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 *

1. INTRODUCTION *

2. OVERVIEW OF THREE CLINICAL TRIALS *

2.1 Study 230 *

Efficacy results *

Table 230-1. Disposition of patients entering trial *

Treatment differences in BP at last visit *

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

Blood pressures over time *

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

Subgroup results *

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

2.2 Study 231 *

Efficacy results *

Table 231-1. Disposition of patients entering trial *

Treatment differences in BP at last visit *

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

Blood pressures over time *

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

Subgroup results *

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

2.3 Study 175 *

Efficacy results *

Table 175-1. Disposition of patients entering trial *

Treatment differences in BP at last visit *

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

Blood pressures over time *

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

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

Subgroup results *

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

3. 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*

Lost to follow-up

Lack of response

Adverse event

Consent withdrawal

Sponsor/Investigator decision

37 (12.1%)

5 (1.6%)

8 (2.6%)

9 (2.9%)

10 (3.3%)

5 (1.6%)

37 (12.2%)

4 (1.3%)

13 (4.3%)

6 (2.0%)

8 (2.6%)

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)

 

Candesartan

(N=306)

Losartan

(N=303)

Difference#

(95% CI)

p-value

Trough BP

N=306

N=303

   

sitting DBP*

-10.5

-9.1

-1.5 (-2.9, -0.06)

0.041

sitting SBP

-13.4

-10.1

-3.4 (-5.7, -1.0)

0.005

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, -1.2)

0.0032

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

Trough sitting DBP

Trough sitting SBP

Candesartan

Losartan

Candesartan

Losartan

 

N

Mean

N

Mean

N

Mean

N

Mean

Baseline

307

100.4

303

100.2

307

153.6

303

152.2

DB Wk1

304

93.1

302

93.2

304

144.0

302

143.9

DBWK2

300

91.4

297

92.5

300

141.1

297

142.2

DBWK4

292

89.5

292

90.4

292

139.0

292

140.4

DBWK8

284

89.8

280

90.9

284

139.6

280

141.2

DBWK8

(LOCF)

306

90.2

303

91.5

306

140.4

303

142.2

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

141.1

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 (D ) and 95% CI of BPs by subgroups

 

N

Trough sitting DBP

Trough sitting SBP

 

C / L

D (95% CI)

D (95% CI)

Male

Female

178/178

128/125

-1.6 (-3.4, 0.2)

-1.2 (-3.1, 0.7)

-3.0 (-5.7, -0.3)

-3.0 (-6.5, 0.4)

Caucasian

Black

Asian

Other

211/213

61/59

4/8

30/23

-2.6 (-4.1, -1.0)

1.3 (-1.6, 4.3)

0 (-9.1, 9.1)

0.2 (-3.8, 4.3)

-4.1 (-6.5, -1.6)

-1.4 (-6.9, 4.1)

6.6 (-2.0, 15.2)

0.2 (-6.8, 7.2)

< 65 yrs old

³ 65 yrs old

244/247

62/56

-1.7 (-3.2, -0.2)

-0.6 (-3.5, 2.3)

-3.1 (-5.5, -0.8)

-2.7 (-7.9, 2.4)

Reviewer’s analysis D : 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

Lost to follow-up

Lack of response

Adverse event

Consent withdrawal

Sponsor/Investigator decision

15 (4.5%)

2 (0.6%)

2 (0.6%)

6 (1.8%)

2 (0.6%)

3 (0.9%)

20 (6.2%)

3 (0.9%)

5 (1.6%)

5 (1.6%)

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)

 

Candesartan

(N=332)

Losartan

(N=322)

Difference#

(95% CI)

p-value

Trough BP

N=332

N=322

   

sitting DBP*

-10.9

-8.7

-2.2 (-3.4, -1.0)

0.0005

sitting SBP

-13.3

-9.8

-3.5 (-5.5, -1.5)

0.0007

Peak BP

N=312

N=294

   

sitting DBP

-11.6

-10.1

-1.5 (-2.9, -0.1)

0.038

sitting SBP

-15.2

-12.6

-2.6 (-4.8, -0.5)

0.017

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

Trough sitting DBP

Trough sitting SBP

Candesartan

Losartan

Candesartan

Losartan

 

N

Mean

N

Mean

N

Mean

N

Mean

Baseline

332

100.1

322

99.9

332

152.6

322

152.0

DB Wk1

332

92.5

319

93.3

332

142.8

319

144.2

DBWK2

330

91.7

319

93.0

330

141.2

319

143.2

DBWK4

328

89.0

317

90.3

328

139.2

317

141.1

DBWK8

321

89.1

306

90.7

321

138.9

306

141.7

DBWK8

(LOCF)

