**CLINICAL REVIEW**

Application Type NDA #20-838

Submission Number S-025

Submission Code

Reviewer Name Mehul Desai, M.D.

Review Completion Date 3-Jan-2005

Established Name Candesartan Cilexitil

(Proposed) Trade Name Atacand^^

Therapeutic Class angiotensin receptor antagonist

Applicant AstraZeneca

Priority Designation Standard

Formulation oral

Dosing Regimen initial dose of 4 mg qd up titrated to 32 mg qd

Indication heart failure

Intended Population "preserved EF (\> 40%)"

**Table of Contents**

[1 Executive Summary 1](#executive-summary)

[1.1 Recommendation on Regulatory Action
1](#recommendation-on-regulatory-action)

[1.2 Recommendation on Postmarketing Actions
2](#recommendation-on-postmarketing-actions)

[1.3 Summary of Clinical Findings 2](#summary-of-clinical-findings)

[1.3.1 Brief Overview of Clinical Program
2](#brief-overview-of-clinical-program)

[1.3.2 Efficacy 3](#efficacy)

[1.3.3 Safety 3](#safety)

[1.3.4 Dosing Regimen and Administration
3](#dosing-regimen-and-administration)

[1.3.5 Drug-Drug Interactions 3](#drug-drug-interactions)

[1.3.6 Special Populations 4](#special-populations)

[2 Introduction and Background 4](#introduction-and-background)

[2.1 Product Information 4](#product-information)

[2.2 Currently Available Treatment for Indications
4](#currently-available-treatment-for-indications)

[2.3 Availability of Proposed Active Ingredient in the United States
4](#availability-of-proposed-active-ingredient-in-the-united-states)

[2.4 Important Issues With Pharmacologically Related Products
5](#important-issues-with-pharmacologically-related-products)

[2.5 Presubmission Regulatory Activity
5](#presubmission-regulatory-activity)

[3 Significant Findings from Other Review Disciplines
5](#significant-findings-from-other-review-disciplines)

[3.1 CMC (and Product Microbiology, if Applicable)
5](#cmc-and-product-microbiology-if-applicable)

[3.2 Animal Pharmacology/Toxicology 5](#animal-pharmacologytoxicology)

[4 Data Sources, Review Strategy, and Data Integrity
5](#data-sources-review-strategy-and-data-integrity)

[4.1 Sources of Clinical Data 5](#sources-of-clinical-data)

[4.2 Tables of Clinical Studies 5](#tables-of-clinical-studies)

[4.3 Review Strategy 6](#review-strategy)

[4.4 Data Quality and Integrity 6](#data-quality-and-integrity)

[4.5 Compliance with Good Clinical Practices
6](#compliance-with-good-clinical-practices)

[4.6 Financial Disclosures 6](#financial-disclosures)

[5 Clinical Pharmacology 6](#clinical-pharmacology)

[5.1 Pharmacokinetics 6](#pharmacokinetics)

[5.2 Pharmacodynamics 7](#pharmacodynamics)

[6 Integrated Review of Efficacy 7](#integrated-review-of-efficacy)

[6.1 Indication: Preserved EF 7](#indication-preserved-ef)

[6.1.1 Methods 7](#methods)

[6.1.2 General Discussion of Endpoints
7](#general-discussion-of-endpoints)

[6.1.3 Study Design 9](#study-design)

[6.1.4 Efficacy Findings 10](#efficacy-findings)

[6.1.5 Efficacy Conclusions 12](#efficacy-conclusions)

[7 Integrated Review of Safety 13](#integrated-review-of-safety)

[7.1 Methods and Findings 13](#methods-and-findings)

[7.1.1 Deaths 13](#deaths)

[7.1.2 Other Serious Adverse Events 14](#other-serious-adverse-events)

[7.1.3 Dropouts and Other Significant Adverse Events
16](#dropouts-and-other-significant-adverse-events)

[7.1.4 Common Adverse Events 17](#common-adverse-events)

[7.1.5 Laboratory Findings 19](#laboratory-findings)

[7.1.6 Vital Signs 21](#vital-signs)

[7.2 Adequacy of Patient Exposure and Safety Assessments
24](#adequacy-of-patient-exposure-and-safety-assessments)

[7.2.1 Description of Primary Clinical Data Sources (Populations Exposed
and Extent of Exposure) Used to Evaluate Safety
24](#description-of-primary-clinical-data-sources-populations-exposed-and-extent-of-exposure-used-to-evaluate-safety)

[7.3 Summary of Selected Drug-Related Adverse Events, Important
Limitations of Data, and Conclusions
25](#summary-of-selected-drug-related-adverse-events-important-limitations-of-data-and-conclusions)

[8 Additional Clinical Issues 25](#additional-clinical-issues)

[8.1 Dosing Regimen and Administration
25](#dosing-regimen-and-administration-1)

[8.2 Drug-Drug Interactions 25](#drug-drug-interactions-1)

[8.3 Special Populations 26](#special-populations-1)

[8.4 Pediatrics 26](#pediatrics)

[8.5 Advisory Committee Meeting 26](#advisory-committee-meeting)

[8.6 Literature Review 27](#literature-review)

[9 Overall Assessment 27](#overall-assessment)

[9.1 Conclusions 27](#conclusions)

[9.2 Recommendation on Regulatory Action
28](#recommendation-on-regulatory-action-1)

[9.3 Recommendation on Postmarketing Actions
28](#recommendation-on-postmarketing-actions-1)

[9.4 Labeling Review 28](#labeling-review)

[My labeling recommendations are as follows:
28](#my-labeling-recommendations-are-as-follows)

[10 Appendices 29](#appendices)

[10.1 Review of Individual Study Reports
29](#review-of-individual-study-reports)

[10.1.1 CHARM Preserved 29](#charm-preserved)

[10.2 Line-by-Line Labeling Review 38](#line-by-line-labeling-review)

[References 39](#references)

**List of Figures**

[Figure 1: Study Design of CHARM (SH-AHS-0003, 0006, 0007)
9](#__RefHeading___Toc92525671)

[Figure 2: Cumulative incidence (%) of confirmed adjudicated CV death or
hospitalization due to CHF over time 11](#__RefHeading___Toc92525672)

[Figure 3: DBP in CHARM Preserved 22](#__RefHeading___Toc92525673)

[Figure 4: SBP in CHARM Preserved 23](#__RefHeading___Toc92525674)

[Figure 5: Study Plan for CHARM Program 32](#__RefHeading___Toc92525675)

[Figure 6: Patient Disposition in CHARM Preserved
35](#__RefHeading___Toc92525676)

**List of Tables**

[Table 1: Presubmission Regulatory highlights
5](#__RefHeading___Toc92525677)

[Table 2: Table of Clinical Studies in CHARM Preserved
6](#__RefHeading___Toc92525678)

[Table 3: Efficacy results of primary variable
11](#__RefHeading___Toc92525679)

[Table 4: Comparative event rates in the components of the CHARM Program
12](#__RefHeading___Toc92525680)

[Table 5: Components of Primary endpoint
12](#__RefHeading___Toc92525681)

[Table 6: Primary endpoint (CV death, CHF hospitalizations) by baseline
EF 12](#__RefHeading___Toc92525682)

[Table 7: Summary of AE's, SAE's, and Discontinuations/dose reductions
of study 13](#__RefHeading___Toc92525683)

[Table 8: AE's leading to death in CHARM preserved (cutoff \> 0.3%)
14](#__RefHeading___Toc92525684)

[Table 9: Serious Adverse Events other than Death (Frequency \> 1% on
candesartan) 15](#__RefHeading___Toc92525685)

[Table 10: Summary of discontinuations due to AE's in CHARMED preserved
(cutoff \> 0.5%) 16](#__RefHeading___Toc92525686)

[Table 11: Summary of dose reductions due to AE's in CHARMED preserved
(cutoff \> 0.3%) 17](#__RefHeading___Toc92525687)

[Table 12: Common AE's occurring in CHARM Preserved
17](#__RefHeading___Toc92525688)

[Table 13: Change from baseline in serum potassium (last value carried
forward) 19](#__RefHeading___Toc92525689)

[Table 14: Number (%) of patients with serum K^+^ \> 6 mmol/L any time
after randomization 20](#__RefHeading___Toc92525690)

[Table 15^a^: Listing of patient outliers with respect to serum K^+^
20](#__RefHeading___Toc92525691)

[Table 16: Number (%) of patients with serum creatinine \> 2x baseline
value during study 21](#__RefHeading___Toc92525692)

[Table 17: Change from baseline in hematocrit (%)(last value carried
forward) 21](#__RefHeading___Toc92525693)

[Table 18: Listing of patient outliers with respect to serum hemoglobin
21](#__RefHeading___Toc92525694)

[Table 19: Summary of SBP and DBP outliers
23](#__RefHeading___Toc92525695)

[Table 20: Summary of Exposure in CHARM preserved
24](#__RefHeading___Toc92525696)

[Table 21: % of patients and investigational drug dose by visit and
treatment 24](#__RefHeading___Toc92525697)

[Table 22: CV death and CHF hospitalization by ethnicity in CHARM
Preserved 26](#__RefHeading___Toc92525698)

[Table 23: CV death and CHF hospitalization by ethnicity in overall
CHARM Program 26](#__RefHeading___Toc92525699)

[Table 24: CV death, CHF hospitalizations, and All cause mortality in
Orientals in overall CHARM Program 26](#__RefHeading___Toc92525700)

[Table 25: Summary of clinical trials of ARB use in heart failure
patients 27](#__RefHeading___Toc92525701)

[Table 26: Chronology of the CHARM Program highlights
29](#__RefHeading___Toc92525702)

[Table 27: Summary of Protocol Amendments in the CHARM program
32](#__RefHeading___Toc92525703)

[Table 28: CHARM Preserved patient baseline characteristics
36](#__RefHeading___Toc92525704)

[Table 29: CHARM preserved patient baseline characteristics
36](#__RefHeading___Toc92525705)

[Table 30: Patients (%) using the listed class of drug at the time of
study entry 37](#__RefHeading___Toc92525706)

[Table 31: Subgroup analysis of CV death or CHF hospitalization
38](#__RefHeading___Toc92525707)

**Abbreviations**

AE = adverse event

ARB = angiotensin receptor blocker

CHF = congestive heart failure

CRF = case report form

CSR = clinical study report

CTD = common technical document

CV = cardiovascular

DBP = diastolic blood pressure

EF = ejection fraction

MI = myocardial infarction

NDA = new drug application

NYHA = New York Heart Association

SAE('s) = serious adverse event

SBP = systolic blood pressure

# Executive Summary

## Recommendation on Regulatory Action

> The CHARM Program was a prospective, randomized clinical trial of the
> use of candesartan, a selective angiotensin II receptor blocker, in
> patients with congestive heart failure to decrease cardiovascular
> morbidity and mortality. The 3 sub studies within the CHARM Program
> were: CHARM Alternative, CHARM Added, and CHARM Preserved. The focus
> of this review is CHARM Preserved. Please refer to the review by Dr.
> Khin U for details on CHARM Alternative and CHARM Added.
>
> CHARM Preserved was a prospective, randomized, double-blind, placebo
> controlled study to evaluate the effectiveness of candesartan in
> reducing cardiovascular mortality and/or morbidity in congestive heart
> failure patients (NYHA Class II through IV) with a preserved ejection
> fraction (EF \> 40%). It is important to note that the choice of an EF
> \> 40% to define a subset of the heart failure population as having
> "preserved EF" is arbitrary but very relevant to this review. It is
> possible for patients with an EF around 40% (e.g. 41% to 45% or
> possibly even higher) to have some degree of systolic dysfunction
> making them similar to patients in either the CHARM Alternative or
> CHARM Added study.
>
> In CHARM preserved, an EF \> 40% was used as a surrogate to describe
> heart failure patients as having "diastolic dysfunction." However, a
> purist would require evidence of an upward shift in the end-diastolic
> pressure-volume relation (EDPVR)^1,2^ to describe such a population.
> The characterization of the EDPVR is complicated and is not routinely
> done in clinical practice. The medical literature suggests that CHF
> patients with an EF \> 40% comprise between 20% to 50% of all patients
> with CHF^3^. It seems to be widely accepted that patients with
> diastolic heart failure have a better prognosis compared to patients
> with systolic heart failure, although recent reports seem to refute
> this notion^4^.
>
> The vast majority of research in CHF patients has focused on those
> with an EF [\<]{.underline} 40% while the optimal medical management
> of patients with EF \> 40% has yet to be defined. CHARM Preserved
> represents one of the first attempts to study the effects of a renin
> angiotensin system blocker in patients with a preserved EF in a
> prospective, controlled clinical trial.
>
> The CHARM Preserved study was the sole study submitted by the sponsor
> to support approval in patients with a preserved EF. There were no
> supportive studies for this indication. More than 3000 patients with
> predominantly NYHA Class II and III heart failure were randomly
> assigned to placebo or candesartan and followed up for 2 to 4 years.
> This was a multi-national study enrolling patients from Europe, Asia,
> Africa, and North America. Patients were started on candesartan once
> daily doses of 4 to 8 mg and titrated every two weeks to a maximum
> dosage of 32 mg once daily as tolerated. The primary endpoint was CV
> death or CHF hospitalization. In terms of relevant demographics, the
> mean age of patients enrolled was 67 years, 40 % were female, and more
> than 4% were Black. The most prevalent background therapy in this
> patient population was diuretics. The primary endpoint was reached in
> 333 patients in the candesartan arm and 366 patients in the placebo
> arm: hazard ratio 0.89 (0.77, 1.03), p-value 0.12. CHARM Preserved did
> not achieve its primary pre-specified endpoint. The observed trend
> appears to be driven by patients with an EF between 40 and 50%. By
> arbitrarily defining patients with an EF \> 40% as having a "preserved
> EF", the study likely included patients with systolic dysfunction into
> CHARM Preserved. Based on the CHARM Added and CHARM Preserved
> components reviewed by Dr. U, it is evident that patients with
> systolic dysfunction will benefit from candesartan in terms of CV
> mortality and morbidity. Another possibility for the observed trend is
> that patients with an EF \> 40% represent a unique heart failure
> sub-population that could respond to candesartan but that CHARM
> Preserved was simply underpowered to detect a significant difference.
> Differentiating these two possibilities would require further studies
> by the sponsor.
>
> Candesartan has been approved for the treatment of hypertension since
> 1997 and thus has a large post marketing safety experience. Patients
> in the CHARM Preserved study were followed for a minimum duration of
> 24 months and a mean duration of 35 months. Study drug
> discontinuations were higher in the candesartan arm (18%) versus the
> placebo arm (13%). Three common adverse events of special interest
> that led to discontinuation of study drug were hyperkalemia,
> hypotension, and abnormal renal function. Other common AE's that led
> to study drug discontinuation were dizziness/vertigo and diarrhea. The
> frequencies of the adverse events leading to study drug
> discontinuation were higher on candesartan compared to placebo and
> were consistent across the entire CHARM Program. Other commonly
> occurring adverse events that occurred with a greater frequency on
> candesartan compared to placebo were anemia, dehydration, and fatigue
> and were consistent across the CHARM Program.
>
> In summary, given the single study that failed to meet its primary
> endpoint,
>
> of candesartan for use in a subset of heart failure patients with
> "preserved" EF.

