> ![](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 #:** 20-386

**SERIAL #:** SE1-S028

**DRUG NAME**: COZAAR (Losartan Potassium) tablets

**INDICATION:** Renal Protection

**SPONSOR:** Merck & Co., Inc.

**DOCUMENT REVIEWED**:

1.  Vols. 1 and 2 (CDER REC'D Date: November 13, 2001)

2.  SAS data base in EDR

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

**MEDICAL REVIEWER:** Juan Carlos Pelayo, M.D. (HFD-110)

**PROJECT MANAGER:** Sandra Birdsong (HFD-110)

**STATISTICAL KEY WORDS:** Interim analysis, DSMB, sample size change,
log rank test, O'Brien-Fleming boundary, Cox regression, geographical
region

**Distribution:** NDA 20-386, SE1-S028

HFD-110/Dr. Throckmorton

HFD-110/Dr. Stockbridge

HFD-110/Dr. Pelayo

HFD-110/Ms. Birdsong

HFD-700/Dr. Anello

HFD-710/Dr. Chi

HFD-710/Dr. Mahjoob

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

HFD-710/chron

JHung/301-594-5436/DB1/cozaar.doc/3-1-2002

TABLE OF CONTENTS

0\. SUMMARY [3](#summary)

1\. INTRODUCTION [3](#introduction)

2\. OVERVIEW OF RENAAL STUDY RESULTS
[3](#overview-of-renaal-study-results)

Sample Size Planning [4](#sample-size-planning)

Interim Analysis Plan [4](#interim-analysis-plan)

Randomization [5](#randomization)

Analysis methods [5](#analysis-methods)

Protocol Amendments [6](#protocol-amendments)

Changes in the Conduct of the Study or Planned Analyses
[6](#changes-in-the-conduct-of-the-study-or-planned-analyses)

Efficacy results [7](#efficacy-results)

Baseline [7](#baseline)

Primary endpoint (doubling serum creatinine, ESRD or death)
[7](#primary-endpoint-doubling-serum-creatinine-esrd-or-death)

Table 1. Incidence of adjudicated primary events (Reviewer's Analysis)
[8](#table-1.-incidence-of-adjudicated-primary-events-reviewers-analysis)

Time between components of primary endpoint
[8](#time-between-components-of-primary-endpoint)

Table 2. Time from Doubling of Serum Creatinine to ESRD and From ESRD to
death (Sponsor's analysis, not confirmed by Reviewer)
[8](#table-2.-time-from-doubling-of-serum-creatinine-to-esrd-and-from-esrd-to-death-sponsors-analysis-not-confirmed-by-reviewer)

Losartan effect on primary endpoint over time
[8](#losartan-effect-on-primary-endpoint-over-time)

Subgroup results [9](#subgroup-results)

Table 3. Subgroup results on primary endpoint (Reviewer's analysis)
[9](#table-3.-subgroup-results-on-primary-endpoint-reviewers-analysis)

Results of primary endpoint by geographical region
[10](#results-of-primary-endpoint-by-geographical-region)

Table 4. Primary endpoint by geographical region (Reviewer's analysis)
[10](#table-4.-primary-endpoint-by-geographical-region-reviewers-analysis)

Table 5. Primary endpoint by country (Reviewer's analysis)
[10](#table-5.-primary-endpoint-by-country-reviewers-analysis)

Secondary endpoints [12](#secondary-endpoints)

Table 6. Incidence of secondary endpoints (Reviewer's analysis)
[12](#table-6.-incidence-of-secondary-endpoints-reviewers-analysis)

Progression of Renal Disease [12](#progression-of-renal-disease)

Table 7. Summary of slopes of reciprocal of serum creatinine at
quartiles (Sponsor's results confirmed by Reviewer's analysis)
[12](#table-7.-summary-of-slopes-of-reciprocal-of-serum-creatinine-at-quartiles-sponsors-results-confirmed-by-reviewers-analysis)

Table 8. Comparison of mean slopes for renal progression
[13](#table-8.-comparison-of-mean-slopes-for-renal-progression)

Change in Proteinuria over Time [13](#change-in-proteinuria-over-time)

Predictibility of Proteinuria for Treatment Effect on Primary Endpoint
[13](#predictibility-of-proteinuria-for-treatment-effect-on-primary-endpoint)

Table 9. Adjustment of the Primary endpoint for proteinuria at Month 6
and as a time-varying covariate (Sponsor's results confirmed by
reviewer's analysis)
[13](#table-9.-adjustment-of-the-primary-endpoint-for-proteinuria-at-month-6-and-as-a-time-varying-covariate-sponsors-results-confirmed-by-reviewers-analysis)

4\. CONCLUSIONS [14](#conclusions)

5\. APPENDIX [15](#appendix)

Table A.1 Distribution of time (days) to non-event censoring (Reviewer's
analysis)
[15](#table-a.1-distribution-of-time-days-to-non-event-censoring-reviewers-analysis)

Table A.2. Primary endpoint by subgroups in Asia region excluding Israel
(Reviewer's analysis)
[16](#table-a.2.-primary-endpoint-by-subgroups-in-asia-region-excluding-israel-reviewers-analysis)

Table A.3. Primary endpoint by subgroups in non-Asia region including
Israel (Reviewer's analysis)
[17](#table-a.3.-primary-endpoint-by-subgroups-in-non-asia-region-including-israel-reviewers-analysis)

Table A.4 Baseline characteristics for Asia versus Non-Asia regions
(Reviewer's analysis)
[18](#table-a.4-baseline-characteristics-for-asia-versus-non-asia-regions-reviewers-analysis)

Table A.5 Distribution of proteinuria level (mg/g) \[Reviewer's
analysis\]
[19](#table-a.5-distribution-of-proteinuria-level-mgg-reviewers-analysis)

Figure 1. log(-log(survival)) versus log(days) for the primary endpont,
doubling serum creatlinie, ESRD, or death
[20](#figure-1.-log-logsurvival-versus-logdays-for-the-primary-endpont-doubling-serum-creatlinie-esrd-or-death)

#   {#section .unnumbered}

# 0. SUMMARY

## 

##  This submission contains only one study. The conclusions in Section 4 constitute the summary.

##  

# 1. INTRODUCTION

This statistical review pertains to the results of the RENAAL trial
which is the major component of this submission. Most of the sponsor's
main results have been confirmed by this reviewer's analyses. **Only the
results of the reviewer's analyses will be presented in this review
unless stated otherwise.**

# 

# 2. OVERVIEW OF RENAAL STUDY RESULTS

The RENAAL study is a multi-center, randomized, parallel group,
double-blind trial of losartan versus placebo in patients with type 2
diabetes and nephropathy on a background of conventional
antihypertensive therapy (ACE inhibitor or AIIA therapy excluded). For
inclusion and exclusion criteria, the readers are referred to the
medical reviewer's review.

Following a 6-week of screening period, eligible patients were
stratified by baseline level of proteinuria (urine albumin to urine
creatinine artio from a first morning void above or below 2000 mg/gCr),
and randomized 1:1 to either losartan 50 mg or placebo. The losartan
should be increased to 100 mg daily if at the first month of the study
or at any point following trough blood pressure did not reach the goal
of 140/90 mmHg. After titration occurred, the study design provided the
investigators the flexibility to individualize treatment by adding,
increasing, or changing patient's background medication in order to
achieve trough goal blood pressure of 140/90 mmHg. Additionally, at the
investigator's discretion, patients could begin the study on the lower
dose of 25 mg losartan or placebo or be reduced to that dose if
necessary during the study.

The primary efficacy endpoint was a composite endpoint of doubling serum
creatinine, end-stage renal disease (ESRD), or death for any reason. To
be considered an endpoint, doubling of serum creatinine must have been a
rise in serum creatinine that was at least twice the baseline serum
creatinine value and confirmed by a second serum creatinine measurement,
analyzed by the central laboratory, and drawn no earlier than 4 weeks
following the initial doubling. ESRD was defined as the need for
dialysis or transplantation. The prespecified secondary efficacy
endpoint was a composite of cardiovascular morbidity and mortality
endpoints, which included cardiovascular death, hospitalization for
heart failure, hospitalization for unstable angina, myocardial
infarction, stroke, and revascularization. Other secondary measures
included progression of renal disease assessed by the slope of the
reciprocal of serum creatinine concentration and changes in proteinuria.

## Sample Size Planning 

Sample size estimation was based on the assumption that the 5-year
doubling of serum creatinine/ESRD/death rate in the placebo group would
be 58% and that this rate would be reduced to 46.4% (20% reduction) in
the losartan group. A total of 1320 to 1400 patients are needed to be
able to detect this difference at 4.8% significance level (because of
interim analysis described below) and with power 95%, assuming a minimum
follow-up period of 3.5 years, 2-year enrollment period, proportional
hazards for the treatments, and censoring at discontinuation time for a
discontinuation rate of 13% per year. The protocol originally planned
for 1520 patients to be enrolled over a 1-year period but was amended to
1320 patients when it became clear that enrollment would take 2 years.
The study actually over-enrolled with 1513 patients due to a larger than
anticipated number of screened patients successfully qualifying during
the final months of the 2-year recruitment period.

