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U.S. Department of Health and Human Services

Food and Drug Administration

> Center for Drug Evaluation and Research
>
> Office of Pharmacoepidemiology and Statistical Science
>
> Office of Biostatistics

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

Clinical Studies

+-------------------+--------------------------------------------------+
| **NDA/Serial      | 21-686                                           |
| Number:**         |                                                  |
+-------------------+--------------------------------------------------+
| **Drug Name:**    | Exanta (ximelagatran)                            |
+-------------------+--------------------------------------------------+
| *                 | • Prevention of VTE in patients undergoing knee  |
| *Indication(s):** | replacement surgery                              |
|                   |                                                  |
|                   | • Long term secondary prevention of VTE after    |
|                   | standard treatment for an episode of acute VTE   |
+-------------------+--------------------------------------------------+
| **Applicant:**    | Astra Zeneca                                     |
+-------------------+--------------------------------------------------+
| **Date(s):**      | Received 12/23/03                                |
+-------------------+--------------------------------------------------+
| **Review          | Standard review                                  |
| Priority:**       |                                                  |
+-------------------+--------------------------------------------------+
| **Biometrics      | Division of Biometrics II                        |
| Division:**       |                                                  |
+-------------------+--------------------------------------------------+
| **Statistical     | Dionne L. Price, Ph.D.                           |
| Reviewer:**       |                                                  |
+-------------------+--------------------------------------------------+
| **Concurring      | Stella Grosser, Ph.D.                            |
| Reviewers:**      |                                                  |
|                   | S. Edward Nevius, Ph.D.                          |
+-------------------+--------------------------------------------------+
| **Medical         | Division of Gastrointestinal and Coagulant Drug  |
| Division:**       | Products                                         |
+-------------------+--------------------------------------------------+
| **Clinical        | Ruyi He, M.D.                                    |
| Team:**           |                                                  |
|                   | Kathy Robie-Suh, M.D.                            |
+-------------------+--------------------------------------------------+
| **Project         | Alice Kacuba                                     |
| Manager:**        |                                                  |
+-------------------+--------------------------------------------------+
|                   |                                                  |
+-------------------+--------------------------------------------------+
|                   |                                                  |
+-------------------+--------------------------------------------------+
| **Keywords:** NDA |                                                  |
| review, clinical  |                                                  |
| studies           |                                                  |
+-------------------+--------------------------------------------------+
|                   |                                                  |
+-------------------+--------------------------------------------------+
|                   |                                                  |
+-------------------+--------------------------------------------------+
|                   |                                                  |
+-------------------+--------------------------------------------------+

Table of Contents

[1. EXECUTIVE SUMMARY 3](#executive-summary)

[1.1 Conclusions and Recommendations
3](#conclusions-and-recommendations)

[1.2 Brief Overview of Clinical Studies
3](#brief-overview-of-clinical-studies)

[1.3 Statistical Issues and Findings
4](#statistical-issues-and-findings)

[2. INTRODUCTION 5](#introduction)

[2.1 Overview 5](#overview)

[2.2 Data Sources 5](#data-sources)

[3. STATISTICAL EVALUATION 7](#statistical-evaluation)

[3.1 Evaluation of Efficacy 7](#evaluation-of-efficacy)

[3.1.1 SH-TPO-0010(EXULT A) 7](#sh-tpo-0010exult-a)

[3.1.2 SH-TPO-0012(EXULT B) 10](#sh-tpo-0012exult-b)

[3.1.3 Additional Studies 13](#additional-studies)

[3.1.4 SH-TPV-0003(THRIVE III) 13](#sh-tpv-0003thrive-iii)

[3.2 Evaluation of Safety 17](#evaluation-of-safety)

[4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
18](#findings-in-specialsubgroup-populations)

[4.1 Gender, Race and Age 18](#gender-race-and-age)

[4.1.1 SH-TPO-0010(EXULT A) and SH-TPO-0012(EXULT B)
18](#sh-tpo-0010exult-a-and-sh-tpo-0012exult-b)

[4.1.2 SH-TPV-0003(THRIVE III) 19](#sh-tpv-0003thrive-iii-1)

[4.2 Other Special/Subgroup Populations
19](#other-specialsubgroup-populations)

[5. SUMMARY AND CONCLUSIONS 19](#summary-and-conclusions)

[5.1 Statistical Issues and Collective Evidence
19](#statistical-issues-and-collective-evidence)

[5.2 Conclusions and Recommendations
20](#conclusions-and-recommendations-1)

[6. APPENDIX 21](#appendix)

[6.1 EXULT A 21](#exult-a)

[6.2 EXULT B 27](#exult-b)

[6.3 THRIVE III 29](#thrive-iii)

# 1. EXECUTIVE SUMMARY {#executive-summary .unnumbered}

## 1.1 Conclusions and Recommendations {#conclusions-and-recommendations .unnumbered}

##  {#section .unnumbered}

Astra Zeneca has proposed Exanta (ximelagatran) tablets for the
prevention of venous thromboembolism (VTE) in patients undergoing knee
replacement surgery and for the long term secondary prevention of VTE
after standard treatment for an episode of acute VTE. The applicant
claimed that ximelagatran reduced the incidence of total VTE and/or
mortality in patients undergoing total knee replacement and that
ximelagatran reduced the recurrence of VTE events among patients who
previously received 6 months of anticoagulation therapy for an acute
VTE. Based on my evaluation of NDA 21-686, I concluded that statistical
evidence supported the efficacy of ximelagatran for the proposed
indications. However, several additional issues required consideration
to completely ascertain the strength of the efficacy results. The issues
were beyond the scope of this review and included the adequacy of the
period of follow-up for the short term indication, the appropriateness
of warfarin as a comparator, and concerns regarding the safety profile
of the drug. These concerns are addressed in the clinical review of Dr.
Ruyi He.

## 1.2 Brief Overview of Clinical Studies {#brief-overview-of-clinical-studies .unnumbered}

Support for the oral anticoagulant, ximelagatran, was primarily derived
from three studies. Two studies, EXULT A and EXULT B, investigated the
superiority of ximelagatran to warfarin in the prevention of VTE. A
single study, THRIVE III, investigated the superiority of ximelagatran
to placebo in the long term secondary prevention of VTE.

