Application Type NDA
20-838
Submission Number S-022
Submission Code SE
1
Reviewer Name Khin
Maung U, MD
Review Completion Date
Established Name Candesartan
Cilexetil
(Proposed) Trade Name Atacandâ
Therapeutic Class Selective
AT1 subtype angiotensin
II receptor
antagonist
Applicant AstraZeneca
LP
Priority Designation P
Formulation oral
Dosing Regimen Initial
dose 4 mg q.d., up-titrated
to a target dose of
32 mg q.d.
Indication Treatment of heart failure
(Labeling claim = Treatment with Atacandâ reduces relative risk of death from cardiovascular
causes or hospitalization for heart failure, and improves symptoms)
Intended Population Patients
with chronic heart failure
(NYHA functional
class II – IV)
1.1 Recommendation on Regulatory
Action
1.2 Recommendation on Postmarketing
Actions
1.2.1 Risk
Management Activity
1.2.2 Required
Phase 4 Commitments
1.3 Summary of Clinical Findings
1.3.1 Brief
Overview of Clinical Program
1.3.4 Dosing
Regimen and Administration
2.2 Currently Available Treatment for
Indications
2.3 Availability of Proposed Active
Ingredient in the United States
2.4 Important Issues with
Pharmacologically Related Products
2.5 Pre-submission Regulatory
Activity
2.6 Other Relevant Background
Information
3 Significant
Findings from Other Review Disciplines..
3.1 CMC (and Product Microbiology, if
Applicable)
3.2 Animal Pharmacology/Toxicology
4 Data
Sources, Review Strategy, and Data Integrity
4.2 Tables of Clinical Studies
4.4 Data Quality and Integrity
4.5 Compliance with Good Clinical
Practices
5.3 Exposure-Response Relationships
5.3.1 Total
exposure of candesartan
6 Integrated
Review of Efficacy
6.1.2 General
Discussion of Endpoints
7.1.2 Other
Serious Adverse Events
7.1.3 Discontinuations
and Other Significant Adverse Events
7.1.8 Postmarketing
Experience
7.2 Adequacy of Patient Exposure and
Safety Assessments
7.2.1 Extent
of exposure (dose/duration)
7.2.3 Additional
submissions, including safety update
7.3 Summary of Selected Drug-Related
Adverse Events, Important Limitations of Data, and Conclusions
7.3.6 Abnormal
hepatic function
7.3.8 Rare
Adverse events in CHARM-Pooled (SH-AHS-0003, -0006, -0007) Studies:
7.4 Is there is relationship between
the dose of candesartan and the important adverse events?
7.4.2 Relationship
of dose of candesartan to permanent study drug discontinuation due hypotension
7.5.1 Summary
of safety for CHARM-Added (SH-AHS-0006) Study:
7.5.2 Summary
of safety for CHARM-Pooled (SH-AHS-0003, -0006, -0007) Studies:
7.5.3 Pooling
Data Across Studies to Estimate and Compare Incidence
8.1 Dosing Regimen and Administration
8.1.1 Dose of
Candesartan (or ARB)
8.2.1 Is there
an interaction of candesartan with b-blockers?
8.2.2 Is there
an interaction of candesartan with spironolactone or aldosterone blockers?
8.2.3 Is there
an interaction of candesartan with digoxin?
8.3.1 CHF
patients with symptomatic hypotension.
8.3.2 CHF
patients with impaired renal function (creatinine increase)
8.3.3 CHF
patients with hyperkalemia
8.3.4 Geriatric
patients with CHF
8.5.2 Are the
effects of ARBs additive on top of ACE-inhibitors?
8.7 Advisory Committee Meeting
8.8 Postmarketing Risk Management
Plan
9.2 Recommendation on Regulatory
Action
9.3 Recommendation on Postmarketing
Actions
9.3.1 Risk
Management Activity
10.1 Review of Individual Study Reports
10.1.1 Appendix
PK1 Study EC602
10.1.2 Appendix
PK2 Study EC605-A (PK component)
10.1.3 Appendix
PK3 Study EC608
10.1.5 Appendix
PD1 Study EC602:
10.1.6 Appendix
PD2 Study EC605-A (PD component)
10.1.7 Appendix
PD3 Study EC604 (STRETCH Study)
10.1.8 Appendix
PD4 Study EC610
10.1.9 Appendix
PD5 Study EC614
10.1.10 Appendix
PD6 SH-AHS-0001
10.1.11 Appendix
PD7 Study OCT105
10.1.12 Appendix
PD8 Study OCT106
10.1.13 Appendix
PD9 Study CPH101
10.1.14 Appendix
PD10 Study CPH103
10.1.15 Appendix
PD11 Study CPH104
10.1.16 Appendix
PD12 Study SH-AHS-0004 (Ellis Study)
10.1.17 Appendix
PD13 Study SH-AHS-0005 (Vaile study)
10.1.18 Appendix
PD14 Study Hikosaka (Publication)
10.1.19 Apendix
15 CHARM-Added (SH-AHS-0006) Trial
10.1.20 Appendix
16 CHARM-Pooled studies
10.2 Line-by-Line Labeling Review
Table 1 Endpoints in the
CHARM-Alternative study (SH-AHS-0003), CHARM-Added study (SH-AHS-0006) and the
CHARM Program (Pooled studies SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007)............................................................................. 25
Table 2 List
of Clinical Efficacy Trials.................................................................................................................................. 30
Table 3 Studies of CHF patients
treated with ACE inhibitors AND Candesartan or placebo.......................................... 31
Table 4
List of Clinical pharmacology studies as submitted by the sponsor............................................................... 37
Table 5 Studies of patients with
CHF treated with candesartan or placebo in which changes in hemodynamics,
neurohormones changes and/or exercise tolerance were measured......................................................................................................................... 37
Table 6
Clinical studies of pharmacokinetics..................................................................................................................... 38
Table 7
Study EC608 – Summary statistics for candesartan and enalaprilat
pharmacokinetic parameters separated by renal groups after repeat dose
administration................................................................................................................................................. 40
Table 8 Study CPH102 – Pharmacokinetic parameters of
M-I and M-II after administration of candesartan cilexetil in multiple doses of
4 mg/day in 5 patients with CHF.......................................................................................................................................... 41
Table 9 Study CPH102 – Urinary
excretions of M-I and M-II.............................................................................................. 41
Table 10 Studies of patients with CHF treated with
candesartan or placebo in which hemodynamics, neurohormonal changes and/or
exercise tolerance were measured..................................................................................................................................... 42
Table 11 Studies of patients with
CHF treated with candesartan showing the PD endpoints (statistically
significant changes, except where mentioned as NS)................................................................................................................................................................. 43
Table 12 Study EC602: PCWPmean –Mean AUC0-12 ±SD
(difference to pre-dose [0h], Peak Change±SD (Efficacy (ITT) Population) 44
Table 13 Study EC602: PAPmean –Mean AUC0-12 ±SD
(difference to pre-dose [0h], Peak Change±SD (Efficacy (ITT) Population) 45
Table 14 Study EC605-A: Pulmonary capillary wedge pressure – One-way
ANCOVA................................................... 45
Table 15 Hemodynamic parameters in
study CPH103 (Translated page 118 of Japanese report).................................... 46
Table 16 Ejection fraction and its
% difference at “run-in” and “end-of-treatment”.......................................................... 46
Table 17 Study EC604 – Results of
the non- parametric ANCOVA on the change in the cardiothoracic ratio between
baseline (Visit 5) and last value – Intent-to-treat population ( n= 807)............................................................................................................. 47
Table 18 Study EC604 – Results of
the non-parametric ANCOVA on the change in the cardiothoracic ratio between
baseline (Visit 5) and last value............................................................................................................................................................................... 47
Table 19 Study EC605-A Neurohormonal variables............................................................................................................ 49
Table 20 Studies of CHF patients
treated with ACE inhibitors AND Candesartan or placebo........................................ 54
Table 21 The numbers of patients
who received ACE inhibitors at heart failure dose and low dose, who were
assigned to candesartan or placebo (Safety Population)............................................................................................................................................... 56
Table 22 Number of patients with
events added (+) or subtracted (-) due to reclassification at the re- opening
of the database. 59
Table 23 Interim results for CHARM-Pooled............................................................................................................................. 61
Table 24 Confirmed adjudicated CV
death or hospitalization due to CHF.
