**[Statistical Review and Evaluation]{.underline}**

**NDA #:** 20-757

**Applicant:** Sanofi-Synthelabo

**Name of Drug:** Irbesartan

**Indication:** Treatment of renal disease

**Document reviewed:** Electronic submission

**Date of submission:** August 3, 2001

**Statistical Reviewer:** John Lawrence, Ph.D. (HFD--710)

**Medical Reviewer:** Juan-Carlos Pelayo, M.D. (HFD--110)

**[1 Introduction]{.underline}**

This is a review of Studies CV131-048 (The Collaborative Study Group
Trial: the Effects of Irbesartan on Morbidity and Mortality in
Hypertensive Patients with Type II Diabetes and Diabetic Nephropathy)
and EFC2481 (IRbesartan MicroAlbuminuria in type 2 diabetes). These were
the main studies conducted in support of this application.

**[2.1 Study Design]{.underline}**

1715 hypertensive patients (SeSBP \> 135 mmHg and/or SeDBP \> 85 mmHg in
an untreated patient, or receiving antihypertensive medication) with
type 2 diabetes mellitus and overt nephropathy (urine protein excretion
\> 900 mg/24 hours) were randomized into one of three treatment groups-
once daily administration of placebo, irbesartan, or the active control
amlodipine. Patients in the irbesartan group were initially given 75 mg,
and were force-titrated up to 150 mg at week 2, and up to the final dose
of 300 mg at week 4. Patients in the amlodipine group were initially
given 2.5 mg, and were force-titrated up to 5 mg at week 2, and up to
the final dose of 10 mg at week 4. Additional antihypertensive agents
were encouraged to attain equal degrees of blood pressure reduction
within all treatment groups. Downward titration was permitted per
protocol at the discretion of the Investigator. The demographic
characteristics of the patients in each group appear in Table 2.1.1.
There do not appear to be any major differences in the baseline
characteristics of the three groups. There was expected to be an
enrollment period of approximately 2 years and the study was expected to
end 2 years after the last patient was recruited.

**Table 2.1.1** Characteristics of the patients in the two groups at
baseline. For continuous variables, this table shows the group mean
standard deviation. \[*Reviewer's analysis*\]

+--------------------------+-------------+-------------+---------------+
| # Characteristic         | **I         | **A         | **Placebo**   |
|                          | rbesartan** | mlodipine** |               |
+--------------------------+-------------+-------------+---------------+
| N                        | 577         | 559         | 563           |
+--------------------------+-------------+-------------+---------------+
| Age (years)              | 59 7        | 58 8        | 59 8          |
+--------------------------+-------------+-------------+---------------+
| Gender (Male/Female)     | 376/ 201    | 356/ 203    | 401/ 162      |
+--------------------------+-------------+-------------+---------------+
| Race                     | 436/ 63/ 78 | 384/ 84/ 91 | 411/ 77/ 75   |
| (Caucasian/Black/Other)  |             |             |               |
+--------------------------+-------------+-------------+---------------+
| Baseline SeDBP           | 87 11       | 87 11       | 87 11         |
+--------------------------+-------------+-------------+---------------+
| Baseline SeSBP           | 160 20      | 159 19      | 158 21        |
+--------------------------+-------------+-------------+---------------+
| Log of baseline urinary  | 8.0 0.8     | 8.0 0.8     | 8.0 0.8       |
| protein excretion rate   |             |             |               |
+--------------------------+-------------+-------------+---------------+

**[2.2 Planned Statistical Analysis]{.underline}**

The primary endpoint was the time to the first occurrence of doubling of
serum creatinine, end-stage renal disease (ESRD), or all cause
mortality. ESRD was defined by renal transplantation, need for dialysis,
or serum creatinine 6 mg/dL. The primary analysis used the logrank test
to compare the distribution of the time to the composite event in the
irbesartan group versus the placebo group. The comparison of the
irbesartan group to the active control amlodipine was a secondary
analysis and therefore, no adjustment for multiplicity was used for
these two comparisons.

There were four interim analyses. The actual number and timing of these
interim analyses were not specified in advance. The stopping boundaries
were defined using the Lan-DeMets alpha-spending function of the
O'Brien-Fleming type. The information times of the interim analyses and
the nominal critical values appear in Table 2.2.1. This reviewer used
the Lan-DeMets software from the University of Wisconsin and found close
agreement between the limits that were used by the sponsor and the
limits that were found by this reviewer.