EXULT A and EXULT B were randomized, double-blind, multi-center studies
conducted in patients undergoing total knee replacement. Eligible
participants in the former study were randomized to ximelagatran 24 mg,
ximelagatran 36 mg, or warfarin. Patients in the latter study were
randomized to ximelagatran 36 mg or warfarin. Due to varying appearances
and dosing schedules, the treatments were administered utilizing a
double-dummy design. Patients received treatment twice daily for 7 to 12
days. The primary measure of efficacy was the incidence of total VTE
and/or all-cause mortality where total VTE was defined as distal and/or
proximal deep vein thrombosis and/or symptomatic pulmonary embolism.
Treatment group differences were assessed using a
Cochran-Mantel-Haenszel chi-square test stratified by type of surgery.

THRIVE III was a randomized, double-blind, placebo-controlled,
multi-center study to assess the efficacy of ximelagatran 24 mg given as
a prolonged prophylaxis after a six-month anticoagulation treatment. The
pool of eligible patients included individuals who had an objectively
verified, symptomatic VTE and had received anticoagulation treatment for
approximately six months. Two to seven days prior to randomization,
patients were instructed to terminate their anticoagulation treatment.
Study participants were randomized to ximelagatran 24 mg or placebo
administered twice daily for 18 months. The primary measure of efficacy
was the time to the first VTE event. The analysis employed a log-rank
test to assess the treatment differences.

## 1.3 Statistical Issues and Findings {#statistical-issues-and-findings .unnumbered}

One methodological issue arose during the course of my review. In THRIVE
III, analyses of the outcomes utilized the statistical methodology of
survival analysis. An underlying assumption of the methodology, as
applied by the applicant, is that all study participants will experience
a recurrence. However in THRIVE III, a substantial number of
participants may never experience a recurrence; therefore, caution
should be exercised when interpreting conclusions from the planned
analysis. I subsequently dichotomized the response and performed an
analysis similar to that of EXULT A and EXULT B. My analysis was
post-hoc; however, the sole purpose was to validate the conclusions.

## The evidence taken collectively from EXULT A and EXULT B indicated statistical support of the efficacy of the ximelagatran for short-term use. When comparing ximelagatran 36 mg to warfarin, a significant reduction in the incidence of VTE and/or all-cause mortality was demonstrated in both studies. The magnitude of the reduction was 7.3% and 9.3% (ximelagatran 36 mg versus warfarin) in the two studies, respectively. A 24 mg dose of ximelagatran was additionally included in EXULT A; however, the dose failed to demonstrate a significant difference in the reduction of total VTE and/or all-cause mortality as compared to warfarin. The evidence from THRIVE III indicated statistical support of ximelagatran for the long term secondary prevention of VTE. Specifically, ximelagatran 24 mg (administered twice daily for 18 months) significantly reduced the recurrence rate of VTE events compared to placebo. The estimated cumulative risk of a recurrent VTE was 2.8% for patients randomized to ximelagatran and 12.6% for patients randomized to placebo. {#the-evidence-taken-collectively-from-exult-a-and-exult-b-indicated-statistical-support-of-the-efficacy-of-the-ximelagatran-for-short-term-use.-when-comparing-ximelagatran-36-mg-to-warfarin-a-significant-reduction-in-the-incidence-of-vte-andor-all-cause-mortality-was-demonstrated-in-both-studies.-the-magnitude-of-the-reduction-was-7.3-and-9.3-ximelagatran-36-mg-versus-warfarin-in-the-two-studies-respectively.-a-24-mg-dose-of-ximelagatran-was-additionally-included-in-exult-a-however-the-dose-failed-to-demonstrate-a-significant-difference-in-the-reduction-of-total-vte-andor-all-cause-mortality-as-compared-to-warfarin.-the-evidence-from-thrive-iii-indicated-statistical-support-of-ximelagatran-for-the-long-term-secondary-prevention-of-vte.-specifically-ximelagatran-24-mg-administered-twice-daily-for-18-months-significantly-reduced-the-recurrence-rate-of-vte-events-compared-to-placebo.-the-estimated-cumulative-risk-of-a-recurrent-vte-was-2.8-for-patients-randomized-to-ximelagatran-and-12.6-for-patients-randomized-to-placebo. .unnumbered}

# 2. INTRODUCTION {#introduction .unnumbered}

## 2.1 Overview {#overview .unnumbered}

Astra Zeneca has proposed Exanta (ximelagatran), an oral anticoagulant,
for the following indications: prevention of venous thromboembolism
(VTE) in patients undergoing total knee replacement, long term secondary
prevention of VTE after standard treatment for an episode of acute VTE,
and prevention of stroke and other thromboembolic complications
associated with atrial fibrillation. According to the applicant, "The
development program for ximelagatran has been designed to offer an oral
alternative anticoagulant to VKAs for major indications." Exanta was
introduced to the Division of Gastrointestinal and Coagulant Drug
Products through\
IND 56, 611. The development plan was discussed via several meetings and
correspondences. Discussion topics focused on the appropriateness of
various clinically defined outcomes, the justification of the proposed
non-inferiority margin for specified studies, and the number and type of
studies required for the proposed indications. The current submission
includes studies investigating the superiority of ximelagatran to
warfarin in prevention of VTE in patients undergoing knee replacement,
the superiority of ximelagatran to placebo in the secondary prevention
of VTE, and the non-inferiority of ximelagatran to warfarin in the
prevention of complications associated with atrial fibrillation. This
review will focus on the former two indications only. The latter
indication will be reviewed by the Division of Cardio-Renal Drugs.

## Data Sources

Primary support for ximelagatran for the prevention of VTE was derived
from two randomized, double-blind, multi-center studies, namely, EXULT A
and EXULT B. Support for the long term secondary prevention indication
was derived from THRIVE III, a randomized, double-blind, multi-center
study. The drug application was electronic. The study reports and data
were archived in the Food and Drug Administration internal document room
under the network path location \\\\CDSEUB1\\N21686\\N_000\\2003-12-23.
A summary of the studies is provided in Table 1.

