> ![](media/image1.png){width="1.1in" height="1.1in"}**DEPARTMENT OF
> HEALTH AND HUMAN SERVICES**

**PUBLIC HEALTH SERVICE**

**FOOD AND DRUG ADMINISTRATION**

**CENTER FOR DRUG EVALUATION AND RESEARCH**

**STATISTICAL REVIEW AND EVALUATION**

**NDA #:** 20-838

**SERIAL #:** SE4-S015

**DRUG NAME**: ATACAND (candesartan cilexetil) Tablets

**INDICATION:** Hypertension

**SPONSOR:** AstraZeneca LP

**DOCUMENT REVIEWED**:

1.  Vols. 1.1, 1.5, 1.37, 1.52, 1.71 (CDER REC'D Date: September 27,
    2001), Supplemental new correspondence (CDER REC'D Date: 4/16/02)

2.  SAS database in EDR

**STATISTICAL REVIEWER:** H.M. James Hung, Ph.D. (HFD-710)

**MEDICAL REVIEWER:** Steve Fredd, M.D. (HFD-110)

**PROJECT MANAGER:** Edward Fromm (HFD-110)

**STATISTICAL KEY WORDS:** ANCOVA, LOCF, Least square mean

**Distribution:** NDA 20-838, SE4-S015

HFD-110/Dr. Throckmorton

HFD-110/Dr. Stockbridge

HFD-110/Dr. Steve Fredd

HFD-110/Mr. Fromm

HFD-700/Dr. Anello

HFD-710/Dr. Chi

HFD-710/Dr. Mahjoob

#######  HFD-710/Dr. Hung

HFD-710/chron

JHung/301-594-5436/DB1/atacand.doc/5-17-2002

# TABLE OF CONTENTS

0\. SUMMARY [3](#summary)

1\. INTRODUCTION [3](#introduction)

2\. OVERVIEW OF THREE CLINICAL TRIALS
[3](#overview-of-three-clinical-trials)

2.1 Study 230 [3](#study-230)

Efficacy results [4](#efficacy-results)

Table 230-1. Disposition of patients entering trial
[4](#table-230-1.-disposition-of-patients-entering-trial)

Treatment differences in BP at last visit
[5](#treatment-differences-in-bp-at-last-visit)

Table 230-2. Least square mean change from baseline to double-blind week
8 (ITT population)
[5](#table-230-2.-least-square-mean-change-from-baseline-to-double-blind-week-8-itt-population)

Blood pressures over time [5](#blood-pressures-over-time)

Table 230-3. Mean trough sitting blood pressures over time
[5](#table-230-3.-mean-trough-sitting-blood-pressures-over-time)

Subgroup results [6](#subgroup-results)

Table 230-5. Mean difference () and 95% CI of BPs by subgroups
[6](#table-230-5.-mean-difference-and-95-ci-of-bps-by-subgroups)

2.2 Study 231 [6](#study-231)

Efficacy results [6](#efficacy-results-1)

Table 231-1. Disposition of patients entering trial
[6](#table-231-1.-disposition-of-patients-entering-trial)

Treatment differences in BP at last visit
[7](#treatment-differences-in-bp-at-last-visit-1)

Table 231-2. Least square mean change from baseline to double-blind week
8 (ITT population)
[7](#table-231-2.-least-square-mean-change-from-baseline-to-double-blind-week-8-itt-population)

Blood pressures over time [7](#blood-pressures-over-time-1)

Table 231-3. Mean trough sitting blood pressures over time
[8](#table-231-3.-mean-trough-sitting-blood-pressures-over-time)

Subgroup results [8](#subgroup-results-1)

Table 231-4. Mean difference () and 95% CI in BPs by subgroups
[8](#table-231-4.-mean-difference-and-95-ci-in-bps-by-subgroups)

2.3 Study 175 [8](#study-175)

Efficacy results [9](#efficacy-results-2)

Table 175-1. Disposition of patients entering trial
[9](#table-175-1.-disposition-of-patients-entering-trial)

Treatment differences in BP at last visit
[10](#treatment-differences-in-bp-at-last-visit-2)

Table 175-2. Least square mean change from baseline to double-blind week
8 (ITT population)
[10](#table-175-2.-least-square-mean-change-from-baseline-to-double-blind-week-8-itt-population)

Blood pressures over time [10](#blood-pressures-over-time-2)

Table 175-3. Mean trough sitting blood pressures over time
[10](#table-175-3.-mean-trough-sitting-blood-pressures-over-time)

Table 175-4. Mean trough sitting DBP over DB visits
[11](#table-175-4.-mean-trough-sitting-dbp-over-db-visits)

Subgroup results [11](#subgroup-results-2)

Table 175-5. Mean difference () and 95% CI in BPs by subgroups
[11](#table-175-5.-mean-difference-and-95-ci-in-bps-by-subgroups)

3\. CONCLUSIONS [11](#conclusions)

