Clinical Review for NDA 21-686

> NDA: 21-686
>
> Sponsor: AstraZeneca
>
> Drug name: Exanta (ximelagatran) Tablets

Indications:

1)  Prevention of venous thromboembolism (VTE; defined as deep

> vein thrombosis \[DVT\], pulmonary embolism \[PE\], or both), in
> patients undergoing knee replacement surgery;

2)  Long-term secondary prevention of VTE after standard treatment for
    an episode of acute VTE;

3)  Prevention of stroke and other thromboembolic complications

> associated with atrial fibrillation (AF). (see Medical Officer's
> review from the Division of Cardio-Renal Drug Products for details)

Date submitted: December 23, 2003

Date received: December 23, 2003

Review completed: August 5, 2004

Reviewer: Ruyi He, M.D.

NOTE: This is a preliminary/draft review that is not intended to provide
any recommendations on the approvability of NDA 21,686. Any opinions
expressed in the review do not necessarily reflect those of the
Division/Office.

# 

# Table of Contents

Table of Contents [2](#table-of-contents)

Executive Summary [5](#executive-summary)

I. Summary of Clinical Findings [5](#i.-summary-of-clinical-findings)

A. Brief Overview of Clinical Program
[5](#a.-brief-overview-of-clinical-program)

B. Efficacy [6](#b.-efficacy)

C. Safety [7](#c.-safety)

D. Dosing [11](#__RefHeading___Toc77047730)

E. Special Populations [11](#e.-special-populations)

Clinical Review [14](#clinical-review)

I. Introduction and Background [14](#i.-introduction-and-background)

A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's
Proposed Indication(s), Dose, Regimens, Age Groups
[14](#a.-drug-established-and-proposed-trade-name-drug-class-sponsors-proposed-indications-dose-regimens-age-groups)

B. State of Armamentarium for Indication(s)
[14](#b.-state-of-armamentarium-for-indications)

C. Important Milestones in Product Development
[15](#c.-important-milestones-in-product-development)

D. Other Relevant Information [15](#d.-other-relevant-information)

E. Important Issues with Pharmacologically Related Agents
[15](#e.-important-issues-with-pharmacologically-related-agents)

II\. Clinically Relevant Findings From Chemistry, Animal Pharmacology
and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
Consultant Reviews
[15](#ii.-clinically-relevant-findings-from-chemistry-animal-pharmacology-and-toxicology-microbiology-biopharmaceutics-statistics-andor-other-consultant-reviews)

III\. Human Pharmacokinetics and Pharmacodynamics
[16](#human-pharmacokinetics-and-pharmacodynamics)

A. Pharmacokinetics [16](#a.-pharmacokinetics)

B. Pharmacodynamics [17](#b.-pharmacodynamics)

IV\. Description of Clinical Data and Sources
[18](#iv.-description-of-clinical-data-and-sources)

A. Overall Data [18](#a.-overall-data)

B. Tables Listing the Clinical Trials
[19](#b.-tables-listing-the-clinical-trials)

C. Postmarketing Experience [19](#c.-postmarketing-experience)

D. Literature Review [20](#d.-literature-review)

V. Clinical Review Methods [20](#v.-clinical-review-methods)

A. How the Review was Conducted [20](#a.-how-the-review-was-conducted)

B. Overview of Materials Consulted in Review
[21](#b.-overview-of-materials-consulted-in-review)

C. Overview of Methods Used to Evaluate Data Quality and Integrity
[21](#c.-overview-of-methods-used-to-evaluate-data-quality-and-integrity)

D. Were Trials Conducted in Accordance with Accepted Ethical Standards
[22](#d.-were-trials-conducted-in-accordance-with-accepted-ethical-standards)

E. Evaluation of Financial Disclosure
[22](#e.-evaluation-of-financial-disclosure)

VI\. Integrated Review of Efficacy
[22](#vi.-integrated-review-of-efficacy)

A. Brief Statement of Conclusions
[22](#a.-brief-statement-of-conclusions)

B. General Approach to Review of the Efficacy of the Drug
[23](#b.-general-approach-to-review-of-the-efficacy-of-the-drug)

C. Detailed Review of Trials by Indication
[24](#c.-detailed-review-of-trials-by-indication)

D. Efficacy Conclusions [24](#d.-efficacy-conclusions)

VII\. Integrated Review of Safety
[27](#vii.-integrated-review-of-safety)

A. Brief Statement of Conclusions
[27](#a.-brief-statement-of-conclusions-1)

B. Description of Patient Exposure
[31](#b.-description-of-patient-exposure)

C. Methods and Specific Findings of Safety Review
[33](#c.-methods-and-specific-findings-of-safety-review)

D. Adequacy of Safety Testing [84](#d.-adequacy-of-safety-testing)

E. Summary of Critical Safety Findings and Limitations of Data
[84](#e.-summary-of-critical-safety-findings-and-limitations-of-data)

VIII\. Dosing, Regimen, and Administration Issues
[85](#viii.-dosing-regimen-and-administration-issues)

IX\. Use in Special Populations [85](#ix.-use-in-special-populations)

A. Evaluation of Sponsor's Gender and Age Effects Analyses and Adequacy
of Investigation
[85](#a.-evaluation-of-sponsors-gender-and-age-effects-analyses-and-adequacy-of-investigation)

B. Evaluation of Evidence for Race, or Ethnicity Effects on Safety or
Efficacy
[86](#b.-evaluation-of-evidence-for-race-or-ethnicity-effects-on-safety-or-efficacy)

C. Evaluation of Pediatric Program
[86](#c.-evaluation-of-pediatric-program)

D. Comments on Data Available or Needed in Other Populations
[87](#d.-comments-on-data-available-or-needed-in-other-populations)

**Appendix A: List of
abbreviations.............................................................89**

**Appendix B: Individual More Detailed Study
review...........................\.........\...91**

A.  STUDY SH-TPO-0010 (EXULT
    A)..........................................\....91

B.  STUDY SH-TPO-0012 (EXULT
    B).............................................115

C.  Study SH-TPV-0003 (THRIVE
    III)..........................................142

**Clinical Review for NDA 21-686**

# Executive Summary

## I. Summary of Clinical Findings 

### A. Brief Overview of Clinical Program

EXANTA ® (ximelagatran) is an oral anticoagulant and a prodrug of
melagatran, a potent, reversible, competitive and direct inhibitor of
thrombin. Ximelagatran prevents a key step in the coagulation cascade,
the conversion of fibrinogen to fibrin.

Ximelagatran is in development for several indications, of which the
following 3 are being

submitted in this application: prevention of VTE (defined as deep vein
thrombosis \[DVT\], pulmonary embolism \[PE\], or both), in patients
undergoing knee replacement surgery; 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 (AF). All 3 indications are for the adult population only.

The studies were designed to demonstrate that fixed doses of
ximelagatran, without coagulation

monitoring or dosage adjustment, offers superiority to placebo (VTE
Secondary Prevention),

superiority to warfarin (Knee Replacement Surgery), and non-inferiority
to warfarin (Atrial

Fibrillation).

The development program includes 82 clinical studies with ximelagatran
and/or melagatran

(60 Phase I studies and 22 Phase II and III studies), in which 30,698
subjects were randomized. A total of 17,593 randomized subjects received
the oral prodrug ximelagatran, or the active drug melagatran. In the
long-term treatment populations, 6931 patients received ximelagatran,
5024 of whom received treatment for at least 6 months and 3509 for at
least a year in patients with atrial fibrillation (up to 2.5 years in
the pivotal SPORTIF studies and up to 4 years in the ongoing SPORTIF IV
study).

Each Phase 3 study was conducted as a multi-center, randomized,
parallel-group, comparator-controlled design. All studies were
double-blind except for SH-TPA-0003 (SPORTIF III for the indication of
prevention of stroke in patients with AF; which was an open-label in
design). All studies used a central laboratory for all
protocol-specified laboratory measurements.

For the indication of prevention of VTE in patients undergoing elective
knee replacement surgery, the sponsor conducted three Phase 3 studies in
comparison with warfarin in patients undergoing primary, elective total
knee replacement (TKR) surgery (SH-TPO-0006, EXULT A and EXULT B). A
total of 5284 patients were randomized in these three studies (1927 to
ximelagatran 36 mg bid, 2247 to warfarin, and 1110 to ximelagatran 24 mg
bid).

To support the indication of prolonged prophylaxis of VTE after a
six-month anticoagulation treatment for VTE, the sponsor provided only
one 18-month study, SH-TPV-0003 (THRIVE III). A total of 1233 patients
were randomized, with 914 completing the 15-month duration (475 on
ximelagatran 24 mg bid and 439 on placebo) and only 193 completing the
entire 18-month study (107 on ximelagatran 24 mg bid and 86 on placebo).

For the indication of prevention of stroke and systemic embolic events
in patients with nonvalvular atrial fibrillation, Division of
Cardio-Renal drug products (HFD-110) is conducting the review for both
efficacy and safety.

### B. Efficacy

**Indication 1: prevention of VTE in patients undergoing elective total
knee replacement (TKR) surgery**

Oral ximelagatran 36 mg bid were superior to warfarin in reducing total
VTE and/or all- cause mortality at end of 7-12 days therapy among
patients undergoing TKR surgery in two Phase 3 studies.

In the pooled EXULT A and EXULT B analyses, the incidence of total VTE
and/or all-cause

mortality among patients undergoing TKR was 21.7% for patients in the
ximelagatran 36 mg

group and 30.2% for patients in the warfarin group (p\<0.001). However,
the benefit was mainly due to a reduction in asymptomatic distal DVT
diagnosed by venography which is not clinically meaningful. There were
no clinically or statistically significant differences between
ximelagatran and warfarin groups in reducing the frequency of proximal
DVT, PE, and/or all-cause mortality in this population.

There are several major problems with using warfarin as an active
comparator in these two studies. Warfarin is not approved for this short
term indication. The comparison is unfair, because warfarin will take
about 3-5 days to reach therapeutic level, while Exanta reaches
therapeutic levels within hours. Mean days of exposure were 8.1 days for
ximelagatran and 6.7 days for warfarin in these two studies. The results
show that 33.1% - 35.2% of patients receiving warfarin had an INR less
than 1.8 at postoperative day 3, and 24.0 -- 26.9% % of patients
receiving warfarin had an INR less than 1.8 at end of treatment (day 7
-- 12). Because this study is designed to show superiority of
ximelagatran, efficacy results for ximelagatran in these studies may
still be acceptable, since warfarin may be considered to be placebo.

In EXULT A ximelagatran 24 mg bid was not superior to warfarin in
reducing total VTE and/or all-cause mortality (27.6% warfarin vs 24.9%
ximelagatran 24 mg) at end of 7-12 days therapy.

**Indication 2: long-term secondary prevention of VTE after standard
treatment for an**

**episode of acute VTE**

Ximelagatran significantly reduced the recurrence rate of symptomatic,
objectively confirmed VTE (the primary variable of the study) as
compared to placebo over 18 months of treatment (cumulative risk of 2.8%
versus 12.6%; hazard ratio 0.16; p\<0.0001). The number of patients with
a VTE event was 12 in the ximelagatran group and 71 in the placebo
group. The number of patients with a PE event was lower in the
ximelagatran group compared to the placebo group (2 and 23)
respectively. The results for the secondary variable, all-cause
mortality, showed no significant difference between the treatment groups
(1.1% vs 1.4% for patients on ximelagatran and placebo, respectively)
during the 18 months.

### C. Safety

**C.1. Safety of ximelagatran in patients undergoing a surgical
procedure (use [\<]{.underline} 35 days)**

A total of 1913 patients were exposed to ximelagatran 36 mg bid, 1097
patients were exposed to ximelagatran 24 mg bid, and 2226 patients were
exposed to warfarin with a mean duration of exposure of 8 days for the
ximelagatran groups.

Overall, more than 55% of patients in each treatment group experienced
at least 1 adverse event (AE). Post-operative complications were mostly
related to bleeding and were reported at a higher frequency in the
ximelagatran groups (17% at 36 mg, 23% at 24 mg) than in the warfarin
groups (15% and 20%, respectively).

There were 18 deaths (12 patients exposed to ximelagatran and 6 patients
exposed to warfarin). Of the 12 fatal SAEs reported among the 3010
patients who received ximelagatran (0.4%), 2 were fatal bleeding events
(both on ximelagatran 36 mg). Six were fatal events in which 'PE could
not be excluded'. The last 4 fatal SAEs in patients who received
ximelagatran were adjudicated as 'death not associated with VTE or
bleeding'. The investigators reported the causes of death in 1 patient
on treatment as sudden death, and in the other 3 patients after
treatment as intestinal perforation, acute MI, and pneumonia. Of the 6
deaths reported among the 2226 patients who received warfarin (0.3%), 2
were fatal events in which 'PE could not be excluded'. The causes of
death in 2 patients on treatment were arrhythmia and MI and in the other
2 after treatment were colon carcinoma and AMI.

There were more adverse events leading to discontinuation of study drug
(DAEs) in the ximelagatran 36-mg group (2.6%) than in the warfarin group
(2.0%) and in the ximelagatran 24-mg group compared to warfarin group
(3.1% versus 2.1%, respectively) with postoperative complication, the
most common adverse event leading to study drug discontinuation.

With respect to on-treatment adjudicated events, major bleeding occurred
in 0.9% of patients treated with ximelagatran 36 mg, compared to 0.5% of
patients treated with warfarin. There were 2 fatal bleeding events (both
on ximelagatran 36 mg). Major/minor bleeding occurred in 5.1% of
patients treated with ximelagatran 36 mg and 4.1% of patients treated
with warfarin.

Incidences of ALAT elevation reported as AEs were higher in the 36-mg
ximelagatran group (2.1%) than other groups (1.3-1.5% warfarin; 1.4%
ximelagatran 24-mg). There were no hepatobiliary fatal SAEs, non-fatal
SAEs or DAEs in either ximelagatran group. During the follow-up period
(4-6 weeks), 8 patients in the ximelagatran group, and 1 in the warfarin
group had their first ALAT elevation \>3x ULN. However, patients were
only followed up for 4-6 weeks post operation. Drug effects on liver
toxicity beyond 4-6 weeks are unknown. It should be noted that in
studies with long-term exposure to ximelagatran elevation of hepatic
enzymes was typically seen between 2^nd^ and 6^th^ month after starting
ximelagatran.

In both studies Exult A and Exult B, the proportion of patients with
coronary artery disease adverse events (MI or ischemia/angina) was
significantly higher in the ximelagatran groups than in the warfarin
groups. In patients undergoing TKR surgery (Exult A and Exult B),
proportion of patients with coronary artery disease adverse events was
statistically significantly higher in the ximelagatran group (20/2677,
0.75%) than in the warfarin group (5/1907, 0.26%) (p=0.02800). The
proportion of patients with MI was also higher in the ximelagatran group
(16/2677, 0.60%) than in the warfarin group (4/1907, 0.21%) in the TKR
population (p=0.04951). There were no appreciable differences between
the treatment groups for underlying diseases including hypertension,
hypercholesterolemia, diabetes mellitus, coronary atherosclerosis, as
well as age, gender and weight. Considering ximelagatran as an
anticoagulant with potential to treat MI, these results are worrisome.

Overall, these studies raised some safe concerns for use of oral
ximelagatran 36 mg bid for 7 to 12 days after surgery (beginning the
morning after surgery) in the prevention of VTE in patients undergoing
elective knee replacement surgery. There is a potential risk of higher
coronary artery disease adverse events including acute myocardial
infarction. Potential long-term use that will cause liver toxicity is
high. Also, major bleeding events were higher in patients treated with
ximelagatran than in patients treated with warfarin. The long-term
follow up (6 months) data may also be considered to adequately assess
liver toxicity for short-term use of ximelagatran.

**C.2. Safety of ximelagatran in patients with long-term exposure (\> 35
days)**

A total of 6931 patients received doses from 20 to 60 mg of
ximelagatran, for a median of 370 days. A total of 5024 patients were
exposed to ximelagatran for at least 6 months and 3509 for at least 12
months. A total of 6216 patients were exposed for a median of 455 days
to warfarin (n=4967) and placebo (n=1249).

**C.2.1. Death**

There were 224 deaths during active treatment, 112 in the ximelagatran
treatment groups and 112 in the comparator groups. A further 331
patients died after stopping study drug (166 in the ximelagatran group
and 165 in the comparator group). There was no differences between the
treatment groups. The most common fatal SAE was myocardial infarction.

**C.2.2. Non-fatal SAE**

A total of 26.3% of patients in the ximelagatran group and 27.1% of
patients in the comparator group experienced a non-fatal SAE during
treatment. A further 5.5% of patients in the ximelagatran group and 4.3%
of patients in the comparator group experienced a non-fatal SAE after
stopping study drug. The most common non-fatal SAEs were cardiovascular
events. The most common non-fatal SAEs considered to be causally related
to ximelagatran were increases in hepatic transaminases.

**C.2.3. Discontinuation**

The proportion of patients who discontinued study drug was higher in the
ximelagatran group (1189/6931, 17.2%) than in the comparator group
(801/6216, 12.9%). This was mostly due to the discontinuation of study
drug due to elevated hepatic transaminases. Data from discontinuation of
ximelagatran secondary to AEs indicate that "coronary artery disorders
(CAD)" were more common in the ximelagatran group than in the comparator
group (0.6% vs. 0.3%, respectively) whereas thromboembolic events were
less common DAEs in the ximelagatran group (0.4% vs.1.3%, respectively),
because of a placebo control. Other common causes of discontinuations
included bleeding events, with no difference between ximelagatran and
the comparators, except for haematuria and rectal haemorrhage/ melaena,
which caused slightly more discontinuations in the ximelagatran group
than in the comparator groups.

**C.2.4. Bleeding Events**

In patients with atrial fibrillation (AF), ximelagatran 36 mg was
associated with fewer major bleeding events than warfarin (AF pool; 2.4%
and 3.4% for the ximelagatran and warfarin group, respectively,
p=0.0288). However, there were no significant differences for major
bleeding events between the groups in each of the 2 pivotal studies
(SH-TPA-0003 and STP-0005). In patients with acute VTE, ximelagatran 36
mg was associated with numerically fewer major bleeding events than
enoxaparin/warfarin. In patients undergoing extended secondary
prophylaxis for VTE, ximelagatran 24 mg was associated with a similar
incidence of major bleeding events to placebo. A total of 38 patients
experienced bleeding-related SAEs with a fatal outcome, 19 cases in each
treatment group (ximelagatran or comparator).

**C.2.5. Hepatobiliary Toxicity**

In patients receiving long-term administration of ximelagatran (\>35
days) an increase in ALAT \>3xULN occurred in 6-13% (average 7.6%,
531/6948) compared to 0-2% (average 1.1%, 68/6230) of patients receiving
comparator treatments. Including local laboratory data, 620 patients
showed an ALAT elevation \>3xULN during the studies, 546 patients in the
ximelagatran group (cumulative incidence 7.8%) and 74 patients in the
comparator group (cumulative incidence 1.1%). Among the 531 patients in
the ximelagatran group who presented with an ALAT \>3xULN, 206 (39%)
completed the study on study drug. The remaining 325 patients (61%)
discontinued study drug prematurely.

The time pattern of ALAT elevations was consistent across patients. The
increase typically occurred between 1 and 6 months after the initiation
of ximelagatran. Before and after this time frame the incidence of ALAT
increase was similar to that in the comparator groups. Of the 531
ximelagatran-treated patients who had an ALAT elevation \>3xULN recorded
by the central laboratory, 502 (95%) had their ALAT return to \<2xULN
(235 with study drug continued). Most cases show a peak of ALAT within
the first 2 to 3 months post-randomization and a decline back towards
baseline within about 6 months post-randomization in patients who
discontinued or in patients continued on ximelagatran.

Eighteen patients who discontinued study drug with elevations of ALAT
subsequently resumed treatment after ALAT had returned to the normal
range. Of these 18 patients, 2 again experienced elevations of ALAT
after drug was resumed.

An evaluation of potential risk factors for increase in ALAT indicated
an increased risk in the

post acute coronary syndrome (ACS) (p=0.0009), VTE-treatment (VTE-T)
populations (p=0.0003), in female patients (p=0.0002), in patients with
low BMI (\<27 kg/m^2^) (p\<0.0001), and in patients receiving
concomitant treatment with statins (p=0.019). Asian patients were found
to have a decreased risk (p=0.0038). Although a single factor identified
above may not be strong enough to eliminate the subgroup population,
consideration may be given to contraindicating ximelagatran in patients
who have 2 or more risk factors, such as, female patients with low body
weight or who are taking a statin.

ALAT \>3xULN was associated with bilirubin \>2xULN (within one month
following the rise in

ALAT) in 0.53% (37/6948) of all patients who were exposed to
ximelagatran \>35 days as compared to 0.08% (5/6230) of patients exposed
to comparators. Concomitant elevations of ALAT \>3xULN and bilirubin
\>2xULN were observed during the first month of ximelagatran therapy in
6 of 37 patients. Nine ximelagatran-treated patients (24.3%, 9/37) died
with concomitant ALAT \>3xULN and bilirubin \>2xULN. Among these, 3 died
from heart failure; 3 died from carcinomas with hepatic metastases; 2
(ID# 7259, and 7859) died from GI bleeding with coagulopathy (1 with
biopsy documented hepatic necrosis) and 1 (ID# 5442) died from hepatitis
B. Liver failure/toxicity by ximelagatran might have caused or at least
contributed to these deaths. Only one autopsy was done in these 9 deaths
and it showed a small, friable and diffusely mottled liver suggestive of
severe diffuse hepatic necrosis.

**C.2.6. Adverse Events of Coronary Artery Disease**

In all study populations except the post acute coronary syndrome, the
proportion of patients with coronary artery disease adverse events was
higher in the ximelagatran groups than in the comparator groups (7.0%
and 6.7% for the AF pool, 1.3% and 0.1% for the VTE-treatment (VTE-T)
pool and 2.6% and 2.0% for the VTE-prevention (VTE-P) pool, for the
ximelagatran and comparator groups, respectively). This trend was
consistent across the pools for myocardial infarction.

The proportion of patients with coronary artery disease adverse events
was statistically significantly higher in the ximelagatran group
(32/1848, 1.7%) than in the warfarin/placebo group (12/1859, 0.7%) in
the VTE (VTE-T + VTE-P) population (p=0.00411). The proportion of
patients with MI was also significantly higher in the ximelagatran group
(13/1848, 0.7%) than in the warfarin/placebo group (3/1859, 0.16%) in
the VTE population (p=0.01183). There were no appreciable differences
between the treatment groups for underline diseases including
hypertension, diabetes mellitus, hypercholesterolemia, coronary
atherosclerosis, as well as age, gender and weight. Considering
ximelagatran as an anticoagulant with potential to treat MI, these
results are worrisome.[]{#__RefHeading___Toc77047730 .anchor}

### D. Dosing

For the indication of prevention of VTE in patients undergoing elective
knee replacement surgery, the proposed dose is oral ximelagatran 36 mg
bid for up to 12 days. For the indication of prolonged prophylaxis VTE
after a six-month anticoagulation treatment for VTE, the proposed dose
is oral ximelagatran 24 mg bid.

In term of hepatobiliary toxicity, there was not a marked dose response
over the dose range 24 mg to 60 mg ximelagatran, but there was a
noticeably lower incidence of elevation of liver transaminases at the 24
mg dose compared to the higher doses.

### E. Special Populations

**For short-term use ([\<]{.underline} 35 days)**

For the indication of prevention of VTE in patients undergoing elective
knee replacement surgery, the majority of the patients were female
(61.5%); most were Caucasian (95.1%); and most were greater than 64
years of age (65.6%). The mean age was approximately 67 years, but
ranged from 26 years to 91 years. Almost half the patients had a body
mass index \>30 kg/m^2^, which is typical for TKR surgery patients but
higher than the general population.

The incidence of VTE and/or all-cause mortality was significantly higher
in female and older patients. Results for these subgroups are summarized
in the following Table:

**Table 1: Incidence of total VTE and/or all-cause mortality for
selected subgroups (efficacy ITT population) -- Pooled 36 mg bid**

![](media/image1.png){width="4.125694444444444in" height="1.85in"}The
subgroup factors that had no significant impact on the incidence of
total VTE and/or all-cause mortality were: race, body mass index,
estimated CrCL, general anaesthesia (yes/no), time to first dose, and
time to ambulation.

