NDA 20‑386, COZAAR (Losartan) Page 1

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CENTER FOR DRUG EVALUATION AND RESEARCH

STATISTICAL REVIEW AND EVALUATION

(Addendum)

NDA #: 20‑386

SERIAL #: SEl‑S028

DRUG NAME: COZAAR (Losartan Potassium) tablets

**INDICATION:** Renal Protection

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

**DOCUMENT REVIEWED:**

1\. Vols. 1 and 2 (CDER RECD 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/DB 1/cozaar.doc/4‑1‑2002

NDA 20‑386, COZAAR (Losartan) Page 2

**SUMMARY**

This addendum is to remove the p‑values of the component events
(doubling serum creatinine, ESRD or death) as the \"first\" event of the
primary composite endpoint, given in Table 1 of my review of March 1,
2002. The removal is to avoid possible misinterpretation of these
p-values which originally were provided purely for the description
purpose, not for statistical testing. As the result, Table 1 in the
original review is changed to Table 1a give below.

**Table [1a.]{.underline} Incidence of adjudicated [primary]{.underline}
events (Reviewer\'s Analysis)**

+------------------+-----------+------------+-----------------+-------+
|                  | Losartan  | Placebo    | Hazard ratio    | p     |
|                  |           |            |                 | -valu |
|                  | =751      | =762       | 95.2% CI        | e^\$^ |
+------------------+-----------+------------+-----------------+-------+
| **Primary        |           |            |                 |       |
| event**          |           |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| Doubling serum   | 327       | 359        | 0.84 (0.72,     | 0.022 |
|                  | (43.5%)   | (47.1%)    | 0.97)           |       |
| creatinine, ESRD |           |            |                 |       |
| or               | Median    | Median     |                 |       |
|                  | time      | time       |                 |       |
| death            |           |            |                 |       |
|                  | = 1303    | =1373 day  |                 |       |
|                  | days      | s          |                 |       |
+------------------+-----------+------------+-----------------+-------+
| **Decomposition  | **primary |            |                 |       |
| of the** ls\`    | event**   |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| Doubling of SC   | 162       | 198        | 0.75 (0.61,     |       |
|                  | (21.6%)   | (26.0%)    | 0.92)           |       |
+------------------+-----------+------------+-----------------+-------+
| ESRD             | 64 (8.5%) | 65 (8.5%)  | 0.93 (0.65,     |       |
|                  |           |            | 1.31)           |       |
+------------------+-----------+------------+-----------------+-------+
| Death            | 101       | 96 (12.6%) | 0.98 (0.74,     |       |
|                  | (13.5%)   |            | 1.30)           |       |
+------------------+-----------+------------+-----------------+-------+
|                  |           |            |                 |       |
+------------------+-----------+------------+-----------------+-------+
| **1st 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)

As said in the conclusion section of my review of March 1, 2002, 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.
Approximately a half of the primary composite events were doubling of
serum creatinine and the other half were ESRD or death as the first
event. The treatment difference seemed to be largely shown by doubling
of serum creatinine. However, in the patients with doubling serum
creatinine, 51 % developed ES1RD in the losartan group and 65% in the
placebo group; mean time from doubling serum creatinine to ES1RD was
about 30 days longer in the losartan group in these patients. In
addition, during the study period, 19.5% of the losartan patients and
25.5% of the placebo patients developed ESRD; thus, losartan appeared to
give a 29% reduction in risk of having an ES1tD (p = 0.002). There is
little difference in death rate between the losartan group and the
placebo group.