each response beginning with 1 that 
implies the lowest level of functioning and summing items within each domain, dividing by the 
range and multiplying by 100.10 Missing values within each domain are assigned the average of 
the answered items within that same domain, presuming that at least half of the items within that 
domain are completed. Scale scores are transformed into values ranging from 0 to 100, with higher 
scores indicating more favorable health status.10
The answers provided by participants to the KCCQ’s questions are used to calculate scores for the 
following 10 scales:
!
Physical Limitation: a measure of how much a patient’s routine activities are hampered by 
symptoms of HF
!
Symptom Stability: a measure of whether a participant’s symptoms have changed over the 
past 2 weeks


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!
Symptom Frequency: a measure of how often a participant has HF symptoms
!
Symptom Burden: a measure of how much the participant’s symptoms bother them
!
Total Symptom: a combined measure of the symptom frequency and burden scales
!
Social Limitation: a measure of how much a participant’s social and work activities are limited
by their HF symptoms
!
Self-Efficacy: a measure of how well a participant can manage her care, find answers and help
!
Quality of Life: a measure of the overall impact of a participant’s HF on their perceived quality 
of life
!
Clinical Summary: a combined measure of symptoms and physical limitations, congruent with 
the considerations a physician uses in assigning their NYHA classification
!
Overall Summary: a combined measure of the participant’s physical limitation, total 
symptom, social limitation, and quality of life scores.
In this study, at screening/baseline, KCCQ overall summary score will be evaluated to determine 
participant eligibility into the study. All other KCCQ domains and summary scores will also be 
calculated at baseline and at subsequent post-baseline time points respectively.
8.1.2.
Actigraphy Measurements
Once randomized into the study, data from the Fitbit device on each participant will be collected 
continuously pertaining to the total step counts and total floors climbed for the entire duration of 
the study. Actigraphy measures (ie, step counts and floors climbed) will be examined in relation 
to the PRO measures and clinical outcomes to better characterize treatment effect on daily activity.
8.2.
Exploratory Assessments
8.2.1.
Patient Global Impression of Change (PGIC) Scores
The PGIC is a global index that is used to rate the overall status of the participant related to the 
participant’s condition. It is rated by the participant and is based on the single question, “Since the 
start of the treatment you’ve received in this study, your heart failure symptoms are”, where 1=very 
much improved, 2=somewhat improved, 3=a little improved, 4=no change, 5=a little worse, 
6=somewhat worse, and 7=very much worse. Refer to Section 10.4, Appendix 4: Patient Global 
Impression of Change (PGIC).
8.2.2.
Patient Global Impression of Severity (PGI-S) Scores
The PGI-S is a global index that is used to rate the severity of a specific condition. It is rated by 
the participant and is based on the single question, “Considering all aspects of your heart failure 
symptoms right now, would you say your heart failure symptoms are”, where 1=none, 2=mild, 
3=moderate, 4=severe, and 5=very severe. Refer to Section 10.5, Appendix 5: Patient Global 
Impression of Severity (PGI-S).


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8.2.3.
Participant Satisfaction Survey
An optional participant satisfaction survey to assess the participant’s satisfaction with the virtual 
design of the study and use of the Fitbit device in the study will be provided to the participant at 
the end of study. Refer to Section 10.6, Appendix 6: Participant Satisfaction Survey.
8.2.4.
Healthcare Resource Utilization and Health Economics
Healthcare Resource Utilization (HRU) and health economics data associated with medical 
encounters will be collected for all participants during the study. Protocol-mandated procedures, 
tests, and encounters are excluded. The data collected may be used to conduct exploratory 
economic analyses and will include:
!
number and duration of first hospitalizations/readmissions (overall inpatient visit length of 
stay) for HF or any other reason
!
number and duration of first hospitalizations/readmissions (overall inpatient visit length of 
stay) for any other events
!
number of emergency room visits
!
discharge destination
8.3.
Adverse Events and Serious Adverse Events and Special Situations
Participants will be instructed to self-report any adverse events to a call center. In addition, this 
information may be discovered by the call center during interaction with the participant. Once 
identified, the call center will complete and submit a solicited safety reporting form to Janssen 
Global Medical Safety (GMS) per the sponsor’s standard operating procedure. Queries for these 
cases will go to the call center/and virtual principal investigator as appropriate. If follow-up is 
needed with the participant’s treating physician, it will be done either through the virtual principal 
investigator, who may contact the treating physician directly, as agreed upon in the ICF. All SAEs
will be assessed by Janssen GMS for potential suspected unexpected serious adverse reactions 
(SUSARs) for expedited regulatory reporting.
Medical claims adverse event data will be reviewed and evaluated including potential SUSAR 
assessment and regulatory reporting in aggregate at the end of the 3-month, double-blind treatment 
period when the unblinded data are available. In addition, for this time period, self-reported 
adverse events from the call center will be summarized in a listing. Serious adverse event data 
from medical claims for the 9-month study period will be aggregated by treatment assignment.
Self-reported adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be reported by preferred term and by T2DM and non-T2DM. 
Adverse events collected from medical claims will be aggregated based on diagnosis codes for the 
incidences of non-endpoint SAEs (ie, SAEs leading to hospitalizations, ED visits) and adverse 
events of interest between groups reported by T2DM and non-T2DM. Discontinuations will be 
summarized based on any available data.


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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
Adverse events will be captured through medical claims (from the time of informed consent to the 
end of study) and by the call center (from the time of informed consent until 30 days after the end 
of treatment). After the treatment period plus 30 days, serious adverse events will be identified 
solely through medical claims data. Adverse events that occur during the treatment period plus 
30 days identified from medical claims will be aggregated by treatment assignment when 
unblinding is available. In addition, for this time period, self-reported adverse events from the call 
center will be summarized in a listing. Serious adverse event data from medical claims for the 
9-month study period will be aggregated by treatment assignment.
8.3.2.
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the virtual principal investigator (and the head of the 
investigational institute where required) all SUSARs. The virtual principal investigator (or sponsor 
where 
required) 
must 
report 
SUSARs 
to 
the 
appropriate 
Independent 
Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities 
unblinded. The virtual principal investigator and IEC/IRB will receive a blinded SUSAR summary, 
unless otherwise specified.
8.3.3.
Pregnancy
Female participants and male participants with a partner becoming pregnant will be instructed to 
call the call center for any pregnancy. The call center will report the pregnancy to the sponsor 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification form. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered adverse events and must also be self-reported by the 
participants to the call center. Any participant who becomes pregnant during the study must be 
promptly discontinued from the study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
8.3.4.
Adverse Events of Interest
Adverse events of interest include all severe hypoglycemic events, acute kidney injury, fractures, 
diabetic ketoacidosis, and lower limb amputation.
In addition, the following adverse events will be examined: hypotension; Fournier’s gangrene; 
genital mycotic infections; urinary tract infections (including urosepsis and pyelonephritis); 
increased urination; and hypersensitivity reactions including angioedema and anaphylaxis.


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9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the effectiveness and safety data is 
outlined below. Specific details will be provided in the SAP.
The primary study objective will be addressed by comparing the mean change in KCCQ TSS from 
baseline to Month 3 between the study intervention groups. The key secondary study objective 
will involve a comparison between the 2 randomized groups in terms of the mean difference in 
daily step counts from baseline to Month 3. For analyzing the primary, secondary, and exploratory 
objectives, an intent-to-treat (ITT) population comprising of all randomized participants will be 
used. Specific imputation rules for missing data (eg, missing KCCQ TSS, daily step count) will be 
applied, if warranted, and will be specified in the SAP before the final database lock. Descriptive 
statistics such as mean, median, standard deviation, interquartile range, minimum and maximum 
will be used to summarize continuous variables. Counts and proportions will be used to summarize 
categorical variables. Graphical data displays (eg, box plots) may be employed to summarize data. 
For time to event variables, Kaplan-Meier estimates over time will be plotted. All statistical tests 
will be two-sided and performed at the 5% significance level unless otherwise specified. No 
multiplicity adjustment to the overall Type I error rate will be applied when analyzing the 
exploratory variables.
9.1.
Statistical Hypotheses
For the primary effectiveness endpoint, the null hypothesis is that the canagliflozin 100 mg is not 
different from placebo with respect to the mean KCCQ TSS change from baseline at Month 3. For 
the first key secondary effectiveness endpoint of daily step count, the null hypothesis is that 
canagliflozin 100 mg is not different from placebo with respect to the mean daily step count.
9.2.
Sample Size Determination
The primary effectiveness endpoint is the change from baseline in the KCCQ TSS at the end of 
the 3-month double-blind treatment period. Although a 5-point improvement in the KCCQ TSS is 
generally viewed as clinically meaningful,5,29 recent studies16,21 have shown that improvements in 
the range of 3 to 5 points on the KCCQ TSS are equally meaningful in the overall HF-related 
health status measured by the KCCQ over a 12-week time period. Based on the evidence from 
these studies, the current study is powered to detect a mean change from baseline of 3 points in 
the KCCQ TSS between canagliflozin 100 mg and placebo groups at 12 weeks. Assuming a 
significance level of 5% and a standard deviation of 18 points for mean change in KCCQ TSS, a 
total of 1,900 participants will be randomized in this study providing approximately 95% power. 
This sample size is adequate to account for a potential 5% dropout rate.


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9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Table 3:
Analysis Populations
Population
Description
Enrolled
All participants who sign the ICF
Intent-to-Treat 
(ITT)
All randomized participants
Per Protocol 
(PP)
A subset of the ITT population. Randomized participants who received study drug and with 
major protocol deviations will be excluded from the PP population. Major protocol deviations 
will be defined in the SAP.
9.4.
Statistical Analyses
9.4.1.
Handling of Missing Data
Missing data affecting the primary endpoint change in KCCQ TSS will be addressed via the 
MMRM method that assumes missingness at random (MAR). Specific imputation rules including 
statistical modeling approaches may be employed when such an assumption is not valid. In cases 
where individual items in the KCCQ domains are missing or not completed at required times, 
appropriate rules to impute missing item scores will be specified based on the KCCQ manual. 
Sensitivity analyses will be conducted to assess impact of missing data on key study results. 
Further details about the imputation rules and sensitivity analyses will be provided in the SAP.
9.4.2.
Effectiveness Analyses
9.4.2.1.
Primary and Secondary Effectiveness Analyses
The primary and key secondary effectiveness analyses will be based on the ITT analysis population 
(using all randomized participants).
As KCCQ TSS is measured repeatedly over time (ie, at baseline, Week 2, Week 4, Week 6, and 
Week 12 respectively), the primary effectiveness endpoint (change in KCCQ TSS from baseline 
to Month 3) will be analyzed by a mixed effect model repeated measures (MMRM) method 
simultaneously adjusting for study intervention group, stratification factor (HFrEF versus HFpEF), 
time, time by study intervention group, and baseline KCCQ TSS value as covariates. An 
unstructured covariance structure will be assumed across study intervention groups to model the 
within-participant errors. The primary comparison will be based on the difference in least squares 
between treatments at Month 3. The treatment difference in the least squares means and their 2-
sided 95% confidence interval (CI) will be provided. An MMRM model accounts for data missing 
at random.
A responder analysis will also be performed when comparing proportions of participants with a 5-
(or 10-) point improvement in KCCQ TSS from baseline between the study intervention groups. 
This will be based on a two-sample difference in proportions test along with a 95% confidence 
interval for the difference in 2 proportions. Additionally, empirical cumulative distribution 
functions of the KCCQ TSS and other domain scores will be presented.


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The primary effectiveness endpoint will also be analyzed by subgroups defined by age, gender, 
race and key baseline disease/demographic characteristics using the MMRM approach described 
above. Further details will be provided in the SAP. Quantitative and/or qualitative interactions for 
each subgroup and treatment will be identified. Qualitative interactions will be investigated further 
by the Gail and Simon test9 and interpreted accordingly.
The first key secondary endpoint of daily step count will be tested once the primary endpoint is 
shown to be significant at the 5% significance level using a two-sided t-test. This approach will 
control for the overall Type I error rate at 5%.
For the second key effectiveness endpoint, an MMRM model (like that used in the analysis of the 
primary endpoint) will be employed to summarize changes in KCCQ individual domain scores 
(physical limitation, quality of life, clinical summary, and overall) from baseline to Month 3. This 
hypothesis will be independently tested at 5% without any control for overall Type I error rate.
9.4.2.2.
Exploratory Analyses
Exploratory analyses will be performed with no adjustment for multiplicity and include the 
following:
!
summary statistics of PGIC and PGI-S scores
!
associations (correlations and/or categorical association measures) between digital markers 
(step count and floors climbed) and clinical events such as need for outpatient intravenous 
therapies, ED visits, and hospitalizations
!
tabulation and comparison of total HRU and health economics data across groups.
!
descriptive statistics (eg, mean, median, and standard deviation) of daily floors climbed
!
association between the KCCQ change from baseline to Month 3 and the PGIC at Month 3 
will be examined and summarized
!
time to death
!
descriptive statistics of the participant's satisfaction with his/her experience with the virtual 
design at the end of the study.
9.4.3.
Adverse Events Analysis
Adverse events reported to the call center will be assessed by Janssen GMS for causality and 
meeting SUSAR reporting requirements. Self-reported adverse events will be coded according to 
MedDRA and will be reported by preferred term by T2DM and non-T2DM. Adverse events 
collected from medical claims will be aggregated based on diagnosis codes for the incidences of 
non-endpoint SAEs (ie, SAEs leading to hospitalizations, ED visits) and adverse events of interest 
between groups reported by T2DM and non-T2DM. Discontinuations will be summarized based 
on any available data. Adverse events reported from the call center will be reported separately 
from those obtained from the medical claims data. Self-reported adverse events from the call center 
will be summarized in a listing.


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9.4.4.
Healthcare Resource Utilization and Health Economics Analyses
Healthcare resource utilization (HRU) and health economics data will be descriptively summarized 
by intervention group.
9.5.
Interim Analysis
No interim analysis is planned for this study.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Abbreviations
ACEi
angiotensin-converting enzyme inhibitor
AE
adverse event
AHA
antihyperglycemic agent
ARB
angiotensin II receptor blocker
ARNi
angiotensin receptor-neprilysin inhibitor
BB
beta blocker
CANVAS
short title for study, Canagliflozin Cardiovascular Assessment Study
CANVAS-R
short title for study, Canagliflozin Cardiovascular Assessment Study-Renal
CI
confidence interval
CREDENCE
short title for study, Canagliflozin and Renal Events in Diabetes with Established Nephropathy 
Clinical Evaluation Trial
CV
cardiovascular
CVD
cardiovascular disease
DKA
diabetic ketoacidosis
DMC
Data Monitoring Committee
ED
emergency department
EHR
electronic health record
EMPA
empagliflozin
ESKD
End Stage Kidney Disease
GCP
Good Clinical Practice
GMS
Global Medical Safety
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced ejection fraction
HHF
hospitalization for heart failure
HR
hazard ratio
HRU
healthcare resource utilization
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INVOKANA
canagliflozin
IRB
Institutional Review Board
ITT
intent-to-treat
IxR
interactive web response system
KCCQ
Kansas City Cardiomyopathy Questionnaire
MACE
major adverse cardiovascular events
MAR
missing at random
MDDT
Medical Device Development Tools
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MMRM
mixed effect model repeated measure
NYHA
New York Heart Association
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PQC
Product Quality Complaint
PRO
patient-reported outcome(s) (paper)
SAE
serious adverse event
SAP
statistical analysis plan
SGLT2
sodium-glucose co-transporter 2
SGLT2i
sodium-glucose co-transporter 2 inhibitor
SoA
schedule of activities


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SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TSS
Total Symptom Score
US
United States


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10.2
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Virtual Principal Investigator Responsibilities
The virtual principal investigator or designee is responsible for ensuring that the study is performed 
in accordance with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and 
applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Amendments
The sponsor will not modify this protocol without a formal amendment by the sponsor. All 
protocol amendments must be issued by the sponsor. Protocol amendments must not be 
implemented without prior IEC/IRB approval, or when the relevant competent authority has raised 
any grounds for non-acceptance, except when necessary to eliminate immediate hazards to the 
participants, in which case the amendment must be promptly submitted to the IEC/IRB and 
relevant competent authority. When the change(s) involve only logistic or administrative aspects 
of the study, the IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the virtual principal investigator or designee will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 
situation and agree on an appropriate course of action. These will be recorded by the sponsor.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention 
to the drug depot:
!
protocol and amendment(s), if any, signed and dated by the principal investigator
!
a copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 


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specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.
!
name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If the principal investigator 
is a member of the IEC/IRB, documentation must be obtained to state that this person did not 
participate in the deliberations or in the vote/opinion of the study.
!
regulatory authority approval or notification, if applicable
!
signed and dated statement of virtual principal investigator (eg, Form FDA 1572) and current 
curriculum vitae (CV), if applicable
!
documentation of virtual principal investigator or designee qualifications (eg, curriculum 
vitae)
!
completed virtual principal investigator or designee financial disclosure form, where required
!
signed and dated clinical trial agreement, which includes the financial agreement
!
any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first
participant:
!
completed virtual principal investigator or designee financial disclosure forms
!
documentation of virtual principal investigator or designee qualifications (eg, curriculum 
vitae).
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the virtual principal investigator or designee (or sponsor where 
required) will provide the IEC/IRB with current and complete copies of the following documents 
(as required by local regulations):
!
final protocol and, if applicable, amendments
!
sponsor-approved ICF (and any other written materials to be provided to the participants)
!
Investigator's Brochure, Canigliflozin11 (or equivalent information) and amendments/addenda
!
sponsor-approved participant recruiting materials
!
information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable
!
virtual principal investigator or designee curriculum vitae or equivalent information (unless 
not required, as documented by the IEC/IRB)
!
information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants
!
any other documents that the IEC/IRB requests to fulfill its obligation.