332

89.2

322

91.2

332

139.2

322

142.3

48hr FU

298

90.6

280

93.9

298

141.6

280

146.7

WK2 FU

318

88.6

308

88.5

318

138.2

308

139.4

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 (D ) and 95% CI in BPs by subgroups

 

N

Trough sitting DBP

Trough sitting SBP

 

C / L

D (95% CI)

D (95% CI)

Male

Female

192/188

140/134

-2.3 (-3.8, -0.8)

-2.0 (-3.9, -0.0)

-3.6 (-6.0, -1.1)

-3.6 (-7.0, -0.3)

Caucasian

Black

Asian

Other

246/236

59/54

3/4

24/28

-2.2 (-3.6, -0.8)

-1.7 (-4.6, 1.2)

-7.4 (-17.4, 2.6)

-2.9 (-6.9, 1.2)

-3.7 (-6.1, -1.4)

-4.0 (-8.6, 0.7)

1.3 (-21.8, 24.3)

-3.0 (-8.8, 2.7)

< 65 yrs old

³ 65 yrs old

278/273

54/49

-1.9 (-3.3, -0.6)

-3.5 (-6.3, -0.6)

-3.5 (-5.7, -1.3)

-4.1 (-8.7, 0.5)

Reviewer’s analysis D : 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 ³ 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

Lost to follow-up

Lack of response

Adverse event

Consent withdrawal

7 (4.3%)

2 (1.2%)

1 (0.6%)

2 (1.2%)

2 (1.2%)

16 (9.4%)

2 (1.2%)

5 (2.9%)

6 (3.5%)

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)

 

Candesartan

(N=160)

Losartan

(N=169)

Difference#

(95% CI)

p-value

Trough BP

N=160

N=169

   

sitting DBP*

-11.0

-8.9

-2.2 (-3.9, -0.4)

0.016

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, -0.9)

0.005

sitting SBP

-16.5

-14.4

-2.0 (-5.4, 1.3)

0.24

Standing DBP

-11.5

-9.4

-2.2 (-4.2, -0.1)

0.038

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

Trough sitting DBP

Trough sitting SBP

Candesartan

Losartan

Candesartan

Losartan

 

N

Mean

N

Mean

N

Mean

N

Mean

Baseline

160

100.3

169

100.5

160

152.9

169

154.1

DB Wk2

160

91.5

168

93.5

160

142.1

168

146.1

DBWK4

157

90.8

165

92.0

157

141.3

165

144.9

DBWK6

157

88.0

161

90.0

157

139.3

161

141.6

DBWK8

155

89.2

157

90.9

155

140.3

157

143.2

DBWK8

(LOCF)

160

89.3

169

91.5

160

140.7

169

143.9

WK2 FU

158

88.9

165

89.0

158

140.3

165

140.5

Sponsor’s results confirmed by the reviewer’s analysis

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

Not up-titrated group

Up-titrated group

Candesartan

Losartan

Candesartan

Losartan

 

N

Mean

N

Mean

N

Mean

N

Mean

Baseline

75

98.4

74

99.1

85

102.1

95

101.6

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

(LOCF)

75

85.8

74

87.8

85

92.4

95

94.4

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 (D ) and 95% CI in BPs by subgroups

 

N

Trough sitting DBP

Trough sitting SBP

 

C / L

D (95% CI)

D (95% CI)

Male

Female

90/99

70/0

-3.0 (-5.4, -0.6)

-0.9 (-3.2, 1.5)

-2.6 (-6.0, -1.1)

-1.2 (-7.0, -0.3)

Caucasian

Black

Asian

Other

127/131

18/22

7/3

8/13

-2.5 (-4.3, -0.7)

-0.1 (-6.0, 5.9)

3.0 (-2.8, 8.7)

2.2 (-4.6, 8.9)

-2.3 (-5.5, 0.9)

1.3 (-8.6, 11.5)

1.5 (-21.8, 18.6)

0.2 (-8.8, 12.3)

< 65 yrs old

³ 65 yrs old

137/133

23/36

-2.6 (-4.4, -0.8)

-0.3 (-4.9, 4.2)

-1.8 (-5.7, 1.4)

-2.6 (-8.7, 4.8)

Reviewer’s analysis D : 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.