## Recommendation on Postmarketing Actions

N/A

## Summary of Clinical Findings

### Brief Overview of Clinical Program

CHARM Preserved was one component of the overall CHARM program that
evaluated the efficacy of candesartan to reduce cardiovascular morbidity
and mortality in patients with congestive heart failure. CHARM Preserved
focused on the subset of patients with an arbitrarily defined EF of
greater than 40%. The sponsor provided results from one adequate and
well controlled study to support the use of candesartan in this subset
population. There were no supportive studies in this subpopulation.

CHARM Preserved was a prospective, randomized, double-blind, placebo
controlled study to evaluate the effectiveness of candesartan in
reducing cardiovascular mortality and CHF hospitalizations in congestive
heart failure patients (NYHA Class II through IV) with a preserved
ejection fraction (EF \> 40%).

### Efficacy

The CHARM Preserved study was the sole study submitted by the sponsor to
support approval in patients with a preserved EF. There were no
supportive studies for this particular subset of heart failure patients.
More than 3000 patients with predominantly NYHA Class II and III heart
failure were randomly assigned to placebo or candesartan and followed up
for 2 to 4 years. The primary endpoint was time to CV death or CHF
hospitalization. The patients in the two arms of the study were similar
at baseline in terms of demographics and pre-study medications. The mean
age of patients enrolled was 67 years and the mean EF was 54%. More than
1/3 of the patients enrolled had an EF between 40 and 50. Approximately
75% of patients were being treated with diuretics at the time of
randomization. The primary endpoint was reached in 333 patients in the
candesartan arm and 366 patients in the placebo arm: hazard ratio 0.89
(0.77, 1.03), p-value 0.12. CHARM Preserved did not achieve its primary
pre-specified endpoint. Neither component of the primary endpoint
reached a statistically significant p-value of \< 0.05.

### Safety

Candesartan has been approved for the treatment of hypertension since
1997 and thus has a large post marketing safety experience. There were
no unexpected safety findings from CHARM Preserved. The mean duration in
study was 35 months. Study drug discontinuations were higher on
candesartan arm versus placebo. Three common adverse events of special
interest that led to discontinuation of study drug were hyperkalemia,
hypotension, and abnormal renal function. Other common AE's that led to
study drug discontinuation included dizziness/vertigo and diarrhea.

Other commonly occurring adverse events that occurred with a greater
frequency on candesartan compared to placebo were anemia, dehydration,
and fatigue and were consistent across the CHARM Program.

### Dosing Regimen and Administration

Patients randomized to the candesartan arm were started on daily doses
of either 4 or 8 mg and titrated every two weeks to a maximum dose of 32
mg once daily.

### Drug-Drug Interactions

N/A

### Special Populations

CHARM Preserved was not designed to evaluate the efficacy of candesartan
as a function of sex or ethnicity. The effect of candesartan appeared
similar in female and male patients. A subgroup analysis of the primary
endpoint by ethnicity revealed that in Orientals, the effect of
candesartan was negative. The hazard ratio for cardiovascular mortality
and CHF hospitalizations was 3.7 \[95%CI (1.2, 12), p-value 0.026.\]. A
total of 42 Oriental patients contributed 14 primary events. The
negative effect of candesartan on the primary endpoint in the Oriental
subgroup seen in CHARM Preserved was consistent when analyzing pooled
data across the entire CHARM Program. In the overall CHARM Program, 133
Oriental patients contributed 51 primary events. There is evidence of
statistical heterogeneity in this subgroup.

# Introduction and Background

## Product Information

Candesartan (ATACAND^^) is a selective angiotensin II type 1 (AT~1~)
receptor blocker that is currently approved for the treatment of
hypertensive patients. In the current supplemental NDA, the sponsor has
submitted clinical data in support of the use of candesartan in patients
with congestive heart failure.

## Currently Available Treatment for Indications

Nearly all of the guidelines for the management of heart failure are in
patients with left ventricular systolic dysfunction (EF [\<]{.underline}
40%). Currently there are no consensus guidelines for the treatment of
heart failure patients with preserved ejection fraction (EF \> 40%).
Until CHARM Preserved, there have been no studies of adequate size
evaluating clinically meaningful endpoints to guide management in the
subset of patients with preserved systolic function.

In general terms, management of heart failure patients with preserved EF
(referred to as diastolic heart failure by many) is to reverse the
consequences of diastolic dysfunction (e.g. venous congestion and
exercise intolerance) and secondly to eliminate or reduce factors that
are responsible for diastolic dysfunction (e.g. hypertrophy, fibrosis,
ischemia)^5^. Diuretics are the mainstay of management for venous
congestion while calcium channel blockers are used for their beneficial
effects in terms of myocardial ischemia, hypertension, and/or
hypertrophy. However, neither of these two classes of drugs is labeled
for use in patients with diastolic heart failure. Other agents that may
also be potentially beneficial include beta blockers or renin
angiotensin system blockers.

## Availability of Proposed Active Ingredient in the United States

Candesartan was approved in 1998 for the treatment of hypertension.

## Important Issues With Pharmacologically Related Products

N/A

## Presubmission Regulatory Activity

Discussed here are key regulatory highlights. Please refer to Dr. Khin
U's review for further details. Table 1 below summarizes major
regulatory highlights for this supplemental NDA application.

[]{#__RefHeading___Toc92525677 .anchor}Table 1: Presubmission Regulatory
highlights

  --------------- -------------------------------------------------------
  March 1993      Patent issued for candesartan cilexetil

  June 1998       Candesartan cilexetil approved for the treatment of
                  hypertension

  October 1998    EOP2 meeting regarding the heart failure program

  March 1999      The sponsor submitted the CHARM Program (studies
                  SH-AHS-0003, 0006, and 0007)

  November 2003   Pre supplemental NDA teleconference between Sponsor and
                  FDA to discuss plans for filing.

  June 2004       Supplemental NDA filed
  --------------- -------------------------------------------------------

# Significant Findings from Other Review Disciplines

## CMC (and Product Microbiology, if Applicable)

No chemistry issues affecting approvability were identified.

## Animal Pharmacology/Toxicology

No animal pharmacology/toxicology issues affecting approvability were
identified.

# Data Sources, Review Strategy, and Data Integrity

## Sources of Clinical Data

The sponsor submitted one pivotal study (CHARM Preserved) for the use of
candesartan in patients with a preserved ejection fraction. The
sponsor's sNDA submission was in the electronic CTD format. Case report
forms (CRF's) for death and study drug discontinuations due to AE's,
case report tabulations, and clinical study report were provided by the
sponsor for patients in CHARM Preserved.

## Tables of Clinical Studies

The following table lists the one study that was submitted by the
sponsor in support of the use of candesartan in heart failure patients
with preserved EF. Unlike for the other two components of the CHARM
Program, there were no supportive studies conducted in this subset of
patients with heart failure.

[]{#__RefHeading___Toc92525678 .anchor}Table 2: Table of Clinical
Studies in CHARM Preserved

  ----------------------------------- -----------------------------------
  **Study**                           **Title**

  SH-AHS-0007 (CHARM Preserved)       "Clinical Study of Candesartan in
                                      Patients With Heart Failure and
                                      Preserved Left Ventricular Systolic
                                      Function"
  ----------------------------------- -----------------------------------

## Review Strategy

The focus of this review is CHARM Preserved. The other components of the
CHARM Program (CHARM Alternative and CHARM Added) have been reviewed by
Dr. Khin U. I initially read over the original CHARM protocols and
subsequent protocol amendments. I then read over the sponsor's clinical
study report for CHARM Preserved. This review is primarily based on the
sponsor's clinical study report for CHARM Preserved. With the help of
the Statistical Reviewer Dr. Charles Le, the results of the primary
efficacy variable were validated. Case report forms for death and study
drug discontinuation due to AE's were provided. Selected CRF's were
reviewed in depth.

## Data Quality and Integrity

DSI audits were not felt to be relevant to this efficacy supplement
(Please refer to Dr. Khin U's review of CHARM Added for a detailed
rationale).

## Compliance with Good Clinical Practices

A debarment certification was signed by a representative of the sponsor.

## Financial Disclosures

Please refer to Dr. Khin U's review of CHARM Added for further details.
His review of financial disclosures is applicable to CHARM Preserved.

# Clinical Pharmacology

## Pharmacokinetics

Please refer to the detailed "Clinical Pharmacology and Biopharmaceutics
Review" completed by Dr. Nhi Beasley.

The pharmacokinetics (PK) of candesartan were studied in NYHA Class II
and III heart failure over the dose range of 2 to 16 mg once daily. The
PK was linear over this dose range. No attempt was made to examine PK
differences based on low EF or preserved EF and there is no clear
rationale of why such a difference should exist. In general, the
exposure (as measured by plasma concentration area under the curve) to
candesartan was approximately doubled in patients with NYHA Class II and
III heart failure compared to healthy, young patients. As candesartan is
not a narrow therapeutic index drug, this change in exposure is not
expected to significantly alter its safety profile.

## Pharmacodynamics

Please refer to the detailed "Clinical Pharmacology and Biopharmaceutics
Review" completed by Dr. Nhi Beasley. No specific pharmacodynamic
studies were conducted in patients with preserved EF.

# Integrated Review of Efficacy

## Indication: Preserved EF 

The indication as transcribed from the sponsor's proposed label is shown
below. Highlighted and italicized are sections in the proposed labeling
specifically referring to the patient population with a preserved
ejection fraction.

"ATACAND is indicated for the treatment of heart failure (NYHA class
II-IV). ATACAND reduces the risk of death from cardiovascular causes and
improves symptoms in patients with left ventricular systolic
dysfunction, and ***reduces hospitalizations for heart failure in
patients with*** depressed or ***preserved left ventricular systolic
function***. These effects occur in patients receiving other heart
failure treatments with or without ACE inhibitors, including patients
intolerant to ACE inhibitors, and with or without beta-blockers."

In essence the claim the sponsor seeks based on CHARM Preserved is a
reduction in heart failure hospitalizations in patients with a preserved
EF.

### Methods

In support of the indication for Preserved EF stated above, there was
one adequate and well controlled trial submitted to NDA 20-863,
SH-AHS-0007, "Clinical Study of Candesartan in Patients With Heart
Failure and Preserved Left Ventricular Systolic Function." There were no
supportive studies (e.g. Phase 2 studies) submitted for this indication.

### General Discussion of Endpoints

The endpoints collected during this trial were clinically relevant and
included both morbidity and mortality. The endpoints chosen in the CHARM
program were not inconsistent with endpoints utilized in other large
outcome studies involving patients with heart failure. The components of
the primary and other secondary endpoints collected during the CHARM
program are described below.

**Cardiovascular (CV) death:** All deaths were considered CV unless an
unequivocal non-CV cause could be established. This category included
sudden death, death due to MI, death due to heart failure, death due to
stroke, death due to a CV investigation/procedure/operation, death due
to other CV causes, presumed CV deaths and deaths from unknown causes.

**Hospitalization for heart failure:** A hospitalization was defined as
any overnight stay in a hospital. A CHF hospitalization was defined as
admission to hospital necessitated by heart failure and primarily for
the treatment of heart failure. A patient admitted for this reason was
to demonstrate signs and symptoms of worsening heart failure and require
treatment with intravenous diuretics.

> Signs or symptoms of worsening heart failure could include at least
> one of the following:

-   Increasing dyspnea on exertion

-   Orthopnea

-   Nocturnal dyspnea

-   Increasing peripheral edema

-   Increasing fatigue/decreasing exercise tolerance

-   Renal hypoperfusion/ worsening renal function

-   Elevated JVP

-   Radiologic signs of CHF

**All cause mortality:** Death from any cause

**Myocardial infarction (MI):** A diagnosis of MI was to be made if the
following conditions were met:

-   Creatinine kinase (CK) or CKMB \> 2x upper limit of normal (ULN)
    ***or***

-   CK \> 3 x ULN immediately following PTCA ***or***

-   Troponin I or troponin T \> 2 x ULN in hospitals where CK
    measurement unavailable

> **AND**

-   ECG demonstrated development of pathological Q waves and/or the
    development or disappearance of localized ST-elevations combined
    with the development of T inversion in at least two of the routine
    standard leads and clinical history consistent with myocardial
    infarction.