Number of patients with at least one event by treatment group and events
per 1000 years of follow-up. Follow-up
time is calculated to first event. ITT/Safety population ( SH-AHS-0006) 63
Table 25 Confirmed adjudicated CV
death or hospitalization due to CHF. Comparison of candesartan versus placebo
with Cox regression. ITT/Safety population (SH-AHS-0006)............................................................................................................................ 63
Table 26 Confirmed adjudicated
all-cause death or hospitalization due to CHF.
Number of patients with at least one event by treatment group and events
per 1000 years of follow-up. Follow-up
time is calculated to first event.
ITT/Safety population (SH-AHS-0006) 64
Table 27 Confirmed adjudicated
all-cause death or hospitalization due to CHF.
Comparison of candesartan versus placebo with Cox regression. ITT/ Safety population (SH-AHS-0006)..................................................................................................... 64
Table 28 Confirmed adjudicated CV death or hospitalization due to CHF or
nonfatal MI. Number of patients with at
least one event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population (SH-AHS-0006)....................................................................................................................................................................................... 65
Table 29 Confirmed adjudicated CV
death or hospitalization due to CHF or non-fatal MI. Comparison of candesartan
vs. placebo with Cox regression. ITT/Safety population (SH-AHS-0006)....................................................................................................... 65
Table 30 Components of primary and
secondary variables. Number of patients
with at least one event by treatment group and events per 1000 years of
follow-up. Follow-up time is calculated
to first event. ITT/Safety population
(SH-AHS-0006).... 66
Table 31 Components of primary and
secondary variables. Comparison of
candesartan versus placebo with Cox regression.
ITT/ Safety population (SH-AHS-0006)................................................................................................................................................ 66
Table 32 Number, proportion, and
annualized incidence of deaths attributed to different causes in the 3 CHARM
Trials and the overall CHARM Program8 (based on data from
Circulation 2004; 110:2180-3)........................................................................ 67
Table 33 Endpoints in the
CHARM-Added study (SH-AHS-0006)...................................................................................... 68
Table 34 Total number and total
duration (days) of hospitalizations and percentage of time on each unit of care
subdivided with respect to treatment and primary reason for
hospitalization. ITT/Safety population
(SH-AHS-0006).................................... 69
Table 35 Number of patients and
change from baseline to LVCF in NYHA class by treatment. ITT/ Safety population
(SH- AHS- 0006) 69
Table 36 NYHA class shift table by
treatment. ITT/Safety Population. ( SH-AHS-0006).................................................. 70
Table 37 The numbers of patients
who received ACE inhibitors at heart failure dose and low dose, who were
assigned to candesartan or placebo (Safety Population)............................................................................................................................................... 70
Table 38 Comparison of the primary
efficacy endpoints for patients treated with candesartan versus those treated
with candesartan plus an ACE inhibitor........................................................................................................................................................................ 72
Table 39 CV death or CHF
hospitalization by subgroup: dose of study drug, (events per 1000 years of
follow-up), Study SH-AHS-0006 73
Table 40 CV death or CHF
hospitalization by subgroup: dose of study drug (Cox regression), Study
SH-AHS-0006 73
Table 41 The numbers and event
rates (primary efficacy endpoint of CV mortality or CHF hospitalization,
confirmed, adjudicated) of patients who received high or low dose candesartan
plus ACE inhibitors at heart failure dose or low dose – CHARM-Added
(SH-AHS-0006) Study..................................................................................................................................................................................... 74
Table 42 Comparison of the effect
of high or low dose candesartan plus ACE inhibitor at heart failure dose or low
dose on the primary endpoint of time to CV mortality or CHF hospitalization
(confirmed, adjudicated) using Cox Regressiona – CHARM-Added
(SH-AHS-0006) Study........................................................................................................................................................................... 75
Table 43 The numbers and event
rates (secondary efficacy endpoint of all-cause mortality or CHF
hospitalization, confirmed, adjudicated) of patients who received high or low
dose candesartan plus ACE inhibitors at heart failure dose or low dose–
CHARM-Added (SH-AHS-0006) Study........................................................................................................................................................................... 75
Table 44 Comparison of the effect of high or low dose candesartan plus ACE
inhibitor at heart failure dose or low dose on the secondary efficacy endpoint
of all-cause mortality or CHF hospitalization (confirmed, adjudicated) using
Cox Regressiona – CHARM-Added (SH-AHS-0006) Study................................................................................................................................................................. 75
Table 45 The numbers and event
rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or
non-fatal MI, confirmed, adjudicated) of patients who received high or low dose
candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added
(SH-AHS-0006) Study............................................................................................................................................ 76
Table 46 Comparison of the effect of high or low dose candesartan plus ACE
inhibitor at heart failure dose or low dose on the secondary efficacy endpoint
of CV mortality or CHF hospitalization or non-fatal MI (confirmed, adjudicated)
using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................................................................ 76
Table 47 Endpoints in the
CHARM-Alternative study (SH-AHS-0003), CHARM-Added study (SH-AHS-0006) and the
CHARM Program (Pooled studies SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007)............................................................................. 77
Table 48 Number (%) of patients
with the most commonly reporteda AEs leading to death, sorted by
descending frequency in the total population during study. ITT/Safety
population (SH-AHS-0006)............................................................................... 84
Table 49 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs leading to
death, sorted by descending frequency in the total population during study.
ITT/Safety population (SH-AHS-0003, -0006, -0007)................. 84
Table 50 Comparison of the leading
causes of death in the CHARM studies.................................................................... 85
Table 51 Number (%) of patients
with the most commonly reporteda SAEs other than death, sorted by
descending frequency. ITT/Safety population (SH-AHS-0006)................................................................................................................................................ 86
Table 52 Number (%) of patients
with symptomatic CHF with the most commonly reporteda SAEs other
than death, sorted by descending frequency. ITT/Safety population (SH-AHS-0003,
-0006, -0007)................................................................................. 87
Table 53 Number (%) of patients
with the most commonly reporteda AEs leading to discontinuation of
investigational product, sorted by descending frequency. ITT/Safety population
(SH-AHS-0006).................................................................................. 88
Table 54 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs leading to
discontinuation of the investigational product, sorted by descending frequency.
ITT/Safety population (SH-AHS-0003, -0006, -0007) 89
Table 55 AEs in relation to
withdrawal of study drug in ATLAS trial12 (Based on data from
Circulation 1999; 100: 2312-8.) 89
Table 56 Permanent discontinuation
and at least one discontinuation of investigational product due to any cause,
an AE or an abnormal laboratory value. Number of patients with at least one event
by treatment group and events per 1000 years of follow-up. Follow-up time is
calculated to first event. ITT/Safety population (SH-AHS-0006).................................................................... 90
Table 57 Permanent discontinuation
and at least one discontinuation of investigational product due to any cause,
an AE or an abnormal laboratory value. Comparison of candesartan versus placebo
with Cox regression. ITT/Safety population (SH-AHS-0006) 90
Table 58 Permanent discontinuation,
at least one discontinuation and decreased dose of investigational product due
to any cause, an AE, an abnormal laboratory value, hypotension, hyperkalemia or
increased creatinine. The difference in proportion (%) between treatments. ITT/Safety population (SH-AHS-0006)............................................................................................................................ 91
Table 59 Exploratory safety
variables for patients with symptomatic CHF.