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This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study, the principal investigator (or sponsor where required) will send the following 
documents and updates to the IEC/IRB for their review and approval, where appropriate:
!
protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)
!
revision(s) to ICF and any other written materials to be provided to participants
!
if applicable, new or revised participant recruiting materials approved by the sponsor
!
new edition(s) of the Investigator's Brochure, Canigliflozin11 and amendments/addenda
!
summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)
!
reports of adverse events that are of interest, special interest, serious, unlisted/unexpected, and 
associated with the study intervention
!
new information that may adversely affect the safety of the participants or the conduct of the 
study
!
deviations from or changes to the protocol to eliminate immediate hazards to the participants
!
report of deaths of participants under the virtual principal investigator's care
!
notification if a new virtual principal investigator is responsible for the study
!
development Safety Update Report and Line Listings, where applicable
!
any other requirements of the IEC/IRB.
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the virtual principal investigator or designee (or sponsor where required) 
will notify the IEC/IRB about the study completion (if applicable, the notification will be 
submitted through the head of investigational institution).
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.


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FINANCIAL DISCLOSURE
The virtual principal investigator or designee will provide the sponsor with sufficient, accurate 
financial information in accordance with local regulations to allow the sponsor to submit complete 
and accurate financial certification or disclosure statements to the appropriate regulatory 
authorities. The virtual principal investigator is responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.
INFORMED CONSENT (REMOTE E-CONSENT) PROCESS
Each participant must give remote e-consent according to local requirements after the nature of 
the study has been fully explained. The remote e-consent must be electronically signed within the 
study app before the performance of any study-related activity. The remote e-consent that is/are 
used must be approved by both the sponsor and by the reviewing IRB and be in a language that 
the participant can read and understand. The remote e-consent should be in accordance with 
principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, 
applicable regulatory requirements, and sponsor policy. After having obtained the consent, a copy 
of the remote e-consent must be sent to the participant.
In this study, a remote e-consent process will be utilized. Before enrollment in the study, the 
participant will have an opportunity to read through the remote e-consent which will detail the 
aims, methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail. The remote e-consent will explain that their 
participation is voluntary and that they may withdraw consent to participate at any time. They will 
be informed that choosing not to participate will not affect the care they will receive. Finally, they 
will be told that their records may be accessed by health authorities and authorized sponsor 
personnel without violating their confidentiality, to the extent permitted by the applicable law(s) 
or regulations. By electronically signing the remote e-consent the participant is authorizing such 
access, which includes permission to obtain information about his or her survival status. It also 
denotes that they are agreeing to allow recontact by the study sponsor for the purpose of obtaining 
consent for additional evaluations, if needed.
If the participant has any questions about the study related to the remote e-consent process prior 
to providing their electronic signature, they will be provided with an opportunity to discuss these 
questions with the virtual principal investigator via phone and/or a contact at the study call center. 
Once the participant understands all aspects of the remote e-consent, consent should be 
appropriately recorded by means of the participant’s personally dated signature via electronic 
signature. After having obtained the consent, the participant will receive a copy of the remote 
e-consent via email (after the participant has verified his or her email address) for their records.


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DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities.
The participant has the right to request through the virtual principal investigator access to his or 
her personal data and the right to request rectification of any data that are not correct or complete. 
Reasonable steps will be taken to respond to such a request, taking into consideration the nature 
of the request, the conditions of the study, and the applicable laws and regulations.
COMMITTEES STRUCTURE
An Independent Scientific Advisory Committee comprised of experts in the management of 
patients with HF and sponsor representatives will be commissioned for this study. Committee 
membership and responsibilities will be documented in the committee charter(s).
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding JNJ-28431754 (canagliflozin)
or the sponsor's operations (eg, patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the sponsor to the 
investigator and not previously published, and any data, generated as a result of this study, are
considered confidential and remain the sole property of the sponsor. The virtual principal 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study and will not use it for other purposes without the sponsor's prior written 
consent.
The virtual principal investigator understands that the information developed in the study will be 
used by the sponsor in connection with the continued development of JNJ-28431754 
(canagliflozin), and thus may be disclosed as required to other clinical investigators or regulatory 
agencies. To permit the information derived from the clinical studies to be used, the virtual 
principal investigator is obligated to provide the sponsor with all data obtained in the study.


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The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data as per protocol. Recruitment performance or specific expertise related to the 
nature and the key assessment parameters of the study will be used to determine a coordinating 
investigator for the study, if appropriate.
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data and 
information without approval from the virtual principal investigator. The virtual principal 
investigator has the right to publish data after the primary data are published. If the virtual principal 
investigator wishes to publish information from the study, a copy of the manuscript must be 
provided to the sponsor for review at least 60 days before submission for publication or 
presentation. Expedited reviews will be arranged for abstracts, poster presentations, or other 
materials. If requested by the sponsor in writing, the investigator will withhold such publication 
for up to an additional 60 days to allow for filing of a patent application. In the event that issues 
arise regarding scientific integrity or regulatory compliance, the sponsor will review these issues 
with the investigator. The sponsor will not mandate modifications to scientific content and does 
not have the right to suppress information. For multicenter study designs and substudy approaches, 
secondary results generally should not be published before the primary endpoints of a study have 
been published. Similarly, the principal investigator will recognize the integrity of the study by 
not submitting data for publication data until the results from the completed study have been 
submitted for publication, within 18 months after the study end date. Authorship of publications 
resulting from this study will be based on the guidelines on authorship, such as those described in 
the International Committee of Medical Journal Editors Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals, which state that the 
named authors must have made a significant contribution to the conception or design of the work; 
or the acquisition, analysis, or interpretation of the data for the work; and drafted the work or 
revised it critically for important intellectual content; and given final approval of the version to be 
published; and agreed to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence and the results of clinical studies as required 
by law.


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DATA QUALITY ASSURANCE
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded as a basis for standard medical care must be available for the following: participant 
identification, eligibility, and study identification; record of all adverse events and follow-up of 
adverse events; and date of study completion and reason for early discontinuation of study 
intervention or withdrawal from the study, if applicable. Many of the assessments in this study 
(date of signed informed consent, activity data, KCCQ data) will be collected directly from the 
participant and therefore the data received is from a direct source.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the virtual principal investigator or designee before the study.
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, baseline KCCQ) and 
documented in the source documents.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the virtual principal investigator/call center will 
maintain all source documents that support the data collected from each participant, as well as all 
study documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The virtual principal investigator/call center will take measures to prevent accidental or premature 
destruction of these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the virtual principal investigator/call center as to when these 
documents no longer need to be retained.
If the virtual principal investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the virtual principal investigator relocate or dispose of any 
study documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the virtual principal investigator/call center must permit 
access to such reports.


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STUDY AND SITE CLOSURE
Study Termination
The sponsor reserves the right to terminate the study at any time for any reason at the sole 
discretion of the sponsor.


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Appendix 3: Kansas City Cardiomyopathy Questionnaire (KCCQ)
Appendix 3 provides a representative example of the scale questions that will be used in this study.


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10.4
Appendix 4: Patient Global Impression of Change (PGIC)
Appendix 4 provides a representative example of the scale questions that will be used in this study.
Since the start of the treatment you’ve received in this study, your heart failure symptoms are: 
(select one response)
1.
Very much improved
2.
Somewhat improved
3.
A little improved
4.
No change
5.
A little worse
6.
Somewhat worse
7.
Very much worse


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Appendix 5: Patient Global Impression of Severity (PGI-S)
Appendix 5 provides a representative example of the scale question that will be used in this study.
Considering all aspects of your heart failure symptoms right now, would you say your heart failure 
symptoms are: (select one response)
1.
None
2.
Mild
3.
Moderate
4.
Severe
5.
Very Severe




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Appendix 7: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to All Adverse 
Events under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:
!
results in death
!
is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)
!
requires inpatient hospitalization or prolongation of existing hospitalization
!
results in persistent or significant disability/incapacity
!
is a congenital anomaly/birth defect
!
is a suspected transmission of any infectious agent via a medicinal product.
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study intervention and the event (eg, death from anaphylaxis), the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a component 
of the study endpoint (eg, all-cause mortality).


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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For JNJ-28431754 (canagliflozin), the expectedness of an 
adverse event will be determined by whether or not it is listed in the IB.
ATTRIBUTION DEFINITIONS
Assessment of Causality
The causal relationship to study treatment is determined by Janssen Global Medical Safety (GMS). 
The following selection should be used to assess all adverse events (AE).
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
SEVERITY CRITERIA
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:
!
overdose of a sponsor study intervention
!
suspected abuse/misuse of a sponsor study intervention
!
accidental or occupational exposure to a sponsor study intervention
!
any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study 
intervention
!
unexpected therapeutic or clinical benefit from use of a sponsor study intervention
!
medication error, intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson & 


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Johnson medicinal product, eg, product name confusion, product label confusion, intercepted 
prescribing or dispensing errors)
!
exposure to a sponsor study intervention from breastfeeding.
Special reporting situations should be reported. Any special reporting situation that meets the 
criteria of a serious adverse event should also be reported.
PROCEDURES
All Adverse Events
Adverse events, regardless of seriousness, severity, or presumed relationship to study intervention, 
must be recorded using medical terminology on the solicited AE form. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection").
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:
!
study number
!
statement, in the local language(s), that the participant is participating in a clinical study
!
call center name and 24-hour contact telephone number
!
site number
!
participant number
!
any other information that is required to do an emergency breaking of the blind.
Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the participant's participation in the study, must be followed until any of 
the following occurs:
!
the event resolves
!
the event stabilizes
!
the event returns to baseline, if a baseline value/status is available
!
the event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
!
it becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)


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!
suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a participant's participation in a study must be reported as a 
serious adverse event, except hospitalizations for the following:
!
hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)
!
surgery or procedure planned before entry into the study (must be documented). Note: 
hospitalizations that were planned before the signing of the ICF, and where the underlying 
condition for which the hospitalization was planned has not worsened, will not be considered 
serious adverse events. Any adverse event that results in a prolongation of the originally 
planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a participant in a study within 24 hours of the last dose of study intervention, 
whether or not the event is expected or associated with the study intervention, is considered a 
serious adverse event.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of participants, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates will 
be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported by the call center to the sponsor within 24 hours after being 
made aware of the event.
If the product defect is combined with a serious adverse event, the call center must report the PQC 
to the sponsor according to the serious adverse event reporting timelines (refer to Section 8.3.1, 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information). 
A sample of the suspected product should be maintained for further investigation if requested by 
the sponsor.


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Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.


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10.8
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
02 June 2020
Amendment 1
07 February 2020
Original Protocol
07 November 2019
Amendment 2 (02 June 2020)
Overall Rationale for the Amendment: The overall reasons for the amendment are to 1) clarify 
inclusion/exclusion criteria for recruitment centers, 2) more accurately identify patients with heart 
failure in inclusion/exclusion criteria, and 3) represent patients with heart failure in medical claims 
over time and between sites of care.
Section Number
and Name
Description of Change
Brief Rationale
1.1. Synopsis (Objectives and 
Endpoints, Overall Design, 
Secondary and Exploratory 
Evaluations, Statistical
Methods);
1.3. Schedule of Activities 
(SoA);
3. Objectives and Endpoints;
4.1. Overall Design;
8.1. Effectiveness Assessments;
9.4.2.2. Exploratory Analyses
The term ‘stairs’ was changed to ‘floors’.
To align with the data 
obtained from the Fitbit 
device, which reports this 
metric as ‘floors’ climbed 
not ‘stairs’ climbed.
1.1. Synopsis (Adverse Event 
Data Collection, Adverse Event 
Evaluations);
3. Objectives and Endpoints
The word ‘self-reported’ was replaced by 
‘adverse’ and ‘date of the first dose of study 
intervention’ was replaced by ‘time of informed 
consent’.
To ensure consistency for 
adverse event (AE) 
collection and timepoints 
across the protocol.
1.1. Synopsis (Adverse Event 
Data Collection, Adverse Event 
Evaluations);
3. Objectives and Endpoints
The word ‘adverse event’ was added with 
respect to medical claims data.
To clarify that medical 
claims data include AE
data.
1.1. Synopsis (Overall Design);
1.3. Schedule of Activities 
(SoA);
4.1. Overall Design;
4.2. Scientific Rationale for 
Study Design;
5.1. Inclusion Criteria 
(Criterion #4)
The upper threshold of the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) for 
baseline overall summary score was changed 
from <80 to ≤80.
To include participants 
with KCCQ summary 
score of 80.
1.1. Synopsis (Overall Design);
1.3. Schedule of Activities 
(SoA);
4.1. Overall Design;
4.2. Scientific Rationale for 
Study Design;
The lower threshold (<40) of the KCCQ for 
baseline overall summary score was removed.
To ensure that a larger 
number of participants 
have an opportunity to 
experience measurable 
health status benefit from 
treatment as there is no a 


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Section Number
and Name
Description of Change
Brief Rationale
5.1. Inclusion Criteria 
(Criterion #4)
priori reason to presume 
that more symptomatic 
participants can’t benefit 
from treatment.
4.2. Scientific Rationale for 
Study Design
The participant eligibility was extended to 
include those with New York Heart Association 
(NYHA) Class IV.
1.1. Synopsis (Overall Design);
4.1. Overall Design
‘Dates of deaths’ was added to the list of study 
assessments.
To correlate with the 
exploratory endpoint ‘time 
to death’ and also for 
consistency.
1.1. Synopsis (Secondary and 
Exploratory Evaluations, 
Statistical Methods);
9.4.2.2. Exploratory Analyses
The ‘time to death’ evaluation was added to the 
list of secondary and exploratory evaluations.
To maintain consistency 
across the protocol. The 
term was omitted by 
mistake in the previous 
versions.
1.1. Synopsis (Intervention 
Groups and Duration);
4.1. Overall Design
The term ‘claims’ was deleted from collection of 
data during the no treatment period.
To explain the wider scope 
of data collection during 
the no treatment period 
(not just claims data).
1.1. Synopsis (Adverse Event 
Analyses);
8.3. Adverse Events and 
Serious Adverse Events and 
Special Situations;
9.4.3. Adverse Events Analysis
The term ‘self-reported’ was added.
To clarify AE analysis 
process
1.2. Schema
The study schema was updated.
To align with the changes 
in the study design and 
Schedule of Activities.
1.3. Schedule of Activities 
(SoA)
Kept Screening and Baseline in separate 
columns.
To clarify that Screening 
and Baseline are 2 distinct 
periods in this study.
1.3. Schedule of Activities 
(SoA);
4.2. Scientific Rationale for 
Study Design;
5. Study Population
Screening window was increased from 21 days 
to 28 days.
To increase the screening 
period from 21 days to 28 
days to accommodate 
various study set up 
activities like electronic 
health record (EHR) 
reviews, app set-up and 
coordination of 
consenting, participants 
discussing with their 
physicians, families, etc 
and to keep the 7-day 
baseline period and specify 
the baseline activities.
4.2. Scientific Rationale for 
Study Design (Length of Study 
Periods)
Provided clarity on requirement of baseline 
period of 7 days. The text was modified as: The 
screening period of 3 weeks 28 days allows for 
an appropriate length of time for screening 
procedures to determine study eligibility (with 
EHR reviews, app set-up, completion of the 
KCCQ, and consenting). The baseline period 
of 7 days begins upon randomization and 
allows for shipment of the study drug and 
Fitbit device to the participant.
2. Introduction;
4.2.1. Study-Specific Ethical 
Design Considerations
Information on Food and Drug Administration
approval of dapagliflozin was added.
To explain the 
dapagliflozin information 
and to illustrate the benefit 
of including participants 
with heart failure with 
preserved ejection fraction 
(HFpEF) in this study.