The CHARM Program utilized a Clinical Endpoints Committee (CEC). The
Chair of the Committee was Dr. Scott Solomon. The objectives of the
Committee were to classify deaths and to adjudicate CHF hospitalizations
and MI's in a consistent and unbiased manner. The adjudication process
was identical for all three components of the CHARM Program. The CEC
adjudicated data were used in the analyses of the primary and secondary
endpoints. Adjudication was done in a blinded manner. One member of the
Committee reviewed each case that was submitted for adjudication. If the
CEC member agreed with the principal investigator's (PI) endpoint
diagnosis, the endpoint was considered adjudicated. If the CEC member
disagreed with the PI, the endpoint was given to the Chairman for
review, discussion, and final adjudication.

### Study Design

CHARM Preserved (SH-AHS-0007) was an adequate and well controlled study
submitted in support of the use of candesartan in patients with
preserved systolic function (EF \> 40%.)

CHARM Preserved was a randomized, double-blind, placebo controlled,
parallel group, multi-centered study to evaluate the influence of
candesartan (4 mg once daily titrated to target dose of 32 mg once
daily) on mortality and morbidity endpoints in patients with preserved
left ventricular (LV) systolic function.

A pictorial of the study design is shown in Figure 1 below. Following
randomization, patients were to have study drug titrated every two weeks
as tolerated to a maximum dose of 32 mg once daily.

![](media/image1.png){width="6.4944444444444445in"
height="1.7604166666666667in"}

[]{#__RefHeading___Toc92525671 .anchor}Figure 1: Study Design of CHARM
(SH-AHS-0003, 0006, 0007)

Source: Figure 1 of SH-AHS-0007 CSR

In order to preserve the blind, placebo tablets were identical in
appearance to the active drug. The biostatistician of the Safety
Committee was the only person that could be unblinded to the data while
the CHARM program was in process.

Study randomization was done centrally using an Interactive Voice
Response System. Patients were randomized in blocks of four. Patients
were randomized to candesartan or placebo in a ratio of 1:1.

As discussed above, the CHARM Program also consisted of a CEC, which
adjudicated endpoint events in a blinded manner. In addition, there was
also a Data Safety Committee that functioned independently of all other
individuals and bodies associated with the conduct of the CHARM Program
(e.g. investigators, Steering Committee, and Study Sponsor). The Safety
Committee received safety data on a monthly basis and was responsible
for reviewing the safety data continually during the program.

A data analysis plan was formulated but not finalized until
approximately 2 weeks after study closure.

Placebo was the control treatment in all 3 components of the CHARM
program including CHARM Preserved.

The duration of the studies the CHARM Program appeared to be adequate.
The patient recruitment period was 16 months. The total study duration
could range from 32 to 48 months depending on when a patient was
randomized. The minimum duration of patient follow-up post randomization
was to be 2 years.

The CHARM Program enrolled patients 18 years of age or older with
symptomatic heart failure (NYHA Class II -- IV). There were additional
study specific inclusion criteria for each component of the CHARM
Program. Please refer to section 10.1.1.2 in the Appendix for details
regarding inclusion/exclusion criteria.

The current maximum approved dose of candesartan for the approved
indication of hypertension is 32 mg once daily. The CHARM Program was
designed as a dose titration study utilizing maximally tolerated doses
of candesartan up to 32 mg.

### Efficacy Findings 

CHARM Preserved was the lone study in support of the proposed indication
in patients with preserved left ventricular systolic function. The study
did not achieve its primary pre-specified endpoint of a statistically
significant reduction in CV mortality or CHF hospitalizations (p-value
of 0.12.)

CHARM Preserved randomized a total of 3025 patients of whom 2 did not
receive any study drug. Thus, a total of 3023 patients were evaluable in
the ITT population. Three patients in the ITT population were lost to
follow-up (2 on placebo, 1 on candesartan). The mean age of study
patients was 67 [+]{.underline} 11 years. Forty percent of the patients
were female, 90% were European, and more than 98% were of Class II/III
NYHA class. The etiology of CHF was ischemic heart disease in more than
50% of patients followed by hypertension in approximately 23% of
patients. The mean ejection fraction in randomized patients was 54%. The
percentage of patients on digitalis glycosides, diuretics,
beta-blockers, calcium channel blockers, vasodilators, long acting
nitrates, and ACE inhibitors was 28%, 75%, 56%, 69%, 38%, 33%, and 19%
respectively.

The baseline characteristics of the two treatment groups were generally
similar as shown in Table 28 and Table 29 in the Appendix of this
review. Shown in these tables are risk factors for congestive heart
failure as well as risk factors for cardiovascular disease for the two
treatment groups. The use of various medications at baseline and at
study closure are listed in Table 30 located in the Appendix.

The results of the primary efficacy variable are shown below. The
results were confirmed independently by Dr. Charles Le, FDA
statistician.

[]{#__RefHeading___Toc92525679 .anchor}Table 3: Efficacy results of
primary variable

+-------------------+-------------+-----------+-------------+--------+
|                   | **Ca        | **        | **Hazard    | **p-V  |
|                   | ndesartan** | Placebo** | ratio**     | alue** |
|                   |             |           |             |        |
|                   | **(N =      | **(N =    | **(95%      |        |
|                   | 1514)**     | 1509)**   | CI)**       |        |
+-------------------+-------------+-----------+-------------+--------+
| CV death or       | 333         | 366       | 0.89        | 0.12   |
|                   |             |           |             |        |
| CHF               |             |           | (0.77,      |        |
| hospitalization   |             |           | 1.03)       |        |
+-------------------+-------------+-----------+-------------+--------+

Note: This data in this table obtained from Table 24 of SH-AHS-0007 CSR

The primary endpoint is displayed graphically in a Kaplan-Meier plot in
Figure 2 below. []{.mark}

![](media/image2.png){width="5.877083333333333in"
height="4.550694444444445in"}

[]{#__RefHeading___Toc92525672 .anchor}Figure 2: Cumulative incidence
(%) of confirmed adjudicated CV death or hospitalization due to CHF over
time

Source: Figure 4 of SH-AHS-0007 CSR

As seen in the table and figure above, the CHARM Preserved study did not
meet its primary objective. It is important to note that the incidence
of cardiovascular mortality and morbidity was lower in CHARM Preserved
compared to the other two components of the CHARM Program as shown in
Table 4 below.

[]{#__RefHeading___Toc92525680 .anchor}Table 4: Comparative event rates
in the components of the CHARM Program

  -------------------------------- ------------------- ------------------
                                   **Events per 1000   
                                   follow-up years**   

                                   **Placebo**         **Candesartan**

  SH-AHS-003 ("Alternative")       182                 138

  SH-AHS-006 ("Added")             166                 141

  SH-AHS-0007 ("Preserved")        91                  81
  -------------------------------- ------------------- ------------------

Note: Data in this table obtained from Table 24, Table 23, and Table 23
of SH-AHS-0003, SH-AHS-0006, and SH-AHS-0007 CSR respectively.

In terms of the individual components contributing to the primary
endpoints, there was no statistically significant difference in terms of
CV death or in terms of CHF hospitalization as shown in the table below.

[]{#__RefHeading___Toc92525681 .anchor}Table 5: Components of Primary
endpoint

+-------------------+-------------+-----------+-------------+--------+
|                   | **Ca        | **        | **Hazard    | **p-V  |
|                   | ndesartan** | Placebo** | ratio**     | alue** |
|                   |             |           |             |        |
|                   | **(N =      | **(N =    | **(95%      |        |
|                   | 1514)**     | 1509)**   | CI)**       |        |
+-------------------+-------------+-----------+-------------+--------+
| CV death          | 170         | 170       | 0.989       | 0.918  |
|                   |             |           |             |        |
|                   |             |           | (0.80,      |        |
|                   |             |           | 1.22)       |        |
+-------------------+-------------+-----------+-------------+--------+
| CHF               | 241         | 276       | 0.853       | 0.072  |
| hospitalization   |             |           | (0.718,     |        |
|                   |             |           | 1.014)      |        |
+-------------------+-------------+-----------+-------------+--------+

Note: The data in this table obtained from Table 30 of SH-AHS-0007 CSR

Various subgroup analyses (e.g. age, sex, and ethnicity) of the primary
endpoint are discussed in detail in the Appendix of this review.
[]{.mark}

The result of one relevant subgroup analysis is shown in Table 6 below.

[]{#__RefHeading___Toc92525682 .anchor}Table 6: Primary endpoint (CV
death, CHF hospitalizations) by baseline EF

  ---------------------------------------------------------------------------------------------
  **Variable**     **Group**          **N**   **Cand \#  **Placebo   **Hazard     **P-value**
                                              of         \# of       ratio (95%   
                                              events**   events**    CI)**        
  ---------------- ------------------ ------- ---------- ----------- ------------ -------------
  LVEF             \< 0.50            1072    106        131         0.78 (0.60,  0.055
                                                                     1.01)        

                   [\>]{.underline}   1951    227        235         0.95 (0.79,  0.592
                   0.50                                              1.14)        
  ---------------------------------------------------------------------------------------------

The tabular results of the secondary endpoints are not displayed in this
review. The pre-specified secondary endpoint of time from randomization
to all cause death and CHF hospitalization was not statistically
significant between the two study groups. Similarly the other secondary
endpoint consisting of time from randomization to CV death, CHF
hospitalization or non-fatal MI was not statistically significant
between the two study arms.

### Efficacy Conclusions

The CHARM Preserved study was the sole study submitted by the sponsor to
support approval in patients with a preserved EF. There were no
supportive studies for this particular subset of heart failure patients.
More than 3000 patients with predominantly NYHA Class II and III heart
failure were randomly assigned to placebo or candesartan and followed up
for 2 to 4 years. The primary endpoint was CV death or CHF
hospitalization. The patients in the two arms of the study were similar
at baseline in terms of demographics and pre-study medications. The mean
EF of patients enrolled was 54%. The primary endpoint was reached in 333
patients in the candesartan arm and 366 patients in the placebo arm:
hazard ratio 0.89 (0.77, 1.03), p-value 0.12. CHARM Preserved did not
achieve its primary pre-specified endpoint.

# Integrated Review of Safety

## Methods and Findings

The information presented in the safety section of this review was
primarily obtained from the sponsor's clinical study report. Line
listings of all patient deaths in the candesartan arm were reviewed.
Death narratives of selected cases were also reviewed with referencing
of the case report forms. []{.mark}

Table 7 below summarizes the overall AE experience in CHARM preserved.
There were nominally more deaths on the candesartan arm compared to the
placebo arm during the study period (238 P vs 244 C). The were a greater
number of discontinuations due to AE's and dose reductions due to AE's
in the candesartan arm compared to the placebo arm. A more detailed
discussion of these safety findings are provided later in this review.

[]{#__RefHeading___Toc92525683 .anchor}Table 7: Summary of AE's, SAE's,
and Discontinuations/dose reductions of study

drug due to AE's

+---------------------+--------------------------+---------------------+
|                     | **Placebo**              | **Candesartan**     |
|                     |                          |                     |
|                     | **(n = 1509)**           | **(n = 1514)**      |
+=====================+==========================+=====================+
| Any AE during study | 1060 (70%)               | 1074 (71%)          |
+---------------------+--------------------------+---------------------+
| Serious AE's        | 238 (16%)                | 244 (16%)           |
| leading to death    |                          |                     |
| during study        |                          |                     |
+---------------------+--------------------------+---------------------+
| Serious AE's not    | 963 (64%)                | 939 (62%)           |
| leading to death    |                          |                     |
| during study        |                          |                     |
+---------------------+--------------------------+---------------------+
| Discontinuations    | 192 (13%)                | 269 (18%)           |
| due to AE's         |                          |                     |
+---------------------+--------------------------+---------------------+
| Dose reductions due | 125 (8%)                 | 192 (13%)           |
| to AE's             |                          |                     |
+---------------------+--------------------------+---------------------+

Note: This data in this table obtained from Table 65 of SH-AHS-0007 CSR

### Deaths

There were a total of 482 deaths during the study of which 238 occurred
in patients randomized to placebo and 244 in patients randomized to
candesartan. Table 8 shows the most common AE's leading to death. The
etiologies of death in the two treatment arms were similar. The most
common etiologies of death were not unexpected given the patient
population enrolled into the study. The most common etiologies of death
in CHARM Preserved were similar to the etiologies in the overall CHARM
Program and were mainly cardiovascular in nature (e.g. sudden death,
heart failure, myocardial infarction). Line listings of all deaths,
located in the sponsor's clinical study report SH-AHS-0007, Appendix
12.2.7.2, that included the sponsors "Preferred Term" and the
investigator's terms were reviewed. In general, the sponsor's coding of
adverse events based on the investigator's verbatim term was acceptable.
Line listings from all deaths in the candesartan arm were reviewed.
Narratives of death from selected cases and their respective case report
forms (CRF's) were also reviewed.

[]{#__RefHeading___Toc92525684 .anchor}Table 8: AE's leading to death in
CHARM preserved (cutoff [\>]{.underline} 0.3%)

  -------------------------------------------------------------------------------------------------
                                **Placebo**                    **Cand**                 
  ----------------------------- -------------- --------- ----- -------------- --------- -----------
  **Preferred term**            **(N=1509)**                   **(N=1514)**             

                                **N**          **(%)**         **N**          **(%)**   

  Sudden death                  68             (4.5)           68             (4.5)     

  Cardiac failure/cardiac                                                               

  failure aggravated^b^         53             (3.5)           41             (2.7)     

  Myocardial infarction         20             (1.3)           18             (1.2)     

  Pneumonia                     19             (1.3)           14             (0.9)     

  Cerebrovascular disorder      14             (0.9)           11             (0.7)     

  Death                         11             (0.7)           7              (0.5)     

  Sepsis                        9              (0.6)           6              (0.4)     

  Respiratory insufficiency     8              (0.5)           5              (0.3)     

  Pulmonary oedema              6              (0.4)           6              (0.4)     

  Renal failure acute           6              (0.4)           5              (0.3)     

  Accident and/or injury        6              (0.4)           4              (0.3)     

  Pulmonary carcinoma           5              (0.3)           5              (0.3)     

  Renal failure nos             4              (0.3)           5              (0.3)     

  Coronary artery disorder      5              (0.3)           3              (0.2)     
  -------------------------------------------------------------------------------------------------

Note: This data in this table obtained from Table 67 of SH-AHS-0007 CSR

### Other Serious Adverse Events

Table 9 below lists serious adverse events (SAE's) other than death that
occurred on treatment in CHARM preserved. The table lists SAE's
occurring at a frequency of at least 1% based on the candesartan arm.
The 4 most common serious adverse events not leading to death on the
candesartan arm were cardiac failure, angina pectoris, atrial
fibrillation, and pneumonia. In general the frequency of these SAE's was
similar or lower to that observed in the placebo arm.