Number of patients with at least one event by treatment group and events
per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety
population. (SH-AHS-0003, -0006, -0007)................................................................................................................................................................................................ 92
Table 60 Exploratory safety variables for patients with symptomatic CHF.
Comparison of candesartan versus placebo with Logrank test. ITT/Safety
population. (SH-AHS-0003, -0006, -0007).................................................................................................... 92
Table 61 Exploratory safety
variables for patients with symptomatic CHF. The proportions of patients (%)
with an event. ITT/Safety population. (SH-AHS-0003, -0006, -0007)......................................................................................................................... 93
Table 62 Exploratory safety
variables for patients with symptomatic CHF. The difference in proportion (%)
between treatments. Chi- square test. ITT/ Safety population. (SH-AHS-0003,
-0006, -0007)........................................................................................... 94
Table 63 Exploratory safety
variables. Comparison of candesartan cilexetil versus placebo with Cox
regression test with 33 pre-specified baseline factors as covariates for the
total population. ITT/Safety Population. (SH-AHS-0003, -0006, -0007).... 94
Table 64 Exploratory safety
variables. Comparison of candesartan cilexetil versus placebo with Cox
regression with 33 pre-specified baseline factors as covariates for the
subpopulation. ITT/Safety Population. (SH-AHS-0003, -0006)................................. 94
Table 65 Discontinuation of
investigational product due to hypertension, hyperkalemia and increased
creatinine in patients with a history of diabetes for the total population. The
proportions of patients (%) with an event. ITT/Safety Population. (SH-AHS-0003,
-0006, -0007)................................................................................................................................................................................................ 95
Table 66 Permanent discontinuation
of investigational product in patients with a history of diabetes for the total
population. The difference in proportion (%) between treatments. Chi square
test. ITT/Safety Population (SH-AHS-0003, -0006, -0007).... 95
Table 67 Adverse Events leading to dose reduction or discontinuation of
study treatment in VALIANT trial25 (Based on data from N Engl J Med
2003; 349: 1893-1906.)................................................................................................................................................. 96
Table 68 Adverse events causing
discontinuation in the OPTIMAAL trial22 (Based on data from Lancet
2002; 360: 752-60.) 96
Table 69 Number (%) of patients
with the most commonly reporteda AEs leading to dose reduction of investigational
product, sorted by descending frequency in the total population on treatment.
ITT/Safety population (SH-AHS-0006)................... 98
Table 70 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs leading to
dose reduction of the investigational product, sorted by descending frequency
in the total population on treatment. ITT/Safety population (SH-AHS-0003,
-0006, -0007)........................................................................................................................................................................... 99
Table 71 Number (%) of patients who
had at least one adverse event in any category, and total numbers of adverse
events. ITT/Safety population (SH-AHS-0006).............................................................................................................................................. 101
Table 72 Number (%) of patients
with symptomatic CHF with at least one adverse event in any category, and total
numbers of adverse events. ITT/Safety population (SH-AHS-0003, -0006, -0007)..................................................................................... 102
Table 73 Number (%) of patients who
had at least one adverse event in any category, and total numbers of adverse
events for the subpopulation ITT/Safety population (SH-AHS-0003, -0006).................................................................................... 102
Table 74 Number (%) of patients
with the most commonly reporteda AEs, sorted by descending frequency
in the total population during study.
ITT/Safety population (SH-AHS-0006)............................................................................................................. 103
Table 75 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs, sorted by
descending frequency in the total population during study. ITT/ Safety
population (SH-AHS-0003, -0006, -0007)............................................ 104
Table 76 Number (%) of patients
with increase in serum creatinine ³ 2 x from baseline value. ITT/Safety population (North
America) (SH-AHS-0003, -0006,-0007)..................................................................................................................................................... 106
Table 77 Number (%) of patients
with serum potassium to ³ 6 mmol/L at any time after randomization. ITT/Safety population (North
America) (SH-AHS-0003, -0006,-0007)............................................................................................................................ 106
Table 78 Number (%) of patients
with increase in serum creatinine ³ 2 x from baseline value. ITT/Safety population (
North America) (SH- AHS- 0003, -0006).............................................................................................................................................................. 106
Table 79 Number (%) of patients
with serum potassium to ³ 6 mmol/L at any time after randomization. ITT/Safety population (North
America) (SH-AHS-0003, -0006)...................................................................................................................................... 106
Table 80 Estimated Means and 95% CI for the change from baseline to LVCF
for BP variables with Region as an ANOVA factor for the total population.
ITT/Safety Population. (SH-AHS-0003, -0006, -0007)............................................................................. 111
Table 81 Comparison for Change in BP variables with Region as an ANOVA
factor for the total population. ITT/Safety Population. ( SH-AHS-0003, -0006,
-0007).................................................................................................................................................... 111
Table 82 Number (%) of patients with decrease in SBP to £ 80 mm Hg or DBP to £40 mm Hg at any time
after randomization for the total population. ITT/safety population.
(SH-AHS-0003,-0006, -0007).............................................................................. 111
Table 83 Number (%) of patients with decrease in SBP to £ 80 mm Hg at any time
after randomization for the subpopulation. ITT/safety population. (SH-AHS-0003,
-0006).................................................................................................................................. 111
Table 84 Number (%) of patients
with decrease in DBP to £ 40 mm Hg at any time after randomization for the subpopulation.
ITT/safety population. (SH-AHS-0003, -0006).................................................................................................................................. 112
Table 85 Overview of exposure.
ITT/Safety population (SH-AHS-0006)........................................................................... 114
Table 86 Overview of exposure in
patients with symptomatic CHF.