**For long-term use (\> 35 days)**

For the indication of prolonged prophylaxis of VTE after a six-month
anticoagulation treatment for an episode of acute VTE, the majority of
the patients were male (54%), Caucasian (93%), and less than 60 years of
age (52%). The mean age was approximately 57 years, but ranged from 18
years to 90 years. Subgroup factors that had no significant impact on
the VTE events were: sex, age, race, body mass index, estimated CrCL,
initial proximal/or distal DVT (yes/no), previous VTE events (yes/no).

An evaluation of potential risk factors for increase in ALAT indicated
an increased risk in the

Post ACS (p=0.0009), and VTE-T (p=0.0003) populations and also in female
patients (p=0.0002), patients with low BMI (\<27 kg/m^2^) (p\<0.0001)
and patients receiving concomitant treatment with statins (p=0.019);
Asian patients were found to have a decreased risk (p=0.0038). Although
single factor identified above may not be strong enough to eliminate the
subgroup population, consideration may be given to contraindicating
ximelagatran in patients who have 2 or more factors, such as, female
patients with low body weight or who are taking a statin.

All three indications are for the adult population only. AstraZeneca
requests a waiver for pediatric studies for the indications claimed in
this application. It is unlikely that a substantial number of pediatric
patients will be treated with EXANTA for the claimed indications. The
estimated number of pediatric patients diagnosed with atrial
fibrillation in the US in 2002 is less than 1,500 children. The
estimated total number of pediatric patients treated for VTE (of which
prevention of recurrent events, the indication claimed in this
application, is a subset of patients) in the US in 2002 is less than
3,000 children. The estimated cumulative number of pediatric patients
diagnosed with conditions for which EXANTA will be indicated is less
than 5,000 children. Thus, the number of pediatric patients likely to be
treated with EXANTA for the claimed indications is well below the number
defined as a substantial number in the Pediatric Final Rule. Therefore,
I recommend that the sponsor's requests for waiver of the requirements
to conduct pediatric studies be granted for the indications claimed in
this application.

**Subjects with renal impairment**

Melagatran, the active metabolite of ximelagatran, is eliminated
primarily via renal excretion. Renal function decreases with age and the
target patient population for ximelagatran is of older age (median age
about 65 years). As expected, subjects with severe renal impairment had
higher plasma concentrations of melagatran. The mean (SD) half-lives of
melagatran were 6.8 (2.0) h and 9.3 (3.5) h after subcutaneous injection
melagatran and oral ximelagatran dosing, respectively, in the subjects
with renal impairment. These half-lives were about 3-fold higher than
for control subjects with normal renal function. Therefore, usage of
ximelagatran in patients with severe (CrCL \< 30mL/min) renal impairment
is not recommended. A dosing reduction should be considered for the
patients who have moderate renal impairment (CrCL \< 80mL/min).

**Subjects with hepatic impairment**

The absorption of ximelagatran and the metabolic biotransformation to
its active form, melagatran, are not influenced for subjects with mild
and moderate hepatic impairment. However, patients who have abnormal
liver function or history of liver diseases have been excluded from the
studies. Due to high risk of liver toxicity, the use of ximelagatran in
patients with hepatic disease and/or ALT \> 2 times the upper limit of
normal at the start of therapy is contraindicated.

# Clinical Review 

## I. Introduction and Background

### A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's Proposed Indication(s), Dose, Regimens, Age Groups

EXANTA ® (ximelagatran) is an oral anticoagulant and a prodrug of
melagatran, a potent, reversible, competitive and direct inhibitor of
thrombin.

Ximelagatran is in development for several indications, of which the
following 3 are being

submitted in this application: prevention of VTE (defined as deep vein
thrombosis \[DVT\], pulmonary embolism \[PE\], or both) in patients
undergoing knee replacement surgery; 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 (AF). All 3 indications are for the adult population only.

For the indication of prevention of VTE in patients undergoing knee
replacement surgery, the proposed dosing is EXANTA 36 mg twice-daily for
a treatment period of 7 to 12 days.

Provided hemostasis has been established, the first dose should be given
the morning after surgery, but no sooner than 12 hours from the time of
surgery. For the indication of long-term secondary prevention of VTE, it
is proposed that patients who have received standard anticoagulant
treatment for DVT or PE be treated with EXANTA 24 mg twice-daily. For
the indication in patients with atrial fibrillation, please see Medical
Officer's review from the Division of Cardio-Renal Drug Products for
details. No dosage adjustment is necessary with EXANTA in patients with
a creatinine clearance (CrCL) [\>]{.underline}30 mL/min. Usage of EXANTA
in patients with severe renal impairment (CrCL \<30 mL/min) is not
recommended. The use of EXANTA in patients with hepatic disease and/or
ALT \>2 times the upper limit of normal at the start of therapy is
contraindicated.

### B. State of Armamentarium for Indication(s) 

Warfarin is approved for:

-   the prophylaxis and/or treatment of venous thrombosis and its
    extension, and PE;

-   the prophylaxis and/or treatment of the thromboembolic complications
    associated with atrial fibrillation and/or cardiac valve
    replacement;

-   reducing the risk of death, recurrent MI, and thromboembolic events
    such as stroke or systemic embolization after MI.

The "Dosage and Administration" section of warfarin labeling refers to
"longer term therapy" for indications such as VTE, in patients with
A-Fib or mechanical and bioprosthetic heart valves. It also states that
the duration of therapy in each patient should be individualized and
anticoagulant therapy should be continued until the danger of thrombosis
and embolism has passed. Thus, the indications and dosing
recommendations for warfarin are sufficiently broad to encompass
extended prophylaxis of DVT.

Lovenox (enoxaparin sodium), a low molecular weight heparin, is approved
for the indication of the prophylaxis of DVT in patients undergoing knee
replacement surgery. Arixtra (fondaparinux sodium) injection, a
synthetic inhibitor of activated Factor X (Xa), is approved for the
indication of the prophylaxis of DVT in patients undergoing hip or knee
replacement surgery.

### C. Important Milestones in Product Development

### The clinical studies conducted in the United States to support the proposed indications were conducted under INDs 56,611 and 59,151. End of Phase II meetings were held on March 10, 2000, June 16, 2000 and April 6, 2001. The CMC End of Phase II meeting was held on March 27, 2000 and Pre-NDA meeting was held on July 14, 2003. Because significant liver toxicity with use of Exanta was identified during the clinical trials, a special meeting held on October 9, 2003 to discuss the Risk Management Program for Exanta. CDER Office of Drug Safety (ODS) participated in the discussion.

### 

### D. Other Relevant Information 

A Marketing Authorization Application (MAA) was submitted to the
European Union (EU) in

June 2002 and approved by France in December 2003 for the prevention of
VTE in patients undergoing hip or knee replacement surgery. National
Marketing Authorizations for additional 14 countries in EU are issued in
June 2004. UK and Ireland have been withdrawn from the Mutual
Recognition Procedure. However, approved dose in EU is 24 mg twice a
day, instead of 36 mg twice a day proposed in this submission.

### E. Important Issues with Pharmacologically Related Agents

EXANTA ® (ximelagatran) is the first oral direct inhibitor of thrombin.
Iprivask (desirudin for injection) is an iv inhibitor of thrombin that
was approved for the indication of the prevention of VTE in patients
undergoing hip (not knee) replacement surgery.

## II. Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

The prodrug ximelagatran is a poor inhibitor of thrombin, while the
active metabolite, melagatran, is a potent, rapid and reversible direct
thrombin inhibitor. Melagatran prolongs coagulation times in all species
studied and inhibits the thrombin-induced aggregation of human, dog and
rat platelets. In plasma coagulation assays such as Activated Partial
Thromboplastin Time (APTT) and Prothrombin Time (PT) there is a
variation in the response to fixed melagatran plasma concentrations
between available various test kits for each assay. Thrombin Time (TT)
and Ecarin Clotting Time (ECT) are assays that have been used in order
to characterize synthetic or recombinant direct thrombin inhibitors,
such as melagatran and hirudin.

In the Safety Pharmacology study investigating intestinal motility in
rats, the highest dose, 200 mmol/kg (95 mg/kg), of ximelagatran,
inhibited intestinal motility. Oral, but not subcutaneous,
administration of melagatran inhibited gastrointestinal motility at
doses above 10 mmol/kg (4.3 mg/kg). Based on the equal exposure to
melagatran after sc and oral administration it was concluded that the
effect is elicited from the mucosal side of the gastrointestinal tract.
High doses of melagatran given iv to dogs induced vasodilatation and
increased vascular permeability, which was explained by histamine
release. No liver toxicity or cardiac toxicity were reported from
pre-clinical toxicology studies.

## Human Pharmacokinetics and Pharmacodynamics

According to the sponsor's report, ximelagatran has following PK/PD
profiles.

### A. Pharmacokinetics

After oral administration to healthy subjects, the absorption of
ximelagatran and the bioconversion to melagatran is rapid. The
bioavailability of melagatran after oral dosing with ximelagatran to
healthy subjects is about 20%, with low inter- and intra-individual
variability. Melagatran is mainly excreted unchanged in urine with a
renal clearance that corresponds to the glomerular filtration rate. The
half-life of melagatran is about 3 hours after oral dosing with
ximelagatran to young healthy subjects.

The pharmacokinetics of melagatran, following oral administration of
ximelagatran and parenteral administration of melagatran to healthy
subjects, are dose proportional, i.e., the exposure of melagatran
increases linearly in proportion to the given dose (15 to 60 mg). No
time-dependent changes in the pharmacokinetics of melagatran are
observed during repeated oral dosing with ximelagatran to healthy
subjects. The interindividual variability in melagatran exposure is low
(coefficient of variation (CV) \~20%) and the intraindividual
variability is even lower (CV \~10%).

The pharmacokinetics of melagatran, following oral administration of
ximelagatran and parenteral administration of melagatran, are consistent
across the different patient populations studied, and in agreement with
pharmacokinetic properties observed in healthy subjects. After oral
administration of ximelagatran, the half-life of melagatran is about 4
to 5 hours in the patient populations studied, which is longer than in
young healthy subjects. This appears to a large extent to be due to the
age-related lower renal function in patients.

The interindividual variability of melagatran exposure is higher for
patients (CV \~50%) than for healthy volunteers, which to a large extent
appears to be due to the interindividual variability in renal function.
No time-dependent changes in the pharmacokinetics of melagatran are
observed for patients receiving long-term oral treatment with
ximelagatran. The intraindividual variability of melagatran exposure is
low (CV \~25%), suggesting that the pharmacokinetics of melagatran are
predictable and reproducible.

Race has no influence on the absorption and metabolism of ximelagatran.
Compared to patients with normal renal function (CrCL \>80 mL/min), the
melagatran exposure was about 1.5 and 2.5 times higher for patients with
mild renal impairment (CrCL 50 to 80 mL/min) and moderate renal
impairment (CrCL 30 to \<50 mL/min), respectively.

After oral administration of ximelagatran to patients with severe renal
impairment (CrCL 10 to 30 mL/min), the melagatran exposure was 5 times
higher than for control subjects with normal renal function. Compared
with the average for the studied patient populations, melagatran
exposure is increased about 3-fold and the half-life is increased about
2-fold in patients with severe renal impairment. For patients with
end-stage renal disease requiring dialysis, the clearance of melagatran
is low and comparable to the non-renal clearance in healthy subjects.
Melagatran clearance is increased during dialysis, suggesting that
dialysis is effective in accelerating the elimination of melagatran.
Mild to moderate liver impairment has no influence on the absorption or
metabolism of ximelagatran. Gender, age, body weight and obesity have no
influence on the absorption and metabolism of ximelagatran. The
influence of these intrinsic factors on the elimination of melagatran
appears to a large extent to be related to differences in renal
function.

The extent of absorption and conversion of ximelagatran is not affected
by food. Oral

administration of ximelagatran with food causes a 1-hour delay of the
tmax of melagatran but the AUC and Cmax of melagatran are unaffected.
The pharmacokinetics of ximelagatran is not influenced by concomitant
intake of alcohol. *In vivo* drug interaction studies with drugs that
are substrates of CYP3A4 (nifedipine, atorvastatin, amiodarone,
diazepam), CYP2C9 (diclofenac) and CYP2C19 (diazepam) showed no
interaction and confirmed that ximelagatran has a low potential for drug
interactions mediated by cytochrome P450 metabolism. Upon
co-administration of ximelagatran and erythromycin to healthy subjects,
the bioavailability of melagatran increased by approximately 80%.
Erythromycin is known to interact with many drugs, as it is metabolized
by and inhibits CYP3A4. However, this isoenzyme is not judged to be the
site of the interaction as *in vitro* studies with ximelagatran and
melagatran have shown that they are not substrates of CYP3A4.
Concomitant chronic treatments had no significant influence on the
pharmacokinetics of melagatran for any of drugs or drug classes
evaluated in the studied patient populations.

### B. Pharmacodynamics

Statistically significant concentration-response relationships were
detected between melagatran plasma concentrations and inhibition of
thrombin generation, platelet activation and thrombus formation*.* Oral
administration of ximelagatran results in a predictable and rapid onset
of action as indicated by statistically significant inhibition of
thrombin generation, platelet activation and thrombus formation measured
at 2 hours post-dosing.

Melagatran induces a relatively small prolongation of the Capillary
bleeding time (CBT) (up to 35%) following doses of 24 to 72 mg oral
ximelagatran*.* These prolongations were additive with

therapeutic doses of ASA and diclofenac (up to 43% prolongation in
combination) but synergistic with a therapeutic dose of clopidogrel (98%
prolongation in combination).

Oral ximelagatran prolongs to varying degrees and with varying
sensitivity conventional coagulation-time assays such as the activated
partial thromboplastin time (APTT), activated clotting time (ACT),
thrombin time (TT) and prothrombin time/international normalized ratio
(PT/INR*).* The coagulation time assay prolongations occur in a
concentration-dependent and non-linear (APTT, ACT, PT/INR) or linear
(TT) manner. The APTT, ACT, and PT/INR

assays are rather insensitive and show variable responses to melagatran
concentrations

whereas the TT is very sensitive to melagatran plasma concentrations.
The ecarin clotting time (ECT), an experimental assay that is not widely
available, was prolonged by melagatran in a concentration-dependent and
linear manner. Oral dosing with ximelagatran results in a predictable
and rapid onset of anticoagulation. The APTT is prolonged within 20
minutes of dosing with oral ximelagatran and peak prolongations are
observed 2 hours postdosing. Melagatran-induced prolongation of the APTT
is largely independent of the intrinsic (age, renal impairment, mild to
moderate hepatic impairment, obesity, ethnicity, and disease) and
extrinsic (food, alcohol, ASA, diclofenac, clopidogrel, amiodarone,
atorvastatin, erythromycin, digoxin) factors studied.

The offset of action of 24 or 36 mg ximelagatran is rapid, with low but
pharmacologically active concentrations of melagatran remaining for
approximately 12 to 24 hours following the last dose.

There are no currently available haemostatic agents that have been
demonstrated to have clinical value in reversing the anticoagulant
effects of ximelagatran.

## IV. Description of Clinical Data and Sources 

### A. Overall Data

The development program for ximelagatran has been designed to offer an
oral alternative

anticoagulant to warfarin for major indications. Ximelagatran has been
evaluated in various

patient populations in large controlled, worldwide, clinical studies.

The development program includes 82 clinical studies with ximelagatran
and/or melagatran

(60 Phase 1 studies and 22 Phase 2 and 3 studies), in which 30698
subjects were randomized. A total of 17593 randomized subjects received
the oral prodrug ximelagatran, or the active drug melagatran. In the
long-term treatment populations, 6931 patients received ximelagatran,
5024 of whom received treatment for at least 6 months and 3509 for at
least a year (up to 2.5 years in the pivotal SPORTIF studies and up to 4
years in the ongoing SPORTIF IV study).

The design of the clinical studies has varied between indications but
some important features

are common to most of them, as described below:

Overall design: Each Phase 3 study was conducted as a multi-center,
randomized, parallel-group, comparator-controlled design. All studies
were double-blind except for SH-TPA-0003

(SPORTIF III; which was open-label in design). All studies used a
central laboratory for all

protocol-specified laboratory measurements.

Control groups and randomization: Each Phase 3 study included a control
group and treatment allocation randomized by a central randomization
service (interactive voice response system \[IVRS\]) to reduce bias.

Independent adjudication of clinical endpoint events: In each pivotal
study, the endpoint events (efficacy, all-cause mortality, and bleeding
events) were identified and assessed by the investigator but the primary
efficacy evaluation was based on endpoint events confirmed by an
independent expert adjudication committee who were blinded to the
treatment taken by the patient.

Independent committees: In addition to the independent committee
adjudicating the endpoint

events, each study incorporated an Independent Drug Safety Monitoring
Board (DSMB;

responsible for reviewing safety during the conduct of the study), and
an Independent Executive Committee (EC; responsible for oversight of the
conduct and reporting of the study).

### B. Tables Listing the Clinical Trials

> ![](media/image2.png){width="5.996527777777778in" height="3.14375in"}

### C. Postmarketing Experience

There are no postmarketing data available as of July 2004.

### D. Literature Review

The reviewer has searched the literatures related to ximelagatran up to
July 2004 and incorporated them into the review.

## V. Clinical Review Methods

### A. How the Review was Conducted

The efficacy evaluation of the indication for prevention of VTE in
patients undergoing knee replacement surgery is based on 2 clinical
trials conducted by the sponsor (EXULT A and EXULT B). The sponsor
conducted 3 multi-center, double-blind, parallel-group, Phase 3 studies
in patients undergoing primary, elective TKR surgery (SH-TPO-0006, EXULT
A and EXULT B). A total of 5284 patients were randomized in these 3
studies (1927 to ximelagatran 36 mg bid, 2247 to warfarin, and 1110 to
ximelagatran 24 mg bid). All 3 studies evaluated ximelagatran
administered postoperatively (beginning the morning after surgery) for 7
to 12 days compared to warfarin titrated to an INR of 2.5 (INR range 1.8
to 3.0) that was initiated the evening of the day of surgery.

Ximelagatran 36 mg bid was used in both studies EXULT A and EXULT B and
ximelagatran 24 mg bid only was used in study SH-TPO-0006. The sponsor
proposed 36 mg bid for this indication. Therefore, in this review, I
mainly examine studies EXULT A and EXULT B for the efficacy evaluation
of indication for prevention of VTE in patients undergoing knee
replacement surgery.

For the indication of prolonged prophylaxis of VTE after a six-month
anticoagulation treatment, the sponsor provided only one study,
SH-TPV-0003 (THRIVE III). This was a multi-center, double-blind,
parallel-group, placebo control study. Ximelagatran 24 mg bid or placebo
were given as prolonged prophylaxis after a 6-month anticoagulation
treatment for VTE. A total of 1233 patients were randomized, with 903
completing the study on the study drug (468 on ximelagatran 24 mg bid
and 435 on placebo).

The medical officers from the Division of Cardio-Renal Drug Products
will conduct the review for the indication of prophylaxis of stroke in
patients with atrial fibrillation.

The safety evaluation included assessment of the data from all clinical
studies which were divided into short term use ([\<]{.underline}35 days)
and long-term use (\> 35 days). There is no post-marketing safety data
available.

Data from 10 Phase 2 and Phase 3 studies are presented in 4 pools based
on the indication that was investigated. These indications were AF, VTE
treatment (VTE-T), VTE secondary prevention (VTE-P) and post ACS. A
fifth pool, the long-term exposure (LTE) pool, combines data from all of
these indications.

The long-term (\>35 days) safety of ximelagatran has been studied in a
large population of 6931 patients comprising 3838 patients with atrial
fibrillation (AF), 1236 patients for treatment (VTE-T), 612 patients for
secondary prevention (VTE-P) of VTE and 1245 patients with recent acute
coronary syndrome (post ACS). These 6931 patients received doses from 20
to 60 mg, for a median of 370 days, representing an overall exposure of
6768 patient-years. A total of 5024 patients were exposed to
ximelagatran for at least 6 months (\>180 days) and 3509 for at least 12
months (\>360 days). All the studies were controlled, thus enabling
comparison with a cohort of 6216 patients exposed for a median of 455
days mainly to the reference anticoagulant warfarin (n=4967), but also
to placebo in a smaller number of patients (n=1249).

### B. Overview of Materials Consulted in Review

In this review, I have examined material in following sections: Cover
letter, Labeling, Summaries, and clinical study reports, including data
listings and case report forms (CRF).

### C. Overview of Methods Used to Evaluate Data Quality and Integrity

The Division of Scientific Investigations has been consulted to conduct
inspection for the following sites:

![](media/image3.png){width="5.800694444444445in" height="2.8in"}

![](media/image4.png){width="5.784027777777778in"
height="2.5416666666666665in"}

### D. Were Trials Conducted in Accordance with Accepted Ethical Standards

The sponsor has submitted informed consent with each clinical trial
protocol. According to the sponsor, the protocol and all amendments for
this study were reviewed by an Independent Ethics Committee (IEC), and
monitoring and audit procedures performed prior to, during, and upon
completion of this study have verified that this study was conducted in
accordance with the ethical principles.

### E. Evaluation of Financial Disclosure

The sponsor submitted a FDA Form 3454 certifying that no investigator of
any of the covered clinical studies had any financial interests to
disclose.

## VI. Integrated Review of Efficacy 

### A. Brief Statement of Conclusions

**Indication 1: prevention of VTE in patients undergoing elective knee
replacement surgery**

Oral ximelagatran 36 mg bid was superior to warfarin in reducing total
VTE and/or all- cause mortality among patients undergoing TKR surgery in
2 large Phase III studies.

In the pooled EXULT A and EXULT B analyses, the incidence of total VTE
and/or all-cause

mortality among patients undergoing TKR was 21.7% for patients in the
ximelagatran 36 mg

group and 30.2% for patients in the warfarin group, for an absolute risk
reduction (ARR) of 8.6% (p\<0.001). The ARR of 8.6% provided an number
needed to treat (NNT, 1/ARR) of 12 (95% CI: 9 to 18).

The benefit was mainly due to a reduction in asymptomatic distal DVT
diagnosed by venography which is not clinically meaningful. There were
no clinically or statistically significant differences between
ximelagatran and warfarin in reducing the frequency of proximal DVT, PE,
and/or all-cause mortality in this population.

There are several major problems for comparison with warfarin as an
active comparator in these two studies. Warfarin is not approved for the
indication of prevention of DVT in patients undergoing elective knee
replacement surgery. The comparison is unfair, because warfarin will
take about 3-5 days to reach therapeutic level, while Exanta reaches
therapeutic levels within hours. The results show that 33.1% - 35.2% of
patients receiving warfarin had an INR less than 1.8 at postoperative
day 3, and 24 -- 26.9% % of patients receiving warfarin had an INR less
than 1.8 at end of treatment (day 7 -- 12). Because the study is
designed to show superiority of ximelagatran, efficacy results for
ximelagatran in these studies are still acceptable, considering warfarin
group as placebo.

**Indication 2: Prolonged prophylaxis VTE after a six-month
anticoagulation treatment for a acute episode of VTE**

Ximelagatran significantly reduced the recurrence rate of symptomatic,
objectively confirmed VTE (the primary variable of the study) as
compared to placebo over 18 months of treatment (cumulative risk of 2.8%
versus 12.6%; hazard ratio 0.16; p\<0.0001). The number of patients with
a VTE event was 12 in the ximelagatran group and 71 in the placebo
group. The number of patients with a PE event was lower in the
ximelagatran group compared to the placebo group (2 and 23 in
ximelagatran and placebo group respectively).

The results for the secondary variable, all-cause mortality, showed no
significant difference between the treatment groups (1.1% vs 1.4% for
patients on ximelagatran and placebo, respectively) during the 18
months.

### B. General Approach to Review of the Efficacy of the Drug

The efficacy evaluation of indication for prevention of VTE in patients
undergoing knee

replacement surgery is based on 2 clinical trials conducted by the
sponsor (EXULT A and EXULT B).

For the indication of prolonged prophylaxis VTE after a six-month
anticoagulation treatment, the sponsor provided only one study,
SH-TPV-0003 (THRIVE III). This was a multi-center, double-blind,
parallel-group, placebo control study and this study was reviewed in
detail.