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Section Number
and Name
Description of Change
Brief Rationale
2.2. Benefit/Risk Assessment
The text ‘or for use in patients with HFpEF ’ 
was added.
To indicate that there may 
be a benefit in HFpEF 
participants where 
dapagliflozin doesn’t have 
an indication.
4.1. Overall Design
Specified that inclusion/exclusion criteria, 
healthcare resource utilization, and relevant 
concomitant medications will be included in the 
claims data monitoring.
To maintain consistency 
with the other sections of 
the protocol.
4.2. Scientific Rationale for 
Study Design;
Information of KCCQ was updated.
To update that KCCQ was 
recently qualified by 
Center for Drug 
Evaluation and Research 
as a patient reported 
outcome instrument for 
use in clinical trials in 
heart failure.
4.2. Scientific Rationale for 
Study Design;
8.1.2. Actigraphy 
Measurements
Added description on actigraphy measurements.
To add the description on 
Fitbit data collection that 
was missed in the previous 
protocol version.
4.4. End of Study Definition
The following text was modified as: A 
participant will be considered to have ended
completed the treatment period of the study (at 
3 months), regardless of whether the participant 
has completed is on the study intervention, if he 
or she has completed assessments at Month 3 of 
the double-blind treatment period, or withdrew 
earlier from the treatment, or at the time of death 
for participants who died prior to the Month 3 
visit assessment.
To clarify that the 
participant could have 
ended the treatment period 
but not have completed the 
study intervention.
4.4. End of Study Definition
The term ‘clinical research organization’ was 
added.
To clarify that the study 
partner prefers to a clinical 
research organization 
partner and not participant.
5.1. Inclusion Criteria;
5.2. Exclusion Criteria;
5.2. Exclusion Criteria (Criteria 
#1, 3, 5, 6, and 7)
Clarified that each potential participant was
required to satisfy the inclusion/exclusion 
criteria ‘prior to enrollment (consent date)’.
The extra term ‘prior to enrollment ’ was deleted 
from exclusion criteria 1, 3, and 5.
The extra term ‘of the screening visit’ was 
deleted from exclusion criterion 6.
The extra term ‘of consent’ was deleted from 
exclusion criterion 7.
To clarify the timing for 
fulfillment of 
inclusion/exclusion 
criteria.
5.1. Inclusion Criteria 
(Criterion #3)
Definitions of heart failure with reduced ejection 
fraction (HFrEF) and HFpEF were updated. 
Added spironolactone and eplerenone to the 
definition of HFpEF.
To clarify and align with 
the information received 
from site principal 
investigators and Steering 
Committee on definitions 
of HFrEF and HFpEF for 
this virtual study and 
diagnosis confirmation 
within 18 months instead 
of 1 year.


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Section Number
and Name
Description of Change
Brief Rationale
5.2. Exclusion Criteria 
(Criterion #4)
The text ‘from the most recent assessment’ was 
added.
To clarify the timing of 
assessment of stage 4 or 5 
chronic kidney disease for 
exclusion of participants 
from the study.
5.2. Exclusion Criteria 
(Criterion #8)
The text ‘any condition for which, in the opinion 
of the investigator, participation would not be in 
the best interest of the participant (eg, 
compromise the well-being) or that could 
prevent, limit, or confound the protocol-
specified assessments’ was added.
To explicitly describe the 
exclusion of participants 
with compromised well-
being or whose 
participation could 
prevent, limit, or confound 
the protocol-specified 
assessments.
5.2. Exclusion Criteria 
(Criterion #12)
The text ‘receiving an investigational study 
medication’ was added.
To clarify that participants 
with ongoing treatment 
with an investigational 
agent should be excluded 
from the study, but those 
in studies without an 
investigational agent are 
eligible to participate.
5.2. Exclusion Criteria 
(Criterion #13)
A new exclusion criterion #13 was added:
‘has a left ventricular assist device’.
To exclude the factors that 
can alter the health status 
and would confound the 
ability to define a benefit 
from treatment with the 
study drug.
5.2. Exclusion Criteria 
(Criterion #14)
A new exclusion criterion # 14 was added:
‘patient identity or association with enrolling 
network cannot be verified’.
To exclude those 
participants whose identity 
cannot be verified.
5.4. Screen Failures
Updated the criteria for rescreening of 
participants.
To allow and outline for 
the rescreening of 
participants.
5.4. Screen Failures
The following text was modified as: All 
potential participants who electronically sign the 
remote e consent opt in to participate in the 
study on the website will receive a unique 
identifier in the study database held by a third-
party representative.
To emphasize that the 
participants will receive a 
unique study number when 
they opt in to participate in 
the study which is prior to 
enrollment (signing of 
consent).
6.3. Measures to Minimize 
Bias: Randomization and 
Blinding
The following text was modified as: The IxR 
will provide the kit number of the study 
intervention bottle(s) to be dispensed for each 
randomly assigned participant to begin dosing
on Day 1 of the double-blind treatment period.
To indicate that the kit 
numbers are not assigned 
on Day 1 but that study 
intervention dosing should 
begin on Day 1.
6.4. Study Intervention 
Compliance
Re-education of the participant on importance of 
dairy completion was added.
To indicate that diary 
should be completed to 
track the study 
intervention compliance 
data.
7.2. Participant 
Discontinuation/Withdrawal 
from the Study
The following text was modified as: If 
applicable, the participant is lost to follow-up, 
vital status will still be attempted to be 
obtained for collection at study end through the 
participant’s physician, medical claims, or 
To specify that vital status 
should be obtained, if 
possible, in case 
participant is lost to 
follow-up.


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Section Number
and Name
Description of Change
Brief Rationale
public information according to local guidelines 
and as allowed by local regulations
7.2. Participant 
Discontinuation/Withdrawal 
from the Study
The information on home and work contact 
numbers were removed.
To indicate that the app 
can only store smartphone 
contact number.
7.2. Participant 
Discontinuation/Withdrawal 
from the Study
The following text was added: Follow-up can 
also be done with the help of the study site 
personnel.
To specify that besides the 
call center, study site can
also help with follow-up.
8. Study Assessments and 
Procedures (Overview)
The following text was deleted: Health Resource 
Utilization (HRU) and health economics data 
will be collected. Refer to Section 8.2.4, 
Healthcare Resource Utilization and Health 
Economics for details.
To remove duplicate 
information.
8.2.4. Healthcare resource 
Utilization and Health 
Economics
Added ‘discharge destination’ information to the 
list of healthcare resource utilization and health 
economics data
To maintain consistency 
with text in the other 
sections of the protocol.
8.3. Adverse Events and 
Serious Adverse Events and 
Special Situations
The text was modified to indicate that the 
principal investigator may contact the treating 
physician as agreed in the informed consent 
form.
To update how the 
principal investigator may 
contact the participant’s 
treating physician based on 
the confirmed process.
8.3. Adverse Events and 
Serious Adverse Events and 
Special Situations;
9.4.3. Adverse Events Analysis
Emergency department visits was added as a 
criteria for aggregation of AEs collection from 
claims.
To be consistent by 
including criteria for 
aggregation of AEs
collection from claims in 
this section.
8.3.1. Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information
The following text was modified as: All 
participant reported adverse events suspected to 
be related to the study intervention, whether 
serious or non-serious, will be collected from the 
time a signed and dated ICF is obtained until the
participant completes their participation in the 3-
month treatment period plus 30 days.
To clarify that all AEs (not 
just those suspected to be 
related to study 
intervention) should be 
collected.
8.3.4. Adverse Events of 
Interest
Additional adverse events of interest were 
specified.
To expand the scope of 
AEs of interest to be 
collected in the study.
9.3. Populations for Analyses 
(Table 2)
Updated the definition of ‘per protocol’ 
population.
To clarify the definition of 
per protocol population.
10.2. Appendix 2: Regulatory, 
Ethical, and Study Oversight 
Considerations (Regulatory and 
Ethical Considerations 
[Protocol Amendments])
The following text was deleted: The data 
recorded in the source documents will reflect 
any departure from the protocol, and the source 
documents will describe this departure and the 
circumstances requiring it.
To remove non-applicable 
data source in this virtual 
study.
10.2. Appendix 2: Regulatory, 
Ethical, and Study Oversight 
Considerations (Regulatory and 
Ethical Considerations 
[Protocol Amendments])
Specified that the departure from the protocol 
information will be recorded by the sponsor.
To provide clarity on who 
will record the departure 
from protocol information.
10.6. Appendix 6: Participant 
Satisfaction Survey
Added numeric grading of 1 to 5.
To provide the scoring 
used on the participant 
satisfaction survey which 
was omitted in previous 
versions.


JNJ-28431754 (canagliflozin) (INVOKANA)
Clinical Protocol 28431754HFA3002 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
70
Approved, Date: 23 February 2021
Section Number
and Name
Description of Change
Brief Rationale
10.7. Appendix 7: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting (Product Quality 
Complaint Handling)
Modified the text to indicate that instead of 
study site personnel, the call center will report 
the product quality complaint to the sponsor in 
case a product defect is combined with serious 
AE.
To provide clarity and for 
consistency across the 
study.
References
New references (#1, 3, 14) were added. Other 
reference numbers cited within the protocol 
were updated.
References added to 
support the study.
6.1. Study Interventions 
Administered
Assigned table number to ‘Description of Study 
Interventions’ table. Table numbering of other 
tables were updated.
Minor errors were noted.
8.3.3. Pregnancy
The following text was modified as ‘Any 
participant who becomes pregnant during the 
study must be promptly withdrawn
discontinued from the study and discontinue 
further study intervention’.
Throughout the protocol
Minor grammatical, formatting, or consistency 
changes were made.
Amendment 1 (07 February 2020)
Overall Rationale for the Amendment: The overall reason for the amendment is to remove 
Return of Results (RoR) to align with Janssen standard operating procedure (SOP), update the 
study overview schema to align with the protocol, and to define that the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) overall summary score will be used for the baseline 
assessment.
Section Number
and Name
Description of Change
Brief Rationale
Synopsis Overall Design; 1.3 
Schedule of activities (SoA); 
4.1. Overall Design; 4.2. 
Scientific Rationale for Study 
Design; 5.1. Inclusion Criteria; 
8.1.1. KCCQ Scores
Clarified that KCCQ overall summary score will 
be evaluated at Screening/Baseline to determine 
participant eligibility and other KCCQ domains 
and summary scores will be calculated at 
baseline and subsequent postbaseline timepoints, 
respectively.
To clarify that KCCQ 
baseline overall summary 
score will be used to 
determine participant 
eligibility at 
screening/baseline.
Synopsis Objectives and 
Endpoints; Synopsis 
Intervention Groups and 
Duration; 3. Objectives and 
Endpoints; 4.1 Overall Design
The term of “Return of Results (RoR)” was 
removed and term “Participant Unblinding” was 
added.
Text related to RoR including exploratory 
objective and endpoint was deleted.
Janssen SOP does not 
allow for “RoR” to 
participants for an 
approved drug.
1.2 Schema
Schematic Overview of the Study was replaced 
with an updated figure (1).
To align with protocol.
1.3 Schedule of activities (SoA)
SoA was updated to clarify study day for date of 
first dose and other timepoints. Also, footnote
“d” related to claims data collection and 
reporting of adverse events were updated.
To specify the timepoints 
(in days) for clarity and 
added a baseline period of 
up to 7 days before Day 1.
Title Page
EudraCT number deleted
EudraCT number is not 
applicable for the current 
study.
6.3 Measures to Minimize Bias: 
Randomization and Blinding
Information related to blind breaking was 
updated. Clarified that “Study Responsible 
Physician “or “other sponsor physician” 
designee may in an emergency determine the 
To update appropriate 
process for study
unblinding.


JNJ-28431754 (canagliflozin) (INVOKANA)
Clinical Protocol 28431754HFA3002 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
71
Approved, Date: 23 February 2021
Section Number
and Name
Description of Change
Brief Rationale
identity of the study intervention by contacting 
the IxR.
9.4.3 Adverse event analysis
Clarified that adverse events reported from call 
center will be reported separately from those 
obtained from claims data.
To clarify the adverse 
event reporting
10.7 Appendix 7: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting
Clarified that the causal relationship to the study 
treatment is determined by Janssen Global 
Medical Safety.
Text related to responsibility of virtual principal 
investigator was deleted.
To align with the protocol 
and the design of the study 
and to remove incorrect 
text.
Clarified the responsibility 
of virtual principal 
investigator.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.


JNJ-28431754 (canagliflozin) (INVOKANA)
Clinical Protocol 28431754HFA3002 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
72
Approved, Date: 23 February 2021
11.
REFERENCES
1.
Bertram Pitt, Pfeffer MA, Assmann SF, et al.  Spironolactone for Heart Failure with Preserved Ejection 
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Butler J (2017), Hamo CE, Filippatos G, et al. The potential role and rationale for treatment of heart failure 
with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail. 2017;19(11):1390-1400.
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Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA 
Guideline for the Management of Heart Failure. JACC. 2017;70(6):776-803.
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DDT COA #000084: Kansas City Cardiomyopathy Questionnaire (KCCQ). https://www fda.gov/drugs/ddt-
coa-000084-kansas-city-cardiomyopathy-questionnaire-kccq.
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Dreyer RP (2016), Jones PG, Kutty S, Spertus JA. Quantifying clinical change: discrepancies between patients' 
and providers' perspectives. Qual Life Res. 2016 Sep;25(9):2213-2220.
6.
European Medicines Agency (EMEA) (2012). Guideline on clinical investigation of medicinal products in the 
treatment or prevention of diabetes mellitus. 14 May 2012; CPMP/EWP/1080/00 Rev. 1. Committee for 
Medicinal Products for Human Use (CHMP).
7.
Food and Drug Administration (FDA) (2008). Guidance for industry: Diabetes Mellitus: Developing drugs and 
therapeutic biologics for treatment and prevention. U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER), February 2008, Clinical/Medical.
8.
Food and Drug Administration (FDA) (2019). Treatment for heart failure: Endpoints for drug development, 
Guidance for Industry. Draft guidance un 2019; US Department of Health and Human Service, Food and Drug 
Administration.
9.
Gail M (1985), Simon R. Testing for qualitative interactions between treatment effects and patient subsets. 
Biometrics. 1985 Jun;41(2):361-372.
10.
Green CP (2000), Porter CB, Bresnahan DR, et al. Development and evaluation of the Kansas City 
Cardiomyopathy Questionnaire: A new health status measure for heart failure. J Am Coll Cardiol 
2000;35:1245-1255.
11.
Investigator's Brochure: JNJ-28431754 (Canagliflozin) Edition 15. Janssen Research and Development, LLC 
(9 Nov 2017).
12.
Joseph SM (2013), Novak E, Arnold SV, et al. Comparable performance of the Kansas City Cardiomyopathy 
Questionnaire in patients with heart failure with preserved and reduced ejection fraction Circ Heart Fail. 2013 
Nov;6(6):1139-1146.
13.
Kelkar AA (2016), Spertus J, Pang P, et al. Utility of patient-reported outcome instruments in heart failure.
JACC Heart Failure 2016;4(3):165-175.
14.
Mahaffey KW (2019), Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in 
type 2 diabetes and chronic kidney disease in primary and secondary cardiovascular prevention groups: results 
from the randomized CREDENCE trial. Circulation. 2019 Aug 27;140(9):739-750.
15.
Mahaffey KW (2018), Neal B, Perkovic B, et al. Canagliflozin for primary and secondary prevention of 
cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). 
Circulation. 2018 Jan 23;137(4):323-334.
16.
McMurray JJV (2019), Solomon SD, Inzucchi SE, et al; DAPA-HF Trial Committees and Investigators. 
Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019 Sep 19.
17.
Medical Device Development Tools Program (2016). Medical Development Tool Qualification Decision 
Summary for Kansas City Cardiomyopathy Questionnaire (KCCQ). Available from: 
https://www.fda.gov/downloads/MedicalDevices/ScienceandResearch/MedicalDeviceDevelopmentToolsMDD
T/UCM581761.pdf. Accessed on 13 November 2017.
18.
Monami M (2014), Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-
analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24(7):689-697.