## Interim Analysis Plan 

The original plan allowed for a single efficacy interim analysis and a
series of safety-only analyses. The preplanned interim analysis was to
be performed when half of the expected events (284 of 568 events)
associated with the sample size and event rate estimates had been
observed or the last patient entered had been followed for 2 years,
whichever came first. This interim analysis would use the
O'Brien-Fleming stopping boundary as a guideline for any recommendation
of early termination due to overwhelming efficacy (as measured by the
composite for the hard endpoints of ESRD and death only). According to
this boundary, the critical p-value at the interim analysis had to be
0.0035 for both the primary endpoint and the composite of the 2 hard
endpoints, resulting in the final evaluation a of 0.049. However, at the
routine DSMB meetings at which the safety data were unblinded, the
committee also considered stopping the study if losartan was superior to
placebo with respect to the primary endpoint and also with respect to
the composite of the 2 "hard" endpoints, ESRD and death at a two-sided
--level of 0.0001. The DSMB planned 10 unblinded looks at death and ESRD
during the course of the study. Each of these looks was provided at a of
0.0001 to allow the DSMB to stop the study, if losartan was extremely
superior to placebo. The total adjustment for these evaluations was
0.001. This was subtracted from the original a of 0.049, to give the
final evaluation a of 0.048, required for the primary hypothesis. For
other outcomes, a p-value of \<0.05 was considered to indicate
statistical significance. All statistical tests were two-sided.

The Steering Committee could, at any point during the study, consider
whether external circumstances (e.g., results from other diabetic
studies, IRB issues with placebo control, etc.) had occurred that would
make it difficult to keep patients in the study. Any decision to end
RENAAL for external reasons would be made independently of the unblinded
interim data; therefore, for the end-of-study analyses, the only
statistical adjustment would be due to the interim analysis by the DSMB.

## Randomization 

According to the sponsor's response to this reviewer' request, the date
of randomization was not specifically collected for RENAAL. The sponsor
used the date of the first dose of study drug as the date of the start
of the study for the purpose of time to event analysis. The decision to
use this date for endpoint analyses was made prior to unblinding the
database. The next closest date to date of randomization is date of the
"randomization" visit but there is no guarantee that randomization
actually took place at that visit.. Among the 1513 randomized patients,
the dates differ in only 12 patients, and in 11 of the 12 they differ by
only 1 day and in the other case they differ by 12 days.

## Analysis methods 

The statistical analysis for efficacy and safety will be based on
intent-to-treat principle. The primary analysis of the composite
endpoint will be based on the time to the first event (i.e., doubling
serum creatinine, ERD or death). The components of this endpoint will be
analyzed in a similar fashion. For all time to event variables, the
relative risk for each event, its confidence interval and the test for
treatment difference will be based on the Cox regression model.
According to the original protocol, the model will contain treatment
group indicator, an indicator variable for the stratification factor of
proteinuria at baseline and a factor for country. The treatment by
country interaction will also be assessed using Cox regression (=0.10).
Life table event rates and mortality curves will be based on the
product-limit estimates. In the protocol amendments, country was changed
to region (North America \[United States + Canada + Puerto Rico\], Latin
America, Europe \[Eastern + Western\], and Asia).

The renal function measured as the reciprocal of serum creatinine (1/Cr)
across over time during the trial will be analyzed. The rate of decline
in renal function will be assessed by the slope of the observed 1/Cr
over the quarterly follow-up period. As the primary analysis, a linear
random-effects model will be used to compare slopes in renal function.
Region, strata of proteinuria at baseline and baseline serum creatinine
values will be included in the model as fixed covariates. Supportive
analyses include an ANCOVA analysis to compare the treatment effect with
the dependent variable of an individual chronic slope. If normality
assumption is not appropriete, the same ANCOVA model will be performed
with the dependent variable of the rank of an individual chronic slope.

Proteinuria which is the ratio of urine albumin to urine creatinine will
be analyzed. The primary analysis will be based on the
intention-to-treat approach. All the observed proteinuria values during
the quarterly follow-up period from all patients will be included in the
analysis according to the treatment group to which they are randomized,
regardless of whether patients discontinue double-blind therapy or have
the events of doubling of serum creatinine before the study is completed
(3.5 years from last patient randomized). Note that the follow-up time
for the secondary endpoint is defined as the period from randomization
to the last measurement of proteinuria before ESRD during the study. The
mixed-effects (longitudinal) model will be used with terms including
treatment (losartan/placebo), time, region and baseline proteinuria
levels. A natural logarithm transformation will be applied for the
proteinuria data for the mixed model. The mean change profiles over time
will be plotted to show the time course of the treatment effect on
proteinuria. Interaction between treatment and time for the mean changes
of the proteinuria levels will be explored.

## Protocol Amendments

There appeared to be six protocol amendments. Only the following
amendment may potentially have a substantive effect on statistical
evaluation.

######## *Amendment 147-03*

Since patient enrollment had been slower than anticipated in the
protocol, recruitment of 1520 patients would not be achieved in the
projected timeframe. An enrollment period of approximately 2 years was
estimated to allow recruitment of at least 1320 patients required to
achieve 95% power. In addition, the interim analysis stopping rules were
updated. For the purpose of the DSMB review only, an interim analysis
(=0.0035) would be performed by the Merck statistician assigned to the
DSMB when half of the expected events associated with this sample size
and event rate estimates have been observed or the last patient entered
has been followed for 1.75 years, whichever came first.

## Changes in the Conduct of the Study or Planned Analyses

The study was to be completed in March of 2002, 3.5 years from last
patient in. However, the Steering Committee, whose obligation was to
keep abreast of current research in the field and continually
re-evaluate the ethical context of the trial, voted unanimously to end
the study early, while blinded, for reasons unrelated to the study data.
The reason for this decision was documented in the minutes of the
Steering Committee meeting on 10-Feb-2001 and is described in the
following paragraph taken from a letter that was sent to all
investigators:

"At its meeting on 10-Feb-2001, the RENAAL Steering Committee took this
action due to increasing evidence that ACE inhibitors are effective in
reducing cardiovascular events in patients with characteristics similar
to RENAAL patients. This decision to discontinue was in part due to
soon-to-be-published information showing that cardiovascular events are
reduced by ACE inhibitors in diabetic patients with renal impairment.
The action of the Steering Committee was taken on the basis of external
evidence only and was therefore independent of any knowledge of the
results of the trial. The Steering Committee was and remained blinded
until the results of the trial were analyzed and presented. The
Committee further recommended that physicians caring for patients in the
RENAAL trial make this information available to their patients and
strongly consider addition of therapy aimed at blockade of the
renin-angiotensin-aldosterone system (RAAS). In the usual care arm of
the RENAAL Study, patients were receiving antihypertensive therapy,
excluding agents that block the RAAS."

The "soon-to-be-published information" referred to data from the HOPE
diabetic subpopulation, which demonstrated that in over 900 patients
with or without renal insufficiency, there appeared to be significantly
less cardiovascular events in patients receiving an ACE inhibitor. The
endpoint cutoff date for this study was 10-Feb-2001, i.e., any endpoint
occurring on or before February 10 was adjudicated. Endpoints occurring
after this date were not collected with the exception of any possible
silent myocardial infarctions detected by the core lab on the final
visit ECGs.

## Efficacy results

A total of 1513 patients at 250 centers from 28 countries were
randomized. The total number of the primary endpoint events is 686,
larger than the planned number of 568, despite the early ending of the
trial by about 1-2 months.

### Baseline

Two treatment groups were comparable with respect to baseline
demographic characteristics, medical history, electrocardiographic
changes, and drug therapy, as shown in Table 7 of the sponsor's study
report.

### Primary endpoint (doubling serum creatinine, ESRD or death)

The sponsor's analysis on the primary efficacy endpoint, doubling of
serum creatinine, ESRD or death, was based on the Cox regression model
using baseline proteinuria as a stratification factor and geographical
region (Asia pacific, Europe, Latin America, North America) as the
adjustment factor. As noted above, according to the sponsor, the date of
randomization was not specifically collected for RENAAL. The sponsor
used the date of the first dose of study drug as the date of the start
of the study for the purpose of time to event analysis. The next closest
date to date of randomization is date of the "randomization" visit but
there is no guarantee that randomization actually took place at that
visit. Among the 1513 randomized patients, the dates differ in only 12
patients, and in 11 of the 12 they differ by only 1 day and in the other
case they differ by 12 days. Using the date of the "randomization" visit
for analysis, the results changed little.

The censoring distribution with respect to the primary endpoint was
comparable between the two treatment groups (Table A.1 in the Appendix).
As shown in Table 1, the rate of the composite endpoint of doubling
serum creatinine, ESRD or death was significantly lower in the losartan
group than in the placebo group (hazard ratio of 0.84 with 95.2% CI of
0.72 to 0.97, p = 0.022). This treatment difference seemed to be largely
attributed to the difference in doubling of serum creatinine. The hazard
ratio of ESRD was 0.93. The hazard ratio of all cause death was 0.98.
ESRD or death constituted approximately 50% of the primary composite
events as the first endpoint. However, on a whole, the losartan group
had a significantly fewer ESRD events (hazard ratio of 0.71 with 95.2%
CI of 0.57 to 0.89, p = 0.002). The mortality rate differed little
between the two treatment groups.