ITT/Safety population (SH-AHS-0003, -0006, -0007) 115
Table 87 Exposure and number of
patients with symptomatic CHF by time in the component studies. ITT/Safety
population (SH-AHS-0003, -0006, -0007)......................................................................................................................................................................... 115
Table 88 Overview of exposure in
the ITT/Safety population for the subpopulation. (SH-AHS-0003, -0006)............. 116
Table 89 Exposure and number of
patients for the subpopulation by time in the study. ITT/Safety population. (SH-AHS-0003, -0006) 116
Table 90 Number (%) of patients
with any of the preferred terms hypotension, hypotension postural,
dizziness/vertigo, syncope, circulatory failure or collapse not otherwise
specified (NOS). ITT/Safety population
(SH-AHS-0006)................................. 118
Table 91 Number (%) of patients with any of the preferred terms
hypotension, hypotension postural, dizziness/vertigo, syncope, circulatory
failure or collapse not otherwise specified (NOS). ITT/Safety population
(SH-AHS-0003, -0006, -0007)............ 119
Table 92 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs, sorted by
descending frequency in the total population during study. ITT/Safety
population (SH-AHS-0003, -0006, -0007)............................................. 120
Table 93 Number (%) of patients
with fatal preferred terms hypotension, hypotension postural, dizziness/
vertigo, syncope, circulatory failure or collapse not otherwise specified
(NOS). ITT/ Safety population (SH-AHS-0003, -0006, -0007)........... 120
Table 94 Number (%) of patients
with any of the preferred terms renal function abnormal/ renal dysfunction
aggravated, renal failure acute, renal failure not otherwise specified (NOS),
uremia, non-protein nitrogen increased, renal failure aggravated, blood urea
nitrogen increased, acute pre-renal failure or anuria. ITT/Safety population
(SH-AHS-0006).............................................. 122
Table 95 Number (%) of patients
with any of the preferred terms renal function abnormal/renal dysfunction
aggravated, renal failure acute, renal failure NOS, uremia, non-protein
nitrogen increased, renal failure aggravated, blood urea nitrogen increased,
acute pre-renal failure or anuria. ITT/Safety population (SH-AHS-0003, -0006
and -0007)............................................................... 124
Table 96 Number (%) of patients
with fatal renal function, abnormal/renal dysfunction, aggravated, renal
failure acute, renal failure, NOS, uremia, non-protein nitrogen increased,
renal failure aggravated, blood urea nitrogen increased, acute pre-renal
failure or anuria. ITT/Safety population (SH-AHS-0003, -0006, -0007)................................................................................................... 124
Table 97 Permanent discontinuation
due to pooled adverse events related to abnormal renal functiona or
hypotensive eventsb or hyperkalemiac on treatment with
candesartan cilexetil or placebo. Specified concomitant medication at the start
of the event. ITT/safety population (SH-AHS-0003, -0006, -0007)d...................................................................................................................... 125
Table 98 Number (%) of patients with any of the preferred terms angina
pectoris/angina pectoris aggravated, myocardial infarction or coronary artery
disorder. ITT/Safety population (SH-AHS-0003, -0006, -0007)...................................................... 131
Table 99 Number (%) of patients
with any of the preferred terms angina pectoris/angina pectoris aggravated,
myocardial infarction or coronary artery disorder leading to death. ITT/Safety
population (SH-AHS-0003, -0006, -0007)......................... 132
Table 100 The numbers and
frequencies of permanent study drug discontinuation due to an adverse event
or an abnormal laboratory valuea in patients who received high
or low dose candesartan plus ACE inhibitors at heart failure dose or low dose–
CHARM-Added (SH-AHS-0006) Study............................................................................................................................................................... 134
Table 101 The numbers and
frequencies of permanent study drug discontinuation due to hypotension
in patients who received high or low dose candesartan plus ACE inhibitors at
heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study 135
Table 102 The numbers and
frequencies of permanent study drug discontinuation due to hyperkalemia
in patients who received high or low dose candesartan plus ACE inhibitors at
heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study 135
Table 103 The numbers and frequencies of permanent study drug
discontinuation due to increased creatinine in patients who received
high or low dose candesartan plus ACE inhibitors at heart failure dose or low
dose– CHARM-Added (SH-AHS-0006) Study 135
Table 104 The numbers and frequencies of dose reductions of study
drug due to an adverse event or an abnormal laboratory valuea in
patients who received high or low dose candesartan plus ACE inhibitors at heart
failure dose or low dose– CHARM-Added (SH-AHS-0006) Study......................................................................................................................................................................... 136
Table 105 Incidence of the primary
composite endpoint and its components in RENAAL study24 (Based on
data from N Engl J Med 2001; 345: 861-9.).......................................................................................................................................................................... 142
Table 106 Cardiovascular mortality
and morbidity in VALIANT trial25 (Based on data from N Engl J Med
2003; 349: 1893-1906.) 143
Table 107 Target doses of ACE
inhibitors for heart failure used in studies that demonstrate a reduction in
mortality and morbidity 145
Table 108 CV death or
hospitalization due to CHF (confirmed adjudicated) by use of ACE-inhibitors in
study SH-AHS-0006. Comparison of
candesartan vs. placebo with Cox regression.
ITT/Safety population.................................................................... 146
Table 109 Comparison of the primary
efficacy endpoints for patients treated with candesartan versus those treated
with candesartan plus an ACE inhibitor...................................................................................................................................................................... 147
Table 110 Effect of high and low
dose lisinopril on major clinical events (ATLAS Study)12 (Based on
data from Circulation 1999; 100: 2312-8.).............................................................................................................................................................................................. 147
Table 111 Echocardiographic Characteristics of the CHF Patients
Participating in the Low-Dose (5 mg/ day) Versus High-Dose (40 mg/ day)
Enalapril Study13................................................................................................................................................................ 148
Table 112 Primary and secondary
endpoints and exploratory analyses in CIBIS-II study35 (Based on
data from Lancet 1999; 353: 9-13.) 151
Table 113 Comparative Effects of Two Different Treatment Strategies in
Patients Receiving Low Doses of Angiotensin-Converting Enzyme (ACE) Inhibitors
(Based on data from Am J Med 2001; 110: 81S-94S)44................................................................... 156
Table 114 CV death or
hospitalization due to CHF (confirmed adjudicated) by use of b-blockers in study
SH-AHS-0006. Comparison of candesartan
vs. placebo with Cox regression.
ITT/Safety population.................................................................... 157
Table 115 The numbers and event
rates (primary efficacy endpoint of CV mortality or CHF hospitalization,
confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline –
CHARM-Added (SH-AHS-0006) Study............... 158
Table 116 Comparison of the effect of high or low dose candesartan on CHF
patients who did or did not receive b-blockers at baseline on the primary endpoint of time
to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox
Regressiona – CHARM-Added (SH-AHS-0006) Study....................................................................................................................................................... 158
Table 117 The numbers and event
rates (secondary efficacy endpoint of all-cause mortality or CHF
hospitalization, confirmed, adjudicated) of patients who did or did not receive
b-blockers at baseline –
CHARM-Added (SH-AHS-0006) Study.......... 159
Table 118 Comparison of the effect of high or low dose candesartan plus on
CHF patients who did or did not receive b-blockers at baseline on the secondary efficacy
endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated)
using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................... 159
Table 119 The numbers and event
rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or
non-fatal MI, confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline –
CHARM-Added (SH-AHS-0006) Study 159
Table 120 Comparison of the effect of high or low dose candesartan on CHF
patients who did or did not receive b-blockers at baseline on the secondary efficacy
endpoint of CV mortality or CHF hospitalization or non-fatal MI (confirmed,
adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................... 159
Table 121 CV death or hospitalization
due to CHF (confirmed adjudicated) by use of spironolactone in study
SH-AHS-0006. Comparison of candesartan
vs. placebo with Cox regression.
ITT/Safety population.................................................................... 162
Table 122 The numbers and event rates (primary efficacy endpoint of CV
mortality or CHF hospitalization, confirmed, adjudicated) of patients who did
or did not receive spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study...................... 163
Table 123 Comparison of the effect
of high or low dose candesartan on CHF patients who did or did not receive
spironolactone at baseline on the primary endpoint of time to CV mortality or
CHF hospitalization (confirmed, adjudicated) using Cox Regressiona –
CHARM-Added (SH-AHS-0006) Study.......................................................................................................................................... 163
Table 124 The numbers and event
rates (secondary efficacy endpoint of all-cause mortality or CHF
hospitalization, confirmed, adjudicated) of patients who did or did not receive
spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study.. 163
Table 125 Comparison of the effect
of high or low dose candesartan plus on CHF patients who did or did not receive
spironolactone at baseline on the secondary efficacy endpoint of all-cause
mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona
– CHARM-Added (SH-AHS-0006) Study............................................................................................... 163
Table 126 The numbers and event
rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or
non-fatal MI, confirmed, adjudicated) of patients who did or did not receive
spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study 164
Table 127 Comparison of the effect
of high or low dose candesartan on CHF patients who did or did not receive
spironolactone at baseline on the secondary efficacy endpoint of CV mortality
or CHF hospitalization or non-fatal MI (confirmed, adjudicated) using Cox
Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................... 164
Table 128 Deaths due to study group
and cause in the DIG Study50 (Based on data from N Engl J Med 1997;
336: 525-33.) 165
Table 129 Patients hospitalized
during the DIG study50, according to study group and reason for
hospitalization. (Based on data from N
Engl J Med 1997; 336: 525-33.)......................................................................................................................................... 166
Table 130 CV death or
hospitalization due to CHF (confirmed adjudicated) by use of spironolactone in
study SH-AHS-0006. Comparison of
candesartan vs. placebo with Cox regression.