**Table 2.2.1** Nominal critical values and information times of interim
analyses. \[*Source: Appendix 6 of Study Report and confirmed by
reviewer*\]

  ---------------- ---------------- --------------------- ----------------
  **Interim        **Information    **Nominal critical    **Nominal
  Analysis**       Time**           value**               alpha**

  1                6.76%            7.5326                \< 0.0001

  2                15.37%           5.0071                \< 0.0001

  3                33.81%           3.4047                0.0007

  4                50.97%           2.775                 0.0055

  Final            100%             1.98                  0.0477
  ---------------- ---------------- --------------------- ----------------

There was one pre-specified secondary cardiovascular composite endpoint
(cardiovascular death, nonfatal myocardial infarction, hospitalization
for heart failure, permanent neurological deficit attributed to stroke,
or above-the-ankle amputation). The three pre-specified secondary
analyses were: comparison of irbesartan to placebo on this secondary
endpoint and the comparison of irbesartan to amlodipine on both the
primary and secondary endpoints.

**[2.3 Results]{.underline}**

A total of eight patients were lost to follow-up out of the 1715
patients enrolled. Sixteen patients in the study were not randomized but
were included as part of the treatment group corresponding to the
treatment they actually were given (2 in the irbesartan group, 8 in the
amlodipine group, and 6 in the placebo group). 19 patients in the
irbesartan group and 11 patients in the placebo group discontinued
treatment and/or regularly scheduled office visits. However, many of
these patients (6 in irbesartan, 2 in placebo) were counted in the
analysis as having a primary event. Since these are relatively small
numbers, these issues are not likely to cause as much concern in this
study as they would in other studies. Table 2.3.1 shows the number of
events in each of the three arms for the composite endpoint and each of
its components. The Kaplan-Meier curves appear in Figure 2.3.1.

**Table 2.3.1** Number of events in each arm, point estimates of
relative risk, 95% confidence interval for relative risk of event in
irbesartan group relative to placebo. \[*Source: Tables 10.1.1.A and B
of Study Report and confirmed by reviewer*\]. The components are
tabulated in two ways: first by the definition of the primary endpoint
(i.e. counting only the first event for each patient) and second by the
number of patients that had the event at any time during the study.

+-------------------+----------+-------+----------+-------------------+
|                   | **Amlo   | *     | **Irbe   | **RR / 95%CI/     |
|                   | dipine** | *Plac | sartan** | p-value**         |
|                   |          | ebo** |          |                   |
|                   |          |       |          | **Irb vs. Pbo**   |
+-------------------+----------+-------+----------+-------------------+
| N                 | 567      | 569   | 579      |                   |
+-------------------+----------+-------+----------+-------------------+
| Primary Endpoint  | 233      | 222   | 189      | 0.80/(0.66,       |
|                   |          |       |          | 0.97)/            |
| (death, ESRD, 2   |          |       |          |                   |
| SC)               |          |       |          | 0.0234            |
+-------------------+----------+-------+----------+-------------------+
| Decomposition of  |          |       |          |                   |
| Events in         |          |       |          |                   |
| Definition of     |          |       |          |                   |
| Primary Endpoint  |          |       |          |                   |
|                   |          |       |          |                   |
| (counting only    |          |       |          |                   |
| first occurrence  |          |       |          |                   |
| of primary event) |          |       |          |                   |
+-------------------+----------+-------+----------+-------------------+
| Death             | 54       | 64    | 64       | 0.94/(0.67,       |
|                   |          |       |          | 1.33)/0.744       |
+-------------------+----------+-------+----------+-------------------+
| ESRD              | 50 ^†^   | 47    | 43 ^†^   | 0.88/(0.58,       |
|                   |          | ^†^   |          | 1.33)/0.542       |
+-------------------+----------+-------+----------+-------------------+
| 2 SC              | 144 ^†^  | 135   | 98 ^†^   | 0.67/(0.52,       |
|                   |          | ^†^   |          | 0.87)/0.003       |
+-------------------+----------+-------+----------+-------------------+
| Summary of All    |          |       |          |                   |
| Events Occurring  |          |       |          |                   |
| at Any Time in    |          |       |          |                   |
| Study             |          |       |          |                   |
+-------------------+----------+-------+----------+-------------------+
| Death             | 83       | 93    | 87       | 0.92/(0.69,       |
|                   |          |       |          | 1.23)/0.568       |
+-------------------+----------+-------+----------+-------------------+
| ESRD              | 104      | 101   | 82       | 0.77/(0.57,       |
|                   |          |       |          | 1.03)/0.073       |
+-------------------+----------+-------+----------+-------------------+
| 2 SC              | 144      | 135   | 98       | 0.67/(0.52,       |
|                   |          |       |          | 0.87)/0.003       |
+-------------------+----------+-------+----------+-------------------+

^†^24 patients in placebo, 16 patients in irbesartan, and 15 patients in
the amlodipine group reached ESRD and doubling of serum creatinine on
the same date and appear in both rows.