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Clinical Protocol 28431754HFA3002 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
73
Approved, Date: 23 February 2021
19.
Mosenzon O (2019), Wiviott SD, Cahn A, et. al. Effects of dapagliflozin on development and progression of 
kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. 
Lancet Diabetes Endocrinol. 2019 Aug;7(8):606-617.
20.
Nassif ME (2019), Kosiborod M. Effects of sodium-sodglucose cotransporter type 2 inhibitors in heart failure. 
Diabetes Obes Metab. 2019;21(Suppl. 2):19-23.
21.
Nassif ME (2019), Windsor SL, Tang F, et al. Dapagliflozin Effects on Biomarkers, Symptoms, and Functional 
Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial. Circulation. 
2019 Oct 29;140(18):1463-1476.
22.
National Kidney Foundation (2012). KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. 
Am J Kidney DIS. 2012;60(5):850-886.
23.
Nichols GA (2001), Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, 
incidence, and risk factors. Diabetes Care. 2001;24(9):1614-1619.
24.
Nichols GA (2004), Gullion CM, Koro CE, Ephross SA, Brown JB. The incidence of congestive heart failure 
in type 2 diabetes. Diabetes Care. 2004;27(8):1879-1884.
25.
Packer M (2017), Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 
inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA 
Cardiol. 2017;2(9):1025-1029.
26.
Radholm K (2018), Figtree G, Perkovic V, et al. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus. 
Results From the CANVAS Program. Circ. 2018;138:458-468.
27.
Ryan PB (2018), Buse JB, Schuemie MJ, et al. Comparative effectiveness of canagliflozin, SGLT2 inhibitors 
and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 
diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes 
Metab. 2018;20(11):2585-2597.
28.
Sezai A (2019), Sekino H, Unosawa S, et al. Canagliflozin for Japanese patients with chronic heart failure and 
type II diabetes. Cardiovasc Diabetol. (2019) Jun 5;18(1):76.
29.
Spertus J (2005), Peterson E, Conard MW, et al. Monitoring clinical changes in patients with heart failure: a 
comparison of methods. Am Heart J 2005;150(4):707-715.
30.
Zinman B (2015), Wanner C, Lachin JM, et. al. Empagliflozin, cardiovascular outcomes and mortality in type 
2 diabetes. N Engl J Med 2015;373:2117-2128.


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SAP_003.pdf: 
1
Status: FINAL, 19 July 2021
Janssen Research & Development, LLC
Statistical Analysis Plan
Canagliflozin: Impact on Health Status, Quality of Life, and Functional Status in Heart 
Failure 
Protocol 28431754HFA3002; Phase 3B
JNJ-28431754 (canagliflozin) (INVOKANA)
Status:
FINAL
Date:
19 July 2021
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-RIM-294497, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP).
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT04252287


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan 28431754HFA3002
2
Status: FINAL, 19 July 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 3
LIST OF IN-TEXT FIGURES ........................................................................................................................ 3
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Objectives ........................................................................................................................................ 8
1.2.
Study Design.................................................................................................................................... 9
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4.
Sample Size Justification ............................................................................................................... 11
1.5.
Randomization and Blinding .......................................................................................................... 12
1.6.
Study Data Flow............................................................................................................................. 13
2.
GENERAL ANALYSIS DEFINITIONS ..............................................................................................14
2.1.
Time Windows................................................................................................................................ 14
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 16
2.3.
Analysis Sets.................................................................................................................................. 16
2.3.1.
All Randomized Analysis Set...................................................................................................... 16
2.3.2.
Full Analysis Set (FAS)............................................................................................................... 16
2.3.3.
Per Protocol Analysis Set ........................................................................................................... 16
2.3.4.
Safety Analysis Set..................................................................................................................... 17
2.4.
Definition of Subgroups.................................................................................................................. 17
2.5.
Study Day and Relative Day .......................................................................................................... 17
2.6.
Baseline, End of Treatment, and End of Study..............................................................................17
2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 18
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 18
4.
SUBJECT INFORMATION................................................................................................................ 18
4.1.
Demographics and Baseline Characteristics ................................................................................. 18
4.2.
Disposition Information................................................................................................................... 19
4.3.
Treatment Compliance................................................................................................................... 19
4.4.
Extent of Exposure......................................................................................................................... 20
4.5.
Protocol Deviations ........................................................................................................................ 20
4.6.
Prior and Concomitant Medications ............................................................................................... 20
5.
EFFICACY ......................................................................................................................................... 20
5.1.
Analysis Specifications................................................................................................................... 20
5.1.1.
Level of Significance................................................................................................................... 21
5.1.2.
Data Handling Rules................................................................................................................... 21
5.2.
Primary Efficacy Endpoint.............................................................................................................. 22
5.2.1.
Definition..................................................................................................................................... 22
5.2.2.
Estimand..................................................................................................................................... 22
5.2.3.
Analysis Methods........................................................................................................................ 23
5.3.
Secondary Endpoints..................................................................................................................... 26
5.3.1.
Definition..................................................................................................................................... 26
5.3.2.
Estimand..................................................................................................................................... 26
5.3.3.
Analysis Methods........................................................................................................................ 27
5.4.
Exploratory Variables..................................................................................................................... 27
5.4.1.
Definition..................................................................................................................................... 27
5.4.2.
Analysis Methods........................................................................................................................ 28


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan 28431754HFA3002
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Status: FINAL, 19 July 2021
6.
SAFETY............................................................................................................................................. 29
6.1.
Adverse Events .............................................................................................................................. 29
6.2.
Clinical Laboratory Tests................................................................................................................ 31
6.3.
Vital Signs and Physical Examination Findings .............................................................................31
6.4.
Electrocardiogram.......................................................................................................................... 31
6.5.
Other Safety Parameters ............................................................................................................... 31
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 31
8.
BIOMARKERS................................................................................................................................... 31
9.
HEALTH ECONOMICS ..................................................................................................................... 31
REFERENCES............................................................................................................................................ 32
APPENDICES............................................................................................................................................. 34
Appendix 1: The Kansas City Cardiomyopathy Questionnaire (KCCQ)..................................................... 34
Appendix 2: Participant Satisfaction Survey ............................................................................................... 39
Appendix 3: Schedule of Activities.............................................................................................................. 40
Appendix 4: Usage of the Analysis Sets..................................................................................................... 42
Appendix 5: CHIEF-HF Study Data Flow Diagram ..................................................................................... 43
Appendix 6: Patient Global Impression of Change (PGIC)......................................................................... 45
Appendix 7: Patient Global Impression of Severity (PGI-S) ....................................................................... 46
1.
PHYSICAL LIMITATION ................................................................................................................... 46
2.
SYMPTOM STABILITY ..................................................................................................................... 46
3.
SYMPTOM FREQUENCY ................................................................................................................. 47
4.
SYMPTOM BURDEN ........................................................................................................................ 48
5.
TOTAL SYMPTOM SCORE..............................................................................................................48
6.
SELF-EFFICACY............................................................................................................................... 48
7.
QUALITY OF LIFE............................................................................................................................. 49
8.
SOCIAL LIMITATION........................................................................................................................ 49
9.
OVERALL SUMMARY SCORE ........................................................................................................50
10.
CLINICAL SUMMARY SCORE......................................................................................................... 50
LIST OF IN-TEXT TABLES
Table 1: 
Measurement Windows ............................................................................................................ 15
Table 2: 
Demographic Variables............................................................................................................. 18
LIST OF IN-TEXT FIGURES
Figure 1: 
Schematic Overview of the Study............................................................................................. 10


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan 28431754HFA3002
4
Status: FINAL, 19 July 2021
AMENDMENT HISTORY
1st Amendment (December 30, 2020)
Final changes (July 1, 2021)


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan 28431754HFA3002
5
Status: FINAL, 19 July 2021
ABBREVIATIONS
AE
API
adverse event
application program interface
ANOVA
analysis of variance
CDF
cumulative distribution function
CI
confidence interval
CSR
clinical study report
ED
emergency department
EF
ejection fraction
EHR
electronic health record
EOS
end of study
EOT
end of treatment
ES
effect size
FAS
FDA
Full analysis set
Food and Drug Administration
HF
HFpEF
HFrEF
heart failure
heart failure preserved ejection fraction
heart failure reduced ejection fraction
HRU
healthcare resource utilization
ICD
International Statistical Classification of Diseases and Related Health Problems
ICH
International Conference on Harmonisation
IHN
integrated health networks
ITT
intent to treat
IxR
KCCQ
KCCQ-TSS
interactive web response system
Kansas City Cardiomyopathy Questionnaire
Kansas City Cardiomyopathy Questionnaire – Total Symptom Score
LOCF
last observation carried forward
LS
least squares
MedDRA
MMRM
Medical Dictionary for Regulatory Activities
mixed model of repeated measurement
MI
multiple imputation
MID
minimum detectable
NYHA
New York Heart Association
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PI
principal investigator
PP
per protocol
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SD
SE
SGLT2
standard deviation
standard error
sodium glucose cotransporter-2 inhibitor
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEAE
UGT
treatment-emergent adverse event
UDP-Glucuronosyltransferase
US
United States


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan 28431754HFA3002
6
Status: FINAL, 19 July 2021
Amendment Page – Summary of Changes (December 30, 2020)
Section #
Original 
Text/Figure
Amended Text/Figure
Rationale
1.2
Figure 1
Figure 1
Changed entry 
criterion for 
KCCQ <80 
incorporated
1.4
Added text
After approximately 10 months, the 
planned enrollment in this study is not 
expected to reach the target of 1900 
participants by the end of January 30, 2021 
(the scheduled end of study enrollment 
window). Instead, the final anticipated 
enrollment may be in the range of about 
400-480 participants. Consequently, a 
reduction in total sample size of this 
magnitude will have impact on statistical 
power at different effect sizes, as shown by 
the figure below. A large effect size was 
reported in the recently concluded 
DEFINE-HF study17. Additional KCCQ 
domains were also reported in this study 
with robust improvements over 
baseline17,18.
Statement about 
lower than 
expected sample 
size enrollment 
and its impact on 
statistical power
2.3.2.
Added full 
analysis set 
(FAS)
definition
This includes all randomized participants 
who have received at least one dose of study 
intervention/medication and have at least 
one post-baseline KCCQ measurement. 
Analyses of the primary, secondary, and 
exploratory endpoints will be based on the 
full analysis set (FAS).
Primary, 
secondary, and 
exploratory 
endpoints will be 
based on FAS 
(earlier version 
stated as based on 
all randomized set) 
5.2.2.
Population: 
all 
randomized 
set 
Population: FAS - all randomized participants 
with HF (who either have HFrEF or HFpEF, 
regardless of T2DM status) with at least one 
dose of study intervention and at least 1 post-
baseline KCCQ measurement
Changed analysis 
population to FAS
5.2.3.
Added to the 
analysis 
method
Mortality in this short-duration trial is 
expected to be low and to be comparable 
between groups and will be ignored in the 
primary analyses of mean differences in 
changes in KCCQ Total Symptom scores, 
but can be included in the responder analyses 
by assigning them to the lowest response 
(greatest deterioration) category. Should 
there be a >5% mortality rate and if it is 
unequally distributed between treatment 
arms, then joint modeling of survival and 
health status will be performed. A win-ratio 
approach19,20 may also be considered by 
analyzing the KCCQ-TSS score as a 
composite, 
rank-based 
outcome, 
incorporating participant vital status at 12 
Added to the 
analysis method 
regarding missing 
data due to deaths


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weeks along with a change in score from 
baseline 
to 
12 
weeks 
in 
surviving 
participants. This essentially is the rank 
analysis of covariance method, with a 
corresponding win ratio used to estimate the 
magnitude of treatment effect.
5.3.2.
Population: 
all 
randomized 
set
Population: FAS - all randomized participants 
with HF (who either have HFrEF or HFpEF, 
regardless of T2DM status) with at least one 
dose of study intervention and at least 1 post-
baseline KCCQ measurement
Changed analysis 
population to FAS
5.3.3.
Added to 
analysis 
method
The first key secondary endpoint will be 
analyzed following the same approach as 
employed for the primary effectiveness 
endpoint (i.e. using an MMRM model).
Added to analysis 
method regarding 
daily step counts 
from two-sample t-
test to MMRM 
analysis 
References
Added 
references
Nassif, M. et al. (2019). Dapagliflozin 
Effects on Biomarkers, Symptoms, and 
Functional Status in Patients With Heart 
Failure With Reduced Ejection Fraction -
The DEFINE-HF Trial. Circulation, Vol. 
140, No. 18, 1463-1476
Bhatt, D. et al. (2020). Sotagliflozin in 
Patients 
with 
Diabetes 
and 
Recent 
Worsening Heart Failure. N Engl J Med, 
2020; Nov 16
Gasparyan, S. et al. (2019). Adjusted Win 
Ratio 
with 
Stratification: 
Calculation 
Methods and Interpretation, Stat.ME
Wang, D. and Pocock, S. (2016). A win-
ratio approach to comparing continuous 
non-normal outcomes in clinical trials, 
Pharmaceutical Statistics, online 11 March 
2016
Added more 
references 
pertaining to 
sample size section 
and analysis 
methods such as 
win-ratio


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1.
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for the 
28431754HFA3002 (Canagliflozin: Impact on Health Status, Quality of Life, and Functional 
Status in Heart Failure – CHIEF-HF) study. This Phase 3b study is being conducted in the 
United States (US) in participants with symptomatic HF stratified by HF (reduced ejection fraction 
[HFrEF] or preserved ejection fraction [HFpEF]) and compares the effectiveness of canagliflozin 
100 mg versus placebo for improvement in HF symptoms measured by the Kansas City 
Cardiomyopathy Questionnaire - Total Symptom Score (KCCQ-TSS) (see Appendix 1: The 
Kansas City Cardiomyopathy Questionnaire (KCCQ)) after 12 weeks. This document contains 
details of the relevant definitions, data handling conventions and methods for analyses. The 
document will be finalized prior to database lock.
This SAP is based on the clinical study protocol (finalized first on 7 November, and subsequently 
amended on 7 February 2020 (Protocol 28431754HFA3002 Amendment 1, dated 07 February 2020 -
EDMS-ERI-154820237, version 3.0) by Janssen Scientific Affairs, LLC) that provides details on the 
conduct of this study and operational aspects of clinical assessments and timing for completing a 
participant in this study.
Based on the last protocol amendment, changes were made to this SAP on December 30, 2020 and 
are listed on the preceding amendment page in this document. A final version of this SAP with 
editorial changes is posted on 1 July 2021.
1.1.
Objectives
Primary Objective
The primary objective is to determine the superiority of the effectiveness of canagliflozin 100 mg 
daily versus placebo in participants with symptomatic HF in improving the overall KCCQ-TSS.
Secondary Objectives
The first key secondary objective is:
!
to determine the superiority of the effectiveness of canagliflozin 100 mg daily versus placebo 
in improving the total daily step count.
The second key secondary objective is:
!
to determine the superiority of the effectiveness of canagliflozin 100 mg daily versus placebo 
in improving the KCCQ individual domain scores (physical limitation, quality of life, clinical
summary, and overall).
Exploratory Objectives
The exploratory objectives are to assess the effectiveness of canagliflozin 100 mg daily versus 
placebo in participants with symptomatic HF by:


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!
responses on the Patient Global Impression of Change (PGIC) and the Patient Global 
Impression of Severity (PGI-S)
!
healthcare resource utilization (HRU) and health economics data
!
associations (correlations and/or categorical association measures) between digital markers 
(step count and floors climbed), and clinical events such as need for outpatient intravenous 
therapies, emergency department (ED) visits, and hospitalizations
!
daily floors climbed
!
time to first hospitalization/readmission for HF
!
time to first hospitalization/readmission for other events
!
time to death
!
the participant’s satisfaction with their experience with the virtual design at the end of the 
study (see Appendix 2: Participant Satisfaction Survey).
1.2.
Study Design
OVERALL DESIGN
This is a randomized, double-blind, placebo-controlled, decentralized, virtual, superiority study 
conducted in the US in participants with symptomatic HF (stratified by heart failure with HFrEF
or HFpEF). This study examines the improvement in the KCCQ-TSS after 12 weeks of treatment 
with canagliflozin 100 mg or placebo. The study will continue for an additional 6 months without 
further study intervention to collect participant follow-up data from the smartphone, Fitbit, and 
claims in a real-world setting. At the end of the 12-week, double-blind treatment period, 
participants will be informed about their actual treatment allocation, whether they had been 
randomized to canagliflozin or placebo.
The study will enroll participants from large integrated health networks (IHNs) and physician 
practices in the US with the participants conducting many of their study-related activities through 
an app on a smartphone and will provide daily activity data recorded by using a Fitbit device. 
There will be no in-person clinic visits required by the study (see Appendix 3: Schedule of 
Activities).
The study consists of a screening period, a 12-week double-blind treatment period, and a 6-month 
follow-up (no intervention) observational period for each participant. Approximately 1,900 
participants are planned for randomization into the study in a 1:1 ratio to canagliflozin 100 mg 
daily or placebo groups (950 in each study intervention group). After Week 12 (i.e., the end of the 
double-blind treatment period), the study will continue for an additional 6 months when study 
intervention will no longer be provided. Randomization will be performed using the interactive 
web response system (IxR). Participants will be stratified based on HF ejection fraction (EF) type 
– HFrEF or HFpEF.
Data collection from the smartphone, Fitbit device, and claims will continue until Month 9 for all 
endpoints. Specifically, study assessments include the following: KCCQ, PGIC, PGI-S, and an 


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optional participant satisfaction survey at end of study (via smartphone), step count and floors
climbed (via the Fitbit device), medical and pharmacy claims data (including up to 36 months 
history 
for 
eligibility 
confirmation), 
HRU 
and 
health 
economics 
(including 
hospitalization/readmission due to HF or other reason, ED visits, the duration of stay at each 
hospitalization/readmission), review of claims for prohibited medications and new diagnoses that 
may require discontinuation, and adverse events. In addition, information related to outpatient IV 
diuretics, inotropes and vasodilators and in-patient IV therapies as well will be considered relevant. 
Note that claims data that involves up to 36 months history to confirm eligibility into this study
will not be part of the study database for analysis.
Participants will be of any gender, 18 years of age or older, and will have clinically stable, 
symptomatic HF with or without type 2 diabetes mellitus (T2DM) with a KCCQ overall summary 
score ∀80 prior to randomization, which represents New York Heart Association (NYHA) II and 
III participants.
Figure 1: 
Schematic Overview of the Study
1.3.
Statistical Hypotheses for Trial Objectives
The primary effectiveness endpoint is the change in the KCCQ-TSS from baseline to Week 12. 
The null hypothesis to be tested here is that there is no difference between canagliflozin 100 mg 
and placebo in the treatment of symptomatic HF based on the primary effectiveness endpoint. For 


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the first key secondary effectiveness endpoint of change in daily step count from baseline to Week 
12, the null hypothesis to be tested is that canagliflozin 100 mg is not different from placebo with 
respect to the mean change in daily step count.
The two hypotheses described above will be tested using a fixed-sequence (hierarchical) testing 
procedure to control the familywise type I error rate at 5% as follows:
1.
(primary effectiveness endpoint): change from baseline to Week 12 in KCCQ-TSS for 
canagliflozin 100 mg versus the placebo
2.
(first key secondary endpoint): change from baseline to Week 12 in daily step count for 
canagliflozin 10 mg versus placebo.
If the result of the 2-sided p-value from the first hypothesis (i.e., primary effectiveness endpoint) 
test is ≤0.05, then the second hypothesis test result will be interpreted inferentially at the 5%
significance level. This sequential testing approach will control the familywise type I error rate at 
5%.
Hypotheses related to the second key secondary effectiveness endpoint (i.e., KCCQ individual 
domain scores defined by changes in physical limitation, quality of life, clinical summary, and 
overall summary from baseline to Week 12) as well as other exploratory endpoints will be tested 
at the nominal significance level (5%) without adjustment for multiplicity (or controlling type I 
error rate).
1.4.
Sample Size Justification
The primary effectiveness endpoint is the change from baseline in the KCCQ-TSS at the end of 
the 12-week double-blind treatment period. Although a 5-point improvement in the KCCQ-TSS is 
generally viewed as clinically meaningful,2,12 recent studies7,8 have shown that improvements in 
the range of 3 to 5 points on the KCCQ-TSS are equally meaningful in the overall HF-related 
health status measured by the KCCQ over a 12-week time period. In considering the clinical 
significance of scores, it is important to separate mean changes for groups of participants, as 
compared with intra-individual changes. On the TSS, there are 7 items (4 for symptom frequency 
and 3 for severity/burden).3,11 Shifting a response on KCCQ questions 5 and 7 shifts the TSS score 
by 2.083 points on a 100-point scale. A shift in response for questions 3 and 9 shifts the score by 
3.125 points and for items 4, 6, and 8, shifts the score by 4.166 points, assuming no missing 
responses. Thus, an intra-individual change of at least 2 categories (3 if the only change is in items 
5 and 7) would exceed the 5-point threshold that has the been shown to be clinically significant. 
When analyzing groups of participants, the mean difference across the entire population includes 
a distribution of participants with different magnitudes of individual change and a 3- to 5-point 
difference between groups reflects a significantly larger proportion of participants in one group, 
as compared with the other, who have clinically important improvements in their TSS. 
Thus, based on the totality of evidence evaluating the clinical significance of the KCCQ,5,6,9,14 a 
between group difference of 3 points is considered clinically meaningful and  the current study is 
powered to detect a mean change from baseline of 3 points in the KCCQ-TSS between 
canagliflozin 100 mg and placebo groups at Week 12. Assuming a significance level of 5% and a 


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standard deviation (SD) of 18 points for mean change in KCCQ-TSS, a total of 1,900 participants
will be randomized in this study providing approximately 95% power. This sample size is adequate 
to account for a potential 5% to 10% dropout rate - that is, with a dropout as high as 10% [n=1,710], 
the statistical power remains >90%.
After approximately 10 months, the planned enrollment in this study is not expected to reach the 
target of 1900 participants by the scheduled end of study enrollment window in the first quarter of 
2021. Instead, the final anticipated enrollment may only be in the range of about 400-480 
participants. Consequently, a reduction in total sample size of this magnitude will have impact on 
the statistical power for the assumed effect size as well as for various other plausible effect sizes, 
shown by the figures below. At 50% statistical power, an effect size of 3.5 points in the KCCQ 
change score (assuming standard deviation is 18) can be detected with a minimum sample size of 
400. For power ≥80%, the required sample size has to be  at least 445 if the expected mean 
difference in KCCQ-TSS change score over 12 weeks is as high as 4.8, assuming the pooled 
standard deviation is 18. An effect size of this magnitude for the KCCQ-TSS change score was 
reported in the recently concluded DEFINE-HF study17. Robust improvements over baseline were 
also reported for additional KCCQ domains in this study as well as in the SOLOIST study17,18.
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 study intervention groups based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor before initiation of the study.
Randomization will be balanced by using randomly permuted blocks and will be stratified by EF 
(HFrEF or HFpEF) at study entry as recorded in the participant’s electronic health record (EHR).
The interactive web response system (IxR) will generate a randomization code, participant 
randomization number, and kit number once consent is completed and the participant is confirmed 
eligible by the virtual principal investigator. The kit number will dictate the study intervention
assignment and the matching study intervention bottle(s) to be shipped to the participant directly 
from the drug distribution vendor.


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The IxR will provide the kit number of the study intervention bottle(s) to be dispensed for each 
randomly assigned participant of the double-blind treatment period. Based on these randomization 
codes, study intervention will be packaged and labeled in a manner that maintains the double-
blinded nature of the study.
The drug depot will not be provided with randomization codes. The codes will be maintained 
within the IxR, which has the functionality to allow the virtual principal investigator or designee 
to break the blind for an individual participant.
Under normal circumstances, the blind should not be broken until participants have completed the 
12-week, double-blind treatment period. The virtual principal investigator or designee may in an 
emergency determine the identity of the study intervention by contacting the IxR. In the event the 
blind is broken, the sponsor must be informed as soon as possible. The date and reason for the 
unblinding must be documented in the study database. All randomization codes will be released 
after completion of the study. Participants who have had their intervention assignment unblinded 
should continue to perform their scheduled evaluations.
1.6.
Study Data Flow
Data flow in this study is facilitated by an automated integrated process that extracts clinical data 
from 3 sources: PRA mobile health platform [PRA mHP], Care Innovations, and Symphony. 
These data are loaded into PRA’s Common Clinical Data Store (CCDS) where the data is 
accessible by JReview for data validation and analysis, as well as for extraction into RAW and 
SDTM datasets. This automated Extract-Transform-Load (ETL) process will utilize a data 
container on Amazon Web Services (AWS), referred to as the “Data Analytics Container” or 
“DAC”, which is managed by PRA. A more detailed data flow diagram is provided in Appendix 
5 of this SAP.
The PRA mHP platform serves as the main hub for source data capture on the CHIEF-HF study. 
It captures eConsent, information entered by Health Network Systems (HNS) from a participant’s 
electronic medical records (EMRs), participant status overseen by Care Innovations (CI), 
randomization through integration with Endpoint IRT, drug shipment through integration with 
Marken, primary and secondary endpoint data from ePROs (KCCQ, PGI-S, PGIC), dosing 
compliance, as well as activity measured by the Fitbit watch. PRA mHP data will go into the DAC 
via a direct database connection. Medical and pharmacy claims data is contained within Symphony 


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Health Solutions and exists as completely de-identified data. This includes data used in the study 
to review and analyze adverse events, healthcare resource utilization (HRU) and health economics 
(including hospitalization/readmission due to Heart Failure [HF] or other reason, Emergency 
Department (ED) visits, the duration of stay at each hospitalization/readmission), as well as review 
of prohibited medications and new diagnoses that may require discontinuation.
Symphony claims data will be pulled into the DAC for participants randomized into the study via 
PRA mHP eConsent and will be mapped to SDTM as detailed in the SDTM specifications relevant 
to the study protocol and SAP. The collection timeframe for claims associated with AEs of special 
interest will begin on the Informed Consent Date through the End of Treatment + 30 days. The 
collection timeframe for Pharmacy claims of prohibited concomitant medications (SGLT2i) will 
begin on the ICF date through End of Treatment. The collection timeframe for claims associated 
with Health Resource Utilization will begin on the ICF Date through the 9-month observation 
period.
2.
GENERAL ANALYSIS DEFINITIONS
As this is a virtual study, there are no planned in-person clinic visits for measuring key endpoints 
on the study participants. Data collection via smartphone, Fitbit device, and claims will continue 
throughout the 9-month duration of the study. While the focus of the first 12-week, double-blind 
treatment duration is to establish the primary and key secondary objectives related to primary and 
secondary effectiveness endpoints, the latter 6 months (i.e., Month 3 until Month 9) of the study 
(when no study intervention is provided) are aimed to explore multiple objectives by collecting 
additional follow-up data on PROs, daily activity, and HRUs and generate hypotheses of interest
for future studies.
Unless stated otherwise, following the intent-to-treat (ITT) principle, analyses of the primary and 
secondary endpoints will be based on the full analysis set (FAS) and include data collected in the 
12-week, double-blind treatment period. Where meaningful, these analyses may also be repeated 
using the per protocol analysis set. Analysis based on full analysis set (FAS) will also be extended 
to the full study data period (up to the end of the 9-month long study). In a similar way, exploratory 
endpoints will be analyzed according to the randomized intervention groups by using data from 
both the 12-week, double-blind treatment period and the 9-month study duration, respectively.
2.1.
Time Windows
In this virtual study, the randomization date will refer to the day of randomization of an eligible 
participant. Once randomized, study intervention will be shipped and delivered to the randomized 
participant directly, and therefore, the first study intervention may be started by a participant a few 
days after the actual randomization date. This will be considered the date of starting study 
intervention, or, a reference day (Study Day 1). Scheduled study intervention will end after 12 
weeks. After Week 12, participants will be followed up to Month 9 without receiving any further 
study intervention. Total study days will be numbered relative to the Study Day 1 for each 
participant up to the end of the 9-month long study. All measurements will be arranged in a 
chronological order relative to Study Day 1. Participants will be instructed and notified by the 
study app on their smartphone to confirm taking the study intervention on schedule and completing 




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Parameter
Time Interval
(label on output)
Time Interval
(Day)*
Target Time Point (Day)
Week 9 & Week 10
57 to 70
Week 11 & Week 12
71 to 84
…
…
Week 35 & Week 36
238 to 252
*Relative to Study Day 1
** Measurements over a 2-week interval with # 100 daily steps to allow capture of physical activity
2.2.
Pooling Algorithm for Analysis Centers
This is a virtual study with multiple IHNs competitively enrolling HF patients to meet the overall 
study enrollment target. Therefore, from the analytical perspective, no separate sites exist for 
pooling to be applicable.  It will be considered a single center study.
2.3.
Analysis Sets
An overview of the different analysis sets and their usage is presented in Appendix 4: Usage of 
the Analysis Sets.
2.3.1.
All Randomized Analysis Set
The all randomized analysis set includes all participants who are randomly assigned to a study 
treatment. In order to adhere to the ITT principle, analyses based on all randomized analysis set 
will use the following rules:
!
participants will be evaluated according to the study intervention they have been assigned to 
(which may be different from the study intervention they have received)
!
all available data will be included (e.g., including assessment after study intervention 
discontinuation).
2.3.2.
Full Analysis Set (FAS)
This includes all randomized participants who have received at least one dose of study 
intervention/medication and have at least one post-baseline KCCQ measurement. 
!
Randomized participants in this analysis set will be considered regardless of when they 
received/started their first dose of study intervention/medication. 
!
all available data will be included (e.g., including assessment after study intervention 
discontinuation).
Analyses of the primary, secondary, and exploratory endpoints in this study will be based on the 
full analysis set (FAS). 
2.3.3.
Per Protocol Analysis Set
The per protocol analysis set (PP) will consist of all participants who received study intervention 
and who complied with the protocol to allow assessment of the treatment effects. Specifically, this 
includes randomized participants who comply with the study intervention, have at least the key
(ePRO) measurement of KCCQ completed, and do not experience major protocol deviations that 
may have an impact on estimating the treatment effect. The effectiveness analysis for the primary 
and secondary endpoints will be repeated for the PP analysis set.