#### Table 1. Incidence of adjudicated primary events (Reviewer's Analysis)

+------------------+-----------+------------+-----------------+-------+
|                  | Losartan  | Placebo    | Hazard ratio    | p     |
|                  |           |            |                 | -valu |
|                  | (N=751)   | (N=762)    | (95.2% CI)      | e^\$^ |
+------------------+-----------+------------+-----------------+-------+
| ####             |           |            |                 |       |
| ## Primary event |           |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| Doubling serum   | 327       | 359        | 0.84 (0.72,     | 0.022 |
| creatinine, ESRD | (43.5%)   | (47.1%)    | 0.97)           |       |
| or death         |           |            |                 |       |
|                  | Median    | Median     |                 |       |
|                  | time      | time       |                 |       |
|                  |           |            |                 |       |
|                  | = 1303    | =1373 days |                 |       |
|                  | days      |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| **Decomposition  |           |            |                 |       |
| of the 1^st^     |           |            |                 |       |
| primary event**  |           |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| Doubling of SC   | 162       | 198        | 0.75 (0.61,     | 0.006 |
|                  | (21.6%)   | (26.0%)    | 0.92)           |       |
+------------------+-----------+------------+-----------------+-------+
| ESRD             | 64 (      | 65 ( 8.5%) | 0.93 (0.65,     | 0.66  |
|                  | 8.5%)     |            | 1.31)           |       |
+------------------+-----------+------------+-----------------+-------+
| Death            | 101       | 96 (12.6%) | 0.98 (0.74,     | 0.91  |
|                  | (13.5%)   |            | 1.30)           |       |
+------------------+-----------+------------+-----------------+-------+
|                  |           |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| **1^st^          |           |            |                 |       |
| component        |           |            |                 |       |
| endpoint**       |           |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| Doubling of SC   | 162       | 198        | 0.75 (0.61,     | 0.006 |
|                  | (21.6%)   | (26.2%)    | 0.92)           |       |
+------------------+-----------+------------+-----------------+-------+
| ESRD             | 147       | 194        | 0.71 (0.57,     | 0.002 |
|                  | (19.5%)   | (25.5%)    | 0.89)           |       |
+------------------+-----------+------------+-----------------+-------+
| Death            | 158       | 155        | 1.02 (0.81,     | 0.88  |
|                  | (21.0%)   | (20.3%)    | 1.27)           |       |
+------------------+-----------+------------+-----------------+-------+
| ESRD or death    | 255       | 300        | 0.80 (0.68,     | 0.009 |
|                  | (34.0%)   | (39.4%)    | 0.95)           |       |
+------------------+-----------+------------+-----------------+-------+

\$ nominal p-value, pre-specified primary analysis (Cox model using
geographical region as covariate and baseline proteinuria as a
stratification variable)

### Time between components of primary endpoint

### 

From Table 2, the proportion of patients with ESRD who subsequently died
seemed to be higher in the losartan group than in the placebo group.
However, none of the comparisons in this table is a randomized
comparison.

#### Table 2. Time from Doubling of Serum Creatinine to ESRD and From ESRD to death (Sponsor's analysis, not confirmed by Reviewer)

+---------------+---------------+---------+---------------+---------+
|               | Losartan      |         | Placebo       |         |
+---------------+---------------+---------+---------------+---------+
|               | events/sample | Mean    | events/sample | Mean    |
|               | size (%)      |         | size (%)      | fo      |
|               |               | fo      |               | llow-up |
|               |               | llow-up |               |         |
|               |               |         |               | (days)  |
|               |               | (days)  |               |         |
+---------------+---------------+---------+---------------+---------+
| DSC to ESRD   | 83/162        | 279.5   | 129/198       | 252.5   |
|               | (51.2%)       |         | (65.2%)       |         |
+---------------+---------------+---------+---------------+---------+
| ESRD to death | 50/147        | 363.4   | 49/194        | 400.3   |
|               | (34.0%)       |         | (25.3%)       |         |
+---------------+---------------+---------+---------------+---------+

### Losartan effect on primary endpoint over time

The effect of losartan relative to placebo in terms of the hazard of the
primary endpoint did not appear to be constant over the duration of the
trial (see Figure 1, in the Appendix). The hazard curves appeared to be
converging.

#### 

### Subgroup results

There was no noticeable inconsistency in the results over the subgroups
by demographic variables or baseline factors (Table 3).

#### Table 3. Subgroup results on primary endpoint (Reviewer's analysis)

+--------------------+---------------+---------------+---------------+
|                    | Losartan      | Placebo       | Hazard ratio  |
|                    |               |               |               |
|                    | (N=751)       | (N=762)       | (95% CI)      |
+--------------------+---------------+---------------+---------------+
| Female             | 138 / 289 (   | 145 / 268 (   | 0.80 ( 0.64 , |
|                    | 47.8 %)       | 54.1 %)       | 1.01 )        |
| Male               |               |               |               |
|                    | 189 / 462 (   | 214 / 494 (   | 0.90 ( 0.74 , |
|                    | 40.9 %)       | 43.3 %)       | 1.09 )        |
+--------------------+---------------+---------------+---------------+
| Age                | 222 / 503 (   | 246 / 502 (   | 0.83 ( 0.69 , |
|                    | 44.1 %)       | 49.0 %)       | 1.00 )        |
| \< 65 yrs          |               |               |               |
|                    | 105 / 248 (   | 113 / 260 (   | 0.95 ( 0.73 , |
| 65 yrs             | 42.3 %)       | 43.5 %)       | 1.23 )        |
+--------------------+---------------+---------------+---------------+
| Asian              | 49 / 117 (    | 74 / 135 (    | 0.69 ( 0.48 , |
|                    | 41.9 %)       | 54.8 %)       | 0.99 )        |
| Hispanic           |               |               |               |
|                    | 77 / 140 (    | 74 / 137 (    | 1.01 ( 0.74 , |
| black              | 55.0 %)       | 54.0 %)       | 1.39 )        |
|                    |               |               |               |
| white              | 50 / 125 (    | 41 / 105 (    | 0.97 ( 0.64 , |
|                    | 40.0 %)       | 39.0 %)       | 1.47 )        |
|                    |               |               |               |
|                    | 145 / 358 (   | 163 / 377 (   | 0.87 ( 0.69 , |
|                    | 40.5 %)       | 43.2 %)       | 1.09 )        |
+--------------------+---------------+---------------+---------------+
| Proteinuria        | 150 / 501 (   | 161 / 511 (   | 0.91 ( 0.73,  |
|                    | 29.9 %)       | 31.5 %)       | 1.14)         |
| \< 2000 mg/g       |               |               |               |
|                    | 177 / 250 (   | 198 / 251 (   | 0.78 ( 0.64,  |
| 2000 mg/g          | 70.8 %)       | 78.9 %)       | 0.96)         |
+--------------------+---------------+---------------+---------------+
| BMI                | 195 / 437 (   | 226 / 471 (   | 0.87 ( 0.72 , |
|                    | 44.6 %)       | 48.0 %)       | 1.06 )        |
| \< 30 kg/m2        |               |               |               |
|                    | 132 / 314 (   | 133 / 291 (   | 0.88 ( 0.69 , |
| 30 kg/m2           | 42.0 %)       | 45.7 %)       | 1.11 )        |
+--------------------+---------------+---------------+---------------+
| Duration of        | 178 / 387 (   | 204 / 409 (   | 0.88 ( 0.72 , |
| hypertension       | 46.0 %)       | 49.9 %)       | 1.08 )        |
|                    |               |               |               |
| \< 10 yrs          | 149 / 364 (   | 155 / 353 (   | 0.86 ( 0.69 , |
|                    | 40.9 %)       | 43.9 %)       | 1.08 )        |
| 10 yrs             |               |               |               |
+--------------------+---------------+---------------+---------------+
| Total Cholesterol  | 187 / 496 (   | 205 / 489 (   | 0.84 ( 0.69 , |
|                    | 37.7 %)       | 41.9 %)       | 1.03 )        |
| \< 240 mg/dL       |               |               |               |
|                    | 140 / 255 (   | 154 / 273 (   | 0.93 ( 0.74 , |
| 240 mg/dL          | 54.9 %)       | 56.4 %)       | 1.17 )        |
+--------------------+---------------+---------------+---------------+
| Serum Creatinine   | 174 / 482 (   | 173 / 483 (   | 0.97 ( 0.78 , |
|                    | 36.1 %)       | 35.8 %)       | 1.20 )        |
| \< 2 mg/dL         |               |               |               |
|                    | 153 / 269 (   | 186 / 279 (   | 0.77 ( 0.62 , |
| 2 mg/dL            | 56.9 %)       | 66.7 %)       | 0.95 )        |
+--------------------+---------------+---------------+---------------+
| Serum Albumin      | 143 / 207 (   | 145 / 202 (   | 0.87 ( 0.69 , |
|                    | 69.1 %)       | 71.8 %)       | 1.10 )        |
| \< 3.6 mg/dL       |               |               |               |
|                    | 184 / 544 (   | 214 / 560 (   | 0.84 ( 0.69 , |
| 3.6 mg/dL          | 33.8 %)       | 38.2 %)       | 1.02 )        |
+--------------------+---------------+---------------+---------------+
| Serum Uric Acid    | 197 / 459 (   | 203 / 448 (   | 0.90 ( 0.74 , |
|                    | 42.9 %)       | 45.3 %)       | 1.09 )        |
| \< 7 mg/dL         |               |               |               |
|                    | 130 / 292 (   | 156 / 314 (   | 0.83 ( 0.66 , |
| 7 mg/dL            | 44.5 %)       | 49.7 %)       | 1.05 )        |
+--------------------+---------------+---------------+---------------+
| HbA1c              | 5 / 9 ( 55.6  | 2 / 8 ( 25.0  | 2.73 ( 0.53 , |
|                    | %)            | %)            | 14.1 )        |
| \< 10%             |               |               |               |
|                    | 322 / 742 (   | 357 / 754 (   | 0.86 ( 0.74 , |
| 10%                | 43.4 %)       | 47.3 %)       | 1.00 )        |
+--------------------+---------------+---------------+---------------+
| Hemoglobin         | 163 / 315 (   | 178 / 310 (   | 0.81 ( 0.66 , |
|                    | 51.7 %)       | 57.4 %)       | 1.01 )        |
| \< 12 mg/dL        |               |               |               |
|                    | 164 / 436 (   | 181 / 452 (   | 0.90 ( 0.73 , |
| 12 mg/dL           | 37.6 %)       | 40.0 %)       | 1.11 )        |
+--------------------+---------------+---------------+---------------+
| Nonsmoker          | 69 / 147 (    | 61 / 130 (    | 0.98 ( 0.70 , |
|                    | 46.9 %)       | 46.9 %)       | 1.39 )        |
| Smoker             |               |               |               |
|                    | 258 / 604 (   | 298 / 632 (   | 0.84 ( 0.71 , |
|                    | 42.7 %)       | 47.2 %)       | 0.99 )        |
+--------------------+---------------+---------------+---------------+
| Sitting SBP        | 60 / 191 (    | 66 / 187 (    | 0.86 ( 0.61 , |
|                    | 31.4 %)       | 35.3 %)       | 1.22 )        |
| \< 140 mmHg        |               |               |               |
|                    | 267 / 560 (   | 293 / 575 (   | 0.87 ( 0.74 , |
| 140 mmHg           | 47.7 %)       | 51.0 %)       | 1.03 )        |
+--------------------+---------------+---------------+---------------+
| Insulin Use        | 113 / 290 (   | 128 / 313 (   | 0.92 ( 0.71 , |
|                    | 39.0 %)       | 40.9 %)       | 1.18 )        |
| No                 |               |               |               |
|                    | 214 / 461 (   | 231 / 449 (   | 0.83 ( 0.69 , |
| Yes                | 46.4 %)       | 51.4 %)       | 1.00 )        |
+--------------------+---------------+---------------+---------------+
| Dihydropyridine    | 128 / 345 (   | 148 / 351 (   | 0.84 ( 0.66 , |
|                    | 37.1 %)       | 42.2 %)       | 1.06 )        |
| No                 |               |               |               |
|                    | 199 / 406 (   | 211 / 411 (   | 0.89 ( 0.74 , |
| Yes                | 49.0 %)       | 51.3 %)       | 1.08 )        |
+--------------------+---------------+---------------+---------------+
| ACEI or AIIA Use   | 146 / 351 (   | 180 / 386 (   | 0.85 ( 0.68 , |
|                    | 41.6 %)       | 46.6 %)       | 1.06 )        |
| No                 |               |               |               |
|                    | 181 / 400 (   | 179 / 376 (   | 0.88 ( 0.72 , |
| Yes                | 45.3 %)       | 47.6 %)       | 1.08 )        |
+--------------------+---------------+---------------+---------------+
| Beta Blocker Use   | 265 / 614 (   | 298 / 622 (   | 0.84 ( 0.72 , |
|                    | 43.2 %)       | 47.9 %)       | 1.00 )        |
| No                 |               |               |               |
|                    | 62 / 137 (    | 61 / 140 (    | 0.99 ( 0.69 , |
| Yes                | 45.3 %)       | 43.6 %)       | 1.41 )        |
+--------------------+---------------+---------------+---------------+
| Calcium Blocker    | 82 / 219 (    | 89 / 216 (    | 0.84 ( 0.62 , |
| Use                | 37.4 %)       | 41.2 %)       | 1.14 )        |
|                    |               |               |               |
| No                 | 245 / 532 (   | 270 / 546 (   | 0.88 ( 0.74 , |
|                    | 46.1 %)       | 49.5 %)       | 1.05 )        |
| Yes                |               |               |               |
+--------------------+---------------+---------------+---------------+