The medical officers from the Division of Cardio-renal Drug Products
will conduct the review for the indication of prophylaxis of stroke in
patients with atrial fibrillation. Therefore, for the efficacy
evaluation regarding the indication of prophylaxis of stroke in patients
with atrial fibrillation, please see Dr. Desai's Meidcal Officer Review
on this submission.

### C. Detailed Review of Trials by Indication

**Indication 1: prevention of VTE in patients undergoing elective knee
replacement surgery**

The sponsor conducted 3 multi-center, double-blind, parallel-group,
Phase 3 studies in patients undergoing primary, elective TKR surgery
(EXULT A, EXULT B and SH-TPO-0006). A total of 5284 patients were
randomized in these 3 studies (1927 to ximelagatran 36 mg bid, 2247 to
well-controlled warfarin, and 1110 to ximelagatran 24 mg bid). All 3
studies evaluated ximelagatran administered postoperatively (beginning
the morning after surgery) for 7 to 12 days compared to warfarin
titrated to an INR of 2.5 (INR range 1.8 to 3.0) that was initiated the
evening of the day of surgery.

Ximelagatran 36 mg bid was used in both studies EXULT A and EXULT B and
ximelagatran 24 mg bid was used in study SH-TPO-0006. The sponsor
proposed 36 mg bid for this indication. Therefore, in this review, I
mainly examine studies EXULT A and EXULT B. Please see Appendix B for
detailed review of the trials.

**Indication 2: Prolonged prophylaxis VTE after a six-month
anticoagulation treatment for**

**an acute episode of VTE**

The sponsor provided only one study, SH-TPV-0003 (THRIVE III) to support
this indication. This was a multicentre, double-blind, parallel-group,
placebo control study. Ximelagatran 24 mg bid or placebo were given as
prolonged prophylaxis after a 6-month anticoagulation treatment for VTE.
A total of 1233 patients were randomized, with 903 completing the study
on the study drug (468 on ximelagatran 24 mg bid and 435 on placebo).
Please see Appendix B for detailed review of the trial.

**Indication 3: prevention of strokes and systemic embolic event in
patients with nonvalvular atrial fibrillation**

Division of Cardio-Renal Drug Products (HFD-110) was consulted to review
this indication. Please see medical officer's review from HFD-110 for
details.

### 

### D. Efficacy Conclusions

**Indication 1: prevention of VTE in patients undergoing elective knee
replacement surgery**

Oral ximelagatran 36 mg bid was superior to warfarin in reducing total
VTE and/or all- cause mortality among patients undergoing TKR surgery in
2 large Phase 3 studies. Table 3 summarizes primary endpoints- incidence
of total VTE and/or all-cause mortality (efficacy ITT population) from
both studies EXULT A and EXULT B, and Pooled 36 mg bid.

**Table 3: Incidence of total VTE and/or all-cause mortality (efficacy
ITT population) -- EXULT A, EXULT B, and Pooled 36 mg bid**

![](media/image5.png){width="5.242361111111111in"
height="3.1666666666666665in"}

In EXULT A, the incidence of total VTE and/or all-cause mortality among
patients undergoing TKR was 20.3% for patients in the ximelagatran 36 mg
group and 27.6% for patients in the warfarin group, for an absolute risk
reduction (ARR) of 7.3% (p=0.003). The ARR of 7.3% provided a relative
risk reduction (RRR) of 26.5% and a number needed to treat (NNT=1/ARR)
of 14 (95% CI: 8 to 40).

EXULT B replicated the superior efficacy of ximelagatran 36 mg bid
versus warfarin group demonstrated in EXULT A. In EXULT B, the incidence
of total VTE and/or all-cause mortality among patients undergoing TKR
was 22.5% for patients in the ximelagatran 36-mg group and 31.9% for
patients in the warfarin group, for an ARR of 9.3%. (p\<0.001). The ARR
of 9.3% provided an RRR of 29.5% and an NNT (1/ARR) of 11 (95% CI: 8 to
19).

In the pooled EXULT A and EXULT B analyses, the incidence of total VTE
and/or all-cause

mortality among patients undergoing TKR was 21.7% for patients in the
ximelagatran 36 mg

group and 30.2% for patients in the warfarin group, for an ARR of 8.6%
(p\<0.001). The ARR

of 8.6% provided an RRR of 28.1% and an NNT (1/ARR) of 12 (95% CI: 9 to
18).

However, the benefit was mainly due to a reduction in asymptomatic
distal DVT diagnosed by venography which is not clinically meaningful
(Table 4). There were no clinically or statistically significant
differences between ximelagatran and warfarin in reducing the frequency
of proximal DVT, PE, and/or all-cause mortality in this population.

**Table 4: Objectively confirmed symptomatic and asymptomatic VTE over
the entire study (efficacy ITT population) -- EXULT A and B 36 mg bid**

![](media/image6.png){width="5.700694444444444in"
height="3.5416666666666665in"}

In EXULT A, the incidence of proximal DVT, PE, and/or all-cause
mortality among patients undergoing TKR was 2.7% for patients randomized
to ximelagatran 36 mg and 4.1% for patients randomized to warfarin (1.4%
reduction; p=0.171). In EXULT B, the incidence of proximal DVT, PE,
and/or all-cause mortality among patients undergoing TKR was 3.9% for
patients randomized to ximelagatran 36 mg and 4.1% for patients
randomized to warfarin (0.3% reduction; p=0.802).

Approximately 95% of patients in each treatment group had unilateral
surgery performed and, therefore, the reductions in total VTE and/or
all-cause mortality for the combined surgeries approximated the
reduction for patients with unilateral surgery.

In both studies, a higher frequency of total VTE and/or all-cause
mortality was observed across both treatment groups for female patients
(relative to males), older patients (relative to younger patients),
patients enrolled at sites in Canada (relative to those in the United
States and the rest of the world).

In EXULT A ximelagatran 24 mg bid was not superior to warfarin in
reducing the rate of total VTE and/or all-cause mortality (27.6%
warfarin vs 24.9% ximelagatran 24 mg).

### 

There are several major problems for comparison of ximelagatran with
warfarin in these two studies. Warfarin is not approved for this
short-term indication. The comparison is unfair, because warfarin will
take about 3-5 days to reach therapeutic level, while Exanta reaches
therapeutic levels within hours. The results show that 33.1% - 35.2% of
patients receiving warfarin had an INR less than 1.8 by postoperative
day 3, and 24 -- 26.9% % of patients receiving warfarin had an INR less
than 1.8 by end of treatment (day 7 -- 12).

**Indication 2: Prolonged VTE prophylaxis after a six-month
anticoagulation treatment for an acute episode of VTE**

Ximelagatran significantly reduced the recurrence rate of symptomatic,
objectively confirmed VTE as compared to placebo over 18 months of
treatment (cumulative risk of 2.8% versus 12.6%; hazard ratio 0.16;
p\<0.0001). The number of patients with a VTE event was 12 in the
ximelagatran group and 71 in the placebo group. The number of patients
with a PE event was lower in the ximelagatran group compared to the
placebo group (2 and 23 in ximelagatran and placebo group respectively
(Table 5).

**Table 5: The number of patients with VTE events in ximelagatran and
placebo groups**

![](media/image7.png){width="5.3590277777777775in"
height="0.9416666666666667in"}

The results for the secondary variable, all-cause mortality, showed no
significant difference between the treatment groups (1.1% vs 1.4% for
patients on ximelagatran and placebo, respectively) during the 18
months.

## VII. Integrated Review of Safety

### A. Brief Statement of Conclusions

**A1. Safety of Ximelagatran in Patients Undergoing a Surgical Procedure
(use [\<]{.underline}35 days)**

A total of 1913 patients undergoing keen surgery were exposed to
ximelagatran 36 mg bid, 1097 patients were exposed to ximelagatran 24 mg
bid, and 2226 patients were exposed to warfarin with a mean duration of
exposure of 8 days for the ximelagatran groups.

Overall, more than 55% of patients in each treatment group experienced
at least 1 adverse event (AE). The frequency of AEs was similar between
the treatment groups. Post-operative complications were mostly related
to bleeding and were reported at a higher frequency in the ximelagatran
groups (17% at 36 mg, 23% at 24 mg) than in the warfarin groups (15% and
20%, respectively).

There were 18 deaths (12 patients exposed to ximelagatran and 6 patients
exposed to warfarin). Of the 12 fatal SAEs reported among the 3010
patients who received ximelagatran (0.4%), 2 were fatal bleeding events
(both on ximelagatran 36 mg). Six were fatal events in which 'PE could
not be excluded'. The last 4 fatal SAEs in patients who received
ximelagatran were adjudicated as 'death not associated with VTE or
bleeding'. The investigators reported the causes of death in 1 patient
on treatment as sudden death, and in the other 3 patients after
treatment as intestinal perforation, acute MI, and pneumonia. Of the 6
deaths reported among the 2226 patients who received warfarin (0.3%), 2
were fatal events in which 'PE could not be excluded'. The causes of
death in 2 patients on treatment were arrhythmia and MI and in the other
2 after treatment were colon carcinoma and AMI. None of the on-treatment
major bleeding events in the ximelagatran 24 mg group or warfarin group
was fatal.

Adverse events leading to discontinuation of study drug (DAEs) were
higher in the ximelagatran 36 mg group (2.6%) than in the warfarin group
(2.0%) as well as in the ximelagatran 24 mg group compared to warfarin
(3.1% versus 2.1%, respectively) with postoperative complication the
most common reason for a DAE.

With respect to on-treatment adjudicated events, major bleeding occurred
in 0.9% of patients treated with ximelagatran 36 mg, compared with 0.5%
of patients treated with warfarin. Major/minor bleeding occurred in 5.1%
of patients treated with ximelagatran 36 mg and 4.1% of patients treated
with warfarin. Similar results were observed for ximelagatran 24 mg bid
compared with warfarin.

Incidences of ALAT elevation reported as AEs were higher in the 36 mg
ximelagatran group (2.1%) than other groups (1.3-1.5% warfarin; 1.4%
ximelagatran 24 mg). There were no hepatobiliary fatal SAEs, non-fatal
SAEs or DAEs in either ximelagatran group. During the follow-up period
(4-6 weeks), 8 patients in the ximelagatran group, and 1 in the warfarin
group had their first ALAT elevation \>3x ULN. However, patients were
followed up only for 4-6 weeks post operation. Drug effects on liver
toxicity beyond 4-6 weeks are unknown. It should be noted that elevation
of hepatic enzymes was typically seen between 2^nd^ and 6^th^ month
after starting ximelagatran.

In both Exult A and Exult B, the proportion of patients with coronary
artery disease adverse events (MI or ischemia/angina) was higher in the
ximelagatran groups than in the warfarin groups. The proportion of
patients with coronary artery disease adverse events was statistically
significantly higher in the ximelagatran group (20/2677, 0.75%) than in
the warfarin group (5/1907, 0.26%) in the TKR population (Exult A and
Exult B) (p=0.02800). The proportion of patients with MI was also higher
in the ximelagatran group (16/2677, 0.60%) than in the warfarin group
(4/1907, 0.21%) in the TKR population (p=0.04951). There were no
appreciable differences between the treatment groups for underlying
diseases which include hypertension, hypercholesterolemia, diabetes
mellitus, coronary atherosclerosis, as well as age, gender and weight.
Considering ximelagatran as an anticoagulant with potential to treat MI,
these results are worrisome.

**A2.** **Clinical Safety of Ximelagatran in Patients with long-term
exposure (\> 35 days)**

A total of 6931 patients received doses from 20 to 60 mg of ximelagatran
for \> 35 days, with a median of 370 days. A total of 5024 patients were
exposed to ximelagatran for at least 6 months and 3509 for at least 12
months. A total of 6216 patients were exposed for a median of 455 days
to warfarin (n=4967) and placebo (n=1249).

**A2.1 Death**

There were 224 fatal cases during active treatment, 112 in the
ximelagatran treatment groups and 112 in the comparator groups. A
further 331 patients died after stopping study drug (166 in the
ximelagatran group and 165 in the comparator group). There was no
difference between the treatment groups. The most common fatal SAE was
myocardial infarction.

**A2.2 Non-fatal SAE**

A total of 26.3% of patients in the ximelagatran group and 27.1% of
patients in the comparator group experienced a non-fatal SAE during
treatment. A further 5.5% of patients in the ximelagatran group and 4.3%
of patients in the comparator group experienced a non-fatal SAE after
stopping study drug. The most common non-fatal SAEs were cardiovascular
events. The most common non-fatal SAEs considered to be causally related
to ximelagatran were increases in hepatic enzymes.

**A2.3 Discontinuation**

The proportion of patients who discontinued study drug was higher in the
ximelagatran group (1189/6931, 17.2%) than in the comparator group
(801/6216, 12.9%). This was mostly due to the discontinuation of study
drug due to elevated liver function tests. Data from discontinuation of
ximelagatran secondary to AEs indicates that coronary artery disorders
were more common in the ximelagatran group (0.6% vs. 0.3%) whereas
thromboembolic events were more common DAEs in the comparators group
(1.3% vs. 0.4%), because of placebo control. Other common causes of
discontinuations included bleeding events, with no difference between
ximelagatran and the comparators, except for haematuria and rectal
haemorrhage/ melaena, which caused slightly more discontinuations in the
ximelagatran group than in the comparators group.

**A2.4 Bleeding Events**

In patients with AF, ximelagatran 36 mg was associated with fewer major
bleeding events than warfarin (AF pool; 2.4% and 3.4% for the
ximelagatran and warfarin group, respectively, p=0.0288). However, there
were no significant differences for major bleeding events between the
groups in each of 2 pivotal studies (SH-TPA-0003 and STP-0005). In
patients with acute VTE, ximelagatran 36 mg was associated with
numerically fewer major bleeding events than enoxaparin/warfarin. In
patients undergoing extended secondary prophylaxis for VTE, ximelagatran
24 mg was associated with a similar incidence of major bleeding events
to placebo. A total of 38 patients experienced bleeding-related SAEs
with a fatal outcome, 19 cases in each treatment group (ximelagatran or
comparator).

**A2.5 Hepatobiliary toxicity**

In patients receiving long-term administration of ximelagatran (\>35
days) an increase in ALAT \>3xULN occurred in 6-13% (average 7.6%,
531/6948) compared to 0-2% (average 1.1%, 68/6230) of patients receiving
comparator treatments. Including local laboratory data, 620 patients
showed an ALAT elevation \>3xULN during the studies, 546 patients in the
ximelagatran group (cumulative incidence 7.8%) and 74 patients in the
comparator group (cumulative incidence 1.1%). Among the 531 patients in
the ximelagatran group who presented with an ALAT \>3xULN, 206 (39%)
completed the study on study drug. The remaining 325 patients (61%)
discontinued study drug prematurely.

The time pattern of ALAT elevations was consistent across patients. The
increase typically occurred between 1 and 6 months after the initiation
of ximelagatran. Before and after this time frame the incidence of ALAT
increase was similar to comparators. Of the 531 ximelagatran-treated
patients who had an ALAT elevation \>3xULN recorded by the central
laboratory, 502 (95%) had their ALAT return to \<2xULN with treatment
continued in 235 patients (46.8%). Most cases show a peak of ALAT within
the first 2 to 3 months post-randomization and a decline back towards
baseline within about 6 months post-randomization.

Eighteen patients who discontinued study drug with elevations of ALAT
subsequently resumed treatment after ALAT had returned to the normal
range. Of these 18 patients, 2 again experienced elevations of ALAT
after drug was resumed.

An evaluation of potential risk factors for increase in ALAT indicated
an increased risk in the

Post ACS (p=0.0009), and VTE-T (p=0.0003) populations and also in female
patients (p=0.0002) patients with low BMI (\<27 kg/m2) (p\<0.0001) and
patients receiving concomitant treatment with statins (p=0.019); Asian
patients were found to have a decreased risk (p=0.0038). Although single
factor identified above may not be strong enough to eliminate the
subgroup population, presence of 2 or more risk factors, such as, female
patients with low body weight or who are taking a statin, should be
considered a contraindication for ximelagatran.

ALAT \>3xULN was associated with bilirubin \>2xULN (within one month
following the rise in

ALAT) in 0.53% (37/6948) of all patients who were exposed to
ximelagatran \>35 days as compared to 0.08% (5/6230) of patients exposed
to comparators. Nine ximelagatran-treated patients (24.3%, 9/37) died
with concomitant ALAT \>3xULN and bilirubin \>2xULN. Among these, 3 died
from heart failure; 3 died from carcinomas with hepatic metastases; 2
(ID# 7259, and 7859) died from GI bleeding with coagulopathy (1 with
biopsy documented hepatic necrosis) and 1 (ID# 5442) died from hepatitis
B. Liver failure/toxicity by ximelagatran might have caused or at least
contributed to these deaths. Only one autopsy was done in these 9 deaths
and it showed a small, friable and diffusely mottled liver suggestive of
severe diffuse hepatic necrosis.

**A2.6 Adverse Events of Coronary Artery Disease**

In all study populations except the post acute coronary syndromes, the
proportion of patients with coronary artery disease adverse events was
higher in the ximelagatran groups than in the comparator groups (7.0%
and 6.7% for the AF pool, 1.3% and 0.1% for the VTE-T pool and 2.6% and
2.0% for the VTE-P pool, for the ximelagatran and comparator groups,
respectively). This trend was consistent across the pools for myocardial
infarction.

The proportion of patients with coronary artery disease adverse events
was statistically significantly higher in the ximelagatran group
(32/1848, 1.7%) than in the warfarin/placebo group (12/1859, 0.7%) in
VTE (VTE-T + VTE-P) population (p=0.00411). Proportion of patients with
MI was also significantly higher in the ximelagatran group (13/1848,
0.7%) than in the warfarin/placebo group (3/1859, 0.16%) in VTE
population (p=0.01183). There were no appreciable differences between
the treatment groups for underlying diseases. Considering ximelagatran
as an anticoagulant with potential to treat MI, these results are
worrisome.

### B. Description of Patient Exposure

An overview of days of exposure to treatment for the surgical population
who received study drug for [\<]{.underline} 35 days is provided in
Table 6.

![](media/image8.png){width="4.892361111111111in"
height="2.683333333333333in"}

**Table 6: Overview of exposure: Warfarin-comparison Pool**

In the 36-mg (EXULT) Pool, 1913 and 1897 patients were exposed to active
ximelagatran 36 mg and warfarin, respectively. In the 24 mg Pool, 1097
patients received active ximelagatran 24 mg and 1081 patients received
warfarin. In total, the Warfarin-comparison Pool comprised 1913 patients
exposed to ximelagatran 36 mg, 1097 patients exposed to ximelagatran 24
mg, and 2226 patients exposed to warfarin. Mean days of exposure were
8.1 days for ximelagatran 24 mg or 36 mg, 6.7 days for warfarin, which
does not include the first dose of warfarin given the evening of
surgery. More patients (73%) in each of the ximelagatran 24-mg or 36-mg
groups remained on treatment from 7 to 9 days, compared to the warfarin
group (43%). This finding probably reflects warfarin treatment being
withheld due to INRs within normal range.

For non-Surgical Populations who received study drug for \> 35 days,
data from 10 Phase II and Phase III studies, in which patients received
ximelagatran for up to 4 years, are presented in 4 pools based on the
indication that was investigated. These indications were AF, VTE
treatment (VTE-T), VTE secondary prevention (VTE-P) and post ACS. A
fifth pool, the long-term exposure (LTE) pool, combines data from all of
these indications.

The long-term (\>35 days) safety of ximelagatran has been studied in a
large population of 6931 patients comprising 3838 patients with atrial
fibrillation (AF),1236 patients for treatment (VTE-T) and 612 patients
for secondary prevention (VTE-P) of venous thromboembolism (VTE) and
1245 patients with recent acute coronary syndrome (post ACS). These 6931
patients received doses from 20 to 60 mg, for a median of 370 days,
representing an overall exposure of

6768 patient-years. A total of 5024 patients were exposed to
ximelagatran for at least 6 months (\>180 days) and 3509 for at least 12
months (\>360 days). All the studies were controlled, thus enabling
comparison of a cohort of 6216 patients exposed to ximelagatran for a
median of 455 days mainly to the reference anticoagulant warfarin
(n=4967), but also to placebo in a smaller number of patients (n=1249).

**Demographic and other characteristics: the long-term exposure**
(**LTE) pool**

The treatment groups were well-balanced regarding demographic
characteristics. Nearly all (\>93%) of the patients were Caucasian and
the majority (64%) were males. The majority of the females (89%) were
over 45 years of age (an arbitrary cut-off to distinguish females of
childbearing potential). Most patients (64.1%) were 65 years or over
although there was a wide range of ages in the program (18 to 97 years).
Demographic characteristics of all treated patients in the LTE pool are
shown in Table 7.

![](media/image9.png){width="4.7in" height="5.708333333333333in"}**Table
7: Demographic description: LTE pool**

### 

### C. Methods and Specific Findings of Safety Review 

**1: The surgical population who received study drug for
[\<]{.underline} 35 days**

The treatment groups were well-balanced regarding demographic
characteristics. Nearly all (\>94%) of the patients were Caucasian and
there were more females (62%) than males (38%).

Approximately two-thirds of patients were 65 years or older (66%)
although there was a

wide range of ages in the program (24 to 91 years of age). There were
18% to 20% of patients above 100 kgs and about 50% with a BMI \>30
kg/m^2^ . A total of 16 patients had severe renal impairment (CrCL \<30
mL/min) (in violation of entry criteria). Approximately 35% of the
patients had some renal impairment (CrCL \<80 mL/min).

**1.1 Most common AEs --Warfarin-comparison Pool**

Overall, more than 55% of patients in each treatment group experienced
at least 1 AE. The frequency of AEs was similar in the ximelagatran
24-mg and the warfarin groups (66% and 61%, respectively). The frequency
of AEs was similar in the ximelagatran 36-mg and the warfarin groups
(58% and 56%, respectively).

The incidence of SAEs was higher in the ximelagatran treatment groups
than in the concurrent warfarin group (3.8 vs. 3.2% for 36 mg of
ximelagatran vs. warfarin and 3.2% vs. 2.7% for 24 mg of ximelagatran
vs. warfarin).

The incidence of discontinuations was higher in the ximelagatran
treatment groups than in the concurrent warfarin group (2.6% vs. 2.0%
for 36 mg of ximelagatran vs. warfarin and 3.1% vs. 2.1% for 24 mg of
ximelagatran vs. warfarin respectively).

**1.2 Deaths**

There were 18 fatal cases in the Warfarin-comparison Pool (12 patients
exposed to ximelagatran and 6 patients exposed to warfarin) with 4 and 3
fatalities occurring during the

treatment period, respectively.

Of the 12 fatal SAEs reported among the 3010 patients who received
ximelagatran (0.4%), 2 were fatal bleeding events (both on ximelagatran
36 mg). Six were fatal events in which 'PE could not be excluded'. The
last 4 fatal SAEs in patients who received ximelagatran were adjudicated
as 'death not associated with VTE or bleeding'. The investigators
reported the causes of death in 1 patient on treatment as sudden death,
and in the other 3 patients after treatment as intestinal perforation,
acute myocardial infarction, and pneumonia.

Of the 6 fatal SAEs reported among the 2226 patients who received
warfarin (0.3%), 2 were fatal events in which 'PE could not be
excluded'. The last 4 fatal SAEs in warfarin-treated patients were
adjudicated as 'death not associated with VTE or bleeding'. The
investigators reported the causes of death in 2 patients on treatment as
arrhythmia and MI and in the other 2 after treatment as colon carcinoma
and acute myocardial infarction.

Two fatal cases of GI hemorrhage occurred during treatment in the
ximelagatran 36-mg group. The number and percentage of patients who died
during or after treatment in the Warfarin-comparison Pool is presented
in Table 8.

**Table 8: Number (%) of patients with fatal SAEs during or after
treatment, presented by preferred term: The Warfarin- comparison Pool
(exposed safety population)**

![](media/image10.png){width="5.998611111111111in"
height="3.8319444444444444in"}

**1.3 Serious Adverse Events other than deaths -- Warfarin-comparison
Pool**

Within both 36-mg (EXULT) and 24-mg pools, the frequency of non-fatal
SAEs was higher in either ximelagatran treatment group (3.7% and 3.5%)
than in their respective warfarin groups (3.1 and 2.6%) during
treatment.