Adverse events that occurred with frequency that was nominally higher on
candesartan compared to placebo included hypotension, anemia, syncope,
renal failure (acute), GI hemorrhage, renal function abnormal, skin
cellulitis, bradycardia, renal failure NOS, dehydration, respiratory
infection, diarrhea, ventricular tachycardia/arrhythmias, atrial
flutter, hyperkalemia, arteriosclerosis, AV block, hernia, and fracture.
Of these listed AE's, three occurred with a frequency that was 2 fold
higher on candesartan compared to placebo and are highlighted in the
table below. These include dehydration, hyperkalemia, and fracture.

Three adverse events of special interest, hypotension, hyperkalemia, and
renal dysfunction/renal failure occurred more frequently on candesartan
compared to placebo. The adverse events of hypotension and hyperkalemia
were notably higher in the candesartan arm compared to the placebo arm:
hypotension (4.9% vs. 3.6%), hyperkalemia (1.5% vs. 0.4%). The adverse
events of "renal failure acute", "renal function abnormal/renal
dysfunction aggravated", and "renal failure NOS" occurred with a higher
incidence on candesartan compared to placebo.

Another SAE worth noting that occurred with a greater frequency on
candesartan compared to placebo was anemia. There is more discussion of
this AE later in this review.

[]{#__RefHeading___Toc92525685 .anchor}Table 9: Serious Adverse Events
other than Death (Frequency [\>]{.underline} 1% on candesartan)

  -------------------------------------------------------------------------------------
                                    **Placebo on**            **Cand on**     
  --------------------------------- --------------- --------- --------------- ---------
  **Preferred term**                **Treatment**             **Treatment**   

                                    **(n=1509)**              **(n=1514)**    

                                    **n**           **(%)**   **N**           **(%)**

  Cardiac failure/cardiac                                                     

  failure aggravated                303             (20.1)    234             (15.5)

  Angina pectoris/angina                                                      

  pectoris aggravated               195             (12.9)    179             (11.8)

  Fibrillation atrial               103             (6.8)     77              (5.1)

  Pneumonia                         81              (5.4)     76              (5.0)

  Coronary artery disorder          85              (5.6)     69              (4.6)

  Cerebrovascular disorder          83              (5.5)     65              (4.3)

  Myocardial infarction             74              (4.9)     63              (4.2)

  Chest pain                        69              (4.6)     66              (4.4)

  Tachycardia supraventricular      76              (5.0)     55              (3.6)

  Arrhythmia atrial                 73              (4.8)     53              (3.5)

  Hypotension                       54              (3.6)     74              (4.9)

  Accident and/or injury            46              (3.0)     45              (3.0)

  Anaemia                           35              (2.3)     45              (3.0)

  Syncope                           32              (2.1)     43              (2.8)

  Dyspnoea/dyspnea                                                            

  (aggravated)                      39              (2.6)     24              (1.6)

  Arrhythmia ventricular            36              (2.4)     23              (1.5)

  Diabetes mellitus/diabetes                                                  

  mellitus aggravated               30              (2.0)     26              (1.7)

  Renal failure acute               24              (1.6)     30              (2.0)

  Gi haemorrhage                    20              (1.3)     25              (1.7)

  Bronchitis/bronchitis                                                       

  aggravated                        25              (1.7)     24              (1.6)

  Chronic obstruct airways                                                    

  Disease                           27              (1.8)     23              (1.5)

  Pulmonary oedema                  26              (1.7)     21              (1.4)

  Renal function                                                              

  abnormal/renal dysfunction                                                  

  aggravated                        18              (1.2)     28              (1.8)

  Cellulitis skin                   20              (1.3)     24              (1.6)

  Dizziness/vertigo                 24              (1.6)     23              (1.5)

  Hypertension                      32              (2.1)     12              (0.8)

  Bradycardia                       16              (1.1)     25              (1.7)

  Renal failure nos                 14              (0.9)     23              (1.5)

  Urinary tract infection           18              (1.2)     18              (1.2)

  Arthrosis                         21              (1.4)     19              (1.3)

  Dehydration                       10              (0.7)     25              (1.7)

  Respiratory infection             16              (1.1)     20              (1.3)

  Diarrhoea                         15              (1.0)     20              (1.3)

  Tachycardia                                                                 

  ventricular/arrhythmia            14              (0.9)     19              (1.3)

  Atrial flutter                    13              (0.9)     17              (1.1)

  Sick sinus syndrome               16              (1.1)     17              (1.1)

  Hyperkalaemia                     6               (0.4)     22              (1.5)

  Arteriosclerosis                  10              (0.7)     17              (1.1)

  Av block                          12              (0.8)     16              (1.1)

  Hernia                            11              (0.7)     17              (1.1)

  Fracture                          9               (0.6)     18              (1.2)
  -------------------------------------------------------------------------------------

Taken from Table 129 of SH-AHS-0007 CSR

### Dropouts and Other Significant Adverse Events

Dropouts due to AE's and dose reductions due to AE's were greater on the
candesartan arm compared to the placebo arm in CHARM Preserved. This
pattern was observed in all 3 components of the CHARM Program. More
details are provided below.

#### Adverse events associated with dropouts

As shown earlier, the study drug was permanently discontinued due to
AE's in 192 patients randomized to placebo and 269 patients randomized
to candesartan. As shown in Table 10 below, AE's leading to study drug
discontinuation that were at least twice as common on candesartan
compared to placebo were abnormal renal function, hypotension,
hyperkalemia, dizziness/vertigo, renal failure, diarrhea, and nausea.
The sponsor's coding of adverse events based on the investigator's
verbatim terms were acceptable.

[]{#__RefHeading___Toc92525686 .anchor}Table 10: Summary of
discontinuations due to AE's in CHARMED preserved (cutoff
[\>]{.underline} 0.5%)

  --------------------------------------------------------------------------------------
  **Preferred term**             **Placebo**                **Cand**       
  ------------------------------ -------------- ----------- -------------- -------------
                                 **(N=1509)**               **(N=1514)**   

                                 **N**          **(%)**     **N**          **(%)**

  Renal function abnormal        32             (2.1)       68             (4.5)

  Cardiac failure/cardiac        33             (2.2)       43             (2.8)
  failure aggravated                                                       

  Hypotension                    18             (1.2)       40             (2.6)

  Hyperkalaemia                  8              (0.5)       23             (1.5)

  Cerebrovascular disorder       11             (0.7)       14             (0.9)

  Angina pectoris                7              (0.5)       12             (0.8)

  Myocardial infarction          13             (0.9)       6              (0.4)

  Dizziness/vertigo              4              (0.3)       14             (0.9)

  Renal failure nos              4              (0.3)       12             (0.8)

  Diarrhoea                      3              (0.2)       11             (0.7)

  Dyspnoea/dyspnoea (aggravated) 6              (0.4)       8              (0.5)

  Nausea                         4              (0.3)       10             (0.7)

  Pneumonia                      8              (0.5)       6              (0.4)
  --------------------------------------------------------------------------------------

Note: This data in this table obtained from Table 69 of SH-AHS-0007 CSR

Table 11 below summarizes the reductions in dosages of study drugs due
to adverse events. Several of the findings in this table are consistent
with those in Table 10. AE's leading to a reduction in study drug dose
that were at least twice as common on candesartan compared to placebo
were hypotension and hyperkalemia. The frequency of abnormal renal
function was also higher in patients randomized to candesartan compared
to placebo but just missed the two fold threshold. Fatigue was also a
reason for reduction in study drug dose that was twice as frequent on
candesartan relative to placebo.

[]{#__RefHeading___Toc92525687 .anchor}Table 11: Summary of dose
reductions due to AE's in CHARMED preserved (cutoff [\>]{.underline}
0.3%)

  --------------------------------------------------------------------------------------
  **Preferred term**             **Placebo**                  **Cand**       
  ------------------------------ -------------- ------------- -------------- -----------
                                 **(N=1509)**                 **(N=1514)**   

                                 **N**          **(%)**       **N**          **(%)**

  Hypotension                    52             (3.4)         106            (7.0)

  Renal function abnormal        17             (1.1)         30             (2.0)

  Dizziness/vertigo              21             (1.4)         16             (1.1)

  Hyperkalaemia                  5              (0.3)         16             (1.1)

  Fatigue                        5              (0.3)         12             (0.8)

  Cardiac failure aggravated     13             (0.9)         10             (0.7)

  Nausea                         5              (0.3)         6              (0.4)

  Dyspnoea/dyspnoea (aggravated) 6              (0.4)         5              (0.3)

  Asthenia                       3              (0.2)         5              (0.3)
  --------------------------------------------------------------------------------------

Note: This data in this table obtained from Table 70 of SH-AHS-0007 CSR

### Common Adverse Events

Common AE's causing study drug discontinuation or down-titration were
recorded in the CRF. Non-serious AE's that did not lead to drug
discontinuation or dose reduction were not recorded. Assessments for
AE's were made during the up titration period and every 4 months until
the end of the study as shown in Figure 5 in the Appendix.

#### Common adverse event tables

The table below lists AE's occurring with a frequency of
[\>]{.underline} 1% in the candesartan arm on treatment and the
corresponding frequency on the placebo comparator.

Three adverse events that are worth noting and that occurred with a
significantly higher frequency on candesartan compared to placebo were
hypotension, abnormal renal function, and hyperkalemia. These AE's have
also been discussed in a previous section dealing with
discontinuation/dose reduction due to AE's. These AE's occurred at a
consistently higher frequency on candesartan compared to placebo for the
entire CHARM Program.

Other AE's that occurred more frequently on candesartan compared to
placebo and were consistent across the CHARM Program included
dizziness/vertigo, syncope, diarrhea, fatigue, and anemia.

[]{#__RefHeading___Toc92525688 .anchor}Table 12: Common AE's occurring
in CHARM Preserved

(AE's with a frequency [\>]{.underline} 1% in the candesartan arm)

  -------------------------------------------------------------------------------------------
                                          **Placebo on**            **Cand. cil.    
                                                                    on**            
  --------------------------------------- --------------- --------- --------------- ---------
  **Preferred term**                      **treatment**             **treatment**   

                                          **(N=1509)**              **(N=1514)**    

                                          **N**           **(%)**   **N**           **(%)**

  Cardiac failure/cardiac failure                                                   

  aggravated^b^                           321             (21.3)    247             (16.3)

  Angina pectoris/angina                                                            

  pectoris aggravated^b^                  198             (13.1)    182             (12.0)

  Hypotension                             120             (8.0)     236             (15.6)

  Renal function abnormal/renal                                                     

  dysfunction aggravated^b^               74              (4.9)     146             (9.6)

  Pneumonia                               91              (6.0)     78              (5.2)

  Fibrillation atrial                     103             (6.8)     79              (5.2)

  Myocardial infarction                   85              (5.6)     74              (4.9)

  Coronary artery disorder                89              (5.9)     73              (4.8)

  Cerebrovascular disorder                86              (5.7)     68              (4.5)

  Chest pain                              71              (4.7)     72              (4.8)

  Hyperkalemia                            18              (1.2)     63              (4.2)

  Tachycardia supraventricular            76              (5.0)     55              (3.6)

  Arrhythmia atrial                       73              (4.8)     53              (3.5)

  Sudden death                            57              (3.8)     55              (3.6)

  Accident and/or injury                  49              (3.2)     46              (3.0)

  Dizziness/vertigo^b^                    51              (3.4)     62              (4.1)

  Anaemia                                 35              (2.3)     46              (3.0)

  Syncope                                 32              (2.1)     46              (3.0)

  Dyspnoea/dyspnoea                                                                 

  (aggravated)^b^                         48              (3.2)     39              (2.6)

  Dyspnea                                 45              (3.0)     34              (2.2)

  Diarrhea                                23              (1.5)     33              (2.2)

  Acute renal failure                     26              (1.7)     31              (2.0)

  Renal failure NOS                       17              (1.1)     25              (1.7)

  Pulmonary edema                         28              (1.9)     26              (1.7)

  Bronchitis                              24              (1.6)     26              (1.7)

  Bradycardia                             16              (1.1)     25              (1.7)

  Diabetes mellitus                       27              (1.8)     26              (1.7)

  Dehydration                             10              (0.7)     25              (1.7)

  GI hemorrhage                           22              (1.5)     26              (1.7)

  Cellulitis skin                         20              (1.3)     24              (1.6)

  Ventricular arrhythmia                  36              (2.4)     23              (1.5)

  Chronic obstr airways disease           27              (1.8)     23              (1.5)

  Nausea                                  15              (1.0)     23              (1.5)

  Fatigue                                 12              (0.8)     21              (1.4)

  Respiratory infection                   16              (1.1)     21              (1.4)

  Abdominal pain                          13              (0.9)     21              (1.4)

  Arthrosis                               21              (1.4)     19              (1.3)

  Fracture                                12              (0.8)     19              (1.3)

  Atrial flutter                          13              (0.9)     19              (1.3)

  Urinary tract infection                 18              (1.2)     18              (1.2)

  Sick sinus syndrome                     16              (1.1)     18              (1.2)

  Hernia                                  11              (0.7)     17              (1.1)

  AV block                                12              (0.8)     16              (1.1)

  Arteriosclerosis                        10              (0.7)     17              (1.1)

  Headache                                13              (0.9)     15              (1.0)
  -------------------------------------------------------------------------------------------

Note: The data in this table taken from Table 120 of SH-AHs-0007 CSR

### Laboratory Findings

Laboratory tests were obtained at the local hospital laboratory at the
discretion of the investigator when deemed necessary. It was recommended
that the investigator check serum creatinine and serum potassium
approximately 2 weeks after each increase in dose. In a subset of sites
in the study (specifically the North American sites), samples were to be
sent to a core laboratory at the following time points: randomization,
end of dose titration, thereafter yearly and, where possible, if the
study medication is stopped. The labs included CBC, electrolytes, serum
creatinine, serum ASAT, serum ALAT, serum ALP, and serum bilirubin.
Please refer to the schedule of study activities in Figure 5 of the
Appendix.