![](media/image1.wmf){width="4.320138888888889in"
height="3.3381944444444445in"}**Figure 2.3.1** Kaplan-Meier curves for
estimated event-free survival in three arms.

From the curves in Figure 2.3.1 and the counts of number of events in
Table 2.3.1, it is apparent that the patients in the irbesartan group
had fewer events than the patients in either the placebo arm or the
amlodipine arm. The p-value for the primary analysis (irbesartan versus
placebo on time to the composite endpoint using the logrank test) is
0.0234 \[*Source: Tables 10.1.1.A of Study Report and confirmed by
reviewer*\]. Most of the apparent reduction in relative risk is from the
creatinine component. Note that serum creatinine 6 mg/dL is included in
the definition of ESRD. If one excludes those patients who met the
definition of ESRD because of high serum creatinine, then there are
numerically fewer patients in the placebo group who reached the primary
endpoint due to ESRD (23 patients in the placebo group and 27 patients
in the irbesartan group). Moreover, when the components are analyzed
individually, a significant difference only appears in the serum
creatinine component. Although this composite endpoint was pre-specified
as the primary endpoint, one can argue that the benefit was only shown
on a surrogate endpoint (SC). One patient in the placebo group
progressed to ESRD and was alive at the end of the study, but the date
of the event was unknown. In the sponsor's analysis, this patient was
included in the counts of events, but not included in the logrank
analysis. Since the patient was in the placebo group, this is a
conservative way of handling the missing value and this reviewer would
prefer to use a less conservative approach that adheres to the
intention-to-treat principle, viz. performing an analysis that counts
this patient as having an event at a time that is interval censored. As
a way of checking the robustness of the primary analysis, this reviewer
tried imputing 0, 700, or 1400 days as the time of the event for this
patient. In all three cases, the p-value was even more significant than
the analysis that ignores this patient. Likewise, there were two
patients in the amlodipine group that had a missing date for the time to
ESRD and were not included in the secondary analysis comparing
irbesartan to amlodipine. For those patients had missing serum
creatinine measurements, it is possible to use interval censoring
techniques or a worst case analysis (i.e. assume all patients in the
treatment group had an event and those in the placebo group did not).
However, since there were so few patients (19 in the irbesartan group
and 11 in the placebo group) and many of them had events, it is unlikely
that these alternative analyses will be useful. Moreover, a mixed
effects model showed that the mean rate of change of serum creatinine
was significantly smaller in patients in the irbesartan group relative
to either placebo or amlodipine (p=0.004 and p=0.013 respectively from
Section 10.4.1 of the Study Report). Hence, it is possible that the
missing serum creatinine levels, if missing at random, would bias the
results against the irbesartan treatment.

For the secondary analyses, there was an estimated 23% reduction in risk
on the primary endpoint relative to amlodipine (p=0.0064). Again, this
apparent effect is explained mainly by changes in SC. There was no
significant difference observed on the secondary cardiovascular endpoint
relative to either placebo or amlodipine (p=0.45 and p=0.69
respectively).

**[2.4 Safety]{.underline}**

The ten most common adverse events are listed in Table 2.4.1. There
appears to be a difference in the reports of edema in the amlodipine
group relative to the other two groups. There does not appear to be a
difference between irbesartan and placebo in the number of any specific
adverse event.