Including both during study treatment and after study treatment periods,
the most frequently occurring non-fatal SAEs were postoperative
complications and myocardial infarction, which occurred more frequently
in the ximelagatran groups, and atrial fibrillation, which occurred more
frequently in the warfarin group.

The number of patients with the most commonly reported non-fatal SAEs
during and after

treatment is presented in Table 9.

**Table 9 Number (%) of patients with the most commonly reported non-
fatal SAEs during and after treatment: The Warfarin- comparison Pool
(exposed safety population)**

![](media/image11.png){width="5.995833333333334in"
height="3.113888888888889in"}

Please see the section of 1.7: coronary artery disease adverse events
for more details about the adverse events related to myocardial
infarction and coronary artery diseases.

**1.4 Discontinuations due to AEs - Warfarin-comparison Pool**

Discontinuations due to AEs (DAE) were slightly higher in the
ximelagatran 36-mg group (2.6%) than warfarin (2.0%) as well as in the
ximelagatran 24-mg group comparison to warfarin (3.1% versus 2.1%,
respectively); this was driven by an excess of bleeding-related AEs.
Regardless of treatment group, the most common reason for a DAE was
postoperative complication, with a similar incidence between treatment
groups.

1.5 Bleeding events in the Warfarin-comparison Pool

Major bleeding events were uncommon overall and higher in ximelagatran
groups than warfarin groups during the treatment period (0.9%
ximelagatran 36 mg, 0.5% warfarin; 0.9% ximelagatran 24 mg, 0.6%
warfarin). In the 36-mg Pool, the difference in the frequencies of major
bleeding events between ximelagatran and warfarin was 0.4% (95% CI,
--0.1% to1.0%). Similar results were noted for the 24-mg Pool
(ximelagatran-warfarin, 0.3%; 95% CI, -0.5% to 1.0%). The proportions of
patients with on-treatment major bleeding events in the
Warfarin-comparison Pool, for both the 36-mg and 24-mg Pools, are
summarized in Table 10.

**Table 10 Number (%) of patients with on- treatment adjudicated major
bleeding events: Warfarin- comparison Pool (exposed safety population)**

![](media/image12.png){width="5.997916666666667in"
height="2.421527777777778in"}

Adjudication criteria for major bleeding were medical or surgical
intervention for the reported

bleeding event and/or bleeding index \>2. The distribution of all major
bleeding events by adjudication criteria was similar to the distribution
of on-treatment events.

In the 36-mg Pool, the most common locations of on-treatment major
bleeding events in the ximelagatran group were wound hematoma,
gastrointestinal bleeding, and wound bleeding. Events in these locations
occurred with comparable frequency in the warfarin group. In the 24-mg
Pool, wound hematoma and gastrointestinal bleeding were more frequent in
the ximelagatran group than in the warfarin group, while wound bleeding
occurred only in the warfarin group. There were no major nasal or
urinary bleeding events in any treatment group.

The frequencies of patients with on-treatment major/minor bleeding
events were higher in ximelagatran groups than warfarin groups (5.1%
ximelagatran 36 mg, 4.1% warfarin; 5.7%

ximelagatran 24 mg, 4.7% warfarin).

Two fatal on-treatment major bleeding events occurred in the
ximelagatran 36-mg group; both

events were coded as GI hemorrhage. None of the on-treatment major
bleeding events in the ximelagatran 24-mg group was fatal. There were no
fatal on-treatment bleeding events in the warfarin-groups.

Two critical-site on-treatment bleeding events occurred during
ximelagatran treatment (0.9%).

One patient (SH-TPO-0012-029-10779) treated with ximelagatran 36 mg
developed postoperative confusion just after surgery. A CT scan revealed
a subdural hematoma. The other patient (SH-TPO-0010-016-2131), who was
treated with ximelagatran 24 mg, was found by CT scan to have a left
frontal brain hemorrhage after 6 days of postoperative confusion; a
biopsy

revealed a malignant glioma; the reported AE was coded as cerebral
hemorrhage. No

bleeding at other critical sites (intraspinal, intraocular,
retroperitoneal, or pericardial) was

reported in the ximelagatran groups. None of the major bleeding events
reported in warfarin-treated patients occurred at a critical site
(intracranial, intraspinal, intraocular, retroperitoneal,

or pericardial).

In the ximelagatran groups, on-treatment major bleeding events included
GI bleeding in

9 patients (5 in the 36-mg group, 4 in the 24-mg group), with 2 events
in the 36-mg group

reported as fatal bleeding SAEs as noted above. Additional on-treatment
major bleeding events included 12 wound hematomas (7 in the 36-mg group,
5 in the 24-mg group) and 5 wound-bleeding events (all in the 36-mg
group). Medical or surgical intervention for the bleeding event was
required in 14 ximelagatran-treated patients (11 in the 36-mg group, 3
in the 24-mg group). These interventions included evacuation/aspiration
of clot or hematoma, incision and drainage, wound irrigation and
debridement, closure of wound, re-operation, endoscopy, laparotomy and
gastrostomy for ulcers and evacuation of subdural hematoma.

In the warfarin-treated groups, on-treatment major bleeding events
included GI bleeding in

3 patients and haemarthroses in 2 patients. Additional on-treatment
major bleeding events

included 5 wound hematomas and 2 wound-bleeding events. Medical or
surgical intervention for the bleeding event was required in 6
warfarin-treated patients. The interventions included
evacuation/aspiration of blood or hematoma, surgical drainage,
debridement of wound haematoma, re-operation and removal of blood from
knee, and transfusion.

**1.5.1 Incidence of reported bleeding events**

Fewer than 8% of patients in each treatment group had a reported
bleeding event during study treatment. Two patients in the ximelagatran
36-mg group had fatal nonsurgical bleeding events of GI hemorrhage.

In the 36-mg Pool, the frequency of patients with a reported bleeding
event was higher in the ximelagatran group than in the warfarin group
(7% and 5%, respectively). Overall, the proportions of patients who had
at least 1 reported bleeding event were higher in the ximelagatran
treatment groups (6.7% and 7.2% respectively) than in the warfarin
groups (5.0 and 5.6% respectively), as were the proportions of patients
who had an event that led to discontinuation of study treatment (1.1% in
ximelagatran group vs. 0.5% in warfarin groups). There was no
appreciable difference among groups with respect to SAEs of bleeding.

The overall frequencies of on-treatment reported bleeding events for the
36-mg and 24-mg Pools are shown in Table 11.

**Table 11: Number (%) of patients who had an on-treatment reported
bleeding event in any category: Warfarin-comparison Pool (exposed safety
population)**

![](media/image13.png){width="4.792361111111111in"
height="3.0166666666666666in"}

The overall incidence of adjudicated bleeding with ximelagatran was low
and considered to be clinically acceptable.

**1.5.2 Conclusions on bleeding**

A numerically higher frequency of bleeding events was observed for
ximelagatran in the oral

only, post-operative program for TKR when compared with warfarin. The
overall incidence of bleeding with ximelagatran was low and considered
to be clinically acceptable.

With respect to on-treatment adjudicated events, major bleeding occurred
in 0.9% of patients treated with ximelagatran 36 mg, compared with 0.5%
of patients treated with warfarin. Major/minor bleeding occurred in 5.1%
of patients treated with ximelagatran 36 mg and 4.1% of patients treated
with warfarin. Similar results were observed for ximelagatran 24 mg bid
compared with warfarin.

Fewer than 8% of patients in any of the ximelagatran or warfarin groups
had a reported bleeding event during study treatment, and most events
were non-serious. There was no apparent relationship between
ximelagatran dose and bleeding risk, as indicated by similar proportions
of patients with bleeding events (major and major/minor) in the
ximelagatran 36-mg and 24-mg groups in Study SH-TPO-0010.

Subgroup analyses of major/minor bleeding events in the 36-mg and 24-mg
comparison groups did not reveal a subgroup with a clinically important
difference in bleeding risk from the entire population (ie, one which
might require dose adjustment). In general, treatment differences were
consistent across subgroups.

**1.6 Analysis of ALAT elevations in the Surgical population**

Since ALAT is a more specific marker of liver cell damage than ASAT, and
because there was no pattern for an increase in alkaline phosphatase
(ALP) or bilirubin in isolation, ALAT forms the basis of the analysis. A
threshold of \>3x ULN ALAT was used to indicate a signal of potential
clinical relevance.

**1.6.1 Studies EXULT A (SH-TPO-0010) and EXULT B (SH-TPO-0012)**

Changes from baseline in clinical chemistry parameters, including
elevations in ALAT,

reflected surgical intervention and postoperative recovery and were
generally comparable in

the ximelagatran and warfarin treatment groups. These changes generally
occurred during the immediate postoperative course of treatment and at
the time of the end of treatment with a return to near baseline levels
at follow-up.

In EXULT A, there were no differences between the ximelagatran groups
and the warfarin

group for patients who had ALAT elevation \>3x ULN at the end of
treatment (6/723, 36-mg;

4/706, 24-mg; 12/704 warfarin). During the follow-up period, 4 patients
in the ximelagatran

36-mg group, 1 patient in the ximelagatran 24-mg group, and 0 in the
warfarin group had their

first ALAT elevation \>3x ULN. Three of the 4 patients in the
ximelagatran 36-mg group had their first ALAT elevation \>30 days after
receiving their last ximelagatran dose while the fourth patient had
their first ALAT elevation 28 days after receiving their last
ximelagatran dose.

In EXULT B, there were no differences between the ximelagatran and
warfarin groups for

patients who had ALAT elevations \>3x ULN at end of treatment (7/1095,
ximelagatran 36-mg

group; 6/1087 warfarin group). During the follow-up period, 4 additional
patients had their

first ALAT elevation \>3x ULN: 3 in the ximelagatran 36-mg group and 1
in the warfarin

group. For all 3 ximelagatran 36 mg patients, the elevations were
resolved within 30 days of elevation, including one patient
(SH-TPO-0012-510-14309) who began a LMWH on postoperative day 11 as
treatment for DVT.

Drug effects on liver toxicity beyond 4-6 weeks are unknown. It should
be noted that elevation of hepatic enzymes was typically seen between
2^nd^ and 6^th^ month after starting ximelagatran (long-term exposure
data).

**1.6.2 Hepatobiliary AEs in the Surgical population Warfarin-comparison
Pool**

Overall frequency of AEs in the liver and biliary system disorder was
slightly higher in

the ximelagatran 36-mg (EXULT) group compared to warfarin (6.7% vs 5.4%)
and in the

ximelagatran 24-mg group, 5.5% ximelagatran 24-mg versus 5.1% warfarin.
This was due to a higher rate of reported GGT increased (ximelagatran:
5.6% in the 36-mg group, 4.4% in the 24-mg group, versus 4.2% in both
warfarin groups).

Incidences of ALAT (SGOT) increased reported as AEs were similar across
the groups (36-mg ximelagatran comparison: 2.1% ximelagatran 36-mg, 1.3%
warfarin; 24-mg comparison group: 1.4% ximelagatran 24-mg, 1.5%
warfarin). There were no hepatobiliary fatal SAEs, non-fatal SAEs or
DAEs in either ximelagatran group.

**1.6.3 Conclusions of hepatobiliary effects in the Surgical
population**

There were no differences in the on-treatment incidences of ALAT
elevation between ximelagatran and warfarin. However, during the
follow-up period (4-6 weeks), 7 patients in the ximelagatran group, and
1 in the warfarin group had their first ALAT elevation \>3x ULN. Drug
effects on liver toxicity beyond 4-6 weeks are unknown. It should be
noted that elevation of hepatic enzymes was typically seen between 2^nd^
and 6^th^ month after starting ximelagatran (long-term exposure data).

**1.7 Coronary artery disease adverse events**

Serious adverse events on coronary artery disease including MI are
summarized in table 12.

**Table 12:** **Summary of** **CAD adverse events following short-term
use of ximelagatram^\#^**

<table>
<colgroup>
<col style="width: 21%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 2%" />
<col style="width: 13%" />
<col style="width: 11%" />
<col style="width: 2%" />
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2">Exult A</td>
<td></td>
<td colspan="2">Exult B##</td>
<td></td>
<td colspan="2">Exult A and B</td>
<td></td>
</tr>
<tr class="even">
<td>Event: N (%)</td>
<td><p>Exanta</p>
<p>N=1526</p></td>
<td colspan="2"><p>Warfarin</p>
<p>N=759</p></td>
<td><p>Exanta</p>
<p>N=1151</p></td>
<td colspan="2"><p>Warfarin</p>
<p>N=1148</p></td>
<td><p>Exanta</p>
<p>N=2677</p></td>
<td colspan="2"><p>Warfarin</p>
<p>N=1907</p></td>
</tr>
<tr class="odd">
<td>MI</td>
<td>11 (0.72)</td>
<td colspan="2"><p>1</p>
<p>(0.13)</p></td>
<td><p>5</p>
<p>(0.43)</p></td>
<td colspan="2"><p>3</p>
<p>(0.26)</p></td>
<td><p>16*</p>
<p>(0.60)</p></td>
<td colspan="2"><p>4*</p>
<p>(0.21)</p></td>
</tr>
<tr class="even">
<td>Other CAD (Angina/ischemia)</td>
<td><p>3</p>
<p>(0.2)</p></td>
<td colspan="2">0</td>
<td><p>1</p>
<p>(0.17)</p></td>
<td colspan="2"><p>1</p>
<p>(0.09)</p></td>
<td><p>4</p>
<p>(0.15)</p></td>
<td colspan="2"><p>1</p>
<p>(0.05)</p></td>
</tr>
<tr class="odd">
<td>Total</td>
<td><p>14</p>
<p>(0.92)</p></td>
<td colspan="2"><p>1</p>
<p>(0.13)</p></td>
<td><p>6</p>
<p>(0.7)</p></td>
<td colspan="2"><p>4</p>
<p>(0.35)</p></td>
<td><p>20**</p>
<p>(0.75)</p></td>
<td colspan="2"><p>5**</p>
<p>(0.26)</p></td>
</tr>
</tbody>
</table>

\*p=0.04951; \*\* p=0.02800

^\#^Excluded 4 patients who did not take study medications, 3 in
ximelagatran group (ID: #3206, #7086 and #10944) and 1 in warfarin group
(ID: #9089) whose death was also adjudicated by the central adjudication
committee as PE.

^\##^one case of sudden death (#15016) in the warfarin group was
included as MI and two cases of sudden deaths in the Exanta group (ID:
#14366 and 12122) were excluded from the analysis.

Summarized from Module 5, vol. 1 Table 54 and vol. 2 Table 11.3.5.1;
vol. 3 Table 55 and vol. 4 Table 11.3.5.1

In both Exult A and Exult B, the proportion of patients with coronary
artery disease adverse events (MI and angina) was higher in the
ximelagatran groups than in the warfarin groups. After combining Exult A
and Exult B, proportion of patients with coronary artery disease adverse
events was statistically significantly higher in the ximelagatran group
(20/2677, 0.75%) than in the warfarin group (5/1907, 0.26%) in the TKR
population (p=0.02800). Proportion of patients with MI was also higher
in the ximelagatran group (16/2677, 0.60%) than in the warfarin group
(4/1907, 0.21%) in the TKR population (p=0.04951). There were no
appreciable differences between the treatment groups for underlying
diseases including hypertension, diabetes mellitus,
hypercholesterolemia, coronary atherosclerosis, as well as age, gender
and weight (Table 13).

**Table 13: Concomitant medical conditions in studies EXULT A and B\
**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\
Ximelagatran Warfarin\
N=2225 N=1575\
n (%) n (%)\
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\
Hypertension 1325 (59.6) 963 (61.1)\
hypercholesterolemia 339 (15.2) 243 (15.4)\
Diabetes mellitus 290 (13.0) 199 (12.6)\
Coronary atherosclerosis 155 (6.9) 99 (6.3)\
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\
N=2677 N=1907

Gender Male 1015 (37.9) 715 (37.5)\
Age, years Mean (SD) 67.7 (9.5) 67.5 (9.5)\
Weight (kg) Mean (SD) 84.3 (18.1) 84.5 (17.7)

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

All of events occurred during the first 2 weeks, except 2 cases of MI in
the ximelagatran group that occurred at day 28 and day 39, and 1 case in
the warfarin group reported at day 21. In the ximelagatran group, 14
cases occurred during the treatment period; 3 cases occurred 1-4 days
after last dose of ximelagatran; 2 cases, beyond 1 week after last dose.
The relationship between last dose and events in 1 other case is
unclear. The diagnoses of MI in 1 patient in the warfarin group is
unclear (PE can not be ruled out). One case was reported at day 21. Four
other cases were reported during the treatment period. Considering
ximelagatran as an anticoagulant with potential to treat MI, these
results are worrisome.

2: The non-surgical population who received study drug for \> 35 days

**2.1 Common adverse events: long-term exposure (LTE) pool**

The overall frequencies of AEs, fatal SAEs, non-fatal SAEs and DAEs
during active treatment

are presented for the LTE pool in Table 14.

**Table 14: Number (%) of patients who had an adverse event: LTE pool**

![](media/image14.png){width="4.142361111111111in"
height="1.5583333333333333in"}

The overall proportion of patients reporting adverse events was high
(85%) due to the severity of the underlying diseases in these
populations but there was no difference between the treatment groups.
The frequency of SAEs (fatal and non-fatal) was similar between the
treatment groups. The proportion of patients who discontinued study drug
was higher in the ximelagatran group (17.2%) than in the comparator
group (12.9%). This was mostly due to discontinuation of study drug due
to elevation of hepatic function tests. The most commonly reported AEs
in the LTE pool are presented in Table 15. Adverse events reported with
a frequency of at least 4.0% in any column are presented. The events are
sorted by the ximelagatran column.

**Table 15: Number (%) of patients with the most commonly reported AEs:
LTE pool**

![](media/image15.png){width="4.125694444444444in"
height="5.084027777777778in"}

2.2 Deaths

The overall mortality in the ITT population was 3.9% in the ximelagatran
group and 4.4% in

the comparator group. AEs that most frequently led to death were
myocardial infarction,

sudden death, cardiac arrest and cardiac failure, events expected for
the 2 populations at risk

of cardiovascular events, AF and post ACS.

2.2.1 Deaths: LTE pool

Death was included in the definition of the endpoints in the studies in
the LTE pool and all

cause mortality is analyzed using the ITT population. Overall mortality
was similar between ximelagatran and comparators.

**Table 16: Risk of death in the LTE pool, estimated relative risk with
95% CI (ITT population)**

![](media/image16.png){width="5.017361111111111in" height="0.75in"}

Because the comparator was placebo in the VTE-P and Post ACS pools, a
higher mortality

might have been expected for the comparator group. Therefore, the
overall mortality has also

been compared between ximelagatran and the active comparator (warfarin).
Overall mortality was similar between ximelagatran (6.5%) and warfarin
(7.1%).

2.2.2 Fatal SAEs in the safety population

There were 224 fatal cases during active treatment, 112 in the
ximelagatran treatment groups and 112 in the comparator groups. A
further 331 patients died after stopping study drug (166 in the
ximelagatran group and 165 in the comparator group).

The most common fatal SAE was myocardial infarction (MI). During active
treatment, the proportion of patients who died due to acute MI was the
same for the 2 treatment groups (0.2%). However, after stopping
treatment fatal acute MIs occurred more frequently in the ximelagatran
group (0.4%) than the comparator group (0.2%).

In the post ACS pool, there was an increased proportion of fatal
myocardial infarctions in the post-treatment period (1.1% vs 0.5%).
There were 29 fatal cases during active treatment, 15 (1.2%) in the
ximelagatran treatment groups and 14 (2.2%) in the placebo group. A
further 35 patients died after stopping study drug, 27 (2.2%) in the
ximelagatran groups and 8 (1.3%) in the placebo group. All deaths during
treatment were reported in terms associated with cardiovascular

disease, with the exception of one suicide in the placebo group.

2.2.3 Fatal SAEs considered causally related by the investigator: LTE
pool

There were no differences between treatments concerning the number of
fatal SAEs considered by the investigators to be causally related to
study drug (Table 17).

**Table 17: Number (%) of patients with fatal serious adverse event
considered causally related by the investigator: LTE pool**

+-----------------------------------------------------------------------+
| **During the treatment After treatment**                              |
|                                                                       |
| **ximelagatran Comparators ximelagatran Comparators**                 |
|                                                                       |
| **n=6931 n=6216 n=6819 n=6104**                                       |
|                                                                       |
| n (%) n (%) n (%) n (%)                                               |
+-----------------------------------------------------------------------+
| Total 14 (0.2) 10 (0.2) 5 (0.1) 8 (0.1)                               |
|                                                                       |
| GI haemorrhage 1 1                                                    |
|                                                                       |
| Haematemesis 1 1                                                      |
|                                                                       |
| Hepatitis infectious 1                                                |
|                                                                       |
| Myocardial infarction 1                                               |
|                                                                       |
| Cardiac arrest 1 2                                                    |
|                                                                       |
| Cardio-respiratory arrest 1                                           |
|                                                                       |
| Fibrillation ventricular 1                                            |
|                                                                       |
| Cerebral haemorrhage 2 2 1 2                                          |
|                                                                       |
| Cerebrovascular disorder 1 1 2                                        |
|                                                                       |
| Haemorrhage intracranial 1 1                                          |
|                                                                       |
| Subarachnoid haemorrhage 1                                            |
|                                                                       |
| Aspiration pneumonia 1                                                |
|                                                                       |
| Bronchitis aggravated 1                                               |
|                                                                       |
| Hypoxia 1                                                             |
|                                                                       |
| Resp distress syndrome adult 1                                        |
|                                                                       |
| Respiratory disorder 1                                                |
|                                                                       |
| Retroperitoneal haemorrhage 1                                         |
|                                                                       |
| Myeloid metaplasia 2                                                  |
|                                                                       |
| Pulmonary carcinoma 1                                                 |
|                                                                       |
| Sudden death 3 1                                                      |
|                                                                       |
| Sepsis 1                                                              |
+-----------------------------------------------------------------------+

2.2.4 Comparison of deaths between pools

There was a similar mortality rate in patients taking ximelagatran and
those taking comparators in all pools. The most frequent AEs leading to
death were driven by the 2 populations at risk of cardiovascular events,
AF and post ACS: myocardial infarction, sudden death, cardiac arrest,
cardiac failure. There were no obvious differences in the rates of such
fatal cardiac events between groups, except for an excess of myocardial
infarctions in patients who had discontinued ximelagatran and this was
seen in the post ACS pool. Most of these AMIs started during treatment.

2.3 Serious adverse events other than death

There was a higher frequency of SAEs in the hepatobiliary in the
ximelagatran groups relative to comparator treatment in all pools.

A higher frequency of SAEs related to coronary artery disease was seen
in the ximelagatran groups in all pools with the exception of the Post
ACS pool.

Subjects in the safety population who experienced non-fatal SAEs during
or after active study treatment are included in the following tables.

**Table 18 Number (%) of patients with the most commonly reported
non-fatal serious adverse events: LTE pool**

![](media/image17.png){width="5.998611111111111in"
height="5.240972222222222in"}

A total of 26.3% of patients in the ximelagatran group and 27.1% of
patients in the comparator group experienced a non-fatal SAE during
treatment. A further 5.5% of patients in the ximelagatran group and 4.3%
of patients in the comparator group experienced a non-fatal SAE after
stopping study drug.

The most common non-fatal SAEs were cardiovascular events which reflect
the diseases under study. The most common non-fatal SAEs considered to
be causally related to ximelagatran were increases in hepatic enzymes.

The profile of the non-fatal SAEs was consistent with the pattern of all
AEs in the pool. There was a higher reporting frequency of SAEs in the
hepatobiliary organ system in the ximelagatran groups compared to
warfarin or placebo in all pools.

A higher frequency of SAEs related to coronary artery disease was seen
in the ximelagatran groups in all pools with the exception of the Post
ACS pool.

2.4 **Discontinuation of Study Drug due to an Adverse Event (DAE)**

The most common AEs causing discontinuation of study drug for the LTE
pool are presented in Table 19.

**Table 19: Number (%) of patients with the most commonly reported DAEs:
LTE pool**

![](media/image18.png){width="4.142361111111111in"
height="3.2666666666666666in"}

The proportion of patients who discontinued study drug was higher in the
ximelagatran group (17.2%) than in the comparator group (12.9%). This
was mostly due to the discontinuation of study drug due to increased
liver function tests (LFTs).