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2.3.4.
Safety Analysis Set
The safety analysis set includes all randomized participants who received at least 1 dose of study 
intervention. Summary of available safety data from all sources (claims and patient reported) will 
be based on this analysis set.
2.4.
Definition of Subgroups
Analysis for the primary effectiveness endpoint will be performed for the subgroups identified 
below.
Subgroup
Definition
Region∃∃
US - East, West, North and South
Age Group
! 18-25
! 26-50
! 51-64
! %65
Gender
! Male
! Female
Race
! White
! Non-White
Diabetes type
! T2DM
! No-T2DM
HF – Ejection Fraction type
! pEF (preserved ejection fraction)
! rEF (reduced ejection fraction)
∃∃Information on region will be based on details available through IHNs.
Additional subgroups may be identified (including those based on combinations of T2DM and HF 
ejection fraction types) before finalizing the database.
2.5.
Study Day and Relative Day
Study Day 1 refers to the start of the first study intervention administration. All assessments 
recorded via the smartphone/mobile app and/or Fitbit device will be assigned a day relative to this 
date.
Relative day for a specific time-point of measurement is defined as:
!
measurement date - (date of Study Day 1) +1, if measurement date is # date of Study Day 1
!
measurement date - date of Study Day 1, if measurement date ∀date of Study Day 1.
2.6.
Baseline, End of Treatment, and End of Study
Baseline is defined as the last observation made prior to the start of the first study intervention
administration. End of Treatment (EOT) observation will refer to the last observation made prior 
to and including the day of the last dose of study intervention, regardless of when the last dose is 
taken. For the PRO measurements, EOT observation will include the last observed value prior to 
the last dose of study intervention, and/or, within a measurement window allowed by the app that 
may overlap the last dose date (i.e., may extend the last dose date by a few days). For the daily 


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activity data, it will represent average from the last 14 days prior to the last dose taken, regardless 
of when the dose is taken.
The EOS value is defined as the observation that is taken on the date of very last available 
postbaseline data in the study period. Unscheduled measurement results are included in this 
definition and will be considered as the last timepoint value if the unscheduled measurement result 
is the last postbaseline result available within the analysis period.
2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
Claims data are generally based on service dates and not on start and end dates for adverse events.  
Consequently, no imputation rule for missing AE dates can be applied. 
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analysis is planned in this study. However, data from the 12-week double-blind 
treatment period will be summarized/analyzed and reported out first as soon as the last randomized 
participant has completed the treatment period. Data from the full 9-month study period will be 
reported   after the follow-up is completed on all study participants.
4.
SUBJECT INFORMATION
The number of participants in each analysis set will be summarized and listed by intervention 
group, and overall. In addition, the distribution of participants by region within the US and 
recruiting networks will be presented, unless otherwise noted.
4.1.
Demographics and Baseline Characteristics
Table 2 presents a list of the demographic variables that will be summarized by each intervention
group, and both combined for the full analysis set (FAS). Demographics will also be summarized 
by various IHNs (or regions) using the FAS as well as the all randomized analysis set.
Table 2: 
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, standard deviation [SD], 
median and range [minimum and maximum], and IQ range).
Categorical Variables
Age (18-25 years, 26-50 years, 51-64 years, and 
#65 years)
Frequency distribution with the number and percentage of 
participants in each category.
Sex (male, female)
Racea (American Indian or Alaska Native, Asian, 
Black or African American, Native Hawaiian, or,
other Pacific Islander, White, Other)
Diabetes status at baseline (T2DM or no T2DM)
HF ejection fraction type (HFrEF or HFpEF)
a
If multiple race categories are indicated the Race is recorded as 'Multiple'.


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4.2.
Disposition Information
Total number of screened participants and number of screen failures will be provided. The total
number of participants randomized into the study will be provided. Randomized participants who 
complete the 12-week, double-blind treatment period and who do not discontinue study 
intervention prematurely are considered study intervention completers.
The number of participants in the following disposition categories will be provided for the 12-
week, double-blind treatment period by intervention group and overall:
!
participants randomized
!
Participants treated with study agent.
!
participants receiving study intervention
!
participants completing the double-blind treatment period
!
participants who discontinued study intervention
!
participants who terminated study prematurely
!
reasons for discontinuation of study intervention and termination of study
!
participants who were unblinded during the double-blind treatment period.
The distribution of the time to study termination for the 12-week, double-blind treatment period 
will be displayed with Kaplan-Meier curves. Participants who terminate study participation 
prematurely at any time will be considered an ‘Event’ and their date of study termination will be 
used in the time to study termination calculation. In this analysis, participants who complete the 
12-week, double-blind treatment period will be considered ‘censored’ and the date of double-blind 
treatment period completion will serve as the time of censoring.
4.3.
Treatment Compliance
Participants will be instructed and notified by the study app weekly to confirm the number of study 
intervention capsules that they took that week. Study intervention compliance data will be 
monitored bi-weekly for ensuring compliance is %80%.
Compliance with the study intervention is defined in this study in terms of the total number of 
doses received during the total treatment period of 12 weeks and not in terms of maintained drug 
concentration while participating in the study. Participants who take study intervention as 
instructed %80% of the total study intervention duration will thus be considered compliant.
For the double-blind study intervention period, compliance (%) = 100 x number of days taking 
study intervention (pills)/total study intervention duration (including days off study intervention).
The number and percentage of participants who have >80% study intervention compliance through 
Week 12 (end of double-blind treatment period) will be provided by randomized group.


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4.4.
Extent of Exposure
The number and percentage of participants who receive study intervention will be summarized by 
randomized group.
Descriptive statistics for study intervention duration (N, mean, SD, median, and range [minimum, 
maximum]) will be presented by randomized group based on the safety analysis set. Person-years 
of exposure to study intervention are calculated [as days of intervention/365.25] and will be 
presented by randomized group.
Duration of study intervention will be summarized in the following duration categories: [∀1 week, 
1-∀2 weeks, 2-∀3 weeks, …, 11-≤12 weeks] by randomized group and presented graphically in a 
histogram.
Cumulative study intervention exposure [#1 week, #2 weeks, …, #12 weeks] will also be 
summarized.
Study intervention duration is defined as (date of last dose of study intervention – date of first dose 
of study intervention) +1.
4.5.
Protocol Deviations
In general, a list of major protocol deviations will be produced for the final clinical study report 
(CSR) and these major deviations from protocol may have the potential to impact participants’ 
rights, safety, or well-being, or the integrity and/or result of the clinical study. Participants with 
major protocol deviations will be identified prior to database lock and summarized 
4.6.
Prior and Concomitant Medications
In this pragmatic virtual study, other than history on prior medications up to 36 months, no 
additional information including specific start/end dates of using prior medications will be 
available. However, dates of prescription-fills for specific concomitant/prohibited medications 
collected through the claims/pharmacy database for the duration of the study may be available.
The concomitant medication use during study may be categorized into broad classes of glucose-
lowering agents (such as insulin, metformin, sulfonylurea, DPP-4 inhibitor, GLP-1 receptor 
agonist), renal and cardiovascular (CV) protective agents (such as RAAS inhibitor [including 
sac/val], statin, antithrombotics, beta-blockers, diuretics, IV in-patient diuretics, vasodilators, 
inotropes, anti-infectives) and UGT inducers (such as carbamazepine, phenytoin, phenobarbital, 
tiprnavir, rifampicin, testosterone, propionate, nelfinavir, ritonavir, efavirenz, lamotrigine) 
respectively.
5.
EFFICACY
5.1.
Analysis Specifications
Descriptive statistics for continuous variables include count (n), mean, SD, standard error (SE), 
median, minimum, and maximum. Descriptive statistics for categorical variables include 
participant counts and percentages.


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5.1.1.
Level of Significance
A 5% level of significance will be used for all analyses. All statistical tests and 95% confidence 
intervals presented in the analyses of endpoints will be 2-sided.
5.1.2.
Data Handling Rules
This study will obtain mainly 3 types of data for statistical analysis: the smartphone/app-based 
PRO data, the activity data collected from the Fitbit device and the claims data on adverse events 
(including clinical outcomes, prescription fills, and related HRU). In addition, participant’s self-
reported AE data collected via a Call Center will be directly sent over to Janssen Safety separately 
and is described below as well. All data will be received and processed by PRA (3rd party vendor, 
see Appendix 5: CHIEF-HF Study Data Flow Diagram) into analysis files based on specifications 
provided by the sponsor/study SAP unless specified otherwise.
Smartphone Data - PRO Measures
PRO data (ie, KCCQ, PGIC and PGI-S, participant satisfaction survey) will be collected via the 
smartphone apps available with participants. Based on the administration of the KCCQ at 
screening/baseline through an app, an overall summary score will be produced to decide eligibility 
of individual participant into the study. The individual domains and summary scores of KCCQ 
will be calculated using the scoring algorithm provided in the KCCQ manual at specified time 
points during the study. Missingness in these PRO measures may result from participants not 
completing the questionnaires on the smartphone app at the scheduled times during the study 
period for various reasons including non-compliance with the protocol, discontinuation due to AE, 
loss to follow up, etc.
Missing and incomplete data in KCCQ PRO measure may be of 2 types: missing at the form-level 
and at the item-level. Form-level missing data refers to a participant missing an entire PRO 
assessment for a scheduled time point. If not otherwise specified, analyses will be conducted on 
all available data and form-level missing data will not be imputed. For the KCCQ, derivation of
individual domain scores in the presence of missing item-level responses will follow algorithms 
specified in the KCCQ manual. PRA will calculate baseline KCCQ overall summary score based 
on the KCCQ app and include in the analysis database. For calculation of all other KCCQ domain 
scores (including the KCCQ-TSS) at baseline and at all post-randomization time points, scoring 
instructions available per the KCCQ manual with Janssen will be followed (see Appendix 8). For 
the PGIC and PGI-S measures, a single imputation (ie, last observed scores carried forward) for 
missing post-baseline scores will be used as a conservative rule. Vertical file formats will be 
prepared for all PRO data, reading one record per patient for each measurement time (ie, baseline, 
Weeks 2, 4, 6, and 12, and Months 6 and 9, respectively).
Fitbit Data - Clinical (Activity) Measures
Data from the Fitbit device pertaining to the daily total step counts and daily total floors climbed
will be aggregated over 2-week intervals for the entire study duration (see Table 1). Due to the 
general sedentary nature of HF patients, Fitbit recorded ∀100 steps taken in a day will not be 


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considered in the calculation of averages for daily step counts . If missing %7 days (50%) in a 
2-week interval, the corresponding 2-week interval average will be set to missing.
In case of premature discontinuation of the study intervention, the average of the last non-missing 
14-day window prior to the last dose of study intervention will always be used as an EOT value. 
If the EOT value corresponding to the period (EOT-14, EOT-1) is missing (not valid), the EOT 
period will be rolled back by one day, ie, (EOT-15, EOT-2), (EOT-16, EOT-3), until a non-missing 
(valid) value is available. This corresponds to a last observation carried forward (LOCF) up to 
Week 12/EOT approach. If no post-baseline daily activity data have been collected for at least 7 
days over a 14-day time window, no EOT value will be computed, and the post-baseline value will 
be set to missing.
Baseline for daily step count and daily floors climbed variables will be defined by averaging the 
daily values over a 14-day interval starting with the first dose date. These data will be organized 
into a vertical file format to read one record per participant for averages over each 2-week interval 
during the entire study (including the EOT/EOS values, as applicable).
Claims Data – AEs, HRUs, Clinical Outcomes
Claims data pertaining to AEs of interest (as defined in the protocol), number of prescription fills, 
HRUs, and clinical outcomes reported with appropriate ICD codes applied at the individual 
participant level will be organized with one record for each incident (ie, hospitalization, etc.) date.
Adverse events of interest include all severe hypoglycemic events, acute kidney injury, fractures, 
diabetic ketoacidosis, and lower limb amputation.
In addition, the following adverse events will be examined: hypotension; Fournier’s gangrene; 
genital mycotic infections; urinary tract infections (including urosepsis and pyelonephritis); 
increased urination; and hypersensitivity reactions including angioedema and anaphylaxis.
Self-reported AE data – Data from participants self-reporting adverse events (AEs) to a Call 
Center (set up by Care Innovations) will be manually submitted directly to the Sponsor (i.e. Janssen 
Safety [GMS]) for appropriate evaluation and analysis. Janssen Safety (GMS) will extract 
participant-reported AEs and transfer data to PRA for upload into the CCDS. Self-reported events 
will be captured from the date of the first dose of study intervention through the end of treatment 
(Month 3) plus 30 days. A listing of these self-reported AE may be produced based on available 
data.
5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary effectiveness endpoint is the change in the KCCQ-TSS from baseline to Week 12.
5.2.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 5 attributes (ICH E9 [R1]).4


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!
Population: FAS: all randomized participants with HF (who either have HFrEF or HFpEF, 
regardless of T2DM status) with at least one dose of study intervention and at least 1 post-
baseline KCCQ measurement
!
Treatment: canagliflozin 100 mg or placebo
!
Variable: change from baseline to Week 12 post first dose in the KCCQ-TSS
!
Intercurrent events: treatment discontinuations (either due to AE or other reasons) or treatment 
switching; use treatment policy strategy to address intercurrent events (i.e., use all available 
measurements collected during Week 12 , regardless of the occurrence of the intercurrent 
event); events of “loss to follow up” or “study withdrawal” or “death” are not considered 
intercurrent events but rather missing data.
!
Population-level summary: difference in mean change from baseline to Week 12 in the 
KCCQ-TSS between randomized groups.
In other words, the main quantity to estimate for the primary effectiveness endpoint is the mean 
difference between the 2 treatment groups (canagliflozin 100 mg and placebo) of 
the change 
from baseline to Week 12 in the KCCQ-TSS.
5.2.3.
Analysis Methods
The primary effectiveness endpoint analysis will be based on the full analysis set (FAS).
Considering the repeated measurements of the KCCQ-TSS in the double-blind treatment period
(ie, at baseline, Weeks 2, 4, 6, and 12 respectively), the primary effectiveness endpoint (change in 
the KCCQ-TSS from baseline to Week 12) will be analyzed by a MMRM method simultaneously 
adjusting for treatment, stratification factor (HFrEF or HFpEF), time, time by treatment, and 
baseline KCCQ-TSS value as covariates. Time is repeated within participants and an unstructured 
covariance structure will be assumed across treatment groups to model the within-participant
errors. Fixed effects tests will be computed using the Kenward-Roger method to determine the 
degrees of freedom of the denominator. In case of convergence issues, alternative variance-
covariance structures will be evaluated in the following order, with the first structure in the 
following list that converges being used in the analysis: heterogeneous Toeplitz, standard Toeplitz, 
and AR (1) with separate participant random effect. The primary comparison will be based on the 
difference in the LS mean changes from baseline to Week 12 between treatments. The treatment 
difference in the LS means, corresponding 95% confidence intervals (CI) and associated p-value
will be calculated. The LS means ±SE of change from baseline values estimated by MMRM will 
be plotted by each timepoint for each intervention group.
PROC MIXED DATA=analysis_dataset;
CLASS treatment time ptid;
MODEL change = treatment time treatment*time baseline strat_var/DDFM=KR;
REPEATED time / SUBJECT=ptid TYPE=UN;
LSMEANS treatment;
LSMEANS treatment*time/pdiff cl;
RUN;


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An MMRM model assumes the KCCQ-TSS data missing at random (MAR). A sensitivity analysis 
may be  performed involving multiple imputation (MI) modeling approach for missing KCCQ-
TSS values when the MAR assumption is considered not valid. Implementing the MI process 
requires 3 steps: 1) each missing value is imputed multiple times, based on statistical modeling,
resulting in repetitions of the original dataset, along with the newly imputed values (implemented 
in the Statistical Analysis System [SAS] using PROC MI); 2) each dataset is analyzed using an 
MMRM model (implemented in SAS using PROC MIXED). The LS means and SEs from each 
analysis will be output to a SAS dataset; 3) results from the analyses performed on multiple 
datasets in step #2 are combined to provide valid statistical inference (implemented in SAS using 
PROC MIANALYZE).1
A complete SAS code for MMRM model and implementation of the MI approach described above 
will be added to the final SAP appendix or to the final study report. Mortality in this short-duration 
trial is expected to be low and to be comparable between groups and will be ignored in the primary 
analyses of mean differences in changes in KCCQ total symptom scores, but can be included in 
the responder analyses (described below) by assigning them to the lowest response (greatest 
deterioration) category. Should there be a >5% mortality rate in this study, and if it is unequally 
distributed between treatment arms, then joint modeling of survival and health status (e, g.,KCCQ)
will be performed. A win-ratio approach19,20 may also be considered by analyzing the KCCQ-TSS 
score as a composite, rank-based outcome, incorporating participant vital status at 12 weeks along 
with a change in score from baseline to 12 weeks in surviving participants. This essentially is the 
rank analysis of covariance method, with a corresponding win ratio used to estimate the magnitude 
of treatment effect.
An exploratory responder analysis will be performed when comparing proportions of participants
with a 5- (or 10-) point improvement in the KCCQ-TSS from baseline to Week 12 between the 
groups. This will be based on a 2-sample difference in proportions test along with a 95% 
confidence interval for the difference in 2 proportions.
The mean differences between the groups will be augmented with both responder analyses and 
empirical cumulative distribution and probability density function curves. Specifically, the 
empirical cumulative distribution function (CDF) of the change from baseline in KCCQ-TSS will 
be generated. CDF shows the proportion of the population scoring less than or equal to each 
possible change score. CDFs are useful as they graphically characterize the treatment effect or 
differences between groups. It also enables a ready assessment of different magnitudes of clinical 
change (e.g., 5, 10, and #20-point changes, corresponding with small to moderate, moderate to 
large, and large to very large clinical changes). CDFs and histograms will be shown for changes 
from baseline to Week 12 in the KCCQ TSS. For all CDF plots, the x-axis is the score change 
from baseline to final time point (i.e., Week 12) for the KCCQ-TSS. The y-axis is the cumulative 
proportion of the participants in each of the corresponding categories that reach the score change 
on the x-axis.
According to the Food and Drug Administration’s (FDA’s) guidance on PRO measures, a 
responder is defined by the empirically determined score change in a measure, experienced by an 
individual patient over a predetermined time period that has been demonstrated in the target 