#  

# 0. SUMMARY

## 

This NDA provides three main clinical trials (two CLAIM studies and one
CANDLE study) for comparison of the candesartan 16 mg to 32 qd mg
regimen with the losartan 50 mg to 100 mg qd regimen. The two CLAIM
studies showed that the candesartan regimen gave a statistically
significantly greater reduction in blood pressures than the losartan
regimen when given by forced titration. The difference was 1 to 2.2 mm
Hg in trough sitting DBP and about 3.5 mm Hg in trough sitting SBP. When
given by optional titration, the candesartan regimen also gave a
statistically significantly greater reduction in trough sitting
diastolic blood pressure. The difference was 2.2 mm Hg in trough sitting
DBP. The difference in trough sitting SBP was \< 2 mm Hg, not
statistically significant.

Over the course of each study, the candesartan group appeared to have
lower mean blood pressures than the losartan group. In all the studies,
the mean blood pressures in both treatment groups were greatly reduced
in the first two weeks and then seemed to stabilize afterwards.

Candesartan had a favorable trend in gender, race and age subgroups,
except small subgroups.

##  

##  

# 1. INTRODUCTION

This statistical review pertains to the three clinical studies, CLAIM
(Studies 230 and 231) and CANDLE (Study 175). Most of the sponsor's main
results were confirmed by the reviewer's analyses and reported in this
review unless stated otherwise.

# 

# 2. OVERVIEW OF THREE CLINICAL TRIALS

## 2.1 Study 230

This was a multicenter, double-blind, randomized, parallel-group,
forced-titration study to evaluate the anti-hypertensive efficacy of
candesartan 16 mg forced titrated to 32 mg in comparison to losaran 50
mg forced titrated to 100 mg in the patients with mild-to-moderate
essential hypertension (sitting DBP of 95 mm Hg to 114 mm Hg inclusive).
The doses were selected to represent the labeled maximum doses of
candesartan and losartan. All treatments were given once daily.

Following a 4 to 5 week placebo run-in period, qualified study patients
were randomized in 1:1 ratio to candesartan 16 mg or losartan 50 mg.
After two weeks of randomized treatment, all patients doubled their
current dose of candesartan or losartan and continued treatment for an
additional 6 weeks. Patients were also seen 48 hours following their
last dose of study medication and 2 weeks after they discontinued
therapy with the study medication for follow-up visits.

The primary efficacy measure was the mean change in trough sitting DBP
from baseline to the double-blind week 8 visit. Secondary measures
include sitting systolic pressures and peak blood pressures at week 1,
week 2 and week 8, and proportion of responders and controlled patients
based on trough sitting DBP and SBP at week 8. The primary analysis is
based on ITT principle and the last value carried forward strategy for
incompleters.

The sample size of 735 patients to be enrolled from 75 investigative
sites was planned to detect a difference in mean change from baseline in
trough sitting DBP of 2.0 mm Hg between the two treatment groups at
2-sided alpha level of 0.05 and power of 95%, assuming a standard
deviation of 7.5 mm Hg.

### Efficacy results

A total of 613 patients out of 926 patients screened were randomized at
72 sites. Of these patients, 12.1% patients in the candesartan group and
12.4% patients in the losartan group discontinued treatment during the
double-blind phase of the study. The distribution of patients
discontinuing treatment by reason was similar in the two treatment
groups (Table 230-1). Numerically, the losartan group appeared to have a
bit larger proportion of discontinuation due to lack of response whereas
the candesartan group appeared to have a bit larger proportion of
discontinuation due to adverse event.

##### Table 230-1. Disposition of patients entering trial

+----------------------------------+-----------------+-----------------+
|                                  | Candesartan     | Losartan        |
+----------------------------------+-----------------+-----------------+
| Randomized to double-blind       | 307             | 304             |
+----------------------------------+-----------------+-----------------+
| Discontinued\*                   | 37 (12.1%)      | 37 (12.2%)      |
|                                  |                 |                 |
| Lost to follow-up                | 5 (1.6%)        | 4 (1.3%)        |
|                                  |                 |                 |
| Lack of response                 | 8 (2.6%)        | 13 (4.3%)       |
|                                  |                 |                 |
| Adverse event                    | 9 (2.9%)        | 6 (2.0%)        |
|                                  |                 |                 |
| Consent withdrawal               | 10 (3.3%)       | 8 (2.6%)        |
|                                  |                 |                 |
| Sponsor/Investigator decision    | 5 (1.6%)        | 6 (2.0%)        |
+----------------------------------+-----------------+-----------------+
| Completed study                  | 268 (87.3%)     | 267 (87.8%)     |
+----------------------------------+-----------------+-----------------+

Sponsor's results confirmed by reviewer's analysis

\* 2 additional patients in the candesartan group due to an adverse
event while in the follow-up phase and thus not during the double-blind
period.