Apart from increases in hepatic enzymes, the most frequent reasons for
discontinuations were related to coronary artery disorder in the
ximelagatran group (0.6% vs. 0.3%). Thromboembolic events were more
common DAEs in the comparators group (1.3% vs. 0.4%), because of placebo
control in secondary prevention study.

Other common causes of discontinuations included bleeding events, with
no difference between ximelagatran and the comparators, except for
hematuria and rectal haemorrhage/melaena, which caused slightly more
discontinuations in the ximelagatran group than in the comparators
group.

**2.5 Bleeding Events**

2.5.1 Major bleeding events

The risk of a major bleeding event is summarized by treatment group in
Table 20.

**Table 20: Risk of a major bleeding event per patient year**

![](media/image19.png){width="5.997916666666667in"
height="4.053472222222222in"}

In patients with AF, ximelagatran 36 mg was associated with
statistically significantly fewer major bleeding events than warfarin
(AF pool; 2.4% and 3.4% for the ximelagatran and warfarin group,
respectively, p=0.0288). However, there were no significant differences
for major bleeding events between the groups in each of 2 pivotal
studies (SH-TPA-0003 and STP-0005). In patients with acute VTE,
ximelagatran 36 mg (1.1%, 14/1240) was associated with numerically fewer
major bleeding events than enoxaparin/warfarin (2.1%, 26/1249).

In patients undergoing extended secondary prophylaxis for VTE,
ximelagatran 24 mg was associated with a similar incidence of major
bleeding events to placebo (1% and 0.8%, respectively).

2.5.2 Major/minor bleeding events

The risk of a major/minor bleeding event is summarized by treatment
group in Table 21.

**Table 21: Risk of a major/minor bleeding event per patient year**

![](media/image20.png){width="5.99375in" height="4.126388888888889in"}In
patients with AF, ximelagatran 36 mg was associated with statistically
significantly fewer major/minor bleeding events than warfarin (AF pool;
32.0% and 39.1% for the ximelagatran and warfarin groups, respectively,
p\<0.0001). In patients with acute VTE, ximelagatran 36 mg was
associated with numerically fewer major/minor bleeding events than
enoxaparin/warfarin (5.5% vs. 7.0%).

In patients undergoing extended secondary prophylaxis for VTE,
ximelagatran 24 mg was associated with a numerically more major/minor
bleeding events than placebo (21.9% and 18.2% for the ximelagatran and
the placebo group, respectively).

In the dose-finding study in post ACS patients, the risk of a
major/minor bleeding event with ximelagatran plus ASA increased with
increasing dose. Patients who received ximelagatran plus ASA had
statistically significantly more major/minor bleeding events than
patients who received placebo plus ASA (pooled doses; 19.8% and 11.3%
for the ximelagatran plus ASA, and the placebo plus ASA, respectively,
p\<0.0001).

2.5.3 Fatal bleeding events

The incidence of fatal bleeding events (adjudicated fatal events, and
bleeding-related serious

adverse events leading to death) is summarized by treatment group in
Table 22.

**Table 22: Summary of fatal bleeding events, by study**

![](media/image21.png){width="5.259027777777778in"
height="2.5416666666666665in"} OT: on treatment

In addition to the 13 patients with bleeding-related serious adverse
events leading to death whilst on treatment in Table 20 (safety
population), a further 16 patients had bleeding-related serious adverse
events leading to death after stopping treatment. Of these 16 patients,
7 had received ximelagatran and 9 had received warfarin. Thus in total,
29 patients experienced bleeding-related SAEs with a fatal outcome.

Almost all fatal bleeding events were intracranial (17 cases) or
gastrointestinal (10 cases), except 1 case of pericardial and 1 case of
retroperitoneal bleeding.

Of the 29 patients who experienced bleeding-related SAEs with a fatal
outcome, 13 were not included in the "on treatment" analysis of bleeding
outcomes. Ten events were intracerebral haemorrhages that were
adjudicated as strokes by the adjudication committee.

Patient SH-TPV-0002-701-4723 was not included in the OT-analysis as a
fatal bleed. This patient had a "Bleeding per rectum" that started 30
days after last study drug intake and therefore the adjudication
committee classified this as \"Death not associated with VTE or
bleeding\".

Conversely, 7 patients in the ximelagatran group and 2 patients in the
warfarin group who had a fatal major bleed according to the adjudication
committee are not included in the 29 patients who experienced
bleeding-related SAEs with a fatal outcome. Eight patients were not
captured by the search on bleeding terms because the term used by the
investigator to describe the AE leading to death did not match the
preferred terms used to identify patients with bleeding events. The
remaining patient (SH-TPA-0003-316-2826) in the ximelagatran group died
after discontinuing study drug and is therefore not shown in the AE
tables.

In summary, a total of 38 patients experienced bleeding-related SAEs
with a fatal outcome, 19 cases in each treatment group (ximelagatran or
comparator).

**2.5.4 Overview of reported bleeding-related adverse events across
indication pools**

An overview of the incidence of bleeding adverse events is summarized by
treatment for the individual pools in Table 23.

**Table 23: Number (%) of patients who had bleeding-related adverse
events**

![](media/image22.png){width="5.9944444444444445in"
height="2.0840277777777776in"}

In patients with AF, the incidence of reported bleeding adverse events
with ximelagatran 36 mg (32.6%) was less than that observed with
warfarin (40.1%). The incidence of serious adverse events and
discontinuations due to a bleeding adverse event was low and similar in
both treatment groups.

In patients with acute VTE, the incidence of reported bleeding adverse
events with ximelagatran 36 mg (18.3%) was less than that observed with
enoxaparin/warfarin (25.4%). The incidence of serious adverse events and
discontinuations due to a bleeding adverse event was low and similar in
both treatment groups.

In patients undergoing extended secondary prophylaxis for VTE, the
incidence of reported bleeding adverse events with ximelagatran 24 mg
was numerically greater than that observed with placebo. The incidence
of serious adverse events and discontinuations due to a bleeding adverse
event was low and similar in both treatment groups.

The incidence of reported bleeding adverse events in patients receiving
ximelagatran and ASA (20.1%) was higher than that observed with placebo
and ASA (11.4%). The incidence of serious adverse events and
discontinuations due to a bleeding adverse event with ximelagatran plus
ASA was low (2.7% and 4.5% for serious adverse events and
discontinuations due to adverse events, respectively), but higher than
that observed with placebo and ASA (1.1% and 0.9% for serious adverse
events and discontinuations due to adverse events, respectively).

In AF patients, the most commonly reported bleeding related AEs for
ximelagatran-treated patients were purpura (which was the preferred term
used to code unspecified hematomas, bruises and petechiae) (11.1%),
epistaxis (7.2%), haematuria (5.4%) and rectal haemorrhage (2.9%).

In patients with an acute VTE, the most commonly reported bleeding
related AEs for ximelagatran-treated patients were purpura (4.6%),
epistaxis (3.2%), haematuria (2.8%) and gingival bleeding (2.0%).

In patients undergoing extended secondary prophylaxis for VTE the most
commonly reported bleeding related AEs for ximelagatran-treated patients
were haematuria (6.0%), purpura (4.7%), melaena (3.6%), and rectal
haemorrhage (1.6%).

The most commonly reported bleeding AEs in patients receiving
ximelagatran and ASA were epistaxis (4.9%), haematuria (4.9%), melaena
(3.7%) and purpura (3.6%).

2.5.5 Relationship between exposure to melagatran and bleeding events

The association between AUC and the cumulative risk of a major/minor
bleeding event is summarized for ximelagatran-treated patients in the AF
pool in Table 24.

**Table 24: Association between AUC and cumulative risk of having a
bleeding event (major or minor) after one year in the study**

![](media/image23.png){width="5.567361111111111in"
height="1.4666666666666666in"}

The risk of having a major/minor bleeding event with ximelagatran 36 mg
increases with increasing AUC values (hazard ratio 1.17, 95% CI: 1.12,
1.21)

There was no statistically significant relationship between the risk of
having a major/minor bleeding event with ximelagatran 24 mg and
increasing AUC values (hazard ratio 1.08, 95% 0.90, 1.29).

**2.5.6 Subgroup analyses of bleeding events:**

Within-treatment group comparisons suggested that, for both ximelagatran
and warfarin, patients [\>]{.underline}75 years old, and those with
prior stroke/TIA, were at an increased risk of major/minor bleeding. In
the ximelagatran group only, CrCL \<80 mL/min, previous CAD and diabetes
mellitus were also suggested to be associated with an increased risk of
major/minor bleeding events. In the warfarin group, the same conclusion
was suggested for patients with paroxysmal AF and those who had
previously taken aspirin.

For the majority of subgroups investigated, patients were statistically
significantly less likely to have a major/minor bleed with ximelagatran
36 mg than warfarin. Two significant treatment by risk factor
interactions were detected, for CrCL \<80 mL/min (p\<0.001) and diabetes
mellitus (p=0.002). In terms of the key demographic characteristics, the
following subgroups were statistically significantly less likely to have
a major bleed with ximelagatran 36 mg than warfarin patients with a CrCL
[\>]{.underline}80 mL/min, patients less than 75 years old, patients
with a BMI [\>]{.underline}25, males and females, patients with a weight
[\>]{.underline}50 kg and Caucasians.

There were no subgroups that were statistically significantly less
likely to have a major/minor bleed with warfarin compared to
ximelagatran.

**2.6 Hepatobiliary effects**

It should be noted that the following patients have been excluded from
the studies:

-   Patients with known clinically significant liver disease (as judged
    by the investigator) or persistent ASAT and/or ALAT \> 3 x ULN
    (defined by central laboratory)

-   Patients with continuous treatment with NSAID or Known drug
    addiction and/or alcohol abuse

In studies with ximelagatran (bid, fixed dose), from June 2000, liver
enzymes were monitored

at least monthly for the first 6 months and if ALAT increased to
\>3xULN, were monitored

weekly; if ALAT reached \>7xULN study drug was stopped. From 2 November
2001, this

algorithm was changed. The threshold for beginning weekly monitoring was
reduced from

3xULN to 2xULN and the threshold for discontinuation of study drug was
revised from

7xULN to 5xULN (or persistent increase \>3xULN for up to 4-8 weeks). In
the program,

40% of the ximelagatran-treated patients who had an ALAT \>3xULN were
monitored using

the more stringent algorithm.

2.6.1 Patients contributing to ALAT measurement

The number of randomized patients contributing to ALAT testing is shown
in Table 25.

**Table 25: Number of patients randomized, and contributing ALAT
measurements over time in the long-term studies (ITT population) -
Central laboratory data only**

![](media/image24.png){width="5.517361111111111in"
height="2.3666666666666667in"}

Of the 6948 patients randomized to ximelagatran, 6840 contributed at
least one ALAT measurement and 5528 had an ALAT measurement at the
6-month visit.

2.6.2 Elevations in liver function tests (LFTs)

The distribution of patients with elevated ALAT, ASAT, ALP and total
bilirubin, according to

various multiples of ULN is shown for the LTE pool in Table 26 (Central
laboratory data

only).

**Table 26: Cumulative incidence of patients with elevated ALAT,
bilirubin, ASAT, G-GT and ALP (ITT population): LTE pool - Central
laboratory data only**

![](media/image25.png){width="5.175694444444445in" height="3.575in"}

The pooled data shows a similar pattern to that seen in the individual
studies. ALAT showed a significant increase in ximelagatran-treated
patients compared to those treated with comparators at all thresholds.
ASAT increased in conjunction with ALAT. There was no similar increase
for ximelagatran relative to comparators in total bilirubin and ALP.

ALAT is the main marker of a hepatic effect in the ximelagatran group
compared to the comparator. There is a strong correlation with ASAT, but
ALAT is generally higher and is known to be more specific to the liver.
The elevation in the other tests is not as different between groups, and
there is no correlation between ALAT and ALP or bilirubin. These
features point to a predominantly hepatocellular type of hepatic injury,
as opposed to a cholestatic type.

As ALAT is a more specific marker of liver cell damage than ASAT, and
there was no pattern

for an increase in ALP or bilirubin in isolation, ALAT was used for
monitoring and management decisions and forms the basis of the analysis.
A threshold of \>3xULN ALAT is generally considered to represent a
clinically significant elevation. Lower cut-off levels are considered to
be less informative due to the commonness of slight elevations in
untreated populations. Therefore, ALAT values of \>3xULN have been used
to indicate a signal of potential clinical relevance.

2.6.3 ALAT elevation according to various thresholds

The distribution of patients with elevated ALAT according to various
multiples of the upper limit of the normal range is shown by study for
patients treated with ximelagatran in Table 27 and for patients treated
with comparator in Table 26. These tables present central laboratory
data only.

**Table 27 Cumulative incidence of ximelagatran-treated patients with
elevated ALAT by study (ITT population) - Central laboratory data only**

![](media/image26.png){width="5.184027777777778in"
height="2.3666666666666667in"}

**Table 28 Cumulative incidence of comparator-treated patients with
elevated ALAT by study (ITT population) - Central laboratory data only**

![](media/image27.png){width="5.2340277777777775in"
height="2.433333333333333in"}

There was a higher incidence of ALAT elevation in ximelagatran --treated
patients regardless of the threshold (xULN) and the effect was
consistent across all studies.

Overall, approximately twice as many ximelagatran-treated patients
experienced an ALAT elevation \>ULN (30.0% vs 15.2%). There were
approximately 4 times as many ximelagatran-treated patients who
experienced an increase in ALAT \>2xULN (12.1% vs 2.9%) and this
difference increased to 7-fold at \>3xULN. The additional data obtained
from local laboratories did not affect the patterns seen in the Central
laboratory data.

**2.6.4 Patients with ALAT\>3xULN measured at the Central laboratory**

The number of patients with an increase in ALAT \>3xULN is presented for
both ximelagatran and the comparators in Table 29.

**Table 29 Elevations of ALAT \>3xULN (ITT population) - Central
laboratory data only**

![](media/image28.png){width="5.517361111111111in"
height="2.933333333333333in"}

In patients receiving long-term administration of ximelagatran (\>35
days) an increase in ALAT \>3xULN occurred in 6-13% (average 7.6%,
531/6948) compared to 0-2% (average 1.1%, 68/6230) of patients receiving
comparator treatments.

The overall incidence of ALAT \> 3xULN in SH-TPA-0002/4 after 2 years of
treatment was 6.4% (12/187) in the ximelagatran group and 0% (0/67) in
the warfarin group. The incidence was comparable in the other 2 studies
in AF patients, SH-TPA-0003 (6.3%) and SH-TPA-0005 (6.0%); the incidence
in the warfarin group was 0.8% in both of these studies. The incidence
in both the ximelagatran group and the warfarin group was higher in
VTE-T patients (9.6% and 2.0%, respectively). The higher incidence in
the warfarin group may have been due to the enoxaparin given as part of
the treatment regimen in the comparator group. In the post ACS study,
SH-TPC-0001, the incidence was notably higher in the ximelagatran 36, 48
and 60 mg dose groups (12 to 13%) but the incidence in the 24 mg group
was similar to that seen in AF patients (6.5%).

There were a further 11 patients who had an ALAT elevation \>3xULN
recorded after study closure and are therefore excluded from the ITT
analyses of these data. These 11 patients comprised 9 patients in study
SH-TPV-0002/5 (6 in the ximelagatran group and 3 in the
enoxaparin/warfarin group) and 2 patients in study SH-TPC-0001 (1 in the
ximelagatran 36 mg group and 1 in the placebo group). Finally, Patient
012-205 in study SH-TPA-0004 had an ALAT elevation \>3xULN after 2.5
years of treatment with ximelagatran. This patient is not included in
the analysis because only data up to 30 June 2001 (the date of the
interim CSR ) from this ongoing study have been integrated in the safety
database.

**2.6.5 Time course of ALAT elevations**

As shown in the previous section, 599 patients showed an ALAT elevation
\>3xULN during the studies, 531 patients in the ximelagatran group
(cumulative incidence 7.6%) and 68 patients in the comparator group
(cumulative incidence 1.1%). Note that this is the central laboratory
data only. Including local laboratory data, 620 patients showed an ALAT
elevation \>3xULN during the studies, 546 patients in the ximelagatran
group (cumulative incidence 7.8%) and 74 patients in the comparator
group (cumulative incidence 1.1%).

The time pattern of ALAT elevations was consistent. The increase
typically occurred between 1 and 6 months after the initiation of
ximelagatran. Before and after this time frame the incidence of ALAT
increase was similar to comparators. The divergence occurred largely up
to 6 months and thereafter the additional increment was 1.0% for
ximelagatran and 0.4% for comparators. Figure 1 shows the number of
patients presenting for the first time with an increase in ALAT \>3xULN
during each month of treatment.

**Figure 1: Number of new patients with ALAT \>3xULN by month since
randomization (ITT population): LTE pool -- Central laboratory data
only**

![](media/image29.png){width="4.809027777777778in" height="2.95in"}

The figure shows the number of patients presenting with ALAT \>3xULN for
the first time and it should be noted that there were 6948 patients in
the ximelagatran group and 6230 in the comparator group. In the first
month of treatment there was no difference in the incidence of ALAT
\>3xULN between ximelagatran (23 cases) and comparator-treated patients
(25 cases). The difference became significant at 2 months. Of the 531
ximelagatran-treated patients who had ALAT \>3xULN, 495 (93.0%) were
detected during the first 6 months and 519 (97.7%) were detected within
the first 12 months. Beyond 12 months, few new patients presented with
ALAT \>3xULN.

Regardless of the magnitude of the ALAT increase examined, the time
pattern was consistent. In the ximelagatran group, the majority of
patients who experienced an elevation in ALAT presented between 2 and 4
months. Beyond 12 months the incidence of increased ALAT was similar to
the comparators.

2.6.6 Recovery of elevated ALAT values towards normal

Among the 531 patients in the ximelagatran group who presented with an
ALAT \>3xULN, 206 (39%) completed the study on study drug. The remaining
325 patients (61%) discontinued study drug prematurely. The analysis of
the reduction of elevated ALAT toward normal is presented in Table 30.

**Table 30 Number of ximelagatran-treated patients with ALAT\>3xULN,
measured at the Central laboratory by magnitude of last recorded ALAT
measurement (ITT population): LTE pool**

![](media/image30.png){width="5.334027777777778in"
height="1.1916666666666667in"}

This table includes ximelagatran-treated patients who had an ALAT
\>3xULN recorded at the Central laboratory during the studies
categorized by their maximal ALAT elevation (\>3, \>5 or \>10xULN). For
each category, the number of patients who had a last recorded ALAT value
of \<1, \<2, \<3 or \>3xULN, is shown. The table is further subdivided
into those patients who continued on study drug and those who stopped
study drug. For example, from the second column of the table it can be
seen that 84 patients who had a maximal ALAT elevation of \>3xULN but
\<5xULN, had returned to an ALAT [\<]{.underline}1xULN at their last
recorded measurement, while continuing to take study drug. From the
penultimate column in the table it can be seen that 8 patients who had a
maximal ALAT elevation of \>10xULN, still had ALAT \>3xULN at their last
recorded measurement, having stopped taking study drug.

Of the 531 ximelagatran-treated patients who had an ALAT elevation
\>3xULN recorded by the central laboratory, 502 (95%) had their ALAT
return to \<2xULN by the last measurement taken before the cut-off for
this file. So far, it is not possible to identify who the patients are
that will not return to baseline. The mean number of days taken for ALAT
to return to \<2xULN was similar whether the patients continued to take
ximelagatran or not (Table 31).

**Table 31 Mean number of days between first ALAT elevation \>3xULN
(measured at the Central laboratory) to normalization for
ximelagatran-treated patients (ITT population): LTE pool**

![](media/image31.png){width="5.325694444444444in"
height="1.0916666666666666in"}

Most cases show a peak of ALAT within the first 2 to 3 months
post-randomization and a decline back towards baseline within about 6
months post-randomization.

The pattern of return to baseline or ULN was similar whether the patient
discontinued study drug or not, and only sustained above ULN in a few
cases.

A total of 35 patients, 30 in the ximelagatran group and 5 in the
comparator group, still had ALAT \>2xULN at the last measurement
(including local laboratory measurements). Of the 30
ximelagatran-treated patients, 11 died while their ALAT was still
elevated; 3 patients had an alternative explanation for the raised LFTs
(alcohol); 2 patients were lost to follow-up and one patient had a final
ALAT measurement that according to the investigator had "decreased to a
medically insignificant level". The remaining 13 patients continued
under surveillance at the time of the cut-off for this file.

**2.6.7 Re-challenge to ximelagatran after temporary discontinuation of
study drug with ALAT elevations**

Eighteen patients who discontinued study drug with elevations of ALAT
subsequently resumed treatment after ALAT had returned to the normal
range. Of these 18 patients, 2 (Patient SH-TPA-0003-017-2619 and Patient
SH-TPA-0005-370-5718) again experienced elevations of ALAT after drug
was resumed.

2.6.8 Elevated ALAT by dose

Table 32 shows the cumulative incidence of ximelagatran-treated patients
with elevated ALAT by dose in study SH-TPC-0001.

**Table 32 Cumulative incidence of ximelagatran-treated patients with
elevated ALAT by dose in study SH-TPC-0001 (ITT population)**

![](media/image32.png){width="5.159027777777778in"
height="1.1666666666666667in"}

There was not a marked dose response over the dose range 24 mg to 60 mg
but there was a noticeably lower incidence of all multiples of ULN at
the 24 mg dose compared to the higher doses.

2.6.9 Combination of ALAT and bilirubin elevation

The combination of transaminase and bilirubin elevation has been
considered to predict the occurrence of severe injury in some patients.
The number of patients in each of the studies that contribute to the LTE
pool who had an increase in total bilirubin \>2xULN within one month
following an increase in ALAT \>3xULN are shown in Table 33.

**Table 33 Concomitant elevations of ALAT \>3xULN and bilirubin \>2xULN
(ITT population) - Central laboratory data only**

![](media/image33.png){width="5.584027777777778in" height="2.475in"}

ALAT \>3xULN was associated with bilirubin \>2xULN (within one month
following the rise in ALAT) in 0.4% (26/6948) of all patients who were
exposed to ximelagatran \>35 days as compared to 0.1% (4/6230) of
patients exposed to comparators.

Additional ALAT and bilirubin data were obtained from tests performed at
local laboratories. These included 11 new cases (10 ximelagatran, 1
comparator) who had an increase in bilirubin \>2xULN within one month
following an increased ALAT \>3xULN. One additional patient (#7859)
described in the section of Deaths in ximelagatran-treated patients with
ALAT \>3xULN (see below) had bilirubin elevation \> 5.6x ULN. This
patient was not included in the sponsor's analysis for combination
elevation. Therefore, at the cut-off date for this file there were 37
such cases in the ximelagatran group and 5 in the comparator group
(0.53% vs 0.08%). The ximelagatran-treated patients who had an increase
in total bilirubin \>2xULN within one month following an increase in
ALAT \>3xULN are summarized in Tables below.

**Table 34 List of ximelagatran-treated patients with concomitant
elevations of ALAT \>3xULN and bilirubin \>2xULN -- Central laboratory
data only**

![](media/image34.png){width="6.5in" height="4.416666666666667in"}

![](media/image35.png){width="6.4in" height="3.933333333333333in"}

**Table 35 List of ximelagatran-treated patients with concomitant ALAT
\>3xULN and bilirubin \>2xULN -- local laboratory data only**

![](media/image36.png){width="6.4in" height="3.933333333333333in"}

**Table 36 List of ximelagatran-treated patients with concomitant ALAT
\>3xULN and bilirubin \>2xULN -- local laboratory data only**

![](media/image37.png){width="6.4in" height="1.3506944444444444in"}

Concomitant elevations of ALAT \>3xULN and bilirubin \>2xULN were
observed during the first month of ximelagatran therapy in 6 of 37
patients.

Two comparator-treated patients with concomitant ALAT \>3xULN and
bilirubin \>2xULN died and both died from pancreatic cancer.

Nine ximelagatran-treated patients who died are presented here more in
detail (including patient \# 7859 who was missed by the sponsor for
concomitant ALAT and bilirubin elevation analysis).