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population to have a significant treatment benefit. This is also often referred to as responsiveness 
or ability of the PRO measure to capture the true underlying change in the patient health status 
over time. Assessing the responsiveness of the PRO measure using an anchor-based approach 
involves comparing the changes in the PRO scores to other clinically meaningful markers or 
anchors that represent a valid measure of clinical change. 
For the anchor-based analysis of the KCCQ-TSS endpoint, participants will be characterized based 
on the PGIC scores at Week 12. The mean change in KCCQ-TSS endpoint observed in the smallest 
improvement category of the PGIC will be examined as a key anchor-based indicator of a 
responder. The definition for a small improvement in PGIC is given as those who improve by one 
category (i.e., from “a little improved” to “somewhat improved”). Specifically, the retrospective 
PGIC responses of “3=a little improved” will be selected to represent time points where 
participants register meaningful changes in their HF symptoms. Each time a participant responds 
with a PGIC score of “3=a little improved”, a KCCQ-TSS change score from the preceding visit 
is computed. For the double-blind treatment period, the PGIC will be collected at 4 time points 
(i.e., Weeks 2, 4, 6, and 12 respectively) which can yield between zero and 4 KCCQ-TSS change 
scores by each participant. For each participant with at least one PGIC response of “3=a little 
improved”, a mean of the individual participant’s KCCQ-TSS change scores is computed. A 
summary of KCCQ-TSS change scores across PGIC categories16 will then be presented.
The KCCQ-TSS change scores may also be standardized into effect size (ES) statistics by dividing 
them by their SD at baseline. The following cutoff values will be used to interpret effect size: small 
ES = 0.2, moderate ES =0.5, and large ES = 0.8. Together with the CDF, results from the anchor-
based methods will be examined and a single responder definition threshold will be determined, if 
the results from the anchor-based assessments in this study differ substantially from prior studies 
examining the clinical meaningfulness of changes in the KCCQ.
In addition, a distribution-based change (i.e., minimum detectable [MID] change) may be explored 
for which the KCCQ-TSS can be derived using the baseline SD. Generally, a value of half the 
baseline SD has been frequently found to correspond to the MID obtained via the anchor-based 
method. A value of 0.2*SD may also be examined.
Subgroup analyses for the change from baseline to Week 12 for the primary effectiveness endpoint 
will be conducted for subgroups (listed in Section 2.4) based on all randomized analysis set. These 
analyses will assess consistency of the overall treatment effect across subgroup variables.
The main MMRM analyses will be repeated with each subgroup tested separately. Intervention 
group differences of LS means as well as corresponding 95% CIs within each subgroup level will 
be presented.
The intervention-by-subgroup interaction p-value will be estimated using a separate MMRM 
model including intervention, baseline KCCQ value, stratification factor (HFrEF/HFpEF), 
subgroup, and intervention-by-subgroup interaction term(s). Interactions with p-value ∀0.1 will be 
investigated further to determine the nature of interaction (quantitative or qualitative) and the 


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association with other subgroups. For qualitative interactions, Gail and Simon (1985) approach15
may be considered.
Results will be presented in a summary table and in a forest plot. The forest plot will display the 
“overall” treatment effect, based on the main MMRM analysis, as a reference line. LS means of 
the intervention group differences, the corresponding 95% CIs, and the numbers of participants in 
the subgroup levels will be presented in the forest plot.
5.3.
Secondary Endpoints
5.3.1.
Definition
The first key secondary effectiveness endpoint is change in the daily step count from baseline to 
Week 12 averaged over two-week intervals. Even though evidence of a meaningful change in daily 
step count in chronic HF patients via Fitbit device is not readily available, there are several studies 
that have conducted six-minute walk tests (6MWT) among HF patients in general and examined a 
minimum clinically important difference in daily step counts under different conditions. A change 
of 30 meters10 (approximately 1000 steps) may be considered in the present study to be of clinical
interest to benchmark the expected mean change in daily step count in this study over the double-
blind treatment period. This expected mean change in daily step count will also be examined in 
relation to variables such as PRO measures (as anchors) and clinical outcomes to better 
characterize treatment effect on daily activity.
As HF patients are generally not consistent in their daily walk patterns, there will be variations in 
levels of their daily activity (whether it is a weekday or a weekend) as well as variability in the
total wear time of the Fitbit device. As a rule, we will consider Fitbit recorded #100 steps13 taken 
in a day in the calculations of averages. This will ensure capturing any meaningful level of physical 
activity while avoiding even smaller variations in daily steps taken by a participant wearing a Fitbit 
device. For each participant, baseline daily step count will be calculated by averaging daily step 
counts from Study Day 1 through Study Day 14. All subsequent post-baseline daily step count data 
will also be averaged in 2-week intervals. The change from baseline to Week 12 in daily step count 
will be based on subtracting the average of daily step count for Week 11 and Week 12 from the 
baseline average for each participant. Additionally, daily step count data will be averaged in 3-, 5-
and 7-day (1-week) intervals at baseline and throughout the treatment period respectively and 
corresponding changes from baseline will be calculated. 
The variable daily floors climbed will also be aggregated in a similar fashion.
5.3.2.
Estimand
The first key secondary estimand to be estimated in the study, is defined by the following -
!
Population: FAS (i.e., all randomized participants with HF who either have HFrEF or HFpEF, 
regardless of T2DM status with at least one dose of study intervention and at least 1 post-
baseline KCCQ measurement)
!
Treatment: canagliflozin 100 mg or placebo


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!
Variable: change from baseline to Week 12 in the daily step count averaged over 2-week 
intervals
!
Intercurrent event: treatment discontinuations (either due to AE or other reasons) or treatment 
switching or temporary disruption in daily activity; use treatment policy strategy to address 
intercurrent events (i.e., use all available measurements collected during study, regardless of 
the occurrence of the intercurrent event); events of “loss to follow up” or “study withdrawal” 
or “death” are not considered intercurrent events but rather missing data.
!
Population-level summary: difference in mean change from baseline to Week 12 in the daily 
step count averaged over 2-week intervals (i.e., difference is based on subtracting the average 
of daily step count for Week 11 and Week 12 from the baseline 14-day average daily step 
count) between two randomized groups.
5.3.3.
Analysis Methods
Daily step counts and daily floors climbed data at baseline will be presented as 14-day averages of 
daily counts starting with the first dose date and ending with Day 14 during the double-blind 
treatment period. This method of averaging will continue until end of Month 9 (Day 252) or, until 
the time of end of study (EOS) observation is available.
The above two key secondary endpoints will be analyzed in two ways –
1) following the same approach as employed for the primary effectiveness endpoint (i.e. using 
an MMRM model adjusting for baseline covariates such as treatment, stratification factor 
and baseline average step count). 
2) by calculating mean change from baseline to Week 12 in daily step counts using the 
corresponding 14-day averages at baseline and Week 12 respectively. That is, the mean 
difference in the 14-day averages in daily step counts or daily floors climbed is calculated 
for each randomized intervention group and difference in mean changes between the 
2 randomized intervention groups will be compared using a 2-sided t-test.
As stated in Section 1.3, the first key secondary endpoint of daily step count will be tested once 
the primary endpoint is shown to be statistically significant at 5% significance level.
Other secondary endpoints refer to changes in the KCCQ individual domain scores (physical 
limitation, quality of life), and the KCCQ clinical summary and overall summary scores from 
baseline to Week 12. The individual KCCQ domain scores as well as the summary scores will be 
produced at each time point (based on the KCCQ algorithm) with changes from baseline calculated 
at each specified post-baseline time point. For these endpoints, an MMRM model (like that 
specified for the analysis of the primary endpoint) will be employed to summarize changes over 
time from baseline to Week 12. Hypotheses related to these domains will be independently tested 
at 5% without any control for overall type I error rate.
5.4.
Exploratory Variables
5.4.1.
Definition
The exploratory endpoints are the following:


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!
mean PGIC scores over time
!
changes in PGI-S scores from baseline to Week 12
!
change in HRU and health economics data
!
number of outpatient intravenous therapies, ED visits, and hospitalizations 
!
time to first hospitalization/readmission for heart failure
!
time to first hospitalization/readmission for other events
!
time to death
5.4.2.
Analysis Methods
The exploratory endpoints listed below will be presented using descriptive statistics at each time 
point measurements are taken. Where specified, 95% confidence intervals (CIs) and p-values will 
be presented but no multiplicity adjustment will be made. Analyses of mean changes from baseline 
to Week 12 and month 9 (Day 252) respectively will be conducted, as described below.
!
Appendix 6: Patient Global Impression of Change (PGIC) is a validated generic tool for 
assessment of overall change in the severity of illness following treatment. Participants rate 
how they feel now compared with how they felt before receiving study intervention on a 7-
point scale where 1 is “Very much improved” and 7 is “Very much worse”. A mean ± SD 
PGIC score for each time point will be calculated by randomized intervention group. 
Distribution of PGIC score at Week 12 will also be presented. Based on the PGIC symmetric 
scale, a dichotomous scale of “Yes” or “No” will be derived. A favorable change is score of 
1-3 = ’Yes’, which means there is significant improvement with the study intervention. If the 
response is 4-7 = ’No’, it is considered no significant change. Change in the KCCQ-TSS from 
baseline to Week 12 by PGIC response at Week 12 will be summarized by treatment group, 
and, also graphically displayed (i.e., x-axis will display categories of PGIC response at Week 
12 and y-axis will display mean change scores from baseline to Week 12 in KCCQ-TSS by 
treatment group).
!
Distribution of participants in PGI-S (see Appendix 7: Patient Global Impression of Severity 
(PGI-S)) response categories will be summarized by randomized intervention group at 
baseline and by Week 12. Mean change in PGI-S score between baseline and Week 12 will 
be summarized by randomized group. Change in the KCCQ-TSS from baseline to Week 12 
by PGI-S response at Week 12 will be summarized.
!
For daily activity measured by daily step counts, total active days (defined as Fitbit recorded 
#100 steps) and percent of active days to total days spent in the study analysis period will be 
summarized for each intervention group using mean and SD. Level of daily activity will also 
be described using categories of total step counts per day – 1) ∀3000 steps per day (low 
activity/sedentary), 2) 3000-5999 (moderate activity), and 3) # 6000 steps per day (high 
activity). Associations between daily step count (categorized into activity levels) and baseline 
characteristics (eg, age, sex, race, T2DM status, EF type, etc.) will be examined using a 1-
way ANOVA for continuous data values and the Fisher exact test for categorical data.
!
Correlation between total step counts per day and clinical events (eg, # of outpatient 
intravenous therapies, # ED visits, # hospitalizations, etc.) will be described for the double-


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blind treatment period and total study duration separately. Relationships between change in 
step counts/floors climbed and incidence of reported clinical outcomes and PRO measures 
will be examined at the end of the double-blind treatment period and end of study separately.
!
Daily floors climbed will be summarized by each intervention group for the double-blind 
treatment period and over the entire study duration separately.
!
Descriptive statistics (ie, N, mean, SD, minimum and maximum) will be presented for total 
HRU and health economics data for each intervention group separately for the double-blind 
treatment period and the observational (no intervention) period. HRUs and health economics 
data typically include information regarding participants using health services for managing 
any 
clinical 
events/illnesses, 
hospitalizations/ED 
visits, 
surgeries, 
medication 
issues/prescription changes, and costs incurred.
!
Descriptive statistics will be presented for participant's satisfaction with his/her experience 
with the virtual design at the end of the study.
!
Using data from claims, the number of outpatient intravenous therapies, ED visits, and 
hospitalizations by each intervention group will be summarized. These summaries will include 
descriptive statistics.
!
Using data from the claims and data on deaths, time to first hospitalization/readmission for 
heart failure, time to first hospitalization/readmission for other events, and time to death will
each be analyzed using a Cox’s regression model both for the double-blind treatment period 
and the entire study duration and include terms for study intervention and stratification factor 
(HFrEF/HFpEF). Hazard ratios, corresponding 95% CIs, and associated p-values will be
presented. Distribution of the times to first hospitalization/readmission for HF, time to first 
hospitalization/readmission for other events, and time to death will be displayed with Kaplan-
Meier curves. Participants who do not experience any such events of interest during the study 
analysis period will be considered ‘censored’ in these analyses.
No adjustment for multiplicity will be performed for the exploratory analyses listed above.
6.
SAFETY
Summaries of safety data will be based on the safety analysis set and will use claims data.
6.1.
Adverse Events
All AE data summaries will be based on the safety analysis set except where stated otherwise. A 
treatment emergent AE is defined as an event that occurs after the first dose of study intervention 
(Study Day 1) and/or worsens in severity during the double-blind treatment period.
Adverse events self-reported to the Call Center will be assessed by Janssen Global Medical Safety 
(GMS) for start and end dates, causality and meeting SUSAR reporting requirements. If the 
specific dates pertaining to the self-reported AEs are unknown, there will be limited follow-up for 
resolution. For any events still ongoing at the end of the study, there will be no follow up (as the 
Call Center will be closed at that point) possible. Adverse events will be coded according to 
MedDRA and will be reported by preferred term for each randomized intervention group. Janssen 
Data Management will request a listing of all AEs/SAEs reported to the Call Center from the 
Janssen GMS. This listing will be shared with PRA (external vendor) to convert the information 


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into the SDTM format and for inclusion in the final SDTM data package for summary by various 
subgroups (e.g., T2DM and non-T2DM).
Adverse events collected through the claims database will be analyzed separately for the 12-week 
treatment period + 30 days after last dose and the 9-month entire study period respectively. It is 
assumed that claims database will have dates of service provided (procedure dates, office visits, 
hospital admissions, etc.) but not actual start/end dates of events prior to claims being filed.
Therefore, no imputation of AE start/end dates will be feasible based on the claims data. Dates of 
service(s) rendered to participants during the study (i.e., starting from the time informed consent 
is signed until the end of double-blind treatment plus 30 days) will be taken into account. The 
claims data will utilize ICD codes to identify the SAEs and AEs of interest which are defined in 
the protocol and for the final analysis. The AEs of interest include all severe hypoglycemic events, 
acute kidney injury, fractures, diabetic ketoacidosis, and lower limb amputation. In addition, 
hypotension, Fournier’s gangrene, genital mycotic infections, urinary tract infections (including 
urosepsis and pyelonephritis), increased urination and hypersensitivity reactions (including 
angioedema and anaphylaxis) will be considered for coding and final analysis.
For the prohibited medications, analysis period will include data from the date of informed consent 
until the end of double-blind treatment period. For all other concomitant mediations, analysis 
period will include data from the date of informed consent until the end of the study.  For the HRU 
data analysis, information collected from date of informed consent until the end of study will be 
considered in the final analysis.  
For both the double-blind treatment period + 30 days after last dose and the 9-month entire study 
period, descriptive summaries (numbers and percentages) of participants having an SAE/AE of 
interest will be produced, including by participant’s diabetes status (T2DM and non-T2DM) and 
by randomized intervention group. Discontinuations (and reported reasons) will be summarized 
by randomized intervention group based on available claims data.
There will be no reconciliation/analysis of SAE/AE data that are self-reported to the Call Center 
with the data obtained from the claims database.
A listing will be presented for treatment emergent hospitalizations and deaths for each randomized 
intervention group. AEs occurring between informed consent and the day prior to the first dose of 
study intervention will also be listed. This listing will be based on participants with informed 
consent into the study. Depending on the claims/pharmacy data, AEs occurring in participants who 
used prohibited (commercially available SGLT2is other than the study intervention, canagliflozin) 
will also be listed.
Based on pharmacy profiles of the participants after-consent in this study, the total number of 
participants concomitantly receiving UGT inducers during the double-blind treatment period will 
be summarized combined across both study intervention groups. If the number of such participants 
is %2% of the total 1,900 targeted for enrollment in this study, the users and non-users of UGT 
inducers will be summarized by each study intervention group as well and examined further (as 