ITT/Safety population.................................................................... 167
Table 131 Incidence of the primary outcome and deaths from any cause in
HOPE study51 (Based on data from N Engl J Med 2000; 342: 145-53)......................................................................................................................................................................................... 171
Table 132 Frequency of primary and
selected secondary outcomes (EUROPA study)53 (Based on data from
Lancet 2003; 362: 782-8) 171
Table 133 Primary endpoints and
cause-specific first events in ANBP2 Study54 (Based on data from N
Engl J Med 2003; 348: 583-92) 172
Table 134 Incidence of Severe
Congestive Heart Failure or Death as the Combined Primary End Point of the
SMILE Study60 (Based on data from N Engl J Med 1995; 332: 80-5)................................................................................................................................. 175
Table 135 Primary and secondary
endpoints (CHARM-Alternative Study)63 (Based on data from Lancet
2003; 362: 772-6). 180
Table 136 Endpoints of LIFE23
study (Based on data from Lancet 2002; 359: 995-1003).................................................. 180
Table 137 Endpoint results in ELITE II trial20 (Based on data
from Lancet 2000; 355: 1582-7)......................................... 181
Table 138 Crude rates and relative risks for pre-specified endpoints in
OPTIMAAL Study22 (Based on data from Lancet 2002; 360: 752-60)............................................................................................................................................................................................... 182
Table 139 Cardiovascular Mortality
and Morbidity* in VALIANT Study25 (Based on data from N Engl J Med
2003; 349; 1893-1906). 183
Table 140 Issues related to the
role of angiotensin receptor blockers in patients with heart failure and left
ventricular dysfunction 192
Table 141 PK parameters for
candesartan.............................................................................................................................. 205
Table 142 Summary of
pharmacokinetic data (geometric mean, min, max)......................................................................... 207
Table 143 PK parameters of
candesartan and enalaprilat (by ANOVA)............................................................................ 209
Table 144 Summary statistics for
candesartan and enalaprilat pharmacokinetic parameters separated by renal
groups after repeat dose administration..................................................................................................................................................................... 210
Table 145 Pharmacokinetic
parameters of M-I and M-II after administration of candesartan cilexetil in
multiple doses of 4 mg/day in 5 patients with chronic congestive heart failure.............................................................................................................. 212
Table 146 Urinary excretions of
M-I and M-II....................................................................................................................... 212
Table 147 PCWPmean
–Mean AUC0-12 ±SD (difference to pre-dose [0h], Peak Change±SD
(Efficacy (ITT) Population) 214
Table 148 PAPmean –Mean
AUC0-12 ±SD (difference to pre-dose [0h], Peak Change±SD (Efficacy
(ITT) Population) 214
Table 149 Neurohormones – Peak
changes of concentration/activity [rennin], post-dose (Efficacy (ITT)
Population) 215
Table 150 Pulmonary capillary
wedge pressure – One-way ANCOVA............................................................................. 216
Table 151 Systemic vascular
resistance – One-way ANCOVA.......................................................................................... 217
Table 152 Symptom score – One-way
ANCOVA.................................................................................................................. 217
Table 153 Neurohormonal variables........................................................................................................................................ 218
Table 154 Total exercise time[s]
(baseline (Visit 5) and last value)) – Intent- to- treat population (n= 807)................ 221
Table 155 Total exercise time[s] –
Per- protocol population (n= 629)................................................................................ 221
Table 156 Results of the ANCOVA on
change in total exercise time from baseline (Visit 5) to last value................... 221
Table 157 Results of the non-
parametric ANCOVA on the change in the cardiothoracic ratio between baseline
(Visit 5) and last value – Intent-to-treat population (n= 807)................................................................................................................................. 223
Table 158 Results of the
non-parametric ANCOVA on the change in the cardiothoracic ratio between
baseline (Visit 5) and last value 224
Table 159 Total exercise time
(bicycle exercise test) [s] – ITT population (n=330).......................................................... 227
Table 160 Changes in Dyspnea
Fatigue Index score – ITT population (n=330).............................................................. 228
Table 161 Total bicycle exercise
time (sec) according to NYHA classification (ITT, n=440)......................................... 230
Table 162 NYHA functional
classification - shift table (Safety population; n = 463)...................................................... 231
Table 163 Chronology of the CHARM
Program highlights................................................................................................. 244
Table 164 Doses of ACE inhibitors
used in studies that demonstrate a reduction in mortality and morbidity........... 246
Table 165 Summary of Protocol
Amendments in the CHARM program............................................................................ 248
Table 166 Patients on expired drug........................................................................................................................................... 251
Table 167 Interim results for CHARM-Pooled......................................................................................................................... 261
Table 168 Number of patients with
events added (+) or subtracted (-) due to reclassification at the re- opening
of the database. 264
Table 169 Number of patients with
protocol deviations....................................................................................................... 265
Table 170 Reasons for exclusion
from PP population and number of patients excluded................................................. 266
Table 171 Confirmed adjudicated CV
death or hospitalization due to CHF. Number of patients with at least one event
by treatment group and events per 1000 years of follow- up. Follow- up time is
calculated to first event. ITT/Safety
population ( H-AHS-0006) 268
Table 172 Confirmed adjudicated CV
death or hospitalization due to CHF. Comparison of candesartan versus placebo
with Cox regression. ITT/Safety
population (SH-AHS-0006).......................................................................................................................... 268
Table 173 Confirmed adjudicated
all-cause death or hospitalization due to CHF. Number of patients with at least
one event by treatment group and events per 1000 years of follow-up. Follow- up
time is calculated to first event. ITT/Safety population (SH-AHS-0006) 269
Table 174 Confirmed adjudicated
all- cause death or hospitalization due to CHF. Comparison of candesartan
versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006)..................................................................................................... 269
Table 175 Confirmed adjudicated CV
death or hospitalization due to CHF or nonfatal MI. Number of patients with at
least one event by treatment group and events per 1000 years of follow-up.
Follow- up time is calculated to first event. ITT/Safety population
(SH-AHS-0006)..................................................................................................................................................................................... 270
Table 176 Confirmed adjudicated CV
death or hospitalization due to CHF or nonfatal MI. Comparison of candesartan
versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006).............................................................................................. 270
Table 177 CV death or CHF hospitalization by subgroup: dose of study drug,
(events per 1000 years of follow-up), Study SH-AHS-0006 271
Table 178 CV death or CHF hospitalization by subgroup: dose of study drug
(Cox regression), Study SH-AHS-0006 271
Table 179 The numbers and event rates (primary efficacy endpoint of CV
mortality or CHF hospitalization, confirmed, adjudicated) of patients who
received high or low dose candesartan plus ACE inhibitors at heart failure dose
or low dose – CHARM-Added (SH-AHS-0006) Study................................................................................................................................................................................... 272
Table 180 Comparison of the effect of high or low dose candesartan plus
ACE inhibitor at heart failure dose or low dose on the primary endpoint of time
to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox
Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................................................................... 273
Table 181 The numbers and event rates (secondary efficacy endpoint of
all-cause mortality or CHF hospitalization, confirmed, adjudicated) of patients
who received high or low dose candesartan plus ACE inhibitors at heart failure
dose or low dose– CHARM-Added (SH-AHS-0006) Study............................................................................................................................................................... 273
Table 182 Comparison of the effect of high or low dose candesartan plus
ACE inhibitor at heart failure dose or low dose on the secondary efficacy
endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated)
using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................................................................................... 274
Table 183 The numbers and event
rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or
non-fatal MI, confirmed, adjudicated) of patients who received high or low dose
candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added
(SH-AHS-0006) Study.......................................................................................................................................... 275
Table 184 Comparison of the effect
of high or low dose candesartan plus ACE inhibitor at heart failure dose or low
dose on the secondary efficacy endpoint of CV mortality or CHF hospitalization
or non-fatal MI (confirmed, adjudicated) using Cox Regressiona –
CHARM-Added (SH-AHS-0006) Study.......................................................................................................................................... 275
Table 185 Components of primary and secondary variables. Number of
patients with at least one event by treatment group and events per 1000 years
of follow-up. Follow-up time is calculated to first event. ITT/Safety
population (SH-AHS-0006).... 276
Table 186 Components of primary and
secondary variables. Comparison of candesartan versus placebo with Cox
regression. ITT/Safety population (SH-AHS-0006).............................................................................................................................................. 276
Table 187 Confirmed adjudicated
all- cause hospitalization. Number of patients with at least one event by
treatment group and events per 1000 years of follow-up. Follow-up time is
calculated to first event. ITT/Safety population (SH-AHS-0006).... 277
Table 188 Confirmed adjudicated
all-cause hospitalization. Comparison of candesartan versus placebo with Cox
regression. ITT/Safety population ( SH- AHS- 0006)........................................................................................................................................... 277
Table 189 The proportion of
patients (%) with confirmed adjudicated fatal or nonfatal MI. ITT/Safety
population (SH-AHS-0006) 277
Table 190 The difference in
proportion (%) of patients with confirmed adjudicated fatal or non- fatal MI
between treatments. Chi-square test.