-   Patient 7259, an 80 year old male, began ximelagatran 36 mg bid
    treatment on 11 June 2001. He experienced elevated liver
    transaminases with biopsy-demonstrated hepatic necrosis and a fatal
    bleed due to a duodenal ulcer. The patient had a medical history of
    hyperlipidemia treated in the past with simvastatin until March
    1999, AF since 1996, hydronephrosis probably related to an ectopic
    ureter insertion, urinary retention, fibromyalgia treated with
    prednisone in the past, coronary artery disease treated with bypass
    grafting in 1999, and right colon cancer diagnosed in 1999.
    Concomitant medications included Lopressor (metoprolol), digoxin,
    and Flomax (tamsulosin). On 30 May 2001, the patient\'s baseline
    liver function tests were normal with ALAT 16 U/L, ASAT 22 U/L, ALP
    67 U/L and total bilirubin 0.9 mg/dL . On 6 August 2001, at the
    Month 2 Visit, his LFTs were mildly elevated, but less than the 3x
    ULN threshold that required discontinuation of study medication . At
    the next scheduled visit (4 September 2001) the transaminases were
    found to be further elevated (ALAT 970 U/L, ASAT 698 U/L, ALP 142
    U/L), leading to weekly LFT monitoring and study drug
    discontinuation on 7 September 2001. Transaminases continued to
    increase. On 19 September 2001, ALAT and ASAT were 1502 U/L and 1355
    U/L, respectively; ALP was 154 U/L; total bilirubin was 2.4 mg/dL
    (nearly twice the ULN) and direct bilirubin was 0.6 mg/dL.
    Serologies for hepatitis A, B, and C, cytomegalovirus, Epstein-Barr,
    and herpes simplex viruses did not show a recent viral infection.
    Carcino-embryonic antigen and antinuclear antibodies were negative.
    Abdominal ultrasound showed normal liver, normal gallbladder, normal
    biliary tree and 2 simple cysts in the right kidney. An abdominal
    and pelvic CT scan performed on 21 September 2001 showed no
    significant new findings compared to a prior examination (3 August
    2000). Liver transaminases peaked on 27 September 2001 and then
    decreased on 4 October 2001. ALP peaked at 198 U/L on 3 October 2001
    and decreased to 170 U/L on 4 October 2001. Total bilirubin was 10.7
    mg/dL on 3 October 2001 and then decreased to 7.9 mg/dL on 4
    October 2001. Prothrombin time (13.6 sec) and INR (1.2), which were
    close to normal on hospital admission (20 September 2001) started to
    increase on 1 October 2001, reaching16.3 sec and 1.7 respectively.
    Conversely, albumin decreased to 2.9 g/dL on 2 October 2001. This
    laboratory profile suggested impairment of his synthetic liver
    function. A liver biopsy performed on (27 September 2001)
    demonstrated \"severe active hepatitis with hepatocyte necrosis,
    areas of collapse and marked bile ductular proliferation consistent
    with acute submassive necrosis.\" The hepatologist considered the
    most likely explanation was medication-induced hepatitis. INR
    remained elevated (1.8 on 8 October 2001) and serum albumin low (2.5
    g/dL on 8 October 2001). platelet count was 65,000/mm^3^ (29 October
    2001). Profound fatigue continued with no evidence of
    encephalopathy. However, he had developed ascites, significant lower
    extremity edema and oliguria. On the morning of 3 November 2001, the
    patient\'s wife found him unresponsive at home. Resuscitation failed
    and the patient was pronounced dead. The cause of death was upper GI
    bleed due to duodenal ulcer. An autopsy confirmed the presence of
    atherosclerotic disease, ischemic heart disease with triple CABG and
    atrial septal defect repair; adenocarcinoma of the colon resected
    with no evidence of recurrence or metastatic disease, and left
    hydronephrosis with no evidence of mechanical obstruction. The
    significant findings were: A large duodenal ulcer (2.5 cm) with
    erosion into pancreas and peripancreatic soft tissue and hemorrhagic
    contents through most of the small intestine with intact bowel. A
    small, friable and diffusely mottled liver suggestive of severe
    diffuse hepatic necrosis. Microscopically, there was extensive liver
    necrosis with hepatocyte dropout and bile duct proliferation,
    similar to that seen in the previous biopsy. A significant amount of
    hepatic parenchyma remained. Tissue architecture showed early
    resolution of the inflammation compared to the previous biopsy.
    There was serous ascites in the abdomen. The spleen was not
    enlarged. Moderate reduction of megakaryocytes in bone marrow. The
    cause of death was an acute gastrointestinal bleed from a duodenal
    ulcer, with a coagulopathic state from hepatic injury contributing
    to death. Both decreased clotting factors and platelet reduction
    cause the coagulopathy, the latter related to a decreased number of
    megakaryocytes in the bone marrow. The autopsy report speculated
    that prednisone therapy may have caused the duodenal ulcer and
    decreased synthesis of thrombopoietin by the liver could have played
    a role in the thrombocytopenia. The investigator assessed the event
    of liver failure as being related and the event of fatal bleed due
    to duodenal ulcer as not related to the study medication.

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-   Patient 5442 was a 73 year old male Caucasian. Relevant medical
    history included diabetes mellitus, systemic lupus erythematosus,
    hypertension, heart disease, gastric ulcer, COPD and cardiac
    arrhythmia. The reason for entering the study was DVT. The patient
    received 36 mg Ximelagatran b.i.d. Transaminases were slightly
    increased (ASAT 60 U/l; ALAT 60 U/l; AP 210 U/l), nine days after
    start of study medication, but this was thought to be due to the
    known lupus erythematosus which was otherwise not active (titer of
    antinuclear antibodies \> 1:80, i.e. normal). Eighteen days after
    commencing study medication, the patient experienced hepatitis type
    B and was hospitalized. Hepatitis serology had been done six days
    before admission because of rising transaminases and showed HBs
    antigen, HBc antibody and HBe antigen 2 positive, while HBs
    antibodies, hepatitis C virus antibodies, HBe antibodies, HAV-Ak-IgM
    and HBc-Ak-IgM were all negative. From this constellation with
    absence of antibodies an acute hepatitis B was diagnosed. With
    regard to the normal incubation time, infection had probably
    occurred before inclusion into the study, but a plausible source of
    infection could not be detected. Transaminases continued to rise.
    Four days after hospitalization, ASAT was 354 U/l, ALAT 367 U/l, AP
    292 U/l and G-GT 54 U/l. LDH had increased to 360 U/l and bilirubin
    was 1.8 mg/dl. Two days later study medication was withdrawn. The
    patient\'s general condition was good, without signs of hepatic
    encephalopathy or failure. Two days after withdrawal of study
    medication, ASAT was 593 U/l, ALAT 518 U/l and bilirubin 4 mg/dl.
    The next day the patient was transferred to an infection treatment
    unit. The patient began to develop icterus and bilirubin tests taken
    ten days, 15 days and 19 days after onset, showed a rapid increase
    to 8 mg/dl, 17.2 mg/dl and 26.8 mg/dl, respectively. Transaminases
    meanwhile decreased slightly. Eleven days after onset of the event,
    the patient complained of nausea and pain in his right flank. Five
    days later, a gastroscopy performed showed multiple gastric ulcers
    covered with fibrin, but no signs of acute bleeding. Quick value,
    which had been around 40% before, dropped to 29 % with an
    international normalized ratio of 2.3. ASAT value was 287 U/l and
    ALAT was 189 U/l approximately three weeks after onset. Therapy
    consisted of low molecular heparin, oral iron substitution,
    pantoprazole, metoclopramide, lactulose, prednisolone, amino acid
    infusions and amoxicilline + clavulanic acid. The patient\'s general
    condition deteriorated. Abdominal computerized tomography performed
    18 days after onset, showed beginning formation of ascites. On that
    day the patient complained of vertigo and nausea and felt very
    tired. The next day repeated enuresis was reported. Agitation, signs
    of hepatic encephalopathy and tarry stools appeared three weeks
    after onset. During the next two days the patient deteriorated
    dramatically. All therapy was stopped because of poor prognosis. The
    patient became comatose and died from hepatic failure two days
    later. Autopsy was not performed. All attending doctors agreed that
    the cause of death was fulminant hepatitis B, but it seemed
    debatable whether this was an acute condition or an exacerbation of
    a chronic disease that had already been present in 2001, but had
    been masked by the immunosuppressive therapy for lupus
    erythematosus. Azathioprine induced hepatotoxicity is another
    aggravating factor under discussion. The investigator considered
    there was a reasonable possibility that the event may have been
    caused by study medication.

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-   Patient 3963 was a 45 year old Caucasian. Relevant medical history
    included constant atrial fibrillation, left heart failure,
    congestive cardiomyopathy, chronic bronchitis, paroxysmal
    ventricular tachycardia and an automatic implantable
    cardioverter/defibrillator. Pre-study stroke prophylaxis consisted
    of warfarin. As study treatment the patient was allocated to receive
    ximelagatran 36 mg b.i.d. Approximately 28 weeks after commencing
    study medication the patient was hospitalized with dyspepsia,
    nausea, vomiting, increased weight and girth. In addition the
    pacemaker had been activated three times for the last few days
    because of ventricular tachycardia. The condition was consistent
    with deterioration of congestive heart failure with increased right
    heart failure, peripheral edema and possible liver enlargement.
    Blood samples including liver enzymes were taken. An ultrasound of
    the liver showed severe intra-abdominal obesity and fatty liver. The
    slightly increased liver enzymes were assessed due to hypoperfusion
    and liver stasis. The patient\'s treatment with diuretics and
    antiarrhythmics was adjusted after which the condition stabilized.
    The day before the planned discharge, the condition aggravated
    acutely with cardiogenic shock. The patient was transferred to
    another hospital where in spite of maximum inotropic support, the
    patient died. The patient died approximately nine days after the
    onset of the event. Cause of death was cardiac failure and shock. An
    autopsy has not been performed. The investigator considered there
    was no reasonable possibility that the events may have been caused
    by study medication. Additional safety surveillance resulted in the
    following information: Approximately 6 months from start of study
    drug (day 190), elevated LFTs were noted by the central laboratory:
    ALT 4.81 x ULN, AST 4.33 x ULN, ALP 1.98 x ULN and Bil 2.77 x ULN.
    Repeat sampling on day 203 showed ALT 1.31 x ULN, AST 1.17 x ULN,
    ALP 1.36 x ULN, and Bil 1.77 x ULN. At this time point the patient
    was re-hospitalized with deterioration of congestive heart failure,
    as described above.

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-   Patient 0430 was a 90 year old Caucasian. Relevant medical history
    included hypertension, myocardial infarction, diabetes, lumbar pain,
    insomnia and bronchopneumopathy. The reason for entering the study
    was an acute coronary syndrome with a peak Troponin I value of 0.44
    (ULN=0.04). The patient received ximelagatran 24 mg b.i.d. and ASA
    160 mg o.d. After four weeks on study drug the patient developed
    right cardiac failure which was considered non-serious. After 17
    days the event was considered medically important and the patient
    was hospitalized. He presented with bilateral lower leg edema and
    jugular turgescence. The patient was hospitalized for worsening of
    right cardiac failure after 16 weeks on study drug. He presented
    with edema. Study drug was withdrawn (total study drug treatment was
    18 weeks) and the patient died from right cardiac failure 3 days
    after stop of study drug. No autopsy was performed. The investigator
    considered that there was no reasonable possibility that the events
    may have been caused by study medication or by other medication.
    Additional safety surveillance resulted in the following
    information: Four and a half months from start of study drug
    (day 132) elevated LFTs were noted by the central laboratory: ALT
    4.42 x ULN, AST 6.35 x ULN, ALP 4.30 x ULN, and Bil 2.23 x ULN. ALT
    had been slightly increased at start of study drug (1.33 x ULN), but
    was normal from day 8 until day 132. ALP was elevated throughout the
    study with a peak at the last sampling on day 132. Bil was slightly
    elevated from day 84. The patient experienced a minor conjunctival
    bleeding 11 days prior to the ALT elevation and muscular pain 4 days
    prior to the ALT elevation. As described above, the patient also had
    hematuria followed by worsening of right cardiac failure with fatal
    outcome at the time of the ALT elevation.

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-   Patient 2893 was a 66 year old Caucasian. Medical history included
    paroxysmal atrial fibrillation, angina pectoris, myocardial
    infarction, chronic obstructive airways disease, cholelithiasis and
    hypercholesterolaemia. Pre-study stroke prophylaxis consisted of
    warfarin. As study treatment the patient was allocated to receive
    ximelagatran 36 mg b.i.d. Approximately 40 weeks after commencing
    study medication, the patient experienced abdominal pain and nausea.
    The patient was hospitalized and hepatic colic was diagnosed. After
    one week in hospital he also experienced severe heart failure. This
    event lasted only one day. The patient remained in hospital. One
    week after the episode with severe heart failure the patient had
    symptoms of ventricular tachycardia. He was treated with DC shock
    and xylocaine. He was discharged from hospital after five weeks, and
    was recovered from all events at that time. Study drug continued
    unchanged. Approximately one year and seven weeks after start of
    study drug the patient suffered from eruption of erysipeloid. He was
    hospitalized one week later and treated with ciprofloxacin. During
    the hospitalization stay, approximately one month after he was
    admitted the patient suffered from abdominal pain due to
    cholelithiasis. The clinical condition deteriorated and he died the
    next day. Cause of death was cardiac arrest. The investigator
    suggested that the abdominal pain surcharged the heart and thereby
    caused the cardiac insufficiency. There was no action taken
    regarding study drug prior to the death. The investigator considered
    there was no reasonable possibility that the events may have been
    caused by study medication. Additional safety surveillance resulted
    in the following information: Local ALT peak was 18.4 x ULN at day
    287, but ALT never exceeded 3 x ULN in central labs.

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-   Patient 1793 was a 69 year old Caucasian. Relevant medical history
    included constant atrial fibrillation and unspecified essential
    hypertension. Pre-study stroke prophylaxis consisted of warfarin. As
    study treatment the patient was allocated to receive ximelagatran 36
    mg b.i.d. Approximately 34 weeks after commencing study medication,
    the patient experienced dyspepsia, icterus and weight loss. The
    patient was hospitalized. Study medication was withdrawn due to the
    event icterus. Metastases in liver were discovered. During the
    hospital stay approximately 12 days later malignant neoplasm was
    discovered in the stomach. Computed tomography, sonogram and
    laparotomy were performed. The patient was given symptomatic
    treatment. Nine days after the operation the patient suddenly died.
    An autopsy was performed which confirmed the cause of death as
    pulmonary embolism. The investigator considered there was no
    reasonable possibility that the events may have been caused by study
    medication. Additional safety surveillance revealed the following
    information: Approximately eight months from start of study drug
    (day 237) elevated LFTs were noted by the central laboratory: ALT
    3.56 x ULN, AST 2.51 x ULN, ALP 3.54 x ULN, and Bil 5.00 x ULN. No
    further central labs were obtained for reasons described above.

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-   Patient 2065 was a 51 year old Caucasian. Relevant medical history
    included sleep apnoea. The reason for entering the study was an
    acute coronary syndrome with a peak CKMB value of 331 (ULN=3). The
    patient received ximelagatran 60 mg b.i.d. and ASA 160 mg o.d. After
    three weeks and five days on study drug treatment the patient had
    icterus. A liver ultrasound was performed showing a 4 times 4 cm
    large tumor in the pancreatic gland. Bilirubin was 141 (normal range
    4-21), ALP was 10.2 (normal range 0.8-4.6) and ALAT was 11.2 (normal
    range \< 0.80). Study drug was withdrawn. The patient was discharged
    after two weeks and six days. Six weeks after stop of study drug the
    patient had visual field loss. A CT-scan of the brain was done.
    Treatment with heparin fraction was given. According to available
    information the event was still present when the patient died. Two
    weeks and six days later the patient was again hospitalized due to
    worsening symptoms of his pancreatic tumor with liver metastasis.
    Ultrasound showed ascites, which was evacuated. No chemotherapy was
    given during this hospitalization. He was discharged after one week
    and four days. The patient died at home three days later because of
    his cancer. The investigator considered that there was no reasonable
    possibility that the events had been caused by the study medication.
    Additional safety surveillance resulted in the following
    information: Expressed as multiples of ULN, ALT peak value was 11.81
    x ULN at day 34, which was 8 days after study drug had been stopped.
    At day 40 ALT was 4.79 x ULN, AST 2.02 x ULN, ALP 2.35 x ULN, and
    Bil 12.45 x ULN. No further central labs were obtained before death.

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-   Patient 4035 was a 76 year old Caucasian. Relevant medical history
    included previous VTE event, hypertension, parkinsonism,
    pyeloglomerulonephritis and coronary disease. The reason for
    entering the study was DVT. The patient received ximelagatran 36 mg
    b.i.d. Fifteen weeks after start of study drug the patient was
    hospitalized due to melaena, decreased haemoglobin and anaemia. HB
    was 8.6. Bleeding from the digestive tract was suspected. Study drug
    was permanently stopped. Blood transfusion (two units of blood) was
    given. Gastroscopy was normal. The patient recovered from the
    bleeding and was discharged from hospital one week after start of
    event. Hb was now 12.0 (normal for this patient). Two weeks after
    discharge from hospital colonoscopy and ultrasonography were done
    that revealed adenocarcinoma of colon. Four weeks after stop of
    study drug the patient was hospitalized for operation of colon
    adenocarcinoma and liver metastases in the right liver lobe.
    Resection of sigmoideum and right liver lobe were done. After six
    days X-ray of abdomen showed fluid levels. An abscess of the
    anastomosis was diagnosed and he was re-operated. Four days later a
    multiorgan failure developed diagnosed with abdominal ultrasound and
    x-ray. The patient was treated with antibiotics, fluid, enoxaparin,
    blood, plasma and digoxin. He died the same day and the probable
    cause of death was the multiorgan failure. The investigator
    considered there was a reasonable possibility that the event
    bleeding from digestive tract may have been caused by study
    medication, but that there was no reasonable possibility that the
    events adenocarcinoma, liver metastases, abscess of anastomosis and
    multiorganic failure may have been caused by study medication.

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-   Patient 7859 (not included in the sponsor's concomitant ALAT and
    bilirubin elevation analysis) was a 77 year old Caucasian and
    initiated on ximelagatran 36 mg bid treatment on 13 August 2001.
    Past medical history included a cholecystectomy, duodenal ulcer,
    sick sinus syndrome, pacemaker insertion, hypertension, carotid
    stenosis, abdominal aortic aneurysm repair (13 April 2001), and
    coronary artery disease. On 15 October 2001 (day 63), safety
    laboratory results demonstrated elevated liver transaminases: ALAT
    216 U/L, ASAT 154 U/L; ALP was 156 U/L and total bilirubin 1.3
    (baseline 1.1) mg/dL. He took his last dose of study medication in
    the evening on day 80. The next day (on 2 November 2001), the
    patient awoke with stomach pain and light-headedness. Bowel
    movements produced bloody stools. He was admitted to hospital that
    same morning. At admission, he had pallor, blood pressure 76/45 mm
    Hg, and heart rate 103/min. Laboratory tests showed hemoglobin of 7
    g/dL, hematocrit 20%, prothrombin time 37 sec, INR 3.4, aPTT 69 sec,
    albumin 2 g/dL, ASAT 629 U/L, ALAT 569 U/L, ALP 173 U/L and plasma
    melagatran was 0.25 M (therapeutic range). During hospitalization,
    he received vitamin K, packed red blood cells (19 units), fresh
    frozen plasma (15 units), cryoprecipitate (30 units) and fluids. On
    03 Nov laboratory tests showed hemoglobin of 9.6 g/L, hematocrit of
    27.3%, prothrombin time 14.5 secs, aPTT 53 secs and INR 1.1. Liver
    enzymes also decreased: ALAT 134 U/L, ASAT 236 U/L and ALP 49U/L,
    but bilirubin was 6.2 (5.6x ULN). The patient underwent a
    gastroscopy that revealed a Bilroth II anastomosis. There was
    bleeding in the pre-anastomotic area and epinephrine was injected to
    attempt to decrease the bleeding. The same day (3 November 2001) he
    presented with signs of respiratory failure. Echocardiogram showed
    55% left ventricular function and no major cardiac abnormalities.
    However, heart rate was 130 to 140/min. Vasopressors were necessary
    to sustain blood pressure and diltiazem was given to decrease the
    heart rate. Synchronized cardioversion failed 4 times to establish
    sinus rhythm. Shock persisted despite resuscitation with fluids, 2
    units of packed RBC, 10 units of fresh frozen plasma and 1 unit of
    platelets. Profound coagulopathy occurred. A consulting surgeon
    deemed operation futile. Support was subsequently withdrawn and the
    patient died on 3 November 2001. No autopsy was conducted but the
    cause of death was considered to be hemorrhage. The investigator
    assessed the event as possibly related to the study medications and
    concluded that the liver problems contributed to the bleeding.

**2.6.10 Deaths in ximelagatran-treated patients with ALAT \>3xULN**

The number of deaths in ximelagatran-treated patients having maximum
ALAT \>3xULN is 19 (3.6%, 19/531) and in patients having maximum ALAT
[\<]{.underline}3xULN is 251 (251/6417, 3.9%) for central laboratory ITT
population. There was no apparent difference in the incidence of death
between ximelagatran-treated patients who experienced an increase in
ALAT \>3xULN (3.6%) and those who did not (3.9%).

In addition to the 19 patients (19/531, 3.6%) who had ALAT \>3xULN
measured at the Central laboratory subsequently died, an additional
patient died after study closure and is therefore not counted in the ITT
analysis and a further 3 patients who had ALAT \>3xULN measured at a
local laboratory subsequently died. Therefore, a total of 23 patients
who had ALAT \>3xULN subsequently died. The one individual who had an
hepatic SAE leading to death was Patient SH-TPV-0002-265-5442 (see
details above). ALAT was elevated 12 days after starting study
medication and he died 6 days thereafter from an acute hepatitis B
rapidly evolving to fulminant hepatitis. This pattern of ALAT elevation
was not consistent with the previously observed pattern of elevations in
patients exposed to ximelagatran. Although ximelagatran was not the
cause of the infectious hepatitis, the investigator could not rule out
the possibility that it aggravated the outcome. Two other patients who
died due to GI hemorrhage with severe coagulopathy had elevated hepatic
enzymes prior to death; both cases (patient 7259 and 7859) were
described above. Clearly, coagulopathy was due to ximelagatran and it
aggravated and contributed to these 2 patients' deaths.

Patients who had ALAT \>3xULN measured at the Central laboratory and
subsequently died are presented in Table 37.

**Table 37: List of ximelagatran-treated patients who had ALAT \>3xULN
measured at the Central laboratory and subsequently died**

![](media/image38.png){width="4.9in" height="4.554861111111111in"}

An additional patient died after study closure and is therefore not
counted in the ITT analysis. Patient SH-TPC-0001-062-0286, an 82 year
old female, died from AMI 2 weeks after stopping study drug
(ximelagatran 36 mg bid) due to a previous AMI.

A further 3 patients who had ALAT \>3xULN measured at a local laboratory
subsequently died. These were as follows:

Patient SH-TPA-0005-0050-8357, a 74-year-old female, died from sepsis
while taking ximelagatran 36 mg bid, and the temporary ALAT elevation
was found during a previous hospitalization for pneumonia.

Patient SH-TPA-0003-217-2893, a 67-year-old male, died while taking
ximelagatran 36 mg bid due to acute cholecystitis and cardiac arrest.
The reported SAE term was abdominal colic.

Patient SH-TPV-0002-504-4035, a 76-year-old male, died due to multiorgan
failure. The patient had been hospitalized for operation of colon
adenocarcinoma and liver metastases in the right liver lobe, 4 weeks
after stop of study drug (ximelagatran 36 mg bid).

Seven of 19 cases (#1793, 3963, 7259, 7859, 5442, 0430 and 2065) have
been discussed above in detail. Patient 2826 died from rupture of aorta
and patient 6603 died 16 months after discontinuing study drug.

**2.6.11 Potential prognostic factors related to ALAT \>3xULN.**

The multivariate analysis of potential prognostic factors for the risk
of ALAT\>3xULN was

performed using a logistic regression model with a stepwise selection
algorithm. The following factors were tested for inclusion; sex (female
vs male), age, (\>=75 vs \<75 years), weight (\>=75 vs \<75 kg), BMI
(\>=27 vs \<27 kg/m2), CrCL (\>=80 vs \<80 mL/min), ethnic origin (Asian
vs rest, i.e. all others), concomitant aspirin use (yes vs no),
concomitant statin use (yes vs no), and patient population (VTE-T vs
rest, VTE-P vs rest and Post ACS vs rest, AF was used as \"baseline\").
Stepwise analyses are presented in Table 38 (for patients in the
ximelagatran group only).