The two treatment groups appeared to be comparable with respect to
baseline characteristics (Sponsor's Table 4 of study report for Study
230) and treatment compliance (Sponsor's Table 14.1.1.03,14.1.1.05,
14.1.1.06). The mean age was 55 years and the average duration of
hypertension is 10+ years. Fifty nine percent of patients were male an
20% were blacks. The mean sitting DBP/SBP was 100/153 mm Hg.

#### Treatment differences in BP at last visit

The primary efficacy variable, change from baseline to double-blind week
8 in trough sitting DBP, showed a greater reduction with candesartan
(Table 230-2). Statistical significance is borderline. The statistical
analysis was based on the model containing center where centers with at
least one treatment arm having less than two patients were pooled using
a prespecified pooling algorithm according to the sponsor's
clarification. Since it was borderline significance, this reviewer did
analysis without adjusting for centers and analysis by pooling all
centers with less than two patients in a treatment arm into one center.
Both analyses gave a smaller p-value and an estimated treatment
difference very similar to the estimate reported in Table 230-2.
Excluding baseline sitting DBP from the model made little change in the
result. Candesartan also gave a statistically significantly greater
reduction in trough sitting SBP and peak sitting DBP/SBP. However, the
differences in all blood pressures were small.

##### Table 230-2. Least square mean change from baseline to double-blind week 8 (ITT population)

+-------------------+----------+----------+------------------+--------+
|                   | Can      | Losartan | Difference#      | p      |
|                   | desartan |          |                  | -value |
|                   |          | (N=303)  | (95% CI)         |        |
|                   | (N=306)  |          |                  |        |
+-------------------+----------+----------+------------------+--------+
| Trough BP         | N=306    | N=303    |                  |        |
+-------------------+----------+----------+------------------+--------+
| sitting DBP\*     | -10.5    | -9.1     | -1.5 (-2.9,      | 0.041  |
|                   |          |          | -0.06)           |        |
+-------------------+----------+----------+------------------+--------+
| sitting SBP       | -13.4    | -10.1    | -3.4 (-5.7,      | 0.005  |
|                   |          |          | -1.0)            |        |
+-------------------+----------+----------+------------------+--------+
| Peak BP           | N=274    | N=266    |                  |        |
+-------------------+----------+----------+------------------+--------+
| sitting DBP       | -12.9    | -9.5     | -3.4 (-5.0,      | \<     |
|                   |          |          | -1.9)            | 0.0001 |
+-------------------+----------+----------+------------------+--------+
| sitting SBP       | -15.5    | -12.0    | -3.5 (-5.8,      | 0.0032 |
|                   |          |          | -1.2)            |        |
+-------------------+----------+----------+------------------+--------+

Sponsor's results confirmed by reviewer's analysis

\* primary endpoint #difference: candesartan minus losartan

#### 

#### 

#### Blood pressures over time

Blood pressures seemed to trend favorably to candesartan over time
(Table 230-3). The

##### 

##### Table 230-3. Mean trough sitting blood pressures over time

+---------+-----+-------+------+-------+-----+-------+------+------+
|         | Tro |       |      |       | Tro |       |      |      |
|         | ugh |       |      |       | ugh |       |      |      |
|         | s   |       |      |       | s   |       |      |      |
|         | itt |       |      |       | itt |       |      |      |
|         | ing |       |      |       | ing |       |      |      |
|         | DBP |       |      |       | SBP |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
|         | Ca  |       | Losa |       | Ca  |       | Losa |      |
|         | nde |       | rtan |       | nde |       | rtan |      |
|         | sar |       |      |       | sar |       |      |      |
|         | tan |       |      |       | tan |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
|         | N   | Mean  | N    | Mean  | N   | Mean  | N    | Mean |
+---------+-----+-------+------+-------+-----+-------+------+------+
| B       | 307 | 100.4 | 303  | 100.2 | 307 | 153.6 | 303  | 1    |
| aseline |     |       |      |       |     |       |      | 52.2 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DB Wk1  | 304 | 93.1  | 302  | 93.2  | 304 | 144.0 | 302  | 1    |
|         |     |       |      |       |     |       |      | 43.9 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK2   | 300 | 91.4  | 297  | 92.5  | 300 | 141.1 | 297  | 1    |
|         |     |       |      |       |     |       |      | 42.2 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK4   | 292 | 89.5  | 292  | 90.4  | 292 | 139.0 | 292  | 1    |
|         |     |       |      |       |     |       |      | 40.4 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK8   | 284 | 89.8  | 280  | 90.9  | 284 | 139.6 | 280  | 1    |
|         |     |       |      |       |     |       |      | 41.2 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK8   | 306 | 90.2  | 303  | 91.5  | 306 | 140.4 | 303  | 1    |
|         |     |       |      |       |     |       |      | 42.2 |
| (LOCF)  |     |       |      |       |     |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
| 48hr FU | 246 | 91.0  | 247  | 93.1  | 246 | 142.9 | 247  | 146  |
+---------+-----+-------+------+-------+-----+-------+------+------+
| WK2 FU  | 269 | 89.5  | 271  | 89.9  | 269 | 140.6 | 271  | 1    |
|         |     |       |      |       |     |       |      | 41.1 |
+---------+-----+-------+------+-------+-----+-------+------+------+

Sponsor's results confirmed by reviewer's analysis

favorable difference in blood pressures seemed to remain at 48 hours
after the last dose. Two

weeks after the last dose, the mean blood pressures were similar between
the two treatment groups. In both treatment groups, blood pressures were
greatly reduced in the first two weeks and then seemed to stabilize
afterwards.