ITT/Safety population (SH-AHS-0006).......................................................................................................................... 277
Table 191 Number of patients and
change from baseline to LVCF in NYHA class by treatment. ITT/Safety population
(SH-AHS-0006) 278
Table 192 NYHA class shift table by
treatment. ITT/Safety Population. (SH-AHS-0006)............................................... 278
Table 193 Diagnosed onset of
diabetes. Number of patients with an event by treatment group and events per
1000 years of follow-up. Follow-up time is calculated to first event.
ITT/Safety population (SH-AHS-0006)............................................... 278
Table 194 Diagnosed onset of
diabetes. Comparison of candesartan versus placebo with Cox regression.
ITT/Safety population (SH-AHS-0006)..................................................................................................................................................................................... 279
Table 195 Development of atrial
fibrillation. The proportions of patients (%) with an event. ITT/ Safety
population (SH-AHS-0006) 279
Table 196 Development of atrial
fibrillation. The difference in proportion (%) between treatments. Chi-square
test. ITT/Safety population (SH-AHS-0006)................................................................................................................................................................... 279
Table 197 Number of deaths due to
cancer by treatment group and events per 1000 years of follow-up. Follow-up
time is calculated to first event. ITT/ Safety population (SH-AHS-0006)............................................................................................................. 279
Table 198 Deaths due to cancer.
Comparison of candesartan versus placebo with Cox regression. ITT/Safety
population (SH-AHS-0006).............................................................................................................................................................................................. 280
Table 199 Total number of clinical
events by variable and treatment. ITT/ Safety population (SH-AHS-0006).......... 280
Table 200 Difference between
treatments by variable. Wilcoxon rank-sum test. ITT/Safety population
(SH-AHS-0006)............... 280
Table 201 Total number and total
duration (days) of hospitalizations and percentage of time on each unit of care
subdivided with respect to treatment and primary reason for
hospitalization. ITT/Safety population
(SH-AHS-0006).................................. 281
Table 202 The numbers and event
rates (primary efficacy endpoint of CV mortality or CHF hospitalization,
confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline –
CHARM-Added (SH-AHS-0006) Study............... 283
Table 203 Comparison of the effect of high or low dose candesartan on CHF
patients who did or did not receive b-blockers at baseline on the primary endpoint of time
to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox
Regressiona – CHARM-Added (SH-AHS-0006) Study....................................................................................................................................................... 283
Table 204 The numbers and event
rates (secondary efficacy endpoint of all-cause mortality or CHF
hospitalization, confirmed, adjudicated) of patients who did or did not receive
b-blockers at baseline –
CHARM-Added (SH-AHS-0006) Study.......... 283
Table 205 Comparison of the effect of high or low dose candesartan plus on
CHF patients who did or did not receive b-blockers at baseline on the secondary efficacy
endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated)
using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................... 284
Table 206 The numbers and event
rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or
non-fatal MI, confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline –
CHARM-Added (SH-AHS-0006) Study 284
Table 207 Comparison of the effect of high or low dose candesartan on CHF
patients who did or did not receive b-blockers at baseline on the secondary efficacy
endpoint of CV mortality or CHF hospitalization or non-fatal MI (confirmed,
adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................... 284
Table 208 The numbers and event rates (primary efficacy endpoint of CV
mortality or CHF hospitalization, confirmed, adjudicated) of patients who did
or did not receive spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study...................... 286
Table 209 Comparison of the effect
of high or low dose candesartan on CHF patients who did or did not receive
spironolactone at baseline on the primary endpoint of time to CV mortality or
CHF hospitalization (confirmed, adjudicated) using Cox Regressiona –
CHARM-Added (SH-AHS-0006) Study.......................................................................................................................................... 286
Table 210 The numbers and event
rates (secondary efficacy endpoint of all-cause mortality or CHF
hospitalization, confirmed, adjudicated) of patients who did or did not receive
spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study.. 286
Table 211 Comparison of the effect
of high or low dose candesartan plus on CHF patients who did or did not receive
spironolactone at baseline on the secondary efficacy endpoint of all-cause
mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona
– CHARM-Added (SH-AHS-0006) Study............................................................................................... 286
Table 212 The numbers and event
rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or
non-fatal MI, confirmed, adjudicated) of patients who did or did not receive
spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study 287
Table 213 Comparison of the effect
of high or low dose candesartan on CHF patients who did or did not receive
spironolactone at baseline on the secondary efficacy endpoint of CV mortality
or CHF hospitalization or non-fatal MI (confirmed, adjudicated) using Cox
Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................... 287
Table 214 Overview of exposure.
ITT/Safety population (SH-AHS-0006)......................................................................... 290
Table 215 Number (%) of patients
who had at least one adverse event in any category, and total numbers of
adverse events. ITT/Safety population (SH-AHS-0006).............................................................................................................................................. 291
Table 216 Number (%) of patients
with the most commonly reporteda AEs, sorted by descending frequency
in the total population during study.