### Results of primary endpoint by geographical region

As suggested in the sponsor's Figure 9, the hazard ratio for the primary
endpoint appeared to be quite different between Asia and other regions.
The Asia region appeared to show a big effect with losartan (45%
reduction in hazard) but other regions showed little or no effect; see
Table 4.

#### Table 4. Primary endpoint by geographical region (Reviewer's analysis)

  ---------------- ------------------ ------------------ ------------------
                   Losartan           Placebo            Hazard ratio (95%
                                                         CI)

  **All regions**  **327/751          **359/762          **0.84 (0.72,
                   (43.5%)**          (47.1%)**          0.98)**

  Asia             49/125 (39.2%)     78/132 (59.1%)     0.55 (0.39, 0.79)

  Europe           58/151 (38.4%)     51/144 (35.4%)     1.05 (0.72, 1.53)

  Latin America    78/137 (56.9%)     80/137 (58.4%)     0.93 (0.68, 1.27)

  North America    142/338 (42.0%)    150/349 (43.0%)    0.94 (0.75, 1.19)
  ---------------- ------------------ ------------------ ------------------

### 

Table 5 summarizes by-country results of the primary endpoint. In Asia,
four countries showed a big effect with losartan (hazard reduction
ranging from 17% to 78%); Singapore having very small and the smallest
sample size in the region showed a reversed trend. In Europe, Spain had
the largest sample size and gave a hazard reduction of 19%; United
Kingdom having the next largest sample size showed no effect or a bit
reversed trend. Other countries had very small sample size and showed
mixed trends. In Latin America, Mexico and Brazil having the largest
sample size showed different trends; the former showed a bit opposite
trend but the latter gave a hazard reduction of 22%. Other countries
also showed mixed trends. In North America, United States showed little
effect with losartan; other countries contributed few events. Overall,
only Asia seemed to show a consistent favorable effect with losartan.
However, Israel contributed a small number of patients and gave the
biggest effect with losartan. By putting Israel in Europe, the hazard
ratio changed to 0.64 with 95% CI of 0.44 to 0.93 for Asia and to 0.87
with 95% CI of 0.61 to 1.24 for Europe. A substantial numerical
difference in hazard ratio between Asia and non-Asia remained.

#### Table 5. Primary endpoint by country (Reviewer's analysis)

+-----------+---------------+-------------+-------------+--------------+
|           |               | Losartan    | Placebo     | Hazard ratio |
|           |               |             |             |              |
|           |               |             |             | (95% CI)     |
+-----------+---------------+-------------+-------------+--------------+
| **All     |               | **327/751   | **359/762   | **0.84       |
| regions** |               | (43.5%)**   | (47.1%)**   | (0.72,       |
|           |               |             |             | 0.98)**      |
+-----------+---------------+-------------+-------------+--------------+
| Asia      | Hong Kong     | 19/46       | 27/46       | 0.57 (0.32,  |
|           |               | (41.3%)     | (58.7%)     | 1.04)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Israel        | 4/19        | 12/18       | 0.22 (0.07,  |
|           |               | (21.1%)     | (66.7%)     | 0.70)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Japan         | 22/44       | 34/52       | 0.73 (0.43,  |
|           |               | (50.0%)     | (65.4%)     | 1.26)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Malaysia      | 2/11        | 4/10        | 0.42 (0.08,  |
|           |               | (18.2%)     | (40.0%)     | 2.31)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Singapore     | 2/5 (40.0%) | 1/6 (16.7%) | 2.12 (0.19,  |
|           |               |             |             | 23.51)       |
+-----------+---------------+-------------+-------------+--------------+
| Europe    | Austria       | 5/8 (62.5%) | 4/7 (57.1%) | 1.17 (0.31,  |
|           |               |             |             | 4.38)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Czech         | 9/17        | 6/16        | 1.63( 0.58,  |
|           | Republic      | (52.9%)     | (37.5%)     | 4.59)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Denmark       | 3/8 (37.5%) | 3/8 (37.5%) | 0.76 (0.15,  |
|           |               |             |             | 3.83)        |
+-----------+---------------+-------------+-------------+--------------+
|           | France        | 5/5 (100%)  | 7/7 (100%)  | 1            |
+-----------+---------------+-------------+-------------+--------------+
|           | Germany       | 3/6 (50.0%) | 2/6 (33.3%) | 1.15 (0.19,  |
|           |               |             |             | 6.97)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Hungary       | 3/5 (60.0%) | 2/5 (40.0%) | 1.43 (0.24,  |
|           |               |             |             | 8.61)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Italy         | 2/13        | 3/13        | 0.55 (0.09,  |
|           |               | (15.4%)     | (23.1%)     | 3.33)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Netherlands   | 4/4 (100%)  | 3/3 (100%)  | 1            |
+-----------+---------------+-------------+-------------+--------------+
|           | New Zealand   | 1/1 (100%)  | 1/2 (50.0%) | 2            |
+-----------+---------------+-------------+-------------+--------------+
|           | Portugal      | 3/5 (60.0%) | 2/5 (40.0%) | 1.23 (0.20,  |
|           |               |             |             | 7.40)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Russian       | 6/14        | 4/12        | 1.34 (0.38,  |
|           | Federation    | (42.9%)     | (33.3%)     | 4.77)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Slovakia      | 1/1 (100%)  | 1/1 (100%)  | 1            |
+-----------+---------------+-------------+-------------+--------------+
|           | Spain         | 14/36       | 14/31       | 0.81 (0.38,  |
|           |               | (38.9%)     | (45.2%)     | 1.69)        |
+-----------+---------------+-------------+-------------+--------------+
|           | United        | 10/28       | 10/28       | 1.02 (0.42,  |
|           | Kingdom       | (35.7%)     | (35.7%)     | 2.45)        |
+-----------+---------------+-------------+-------------+--------------+
| Latin     | Argentina     | 2/9 (22.2%) | 5/8 (62.5%) | 0.32 (0.06,  |
| America   |               |             |             | 1.65)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Brazil        | 17/28       | 20/30       | 0.78 (0.41,  |
|           |               | (60.7%)     | (66.7%)     | 1.49)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Chile         | 7/13        | 8/13        | 0.69 (0.25,  |
|           |               | (53.8%)     | (61.5%)     | 1.91)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Costa Rica    | 12/17       | 8/16        | 1.36 (0.55,  |
|           |               | (70.6%)     | (50.0%)     | 3.34)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Mexico        | 19/33       | 18/34       | 1.08 (0.57,  |
|           |               | (57.6%)     | (52.9%)     | 2.07)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Peru          | 10/21       | 13/21       | 0.69 (0.30,  |
|           |               | (47.6%)     | (61.9%)     | 1.58)        |
+-----------+---------------+-------------+-------------+--------------+
|           | Venezuela     | 11/16       | 8/15        | 2.24 (0.82,  |
|           |               | (68.8%)     | (53.3%)     | 6.08)        |
+-----------+---------------+-------------+-------------+--------------+
| North     | Canada        | .           | 1/1 (100%)  | .            |
| America   |               |             |             |              |
+-----------+---------------+-------------+-------------+--------------+
|           | Puerto Rico   | 2/2 (100%)  | 1/3 (33.3%) | 3            |
+-----------+---------------+-------------+-------------+--------------+
|           | United States | 142/336     | 148/345     | 0.95 (0.76,  |
|           |               | (42.3%)     | (42.9%)     | 1.20)        |
+-----------+---------------+-------------+-------------+--------------+