Table 1: Table of studies

+-----------------+-----------------+-----------------+-----------------+
| **Study         | **Study         | **Treatment     | **Primary       |
| Number**        | Design**        | Arms and Number | measure of      |
|                 |                 | of randomized   | efficacy**      |
| **Number of     |                 | patients (n)**  |                 |
| centers (n)**   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| SH-TPO-0010     | Phase 3,        | •Exanta 24 mg   | Composite       |
|                 | randomized,     | (762)           | endpoint of DVT |
| EXULT A         | double-blind,   |                 | and/or PE       |
|                 | ac              | •Exanta 36 mg   | and/or          |
| Multi-center    | tive-controlled | (775)           |                 |
| (114)           | study in        |                 | all-cause       |
|                 | patients        | •Warfarin (764) | mortality       |
|                 | undergoing      |                 |                 |
|                 | total knee      |                 |                 |
|                 | replacement     |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| SH-TPO-0012     | Phase 3,        | •SKY0401 36 mg  | Composite       |
|                 | randomized,     | (1152)          | endpoint of DVT |
| EXULT B         | double-blind,   |                 | and/or PE       |
|                 | ac              | •Warfarin       | and/or          |
| Multi-center    | tive-controlled | (1151)          |                 |
| (113)           | study in        |                 | all-cause       |
|                 | patients        |                 | mortality       |
|                 | undergoing      |                 |                 |
|                 | total knee      |                 |                 |
|                 | replacement     |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| SH-TPO-0005     | Phase 3,        | •Exanta 24 mg   | Incidence of    |
|                 | randomized,     | (918)           | overall VTE     |
| Multi-center    | double-blind,   |                 |                 |
| (126)           | act             | •Enoxaparin 30  |                 |
|                 | ive-controlled, | mg (920)        |                 |
|                 | ,               |                 |                 |
|                 | non-inferiority |                 |                 |
|                 | study in        |                 |                 |
|                 | patients        |                 |                 |
|                 | undergoing      |                 |                 |
|                 | total hip       |                 |                 |
|                 | arthroplasty    |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| SH-TPO-0006     | Phase 3,        | •Exanta 24 mg   | Incidence of    |
|                 | randomized,     | (348)           | overall VTE     |
| Multi-center    | double-blind,   |                 |                 |
| (77)            | ac              | •Warfarin (332) |                 |
|                 | tive-controlled |                 |                 |
|                 | study in        |                 |                 |
|                 | patients        |                 |                 |
|                 | undergoing      |                 |                 |
|                 | total knee      |                 |                 |
|                 | replacement     |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| SH-TPO-0004     | Phase 2,        | •Exanta 8 mg    | Incidence of    |
|                 | randomized,     | (85)            | overall VTE     |
| Multi-center    | dose-finding,   |                 |                 |
| (55)            | safety, and     | •Exanta 12 mg   |                 |
|                 | p               | (134)           |                 |
|                 | harmacokinetics |                 |                 |
|                 | study in        | •Exanta 18 mg   |                 |
|                 | patients        | (126)           |                 |
|                 | undergoing      |                 |                 |
|                 | total knee      | •Exanta 24 mg   |                 |
|                 | replacement     | (130)           |                 |
|                 |                 |                 |                 |
|                 |                 | •Enoxaparin 30  |                 |
|                 |                 | mg (125)        |                 |
+-----------------+-----------------+-----------------+-----------------+
| SH-TPV-0003     | Phase 3,        | •Exanta 24 mg   | Time to first   |
|                 | randomized,     | (617)           | VTE event       |
| THRIVE III      | double-blind,   |                 |                 |
|                 | pla             | •Placebo (616)  |                 |
| Multi-center    | cebo-controlled |                 |                 |
| (142)           | study in        |                 |                 |
|                 | patients having |                 |                 |
|                 | received        |                 |                 |
|                 | six-month       |                 |                 |
|                 | anticoagulation |                 |                 |
|                 | treatment for   |                 |                 |
|                 | VTE             |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

# 3. STATISTICAL EVALUATION {#statistical-evaluation .unnumbered}

##  {#section-1 .unnumbered}

## 3.1 Evaluation of Efficacy {#evaluation-of-efficacy .unnumbered}

The main body of my evaluation of efficacy will discuss each study
individually.

### *3.1.1 SH-TPO-0010(EXULT A)* {#sh-tpo-0010exult-a .unnumbered}

*Study Design and Endpoints*

Due to the varying appearances and dosing schedules, treatments were
administered utilizing a double-dummy design. After surgery, eligible
patients were randomized to one of the following three treatment
regimens:

-   ximelagatran 24 mg tablet with a 36 mg placebo tablet and placebo
    capsule(s) matching warfarin,

-   ximelagatran 36 mg with a 24 mg placebo tablet and placebo
    capsule(s) matching warfarin, or

-   warfarin 2.5 mg capsule(s) and two placebo tablets matching
    ximelagatran 24 mg and 36 mg.

The first dose of warfarin (and matching placebo) was administered on
the evening of the day of surgery, and subsequent doses were
administered each evening. Ximelagatran (and matching placebo) was
initially administered the morning after surgery. Subsequent doses of
ximelagatran were administered twice daily, in the morning and evening
with doses taken at 12 hour intervals. Of note, the dose of warfarin was
adjusted to maintain a target international normalized ratio of 2.5
(range 1.8 to 3.0). The duration of treatment varied from 7 to 12 days.

The primary measure of efficacy was incidence of total venous
thromboembolism (VTE) and/or all-cause mortality. Total VTE was defined
as distal and/or proximal deep vein thrombosis and/or symptomatic
pulmonary embolism (with objective Independent Central Adjudication
Committee confirmation). Deep vein thrombosis (DVT) was assessed using a
venographic procedure. The diagnosis of pulmonary embolism (PE) was
established by a ventral perfusion lung scan, pulmonary angiography, or
spiral computed tomography. Additional details regarding the methodology
used for assessments and diagnoses of VTE are included in the appendix.
Secondary measures of interest included the incidence of proximal DVT,
PE, and/or all-cause mortality (via Independent Central Adjudication
Committee assessment) and the incidence of total VTE and/or all-cause
mortality (via local assessment).