## Table 2.4.1 Most common clinical adverse events; number and % of subjects.

+---------------------------+-----------+---------------+-------------+
| **Adverse Event**         | **        | *             | **A         |
|                           | Placebo** | *Irbesartan** | mlodipine** |
|                           |           |               |             |
|                           | ##        | **N = 577**   | **N = 559** |
|                           | # N = 563 |               |             |
+---------------------------+-----------+---------------+-------------+
| Edema                     | 211       | 222 (38.5)    | 337 (60.3)  |
|                           | (37.5)    |               |             |
+---------------------------+-----------+---------------+-------------+
| Musculoskeletal Pain      | 215       | 218 (37.8)    | 193 (34.5)  |
|                           | (38.2)    |               |             |
+---------------------------+-----------+---------------+-------------+
| Upper Respiratory         | 143       | 144 (25.0)    | 136 (24.3)  |
| Infection                 | (25.4)    |               |             |
+---------------------------+-----------+---------------+-------------+
| Dizziness                 | 111       | 143 (24.8)    | 97 (17.4)   |
|                           | (19.7)    |               |             |
+---------------------------+-----------+---------------+-------------+
| Fatigue                   | 147       | 134 (23.2)    | 129 (23.1)  |
|                           | (26.1)    |               |             |
+---------------------------+-----------+---------------+-------------+
| Nausea/Vomiting           | 111       | 112 (19.4)    | 108 (19.3)  |
|                           | (19.7)    |               |             |
+---------------------------+-----------+---------------+-------------+
| Diarrhea                  | 83 (14.7) | 102 (17.7)    | 73 (13.1)   |
+---------------------------+-----------+---------------+-------------+
| Headache                  | 110       | 94 (16.3)     | 72 (12.9)   |
|                           | (19.5)    |               |             |
+---------------------------+-----------+---------------+-------------+
| Cough                     | 84 (14.9) | 84 (14.6)     | 96 (17.2)   |
+---------------------------+-----------+---------------+-------------+
| Abnormality Retina        | 68 (12.1) | 75 (13.0)     | 52 (9.3)    |
+---------------------------+-----------+---------------+-------------+

**[2.5 Results by subgroup]{.underline}**

The confidence intervals for the relative risk for the primary endpoint
appear in Figure 2.5.1. Although the study was not powered to show a
treatment effect in each subgroup, these confidence intervals appear to
show that the possible benefit of irbesartan over placebo is greater in
males than in females and is also greater among the White race than it
is among Non-whites. Moreover, the point estimate for the relative risk
among North American patients in the study is 0.95. This appears to be
larger than the relative risk in other regions. There were 204 North
American patients in the irbesartan group and 197 North American
patients randomized to the placebo group.

![](media/image2.png){width="5.059722222222222in"
height="3.4381944444444446in"}

**Figure 2.5.1** Relative risk by subgroups \[*Source: Figure 10.1.2A of
Study Report*\]

**[3.1 Study Design]{.underline}**

Study EFC2481 was a multinational double-blind study comparing two doses
of irbesartan with placebo. 611 patients with Type 2 diabetes mellitus
and SeSBP\>135 mmHg or SeDBP\>85 mmHg or being treated for hypertension
and evidence of microalbuminuria were randomized. After a 3-week placebo
run-in period, patients randomized to one of the irbesartan groups were
given 75 mg for the first two weeks of the double-blind treatment period
and were titrated up to 150 mg for the next two weeks. Those patients
randomized to the 300 mg dose were then titrated up to the final dose at
week 4. Subjects remained on this dosing regimen until month 24. Table
3.1.1 shows the patient demographics.

**Table 3.1.1** Characteristics of the patients in the two groups at
baseline. For continuous variables, this table shows the group mean
standard deviation. \[*Source: Table 8.3 of Study Report*\]

+-------------------------+-----------------+-----------------+--------+
| # Characteristic        | **Irbesartan    | **Irbesartan    | **Pla  |
|                         | 150 mg**        | 300 mg**        | cebo** |
+-------------------------+-----------------+-----------------+--------+
| N                       | 203             | 201             | 207    |
+-------------------------+-----------------+-----------------+--------+
| Age (years)             | 58 8            | 57 8            | 58 9   |
+-------------------------+-----------------+-----------------+--------+
| Gender (Male/Female)    | 134/ 69         | 140/ 61         | 142/   |
|                         |                 |                 | 65     |
+-------------------------+-----------------+-----------------+--------+
| Race                    | 198/ 2/ 3       | 194/ 0/ 7       | 203/   |
| (Caucasian/Black/Other) |                 |                 | 0/ 4   |
+-------------------------+-----------------+-----------------+--------+
| Baseline SeDBP          | 90 9            | 91 10           | 90 9   |
+-------------------------+-----------------+-----------------+--------+
| Baseline SeSBP          | 153 14          | 153 14          | 153 15 |
+-------------------------+-----------------+-----------------+--------+

**[3.2 Planned Statistical Analysis]{.underline}**

The primary endpoint was the time to occurrence of clinical proteinuria
(defined as albuminiria excretion rate greater than 200 g/min and an
increase of 30% from baseline at two consecutive evaluations). Each
active treatment group was compared to placebo using the two-sided
logrank test with a Bonferroni adjustment so that each comparison was
done with a nominal alpha of 0.025. The primary analysis was on the
per-protocol population. Only patients who met all inclusion criteria
and who stayed on double-blind therapy for at least 3 months were
included in the per-protocol population. Also, all patients from site
1004 were removed from the per-protocol population due to significant
lack of compliance. No efficacy interim analyses were planned.