#### Subgroup results

Candesartan appeared to have a favorable trend in change from baseline
in trough sitting blood pressures in most of the subgroups, except
blacks or small subgroups.

##### Table 230-5. Mean difference () and 95% CI of BPs by subgroups

+---------------+----------+---------------------+---------------------+
|               | N        | Trough sitting DBP  | Trough sitting SBP  |
+---------------+----------+---------------------+---------------------+
|               | C / L    | (95% CI)            | (95% CI)            |
+---------------+----------+---------------------+---------------------+
| Male          | 178/178  | -1.6 (-3.4, 0.2)    | -3.0 (-5.7, -0.3)   |
|               |          |                     |                     |
| Female        | 128/125  | -1.2 (-3.1, 0.7)    | -3.0 (-6.5, 0.4)    |
+---------------+----------+---------------------+---------------------+
| Caucasian     | 211/213  | -2.6 (-4.1, -1.0)   | -4.1 (-6.5, -1.6)   |
|               |          |                     |                     |
| Black         | 61/59    | 1.3 (-1.6, 4.3)     | -1.4 (-6.9, 4.1)    |
|               |          |                     |                     |
| Asian         | 4/8      | > 0 (-9.1, 9.1)     | > 6.6 (-2.0, 15.2)  |
|               |          |                     |                     |
| Other         | 30/23    | 0.2 (-3.8, 4.3)     | 0.2 (-6.8, 7.2)     |
+---------------+----------+---------------------+---------------------+
| \< 65 yrs old | 244/247  | -1.7 (-3.2, -0.2)   | -3.1 (-5.5, -0.8)   |
|               |          |                     |                     |
| 65 yrs old    | 62/56    | -0.6 (-3.5, 2.3)    | -2.7 (-7.9, 2.4)    |
+---------------+----------+---------------------+---------------------+

Reviewer's analysis : candesartan minus losartan C: candesartan L:
losartan

## 2.2 Study 231

The trial design of this study is identical to that of Study 230.

### Efficacy results

A total of 655 patients out of 921 patients screened were randomized.
654 patients has at least

##### 

##### Table 231-1. Disposition of patients entering trial

+----------------------------------+-----------------+-----------------+
|                                  | Candesartan     | Losartan        |
+----------------------------------+-----------------+-----------------+
| Randomized to double-blind       | 332             | 322             |
+----------------------------------+-----------------+-----------------+
| Discontinued                     | 15 (4.5%)       | 20 (6.2%)       |
|                                  |                 |                 |
| Lost to follow-up                | 2 (0.6%)        | 3 (0.9%)        |
|                                  |                 |                 |
| Lack of response                 | 2 (0.6%)        | 5 (1.6%)        |
|                                  |                 |                 |
| Adverse event                    | 6 (1.8%)        | 5 (1.6%)        |
|                                  |                 |                 |
| Consent withdrawal               | 2 (0.6%)        | 3 (0.9%)        |
|                                  |                 |                 |
| Sponsor/Investigator decision    | 3 (0.9%)        | 4 (1.2%)        |
+----------------------------------+-----------------+-----------------+
| Completed study                  | 317 (95.5%)     | 302 (93.8%)     |
+----------------------------------+-----------------+-----------------+

Sponsor's results confirmed by reviewer's analysis

one post-baseline site contact. These patients constituted the
intent-to-treat population. Of these patients, 4.5% patients in the
candesartan group and 6.2% patients in the losartan group discontinued
treatment during the double-blind portion of the study. The distribution
of patients discontinuing treatment by reason was similar in the two
treatment groups (Table 231-1).

The two treatment groups appeared to be comparable with respect to
baseline characteristics (Sponsor's Table 4 of study report for Study
231) and treatment compliance (Sponsor's Table 14.1.1.05,14.1.1.06,
14.1.1.03). The mean age was 54 years and the average duration of
hypertension was 9 years. Fifty eight percent of patients were male and
17 percent were blacks. The mean sitting DBP/SBP was 100/152 mm Hg.

#### Treatment differences in BP at last visit

The primary efficacy variable, change from baseline to double-blind week
8 in trough sitting DBP, showed a significantly greater reduction with
candesartan (Table 231-2).