Based on previous studies, a sample size of 1700 was determined to be
sufficient to detect an approximate 7.5% difference in reduction in VTE
between treatment groups and warfarin with 80% power. According to the
applicant, the needed sample size was increased to 2250 to account for
the percentage of patients (at most 25%) not having evaluable venograms.
Of note, 116 international centers participated in the study; however,
patients were only randomized at 114 centers.

*Patient Disposition, Demographic and Baseline Characteristics*

Descriptive demographic and baseline information was summarized using
2285 of the 2301 randomized patients. The excluded patients did not
receive study medication. The ages of patients were between 32 and 89
with a mean age of 68. In the study, approximately 96% of the study
participants were Caucasian, and 4% of the participants were African
American. Females composed 62% of the patient population. Baseline
characteristics included weight, body mass index, nicotine use, alcohol
use, and creatinine clearance. Demographic and baseline characteristics
did not differ between treatment arms. A detailed table outlining the
composition of the study population is presented in the appendix.

Of the 2285 randomized patients, 1851 of the patients had surgery,
received at least one dose of the study medication, and were included in
the efficacy analyses. Approximately 98% of the patients in the analysis
population completed the study. Four patients discontinued due to
adverse events. Specifically, one patient in the warfarin group, one
patient in the ximelagatran 24 mg group, and two patients in the
ximelagatran 36 mg group discontinued due to an adverse event.

*Statistical Methodologies*

The primary analysis employed a Cochran-Mantel-Haenszel chi-square test
stratified by type or surgery (i.e. bilateral or unilateral) to assess
the treatment group differences. Pairwise comparisons between each dose
of ximelagatran and warfarin were examined via a sequential testing
procedure to control the type I error rate. The ximelagatran 36 mg
treatment arm was initially compared to the warfarin arm. The
ximelagatran 24 mg group was subsequently compared to the warfarin group
if the previous comparison was significant at the 0.05 alpha level. The
applicant additionally explored the heterogeneity of the treatment
effect across centers. According to the applicant, "Event rates and
non-evaluability rates were summarized by investigative site and the
possibility of treatment by center interaction was examined for sites
with large numbers of patients." The analysis of secondary endpoints was
identical to the primary analysis; however, no adjustments for multiple
comparisons were made. A blinded interim analysis was planned; however,
the alpha inflation was considered negligible. Details of the interim
analysis are included in the appendix.

Analyses were conducted on the intent-to-treat (ITT) population
including all randomized patients who had elective total knee
replacement and who received at least one dose of the study medication.
The applicant further stated, "No attempt was made to impute data for
those patients who did not have an evaluable venogram (as determined by
central adjudication) and did not experience a symptomatic, objectively
confirmed VTE or death. Thus, the efficacy ITT analysis population
included all patients who had (1) an evaluable venogram or (2)
symptomatic DVT/PE while being treated with study medication
(objectively confirmed by central adjudication) or (3) a fatality while
being treated with study medication."

*Results and Conclusions*

Table 2 depicts results of the applicant's primary analysis. Patients in
the ximelagatran 36 mg group had a significant reduction in the
frequency of total VTE and/or all-cause mortality as compared to
patients in the warfarin group. The reduction in the frequency of the
composite endpoint in patients randomized to ximelagatran 36 mg was 7.3%
relative to patients randomized to warfarin. Moreover, the relative risk
reduction (i.e. risk difference expressed as a percent of the risk in
warfarin) was 26.4%. A significant difference in the incidence of VTE
and/or all-cause mortality was not demonstrated between ximelagatran 24
mg and warfarin. For completeness, the applicant performed a post-hoc
analysis comparing the 24 mg and 36 mg doses of ximelagatran. There was
no significant difference in the composite outcome between the
ximelagatran doses. These findings based on assessments by the
Independent Central Adjudication Committee (ICAC) were further supported
by assessments conducted locally at study centers. Based on my
independent evaluation of the data, I concur with the primary results
and conclusions.

**Table 2: Frequency of total venous thromboembolism and/or all-cause
mortality-ITT population**

(Source: Table 24, Clinical Study Report SH-TPO-0010)

![](media/image2.png){width="6.4875in" height="2.245138888888889in"}

I additionally explored the individual events that composed the primary
endpoint to further elucidate the results in Table 2. My results are
illustrated in Table 3 and are in agreement with the applicant's
results. Of note, asymptomatic DVTs were detected during mandatory
venography, and symptomatic DVTs were diagnosed by compression
ultrasound and confirmed using venograms. As evident from the table,
most events were asymptomatic, distal DVTs.

**Table 3: Symptomatic and asymptomatic events over the treatment
duration -ITT population**

  ------------------- ------------------ ----------------- ---------------
  **Event**           **Ximelagatran 24  **Ximelagatran 36 **Warfarin**
                      mg**               mg**              

  **Number of         614                629               608
  subjects**                                               

  **Asymptomatic      151 (25%)          124 (20%)         166 (27%)
  DVT**                                                    

  Proximal DVT        12 (2%)            13 (2%)           23 (4%)

  Distal DVT          139 (23%)          111 (18%)         143 (24%)

  **Symptomatic DVT** 5 (.8%)            7 (1%)            9 (2%)

  Proximal DVT        1 (.2%)            2 (.3%)           4 (.7%)

  Distal DVT          4 (.7%)            5 (.8%)           5 (.8%)

  **Pulmonary         2 (.3%)            2 (.3%)           0 (0%)
  embolism**                                               

  **Death**           1 (.2%)            1 (.2%)           1 (.2%)
  ------------------- ------------------ ----------------- ---------------

Per the clinical team's request, I also performed the primary analysis
on the safety population including all randomized patients who received
at least one dose of study drug. My results are shown in Table 4.