There are 3 laboratory abnormalities I will discuss in this section: 1)
hyperkalemia, 2) increased serum creatinine and 3) anemia.

***HYPERKALEMIA***

Serum potassium changes from baseline in the two study arms are noted in
Table 13 below. With regards to hyperkalemia, a placebo subtracted 0.09
mmol/L (95%CI  0.03, 0.14) increase in serum potassium was noted on
patients randomized to candesartan. This is consistent with what is
currently noted in the approved candesartan product labeling.

[]{#__RefHeading___Toc92525689 .anchor}Table 13: Change from baseline in
serum potassium (last value carried forward)

  -----------------------------------------------------------------------------------------------
                                      **Placebo on**                **Cand.cil.     
                                                                    on**            
  ----------------------------------- --------------- ------------- --------------- -------------
  **Preferred term**                  **Treatment**                 **Treatment**   

                                      **(n=523)**                   **(n=515)**     

                                      **N**           **(95%CI)**   **N**           **(95%CI)**

  Potassium change from baseline      0.03            (-0.01,       0.12            (0.08, 0.16))
  (mmol/L)                                            0.07))                        
  -----------------------------------------------------------------------------------------------

Taken from Table 161 of Sponsor's SH-AHS-0007 CSR

Table 14 below summarizes the frequency of elevated serum potassium
outliers (as defined by serum K^+^ \> 6 mmol/L) in CHARM persevered. It
is important to note that this table reflects outliers that were
captured by routine blood sampling and does not reflect patients with
hyperkalemia that were reported on CRF's. As shown in Table 15 below,
there was at least once instance of hyperkalemia that was picked up via
review of selected CRF's but that was not reported in the sponsor's list
of serum potassium outliers. Case report forms were not provided in
several cases of hyperkalemia including this patient. As discussed in
earlier portions of this review, CRF's were only provided for deaths and
discontinuations due to AE's. CRF's for serious adverse events and dose
reductions due to AE's were not provided.

[]{#__RefHeading___Toc92525690 .anchor}Table 14: Number (%) of patients
with serum K^+^ [\>]{.underline} 6 mmol/L any time after randomization

  ----------------------------------------------------------------------------------------
                                      **Placebo on**             **Cand.cil.     
                                                                 on**            
  ----------------------------------- --------------- ---------- --------------- ---------
  **Preferred term**                  **Treatment**              **Treatment**   

                                      **(n=523)**                **(n=515)**     

                                      **N**           **(%)**    **N**           **(%)**

  Potassium \> 6 mmol/L               6               1.1        10              1.9
  ----------------------------------------------------------------------------------------

Taken from Table 165 of Sponsor's SH-AHS-0007 CSR

The table below lists patient outliers with respect to serum potassium.
Please refer to Figure 5 for information relating visit number to time
in study. At baseline, 7 of these 10 patients had a serum potassium less
than 5 mmol/L, 2 of 10 had serum potassium \> 5 mmol/L (5.5, 5.6), and
in one a baseline serum potassium was not reported.

[]{#__RefHeading___Toc92525691 .anchor}Table 15^a^: Listing of patient
outliers with respect to serum K^+^

  ------------------------------------------------------------------------------------------------
  **Center**   **Patient**   **Sex**   **Age**   **Visit**   **K^+^ (mmol/L)**    **CRF
                                                                                  available**
  ------------ ------------- --------- --------- ----------- -------------------- ----------------
  1200         22596         Male      57        10          6.3                  No

  1232         30232         Male      60        19          6.2                  No

  1233         30136         Female    76        13          6.2                  Yes

  1239         23881         Male      76        7           6.0                  Yes

  1258         23159         Male      77        10          6.3                  No

  1410         20067         Female    68        10          6.2                  Yes

  1422         20821         Male      74        4           6.3                  Yes

  1532         23948         Male      66        4           6.5                  No

  1561         22157         Female    72        7           6.4                  No

  1587         22281         Female    70        4           7.0                  No

  852^b^       14173         Female    88                    6.6                  Yes
  ------------------------------------------------------------------------------------------------

^a^This table obtained in part from Table 167 of SH-AHS-0007 CSR

^b^This patient was not reported in the sponsor's list of serum
potassium outliers and was discovered through review of selected CRF's
of death. This patient died, reportedly due to ischemic heart disease
and renal failure, and was noted to have a serum potassium of 6.6 mmol/L
prior to her death. This patient's initial visit was on 8/16/99 while
her date of death was 2/2/01.

***INCREASED CREATININE***

An increase in serum creatinine to [\>]{.underline} 2x the baseline
value occurred more frequently on candesartan compared to placebo as
shown in Table 16 below. This finding is consistent with the greater
frequency of adverse event reports of abnormal renal function, renal
impairment, or renal failure seen with candesartan compared to placebo.

[]{#__RefHeading___Toc92525692 .anchor}Table 16: Number (%) of patients
with serum creatinine [\>]{.underline} 2x baseline value during study

  ----------------------------------------------------------------------------------------
                                      **Placebo on**             **Cand.cil.     
                                                                 on**            
  ----------------------------------- --------------- ---------- --------------- ---------
  **Preferred term**                  **Treatment**              **Treatment**   

                                      **(n=525)**                **(n=516)**     

                                      **N**           **(%)**    **N**           **(%)**

  Creatinine [\>]{.underline} 2x      15              2.9        33              6.4
  baseline                                                                       
  ----------------------------------------------------------------------------------------

Taken from Table 164 of Sponsor's SH-AHS-0007 CSR

***DECREASED HEMATOCRIT***

A decrease in hematocrit was noted with candesartan as shown in Table 17
below. A statistically significant decrease in hematocrit was seen on
candesartan compared to placebo. Placebo subtracted change in hematocrit
was -1.13 (95%CI  -1.57, -0.68). Although not shown below, changes in
red cell count and hemoglobin were consistent with the changes seen in
the hematocrit.

[]{#__RefHeading___Toc92525693 .anchor}Table 17: Change from baseline in
hematocrit (%)(last value carried forward)

  -----------------------------------------------------------------------------------------------
                                      **Placebo on**                **Cand.cil.     
                                                                    on**            
  ----------------------------------- --------------- ------------- --------------- -------------
  **Preferred term**                  **Treatment**                 **Treatment**   

                                      **(n=512)**                   **(n=505)**     

                                      **N**           **(95%CI)**   **N**           **(95%CI)**

  Hematocrit change from baseline (%) -0.40           (-0.71,       -1.52           (-1.84,
                                                      -0.08))                       -1.21)
  -----------------------------------------------------------------------------------------------

Taken from Table 161 of Sponsor's SH-AHS-0007 CSR

[]{.mark}

Outliers with respect to hematocrit are summarized below. A case report
form was not available for either of these two cases.

[]{#__RefHeading___Toc92525694 .anchor}Table 18: Listing of patient
outliers with respect to serum hemoglobin

  ------------ ------------- --------- --------- ----------------- -------------- --------------
  **Center**   **Patient**   **Sex**   **Age**   **Hematocrit      **Hematocrit   **CRF
                                                 (%)**             (%)**          available**

  1413         22766         Male      49        21.5 (visit 7)    35.3 (visit 1) No

  1455         22874         Female    79        19.8 (visit 4)    30.3 (visit 1) No
  ------------ ------------- --------- --------- ----------------- -------------- --------------

### Vital Signs

The effects of placebo and candesartan on diastolic blood pressure (DBP)
and systolic blood pressure (SBP) over time are reported in Figure 3 and
Figure 4 below. As would be expected, blood pressure reduction was
greater in the candesartan arm compared to the placebo arm throughout
the study duration.

![](media/image3.png){width="5.257638888888889in"
height="3.908333333333333in"}

[]{#__RefHeading___Toc92525673 .anchor}Figure 3: DBP in CHARM Preserved

Source: Figure 63 of Sponsors SH-AHS-0007 CSR

![](media/image4.png){width="4.877777777777778in"
height="3.490972222222222in"}

[]{#__RefHeading___Toc92525674 .anchor}Figure 4: SBP in CHARM Preserved

Source: Figure 64 of Sponsor's SH-AHS-0007 CSR

The table below summarizes number (%) of patients with decrease in SBP
to \< 80 mmHg or DBP \< 40 mmHg at any time after randomization. This
physical exam finding is supported by reported adverse events of
hypotension that were greater on candesartan compared to placebo: 236
vs. 120 events. In addition, symptoms of dizziness/vertigo were more
common on candesartan compared to placebo (62 vs. 51) as were cases of
syncope (46 vs. 32). Please refer to Table 12 that was described earlier
in this review.

[]{#__RefHeading___Toc92525695 .anchor}Table 19: Summary of SBP and DBP
outliers

  ----------------------------- -------------- --------- ----- -------------- --------- -----------
                                **Placebo**                    **Cand**                 

  **Preferred term**            **(N=1508)**                   **(N=1514)**             

                                **N**          **(%)**         **N**          **(%)**   

  DBP (\< 40 mm Hg)             22             (1.5)           43             (2.8)     

  SBP (\<80 mm Hg)              13             (0.9)           19             (1.3)     
  ----------------------------- -------------- --------- ----- -------------- --------- -----------

(Obtained from Table 177 of SH-AHS-0007 CSR)

## Adequacy of Patient Exposure and Safety Assessments

### Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to Evaluate Safety

#### Demographics

Please refer to Appendix, Table 28 and Table 29 for further details.

#### Extent of exposure (dose/duration)

A summary of the patient exposure is shown in Table 20 below. As shown
in the table below, duration in study and exposure to study drug were
similar in both treatment arms. Patients were exposed to candesartan on
average for approximately 2 ½ years. No one in the study was exposed to
candesartan for more than 4 years.

[]{#__RefHeading___Toc92525696 .anchor}Table 20: Summary of Exposure in
CHARM preserved

  -------------------------------------------------------------------------------------
                     **Time in                        **Time on              
                     Study**                          study                  
                                                      drug**                 
  ------------------ ----------- --------- ---------- ----------- ---------- ----------
  **Time**           **Placebo   **Cand    **Total (n **Placebo   **Cand (n= **Total (n
                     (n =        (n=       = 3023)**  (n =        1514)**    = 3023)**
                     1509)**     1514)**              1509)**                

  [\>]{.underline} 6 1488        1498      2968       1403        1388       2791
  months                                                                     

  [\>]{.underline}   1441        1458      2899       1292        1273       2565
  12 months                                                                  

  [\>]{.underline}   1359        1377      2736       1155        1136       2291
  24 months                                                                  

  [\>]{.underline}   824         833       1657       683         665        1348
  36 months                                                                  

  [\>]{.underline}   0           0         0          0           0          0
  48 months                                                                  

  Patient years      4387        4434      8821       3858        3802       7660

  Mean (months)      35          35^a^     35         31          30         30

  Median (months)    37          37        37         35          35         35
  -------------------------------------------------------------------------------------

Note: This data in this table obtained from Table 63 of SH-AHS-0007 CSR

^a^The table in the original sNDA submission reported this time as 47
months but the sponsor's response to an information request corrected
this value as being 35.1 months.

CHARM preserved was a dose titration trial. Patients were started on
doses of either 4 mg or 8 mg and titrated to a maximum of 32 mg once
daily as tolerated. Table 21 below summarizes the doses that patients
were exposed to in CHARM preserved. Approximately 60% of patients were
on the maximum dose of 32 mg candesartan permitted in the trial by month
6 post randomization (Visit 5). Beyond month 6, the percentage of
patients remaining on the 32 mg dose was relatively stable between 55%
and 60% (these data are not shown in this review).

[]{#__RefHeading___Toc92525697 .anchor}Table 21: % of patients and
investigational drug dose by visit and treatment

<table style="width:100%;">
<colgroup>
<col style="width: 13%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 13%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="2"><strong>Baseline visit</strong></th>
<th colspan="2"><strong>Visit 2</strong></th>
<th colspan="2"><strong>Visit 3</strong></th>
<th colspan="2"><strong>Visit 4</strong></th>
<th colspan="2"><p><strong>Visit 5</strong></p>
<p><strong>(month 6)</strong></p></th>
</tr>
<tr class="odd">
<th></th>
<th><strong>Plac</strong></th>
<th><strong>Cand</strong></th>
<th><strong>Plac</strong></th>
<th><strong>Cand</strong></th>
<th><strong>Plac</strong></th>
<th><strong>Cand</strong></th>
<th><strong>Plac</strong></th>
<th><strong>Cand</strong></th>
<th><strong>Plac</strong></th>
<th><strong>Cand</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td>No study drug</td>
<td></td>
<td></td>
<td>31 (2.1%)</td>
<td>42 (2.8%)</td>
<td>37 (2.5%)</td>
<td>61 (4.1%)</td>
<td>44 (3.0%)</td>
<td>71 (4.8%)</td>
<td>113 (7.8%)</td>
<td>157 (10.7%)</td>
</tr>
<tr class="even">
<td>4 mg</td>
<td>1128 (75%)</td>
<td>1132 (75%)</td>
<td>1100 (73.2%)</td>
<td>1095 (72.6%)</td>
<td>99 (6.7%)</td>
<td>173 (11.5%)</td>
<td>62 (4.2%)</td>
<td>117 (7.9%)</td>
<td>46 (3.2%)</td>
<td>95 (6.5%)</td>
</tr>
<tr class="odd">
<td>8 mg</td>
<td>381 (25%)</td>
<td>382 (25%)</td>
<td>370 (24.6%)</td>
<td>372 (24.7%)</td>
<td>1019 (68.5%)</td>
<td>945 (63.1%)</td>
<td>172 (11.6%)</td>
<td>217 (14.6%)</td>
<td>72 (4.9%)</td>
<td>135 (9.2%)</td>
</tr>
<tr class="even">
<td>16 mg</td>
<td>0</td>
<td>0</td>
<td>1 (0.1%)</td>
<td>0</td>
<td>329 (22.1%)</td>
<td>317 (21.2%)</td>
<td>899 (60.7%)</td>
<td>810 (54.4%)</td>
<td>165 (11.3%)</td>
<td>206 (14.0%)</td>
</tr>
<tr class="odd">
<td>32 mg</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>3 (0.2%)</td>
<td>2 (0.1%)</td>
<td>304 (20.5%)</td>
<td>275 (18.5%)</td>
<td>1061 (72.8%)</td>
<td>876 (59.6%)</td>
</tr>
</tbody>
</table>

Note: This data in this table obtained from Table 64 of SH-AHS-0007 CSR

In general the exposure duration was adequate based on guidelines
provided in ICH E1for a drug intended for chronic use.