##### Table 231-2. Least square mean change from baseline to double-blind week 8 (ITT population)

+-------------------+----------+----------+------------------+--------+
|                   | Can      | Losartan | Difference#      | p      |
|                   | desartan |          |                  | -value |
|                   |          | (N=322)  | (95% CI)         |        |
|                   | (N=332)  |          |                  |        |
+-------------------+----------+----------+------------------+--------+
| Trough BP         | N=332    | N=322    |                  |        |
+-------------------+----------+----------+------------------+--------+
| sitting DBP\*     | -10.9    | -8.7     | -2.2 (-3.4,      | 0.0005 |
|                   |          |          | -1.0)            |        |
+-------------------+----------+----------+------------------+--------+
| sitting SBP       | -13.3    | -9.8     | -3.5 (-5.5,      | 0.0007 |
|                   |          |          | -1.5)            |        |
+-------------------+----------+----------+------------------+--------+
| Peak BP           | N=312    | N=294    |                  |        |
+-------------------+----------+----------+------------------+--------+
| sitting DBP       | -11.6    | -10.1    | -1.5 (-2.9,      | 0.038  |
|                   |          |          | -0.1)            |        |
+-------------------+----------+----------+------------------+--------+
| sitting SBP       | -15.2    | -12.6    | -2.6 (-4.8,      | 0.017  |
|                   |          |          | -0.5)            |        |
+-------------------+----------+----------+------------------+--------+

Sponsor's results confirmed by reviewer's analysis

\* primary endpoint #difference: candesartan minus losartan

#### Blood pressures over time

Blood pressures seemed to trend favorably to candesartan over time
(Table 230-3). The favorable difference in blood pressures seemed to
remain at 48 hours after the last dose. Two weeks after the last dose,
the mean blood pressures were similar between the two treatment groups.
As in Study 230, In both treatment groups, blood pressures were greatly
reduced in the first two weeks and then seemed to stabilize afterwards.

##### Table 231-3. Mean trough sitting blood pressures over time

+---------+-----+-------+------+-------+-----+-------+------+------+
|         | Tro |       |      |       | Tro |       |      |      |
|         | ugh |       |      |       | ugh |       |      |      |
|         | s   |       |      |       | s   |       |      |      |
|         | itt |       |      |       | itt |       |      |      |
|         | ing |       |      |       | ing |       |      |      |
|         | DBP |       |      |       | SBP |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
|         | Ca  |       | Losa |       | Ca  |       | Losa |      |
|         | nde |       | rtan |       | nde |       | rtan |      |
|         | sar |       |      |       | sar |       |      |      |
|         | tan |       |      |       | tan |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
|         | N   | Mean  | N    | Mean  | N   | Mean  | N    | Mean |
+---------+-----+-------+------+-------+-----+-------+------+------+
| B       | 332 | 100.1 | 322  | 99.9  | 332 | 152.6 | 322  | 1    |
| aseline |     |       |      |       |     |       |      | 52.0 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DB Wk1  | 332 | 92.5  | 319  | 93.3  | 332 | 142.8 | 319  | 1    |
|         |     |       |      |       |     |       |      | 44.2 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK2   | 330 | 91.7  | 319  | 93.0  | 330 | 141.2 | 319  | 1    |
|         |     |       |      |       |     |       |      | 43.2 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK4   | 328 | 89.0  | 317  | 90.3  | 328 | 139.2 | 317  | 1    |
|         |     |       |      |       |     |       |      | 41.1 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK8   | 321 | 89.1  | 306  | 90.7  | 321 | 138.9 | 306  | 1    |
|         |     |       |      |       |     |       |      | 41.7 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK8   | 332 | 89.2  | 322  | 91.2  | 332 | 139.2 | 322  | 1    |
|         |     |       |      |       |     |       |      | 42.3 |
| (LOCF)  |     |       |      |       |     |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
| 48hr FU | 298 | 90.6  | 280  | 93.9  | 298 | 141.6 | 280  | 1    |
|         |     |       |      |       |     |       |      | 46.7 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| WK2 FU  | 318 | 88.6  | 308  | 88.5  | 318 | 138.2 | 308  | 1    |
|         |     |       |      |       |     |       |      | 39.4 |
+---------+-----+-------+------+-------+-----+-------+------+------+

Sponsor's results confirmed by reviewer's analysis

#### Subgroup results

In this study, candesartan had a favorable trend in gender, race and age
subgroups (Table 231-4).