Table 4: Frequency of total venous thromboembolism and/or all-cause
mortality-Safety population

  ------------- ----------- ----------- ------------ ----------- -------------
                                        **Ximelag vs             
                                        warfarin**               

  **Treatment   **% (n/N)** **Exact 95% **%**        **95% CI**  **CMH
  group**                   CI**                                 p-value\***

  Ximelag 24 mg 20.2        (17.4,      -1.9         (-6.2, 2.3) 0.692
                (153/757)   23.1)                                

  Ximelag 36 mg 16.6        (14.0,      -5.5         (-9.6,      0.010
                (128/769)   19.3)                    -1.4)       

  Warfarin      22.1        (19.2,                               
                (168/759)   25.1)                                
  ------------- ----------- ----------- ------------ ----------- -------------

\* Treatment differences were tested using the Cochran-Mantel-Haenszel
test, adjusted for the type of surgery performed.

The reduction in the frequency of the secondary composite outcome,
incidence of proximal DVT, PE, and/or all-cause mortality, was not
significantly different between the ximelagatran groups and the warfarin
group. Specifically, incidence of the outcome was 2.5%, 2.7% and 4.1%
for patients randomized to ximelagatran 24 mg, ximelagatran 36 mg, and
warfarin, respectively. Of note, the incidence of proximal DVT, PE
and/or all-cause mortality was computed utilizing the same methodology
as used in the primary analyses; however, the denominator varied due to
the exclusion of patients classified as "indeterminants". A table
detailing the results of the analysis of this secondary endpoint is
included in the appendix.

### *3.1.2 SH-TPO-0012(EXULT B)* {#sh-tpo-0012exult-b .unnumbered}

*Study Design and Endpoints*

The design and endpoints of study SH-TPO-0012 or EXULT B were nearly
identical to that of the previously described study (EXULT A) with
variations in the tested doses and sample sizes. In EXULT B, 2303
patients scheduled to undergo total knee replacement were randomized to
ximelagatran 36 mg or warfarin.

Based on event rates in EXULT A, a sample size of 1720 was determined to
be sufficient to detect a 25% relative risk reduction in VTE with 90%
power. According to the applicant, the needed sample size was increased
to 2300 to account for the percentage of patients (at most 25%) not
having evaluable venograms. Of note, 115 international centers
participated in the study; however, patients were only randomized at 113
centers.

*Patient Disposition, Demographic and Baseline Characteristics*

The ages of patients were between 26 and 91 with a mean age of 67. In
the study, 94% of study participants were Caucasian, and 5% were African
American. Females composed 63% of the patient population. Baseline
characteristics included weight, body mass index, nicotine use, alcohol
use, and creatinine clearance. Demographic and baseline characteristics
were similar across treatment groups. Detailed tables outlining the
composition of the study population with respect to demographic and
baseline characteristics are presented in the appendix.

Of the 2303 randomized patients, 2299 received at least 1 dose of study
medication. Moreover of these 2299 patients, 1949 patients had a
venogram adequate for evaluation and were included in the analysis
population. Approximately 99% of the patients in the analysis population
completed the study. Three patients in the warfarin group and six
patients in the ximelagatran group discontinued due to adverse events.

*Statistical Methodologies*

The primary analysis assessed treatment group differences using a
Cochran-Mantel Haenszel test stratified by type or surgery (i.e.
bilateral or unilateral). Secondary endpoints were analyzed using
similar methodology.

Similar to EXULT A, analyses were conducted on the intent-to-treat (ITT)
population consisting of all randomized patients who had elective total
knee replacement and who received at least one dose of the study
medication. The applicant again stated, "No attempt was made to impute
data for those patients who did not have an evaluable venogram (as
determined by central adjudication) and did not experience a
symptomatic, objectively confirmed VTE or death. Thus, the efficacy ITT
analysis population included all patients who had (1) an evaluable
venogram or (2) symptomatic DVT/PE while being treated with study
medication (objectively confirmed by central adjudication) or (3) a
fatality while being treated with study medication."

*Results and Conclusions*

The results of the applicant's analysis of the primary efficacy outcome
as assessed by the ICAC are depicted in Table 5. Patients in the
ximelagatran 36 mg group had a significant reduction in the frequency of
total VTE and/or all-cause mortality as compared to patients in the
warfarin group. The reduction in the frequency of the composite endpoint
in patients randomized to ximelagatran 36 mg was 9.3% relative to
patients randomized to warfarin. Moreover, the relative risk reduction
(i.e. risk difference expressed as a percent of risk in warfarin) was
29.3%. Based on my independent evaluation of the data, I concur with the
results.

**Table 5: Frequency of total venous thromboembolism and/or all-cause
mortality-ITT population**

(Source: Table 15, Clinical Study Report SH-TPO-0012)

![](media/image3.png){width="6.488194444444445in"
height="2.203472222222222in"}

Table 6 further illustrates the individual components of the endpoint.
Similar to EXULT A, most events were asymptomatic, distal DVTs.

**Table 6: Symptomatic and asymptomatic events over the treatment
duration -ITT population**

  -------------------------- ----------------------- ---------------------
  **Event**                  **Ximelagatran 36 mg**  **Warfarin**

  **Number of subjects**     982                     967

  **Asymptomatic DVT**       214 (22 %)              301 (31 %)

  Proximal DVT               30 (3 %)                33 (3 %)

  Distal DVT                 184 (19 %)              268 (28 %)

  **Symptomatic DVT**        8 (1 %)                 15 (2 %)

  Proximal DVT               2 (.2 %)                1 (.1 %)

  Distal DVT                 6 (.6 %)                14 (1.4 %)

  **Pulmonary embolism**     2 (.2 %)                5 (.5 %)

  **Death**                  4 (.4 %)                2 (.2 %)
  -------------------------- ----------------------- ---------------------

Per the clinical team's request, I also performed the primary analysis
on the safety population including all randomized patients who received
at least one dose of study drug. My results are shown in Table 7.