The differences in hazard ratio of the primary endpoint between Asia and
non-Asia regions seemed to appear in most of the subgroups by baseline
characteristics (Tables A.2 and A.3 in the Appendix). The incidence of
the primary composite endpoint in the placebo group appeared to be
higher in Asia than in non-Asia region whereas the incidence in the
losartan group appeared to be in the same ballpark between the regions.
Table A.4 in the Appendix exhibits the potential differences in baseline
characteristics between Asia and Non-Asia regions. The two regions
appeared to be comparable with respect to most of the baseline
characteristics, except possibly on BMI, Dihydropyridine use, and
proteinuria. Asia region seemed to have a larger proportion of the
patients with proteinuria 2000 mg/g. In this study, proteinuria seemed
to be a strong predictor of the primary composite endpoint, as reported
by the sponsor and in Table 9 of this review. Thus, the apparent
difference in hazard ratio between Asia and non-Asia regions might be
attributed, at least partly, to a higher baseline proteinuria level
(Table A.5 in the Appendix), or to a higher incidence rate of the
primary endpoint in the placebo group in Asia region.

### Secondary endpoints

Losartan seemed to be associated with a larger reduction of
hospitalization for HF. There was no clear suggestion for beneficial
effect on any of other secondary endpoints with losartan (Table 6).

#### Table 6. Incidence of secondary endpoints (Reviewer's analysis)

+------------------+-----------+------------+-----------------+-------+
|                  | Losartan  | Placebo    | Hazard ratio    | p     |
|                  |           |            | (95% CI)        | -valu |
|                  | (N=751)   | (N=762)    |                 | e^\$^ |
+------------------+-----------+------------+-----------------+-------+
| Cardiovascular   | 247       | 268        | 0.90 (0.76,     | 0.25  |
| mor              | (32.9%)   | (35.2%)    | 1.08)           |       |
| tality/morbidity |           |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| Hospitalized for | 89        | 126        | 0.68 (0.52,     | 0.006 |
| HF               | (11.9%)   | (16.5%)    | 0.90)           |       |
+------------------+-----------+------------+-----------------+-------+
| MI               | 50 (      | 68 ( 8.9%) | 0.72 (0.50,     | 0.079 |
|                  | 6.7%)     |            | 1.04)           |       |
+------------------+-----------+------------+-----------------+-------+
| Stroke           | 47 (      | 50 ( 6.6%) | 0.85 (0.64,     | 0.78  |
|                  | 6.3%)     |            | 1.41)           |       |
+------------------+-----------+------------+-----------------+-------+
| Cardiovascular   | 90        | 79 (10.4%) | 1.12 (0.83,     | 0.45  |
| death            | (12.0%)   |            | 1.52)           |       |
+------------------+-----------+------------+-----------------+-------+
| R                | 69 (      | 60 ( 7.9%) | 1.19 (0.84,     | 0.34  |
| evascularization | 9.2%)     |            | 1.68)           |       |
+------------------+-----------+------------+-----------------+-------+
| Hospitalized for | 42 (      | 41 ( 5.4%) | 1.03 (0.67,     | 0.89  |
| Unstable angina  | 5.6%)     |            | 1.59)           |       |
+------------------+-----------+------------+-----------------+-------+

\$ using the same Cox regression model as for the primary endpoint

### Progression of Renal Disease

The rate of decline in renal function was smaller in the losartan group
than in the placebo group

#### Table 7. Summary of slopes of reciprocal of serum creatinine at quartiles (Sponsor's results confirmed by Reviewer's analysis)

+-----------------------+---------+---------+-------------+----------+
|                       | L       | Placebo | Est. renal  | p        |
|                       | osartan |         |             | -value\$ |
|                       |         | (N=762) | loss        |          |
|                       | (N=751) |         | reduction   |          |
+-----------------------+---------+---------+-------------+----------+
| Chronic slope         | N = 693 | N=678   | 25.5%       | \<       |
| (dL/mg/yr)            |         |         |             | 0.0001   |
|                       | -0.10   | -0.13   |             |          |
| (Month 3 and after)   |         |         |             |          |
|                       | -0.052  | -0.070  |             |          |
| Quartiles:            |         |         |             |          |
|                       | -0.020  | -0.028  |             |          |
| 25^th^                |         |         |             |          |
|                       |         |         |             |          |
| 50^th^                |         |         |             |          |
|                       |         |         |             |          |
| 75^th^                |         |         |             |          |
+-----------------------+---------+---------+-------------+----------+
| Overall slope         | N = 745 | N=754   | 18.5%       | 0.011    |
| (dL/mg/yr)            |         |         |             |          |
|                       | -0.11   | -0.14   |             |          |
| (all phases)          |         |         |             |          |
|                       | -0.057  | -0.070  |             |          |
| Quartiles:            |         |         |             |          |
|                       | -0.025  | -0.025  |             |          |
| 25^th^                |         |         |             |          |
|                       |         |         |             |          |
| 50^th^                |         |         |             |          |
|                       |         |         |             |          |
| 75^th^                |         |         |             |          |
+-----------------------+---------+---------+-------------+----------+

Negative slope indicates a loss of renal function

Est. loss reduction is estimated using a linear random effects model
adjusted for region, startum, and baseline serum creatinine

\$ based on two-sample median score nonparametric test

#### Table 8. Comparison of mean slopes for renal progression

+-----------------------+---------+---------+-------------+----------+
| Analysis of slope     | L       | Placebo | Est. renal  | p        |
| (dL/mg/yr)            | osartan |         |             | -value\$ |
|                       |         | (N=762) | loss        |          |
|                       | (N=751) |         | reduction   |          |
+-----------------------+---------+---------+-------------+----------+
| Chronic phase         | -0.060  | -0.070  | 13.9%       | 0.0033   |
+-----------------------+---------+---------+-------------+----------+
| All phases            | -0.067  | -0.077  | 12.7%       | 0.0091   |
+-----------------------+---------+---------+-------------+----------+

Negative slope indicates a loss of renal function

Est. loss reduction is estimated using a linear random effects model
adjusted for region, startum, and baseline serum creatinine

\$ based on two-sample median score nonparametric test

### Change in Proteinuria over Time

Table 14, Figures 6 and 7 of the sponsor's results (not yet confirmed by
reviewer's analysis) appeared to indicate that the Losartan group had a
much greater percent decrease in proteinuria in terms of geometric mean
and median than the placebo group.

### Predictibility of Proteinuria for Treatment Effect on Primary Endpoint

When proteinuria (on the log scale) was adjusted based on the Month 6 or
on the values over the entire study, prior to the primary composite
endpoint, the treatment effect of losartan diminished. This seems to
suggest that proteinuria is a strong predictor for the primary composite
endpoint in this study.