##### Table 231-4. Mean difference () and 95% CI in BPs by subgroups

+---------------+----------+---------------------+---------------------+
|               | N        | Trough sitting DBP  | Trough sitting SBP  |
+---------------+----------+---------------------+---------------------+
|               | C / L    | (95% CI)            | (95% CI)            |
+---------------+----------+---------------------+---------------------+
| Male          | 192/188  | -2.3 (-3.8, -0.8)   | -3.6 (-6.0, -1.1)   |
|               |          |                     |                     |
| Female        | 140/134  | -2.0 (-3.9, -0.0)   | -3.6 (-7.0, -0.3)   |
+---------------+----------+---------------------+---------------------+
| Caucasian     | 246/236  | -2.2 (-3.6, -0.8)   | -3.7 (-6.1, -1.4)   |
|               |          |                     |                     |
| Black         | 59/54    | -1.7 (-4.6, 1.2)    | -4.0 (-8.6, 0.7)    |
|               |          |                     |                     |
| Asian         | 3/4      | -7.4 (-17.4, 2.6)   | > 1.3 (-21.8, 24.3) |
|               |          |                     |                     |
| Other         | 24/28    | -2.9 (-6.9, 1.2)    | -3.0 (-8.8, 2.7)    |
+---------------+----------+---------------------+---------------------+
| \< 65 yrs old | 278/273  | -1.9 (-3.3, -0.6)   | -3.5 (-5.7, -1.3)   |
|               |          |                     |                     |
| 65 yrs old    | 54/49    | -3.5 (-6.3, -0.6)   | -4.1 (-8.7, 0.5)    |
+---------------+----------+---------------------+---------------------+

Reviewer's analysis : candesartan minus losartan C: candesartan L:
losartan

## 2.3 Study 175

This was a multicenter, double-blind, randomized, parallel-group,
optional-titration (titration-to-effect) study to evaluate the
anti-hypertensive efficacy of candesartan 16 mg titrated to 32 mg in
comparison to losaran 50 mg titrated to 100 mg in the patients with
mild-to-moderate essential hypertension (sitting DBP of 95 mm Hg to 114
mm Hg inclusive). Patients with a mean of sitting DBP 90 mm Hg after 4
weeks of treatment were up-titrated to candesartan 32 mg or losartan 100
mg for the remaining 4 weeks of the study. Patients with a mean of
sitting DBP \< 90 mm Hg after 4 weeks of treatment continued on
candesartan 16 mg or losartan 50 mg. All treatments were given once
daily.

Following a 4 to 5 week placebo run-in period, qualified study patients
were randomized in 1:1 ratio to candesartan 16 mg or losartan 50 mg.
After four weeks of randomized treatment, all patients either continued
on the same dose or up-titrated according to the criterion described
above for an additional 4 weeks. Patients were also seen 2 weeks after
they discontinued therapy with the study medication for follow-up
visits.

The primary efficacy measure was the mean change in trough sitting DBP
from baseline to the double-blind week 8 visit. Secondary measures
include sitting systolic pressures and peak blood pressures, standing
blood pressures, and proportion of responders and controlled patients
based on trough sitting DBP and SBP at week 8. The primary analysis is
based on ITT principle and the last value carried forward strategy for
incompleters.

The sample size of 330 patients to be enrolled from 45 investigative
sites was planned to detect a difference in mean change from baseline in
trough sitting DBP of 3.0 mm Hg between the two treatment groups at
2-sided alpha level of 0.05 and power of 95%, assuming a standard
deviation of 7.5 mm Hg.

### Efficacy results

A total of 332 patients out of 460 patients screened were randomized at
40 sites. 329 patients has at least one post-baseline site contact.
These patients constituted the intent-to-treat population. Of these
patients, 4.3% patients in the candesartan group and 9.4% patients in
the losartan group discontinued treatment during the double-blind
portion of the study. The distribution of patients discontinuing
treatment by reason was summarized (Table 175-1). The losartan group
appeared to have more discontinuations due to lack of response or
adverse event.

##### Table 175-1. Disposition of patients entering trial

+----------------------------------+-----------------+-----------------+
|                                  | Candesartan     | Losartan        |
+----------------------------------+-----------------+-----------------+
| Randomized to double-blind       | 162             | 170             |
+----------------------------------+-----------------+-----------------+
| Discontinued                     | 7 (4.3%)        | 16 (9.4%)       |
|                                  |                 |                 |
| Lost to follow-up                | 2 (1.2%)        | 2 (1.2%)        |
|                                  |                 |                 |
| Lack of response                 | 1 (0.6%)        | 5 (2.9%)        |
|                                  |                 |                 |
| Adverse event                    | 2 (1.2%)        | 6 (3.5%)        |
|                                  |                 |                 |
| Consent withdrawal               | 2 (1.2%)        | 3 (1.8%)        |
+----------------------------------+-----------------+-----------------+
| Completed study                  | 155 (95.7%)     | 154 (90.6%)     |
+----------------------------------+-----------------+-----------------+

Sponsor's results confirmed by reviewer's analysis

The two treatment groups appeared to be comparable with respect to
baseline characteristics (Sponsor's Table 4 of study report for Study
175) and treatment compliance (Sponsor's Table 10.1.1.05,10.1.1.06,
10.1.1.03). The mean age was 55 years and the average duration of
hypertension was 9+ years. Fifty eight percent of the patients were male
and 12% blacks. The mean sitting DBP/SBP was 100/154 mm Hg.