Table 7: Frequency of total venous thromboembolism and/or all-cause
mortality-Safety population

  ------------- ------------ ------------ ------------ ----------- -----------
                                          **Ximelag vs             
                                          warfarin**               

  **Treatment   **% (n/N)**  **Exact 95%  **%**        **95% CI**  **CMH
  group**                    CI**                                  p-value**

  Ximelag 36 mg 19.2         (17.0, 21.5) -7.6         (-11.1,     \<0.001
                (221/1151)                             -4.1)       

  Warfarin      26.8         (24.3, 29.4)                          
                (308/1148)                                         
  ------------- ------------ ------------ ------------ ----------- -----------

\* Treatment differences were tested using the Cochran-Mantel-Haenszel
test, adjusted for the type of surgery performed.

The reduction in the frequency of the secondary composite outcome,
incidence of proximal DVT, PE, and/or all-cause mortality, was not
significantly different between the ximelagatran group and the warfarin
group. Specifically, the incidence of the outcome was 3.9% and 4.1% for
patients randomized to ximelagatran 36 mg and warfarin, respectively. Of
note, the incidence of proximal DVT, PE and/or all-cause mortality was
computed utilizing the same methodology as used in the primary analyses;
however, the denominator varied due to the exclusion of patients
classified as "indeterminants". A table detailing the results of the
analysis of the secondary endpoint is included in the appendix.

### *3.1.3 Additional Studies* {#additional-studies .unnumbered}

Three additional controlled studies of the short-term use of
ximelagatran were conducted but were not of primary focus due to the
varying patient populations and/or doses. I will briefly describe those
studies for completeness of review of the NDA submission. SH-TPO-0005
was a randomized, double-blind, active-controlled study of ximelagatran
24 mg and enoxaparin 30 mg for the prevention of VTE following total hip
arthroplasty. Treatments were administered twice daily for 7-12 days
utilizing a double-dummy design. Ximelagatran required oral
administration while enoxaparin was administered subcutaneously. The
primary measure of efficacy was the incidence of total VTE as confirmed
by the ICAC. According to the applicant, "Statistical\
non-inferiority was established if the upper confidence bound around the
between group difference in VTE frequency was less than 5%." The study
failed to demonstrate the non-inferiority of ximelagatran to enoxaparin.
In addition to statistical concerns regarding the non-inferiority
margin, an indication in the hip arthroplasty population was not sought;
therefore, the study was not of focus during the current review.

The applicant described SH-TPO-0004 as a "dose-finding, safety, and
pharmacokinetic study of\
H 376/95 (ximelagatran) as a prophylaxis for thromboembolic
complications after total knee replacement." Patients undergoing knee
replacement were randomized to 8, 12, 18, or 24 mg of ximelagatran or
enoxaparin 30 mg. Ximelagatran was administered orally twice daily under
blinded conditions while enoxaparin was administered subcutaneously
under open-label conditions. The study did not demonstrate a linear dose
response among the four ximelagatran groups. Moreover, pairwise
comparisons between each of the ximelagatran groups and the enoxaparin
group failed to show significant differences in the incidence of VTE.

The design of SH-TPO-0006 mimicked that of EXULT A and EXULT B with
variations in the treatment arms and the definition of the primary
efficacy outcome. Patients were randomized to ximelagatran 24 mg or
warfarin. The primary measure of efficacy was the incidence of VTE. The
study failed to demonstrate a difference in the incidence of VTE between
ximelagatran and warfarin.

### *3.1.4 SH-TPV-0003(THRIVE III)* {#sh-tpv-0003thrive-iii .unnumbered}

*Study Design and Endpoints*

Study SH-TPV-0003 or THRIVE III was a double-blind, placebo-controlled,
multi-center study to assess the efficacy of ximelagatran 24 mg given as
a prolonged prophylaxis after a six-month anticoagulation treatment. The
pool of eligible patients included individuals who had an objectively
verified, symptomatic VTE and had received anticoagulation treatment for
approximately six months. Two to seven days prior to randomization,
patients were instructed to terminate their anticoagulation treatment.
Study participants were randomized to ximelagatran 24 mg or placebo
administered twice daily for 18 months. "Study visits were scheduled at
two weeks and four weeks and then every month (three to five weeks)
during the first six months after randomization and thereafter every
three months (10-14 weeks)."

Based on assumed event rates of 6% and 2% in the placebo and
ximelagatran arms respectively, the applicant determined that a sample
of size 1200 would be sufficient to detect a difference with 90% power.
One hundred and forty-two centers from eighteen countries participated
in the study.

*Patient Disposition, Demographic and Baseline Characteristics*

The ages of randomized patients ranged from 18 and 90 with a mean age of
57. In the study, 93% of study participants were Caucasian, and females
composed 47% of the patient population. Baseline characteristics
included weight, body mass index, nicotine use, alcohol use, and
creatinine clearance. Demographic and baseline characteristics were
similar across treatment groups according to the applicant. Detailed
tables outlining the composition of the study population with respect to
demographic and baseline characteristics are presented in the appendix.

Of the 1233 randomized patients, 10 patients did not have
post-randomization data and were excluded from the efficacy analysis.
Overall, 320 patients discontinued the study prematurely, and 129 of the
discontinuations were caused by adverse events. Specifically, 144
patients within the ximelagatran group discontinued prematurely, and 62
(43%) were caused by adverse events. One hundred and seventy-six
participants in the placebo group discontinued the study prematurely. Of
the 176 participants, 38% discontinued due to an adverse event and 35%
discontinued to the development of a study specific discontinuation
criteria.

*Statistical Methodologies*

The primary measure of efficacy was the time to the first VTE event
calculated as the number of days from randomization until the occurrence
of the first relevant event. Secondary measures of efficacy included the
time until death by any cause, the time to locally confirmed VTE events,
and the time to the composite of VTE and/or death.

The analyses employed log-rank tests to compare recurrence rates between
treatment and groups for the primary and secondary outcomes. Moreover,
Kaplan-Meier estimates and hazard ratios were employed to gain
additional insight.

An interim analysis was in the planned charter for the Safety Committee.
The analysis employed a Peto-type boundary for monitoring a positive
trend in VTE events. The alpha inflation was considered negligible ( =
0.0476).