**Table 38: ALAT \>3xULN, analysis of potential prognostic factor,
stepwise model**

selection algorithm, (ximelagatran group only) (ITT population): LTE
pool

![](media/image39.png){width="5.1506944444444445in"
height="1.2583333333333333in"}

From these analyses 6 risk factors were statistically significant for
the ximelagatran group:

Post ACS population (p=0.0009), VTE-T population (p=0.0003), use of
statins (p=0.019),

BMI \<27 kg/m2 (p\<0.0001), non-Asian race (p=0.0038) and female sex
(p=0.0002, 9.4% vs. 6.7%).

**2.6.12 Relationship between exposure to melagatran and ALAT
elevation.**

Exposure to melagatran has been evaluated in patients in the
non-surgical long-term studies. Individual melagatran AUCs were
estimated by population PK modeling. The distribution of melagatran AUC
in patients with an event is largely within the melagatran AUC range in
patients without an event. These data suggest that for the patient
population and doses studied exposure is not predictive of ALAT \>3xULN
in individual patients.

The calculated cumulative risk (hazard ratio) of an increase in ALAT for
each unit increment of AUC, in each pool, is shown in Table 39. Except
for the VTE-P and post ACS pools, there is a statistically significant
relationship between exposure and the risk of an ALAT elevation above
3xULN in each pool.

**Table 39 Relationship of melagatran AUC to occurrence of ALAT
elevation \>3xULN**

![](media/image40.png){width="5.084027777777778in"
height="1.5833333333333333in"}

**2.6.13 Summary of hepatobiliary toxicity**

In patients receiving long-term administration of ximelagatran (\>35
days) an increase in

ALAT \>3xULN occurred in 6-13% (total: 531/6948, 7.6%) compared to 0-2%
(total: 68/6230, 1.1%) of patients receiving comparator treatments. ASAT
increased in conjunction with ALAT. The time pattern of ALAT elevations
was consistent and typically occurred between 1 and 6 months after the
initiation of ximelagatran. Prior to and after this time frame the
incidence of ALAT increase was similar to comparators. These data are
based on ALAT sampling in 6840 patients.

Among the 531 patients in the ximelagatran group who presented with an
ALAT \>3xULN, 206 (39%) completed the study on study drug. The remaining
325 patients (61%) discontinued study drug prematurely. The hepatic
transaminases returned to \<2xULN in the majority of patients (95%),
whether the patient continued treatment with ximelagatran or not.

An evaluation of potential risk factors for increase in ALAT indicated
an increased risk in the

Post ACS (p=0.0009), and VTE-T (p=0.0003) populations and also in female
patients (p=0.0002) patients with low BMI (\<27 kg/m2) (p\<0.0001) and
patients receiving concomitant treatment with statins (p=0.019); Asian
patients were found to have a decreased risk (p=0.0038). Although any
single factor identified above may not be strong enough to justify to
excluding the subgroup population, the patients who have 2 or more risk
factors should not be given ximelagatran, such as, female patients with
low body weight or who are taking statin.

ALAT \>3xULN was associated with bilirubin \>2xULN (within one month
following the rise in

ALAT) in 0.53% (37/6948) of all patients who were exposed to
ximelagatran \>35 days as compared to 0.08% (5/6230) of patients exposed
to comparators (including 10 ximelagatran and 1 comparator by local
laboratory measurement). A total of 14 ximelagatran-treated patients
(14/37, 35.1%) have no alternative explanation for concomitant ALAT and
bilirubin elevation. Concomitant elevations of ALAT \>3xULN and
bilirubin \>2xULN were observed during the first month of ximelagatran
therapy in 6 of 37 patients. Nine of the ximelagatran-treated patients
who had ALAT \>3xULN and bilirubin \>2xULN (24.3%, 9/37) died with these
elevations. Among them, 3 died from heart failure; 3 died from
carcinomas with hepatic matastases; 2 (ID# 7259, and 7859) died from GI
bleeding with coagulopathy and 1 (ID# 5442) died from hepatitis B. One
patient developed biopsy documented hepatic necrosis with coagulopathy
with a fatal outcome from a duodenal ulcer (#7259). Liver
failure/toxicity by ximelagatran might have caused or at least
contributed to these deaths.

In conclusion, safety data on hepatobiliary toxicity does not support
the safe use of ximelagatran for long-term (\>35 days) treatment of
patients with AF or DVT for either 36 mg bid or 24 mg bid dosing.

2.7 Analysis of adverse events of pancreatic effects

Pancreatic hyperplasia has been observed in pre clinical studies in
rats. A "pancreas sub-study" was performed as part of study SH-TPA-0005
to determine if there was a safety concern for ximelagatran regarding
pancreatic hyperplasia. CCK plasma concentrations were measured after
approximately 3 months of receiving study drug in a subset of patients.
The objective of this assessment was to determine whether ximelagatran
was associated with elevations in plasma CCK after a standard meal
because this is the mechanism by which rats undergo pancreatic trophic
stimulation, possibly leading to pancreatic adenomas and occasionally,
pancreatic carcinoma. In addition, special abdominal CT scans were
performed, which were designed to measure pancreas volume, obtained
prior to drug exposure and then again after 12 months' exposure to study
drug. The objective of this assessment was to determine whether
long-term administration of ximelagatran was associated with increased
pancreas volume because a trophic effect on pancreas would yield
increased volume of pancreatic tissue.

2.7.1 CCK in plasma -- laboratory findings

A total of 130 patients (62 ximelagatran, 68 warfarin) were enrolled in
the CCK subset, of whom 119 (56 ximelagatran, 63 warfarin) provided CCK
plasma data at 3 months. Mean (SD) CCK plasma concentration was
14.97±18.32 picomolar for the ximelagatran-treated patients and
11.39±16.51 picomolar for the warfarin-treated patients. Median CCK
plasma concentration was 6.63 (range 2.00 to 62.50) picomolar for the
ximelagatran-treated patients and 4.50 (range 2.00 to 62.50) picomolar
for the warfarin-treated patients. There was no statistically
significant difference in the plasma concentrations between the 2
groups, p=0.225 (Mann-Whitney test). The data were not normally
distributed and no transformations were applied and hence the
Mann-Whitney test was used.

2.7.2 Pancreas volume -- laboratory findings

Complete sets of pancreatic CT scans were available for a subset of 34
patients in the ximelagatran group and 28 patients from the warfarin
group. The mean ±SD change from baseline in pancreatic volume was
-10.85±13.63 for the ximelagatran group and -10.49±13.85 for the
warfarin group and was statistically significant for both treatment
groups (p=0.0001 and 0.0004, respectively). However, the between group
comparison was not statistically significant, p=0.92 (Student's t-test).
Pancreatic volume change over one year did not correlate with CCK plasma
concentration at 3 months. Treatment, CCK, and treatment-CCK interaction
did not affect pancreatic volume.

2.7.3 Analysis of AEs affecting the pancreas: long-term exposure (LTE)
pool

During the program, 13 patients (2 ximelagatran, 11 comparator) were
diagnosed with a pancreatic cancer. Fifteen patients developed
pancreatitis during active treatment in the program (6 ximelagatran, 9
comparator). A further 2 patients had an AE of pancreatitis in the
follow-up period, one after treatment with ximelagatran
(SH-TPA-0003-096-2960) and one after treatment with warfarin
(SH-TPA-0005-2690-7288).

Taking into account both the AE profile and the sub study data, there is
no safety concern for ximelagatran regarding pancreatic events.

**2.8 Analysis of adverse events of coronary artery disease**

Patients with coronary artery disease (CAD) adverse events are
summarized in Table 40.

**Table 40: Summary of patients with adverse events of coronary artery
diseases (safety population**)

+---------------+-----------------+------------------+---------------+
| Population    | Ximelagatran    | Warfarin         | p-value       |
| with          |                 |                  |               |
|               | (AF, n= 3836)   | (AF, n= 3719)    |               |
| CAD AE        |                 |                  |               |
|               | (VTE-T, n=1236) | (VTE-T, n=1248)  |               |
|               |                 |                  |               |
|               | (VTE-P, n=612)  | (VTE-P, n=611    |               |
|               |                 | placebo)         |               |
|               | n %             |                  |               |
|               |                 | n %              |               |
+---------------+-----------------+------------------+---------------+
| AF: Total CAD | 268. 7.0        | 248. 6.7         | P=0.584       |
|               |                 |                  |               |
| MI            | 62 1.6          | > 52 1.4         |               |
+---------------+-----------------+------------------+---------------+
| VTE-T Total   | 16. 1.3         | 1.  0.1          | P=0.00024     |
| CAD           |                 |                  |               |
|               | 3 0.2           | > 0 0            |               |
| MI            |                 |                  |               |
+---------------+-----------------+------------------+---------------+
| VTE-P Total   | 16. 2.6         | 12. 2.0          | P=0.447       |
| CAD           |                 |                  |               |
|               | 10 1.6          | > 3 0.5          | P=0.05131     |
| MI            |                 |                  |               |
+---------------+-----------------+------------------+---------------+
| VTE Total CAD | 32 1.7          | > 13 0.7         | P=0.00411     |
|               |                 | >                |               |
| MI            | 13 0.7          | > 3 0.16         | P=0.01183     |
+---------------+-----------------+------------------+---------------+

VTE=VTE-T + VTE-P

In all study populations except the post ACS, the proportion of patients
with coronary artery disease adverse events was higher in the
ximelagatran groups than in the comparator groups (7.0% and 6.7% for the
AF pool, 1.3% and 0.1% for the VTE-T pool and 2.6% and 2.0% for the
VTE-P pool, for the ximelagatran and comparator groups, respectively).
This trend was consistent across the pools for myocardial infarction;
however, the difference in event rates (%/patient year) was small (0.9%
and 0.6% for the AF pool, 0.6% and 0% for the VTE-T pool and 1.1% and
0.2% for the VTE-P pool, for the ximelagatran and comparator groups,
respectively). Proportion of patients with coronary artery disease
adverse events was statistically significantly higher in the
ximelagatran group (32/1848, 1.7%) than in the warfarin/placebo group
(12/1859, 0.7%) in VTE (VTE-T + VTE-P) population (p=0.00411).
Proportion of patients with MI was also significantly higher in the
ximelagatran group (13/1848, 0.7%) than in the warfarin/placebo group
(3/1859, 0.16%) in VTE population (p=0.01183). There were no appreciable
differences between the treatment groups for underlying diseases
including hypertension, hypercholesterolemia, diabetes mellitus,
coronary atherosclerosis, as well as age, gender and weight. Considering
ximelagatran as an anticoagulant with potential to treat MI, these
results are worrisome.

**2.9 Clinical Laboratory Evaluations**

The analyses of clinical laboratory data in the individual studies in
this application have not identified any adverse findings with the
exception of increases in LFTs.

Microscopic hematuria was more common in the ximelagatran group than in
the placebo group in the post ACS pool; however, in the warfarin
comparison pools there was no difference.

A reduction in triglycerides, cholesterol and LDL was seen in the
ximelagatran group in the AF pool.

**2.10 ECG analysis in patient studies**

There have been no signals of any relevant effect on QT intervals in
patients exposed to ximelagatran (24 mg bid) in studies investigating
prophylactic treatment after hip and knee replacement operations.

ECG measurements were performed in 2 studies carried out on the
prophylactic effect of ximelagatran on postoperative thrombo-embolism in
patients undergoing total hip or total knee replacement. In these
studies (SH-TPO-0005 and SH-TPO-0006, n=2491) ECG was recorded at
baseline and at the time of venography (6-12 days postoperatively).

The most common ECG abnormality on the day of venography was atrial
arrhythmia and the incidence of this abnormality was comparable in the
ximelagatran and enoxaparin groups. No clinically meaningful differences
between treatment groups were observed in changes from baseline in any
of the ECG parameters during this study.

At the time of venography, heart rate and the QTc interval calculated
using Bazett's formula were increased relative to baseline, while the PR
and QT intervals were reduced. There was little change in the QTc
interval when calculated using Fridericia's formula and the study
specific formula. The mean changes in these ECG parameters were small
and comparable in both treatment groups.

The proportion of subjects with a large increase in QTc
([\>]{.underline}60 ms) from baseline to last day on study drug was
numerically lower among subjects receiving ximelagatran (3.1% - 4.0%).

In SH-TPV-0003 ECG recordings were done at the randomization visit
(Visit 2, before first intake of study drug) and the visits at 2 weeks
(Visit 3) and 9 and 18 months (Visit 6 and 9) after randomization. ECGs
from approximately 250 patients were sent for central reading and
evaluation by one cardiologist. The following ECG variables were
measured: RR interval, PQ interval, QRS duration and QT interval. T-wave
abnormalities and U-waves were to be noted.

There were minor changes in the distribution of T-U fusion and U-wave
abnormalities from baseline to last visit on treatment, but to a similar
extent in the ximelagatran and placebo groups. There was no effect of
ximelagatran on QTc time.

**2.11 Safety in Special Groups and Situations**

**2.11.1 Gender, long-term exposure (LTE) pool**

In the ximelagatran treatment group, increased hepatic enzymes were more
commonly reported for women than for men.

In both treatment groups, coronary artery disorders were more commonly
reported for men than for women (female 8.4% vs male 11.4% in the
ximelagatran group and female 7.7% vs male 9.8% in the comparator
group). In general, bleeding events were more frequently reported for
women than men. For example purpura was reported for 10.7% of females vs
6.6% of males in the ximelagatran group and 16.3% of females vs 9.5% of
males in the comparator group.

**2.11.2 Age, long-term exposure (LTE) pool**

To evaluate the frequency of AEs in older vs younger patients, patients
were grouped into 3 age categories: below 65 years, 65 to 74 years and
75 years and above.

Irrespective of treatment group, the overall frequency of reported AEs
was higher amongst the elderly. Patients aged [\>]{.underline}75 years
reported fewer non-fatal SAEs in the ximelagatran treatment group
compared to the comparator group (30.3% vs 36.3%), while more patients
in the ximelagatran treatment group discontinued study treatment due to
AEs in this age group (20.5% vs 16.1%).

In both treatment groups, the overall AE reporting rate was higher with
increasing age, with the exception of elevated hepatic enzymes which was
reported with a similar frequency in all age groups.

**2.11.3 Race, long-term exposure (LTE) pool**

To evaluate the frequency of AEs in different race groups, the patients
were grouped into four categories: Caucasian, Black, Asian and Other.

In the ximelagatran treatment group, less than 10% of the population
were non-Caucasian races. There was no indication of a different AE
profile in these sub-groups.

**2.11.4 Body weight, LTE pool**

To evaluate the frequency of AEs in different body weight groups,
patients were grouped into 3 weight categories: less than 50 kg, 50 to
100 kg and above 100 kg.

The AE profile was similar in all weight categories. Fewer than 2% of
patients in each treatment group weighed less than 50 kg. The AE profile
was not different in this sub-group.

In the ximelagatran treatment group, elevated hepatic enzymes and
bleeding events were less frequently reported in patients above 100 kg.

**2.11.5 Body mass index (BMI), LTE pool**

To evaluate the frequency of AEs in groups with different BMI, patients
were grouped into 3 BMI categories: less than 25, 25 to 30 and above 30.

For patients in the lowest BMI category, the reporting frequency of
non-fatal SAEs was lower in the ximelagatran treatment group (24.8% vs
28.0%). There was a higher frequency of reported AEs leading to drug
discontinuation in the ximelagatran treatment group compared to
comparators group (19.3% vs 14.9%).

In the BMI category 25-30, there was a higher reporting frequency of
drug discontinuations due to AE in the ximelagatran treatment group
compared to comparators treatment group (18.3% vs 13.2%).

For the ximelagatran treatment group in the BMI category \>30, there was
a higher reporting frequency of AEs leading to drug discontinuations
compared to comparators group (13.8% vs 10.7%).

In the ximelagatran treatment group, reporting frequency of elevated
hepatic enzymes and bleeding events increased with decreasing BMI.

**2.11.6 Influence of renal function, LTE pool**

To evaluate if renal function had any influence on the frequency and
pattern of reported AEs, the patients were grouped into 4 categories:
calculated creatinine clearance below 30, between 30 (inclusive) and 50
(non-inclusive), between 50 (inclusive) and 80 (non-inclusive) or above
80 (inclusive).

Apart from elevated hepatic enzymes, no difference was seen in the
overall AE profile between ximelagatran and comparators for any category
of calculated CrCL.

Patients with calculated creatinine clearance below 30 mL/min were to be
excluded from the clinical studies. Although a few patients (\<1%) in
this category were recruited and the pattern of AEs was not different
from that in other CrCL categories. There was a trend towards an
increased frequency of bleeding-related AEs by decreasing calculated
creatinine clearance in both treatment groups.

There was no indication of an increased frequency of elevated hepatic
enzymes reported as AEs in any calculated CrCL group.

**2.11.7 Subjects with renal impairment**

Melagatran, the active metabolite of ximelagatran, is eliminated
primarily via renal excretion. Renal function decreases with age and, as
the target patient population is of older age (median age about 65
years), patients with severe renal impairment (creatinine clearance of
less than 30 mL/min) have been excluded in the patient studies with
melagatran/ximelagatran. Study SH-TP1-0026 was conducted to investigate
the pharmacokinetics of oral ximelagatran and subcutaneous melagatran in
subjects with severe renal impairment (CrCL 10 to 30 mL/min, n=12).
Subjects with normal renal function (CrCL [\>]{.underline}50 mL/min,
n=12) were included as a control group.

As expected, subjects with severe renal impairment had higher plasma
concentrations of melagatran both after subcutaneous administration of
melagatran and oral dosing of ximelagatran. The renally impaired
subjects had about 4 times higher AUC after subcutaneous melagatran and
about 5 times higher AUC after oral ximelagatran, compared to the
control subjects. The mean (SD) half-lives of melagatran were 6.8 (2.0)
h and 9.3 (3.5) h after sc melagatran and oral ximelagatran dosing,
respectively, in the subjects with renal impairment. These half-lives
were about 3-fold higher than for control subjects. The clearance and
the renal clearance of melagatran were lower in the renally impaired
subjects and were linearly correlated to renal function measured with
iohexol clearance (mean (SD) of 12.5 (5.2) mL/min and 86.5 (9.7) mL/min
for subjects with renal impairment and normal controls).

Study SH-TP1-0027 investigated the effect of melagatran given via
dialysate, compared to dalteparin, in 11 uraemic patients (GFR \<8
mL/min). The frequency of clot formation in tubings and in the dialysis
filter, the iohexol clearance and the filter pressure were comparable
between treatments. The half-life of melagatran was longer when
melagatran was administered between dialyses compared to during
hemodialysis. The clearance of melagatran was increased by about 7-fold
and comparable to the iohexol clearance during haemodialysis.

**2.11.8 Subjects with hepatic impairment**

Study SH-TP1-0013 investigated the influence of hepatic impairment on
the absorption, metabolic biotransformation of ximelagatran to the
active form and excretion in subjects with

mild to moderate hepatic impairment (as defined by Child Pugh score).
Age, weight and gender-matched subjects with normal hepatic function
were included as a control group. After adjusting for differences in
creatinine clearance between the 2 groups, the AUC estimates were
comparable. The results support that the absorption of ximelagatran and
the metabolic biotransformation to its active form melagatran are not
influenced for subjects with mild and moderate hepatic impairment.
However, because of liver toxicity risk, patients who have abnormal
liver function or history of liver diseases have been excluded from the
studies.

**2.11.9 Drug/drug interaction**

Concomitant administration of an anticoagulant and an antiplatelet agent
may result in increased bleeding risk, therefore co-administration
should be undertaken with caution.

The AUC and Cmax of melagatran was increased by approximately 82% and
74%, respectively, after co-administration of a single dose of
ximelagatran and multiple doses of erythromycin (500 mg tid) compared
with ximelagatran alone. The mechanism of this interaction is not known.
Therefore, caution should be exercised in patients who have increased
exposure already, such as patients with moderate renal impairment.

There were no P450-mediated interactions with ximelagatran, in vitro.

**2.11.10 Use in pregnancy and lactation**

Three cases, all from the VTE-T and VTE-P pools, of ximelagatran
exposure during pregnancy have been reported from studies in the present
application. In 2 of the ximelagatran cases the pregnancies were
completed and full-term babies were delivered. For one of these (study
SH-TPV-0002 Subject 063-5395), it was estimated that the maximal
exposure to drug could have been 3 weeks from estimated conception. No
complications were present during the pregnancy and a completely healthy
girl was born. In the other case (study SH-TPV-0003, Subject 653-1285)
the maximal exposure to drug was estimated to be up to 2 months from
estimated conception. A full-term baby was delivered after an uneventful
pregnancy. The boy was found to have a hypospadia that needed surgical
correction. Otherwise the baby was healthy.

The third pregnancy reported on ximelagatran, both pregnancies reported
on warfarin and 3 of the pregnancies on placebo were terminated through
elective abortion, none due to medical reasons.

A study, SH-TP1-0029, was performed with the primary objective to assess
the excretion of ximelagatran and its metabolites into breast milk after
administration of ximelagatran (single 36 mg dose) to breast-feeding
women. Ximelagatran and its 2 intermediates were not detectable in
breast milk. Only trace amounts of melagatran (mean 0.00091% of given
dose ximelagatran 36 mg) were excreted into breast milk. The exposure of
melagatran to a breast-fed child is therefore not believed to be of
concern.

**2.11.11 Overdose**

One case of overdose on melagatran/ximelagatran has been reported in the
present program. For a period of 11 days Patient SH-TPV-0002-231-4935,
received oral ximelagatran 144 mg daily by mistake, instead of 72 mg
daily. No adverse effect was reported.

Ximelagatran doses above the recommended regimen may lead to an
increased risk of bleeding. Overdose associated with bleeding
complications should lead to temporary treatment discontinuation. There
is no antidote but ximelagatran is mainly renally excreted with a short
half life. Therefore, satisfactory diuresis should be maintained.
Melagatran is efficiently eliminated by dialysis. Plasma and blood
products can be administered as needed in case of bleeding.

**2.11.12 Drug abuse**

Based on its pharmacological properties, ximelagatran is not likely to
have a potential for drug abuse. No findings during the clinical study
program indicate that ximelagatran induces drug abuse.

**2.11.13 Withdrawal and rebound**

In Study SH-TPA-0003 (AF population), 11 patients had a stroke after
stopping ximelagatran. Of these 11 patients, 2 had primary events within
30 days of stopping study drug; one was being treated with aspirin and
LMWH (nadroparin), the other was being treated with clopidogrel. The
remaining 9 patients had primary events more than 30 days after stopping
drug. The treatments taken by these 9 patients after stopping study drug
were: Vitamin K antagonists (3 patients), aspirin (2), clopidogrel (2),
LMWH (1) and no treatment (1). There is therefore no indication of a
rebound effect in this study.

A follow-up visit was performed in study SH-TPV-0002/5 (VTE-T
population) at approximately 2 weeks after completing the randomized
treatment period to allow for the observation of any rapid rebound
effect. No patient in the ximelagatran treatment group experienced VTE
events during the 2-week follow-up period.

For post ACS pool, the total frequency of AMIs after stopping treatment
was similar for ximelagatran (1.5%) and placebo (1.4%), and the total
mortality was similar between the treatments. However, after stopping
treatment fatal AMIs occurred more frequently in the ximelagatran group
(0.4%) than the comparator group (0.2%). In the post ACS pool, there was
an increased proportion of fatal myocardial infarctions in the
post-treatment period (1.1% vs 0.5%).

**3 Safety update**

The sponsor submitted a 4-months safety update report on April 23, 2004.
This safety update report included safety information between 27 June
2003 and 23 March 2004. Safety information included in this report
consists of new and follow-up data from recent Phase I studies and
studies in patients. No other safety data are available, as ximelagatran
has not been marketed in any country as of 23 March 2004.