#### Treatment differences in BP at last visit

The primary efficacy variable, change from baseline to double-blind week
8 in trough sitting DBP, showed a significantly greater reduction with
candesartan (Table 175-2). Other blood pressures showed a numerically
trend in favor of candesartan but only the reduction in peak sitting DBP
showed a statistically significant treatment difference.

##### Table 175-2. Least square mean change from baseline to double-blind week 8 (ITT population)

+-------------------+----------+----------+------------------+--------+
|                   | Can      | Losartan | Difference#      | p      |
|                   | desartan |          |                  | -value |
|                   |          | (N=169)  | (95% CI)         |        |
|                   | (N=160)  |          |                  |        |
+-------------------+----------+----------+------------------+--------+
| Trough BP         | N=160    | N=169    |                  |        |
+-------------------+----------+----------+------------------+--------+
| sitting DBP\*     | -11.0    | -8.9     | -2.2 (-3.9,      | 0.016  |
|                   |          |          | -0.4)            |        |
+-------------------+----------+----------+------------------+--------+
| sitting SBP       | -11.9    | -10.0    | -1.9 (-5.0, 1.3) | 0.25   |
+-------------------+----------+----------+------------------+--------+
| Standing DBP      | -9.3     | -7.9     | -1.3 (-3.2, 0.5) | 0.15   |
+-------------------+----------+----------+------------------+--------+
| Standing SBP      | -10.5    | -9.4     | -1.1 (-4.5, 2.2) | 0.51   |
+-------------------+----------+----------+------------------+--------+
| Peak BP           | N=143    | N=147    |                  |        |
+-------------------+----------+----------+------------------+--------+
| sitting DBP       | -12.6    | -9.6     | -2.9 (-5.0,      | 0.005  |
|                   |          |          | -0.9)            |        |
+-------------------+----------+----------+------------------+--------+
| sitting SBP       | -16.5    | -14.4    | -2.0 (-5.4, 1.3) | 0.24   |
+-------------------+----------+----------+------------------+--------+
| Standing DBP      | -11.5    | -9.4     | -2.2 (-4.2,      | 0.038  |
|                   |          |          | -0.1)            |        |
+-------------------+----------+----------+------------------+--------+
| Standing SBP      | -15.2    | -13.7    | -1.5 (-4.8, 1.8) | 0.38   |
+-------------------+----------+----------+------------------+--------+

Sponsor's results confirmed by the reviewer's analysis

\* primary endpoint #difference: candesartan minus losartan

#### Blood pressures over time

Blood pressures seemed to trend favorably to candesartan over time
(Table 175-3). This pattern was observed in the patients who did not
have their doses up titrated and who had (Table 175-4).

Two weeks after the last dose, the mean blood pressures were similar
between the two treatment

##### 

##### Table 175-3. Mean trough sitting blood pressures over time

+---------+-----+-------+------+-------+-----+-------+------+------+
|         | Tro |       |      |       | Tro |       |      |      |
|         | ugh |       |      |       | ugh |       |      |      |
|         | s   |       |      |       | s   |       |      |      |
|         | itt |       |      |       | itt |       |      |      |
|         | ing |       |      |       | ing |       |      |      |
|         | DBP |       |      |       | SBP |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
|         | Ca  |       | Losa |       | Ca  |       | Losa |      |
|         | nde |       | rtan |       | nde |       | rtan |      |
|         | sar |       |      |       | sar |       |      |      |
|         | tan |       |      |       | tan |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
|         | N   | Mean  | N    | Mean  | N   | Mean  | N    | Mean |
+---------+-----+-------+------+-------+-----+-------+------+------+
| B       | 160 | 100.3 | 169  | 100.5 | 160 | 152.9 | 169  | 1    |
| aseline |     |       |      |       |     |       |      | 54.1 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DB Wk2  | 160 | 91.5  | 168  | 93.5  | 160 | 142.1 | 168  | 1    |
|         |     |       |      |       |     |       |      | 46.1 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK4   | 157 | 90.8  | 165  | 92.0  | 157 | 141.3 | 165  | 1    |
|         |     |       |      |       |     |       |      | 44.9 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK6   | 157 | 88.0  | 161  | 90.0  | 157 | 139.3 | 161  | 1    |
|         |     |       |      |       |     |       |      | 41.6 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK8   | 155 | 89.2  | 157  | 90.9  | 155 | 140.3 | 157  | 1    |
|         |     |       |      |       |     |       |      | 43.2 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK8   | 160 | 89.3  | 169  | 91.5  | 160 | 140.7 | 169  | 1    |
|         |     |       |      |       |     |       |      | 43.9 |
| (LOCF)  |     |       |      |       |     |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
| WK2 FU  | 158 | 88.9  | 165  | 89.0  | 158 | 140.3 | 165  | 1    |
|         |     |       |      |       |     |       |      | 40.5 |
+---------+-----+-------+------+-------+-----+-------+------+------+