ITT/Safety population (SH-AHS-0006)............................................................................................................. 291
Table 217 Number (%) of patients
with the most commonly reporteda AEs leading to death, sorted by
descending frequency in the total population during study. ITT/ Safety
population (SH-AHS-0006)............................................................................ 293
Table 218 Number (%) of patients
with the most commonly reporteda SAEs other than death, sorted by
descending frequency in the total population during study. ITT/Safety
population (SH-AHS-0006)............................................................................. 293
Table 219 Number (%) of patients
with the most commonly reporteda AEs leading to discontinuation of
investigational product, sorted by descending frequency in the total population
on treatment. ITT/Safety population (SH-AHS-0006)................. 294
Table 220 Number (%) of patients
with the most commonly reporteda AEs leading to dose reduction of
investigational product, sorted by descending frequency in the total population
on treatment. ITT/Safety population (SH-AHS-0006)................. 295
Table 221 Permanent discontinuation
and at least one discontinuation of investigational product due to any cause,
an AE or an abnormal laboratory value. Number of patients with at least one
event by treatment group and events per 1000 years of follow-up. Follow-up time
is calculated to first event. ITT/Safety population (SH-AHS-0006).................................................................. 296
Table 222 Permanent discontinuation
and at least one discontinuation of investigational product due to any cause,
an AE or an abnormal laboratory value. Comparison of candesartan versus placebo
with Cox regression. ITT/Safety population (SH-AHS-0006) 296
Table 223 Permanent
discontinuation, at least one discontinuation and decreased dose of
investigational product due to any cause, an AE, an abnormal laboratory value,
hypotension, hyperkalemia or increased creatinine. The proportions of patients
(%) with an event. ITT/Safety population (SH-AHS-0006).......................................................................................................................... 297
Table 224 Permanent
discontinuation, at least one discontinuation and decreased dose of investigational
product due to any cause, an AE, an abnormal laboratory value, hypotension,
hyperkalemia or increased creatinine. The difference in proportion (%) between
treatments. Chi-square test. ITT/Safety population (SH-AHS-0006)............................................................................................. 298
Table 225 Number (%) of patients
with any of the preferred terms hypotension, hypotension postural,
dizziness/vertigo, syncope, circulatory failure or collapse not otherwise
specified (NOS). ITT/Safety population
(SH-AHS-0006)............. 299
Table 226 Number (%) of patients
with any of the preferred terms renal function abnormal/ renal dysfunction
aggravated, renal failure acute, renal failure not otherwise specified (NOS),
uremia, non-protein nitrogen increased, renal failure aggravated, blood urea
nitrogen increased, acute pre-renal failure or anuria. ITT/Safety population
(SH-AHS-0006).............................................. 301
Table 227 The numbers and
frequencies of permanent study drug discontinuation due to an adverse event
or an abnormal laboratory valuea in patients who received high
or low dose candesartan plus ACE inhibitors at heart failure dose or low dose–
CHARM-Added (SH-AHS-0006) Study............................................................................................................................................................... 309
Table 228 The numbers and
frequencies of permanent study drug discontinuation due to hypotensiona
in patients who received high or low dose candesartan plus ACE inhibitors at
heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study 309
Table 229 The numbers and
frequencies of permanent study drug discontinuation due to hyperkalemiaa
in patients who received high or low dose candesartan plus ACE inhibitors at
heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study 310
Table 230 The numbers and frequencies of permanent study drug
discontinuation due to increased serum creatininea in
patients who received high or low dose candesartan plus ACE inhibitors at heart
failure dose or low dose– CHARM-Added (SH-AHS-0006) Study.............................................................................................................................................................................................. 310
Table 231 The numbers and frequencies of dose reductionsa
of study drug due to an adverse event or an abnormal laboratory valuea
in patients who received high or low dose candesartan plus ACE inhibitors at
heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study......................................................................................................................................................................... 310
Table 232 Total-pooled patient
population and disposition................................................................................................ 320
Table 233 Number of sites and
randomized patients by country for patients with symptomatic CHF. ITT/Safety
population (SH-AHS-0003, -0006, -0007)......................................................................................................................................................................... 321
Table 234 Number of patients with
protocol deviations in CHARM-Pooled patient population................................... 322
Table 235 Confirmed adjudicated
all-cause death in patients with symptomatic CHF. Number of patients with an
event by treatment group and events per 1000 years of follow-up. Follow-up time
is calculated to event. ITT/Safety population (SH-AHS-0003, -0006, -0007) 324
Table 236 Confirmed adjudicated
all-cause death in patients with symptomatic CHF. Comparison of candesartan
versus placebo with Cox regression. ITT/Safety population (SH-AHS-0003, -0006,
-0007)............................................................................... 324
Table 237 Confirmed adjudicated all-cause death in patients with depressed
LV systolic function. Number of patients with an event by treatment group and
events per 1000 years of follow-up. Follow-up time is calculated to event.
ITT/Safety population (SH-AHS-0003, -0006)..................................................................................................................................................................................... 325
Table 238 Confirmed adjudicated all-cause death in patients with depressed
LV systolic function. Comparison of candesartan versus placebo with Cox
regression. ITT/Safety population (SH-AHS-0003,-0006)........................................................................... 325
Table 239 Confirmed adjudicated components of the primary variable. Number
of patients with event by treatment group and events per 1000 years of
follow-up. Follow-up time is calculated to event. ITT/ Safety population
(SH-AHS-0003, -0006, -0007) 326
Table 240 Confirmed adjudicated components of primary variable. Comparison
of candesartan versus placebo with Cox regression. ITT/Safety population
(SH-AHS-0003, -0006, -0007)................................................................................................... 326
Table 241 Confirmed adjudicated components of the primary variable. Number
of patients with at least one event by treatment group and events per 1000
years of follow-up. Follow-up time is calculated to first event. ITT/Safety
population (SH-AHS-0003, -0006) 327
Table 242 Confirmed adjudicated
components of primary variable. Comparison of candesartan versus placebo with
Cox regression. ITT/Safety population (SH-AHS-0003, -0006)............................................................................................................... 327
Table 243 Number of patients and change from baseline to LVEF in NYHA
class by treatment in patients with symptomatic CHF. ITT/Safety Population.
(SH-AHS-0003, -0006, -0007)....................................................................................................................... 327
Table 244 Number of patients and change from baseline to LVEF in NYHA
class by treatment in patients with depressed LV systolic function. ITT/Safety
Population. (SH-AHS-0003, -0006)............................................................................................. 328
Table 245 Frequency of patients by the outcome of the OTE questionnaire at
last visit. ITT/Safety population....... 330
Table 246 OTE for patients with symptomatic CHF as assessed by a
stratified Wilcoxon-Mann-Whitney test for comparison of the change for the two
treatment groups. The data are stratified according to study. ITT/Safety
population (SH-AHS-0003, -0006, -0007) 330
Table 247 Endpoints in the
CHARM-Alternative study (SH-AHS-0003), CHARM-Added study (SH-AHS-0006) and the
CHARM Program (Pooled studies SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007)........................................................................... 332
Table 248 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs leading to
death, sorted by descending frequency in the total population during study.
ITT/Safety population (SH-AHS-0003, -0006, -0007)............... 335
Table 249 Number (%) of patients
with symptomatic CHF with the most commonly reporteda SAEs other than death,
sorted by descending frequency in the total population during study. ITT/Safety
population (SH-AHS-0003, -0006, -0007)............... 336
Table 250 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs leading to
discontinuation of the investigational product, sorted by descending frequency
in the total population on treatment. ITT/Safety population (SH-AHS-0003,
-0006, -0007)......................................................................................................................................................................... 337
Table 251 Exploratory safety
variables for patients with symptomatic CHF.
Number of patients with at least one event by treatment group and events
per 1000 years of follow-up. Follow-up time is calculated to first event.
ITT/Safety population. (SH-AHS-0003, -0006, -0007).............................................................................................................................................................................................. 338
Table 252 Exploratory safety variables for patients with symptomatic CHF.
Comparison of candesartan versus placebo with Logrank test. ITT/Safety
population. (SH-AHS-0003, -0006, -0007).................................................................................................. 338
Table 253 Exploratory safety
variables for patients with symptomatic CHF. The proportions of patients (%)
with an event. ITT/Safety population. (SH-AHS-0003, -0006, -0007)....................................................................................................................... 339
Table 254 Exploratory safety
variables for patients with symptomatic CHF. The difference in proportion (%)
between treatments. Chi-square test. ITT/ Safety population. (SH-AHS-0003,
-0006, -0007)......................................................................................... 340
Table 255 Exploratory safety
variables. Comparison of candesartan cilexetil versus placebo with Cox
regression test with 33 pre-specified baseline factors as covariates for the
total population. ITT/Safety Population. (SH-AHS-0003, -0006, -0007).. 340
Table 256 Exploratory safety
variables. Comparison of candesartan cilexetil versus placebo with Cox
regression with 33 pre-specified baseline factors as covariates for the
subpopulation. ITT/Safety Population. (SH-AHS-0003, -0006)................ 340
Table 257 Discontinuation of
investigational product due to hypertension, hyperkalemia and increased
creatinine in patients with a history of diabetes for the total population. The
proportions of patients (%) with an event. ITT/Safety Population. (SH-AHS-0003,
-0006, -0007).............................................................................................................................................................................................. 341
Table 258 Permanent discontinuation
of investigational product in patients with a history of diabetes for the total
population. The difference in proportion (%) between treatments. Chi square test.