*Results and Conclusions*

Study participants receiving ximelagatran 24 mg twice daily experienced
a significant reduction in recurrent VTE events as compared to patients
receiving placebo. The estimated cumulative risk of a recurrent VTE
event at the end of 18 months was 2.8% for patients randomized to
ximelagatran and 12.6% for patients randomized to placebo. The hazard or
risk of a recurrent VTE event was smaller for participants in the
ximelagatran group as evidenced by the hazard ratio of 0.16. The results
were supported by the significant reduction in the secondary composite
endpoint (VTE and/or death) among the treated group as compared to the
placebo group. In addition, the risk of death from all causes was
comparable among treatment arms. The estimated cumulative risk over time
of the primary endpoint is displayed in Table 8. Figures 1 and 2 are
graphical depictions of the cumulative risk versus time for the primary
endpoint and the secondary composite endpoint.

**Table 8: Estimated cumulative risk (%) of a VTE event, ITT
population**

(Source: Table 23, Clinical study report SH-TPV-0003)

![](media/image4.png){width="6.493055555555555in"
height="2.540277777777778in"}

Figure 1: Cumulative risk of recurrent VTE events versus time, ITT
population

(Source: Figure 5, Clinical Study Report SH-TPV-0003)

![](media/image5.png){width="4.790972222222222in"
height="2.817361111111111in"}

Figure 2: Cumulative risk of recurrent VTE events and/or all-cause
mortality versus time, ITT population

(Source: Figure 7, Clinical Study Report SH-TPV-0003)

![](media/image6.png){width="4.645833333333333in"
height="2.4791666666666665in"}

Upon exploration of the data, I found that 83 (71 in the placebo arm and
12 in the ximelagatran arm) of the 1223 study participants experienced a
recurrent VTE event. Under this scenario, the analysis employed by the
applicant may result in misleading conclusions; therefore, I performed a
post-hoc categorical data analysis by dividing the population into two
more stringent categories. One category included all patients having a
VTE event and/or discontinuing the study prematurely. All remaining
patients were classified as not having an event. My analysis
demonstrated a significant reduction in recurrence rates for
participants treated with ximelagatran as compared to participants
randomized to placebo.

## 3.2 Evaluation of Safety {#evaluation-of-safety .unnumbered}

The evaluation of safety is deferred to the review of Dr. Ruyi He.

# 4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS {#findings-in-specialsubgroup-populations .unnumbered}

For ease of exposition and completeness, I have included all the
subgroup factors considered by the applicant in the following review of
subpopulations. Although the applicant examined numerous prognostic
factors, I focused primarily on the age, gender, and race factors.

## Gender, Race and Age

### *4.1.1 SH-TPO-0010(EXULT A) and SH-TPO-0012(EXULT B)* {#sh-tpo-0010exult-a-and-sh-tpo-0012exult-b .unnumbered}

The impact of various subgroup factors on the incidence of total VTE
and/or all-cause mortality was investigated by the applicant via
frequency tables and a logistic regression model. The logistic
regression model employed in EXULT A included the following factors:
treatment, gender, age, race, country, type of surgery, body mass index,
creatinine clearance, history VTE, type of anesthesia, time to first
dose, and time to ambulation. The logistic model employed in EXULT B
included an additional factor for time to venography. In addition, the
interaction of each subgroup factor with treatment was also investigated
in both studies.

In EXULT A, the applicant concluded that females, older patients, and
patients enrolled in Canada experienced a higher incidence of VTE. Of
note in EXULT A, 67 patients (14 with VTE) were excluded from the
logistic regression analysis due to missing values. In EXULT B, several
factors were associated with an increased incidence of the event of
interest. Specifically, female patients, older patients, patients
enrolled in Canada, patients with bilateral surgery, patients with a
history of VTE, and patients with earlier scheduled venograms
demonstrated a higher incidence of the outcome. Eighty-six patients were
excluded from the analysis due to missing data. Frequency tables
illustrated a reduced incidence of the outcome of interest among
patients randomized to ximelagatran 36 mg as compared to warfarin in
both studies.

I additionally conducted separate analyses by gender, age, and race. I
initially explored the effect of each subgroup factor on the primary
endpoint using logistic regression models. In EXULT A, older patients
(\> 70) had slightly higher odds of experiencing a VTE and/or death as
compared to younger patients (≤ 70). In EXULT B, older patients (\> 70)
and female patients had slightly higher odds of experiencing a VTE
and/or death as compared to younger patients (≤ 70) and male patients,
respectively. I also investigated the significance of the treatment
effect after adjusting for covariates. The treatment effect was
consistent across the subgroups.

The applicant did not propose any efficacy claims for any subgroup of
patients. Overall, the results were consistent and lend support to the
findings presented in the preceding sections.

### *4.1.2 SH-TPV-0003(THRIVE III)* {#sh-tpv-0003thrive-iii-1 .unnumbered}

The impact of several prognostic factors on the time to the first VTE
event was investigated by the applicant via frequency tables and Cox
regression models. Potential prognostic factors identified by the
applicant included sex, age, creatinine clearance, weight, initial VTE
event, previous VTE events, presence of malignancy, and prothrombotic
state. Separate analyses for each prognostic factor were conducted via
Cox regression models. The between treatment comparisons included
treatment as a covariate in the models while the within treatment
comparisons included the subgroup factors as covariates, respectively.

The applicant's analysis yielded a gender effect. Specifically, females
experienced a lower risk of recurrent VTE events as compared to males.
The treatment effect remained constant across age, race, and gender. I
additionally conducted analyses on the dichotomized VTE outcome. The
results of my analyses are in agreement with those of the applicant.

The applicant did not propose any efficacy claims for any subgroup of
patients. Overall, the results were consistent and lend support to the
findings presented in the preceding sections.

## 4.2 Other Special/Subgroup Populations {#other-specialsubgroup-populations .unnumbered}

No additional analyses on other subgroup populations were warranted.