## Summary of Selected Drug-Related Adverse Events, Important Limitations of Data, and Conclusions

Three adverse events of special interest that are unequivocally drug
related include:

1)  hyperkalemia

2)  hypotension

3)  abnormal renal function

These adverse events are discussed in detail elsewhere in this review.
The dose titration study design used in the CHARM Program make defining
a dose response relationship with respect to these AE's problematic. It
is worth noting again that the patterns of these AE's was consistent
across the CHARM Program.

Other adverse events that are likely related to candesartan include
anemia, fatigue, diarrhea, dizziness/vertigo and dehydration. These AE's
were consistently higher on candesartan compared to placebo across the
CHARM Program.

# Additional Clinical Issues

## Dosing Regimen and Administration

The CHARM Program in general used a regimen of dose titration. The
highest dose of candesartan currently approved is 32 mg. The currently
available tablet strengths are 4, 8, 16, and 32 mg. In CHARM Preserved,
patients randomized to the candesartan arm were started on daily doses
of either 4 or 8 mg and titrated every two weeks to a maximum dose of 32
mg once daily as tolerated.

## Drug-Drug Interactions

N/A

## Special Populations

The responses to candesartan were similar for different age and sex
subgroups. However, there were differences in response to candesartan
seen among different ethnic groups. Table 22 below shows the results of
the primary endpoint (CV mortality and CHF hospitalization) as a
function of ethnicity. Orientals were adversely affected by candesartan
with a statistically significant hazard ratio of 3.73.

[]{#__RefHeading___Toc92525698 .anchor}Table 22: CV death and CHF
hospitalization by ethnicity in CHARM Preserved

  ---------------------------------------------------------------------------------------
  **Variable**     **Group**    **N**   **Cand \#  **Placebo   **Hazard     **P-value**
                                        of         \# of       ratio (95%   
                                        events**   events**    CI)**        
  ---------------- ------------ ------- ---------- ----------- ------------ -------------
  Ethnicity        European     2767    289        336         0.85 (0.72,  0.036
                                                               0.99)        

                   Black        126     16         11          1.20 (0.56,  0.637
                                                               2.59)        

                   Oriental     42      10         4           3.73 (1.17,  0.026
                                                               11.93)       

                   South Asian  29      6          2           2.26 (0.46,  0.32
                                                               11.24)       
  ---------------------------------------------------------------------------------------

Note: The data in this table obtained from Table 102 of SH-AHS-0007 CSR

The adverse effect of candesartan in Orientals seen in CHARM Preserved
was consistent across the overall CHARM Program as shown in Table 23
below.

[]{#__RefHeading___Toc92525699 .anchor}Table 23: CV death and CHF
hospitalization by ethnicity in overall CHARM Program

  ---------------------------------------------------------------------------------------
  **Variable**     **Group**    **N**   **Cand \#  **Placebo   **Hazard     **P-value**
                                        of         \# of       ratio (95%   
                                        events**   events**    CI)**        
  ---------------- ------------ ------- ---------- ----------- ------------ -------------
  Ethnicity        European     6870    1002       1180        0.82 (0.75,  \<0.001
                                                               0.89)        

                   Black        326     46         59          0.71 (0.48,  0.090
                                                               1.05)        

                   Oriental     133     34         17          2.14 (1.19,  0.012
                                                               3.85)        

                   South Asian  93      31         15          1.36 (0.73,  0.330
                                                               2.54)        
  ---------------------------------------------------------------------------------------

Note: The data in this table obtained from Table 12.1.9.4.40 of CHARM
Pooled CSR

The following table summarizes the results in Orientals only by
components of the primary endpoint and also all cause mortality.

[]{#__RefHeading___Toc92525700 .anchor}Table 24: CV death, CHF
hospitalizations, and All cause mortality in Orientals in overall CHARM
Program

  ----------------------------------------------------------------------------------------
  **Variable**      **Group**    **N**   **Cand \#  **Placebo   **Hazard     **P-value**
                                         of         \# of       ratio (95%   
                                         events**   events**    CI)**        
  ----------------- ------------ ------- ---------- ----------- ------------ -------------
  CV death          Oriental     133     19         9           1.90 (0.85,  0.116
                                                                4.22)        

  CHF               Oriental     133     23         11          2.16 (1.05,  0.038
  hospitalization                                               4.46)        

  All cause         Oriental     133     24         13          1.62 (0.82,  0.166
  mortality                                                     3.20)        
  ----------------------------------------------------------------------------------------

Note: The data in this table obtained from Tables 12.1.9.4.47,
12.1.9.4.48, and 12.1.9.4.49 of CHARM Pooled CSR

## Pediatrics

N/A

## Advisory Committee Meeting

There has been no previous Advisory Committee meeting to discuss the
CHARM program.

## Literature Review

Table 25 below summarizes the studies published in the literature to
date regarding the use of angiotensin receptor blockers (ARB's) other
than candesartan in patients with congestive heart failure. The studies
summarized below all evaluated heart failure patients with NYHA Class
II-IV and ejection fractions [\<]{.underline} 40%. The key point is that
no prospective clinical trials evaluating the effects of ARB's in
patients with a preserved ejection fraction have been conducted to date.

[]{#__RefHeading___Toc92525701 .anchor}Table 25: Summary of clinical
trials of ARB use in heart failure patients

+--------------+-------------+------------+------------+------------+
| **Clinical   | **ARB       | **Study    | **         | **         |
| trial**      | used**      | design**   | Population | Literature |
|              |             |            | studied**  | r          |
|              |             |            |            | eference** |
+--------------+-------------+------------+------------+------------+
| ELITE 1      | Losartan    | P, R, DB,  | NYHA       | Pitt B et. |
|              |             | AC         | II-IV,     | al, Lancet |
|              |             | (          |            | 1997;      |
|              |             | captopril) | ***LVEF \< | 349:747-52 |
|              |             |            | 40%***     |            |
+--------------+-------------+------------+------------+------------+
| ELITE 2      | Losartan    | P, R, DB,  | NYHA       | Pitt B et. |
|              |             | AC         | II-IV,     | al, Lancet |
|              |             | (          |            | 2000;      |
|              |             | captopril) | ***LVEF \< | 3          |
|              |             |            | 40%***     | 55:1582-87 |
+--------------+-------------+------------+------------+------------+
| Val-HEFT     | Valsartan   | P, R, DB,  | NYHA       | Cohn J et. |
|              |             | PC         | II-IV,     | al, NEJM   |
|              |             |            |            | 2001;      |
|              |             |            | ***LVEF \< | 3          |
|              |             |            | 40%***     | 45-1667-75 |
+--------------+-------------+------------+------------+------------+

Note: P = prospective, R = randomized, DB = double blind, AC = active
controlled, PC = placebo controlled

ELITE 1, ELITE 2, and Val-HEFT are references 6, 7, 8 in the References
section

# Overall Assessment

## Conclusions 

The CHARM Preserved study was the sole study submitted by the sponsor to
support approval in patients with a preserved EF. There were no
supportive studies for this particular subset of heart failure patients.
More than 3000 patients with predominantly NYHA Class II and III heart
failure were randomly assigned to placebo or candesartan and followed up
for 2 to 4 years. This was a multi-national study enrolling patients
from Europe, Asia, Africa, and North America. Patients were started on
candesartan once daily doses of 4 to 8 mg and titrated every two weeks
to a maximum dosage of 32 mg once daily. The primary endpoint was CV
death or CHF hospitalization. In terms of relevant demographics, the
mean age of patients enrolled was 67 years, 40 % were female, and more
than 4% were Black. The most prevalent background therapy in this
patient population was diuretics. The primary endpoint was reached in
333 patients in the candesartan arm and 366 patients in the placebo arm:
hazard ratio 0.89 (0.77, 1.03), p-value 0.12. CHARM Preserved did not
achieve its primary pre-specified endpoint. The observed trend appears
to be driven by patients with an EF between 40 and 50%. By somewhat
arbitrarily defining patients with an EF \> 40% as having a "preserved
EF", this study likely included some patients more closely related to
those in either of the other two components of the CHARM program with
systolic dysfunction, notwithstanding an EF \> 40%. Based on the CHARM
Added and CHARM Alternative components reviewed by Dr. U, it is evident
that patients with systolic dysfunction will benefit from candesartan in
terms of CV mortality and morbidity. Another possibility is that CHARM
Preserved was simply underpowered to detect a significant difference.
Differentiating these two possibilities would require further studies by
the sponsor.

With regard to safety it is important to note that Oriental patients had
worse outcomes when treated with candesartan compared to Caucasians.
There was evidence of statistical heterogeneity in the Oriental
subgroup. It is acknowledged that post hoc subgroup analyses may be
problematic and may give rise to false positive signals. The clinical
significance of this finding is unclear and it is uncertain whether any
specific labeling changes should be incorporated.

## Recommendation on Regulatory Action

Based on CHARM Preserved (SH-AHS-0007), the sponsor is seeking approval
of candesartan for use in patients with heart failure with a "Preserved"
EF to decrease the need for hospitalization. Given that the single study
submitted in support of the proposed indication failed to meet its
primary endpoint with a p-value less than 0.05,

for the proposed indication.

## Recommendation on Postmarketing Actions 

N/A

## Labeling Review

## My labeling recommendations are as follows:  {#my-labeling-recommendations-are-as-follows .unnumbered}

1)  Acknowledge the existence of CHARM Preserved

2)  Remove pooled study data that incorporates CHARM Preserved.

3)  In the "Indications" section remove the reference to use of
    candesartan in patients with "preserved" left ventricular systolic
    function.

A more detailed line by line review of labeling will be discussed with
other team members during labeling meetings.

# Appendices

## Review of Individual Study Reports

### CHARM Preserved

#### Study dates

[]{#__RefHeading___Toc92525702 .anchor}Table 26: Chronology of the CHARM
Program highlights

  ----------------------------------------- -----------------------------
  Original Protocol                         November 13, 1998

  Amendment #1                              December 10, 1998

  First Patient randomized                  March 22, 1999

  Amendment #2                              March 31, 1999

  Amendment #3                              December 21, 1999

  Amendment #4                              March 7, 2000

  Study Closure                             March 31, 2003

  Statistical Analysis Plan finalized       April 15, 2003

  Database Lock                             June 12, 2003

  Database Re-Locked                        July 4, 2003
  ----------------------------------------- -----------------------------

#### Protocol

***Overall Program Title:***

"Candesartan Cilexitil (Candesartan) In Heart Failure Assessment of
Reduction in Mortality and Morbidity (CHARM)"

***Individual Study Title:***

"Clinical Study (SH-AHS-0003) of Candesartan in Patients With Heart
Failure Who Are ACE Inhibitor Intolerant and Have Depressed Left
Ventricular Systolic Function"

"Clinical Study (SH-AHS-0006) of Candesartan in Patients With Heart
Failure Who Are Treated With ACE Inhibitors and Have Depressed Left
Ventricular Systolic Function"

"Clinical Study (SH-AHS-0007) of Candesartan in Patients With Heart
Failure and Preserved Left Ventricular Systolic Function"

***Objectives of Overall Program (Pooled Analyses):***

Primary: To determine whether candesartan, compared to placebo, reduces
all cause mortality in the pooled population of patients with
symptomatic chronic heart failure (studies SH-AHS-0003, SH-AHS-0006,
SH-AHS-0007).

Secondary: To determine whether candesartan, compared to placebo,
reduces all cause mortality in the pooled population of patients with
depressed LV function (studies SH-AHS-0003, SH-AHS-0006).

***Objectives of Each Study***

Primary: To determine whether candesartan, compared to placebo, reduces
the combined endpoint of cardiovascular mortality or hospitalization for
the management of CHF.

Secondary: To determine whether candesartan, compared to placebo,

-   Reduces the combined endpoint of all cause mortality or
    hospitalization for the management of CHF

-   Reduces the combined endpoint of cardiovascular mortality or
    hospitalization for the management of CHF or nonfatal myocardial
    infarction (MI).

***Inclusion Criteria (Common to all 3 studies in the CHARM Program)***

1.  Male or female, \> 18 years old.

2.  Symptomatic CHF corresponding to NYHA class II-IV for \> 4 weeks
    before randomization.

3.  Informed consent. (Obtained before any study specific procedures
    were carried out).

Criteria specific to CHARM Preserved (SH-AHS-0007)

-   Documentation of left ventricular ejection fraction (LVEF) \> 40% by
    contrast ventriculography, radionuclide ventriculography or
    quantitative echocardiography within the previous month (\<31 days).
    The most recent measurement was used.

-   A history of hospitalisation for a cardiac reason.