ITT/Safety Population (SH-AHS-0003, -0006, -0007).. 341
Table 259 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs leading to
dose reduction of the investigational product, sorted by descending frequency
in the total population on treatment. ITT/Safety population (SH-AHS-0003,
-0006, -0007)......................................................................................................................................................................... 342
Table 260 Number (%) of patients
with symptomatic CHF with at least one adverse event in any category, and total
numbers of adverse events. ITT/Safety population (SH-AHS-0003, -0006, -0007)..................................................................................... 344
Table 261 Number (%) of patients
who had at least one adverse event in any category, and total numbers of
adverse events for the subpopulation ITT/Safety population (SH-AHS-0003, -0006).................................................................................... 344
Table 262 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs, sorted by
descending frequency. ITT/ Safety population (SH-AHS-0003, -0006, -0007)........................................................................................................... 345
Table 263 Number (%) of patients
with increase in serum creatinine ³ 2 x from baseline value. ITT/Safety population (North
America) (SH-AHS-0003, -0006,-0007)..................................................................................................................................................... 346
Table 264 Number (%) of patients
with serum potassium to ³ 6 mmol/L at any time after randomization. ITT/Safety population (North
America) (SH-AHS-0003, -0006,-0007)............................................................................................................................ 346
Table 265 Number (%) of patients
with increase in serum creatinine ³ 2 x from baseline value. ITT/Safety population (
North America) (SH- AHS- 0003, -0006).............................................................................................................................................................. 346
Table 266 Number (%) of patients
with serum potassium to ³ 6 mmol/L at any time after randomization. ITT/Safety population (North
America) (SH-AHS-0003, -0006)...................................................................................................................................... 346
Table 267 Estimated Means and 95% CI for the change from baseline to LVCF
for BP variables with Region as an ANOVA factor for the total population.
ITT/Safety Population. (SH-AHS-0003, -0006, -0007)............................................................................. 350
Table 268 Comparison for Change in BP variables with Region as an ANOVA
factor for the total population. ITT/Safety Population. ( SH-AHS-0003, -0006,
-0007).................................................................................................................................................... 350
Table 269 Number (%) of patients with decrease in SBP to £ 80 mm Hg or DBP to £40 mm Hg at any time
after randomization for the total population. ITT/safety population.
(SH-AHS-0003,-0006, -0007).............................................................................. 350
Table 270 Number (%) of patients with decrease in SBP to £ 80 mm Hg at any time
after randomization for the subpopulation. ITT/safety population. (SH-AHS-0003,
-0006).................................................................................................................................. 351
Table 271 Number (%) of patients
with decrease in DBP to £ 40 mm Hg at any time after randomization for the subpopulation.
ITT/safety population. (SH-AHS-0003, -0006).................................................................................................................................. 351
Table 272 Overview of exposure in
patients with symptomatic CHF.
ITT/Safety population (SH-AHS-0003, -0006, -0007) 353
Table 273 Exposure and number of
patients with symptomatic CHF by time in the component studies. ITT/Safety
population (SH-AHS-0003, -0006, -0007)........................................................................................................................................................................ 354
Table 274 Overview of exposure in
the ITT/Safety population for the subpopulation. (SH-AHS-0003, -0006)........... 354
Table 275 Exposure and number of
patients for the subpopulation by time in the study. ITT/Safety population. (SH-AHS-0003, -0006) 355
Table 276 Number (%) of patients with any of the preferred terms
hypotension, hypotension postural, dizziness/vertigo, syncope, circulatory
failure or collapse not otherwise specified (NOS). ITT/Safety population
(SH-AHS-0003, -0006, -0007)............ 356
Table 277 Number (%) of patients
with symptomatic CHF with the most commonly reporteda AEs, sorted by
descending frequency in the total population during study. ITT/Safety
population (SH-AHS-0003, -0006, -0007)............................................. 357
Table 278 Number (%) of patients
with fatal preferred terms hypotension, hypotension postural, dizziness/
vertigo, syncope, circulatory failure or collapse not otherwise specified
(NOS). ITT/ Safety population (SH-AHS-0003, -0006, -0007)........... 357
Table 279 Number (%) of patients
with any of the preferred terms renal function abnormal/renal dysfunction
aggravated, renal failure acute, renal failure NOS, uremia, non-protein
nitrogen increased, renal failure aggravated, blood urea nitrogen increased,
acute pre-renal failure or anuria. ITT/Safety population (SH-AHS-0003, -0006
and -0007)............................................................... 359
Table 280 Number (%) of patients
with fatal renal function, abnormal/renal dysfunction, aggravated, renal
failure acute, renal failure, NOS, uremia, non-protein nitrogen increased,
renal failure aggravated, blood urea nitrogen increased, acute pre-renal
failure or anuria. ITT/Safety population (SH-AHS-0003, -0006, -0007)................................................................................................... 359
Table 281 Permanent discontinuation
due to pooled adverse events related to abnormal renal functiona or
hypotensive eventsb or hyperkalemiac on treatment with
candesartan cilexetil or placebo. Specified concomitant medication at the start
of the event. ITT/safety population (SH-AHS-0003, -0006, -0007)d...................................................................................................................... 360
Table 282 Number (%) of patients with any of the preferred terms angina
pectoris/angina pectoris aggravated, myocardial infarction or coronary artery
disorder. ITT/Safety population (SH-AHS-0003, -0006, -0007)...................................................... 363
Table 283 Number (%) of patients
with any of the preferred terms angina pectoris/angina pectoris aggravated,
myocardial infarction or coronary artery disorder leading to death. ITT/Safety
population (SH-AHS-0003, -0006, -0007)......................... 363
Figure
1 Mean Serum Concentration of
CV-11974 (Safety population) – Study EC602
Figure
2 AUC0-24 vs.
administered dose (Efficacy (ITT) population) – Study EC602
Figure
3 Cmax vs. administered
dose (Efficacy (ITT) population) – Study EC602
Figure
4 AUC0-24 versus dose on
visits 2 (left) and 6 (right) – EC605-A
Figure
5 Cmax versus dose on
visits 2 (left) and 6 (right) – EC605-A
Figure
7
Study CPH102 – Plasma digoxin concentrations
Figure
14 Cumulative incidence (%) of
confirmed adjudicated CV death
Figure
27 Mean DBP ± SEM (mmHg) by visit for
the total population. ITT/Safety population
Figure
28 Mean SBP ± SEM (mmHg) by visit for
the total population. ITT/Safety population
Figure
29 Mean Pulse Pressure ± SEM (mmHg) by
visit for the total population. ITT/Safety population
Figure
30 Mean heart rate ± SEM (bpm) by visit
for the total population. ITT/Safety population
Figure
52 Mortality by subgroup (ELITE II20)
(Based on data from Lancet 2000; 355: 1582-7.)
Figure
79 Mean Serum Concentration of CV-11974
(Safety population)
Figure
80 AUC0-24 vs. administered
dose (Efficacy (ITT) population)
Figure
81 Cmax vs. administered
dose (Efficacy (ITT) population)
Figure
82 AUC0-24 versus dose on
visits 2 (left) and 6 (right)
Figure
83 Cmax versus dose on
visits 2 (left) and 6 (right)
Figure
86 Plasma digoxin concentrations
Figure
91 Increase in Ejection Fraction by
different treatments after 17 and 43 weeks.
Figure
92 Change in End Diastolic Volume (ml)
by different treatments after 17 & 43 weeks.
Figure
93 Change in End Systolic Volume (ml)
by different treatments after 17 & 43 weeks.
Figure
95 Patient disposition (completion or
discontinuation)
Figure
116 Mean DBP ± SEM (mmHg) by visit for
the total population. ITT/Safety population
Figure
117 Mean SBP ± SEM (mmHg) by visit for
the total population. ITT/Safety population
Figure
118 Mean Pulse Pressure ± SEM (mmHg) by
visit for the total population. ITT/Safety population
Figure
119 Mean heart rate ± SEM (bpm) by visit
for the total population. ITT/Safety population