#### Table 9. Adjustment of the Primary endpoint for proteinuria at Month 6 and as a time-varying covariate (Sponsor's results confirmed by reviewer's analysis)

+-------------------------------+---------+---------+---------+--------+
|                               | L       | Placebo | Est.    | p-v    |
|                               | osartan |         | risk    | alue\$ |
|                               |         | (N=762) |         |        |
|                               | (N=751) |         | re      |        |
|                               |         |         | duction |        |
+-------------------------------+---------+---------+---------+--------+
| Primary endpoint              | 43.3%   | 46.1%   | -2.9%   | 0.73   |
|                               |         |         |         |        |
| Adj. for Month-6 Proteinuria  | 43.5%   | 47.1%   | 1.7%    | 0.83   |
|                               |         |         |         |        |
| Adj. for overall proteinuria  |         |         |         |        |
| changes                       |         |         |         |        |
+-------------------------------+---------+---------+---------+--------+
| ESRD                          | 19.6%   | 25.5%   | 14.1%   | 0.17   |
|                               |         |         |         |        |
| Adj. for overall proteinuria  |         |         |         |        |
| changes                       |         |         |         |        |
+-------------------------------+---------+---------+---------+--------+
| ESRD or death                 | 34.0%   | 39.4%   | 9.5%    | 0.25   |
|                               |         |         |         |        |
| Adj. for overall proteinuria  |         |         |         |        |
| changes                       |         |         |         |        |
+-------------------------------+---------+---------+---------+--------+

Est. risk reduction using a proportional hazards regression model with
adjustment for region and stratum

# 4. CONCLUSIONS

# 

#  There was some evidence that losartan might reduce the incidence of the primary composite endpoint, doubling of serum creatinine, ESRD or death, (reduction of risk = 16% with 95% CI of 3% to 28%, p = 0.022). The strength of evidence did not meet the usual standard of statistical evidence, at least lower by an order of magnitude in p-value. The effect of losartan in terms of the hazard of the primary endpoint did not appear to be constant over the duration of the trial (Figure 1, the hazard curves appeared to be converging). Approximately a half of the primary events were ESRD or death. The treatment difference seemed to be largely attributed to the difference in doubling of serum creatinine. However, in the patients with doubling serum creatinine, 51% developed ESRD in the losartan group and 65% in the placebo group; mean time from doubling serum creatinine to ESRD was about 30 days longer in the losartan group. In addition, 19.5% of the losartan patients and 25.5% of the placebo patients developed ESRD; thus, losartan seemed to be associated with a 29% reduction in risk of having an ESRD (p = 0.002). There is little difference in death rate between the losartan group and the placebo group. 

# 

Proteinuria seemed to be a strong predictor of the primary composite
event in this study. When proteinuria was adjusted based on the Month 6
value or on the values over time, prior to the primary composite
endpoint, the effect of losartan diminished (Table 9).

# The data seemed to suggest that there might be a difference in the effect of losartan in terms of hazard reduction of the primary endpoint between Asia and other regions. The Asia region appeared to show a big effect with losartan whereas other regions as a whole showed little effect (Table 4). Futher exploration seemed to suggest that this apparent difference, if real, might be attributed to a higher incidence rate of the primary endpoint in the placebo group in Asia, or to a higher baseline proteinuria level in Asia (Table A.5).

# 

# The rate of decline in renal function appeared to be smaller in the losartan group than in the placebo group. Losartan seemed to be associated with a reduction of hospitalizations for heart failure. No beneficial effect was found with losartan on cardiovascular mortality or morbidity, myocardial infarction, stroke, revascularization, or hospitalization for unstable angina. This seemed to make it difficult to interpret the apparent benefit with losartan in reduction of hospitalization for heart failure. 

# 5. APPENDIX

#### Table A.1 Distribution of time (days) to non-event censoring (Reviewer's analysis)

+-------------------+------------------------+------------------------+
|                   | Event=doubling serum   |                        |
|                   | creatinine, ESRD, or   |                        |
|                   | death                  |                        |
+-------------------+------------------------+------------------------+
|                   | Losartan               | Placebo                |
|                   |                        |                        |
|                   | (N=751)                | (N=762)                |
+-------------------+------------------------+------------------------+
| \# of censored    | 327 (43.5%)            | 359 (47.1%)            |
| cases             |                        |                        |
+-------------------+------------------------+------------------------+
| Max               | 1615                   | 1613                   |
+-------------------+------------------------+------------------------+
| 99th %tile        | 1580                   | 1579                   |
+-------------------+------------------------+------------------------+
| 95th              | 1522                   | 1504                   |
+-------------------+------------------------+------------------------+
| 90th              | 1475                   | 1445                   |
+-------------------+------------------------+------------------------+
| 75th              | 1376                   | 1376                   |
+-------------------+------------------------+------------------------+
| 50th              | 1199                   | 1196                   |
+-------------------+------------------------+------------------------+
| Mean              | 1212                   | 1201                   |
+-------------------+------------------------+------------------------+
| 25th              | 1040                   | 1026                   |
+-------------------+------------------------+------------------------+
| 10th              | 949                    | 940                    |
+-------------------+------------------------+------------------------+
| 5th               | 914                    | 906                    |
+-------------------+------------------------+------------------------+
| 1st               | 878                    | 885                    |
+-------------------+------------------------+------------------------+
| Min               | 865                    | 873                    |
+-------------------+------------------------+------------------------+

#### Table A.2. Primary endpoint by subgroups in Asia region excluding Israel (Reviewer's analysis)

+------------------------------+----------------+---------------+-----+
|                              | Losartan       | Placebo       | HR  |
|                              |                |               |     |
|                              | (N=106)        | (N=114)       |     |
+------------------------------+----------------+---------------+-----+
| Female                       | 12 / 29 ( 41.4 | 28 / 39 (     | 0   |
|                              | %)             | 71.8 %)       | .38 |
+------------------------------+----------------+---------------+-----+
| Male                         | 33 / 77 ( 42.9 | 38 / 75 (     | 0   |
|                              | %)             | 50.7 %)       | .82 |
+------------------------------+----------------+---------------+-----+
| Age \< 65 yrs                | 32 / 69 ( 46.4 | 45 / 79 (     | 0   |
|                              | %)             | 57.0 %)       | .70 |
+------------------------------+----------------+---------------+-----+
| Age \>= 65 yrs               | 13 / 37 ( 35.1 | 21 / 35 (     | 0   |
|                              | %)             | 60.0 %)       | .51 |
+------------------------------+----------------+---------------+-----+
| Asian                        | 45 / 106 (     | 66 / 114 (    | 0   |
|                              | 42.5 %)        | 57.9 %)       | .64 |
+------------------------------+----------------+---------------+-----+
| BMI \< 30 kg/m2              | 41 / 98 ( 41.8 | 64 / 109 (    | 0   |
|                              | %)             | 58.7 %)       | .62 |
+------------------------------+----------------+---------------+-----+
| BMI \>= 30 kg/m2             | 4 / 8 ( 50.0   | 2 / 5 ( 40.0  | 1   |
|                              | %)             | %)            | .04 |
+------------------------------+----------------+---------------+-----+
| Duration of hypertension \<  | 31 / 69 ( 44.9 | 45 / 78 (     | 0   |
| 10 yrs                       | %)             | 57.7 %)       | .70 |
+------------------------------+----------------+---------------+-----+
| Duration of hypertension \>= | 14 / 37 ( 37.8 | 21 / 36 (     | 0   |
| 10 yrs                       | %)             | 58.3 %)       | .52 |
+------------------------------+----------------+---------------+-----+
| Total Cholesterol \< 240     | 27 / 70 ( 38.6 | 38 / 75 (     | 0   |
| mg/dL                        | %)             | 50.7 %)       | .71 |
+------------------------------+----------------+---------------+-----+
| Total Cholesterol \>= 240    | 18 / 36 ( 50.0 | 28 / 39 (     | 0   |
| mg/dL                        | %)             | 71.8 %)       | .55 |
+------------------------------+----------------+---------------+-----+
| Serum Creatinine \< 2 mg/dL  | 19 / 60 ( 31.7 | 32 / 63 (     | 0   |
|                              | %)             | 50.8 %)       | .52 |
+------------------------------+----------------+---------------+-----+
| Serum Creatinine \>= 2 mg/dL | 26 / 46 ( 56.5 | 34 / 51 (     | 0   |
|                              | %)             | 66.7 %)       | .79 |
+------------------------------+----------------+---------------+-----+
| Serum Albumin \< 3.6 mg/dL   | 20 / 29 ( 69.0 | 29 / 34 (     | 0   |
|                              | %)             | 85.3 %)       | .63 |
+------------------------------+----------------+---------------+-----+
| Serum Albumin \>= 3.6 mg/dL  | 25 / 77 ( 32.5 | 37 / 80 (     | 0   |
|                              | %)             | 46.3 %)       | .62 |
+------------------------------+----------------+---------------+-----+
| Serum Uric Acid \< 7 mg/dL   | 28 / 73 ( 38.4 | 36 / 60 (     | 0   |
|                              | %)             | 60.0 %)       | .55 |
+------------------------------+----------------+---------------+-----+
| Serum Uric Acid \>= 7 mg/dL  | 17 / 33 ( 51.5 | 30 / 54 (     | 0   |
|                              | %)             | 55.6 %)       | .81 |
+------------------------------+----------------+---------------+-----+
| HbA1c \< 10%                 | 1 / 1 ( 100 %) | 1 / 1 ( 100   |     |
|                              |                | %)            |     |
+------------------------------+----------------+---------------+-----+
| HbA1c \>= 10%                | 44 / 105 (     | 65 / 113 (    | 0   |
|                              | 41.9 %)        | 57.5 %)       | .63 |
+------------------------------+----------------+---------------+-----+
| Hemoglobin \< 12 mg/dL       | 28 / 50 ( 56.0 | 43 / 60 (     | 0   |
|                              | %)             | 71.7 %)       | .61 |
+------------------------------+----------------+---------------+-----+
| Hemoglobin \>= 12 mg/dL      | 17 / 56 ( 30.4 | 23 / 54 (     | 0   |
|                              | %)             | 42.6 %)       | .69 |
+------------------------------+----------------+---------------+-----+
| Nonsmoker                    | 12 / 29 ( 41.4 | 14 / 23 (     | 0   |
|                              | %)             | 60.9 %)       | .59 |
+------------------------------+----------------+---------------+-----+
| Smoker                       | 33 / 77 ( 42.9 | 52 / 91 (     | 0   |
|                              | %)             | 57.1 %)       | .64 |
+------------------------------+----------------+---------------+-----+
| Sitting SBP \< 140 mmHg      | 5 / 23 ( 21.7  | 12 / 34 (     | 0   |
|                              | %)             | 35.3 %)       | .61 |
+------------------------------+----------------+---------------+-----+
| Sitting SBP \>=140 mmHg      | 40 / 83 ( 48.2 | 54 / 80 (     | 0   |
|                              | %)             | 67.5 %)       | .57 |
+------------------------------+----------------+---------------+-----+
| Insulin Use No               | 19 / 48 ( 39.6 | 29 / 56 (     | 0   |
|                              | %)             | 51.8 %)       | .71 |
+------------------------------+----------------+---------------+-----+
| Insulin Use Yes              | 26 / 58 ( 44.8 | 37 / 58 (     | 0   |
|                              | %)             | 63.8 %)       | .56 |
+------------------------------+----------------+---------------+-----+
| Dihydropyridine No           | 7 / 24 ( 29.2  | 11 / 23 (     | 0   |
|                              | %)             | 47.8 %)       | .61 |
+------------------------------+----------------+---------------+-----+
| Dihydropyridine Yes          | 38 / 82 ( 46.3 | 55 / 91 (     | 0   |
|                              | %)             | 60.4 %)       | .65 |
+------------------------------+----------------+---------------+-----+
| ACEI or AIIA Use No          | 13 / 42 ( 31.0 | 25 / 53 (     | 0   |
|                              | %)             | 47.2 %)       | .59 |
+------------------------------+----------------+---------------+-----+
| ACEI or AIIA Use Yes         | 32 / 64 ( 50.0 | 41 / 61 (     | 0   |
|                              | %)             | 67.2 %)       | .61 |
+------------------------------+----------------+---------------+-----+
| Beta Blocker Use No          | 39 / 88 ( 44.3 | 60 / 99 (     | 0   |
|                              | %)             | 60.6 %)       | .64 |
+------------------------------+----------------+---------------+-----+
| Beta Blocker Use Yes         | 6 / 18 ( 33.3  | 6 / 15 ( 40.0 | 0   |
|                              | %)             | %)            | .71 |
+------------------------------+----------------+---------------+-----+
| Calcium Blocker Use No       | 6 / 22 ( 27.3  | 11 / 23 (     | 0   |
|                              | %)             | 47.8 %)       | .56 |
+------------------------------+----------------+---------------+-----+
| Calcium Blocker Use Yes      | 39 / 84 ( 46.4 | 55 / 91 (     | 0   |
|                              | %)             | 60.4 %)       | .65 |
+------------------------------+----------------+---------------+-----+
| Proteinuria \< 2000 mg/g     | 15 / 62 ( 24.2 | 22 / 64 (     | 0   |
|                              | %)             | 34.4 %)       | .66 |
+------------------------------+----------------+---------------+-----+
| Proteinuria \>=2000 mg/g     | 30 / 44 ( 68.2 | 44 / 50 (     | 0   |
|                              | %)             | 88.0 %)       | .58 |
+------------------------------+----------------+---------------+-----+