The pre-specified secondary objectives were to evaluate the changes from
baseline in overnight urinary albumin excretion rate, estimated
creatinine clearance, von Willebrand factor, fibrogen, factor VII,
plasminogen activator inhibitor-I, and lipid profile.

**[3.3 Results]{.underline}**

The number of events in each subgroup, as well as the p-value from the
logrank test appears in Table 3.3.1. There is a statistically
significant difference between the 300 mg group and placebo (p=0.0013)
and the 150 mg group showed a numerical trend toward longer
proteinuria-free survival, but did not reach statistical significance
(p=0.096). The analysis on the intent-to-treat population gives similar
results (p=0.0004 for the high dose vs. placebo and p=0.085 for the
low-dose vs. placebo). The Kaplan-Meier curves for the estimated
probability of remaining proteinuria-free appear in Figure 3.3.1.

**Table 3.3.1** Number of events in each arm. \[*Source: Tables 10.1.1.1
of Study Report and confirmed by reviewer*\]

+--------------------------+-------+----------------+----------------+
|                          | *     | **Irbesartan   | **Irbesartan   |
|                          | *Plac | 150 mg**       | 300 mg**       |
|                          | ebo** |                |                |
+--------------------------+-------+----------------+----------------+
| N (per-protocol          | 172   | 160            | 162            |
| population)              |       |                |                |
+--------------------------+-------+----------------+----------------+
| Primary Endpoint         | 27    | 16             | 10             |
| (Proteinuria)            |       |                |                |
+--------------------------+-------+----------------+----------------+
| Nominal p-value vs.      |       | 0.096          | 0.0013\*       |
| placebo                  |       |                |                |
+--------------------------+-------+----------------+----------------+
| Relative risk vs.        |       | .595           | 0.311          |
| placebo                  |       |                |                |
|                          |       | (0.321, 1.105) | (0.146, 0.662) |
| 95% CI for RR            |       |                |                |
+--------------------------+-------+----------------+----------------+

\*Significant at level 0.025 using Bonferroni adjustment.

![](media/image3.png){width="5.983333333333333in"
height="3.198611111111111in"}

**Figure 3.3.1** Kaplan-Meier curves for estimated event-free survival
in three arms \[*Source: Figure 10.1.1.1 of Study Report*\].

The results for the secondary analyses appear in Tables 3.3.2, 3.3.3,
and 3.3.4. The first two variables were only analyzed at 3, 6, 12 18 and
24 months from randomization while the remaining variables were analyzed
at 1-year and 2-years from randomization. Both doses were compared to
placebo and there were no adjustments for multiple testing. The only
striking difference that appears among all of the secondary parameters
was in urinary excretion rate. There were nominally significant
differences in change in urinary excretion rate at every time point
between both doses of irbesartan and placebo. There were no significant
changes in serum creatinine at any time point for any dose of
irbesartan. There did not appear to be any significant difference in the
coagulation parameters in Table 3.3.4 although there was a nominally
significant difference in plasminogen activator inhibitor-I for the high
dose relative to placebo. Finally, there did not appear to be any
significant difference in the mean change in lipid profile in Table
3.3.5 although there was a nominally significant difference in HDL
cholesterol levels for the low dose relative to placebo.

**Table 3.3.2** Results on secondary analyses on change from baseline in
overnight urinary excretion rate. GM = geometric mean, PC = % change,
SEM = standard error of mean. \[*Source: Tables 10.2.1.1A of Study
Report*\]

![](media/image4.png){width="5.99375in" height="3.8in"}

**Table 3.3.3** Results on secondary analyses on change from baseline in
serum creatinine. GM = geometric mean, PC = % change, SEM = standard
error of mean. \[*Source: Tables 10.2.2.1 of Study Report*\]

![](media/image5.png){width="3.770138888888889in"
height="8.093055555555555in"}

**Table 3.3.4** Results on secondary analyses on change from baseline in
von Willebrand factor, fibrogen, factor VII, and plasminogen activator
inhibitor-I. \[*Source: Tables 10.2.3.1 of Study Report*\]

![](media/image6.png){width="5.992361111111111in"
height="5.995833333333334in"}

^a^Unadjusted raw mean change for vWF and Fibrinogen; geometric mean %
change for Factor VII and PAI.