Sponsor's results confirmed by the reviewer's analysis

##### Table 175-4. Mean trough sitting DBP over DB visits

+---------+-----+-------+------+-------+-----+-------+------+------+
|         | Not |       |      |       | Up  |       |      |      |
|         | up  |       |      |       | -ti |       |      |      |
|         | -ti |       |      |       | tra |       |      |      |
|         | tra |       |      |       | ted |       |      |      |
|         | ted |       |      |       | gr  |       |      |      |
|         | gr  |       |      |       | oup |       |      |      |
|         | oup |       |      |       |     |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
|         | Ca  |       | Losa |       | Ca  |       | Losa |      |
|         | nde |       | rtan |       | nde |       | rtan |      |
|         | sar |       |      |       | sar |       |      |      |
|         | tan |       |      |       | tan |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+
|         | N   | Mean  | N    | Mean  | N   | Mean  | N    | Mean |
+---------+-----+-------+------+-------+-----+-------+------+------+
| B       | 75  | 98.4  | 74   | 99.1  | 85  | 102.1 | 95   | 1    |
| aseline |     |       |      |       |     |       |      | 01.6 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DB Wk2  | 75  | 87.0  | 73   | 89.7  | 85  | 95.5  | 95   | 96.4 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK4   | 72  | 83.9  | 70   | 84.2  | 85  | 96.8  | 95   | 97.7 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK6   | 73  | 84.1  | 66   | 84.4  | 84  | 91.5  | 95   | 93.8 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK8   | 71  | 85.6  | 64   | 86.2  | 84  | 92.3  | 93   | 94.2 |
+---------+-----+-------+------+-------+-----+-------+------+------+
| DBWK8   | 75  | 85.8  | 74   | 87.8  | 85  | 92.4  | 95   | 94.4 |
|         |     |       |      |       |     |       |      |      |
| (LOCF)  |     |       |      |       |     |       |      |      |
+---------+-----+-------+------+-------+-----+-------+------+------+

Sponsor's results confirmed by the reviewer's analysis

groups. Standing blood pressures showed a similar pattern (Sponsor's
Tables 10.2.4.02, 10.2.4.05). Also, the mean blood pressures in both
treatment groups were greatly reduced in the first two weeks and then
seemed to stabilize afterwards.

#### Subgroup results

In this study, candesartan had a favorable trend in gender, race and age
subgroups (Table 175-4), except in small subgroups.

##### Table 175-5. Mean difference () and 95% CI in BPs by subgroups

+---------------+----------+---------------------+---------------------+
|               | N        | Trough sitting DBP  | Trough sitting SBP  |
+---------------+----------+---------------------+---------------------+
|               | C / L    | (95% CI)            | (95% CI)            |
+---------------+----------+---------------------+---------------------+
| Male          | 90/99    | -3.0 (-5.4, -0.6)   | -2.6 (-6.0, -1.1)   |
|               |          |                     |                     |
| Female        | 70/0     | -0.9 (-3.2, 1.5)    | -1.2 (-7.0, -0.3)   |
+---------------+----------+---------------------+---------------------+
| Caucasian     | 127/131  | -2.5 (-4.3, -0.7)   | -2.3 (-5.5, 0.9)    |
|               |          |                     |                     |
| Black         | 18/22    | -0.1 (-6.0, 5.9)    | 1.3 (-8.6, 11.5)    |
|               |          |                     |                     |
| Asian         | 7/3      | 3.0 (-2.8, 8.7)     | > 1.5 (-21.8, 18.6) |
|               |          |                     |                     |
| Other         | 8/13     | 2.2 (-4.6, 8.9)     | 0.2 (-8.8, 12.3)    |
+---------------+----------+---------------------+---------------------+
| \< 65 yrs old | 137/133  | -2.6 (-4.4, -0.8)   | -1.8 (-5.7, 1.4)    |
|               |          |                     |                     |
| 65 yrs old    | 23/36    | -0.3 (-4.9, 4.2)    | -2.6 (-8.7, 4.8)    |
+---------------+----------+---------------------+---------------------+

Reviewer's analysis : candesartan minus losartan C: candesartan L:
losartan

Age = (date of randomization -- date of birth)/365

# 3. CONCLUSIONS

Two CLAIM studies showed that the candesartan 16 mg to 32 mg regimen
gave a statistically significantly greater reduction in blood pressures
than the losartan 50 mg to 100 mg regimen when given via
force-titration. The difference was 1 to 2.2 mm Hg in trough sitting DBP
and about 3.5 mm Hg in trough sitting SBP. The CANDLE study showed that
when given by optional titration, the candesartan regimen also gave a
statistically significantly greater reduction in trough sitting
diastolic blood pressure. The difference was 2.2 mm Hg in trough sitting
DBP. The difference in trough sitting SBP was \< 2 mm Hg, not
statistically significant. Over the course of each study, the
candesartan group appeared to have lower mean blood pressures than the
losartan group. In all the studies, the mean blood pressures in both
treatment groups were greatly reduced in the first two weeks and then
seemed to stabilize afterwards.