#### Table A.3. Primary endpoint by subgroups in non-Asia region including Israel (Reviewer's analysis)

+------------------------------+----------------+----------------+----+
|                              | Losartan       | Placebo        | HR |
|                              |                |                |    |
|                              | (N=645)        | (N=648)        |    |
+------------------------------+----------------+----------------+----+
| Female                       | 126 / 260 (    | 117 / 229 (    | 0. |
|                              | 48.5 %)        | 51.1 %)        | 90 |
+------------------------------+----------------+----------------+----+
| Male                         | 156 / 385 (    | 176 / 419 (    | 0. |
|                              | 40.5 %)        | 42.0 %)        | 91 |
+------------------------------+----------------+----------------+----+
| Age \< 65 yrs                | 190 / 434 (    | 201 / 423 (    | 0. |
|                              | 43.8 %)        | 47.5 %)        | 86 |
+------------------------------+----------------+----------------+----+
| Age \>= 65 yrs               | 92 / 211 (     | 92 / 225 (     | 1. |
|                              | 43.6 %)        | 40.9 %)        | 04 |
+------------------------------+----------------+----------------+----+
| Asian                        | 4 / 11 ( 36.4  | 8 / 21 ( 38.1  | 1. |
|                              | %)             | %)             | 21 |
+------------------------------+----------------+----------------+----+
| Hispanic                     | 77 / 140 (     | 74 / 137 (     | 1. |
|                              | 55.0 %)        | 54.0 %)        | 01 |
+------------------------------+----------------+----------------+----+
| black                        | 50 / 125 (     | 41 / 105 (     | 0. |
|                              | 40.0 %)        | 39.0 %)        | 97 |
+------------------------------+----------------+----------------+----+
| white                        | 145 / 358 (    | 163 / 377 (    | 0. |
|                              | 40.5 %)        | 43.2 %)        | 87 |
+------------------------------+----------------+----------------+----+
| BMI \< 30 kg/m2              | 154 / 339 (    | 162 / 362 (    | 0. |
|                              | 45.4 %)        | 44.8 %)        | 97 |
+------------------------------+----------------+----------------+----+
| BMI \>= 30 kg/m2             | 128 / 306 (    | 131 / 286 (    | 0. |
|                              | 41.8 %)        | 45.8 %)        | 87 |
+------------------------------+----------------+----------------+----+
| Duration of hypertension \<  | 147 / 318 (    | 159 / 331 (    | 0. |
| 10 yrs                       | 46.2 %)        | 48.0 %)        | 94 |
+------------------------------+----------------+----------------+----+
| Duration of hypertension \>= | 135 / 327 (    | 134 / 317 (    | 0. |
| 10 yrs                       | 41.3 %)        | 42.3 %)        | 91 |
+------------------------------+----------------+----------------+----+
| Total Cholesterol \< 240     | 160 / 426 (    | 167 / 414 (    | 0. |
| mg/dL                        | 37.6 %)        | 40.3 %)        | 87 |
+------------------------------+----------------+----------------+----+
| Total Cholesterol \>= 240    | 122 / 219 (    | 126 / 234 (    | 1. |
| mg/dL                        | 55.7 %)        | 53.8 %)        | 02 |
+------------------------------+----------------+----------------+----+
| Serum Creatinine \< 2 mg/dL  | 155 / 422 (    | 141 / 420 (    | 1. |
|                              | 36.7 %)        | 33.6 %)        | 07 |
+------------------------------+----------------+----------------+----+
| Serum Creatinine \>= 2 mg/dL | 127 / 223 (    | 152 / 228 (    | 0. |
|                              | 57.0 %)        | 66.7 %)        | 76 |
+------------------------------+----------------+----------------+----+
| Serum Albumin \< 3.6 mg/dL   | 123 / 178 (    | 116 / 168 (    | 0. |
|                              | 69.1 %)        | 69.0 %)        | 93 |
+------------------------------+----------------+----------------+----+
| Serum Albumin \>= 3.6 mg/dL  | 159 / 467 (    | 177 / 480 (    | 0. |
|                              | 34.0 %)        | 36.9 %)        | 88 |
+------------------------------+----------------+----------------+----+
| Serum Uric Acid \< 7 mg/dL   | 169 / 386 (    | 167 / 388 (    | 0. |
|                              | 43.8 %)        | 43.0 %)        | 98 |
+------------------------------+----------------+----------------+----+
| Serum Uric Acid \>= 7 mg/dL  | 113 / 259 (    | 126 / 260 (    | 0. |
|                              | 43.6 %)        | 48.5 %)        | 85 |
+------------------------------+----------------+----------------+----+
| HbA1c \< 10%                 | 4 / 8 ( 50.0   | 1 / 7 ( 14.3   | 4. |
|                              | %)             | %)             | 15 |
+------------------------------+----------------+----------------+----+
| HbA1c \>= 10%                | 278 / 637 (    | 292 / 641 (    | 0. |
|                              | 43.6 %)        | 45.6 %)        | 91 |
+------------------------------+----------------+----------------+----+
| Hemoglobin \< 12 mg/dL       | 135 / 265 (    | 135 / 250 (    | 0. |
|                              | 50.9 %)        | 54.0 %)        | 88 |
+------------------------------+----------------+----------------+----+
| Hemoglobin \>= 12 mg/dL      | 147 / 380 (    | 158 / 398 (    | 0. |
|                              | 38.7 %)        | 39.7 %)        | 93 |
+------------------------------+----------------+----------------+----+
| Nonsmoker                    | 57 / 118 (     | 47 / 107 (     | 1. |
|                              | 48.3 %)        | 43.9 %)        | 10 |
+------------------------------+----------------+----------------+----+
| Smoker                       | 225 / 527 (    | 246 / 541 (    | 0. |
|                              | 42.7 %)        | 45.5 %)        | 88 |
+------------------------------+----------------+----------------+----+
| Sitting SBP \< 140 mmHg      | 55 / 168 (     | 54 / 153 (     | 0. |
|                              | 32.7 %)        | 35.3 %)        | 90 |
+------------------------------+----------------+----------------+----+
| Sitting SBP \>=140 mmHg      | 227 / 477 (    | 239 / 495 (    | 0. |
|                              | 47.6 %)        | 48.3 %)        | 93 |
+------------------------------+----------------+----------------+----+
| Insulin Use No               | 94 / 242 (     | 99 / 257 (     | 0. |
|                              | 38.8 %)        | 38.5 %)        | 98 |
+------------------------------+----------------+----------------+----+
| Insulin Use Yes              | 188 / 403 (    | 194 / 391 (    | 0. |
|                              | 46.7 %)        | 49.6 %)        | 88 |
+------------------------------+----------------+----------------+----+
| Dihydropyridine No           | 121 / 321 (    | 137 / 328 (    | 0. |
|                              | 37.7 %)        | 41.8 %)        | 86 |
+------------------------------+----------------+----------------+----+
| Dihydropyridine Yes          | 161 / 324 (    | 156 / 320 (    | 0. |
|                              | 49.7 %)        | 48.8 %)        | 98 |
+------------------------------+----------------+----------------+----+
| ACEI or AIIA Use No          | 133 / 309 (    | 155 / 333 (    | 0. |
|                              | 43.0 %)        | 46.5 %)        | 89 |
+------------------------------+----------------+----------------+----+
| ACEI or AIIA Use Yes         | 149 / 336 (    | 138 / 315 (    | 0. |
|                              | 44.3 %)        | 43.8 %)        | 96 |
+------------------------------+----------------+----------------+----+
| Beta Blocker Use No          | 226 / 526 (    | 238 / 523 (    | 0  |
|                              | 43.0 %)        | 45.5 %)        | .9 |
+------------------------------+----------------+----------------+----+
| Beta Blocker Use Yes         | 56 / 119 (     | 55 / 125 (     | 1. |
|                              | 47.1 %)        | 44.0 %)        | 03 |
+------------------------------+----------------+----------------+----+
| Calcium Blocker Use No       | 76 / 197 (     | 78 / 193 (     | 0. |
|                              | 38.6 %)        | 40.4 %)        | 88 |
+------------------------------+----------------+----------------+----+
| Calcium Blocker Use Yes      | 206 / 448 (    | 215 / 455 (    | 0. |
|                              | 46.0 %)        | 47.3 %)        | 94 |
+------------------------------+----------------+----------------+----+
| Proteinuria \< 2000 mg/g     | 135 / 439 (    | 139 / 447 (    | 0. |
|                              | 30.8 %)        | 31.1 %)        | 95 |
+------------------------------+----------------+----------------+----+
| Proteinuria \>=2000 mg/g     | 147 / 206 (    | 154 / 201 (    | 0. |
|                              | 71.4 %)        | 76.6 %)        | 84 |
+------------------------------+----------------+----------------+----+