-   No current treatment, or continued need for treatment, with an ACE
    inhibitor, except if the patient fulfils one or more of the
    following conditions (a-d) in which case treatment with an ACE
    inhibitor was allowed at the discretion of the investigator. a)
    Coronary artery disease defined as previous myocardial infarction,
    unstable angina or angina pectoris with a positive stress test or at
    least two-vessel disease demonstrated on coronary angiogram (\>50%
    stenosis in at least 2 major vessels). b) Previous stroke. c)
    Peripheral vascular disease (angiographically proven or prior
    vascular surgery, amputation or intermittent claudication with an
    ankle-brachial pressure index below 0.9). d) Diabetes mellitus with
    at least one other coronary risk factor; s-total cholesterol \>5.2
    mmol/l (200 mg/dL), HDL-cholesterol \<0.9 mmol/l (\<35 mg/dL),
    smoking, treated hypertension, albuminuria or microalbuminuria, or
    any evidence of vascular disease.

> All patients must have heart failure of NYHA class II-IV at the time
> of enrolment. If the patient was being treated with an ACE inhibitor,
> the patient had to have heart failure of NYHA functional class III-IV
> in the last 6 months and should have been treated with a constant dose
> of an ACE inhibitor for at least 30 days before randomization.

-   Signs and symptoms of CHF not caused by renal or liver failure,
    chronic lung disease, anaemia, thyroid or other primary disease.

***Exclusion Criteria (Common to all 3 studies in the CHARM Program)***

1.  Treatment with an angiotensin II type 1 (AT1) receptor blocker
    within 2 weeks before randomization.

2.  Known hypersensitivity to AT1-receptor blocker.

3.  Current serum-creatinine [\>]{.underline}265 μmol/L
    ([\>]{.underline}3 mg/dL). If the patient was in a stable condition
    the sample could be taken within one month before randomization. For
    unstable patients a new sample was recommended.

4.  Current serum-potassium [\>]{.underline}5.5 mmol/L
    ([\>]{.underline}5.5 mEq/L) or a history of marked ACE inhibitor
    induced hyperkalemia resulting in either a serum-potassium
    [\>]{.underline}6.0 mmol/L ([\>]{.underline}6.0 mEq/L) or a
    life-threatening adverse event. If the patient was in a stable
    condition, the sample could be taken within one month before
    randomization. For unstable patients a new sample was recommended.

5.  Known bilateral renal artery stenosis.

6.  Current symptomatic hypotension.

7.  Persistent systolic or diastolic hypertension (systolic \>170 mmHg;
    diastolic \>100 mmHg) despite use of antihypertensive therapy.

8.  CHF secondary to any of the following conditions: a) Critical aortic
    or mitral stenosis b) Non-cardiac disease (eg uncorrected thyroid
    disease) c) Pericardial disease.

9.  Stroke, acute myocardial infarction or open-heart surgery within the
    last 4 weeks before randomization.

10. History of severe obstructive, restrictive or other chronic
    pulmonary disease.

11. Significant liver disease.

12. The following procedures: a) Planned cardiac surgery expected to be
    performed within 4 weeks after randomization. b) Previous heart
    transplants; or heart transplants expected to be performed within
    the next 6 months

13. Presence of any non-cardiac disease (eg cancer) that was likely to
    significantly shorten life expectancy to \<2 years.

14. Pregnant or lactating women or women of childbearing potential who
    were not protected from pregnancy by an accepted method of
    contraception, such as the oral contraceptive pill, an intrauterine
    device or surgical sterilization (all women of childbearing
    potential must have a negative pregnancy test before randomization).

15. Any condition that in the opinion of the investigator would
    jeopardize the evaluation of efficacy or safety or be associated
    with poor adherence to the protocol.

16. Treatment with any investigational agents within 4 weeks before
    randomization.

Summary of Study Plan

[]{#__RefHeading___Toc92525675 .anchor}Figure 5: Study Plan for CHARM
Program

![](media/image5.png){width="6.497916666666667in"
height="5.027083333333334in"}

#### Protocol Amendments

The protocol amendments to the CHARM program are summarized in Table 27
below. The table below includes the specific date of implementation of
each amendment and its relationship to patient recruitment. Particular
attention should be paid to Amendment 4 that is described in the table
below. The change involved increasing the sample size in the overall
CHARM program by 950 patients (15% increase). The increase in sample
size affected each component of CHARM differentially. This change
occurred more than 15 months after the original protocol was first
approved and approximately 12 months after the first patient was
randomized.

[]{#__RefHeading___Toc92525703 .anchor}Table 27: Summary of Protocol
Amendments in the CHARM program

+-----------------+--------------------+---------------+-------------+
| **Number (date  | **Key details of   | **Reason for  | **Persons   |
| of**            | amendment**        | amendment**   | who**       |
+=================+====================+===============+=============+
| **internal      | **(Section of this |               | **          |
| approval)**     | report affected)** |               | initiated** |
+-----------------+--------------------+---------------+-------------+
|                 |                    |               | **          |
|                 |                    |               | Amendment** |
+-----------------+--------------------+---------------+-------------+
| **Amendment     |                    |               |             |
| made before the |                    |               |             |
| start of        |                    |               |             |
| patient         |                    |               |             |
| recruitment**   |                    |               |             |
+-----------------+--------------------+---------------+-------------+
| 1               | Another secondary  | To meet       | AstraZeneca |
|                 | objective was      | planned       |             |
|                 |                    | changes       |             |
+-----------------+--------------------+---------------+-------------+
| (10 December    | added: To          | in European   | Clinical    |
| 1998)           | determine whether  | guidelines    | Study       |
+-----------------+--------------------+---------------+-------------+
|                 | candesartan,       | for heart     | Team        |
|                 | compared to        | failure       |             |
|                 |                    | studies,      |             |
+-----------------+--------------------+---------------+-------------+
|                 | placebo, reduced   | recommending  |             |
|                 | the combined       | that "all-    |             |
+-----------------+--------------------+---------------+-------------+
|                 | endpoint of        | cause death"  |             |
|                 | all-cause death    | is part of    |             |
|                 | and                |               |             |
+-----------------+--------------------+---------------+-------------+
|                 | hospitalisation    | any combined  |             |
|                 | for the            |               |             |
+-----------------+--------------------+---------------+-------------+
|                 | management of CHF. | Endpoints.    |             |
|                 | Changes in the     |               |             |
|                 | primary analysis   |               |             |
|                 | were made to       |               |             |
|                 | reflect changes in |               |             |
|                 | the secondary      |               |             |
|                 | endpoint described |               |             |
|                 | above.             |               |             |
+-----------------+--------------------+---------------+-------------+
|                 |                    |               |             |
+-----------------+--------------------+---------------+-------------+
|                 |                    |               |             |
+-----------------+--------------------+---------------+-------------+
| **Amendments    |                    |               |             |
| made after the  |                    |               |             |
| start of        |                    |               |             |
| patient         |                    |               |             |
| recruitment**   |                    |               |             |
+-----------------+--------------------+---------------+-------------+
| 2               | No substantive     | Editorial/    | Executive   |
|                 | changes made via   | Clarification |             |
| (31 March 1999) | this amendment.    |               | Committee   |
|                 | There were no      | changes       |             |
|                 | changes to the     |               | Astra       |
|                 | primary/secondary  |               | Zeneca      |
|                 | endpoints,         |               | Clinical    |
|                 | analysis,          |               | Study Team  |
|                 | i                  |               |             |
|                 | nclusion/exclusion |               |             |
|                 | criteria that were |               |             |
|                 | made               |               |             |
+-----------------+--------------------+---------------+-------------+
|                 |                    |               |             |
+-----------------+--------------------+---------------+-------------+
|                 |                    |               |             |
+-----------------+--------------------+---------------+-------------+
| 3               | A reference was    | The detailed  | Executive   |
|                 | made to the        | adjudication  |             |
+-----------------+--------------------+---------------+-------------+
| (21 December    | Clinical Endpoint  | plan had not  | Committee   |
| 1999)           | Committee          | been          |             |
+-----------------+--------------------+---------------+-------------+
|                 | Manual of          | developed at  |             |
|                 | Operations         | the time of   |             |
+-----------------+--------------------+---------------+-------------+
|                 | (adjudication      | the original  |             |
|                 | plan).             | protocol.     |             |
+-----------------+--------------------+---------------+-------------+
|                 | Inclusion criteria |               |             |
|                 | (Section 5.3.1)    |               |             |
+-----------------+--------------------+---------------+-------------+
|                 | ACE inhibitors     |               |             |
|                 | were allowed as    |               |             |
+-----------------+--------------------+---------------+-------------+
|                 | concomitant        | Publication   |             |
|                 | treatment for      | of the        |             |
+-----------------+--------------------+---------------+-------------+
|                 | patients           | HOPE-study    |             |
|                 | fulfilling the     | results       |             |
|                 | HOPE-              |               |             |
+-----------------+--------------------+---------------+-------------+
|                 | study inclusion    |               |             |
|                 | criteria.          |               |             |
+-----------------+--------------------+---------------+-------------+
|                 |                    |               |             |
+-----------------+--------------------+---------------+-------------+
|                 |                    |               |             |
+-----------------+--------------------+---------------+-------------+
| 4               | The number of      | To safeguard  | Executive   |
|                 |                    | statistical   |             |
+-----------------+--------------------+---------------+-------------+
| (7 March 2000)  | randomised         | power due to  | Committee   |
|                 | patients in the    | lower than    |             |
|                 |                    | expected      |             |
|                 | overall CHARM      | event rates   |             |
|                 | program was        | in blinded    |             |
|                 | increased by 950   | data.         |             |
|                 | patients           |               |             |
|                 |                    |               |             |
|                 | (6500 to 7450).    |               |             |
|                 | For CHARM          |               |             |
|                 | alternative this   |               |             |
|                 | increase was 300   |               |             |
|                 | patients. For      |               |             |
|                 | CHARM added this   |               |             |
|                 | was 250 patients.  |               |             |
|                 | For CHARM          |               |             |
|                 | preserved this was |               |             |
|                 | 400 patients.      |               |             |
+-----------------+--------------------+---------------+-------------+

Note: Data in this table adapted from Table 12 of SH-AHS-0007 study
report

#### Statistical Considerations

Please refer to the Statistical Review by Dr. Charles Le for a more
detailed discussion.

Interim efficacy analyses were made every 6 months and recommendations
were made to the Steering Committee and Sponsor as to stopping the study
for benefit or harm. The pre-specified primary monitoring variable for
the interim analyses was all-cause mortality. A total of 6 interim
analyses were conducted. According to the statistical review of this
application by Dr. Charles Le, it was felt that the effect of the
interim analyses on the alpha level for the analysis of the primary
endpoint would not be substantial.

Primary Analyses (of each component study of CHARM):

The primary variable (time from randomization to a CV event or the first
occurrence of a CHF hospitalization) was to be analyzed by a two-sided
log rank test. For patients with multiple occurrences of events, the
time to first occurrence was to be used. A p-value below 0.05 was to be
considered statistically significant.

To meet the secondary objectives in each study a log rank test was to be
performed to first compare the incidence curves for the combined
endpoint of all cause mortality or CHF hospitalization and then for the
combined endpoint of CV mortality, CHF hospitalization or non-fatal MI.
A statistically significant difference was to be declared if the p-value
was below 0.05.

The primary and secondary endpoints were to be analyzed using a step
down procedure in which if and only if the previous analysis was
significant at a p value below 0.05, were subsequent analyses of the
secondary endpoints were to occur.

Primary Pooled Analyses (CHARM studies pooled)

Data on all cause mortality was to be pooled from all three component
studies of the CHARM Program (SH-AHS-0003, SH-AHS-0006, SH-AHS-0007).
The primary endpoint of the pooled analysis was to determine if
candesartan, compared to placebo, reduces all cause mortality in this
patient population. A p-value less than 0.05 for the two-sided log-rank
test was to be considered as a confirmation of different incidence
curves for the pooled population.

It was estimated that the annual event rate in the overall CHARM program
would be approximately 11%. It was anticipated that the event rates in
the patient population with a depressed ejection fraction would be
higher: 14% and 11.6% for studies SH-AHS-0003 and SH-AHS-0006
respectively. It was anticipated that the annual event rate in the
patients with preserved ejection fraction would be 8.3%. It was also
anticipated that candesartan arm would reduce the incidence of all cause
mortality relative to the placebo by a minimum of 16%. Under these
assumptions the power of the study was greater than 90% (even if one
were to assume an even smaller overall event rate of 9%). It was
originally expected that 6,500 patients would be required to achieve the
endpoint. However, as discussed above in the protocol amendments
section, the sample size was increased approximately 1 year after the
initiation of the overall CHARM program.

#### Results

Patient Disposition

A total of 3025 patients were recruited from 514 sites. Of the 3025
patients, 2 had no study drug administered and no data available post
randomization. Consequently there were 3023 patients that were analyzed
in the ITT/Safety population. As this was a multi-national study,
patients were enrolled from Europe, Asia, Africa, and North America.
More than one-third of the patients in the study were from the U.S. and
Canada (N = 1112).

As seen in Figure 6 below, 1509 patients were randomized to placebo and
1514 patients were randomized to candesartan. In CHARM preserved, follow
up with respect to vital status was excellent. Of the 3023 patients in
the ITT population, only 1 person was lost to follow-up in the placebo
arm and 2 in the candesartan arm.

![](media/image6.png){width="6.492361111111111in"
height="6.088888888888889in"}

[]{#__RefHeading___Toc92525676 .anchor}Figure 6: Patient Disposition in
CHARM Preserved

Source: Figure 2 of Sponsor's CSR for SH-AHS-0007

Protocol Deviations

There were a total of 324 patients with protocol deviations -- 165 on
placebo and 159 on candesartan. The top two protocol deviations were
inclusion and exclusion criteria deviations and accounted for 75% of the
total protocol deviations. The other common protocol deviations were the
wrong investigational product given and randomization before visit 1.