**Table 3.3.5** Results on secondary analyses on mean change from
baseline in lipid profile. \[*Source: Tables 10.2.4.1A of Study
Report*\]

![](media/image7.png){width="5.997222222222222in" height="5.85625in"}

^a^Geometric mean for triglycerides; raw means for everything else.

**[3.4 Safety]{.underline}**

The ten most common adverse events are listed in Table 2.4.1. There
appears to be a difference in the reports of dizziness and diarrhea in
the 300 mg group relative to placebo and numerically more reports in the
150 mg group relative to placebo. There does not appear to be a
difference between irbesartan and placebo in the number of any other
specific adverse event.

## Table 3.4.1 Most common clinical adverse events; number and % of subjects.

![](media/image8.png){width="5.988194444444445in"
height="2.6819444444444445in"}

**[3.5 Results by subgroup]{.underline}**

The estimates of the relative risk in subgroups appear in Table 3.5.1.
The point estimates are always less than 1 and appear to be particularly
small in females, patients under 59, and patients with normal creatinine
clearance (\>107 ml/min/1.73 m^2^).

**Table 3.5.1** Estimates of Relative Risk in subgroups from Cox model
in per-protocol population \[*Source: Figure 10.1.2C of Study report*\]

![](media/image9.png){width="5.9944444444444445in"
height="3.6590277777777778in"}

The results by country are summarized in Figure 3.5.1. There is one
point in the graph for each country where there were a sufficient number
of patients recruited so that an estimate of the hazard ratio could be
obtained. The y-axis represents the estimated log-hazard ratio for
irbesartan relative to placebo on the primary endpoint. The x-axis
represents the standard error of this estimate. Countries with more
patients have more information about the hazard ratio (smaller standard
error), and therefore appear on the left side of the graph. The dashed
lines represent the overall pooled log-hazard ratio as well as the 95%
confidence bands (pooled estimate 1.96 standard errors). Since all of
the points lie within the confidence bands, there are no countries that
have significantly different treatment effects than what one would
expect given the pooled results. The only country in North America where
patients were recruited in this study is Canada and there were too few
events among Canadian patients to estimate the relative risk in this
subgroup.

![](media/image10.wmf){width="5.85in" height="4.520833333333333in"}

**Figure 3.5.1** Plot of log-hazard ratios for primary endpoint by
country.

**[4. Conclusions]{.underline}**

Two placebo controlled studies appeared to show positive findings on the
primary endpoints for irbesartan 300 mg in the populations studied.
Study CV131-048 showed a statistically significant increase in the time
to a composite endpoint (doubling of serum creatinine, ESRD, all-cause
mortality) with a p-value of 0.023 and also appeared to show superior
efficacy to the active control amlodipine 10 mg. Most of the apparent
benefit seemed to be in delaying increases in serum creatinine. The
effect of irbesartan on the primary endpoint appeared to be smaller in
North America than in other regions. Study EFC2481 showed a
statistically significant increase in the time to occurrence of clinical
proteinuria with a p-value of 0.0013, but failed to show a statistically
significant difference between a lower dose of 150 mg relative to
placebo (p=0.096). There were positive findings on some of the secondary
endpoints: a 23% reduction in relative risk in the irbesartan group
relative to the active control amlodipine on the primary endpoint in
Study CV131-048 and nominally significant differences in change in
urinary excretion rate at every time point and in change in plasma
activator inhibitor-I in Study EFC2481. Diarrhea and dizziness were
reported more often in the irbesartan groups than in the placebo groups
in both trials, but there did not appear to be significantly more
reports of any other adverse event in the irbesartan groups in these
studies.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

John Lawrence, Ph.D.

Mathematical Statistician

This review consists of 16 pages of text, tables, and figures.

Concur: James Hung, Ph.D.

Acting Team Leader, Biometrics I

George Chi, Ph.D.

Division Director, Biometrics I

cc: NDA \# 20-757

HFD-110/Dr. Lipicky

HFD-110/Dr. Pelayo

HFD-110/Mr. Fromme

HFD-700/Dr. Anello

HFD-710/Dr. Chi

HFD-710/Dr. Hung

HFD--710/chron

LAWRENCEJ/594--5375/890343.doc/11/13/2023