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necessary) for any relationship to key study outcomes (eg, PRO endpoints and clinical outcomes 
reported in claims).
6.2.
Clinical Laboratory Tests
Not Applicable.
6.3.
Vital Signs and Physical Examination Findings
Not Applicable.
6.4.
Electrocardiogram
Not Applicable.
6.5.
Other Safety Parameters
Not Applicable.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Not Applicable.
8.
BIOMARKERS
Not Applicable.
9.
HEALTH ECONOMICS
As treatment of participants with symptomatic HF with JNJ-28431754 (canagliflozin)JNJ-
28431754 
(canagliflozin)
versus 
placebo 
may 
result 
in 
lower 
utilization 
of 
hospitalization/readmissions due to HF or other reason, ED visits, the duration of stay at each 
hospitalization/readmission, and discharge destination will be summarized by each intervention 
group. 
Comparison 
will 
be 
made
between
groups
by 
analyzing 
differences 
in 
hospitalizations/readmissions and ED visits using the Fisher exact test. Descriptive statistics (eg, 
mean, median, minimum, and maximum) will be provided for the total length of stay in hospitals 
for each intervention group. Cumulative distribution function of the time to first occurrence of 
hospitalization/readmission will be estimated by the Kaplan-Meier method and tested using a log-
rank test, stratified by the type of HF ejection fraction (ie, HFrEF or HFpEF). In addition, a Cox 
proportional hazards mode with intervention and stratification factor as covariates will be fitted. 
A point-estimate along with 2-sided 95% CI for HR of the intervention effect (in terms of relative 
risk reduction (RRR) = 100 x [1-HR] %) will be provided. The cumulative event rate derived from 
Kaplan-Meier estimate will also be displayed graphically to evaluate the timing of event 
occurrence and the consistency of the treatment effect over time.


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REFERENCES
1.
Berglund P and Heeringa S. Multiple Imputation of Missing Data Using SAS®. 2014. Cary, NC: SAS Institute 
Inc. CDISC. “Analysis Data.
2.
Dreyer RP, Jones PG, Kutty S, Spertus JA. Quantifying clinical change: discrepancies between patients' and 
providers' perspectives. Qual Life Res. 2016 Sep;25(9): 2213-2220.
3.
Green, C., Porter C., Bresnahan D., and Spertus, J. 2000. Development and evaluation of the Kansas City 
Cardiomyopathy Questionnaire: a new health status measure for heart failure. Journal of American College of 
Cardiology. 2000 Apr; 35(5):1245-1255.
4.
International Council For Harmonisation (ICH) of Technical Requirement for Pharmaceuticals for Human Use 
(final version, 2019): ICH Harmonised Guideline – Addendum on estimands and sensitivity analysis in clinical 
trials (to the guideline on Statistical Principles for Clinical Trials) - E9 (R1).
5.
Khariton Y. et al. Association Between Sacubitril/Valsartan Initiation and Health Status Outcomes in Heart 
Failure with Reduced Ejection Fraction: Findings from the CHAMP-HF Registry. Data presented at the 
European Society of Cardiology Heart Failure (ESC-HF); 2018 May 26-29; Vienna, Austria.
6.
Luo N, et al. Relationship between changing patient-reported outcomes and subsequent clinical events in 
patients with chronic heart failure: insights from HF-ACTION, European Journal of Heart Failure (2019) 21, 
63-70.
7.
McMurray JJV, Solomon SD, Inzucchi SE, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin 
in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019 Sep 19.
8.
Nassif ME, Windsor SL, Tang F, et al. Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status 
in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial. Circulation. 
2019 Oct 29;140(18):1463-1476.
9.
Pokharel Y, et al. Association of serial Kansas City Cardiomyopathy Questionnaire assessments with death and 
hospitalization in patients with heart failure with preserved and reduced ejection fraction. A secondary analysis 
of 2 randomized clinical trials. JAMA Cardiology. 2017 Dec 1; 2912):1315-1321.
10.
Shoemaker M, Curtis AB, Vangsnes E, Dickinson, MG. Clinically Meaningful Change Estimates for the Six-
Minute Walk Test and Daily Activity in Individuals With Chronic Heart Failure. Cardiopulm Phys Ther J, 
Sep 2013;24(3), 21-29.
11.
Spertus, J, Jones P. Development and validation of a short version of the Kansas City Cardiomyopathy 
Questionnaire. Circulation: Cardiovascular Quality and Outcomes, 2015; 8:469-476.
12.
Spertus J, Peterson E, Conard MW, et al. Monitoring clinical changes in patients with heart failure: a 
comparison of methods. Am Heart J 2005;150(4):707-715.
13.
Thorup C, Hansen J, Gronkjaer M, et al. Cardiac Patients’ Walking Activity Determined by a Step Counter in 
Cardiac Telerehabilitation: Data From the Intervention Arm of A Randomized Controlled Trial. J Med Internet 
Res 2016 Apr; 18(4); e69.
14.
Vetrovsky T, Siranec M, Parenica J, et al. Effect of a 6-month pedometer-based walking intervention on 
functional capacity in patients with chronic heart failure with reduced (HFrEF) and with preserved (HFpEF) 
ejection fraction: study protocol for two multicenter randomized controlled trials, J Transl Med, 2017; 
15(1):153.
15.
Gail, M. H., and Simon, R. (1985). “Tests for Qualitative Interactions between Treatment Effects and Patient 
Subsets.” Biometrics 41:361–372.
16.
Mehta, L. et al. (2015). Identifying an important change estimate for the multiple sclerosis walking scale-12 
(MSWS-12v1) for interpreting clinical trial results, Multiple Sclerosis Journal – Experimental, Translational, 
Clinical” 1:1-9


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17.
Nassif, M. et al. (2019). Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients 
With Heart Failure With Reduced Ejection Fraction - The DEFINE-HF Trial. Circulation, Vol. 140, No. 18, 
1463-1476
18.
Bhatt, D. et al. (2020). Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J 
Med, 2020; Nov 16
19.
Gasparyan, S. et al. (2019). Adjusted Win Ratio with Stratification: Calculation Methods and Interpretation, 
Stat.ME
20.
Wang, D. and Pocock, S. (2016). A win-ratio approach to comparing continuous non-normal outcomes in 
clinical trials, Pharmaceutical Statistics, online 11 March 2016


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APPENDICES
Appendix 1: The Kansas City Cardiomyopathy Questionnaire (KCCQ)
The KCCQ (Appendix 1: The Kansas City Cardiomyopathy Questionnaire (KCCQ)) is a well-established 
PRO for use in patients with HF, with published validity and reliability and was recently endorsed by the 
Center for Devices and Radiological Health (CDRH, US FDA) as a Certified Outcome Assessment through 
its Medical Device Development Tools Program and is currently under review at the Center for Drug
Evaluation and Research (CDER, US FDA).
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered questionnaire 
developed to independently measure the patient’s perception of their health status, which includes heart 
failure symptoms, impact on physical and social function, and how their heart failure impacts their quality 
of life (QOL) within a 2-week recall period. This questionnaire requires, on average, 4 to 6 minutes to 
complete, with a resulting score of 0 to 100, and higher scores indicating better health.
The intent of the study is to enroll participants with NYHA class II and III. As it would be difficult to verify 
NYHA class with claims and EHR data, the sponsor will use a KCCQ overall summary score at baseline 
of %40 and ∀80, which is highly correlated to class II and III in HFrEF and HFpEF based on the research 
published by Joseph, et al.6 In addition to the KCCQ overall summary score, a baseline KCCQ TSS score 
will also be calculated for each participant.
The 23-item KCCQ quantifies 7 domains of patients’ HF-related health status:
!
Physical Limitation (6 items) 
!
Symptom Stability (1 item) 
!
Symptom Frequency (4 items) 
!
Symptom Burden (3 items) 
!
Self-Efficacy (2 items) 
!
Quality of Life (3 items) 
!
Social Limitations (4 items)
Item responses are coded sequentially (1, 2, 3, etc.) from worst to best status. Scores are generated for each 
domain and scaled from 0 to 100, with 0 denoting the worst and 100 the best possible status. In addition, 
three summary scores are calculated: Total Symptom score (average of Symptom Frequency and Symptom 
Burden), Clinical Summary score (average of Physical Limitation and Total Symptoms), and Overall 
Summary score (average of Physical Limitation, Total Symptoms, Quality of Life, and Social Limitation).
Among the 7 domains and 3 summary scores of KCCQ described above, this study will focus on analyzing 
only two individual domains (physical limitation and quality of life) and three summary scores (clinical 
summary, overall summary, and total symptom).
Below is a representative example of the scale questions that will be used in this study.


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Appendix 4: Usage of the Analysis Sets
Appendix 4 presents an overview of the different analysis sets and their usage.
Analyses/data displays
All randomized analysis set
Full analysis set (FAS)
Safety analysis set
Per protocol set
Patient disposition
Demographics
Baseline characteristics
Medical history
Treatment exposure
Effectiveness: Primary 
endpoint
Effectiveness: Secondary 
endpoints
Effectiveness; Exploratory 
endpoints
Safety endpoints
All other patient listings


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Appendix 5: CHIEF-HF Study Data Flow Diagram




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Appendix 6: Patient Global Impression of Change (PGIC)
Appendix 6 provides a representative example of the scale questions that will be used in this study.
Since the start of the treatment you’ve received in this study, your heart failure symptoms are: (select one 
response)
1.
Very much improved
2.
Somewhat improved
3.
A little improved
4.
No change
5.
A little worse
6.
Somewhat worse
7.
Very much worse


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Appendix 7: Patient Global Impression of Severity (PGI-S)
Appendix 7 provides a representative example of the scale question that will be used in this study.
Considering all aspects of your heart failure symptoms right now, would you say your heart failure 
symptoms are: (select one response)
1.
None
2.
Mild
3.
Moderate
4.
Severe
5.
Very Severe
Appendix 8: KCCQ Score Instructions 
The Kansas City Cardiomyopathy Questionnaire Scoring Instructions 
There are 10 summary scores within the KCCQ, which are calculated as follows: 
1.
PHYSICAL LIMITATION 
•
Code responses to each of Questions 1a-f as follows: 
Extremely limited = 1 
Quite a bit limited = 2 
Moderately limited = 3 Slightly 
limited = 4 
Not at all limited = 5 
Limited for other reasons or did not do = <missing value>
•
If at least three of Questions 1a-f are not missing, then compute  
Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4 
(see footnote at end of this document for explanation of meaning of “actually answered”) 
2.
SYMPTOM STABILITY 
•
Code the response to Question 2 as follows: 
Much worse = 1 


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Slightly worse = 2 Not 
changed = 3 
Slightly better = 4 
Much better = 5 
I’ve had no symptoms over the last 2 weeks = 3 
•
If Question 2 is not missing, then compute  
Symptom Stability Score = 100*[(Question 2) – 1]/4 
3.
SYMPTOM FREQUENCY 
• Code responses to Questions 3, 5, 7 and 9 as follows: 
Question 3
Every morning = 1 
3 or more times a week but not every day = 2 
1-2 times a week = 3 
Less than once a week = 4 
Never over the past 2 weeks = 5  
Questions 5 and 7
All of the time = 1 
Several times a day = 2 
At least once a day = 3 
3 or more times a week but not every day = 4 
1-2 times a week = 5 
Less than once a week = 6 
Never over the past 2 weeks = 7 
Question 9
Every night = 1 
3 or more times a week but not every day = 2 
1-2 times a week = 3 
Less than once a week = 4 
Never over the past 2 weeks = 5 
• If at least two of Questions 3, 5, 7 and 9 are not missing, then compute: 
S3 = [(Question 3) – 1]/4 
S5 = [(Question 5) – 1]/6 
S7 = [(Question 7) – 1]/6 
S9 = [(Question 9) – 1]/4 
Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9) 


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4.
SYMPTOM BURDEN 
•
Code responses to each of Questions 4, 6 and 8 as follows: 
Extremely bothersome = 1 
Quite a bit bothersome = 2 
Moderately bothersome = 3 
Slightly bothersome = 4 
Not at all bothersome = 5 
I’ve had no swelling/fatigue/shortness of breath = 5 
•
If at least one of Questions 4, 6 and 8 is not missing, then compute  
Symptom Burden Score = 100*[(mean of Questions 4, 6 and 8 actually answered) – 1]/4 
5.
TOTAL SYMPTOM SCORE 
= mean of the following available summary scores: 
Symptom Frequency Score 
Symptom Burden Score 
6.
SELF-EFFICACY 
• Code responses to Questions 10 and 11 as follows: 
Question 10
Not at all sure = 1 
Not very sure = 2 
Somewhat sure = 3 
Mostly sure = 4 
Completely sure = 5 
Question 11
Do not understand at all = 1 
Do not understand very well = 2 
Somewhat understand = 3 
Mostly understand = 4 
Completely understand = 5 


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• If at least one of Questions 10 and 11 is not missing, then compute  
Self-Efficacy Score = 100*[(mean of Questions 10 and 11 actually answered) – 1]/4 
7.
QUALITY OF LIFE 
• Code responses to Questions 12, 13 and 14 as follows: 
Question 12
It has extremely limited my enjoyment of life = 1 
It has limited my enjoyment of life quite a bit = 2 
It has moderately limited my enjoyment of life = 3 
It has slightly limited my enjoyment of life = 4 
It has not limited my enjoyment of life at all = 5 
Question 13
Not at all satisfied = 1 
Mostly dissatisfied = 2 
Somewhat satisfied = 3 
Mostly satisfied = 4 
Completely satisfied = 5 
Question 14
I felt that way all of the time = 1 
I felt that way most of the time = 2 
I occasionally felt that way = 3 
I rarely felt that way = 4 
I never felt that way = 5 
• If at least one of Questions 12, 13 and 14 is not missing, then compute  
Quality of Life Score = 100*[(mean of Questions 12, 13 and 14 actually answered) – 1]/4 
8.
SOCIAL LIMITATION 
•
Code responses to each of Questions 15a-d as follows: 
Severely limited = 1 
Limited quite a bit = 2 
Moderately limited = 3 
Slightly limited = 4 
Did not limit at all = 5 


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Does not apply or did not do for other reasons = <missing value>
•
If at least two of Questions 15a-d are not missing, then compute  
Social Limitation Score = 100*[(mean of Questions 15a-d actually answered) – 1]/4 
9.
OVERALL SUMMARY SCORE 
= mean of the following available summary scores: 
Physical Limitation Score 
Total Symptom Score 
Quality of Life Score 
Social Limitation Score 
10.
CLINICAL SUMMARY SCORE 
= mean of the following available summary scores: 
Physical Limitation Score 
Total Symptom Score 
____________________ 
Note: references to “means of questions actually answered” imply the following. 
!
If there are n questions in a scale, and the subject must 
answer m to score the scale, but the subject answers only 
n-i, where n-i >= m, calculate the mean of those 
questions as  
(sum of the responses to those n-i questions) / (n-i) 
not  
(sum of the responses to those n-i questions) / n  
If doing these calculations seems like too much trouble, consider using one of our tools –
available at www.cvoutcomes.org: 
!
SAS or SPSS code
!
Excel spreadsheets
!
Web data services