# 5. SUMMARY AND CONCLUSIONS {#summary-and-conclusions .unnumbered}

#  {#section-2 .unnumbered}

## 5.1 Statistical Issues and Collective Evidence {#statistical-issues-and-collective-evidence .unnumbered}

One methodological issue arose during the course of my review. In THRIVE
III, analyses of the outcomes utilized the statistical methodology of
survival analysis. This methodology uniquely handles "time to event"
data where observations may be censored due to discontinuation or to the
limitation of the study's follow-up time. An underlying assumption of
the methodology, as applied by the applicant, is that all study
participants will experience a recurrence. However in THRIVE III, a
reasonable assumption is that not all study participants will experience
a recurrence. I subsequently dichotomized the response and performed an
analysis similar to that of EXULT A and EXULT B. My analysis was
post-hoc; however, the sole purpose was to validate the conclusions.

## The evidence taken collectively from EXULT A and EXULT B indicated statistical support of the efficacy of the ximelagatran for short-term use. When comparing ximelagatran 36 mg to warfarin, a significant reduction in the incidence of VTE and/or all-cause mortality was demonstrated in both studies. A 24 mg dose of ximelagatran was additionally included in EXULT A; however, the dose failed to demonstrate a significant difference in the reduction of total VTE and/or all-cause mortality as compared to warfarin. The evidence from THRIVE III indicated statistical support of ximelagatran for the long term secondary prevention of VTE. Specifically, ximelagatran 24 mg significantly reduced the recurrence rate of VTE events compared to placebo. {#the-evidence-taken-collectively-from-exult-a-and-exult-b-indicated-statistical-support-of-the-efficacy-of-the-ximelagatran-for-short-term-use.-when-comparing-ximelagatran-36-mg-to-warfarin-a-significant-reduction-in-the-incidence-of-vte-andor-all-cause-mortality-was-demonstrated-in-both-studies.-a-24-mg-dose-of-ximelagatran-was-additionally-included-in-exult-a-however-the-dose-failed-to-demonstrate-a-significant-difference-in-the-reduction-of-total-vte-andor-all-cause-mortality-as-compared-to-warfarin.-the-evidence-from-thrive-iii-indicated-statistical-support-of-ximelagatran-for-the-long-term-secondary-prevention-of-vte.-specifically-ximelagatran-24-mg-significantly-reduced-the-recurrence-rate-of-vte-events-compared-to-placebo. .unnumbered}

## 5.2 Conclusions and Recommendations {#conclusions-and-recommendations-1 .unnumbered}

Astra Zeneca proposes ximelagatran for the prevention of VTE in patients
undergoing knee replacement surgery and for the long term secondary
prevention of VTE after standard treatment for an episode of acute VTE.
The primary claims are that ximelagatran (36 mg) reduces the incidence
of total VTE and/or mortality in patients undergoing total knee
replacement and that

ximelagatran (24 mg) reduces the recurrence of VTE events among patients
who previously received 6 months of anticoagulation therapy for an acute
VTE. My review of the collective evidence suggests statistical support
of the efficacy of ximelagatran**;** however, statistical significance
does not imply clinical meaningfulness. Issues warranting additional
consideration include the adequacy of the period of follow-up for the
short term indication, the appropriateness of warfarin as a comparator,
and concerns regarding bleeding and liver toxicity. Discussion of these
issues as they pertain to the clinical meaningfulness of the reduction
in VTE events and the safety profile of the drug are deferred to the
clinical review of Dr. Ruyi He.

# 6. APPENDIX  {#appendix .unnumbered}

## 6.1 EXULT A {#exult-a .unnumbered}

Additional details regarding the methodology used for assessments and
diagnoses of VTE follow. The details are relevant to the statistical
analyses as the variables were coded in the datasets according to the
classifications described. The information is extracted from the
clinical study report SH-TPO-0010 of NDA 21-686 (pages 47-49).

![](media/image7.png){width="6.148611111111111in"
height="1.2145833333333333in"}

![](media/image8.png){width="5.883333333333334in"
height="2.0236111111111112in"}

![](media/image9.png){width="5.654166666666667in" height="5.04375in"}

![](media/image10.png){width="6.016666666666667in"
height="7.310416666666667in"}

Demographic and baseline characteristics

(Source: Table 16, Clinical Study report SH-TPO-0010)

![](media/image11.png){width="6.486111111111111in"
height="7.082638888888889in"}

Demographic and baseline characteristics continued

(Source: Table 16, Clinical Study report SH-TPO-0010)

![](media/image12.png){width="6.490277777777778in"
height="5.100694444444445in"}

The following information extracted from page 66 of the clinical study
report SH-TPO-0010 outlines the interim analysis.

![](media/image13.png){width="5.510416666666667in"
height="4.590277777777778in"}

**Secondary endpoint: Frequency of proximal DVT, PE, and/or all-cause
mortality**

(Source: Table 25, Clinical Study Report SH-TPO-0010)

![](media/image14.png){width="5.634027777777778in"
height="1.8895833333333334in"}

## 6.2 EXULT B {#exult-b .unnumbered}

**Demographic and baseline Characteristics**

(Source: Table 15, Clinical Study Report SH-TPO-0012)

![](media/image15.png){width="6.497916666666667in"
height="3.3131944444444446in"}

**Demographic and baseline characteristics continued**

[(Source: Table 15, Clinical Study Report SH-TPO-0012)]{.underline}

![](media/image16.png){width="6.496527777777778in"
height="6.690277777777778in"}

**Secondary endpoint: Frequency of proximal DVT, PE, and/or all-cause
mortality**

(Source: Table 26, Clinical Study Report SH-TPO-0012)

![](media/image17.png){width="6.488194444444445in"
height="2.0708333333333333in"}

## 6.3 THRIVE III  {#thrive-iii .unnumbered}

**Demographic and baseline characteristics**

(Source: Table 12, Clinical Study Report SH-TPV-0003)

![](media/image18.png){width="6.4875in" height="1.5819444444444444in"}

**Demographic and baseline characteristics continued**

(Source: Table 12, Clinical Study Report SH-TPV-0003)

![](media/image19.png){width="6.493055555555555in"
height="8.280555555555555in"}

**Demographic and baseline characteristics continued**

(Source: Table 12, Clinical Study Report SH-TPV-0003)

![](media/image20.png){width="6.495138888888889in" height="1.50625in"}