Baseline patient characteristics

In general, patients were well balanced at baseline suggesting
randomization was effective. As shown in Table 28 below, approximately
2/5 of the population was female. Caucasians were the predominant racial
group in the study. Blacks comprised less than 5% of the study
population. The majority of patients were Class II/III heart failure at
baseline. In terms of the etiology of heart failure, the majority of
patients had ischemic heart disease followed by hypertension. These two
etiologies accounted for more than 75% of the etiologies of heart
failure in this population.

[]{#__RefHeading___Toc92525704 .anchor}Table 28: CHARM Preserved patient
baseline characteristics

+-------------+-------------+-------------+-------------+-------------+
|             |             | **Placebo** | **Ca        | **Total**   |
|             |             |             | ndesartan** |             |
+-------------+-------------+-------------+-------------+-------------+
| Total       |             | 1509 (100%) | 1514 (100%) | 3023 (100%) |
| number      |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Sex (male)  |             | 891 (59%)   | 920 (61%)   | 1811 (60%)  |
+-------------+-------------+-------------+-------------+-------------+
| Age         | \< 65 years | 614 (41%)   | 570 (38%)   | 1184 (39%)  |
|             |             |             |             |             |
|             | [\>]{       |             |             |             |
|             | .underline} |             |             |             |
|             | 65 years    |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
|             |             | 895 (59%)   | 944 (62%)   | 1839 (61%)  |
+-------------+-------------+-------------+-------------+-------------+
| Race        | European    | 1393 (92%)  | 1374 (91%)  | 2767 (92%)  |
|             |             |             |             |             |
|             | Black       |             |             |             |
|             |             |             |             |             |
|             | Oriental    |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
|             |             | 57 (4%)     | 69 (5%)     | 126 (4%)    |
+-------------+-------------+-------------+-------------+-------------+
|             |             | 22 (2%)     | 20 (1%)     | 42 (1%)     |
+-------------+-------------+-------------+-------------+-------------+
| Cigarette   | Non-smoker  | 644 (43%)   | 598 (40%)   | 1242 (41%)  |
| smoking     |             |             |             |             |
|             | Current     |             |             |             |
|             | smoker      |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
|             |             | 187 (12%)   | 222 (15%)   | 409 (14%)   |
+-------------+-------------+-------------+-------------+-------------+
| NYHA Class  | II          | 905 (60%)   | 931 (62%)   | 1836 (61%)  |
|             |             |             |             |             |
|             | III         |             |             |             |
|             |             |             |             |             |
|             | IV          |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
|             |             | 584 (39%)   | 556 (37%)   | 1128 (38%)  |
+-------------+-------------+-------------+-------------+-------------+
|             |             | 20 (1.3%)   | 27 (2%)     | 47 (2%)     |
+-------------+-------------+-------------+-------------+-------------+
| h/o         |             | 1038 (69%)  | 1038 (69%)  | 2076 (69%)  |
| previous    |             |             |             |             |
| CHF         |             |             |             |             |
| hosp        |             |             |             |             |
| italization |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| h/o         |             | 659 (44%)   | 681 (45%)   | 1340 (44%)  |
| previous MI |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| h/o         |             | 959 (64%)   | 984 (65%)   | 1943 (64%)  |
| h           |             |             |             |             |
| ypertension |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| h/o         |             | 423 (28%)   | 434 (29%)   | 857 (28%)   |
| diabetes    |             |             |             |             |
| mellitus    |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| CHF         | Ischemic    | 852 (57%)   | 854 (56%)   | 1706 (56%)  |
| etiology    | heart       |             |             |             |
|             | disease     |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
|             | H           | 347 (23%)   | 337 (22%)   | 684 (23%)   |
|             | ypertension |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Idiopathic  | 132 (9%)    | 131 (9%)    | 263 (9%)    |
|             | dilated     |             |             |             |
|             | car         |             |             |             |
|             | diomyopathy |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

Note: data in this table obtained from Table 18 of Sponsor's SH-AHS-0007
clinical study report

As shown in Table 29 below, patients were similar in the two treatment
arms with respect to age, BMI, blood pressure, and ejection fraction.
The mean age of patients studied was approximately 67 years of age. The
mean ejection fraction was 54%.

[]{#__RefHeading___Toc92525705 .anchor}Table 29: CHARM preserved patient
baseline characteristics

  ---------------------------------------------------------------------------
                    **Placebo**           **Candesartan**   **Total**
  ----------------- --------------------- ----------------- -----------------
  Mean Age (years)  67.1 [+]{.underline}  67.2              67.2
                    11.1                  [+]{.underline}   [+]{.underline}
                                          11.1              11.1

  Mean Height (cm)  168.1 [+]{.underline} 168.1             168.1
                    10.1                  [+]{.underline}   [+]{.underline}
                                          10.1              10.1

  Mean Weight (kg)  82.3 [+]{.underline}  83.0              82.7
                    18.8                  [+]{.underline}   [+]{.underline}
                                          19.1              19.0

  Mean BMI          29.0 [+]{.underline}  29.3              29.2
  ((kg/m^2^)        5.6                   [+]{.underline}   [+]{.underline}
                                          5.9               5.8

  Mean ejection     0.54 [+]{.underline}  0.54              0.54
  fraction          0.09                  [+]{.underline}   [+]{.underline}
                                          0.09              0.09

  Mean SBP (mm Hg)  136.3 [+]{.underline} 136.0             136.2
                    18.3                  [+]{.underline}   [+]{.underline}
                                          18.6              18.4

  Mean DBP (mm Hg)  77.8 [+]{.underline}  77.8              77.8
                    10.5                  [+]{.underline}   [+]{.underline}
                                          10.9              10.7
  ---------------------------------------------------------------------------

Note: data in this table obtained from Table 19 of Sponsor's SH-AHS-0007
clinical study report

Table 30 below summarizes the major classes of medicine being used by
patients in the CHARM preserved study at the time of study randomization
and at the closing visit. The use of various medications was similar
between the two treatment groups at the time of randomization.
Approximately ¾ of the study population enrolled were on diuretics at
baseline. Beta blockers and aspirin were used by more than half of the
study population at baseline. Calcium channel blockers were used by less
than 1/3 of the patients at baseline. Of the beta blockers, metoprolol
was the most commonly used agent followed by atenolol. Of the calcium
channel blockers, amlodipine was the most commonly used agent followed
by diltiazem. Of the vasodilators, long acting nitrates was the most
commonly used agent.

At the time of the closing visit, the use of digitalis glycosides,
diuretics, calcium channel blockers, vasodilators, and acetylsalicylic
acid had generally decreased relative to the time of randomization in
both study arms (the exception was calcium channel blocker use in the
placebo arm). The decreased use of digitalis, diuretics, and calcium
channel blockers was disproportionately greater in the candesartan arm
relative to placebo. The use of beta-blockers, ACE inhibitors, and lipid
lowering agents was increased at the closing visit relative to the
randomization visit in both study arms. The increased use was
proportional in both treatment arms.

[]{#__RefHeading___Toc92525706 .anchor}Table 30: Patients (%) using the
listed class of drug at the time of study entry

  -------------------------------------------------------------------------------------------------------------
                    **At                                            **At closing                    
                    randomization**                                 visit**                         
  ----------------- ----------------- ----------------- ----------- ------------- ----------------- -----------
                    **Placebo**       **Candesartan**   **Total**   **Placebo**   **Candesartan**   **Total**

  Digitalis         410 (27%)         432 (29%)         842 (28%)   321 (26%)     292 (23%)         613 (24%)
  glycoside                                                                                         

  Diuretics         1121 (74%)        1138 (75%)        2259 (75%)  914 (73%)     873 (70%)         1787 (71%)

  Beta-blocker      837 (56%)         847 (56%)         1684 (56%)  746 (59%)     712 (57%)         1458 (58%)

  Calcium channel   477 (32%)         467 (31%)         944 (31%)   409 (33%)     349 (28%)         758 (30%)
  blocker                                                                                           

  ACE inhibitors    280 (19%)         296 (20%)         576 (19%)   337 (27%)     297 (24%)         634 (25%)

  Vasodilators      594 (39%)         566 (37%)         1160 (38%)  445 (35%)     419 (33%)         864 (34%)
  (including                                                                                        
  nitrates,                                                                                         
  hydralazine, and                                                                                  
  other agents)                                                                                     

  Lipid lowering    645 (43%)         617 (41%)         1262 (42%)  651 (52%)     644 (51%)         1295 (52%)
  drugs                                                                                             

  Acetylsalicylic   887 (59%)         875 (58%)         1762 (58%)  653 (52%)     663 (53%)         1316 (52%)
  acid                                                                                              
  -------------------------------------------------------------------------------------------------------------

Note: data in this table obtained from Table 20 of Sponsor's SH-AHS-0007
clinical study report

Efficacy

Table 31 below summarizes the results of efficacy in subgroups of
interest based on ITT analysis. The effect on candesartan in various age
and sex subgroups was similar in CHARM Preserved. In Orientals, there
appeared to be a negative effect of candesartan on CV mortality and CHF
hospitalizations.

Another interesting finding based on the table below is that patients
with a baseline EF \< 0.50 seemed to derive benefit whereas patients
with a baseline EF [\>]{.underline} 0.50 did not. It should be noted
that the sponsor's choice of an EF \> 0.40 to define "preserved ejection
fraction" is an arbitrary one. It is likely that at least some patients
with an EF between 0.40 and 0.50 had reduced systolic function and could
have derived benefit from candesartan similar to patients studied in
CHARM Added.

[]{#__RefHeading___Toc92525707 .anchor}Table 31: Subgroup analysis of CV
death or CHF hospitalization

  ---------------------------------------------------------------------------------------------
  **Variable**     **Group**          **N**   **Cand \#  **Placebo   **Hazard     **P-value**
                                              of         \# of       ratio (95%   
                                              events**   events**    CI)**        
  ---------------- ------------------ ------- ---------- ----------- ------------ -------------
  Age (years)      \< 65              1184    72         86          0.90 (0.66,  0.513
                                                                     1.23)        

                   [\>]{.underline}   1032    117        118         0.90 (0.70,  0.424
                   65 - \< 75                                        1.16)        

                   [\>]{.underline}   807     144        162         0.82 (0.65,  0.074
                   75                                                1.02)        

  Sex              Male               1811    195        205         0.91 (0.75,  0.341
                                                                     1.11)        

                   Female             1212    138        161         0.87 (0.69,  0.220
                                                                     1.09)        

  Ethnicity        European           2767    289        336         0.85 (0.72,  0.036
                                                                     0.99)        

                   Black              126     16         11          1.20 (0.56,  0.637
                                                                     2.59)        

                   Oriental           42      10         4           3.73 (1.17,  0.026
                                                                     11.93)       

                   South Asian        29      6          2           2.26 (0.46,  0.32
                                                                     11.24)       

  Region           Western Europe     1377    125        143         0.87 (0.69,  0.262
                                                                     1.11)        

                   Eastern Europe     196     18         12          1.39 (0.67,  0.379
                                                                     2.88)        

                   North America      1112    142        167         0.83 (0.66,  0.096
                                                                     1.03)        

                   USA                734     95         105         0.85 (0.65,  0.261
                                                                     1.13)        

  NYHA             II                 1836    151        164         0.88 (0.71,  0.269
                                                                     1.10)        

                   III                1140    166        195         0.87 (0.71,  0.188
                                                                     1.07)        

                   IV                 47      16         7           1.60 (0.66,  0.300
                                                                     3.91)        

  LVEF             \< 0.50            1072    106        131         0.78 (0.60,  0.055
                                                                     1.01)        

                   [\>]{.underline}   1951    227        235         0.95 (0.79,  0.592
                   0.50                                              1.14)        

  Digitalis during No                 1984    187        186         0.98 (0.80,  0.817
  study                                                              1.20)        

                   Yes                1039    146        180         0.80 (0.64,  0.045
                                                                     1.00)        

  Diuretic during  No                 492     15         19          0.77 (0.39,  0.441
  study                                                              1.51)        

                   Yes                2531    318        347         0.90 (0.77,  0.154
                                                                     1.04)        

  Calcium channel  No                 1718    176        196         0.80 (0.65,  0.033
  blocker during                                                     0.98)        
  study                                                                           

                   Yes                1305    157        170         1.01 (0.82,  0.901
                                                                     1.26)        

  Spironolactone   No                 2239    219        228         0.90 (0.75,  0.249
  during study                                                       1.08)        

                   Yes                684     114        138         0.96 (0.75,  0.754
                                                                     1.23)        

  ACE inhibitors   No                 2008    200        205         0.93 (0.77,  0.470
  during study                                                       1.13)        

                   Yes                1015    133        161         0.85 (0.67,  0.159
                                                                     1.07)        
  ---------------------------------------------------------------------------------------------

Note: This table taken from Table 102 of SH-AHS-0007 CSR

###  {#section .unnumbered}

## Line-by-Line Labeling Review

To be discussed during team meetings.

# References {#references .unnumbered}

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3\) Jessup M, Brozena S. Heart Failure. NEJM 2003; 348: 2007-18.

4\) Senni M, Redfield MM. Heart Failure with Preserved Systolic
Function. A Different Natural History? J. Am Coll Cardiol 2001;
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5\) Gaasch WH, Zile MR. Left Ventricular Diastolic Dysfunction and
Diastolic Heart Failure. Ann Rev. Med 2004; 55:373-94.

6\) Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et.
al. Randomised trial of losartan versus captopril in patients over 65
with heart failure (Evaluation of Losartan in the Elderly Study, ELITE).
Lancet 1997; 349 (9054): 747-52.

7\) Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ,
et. al. Effect of losartan compared with captopril on mortality in
patients with symptomatic heart failure: randomised trial\--the Losartan
Heart Failure Survival Study ELITE II. Lancet 2000; 355 (9215): 1582-87.

8\) Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A
randomized trial of the angiotensin-receptor blocker valsartan in
chronic heart failure. NEJM 2001; 345(23): 1667-75.