#### Table A.4 Baseline characteristics for Asia versus Non-Asia regions (Reviewer's analysis)

+---------------------------------+-----------------+-----------------+
|                                 | Asia\*          | Non-Asia\*      |
|                                 |                 |                 |
|                                 | (N=220)         | (N=1293)        |
+---------------------------------+-----------------+-----------------+
| Female                          | 68 ( 30.9 %)    | 489 ( 37.8 %)   |
|                                 |                 |                 |
| Male                            | 152 ( 69.1 %)   | 804 ( 62.2 %)   |
+---------------------------------+-----------------+-----------------+
| Age \< 65 yrs                   | 148 ( 67.3 %)   | 857 ( 66.3 %)   |
|                                 |                 |                 |
| Age \>= 65 yrs                  | 72 ( 32.7 %)    | 436 ( 33.7 %)   |
+---------------------------------+-----------------+-----------------+
| BMI \< 30 kg/m2                 | 207 ( 94.1 %)   | 701 ( 54.2 %)   |
|                                 |                 |                 |
| BMI \>= 30 kg/m2                | 13 ( 5.9 %)     | 592 ( 45.8 %)   |
+---------------------------------+-----------------+-----------------+
| Duration of hypertension \< 10  | 147 ( 66.8 %)   | 649 ( 50.2 %)   |
| yrs                             |                 |                 |
|                                 | 73 ( 33.2 %)    | 644 ( 49.8 %)   |
| Duration of hypertension \>= 10 |                 |                 |
| yrs                             |                 |                 |
+---------------------------------+-----------------+-----------------+
| Total Cholesterol \< 240 mg/dL  | 145 ( 65.9 %)   | 840 ( 65.0 %)   |
|                                 |                 |                 |
| Total Cholesterol \>= 240 mg/dL | 75 ( 34.1 %)    | 453 ( 35.0 %)   |
+---------------------------------+-----------------+-----------------+
| Serum Creatinine \< 2 mg/dL     | 123 ( 55.9 %)   | 842 ( 65.1 %)   |
|                                 |                 |                 |
| Serum Creatinine \>= 2 mg/dL    | 97 ( 44.1 %)    | 451 ( 34.9 %)   |
+---------------------------------+-----------------+-----------------+
| Serum Albumin \< 3.6 mg/dL      | 63 ( 28.6 %)    | 346 ( 26.8 %)   |
|                                 |                 |                 |
| Serum Albumin \>= 3.6 mg/dL     | 157 ( 71.4 %)   | 947 ( 73.2 %)   |
+---------------------------------+-----------------+-----------------+
| Serum Uric Acid \< 7 mg/dL      | 133 ( 60.5 %)   | 774 ( 59.9 %)   |
|                                 |                 |                 |
| Serum Uric Acid \>= 7 mg/dL     | 87 ( 39.5 %)    | 519 ( 40.1 %)   |
+---------------------------------+-----------------+-----------------+
| HbA1c \< 10%                    | 2 ( 0.9 %)      | 15 ( 1.2 %)     |
|                                 |                 |                 |
| HbA1c \>= 10%                   | 218 ( 99.1 %)   | 1278 ( 98.8 %)  |
+---------------------------------+-----------------+-----------------+
| Hemoglobin \< 12 mg/dL          | 110 ( 50.0 %)   | 515 ( 39.8 %)   |
|                                 |                 |                 |
| Hemoglobin \>= 12 mg/dL         | 110 ( 50.0 %)   | 778 ( 60.2 %)   |
+---------------------------------+-----------------+-----------------+
| Nonsmoker                       | 52 ( 23.6 %)    | 225 ( 17.4 %)   |
|                                 |                 |                 |
| Smoker                          | 168 ( 76.4 %)   | 1068 ( 82.6 %)  |
+---------------------------------+-----------------+-----------------+
| Sitting SBP \< 140 mmHg         | 57 ( 25.9 %)    | 321 ( 24.8 %)   |
|                                 |                 |                 |
| Sitting SBP \>=140 mmHg         | 163 ( 74.1 %)   | 972 ( 75.2 %)   |
+---------------------------------+-----------------+-----------------+
| Insulin Use No                  | 104 ( 47.3 %)   | 499 ( 38.6 %)   |
|                                 |                 |                 |
| Insulin Use Yes                 | 116 ( 52.7 %)   | 794 ( 61.4 %)   |
+---------------------------------+-----------------+-----------------+
| Dihydropyridine No              | 47 ( 21.4 %)    | 649 ( 50.2 %)   |
|                                 |                 |                 |
| Dihydropyridine Yes             | 173 ( 78.6 %)   | 644 ( 49.8 %)   |
+---------------------------------+-----------------+-----------------+
| ACEI or AIIA Use No             | 95 ( 43.2 %)    | 642 ( 49.7 %)   |
|                                 |                 |                 |
| ACEI or AIIA Use Yes            | 125 ( 56.8 %)   | 651 ( 50.3 %)   |
+---------------------------------+-----------------+-----------------+
| Beta Blocker Use No             | 187 ( 85.0 %)   | 1049 ( 81.1 %)  |
|                                 |                 |                 |
| Beta Blocker Use Yes            | 33 ( 15.0 %)    | 244 ( 18.9 %)   |
+---------------------------------+-----------------+-----------------+
| Calcium Blocker Use No          | 45 ( 20.5 %)    | 390 ( 30.2 %)   |
|                                 |                 |                 |
| Calcium Blocker Use Yes         | 175 ( 79.5 %)   | 903 ( 69.8 %)   |
+---------------------------------+-----------------+-----------------+
| Proteinuria \< 2000 mg/g        | 126 ( 57.3 %)   | 886 ( 68.5 %)   |
|                                 |                 |                 |
| Proteinuria \>=2000 mg/g        | 94 ( 42.7 %)    | 407 ( 31.5 %)   |
+---------------------------------+-----------------+-----------------+

#### \* Israel is put in Non-Asia region 

#### Table A.5 Distribution of proteinuria level (mg/g) \[Reviewer's analysis\]

  ------------------- ------------------------- -------------------------
                      Asia                      Other^\$^

  Max                 10150                     12208

  99th %tile          7670                      7537

  95th                5248                      5102

  90th                4602                      4045

  75th                2976                      2433

  50th                1672                      1161

  Mean                2151                      1749

  25th                767                       538

  10th                422                       294

  5th                 319                       203

  1st                 122                       75

  Min                 45                        31
  ------------------- ------------------------- -------------------------

\$ North America, Latin America, Europe

#### Figure 1. log(-log(survival)) versus log(days) for the primary endpont, doubling serum creatlinie, ESRD, or death

![](media/image2.png)