A summary of new safety data associated with the SH-TPA-0004 (SPORTIF
IV) study is included in this section. SH-TPA-0004 (SPORTIF IV) is an
ongoing, open-label, 5-year (recently amended to 10-year) continuation
study of the dose guiding study SH-TPA-0002 (SPORTIF II) in patients
with AF. The 187 patients in the ximelagatran group received 20, 40, or
60 mg (double-blind, SPORTIF II) for 12 weeks. Those patients (n=125)
who continued into the long term study (SPORTIF IV) transferred to a 36
mg bid dose. The warfarin group (67 patients) in SH-TPA-0002 received
open-label warfarin (INR 2-3) and continued into SH-TPA-0004 without
change. The primary objective of SH-TPA-0004 is to evaluate the safety
and tolerability of long-term treatment with fixed oral dose
ximelagatran compared to warfarin.

There were 17 deaths (9.1%) by March 23, 2004 in the ximelagatran group
and 4 deaths (6.0%) in the warfarin group. The breakdown of these
numbers is presented in Table 41.

**Table 41 Total Deaths in Long Term Studies SH-TPA-0002 and
SH-TPA-0004**

![](media/image41.png){width="5.950694444444444in"
height="1.3833333333333333in"}

Although proportion of total deaths was not statistically significantly
higher in the ximelagatran group (17/187, 9.1%) than in the warfarin
group (4/67, 6.0%) (p=0.426), there were numerically more deaths in the
ximelagatran group than in the warfarin group. The reasons for the 5
deaths during this safety update period are listed below.

![](media/image42.png){width="5.7340277777777775in" height="1.825in"}

For detailed evaluation for this study report, please see Medical
Officer's Review dated July 22, 2004 by Dr. Mehul Desai from the
Division of Cardio-renal Drug products.

### 

### D. Adequacy of Safety Testing

Safety testing regarding liver toxicity in patients taking Exanta
[\<]{.underline} 35 days is not adequate. In both study EXULT A and
EXULT B, the patients were only followed up for 4 weeks after operation.

Based on the long-term clinical data, liver enzymes elevations in
patients who taken Exanta were found typically between 2^nd^ month and
6^th^ month after initiation of Exanta. Liver toxicity was not seen
typically during first 4 weeks, even in the patients who had severe
liver failure and died from liver failure. Therefore, it is inadequate
to monitor liver toxicity for only 4-6 weeks. Clinical data with 6 month
follow-up may be needed for adequately assessing liver toxicity
following short term use of Exanta.

### E. Summary of Critical Safety Findings and Limitations of Data 

Safety testing regarding liver toxicity in patients taking Exanta
[\<]{.underline} 35 days is not adequate. In both study EXULT A and
EXULT B, the patients were only followed up for 4 weeks after operation.
Clinical data with 6 month follow-up are needed to assess liver toxicity
following short term use of Exanta.

In patients receiving long-term administration of ximelagatran (\>35
days) an increase in

ALAT \>3xULN occurred in 6-13% (total: 531/6948, 7.6%) compared to 0-2%
(total: 68/6230, 1.1%) of patients receiving comparator treatments. ASAT
increased in conjunction with ALAT. The time pattern of ALAT elevations
was consistent and typically occurred between 1 and 6 months after the
initiation of ximelagatran.

ALAT \>3xULN was associated with bilirubin \>2xULN (within one month
following the rise in

ALAT) in 0.53% (37/6948) of all patients who were exposed to
ximelagatran \>35 days as compared to 0.08% (5/6230) of patients exposed
to comparators (including 10 ximelagatran, 1 comparator by local
laboratory measurement). A total of 14 ximelagatran-treated patients
(14/37, 35.1%) have no alternative explanation for concomitant ALAT and
bilirubin elevation. Nine ximelagatran-treated patients with concomitant
ALAT \>3xULN and bilirubin \>2xULN died (24.3%, 9/37). Among these, 3
died from heart failure; 3 died from carcinomas with hepatic matastases;
2 (ID# 7259, and 7859) died from GI bleeding and 1 (ID# 5442) died from
hepatitis B. One patient developed biopsy documented hepatic necrosis
with coagulopathy with a fatal outcome from a duodenal ulcer (#7259).
Liver failure/toxicity due to ximelagatran might have caused or at least
contributed to these deaths.

The proportion of patients with coronary artery disease adverse events
(MI or ischemia/angina) was significantly higher in the ximelagatran
groups than in the warfarin/placebo groups for both short-term (7-12
days) and long-term (\>35 days) use. In the patients undergoing TKR
surgery (Exult A and Exult B), proportion of patients with coronary
artery disease adverse events was statistically significantly higher in
the ximelagatran group (20/2677, 0.75%) than in the warfarin group
(5/1907, 0.26%) (p=0.02800). Proportion of patients with MI was also
higher in the ximelagatran group (16/2677, 0.60%) than in the warfarin
group (4/1907, 0.21%) in TKR population (p=0.07308). There were no
appreciable differences between the treatment groups for underline
diseases including hypertension, hypercholesterolemia, diabetes
mellitus, coronary atherosclerosis, as well as age, gender and weight.

The proportion of patients with coronary artery disease adverse events
was statistically significantly higher in the ximelagatran group
(32/1848, 1.7%) than in the warfarin/placebo group (12/1859, 0.7%) in
the VTE (VTE-T + VTE-P) population (p=0.00411). The proportion of
patients with MI was also significantly higher in the ximelagatran group
(13/1848, 0.7%) than in the warfarin/placebo group (3/1859, 0.16%) in
the VTE population (p=0.01183). In all study populations except the post
ACS, the proportion of patients with coronary artery disease adverse
events was higher in the ximelagatran groups than in the comparator
groups (7.0% and 6.7% for the AF pool, 1.3% and 0.1% for the VTE-T pool
and 2.6% and 2.0% for the VTE-P pool, for the ximelagatran and
comparator groups, respectively). This trend was consistent across the
pools for myocardial infarction.

## VIII. Dosing, Regimen, and Administration Issues

EXANTA should be taken twice daily, with or without food. Patients
should be advised that if they miss their scheduled dose they should not
double the next dose.

Following are dosage regimens supported by the submitted studies:

**Knee Replacement Surgery**

The treatment is initiated with EXANTA at a dose of 36 mg twice-daily
for a treatment period of 7 to 12 days. Provided hemostasis has been
established, the first dose should be given the morning after surgery,
but no sooner than 12 hours from the time of surgery.

**Long Term Secondary Prevention of Venous Thromboembolic Events**

Patients who have received standard anticoagulant treatment for DVT or
PE are to be treated with EXANTA 24 mg twice-daily.

**Patients with Renal Impairment:** No dosage adjustment is necessary
with EXANTA in patients with a creatinine clearance [\>]{.underline}30
mL/min. Usage of EXANTA in patients with severe (CrCL \<30 mL/min) renal
impairment is not recommended.

**Patients with Hepatic Impairment:** The use of EXANTA in patients with
hepatic disease and/or ALT \>2 times the upper limit of normal at the
start of therapy is contraindicated.

## IX. Use in Special Populations

### A. Evaluation of Sponsor's Gender and Age Effects Analyses and Adequacy of Investigation

In study EXULT A and B for prevention of DVT in patients undergoing
elective knee replacement surgery, the incidence of VTE and/or all-cause
mortality was higher in females and older patients and summarized in
table below.

**Table 42 Incidence of total VTE and/or all-cause mortality for
selected subgroups (efficacy ITT population; blinded ICAC assessment) --
Pooled 36 mg bid**

![](media/image43.png){width="5.317361111111111in"
height="2.3333333333333335in"}

Female sex, older age, and a prior history of VTE are known risk factors
for VTE. The reasons for the increased incidence of total VTE and/or
all-cause mortality in females versus males are unclear. The incidence
of proximal DVT, PE, and/or all-cause mortality was also examined as a
function of these same pre-specified subgroups. The results for the
subgroup comparisons were in agreement with those for total VTE and/or
all-cause mortality; however, there were too few events to perform a
logistic regression analysis involving proximal DVT, PE, and/or
all-cause mortality.

An evaluation of potential risk factors for increase in ALAT indicated
an increased risk in female patients (p=0.0002) patients with low BMI
(\<27 kg/m2) (p\<0.0001) and patients receiving concomitant treatment
with statins (p=0.019).

### B. Evaluation of Evidence for Race, or Ethnicity Effects on Safety or Efficacy

The subgroup factors that had no significant impact on the incidence of
total VTE and/or all cause mortality in patients undergoing elective
knee replacement surgery were: race, body mass index, estimated CrCL,
general anaesthesia (yes/no), time to first dose, and time to
ambulation.

An evaluation of potential risk factors for increase in ALAT indicated
an increased risk in the

Post ACS (p=0.0009), and VTE-T (p=0.0003) populations and also in female
patients (p=0.0002) patients with low BMI (\<27 kg/m2) (p\<0.0001) and
patients receiving concomitant treatment with statins (p=0.019); Asian
patients were found to have a decreased risk (p=0.0038).

### C. Evaluation of Pediatric Program

There are no pediatric data in this submission. AstraZeneca requests
that the requirements to conduct pediatric studies as per the Pediatric
Research Equity Act be waived for the indications claimed in this
application.

It is unlikely that a substantial number of pediatric patients will be
treated with EXANTA for the claimed indications. The estimated number of
pediatric patients diagnosed with atrial fibrillation in the US in 2002
is less than 1,500 children (Mattson Jack Group). The estimated total
number of pediatric patients treated for venous thromboembolism (of
which prevention of recurrent events, the indication claimed in this
application, is a subset of patients) in the US in 2002 is less than
3,000 children (Solucient). The estimated cumulative number of pediatric
patients diagnosed with conditions for which EXANTA will be indicated is
less than 5,000 children. Therefore, the number of pediatric patients
likely to be treated with EXANTA for the claimed indications is well
below the number defined as a substantial number in the Pediatric Final
Rule. Therefore, I recommend that request for waiver of pediatric study
for the indications claimed in this application be granted.

### D. Comments on Data Available or Needed in Other Populations

The sponsor has adequately conducted studies to assess the influence of
renal function, subjects with renal impairment. There are no adequate
data to assess the safety in pregnant women. Ximelagatran is
contraindicated for patients with liver impairment, because of high risk
of liver toxicity. Some findings are summarized below.

**Influence of renal function**

Apart from raised hepatic enzymes, no difference was seen in the overall
AE profile between ximelagatran and comparators for any category of
calculated CrCL.

Patients with calculated creatinine clearance below 30 mL/min were to be
excluded from the clinical studies. Nevertheless, a few patients (\<1%)
in this category were recruited and the pattern of AEs was not different
from that in other CrCL categories. There was a trend towards an
increased frequency of bleeding-related AEs by decreasing calculated
creatinine clearance in both treatment groups.

Melagatran, the active metabolite of ximelagatran, is eliminated
primarily via renal excretion. Renal function decreases with age and, as
the target patient population is of older age (median age about 65
years), patients with severe renal impairment (creatinine clearance of
less than 30 mL/min) have been excluded in the patient studies with
melagatran/ximelagatran. Study SH-TP1-0026 was conducted to investigate
the pharmacokinetics of oral ximelagatran and subcutaneous melagatran in
subjects with severe renal impairment (CrCL 10 to 30 mL/min, n=12).
Subjects with normal renal function (CrCL [\>]{.underline}50 mL/min,
n=12) were included as a control group.

As expected, subjects with severe renal impairment had higher plasma
concentrations of melagatran both after subcutaneous administration of
melagatran and oral dosing of ximelagatran. The renally impaired
subjects had about 4 times higher AUC after subcutaneous melagatran and
about 5 times higher AUC after oral ximelagatran, compared to the
control subjects. The mean (SD) half-lives of melagatran were 6.8 (2.0)
h and 9.3 (3.5) h after sc melagatran and oral ximelagatran dosing,
respectively, in the subjects with renal impairment. These half-lives
were about 3-fold higher than for control subjects. The clearance and
the renal clearance of melagatran were lower in the renally impaired
subjects and were linearly correlated to renal function measured with
iohexol clearance (mean (SD) of 12.5 (5.2) mL/min and 86.5 (9.7) mL/min
for subjects with renal impairment and normal controls).

Study SH-TP1-0027 investigated the effect of melagatran given via
dialysate, compared to dalteparin, in 11 uraemic patients (GFR \<8
mL/min). The frequency of clot formation in tubings and in the dialysis
filter, the iohexol clearance and the filter pressure were comparable
between treatments. The half-life of melagatran was longer when
melagatran was administered between dialyses compared to during
hemodialysis. The clearance of melagatran was increased by about 7-fold
and comparable to the iohexol clearance during haemodialysis.

**Safety in pregnancy**

Three cases, all from the VTE-T and VTE-P pools, of ximelagatran
exposure during pregnancy have been reported from studies in the present
application. In 2 of the ximelagatran cases the pregnancies were
completed and full-term babies were delivered. For one of these (study
SH-TPV-0002 Subject 063-5395), it was estimated that the maximal
exposure to drug could have been 3 weeks from estimated conception. No
complications were present during the pregnancy and a completely healthy
girl was born. In the other case (study SH-TPV-0003, Subject 653-1285)
the maximal exposure to drug was estimated to be up to 2 months from
estimated conception. A full-term baby was delivered after an uneventful
pregnancy. The boy was found to have a hypospadia that needed surgical
correction. Otherwise the baby was healthy.

The third pregnancy reported on ximelagatran, both pregnancies reported
on warfarin and 3 of the pregnancies on placebo were terminated through
elective abortion, none due to medical reasons.

Ximelagatran and its 2 intermediates were not detectable in breast milk.
Only trace amounts of melagatran (mean 0.00091% of given dose
ximelagatran 36 mg) were excreted into breast milk. The exposure of
melagatran to a breast-fed child is therefore not believed to be of
concern.

## XI. Appendix

### Other Relevant Materials \-\-- List of abbreviations

> **ABBREVIATIONS AND CONVENTIONS**
>
> **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**
>
> **Term Abbreviation**
>
> **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**
>
> **ACS Acute coronary syndrome**
>
> **ACT Activated coagulation time**
>
> **AE Adverse event**
>
> **AF Nonvalvular atrial fibrillation**
>
> **ALAT (ALT) alanine aminotransferase**
>
> **ALP Alkaline phosphatase**
>
> **AMI Acute myocardial infarction**
>
> **APTT Activated partial thromboplastin time**
>
> **ASA Acetylsalicylic acid**
>
> **ASAT (AST) aspartate aminotransferase**
>
> **AUC Area under the curve**
>
> **bid Twice daily**
>
> **BMI Body mass index**
>
> **CBT Capillary bleeding time**
>
> **CCK Cholecystokinin**
>
> **CEAC Clinical event adjudication committee**
>
> **CFR Code of Federal Regulations**
>
> **CI Confidence interval**
>
> **Cmax Maximum plasma concentration**
>
> **CrCL Estimated creatinine clearance**
>
> **CSR Clinical study report**
>
> **CT Computerized tomography**

### CV Coefficient of variation 

> **CYP Cytochrome P450**
>
> **DAE Discontinuation of study drug due to an adverse event**
>
> **DTI Direct thrombin inhibitor**
>
> **DVT Deep vein thrombosis**
>
> **ECG Electrocardiogram**
>
> **EU European Union**
>
> **EXULT EXanta Used to Lessen Thrombosis**
>
> **EXULT A SH-TPO-0010 (290A)**
>
> **EXULT B SH-TPO-0012 (290B)**
>
> **GCP Good Clinical Practice**
>
> **H 319/68 Melagatran**
>
> **H 376/95 Ximelagatran**
>
> **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**
>
> **Term Abbreviation**
>
> **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**
>
> **ICAC Independent central adjudication committee**
>
> **ICH International Conference on Harmonization**
>
> **INR International normalized ratio (prothrombin time)**
>
> **ITT Intention-to-treat**
>
> **LMWH Low molecular weight heparin**
>
> **LFT Liver function test**
>
> **LTE Long-term exposure pool**
>
> **MAA Marketing Authorization Application**
>
> **NNT Number needed to treat**
>
> **NOS Non-specific**
>
> **NSAID Nonsteroidal anti-inflammatory drug**
>
> **OS Orthopedic surgery**
>
> **OT On-treatment**
>
> **PD Pharmacodynamics**
>
> **PE Pulmonary embolism**
>
> **PK Pharmacokinetics**
>
> **PT Prothrombin time**
>
> **SAE Serious adverse event**
>
> **sc Subcutaneous**
>
> **SEE Systemic embolic event**
>
> **SPORTIF Stroke Prevention using an ORal Thrombin Inhibitor in atrial
> Fibrillation**
>
> **SPORTIF II SH-TPA-0002**
>
> **SPORTIF III SH-TPA-0003**
>
> **SPORTIF IV SH-TPA-0004**
>
> **SPORTIF V SH-TPA-0005**
>
> **TIA Transient ischemic attack**
>
> **THRIVE THRombin Inhibitor in Venous thromboEmbolism**

**THRIVE III SH-TPV-0003**

> **THR Total hip replacement**
>
> **TKR Total knee replacement**
>
> **tmax Time to reach maximum plasma concentration**
>
> **UFH Unfractionated heparin**
>
> **ULN Upper limit of normal**
>
> **VKA Vitamin K antagonist**
>
> **VTE Venous thromboembolism (includes both distal and proximal deep
> vein thrombosis, plus pulmonary embolism)**

##### VTE-P Long-term secondary prevention after treatment of VTE

> **VTE-T Treatment of VTE**

### B. Individual More Detailed Study Reviews 

**1 STUDY SH-TPO-0010 (EXULT A)**

Exult A was studied between May 2001 and April 2002. Title of the
protocol was "Optimization of Dose of H 376/95 (Oral Direct Thrombin
Inhibitor) Compared to Warfarin (COUMADIN) for the Prevention of Venous
Thromboembolism Following Total Knee Arthroplasty.

**1.1 Objectives:**

The primary objective was to determine the more effective dose of oral
ximelagatran using 2 doses (24 and 36 mg) compared with warfarin for the
prevention of total VTE and/or all-cause mortality in TKR patients after
unilateral or bilateral TKR.

Secondary objectives were to compare ximelagatran with warfarin for the
incidence of proximal DVT and/or PE and/or all-cause mortality, and
total VTE and/or all-cause mortality according to on-site evaluations,
and to compare the incidence of bleeding between treatments.

Efficacy was assessed by the number of patients with confirmed distal
and/or proximal DVT and/or symptomatic PE and/or all-cause mortality
during the treatment period and safety was assessed by standard means
with a focus on bleeding complications.

**1.2 Design:**

A randomized, double-blind, double-dummy, parallel-group multicentre
study designed to determine the more effective dose of oral ximelagatran
at 24 and 36 mg bid begun at least 12 hours after surgery versus oral
warfarin begun the evening of surgery and titrated to a target INR of
2.5 (INR range 1.8 to 3.0) in preventing VTE in patients undergoing TKR.
Treatment duration was 7 to 12 days, with follow-up at 4 to 6 weeks
after surgery.

![](media/image44.png){width="3.775in"
height="1.7916666666666667in"}**1.3 Selection of study population**

**Inclusion criteria**

For inclusion in the study, patients had to fulfill all of the following
criteria:

1\. Be scheduled for elective primary unilateral or bilateral TKR

2\. Be at least 18 years old

3\. Weigh between 88 lbs (40 kg) and 300 lbs (136 kg)

4\. Be a male, or a female that is using a reliable form of
contraception.

5\. Provide written informed consent

**Exclusion criteria**

Any of the following was regarded as a criterion for exclusion from the
study:

1\. Be scheduled for hemiarthroplasty or surface repair or revisionary
surgery

2\. Have had a traumatic epidural/spinal puncture for this surgery (\> 3
attempts or gross bleeding)

3\. Have any condition resulting in immobilization for [\>]{.underline}
3 days

4\. Have treatment with anticoagulant or antiplatelet drugs within 7
days prior to surgery. Aspirin

up to 500 mg daily and non-steroidal anti-inflammatory drugs (NSAIDs)
were allowed.

5\. Have a known disorder associated with an increased risk of bleeding

6\. Have had an ischemic stroke or myocardial infarction within the 30
days prior to surgery

7\. Have had any major surgical procedure within 30 days prior to
surgery

8\. Have significant renal impairment (an estimated creatinine clearance
or CrCL \<30 mL/min)

9\. Have abused drugs and/or alcohol within the last 6 months

10\. Have malignancy currently under active cytotoxic treatment, or
being the reason for joint

replacement surgery

11\. Have a known clinically significant liver disorder, or aspartate
aminotransferase (ASAT)

and/or alanine aminotransferase (ALAT) above 2 times the upper limit of
normal (ULN)

12\. Have thrombocytopenia (platelet count \<100 x 10^9^ /L)

13\. Have a known allergy to contrast media or iodine

14\. Have any condition that would preclude venography

15\. Have been previously randomized into this study or any other study
of melagatran

or ximelagatran

16\. Be mentally or legally incapacitated

17\. Have any condition that may interfere with full participation in
the study or produce a

significant risk to the patient

18\. Have received any investigational agent (drug or device) for any
therapeutic reason

19\. Have planned use of intermittent pneumatic compression or foot pump
device.

20\. Have a contraindication to warfarin

**1.4 Doses and treatment regimens**

Patients were randomized to 1 of 3 treatment groups:

\(1\) ximelagatran 24 mg tablet with a 36 mg placebo tablet given twice
a day in the morning and evening with doses taken at intervals as close
to 12 hours as possible and placebo capsule(s) matching warfarin given
in the evening, **or**

\(2\) ximelagatran 36 mg tablet with a 24 mg placebo tablet given twice
a day in the morning and evening with doses taken at intervals as close
to 12 hours as possible and placebo capsule(s) matching warfarin given
in the evening, **or**

\(3\) warfarin 2.5 mg capsule(s) given once a day in the evening and
titrated to a target INR of 2.5 (range 1.8 to 3.0) and two placebo
tablets matching ximelagatran 24 mg and 36 mg given twice a day in the
morning and evening,

Patients were permitted to take study medication with or without meals.
The first dose of warfarin or placebo was to be administered in the
evening of the day of surgery. The first dose of ximelagatran 24 mg or
placebo and ximelagatran 36 mg or placebo was to be administered the
morning after surgery (no sooner than 12 hours postoperatively). If
adequate hemostasis was not achieved at the scheduled start times or if
the patient was unable to take oral medication, study therapy was to
begin as soon as adequate hemostasis had been achieved or oral intake
was possible. All anticoagulant or antiplatelet medications, except for
aspirin ‹500 mg/day and short-acting NSAIDs were discontinued at least 7
days prior to surgery.

**1.5 Efficacy variable**

**Primary variable**

The primary efficacy variable in this study was the number of patients
with VTE (objectively confirmed DVT and/or PE) and/or all-cause
mortality.

**Secondary variables**

The secondary efficacy variables in this study include incidence of
proximal VTE (venographic assessment of the proximal veins +
symptomatic, objectively confirmed proximal DVT and/or symptomatic PE,
with objective site evaluations, during the treatment period) and/or
all-cause mortality during the treatment period (ITT population), and
incidence of total venous thromboembolism and/or all-cause mortality
(local\
assessment).

**1.6 Statistical Analyses of efficacy variables**

All efficacy parameters were evaluated using centrally adjudicated
events and presented for the efficacy ITT population. The primary
analysis was also presented for patients without any major protocol
violations (per-protocol population).

To address the primary objective of this study, the ximelagatran 36 mg
treatment group was compared to the warfarin treatment group. As part of
this comparison, the incidence of VTE was estimated for each treatment
group by the type of surgery performed (unilateral/bilateral) using the
observed proportions with 95% confidence interval (CI). An estimate of
the between-treatment group difference was also provided with 95% CI.
Treatment differences were tested using the CMH chi-square test,
stratified by type of surgery. If this comparison was statistically
significant (p\<0.05), then the ximelagatran 24 mg treatment group was
to be compared to the warfarin-treatment group, also at a significance
level of 0.05. If the initial comparison of ximelagatran 36 mg and
warfarin was not statistically significant (p\>0.05), then no further
statistical testing was performed. For a complete assessment of efficacy
results, the ximelagatran 24 mg and 36 mg treatment groups were also
compared. All secondary objectives were assessed at a significance level
of 0.05.

**1.7 Protocol deviations**

The numbers of patients with protocol deviations that resulted in data
being excluded from analyses are summarized by treatment group in Table
A1.

Table A1: Number (%) of patients with major protocol deviations
(randomized population)

![](media/image45.png){width="4.784027777777778in" height="3.775in"}

Number (%) of patients with major protocol deviations is similar between
the treatment groups.

**1.8 Disposition**

Of 2656 patients enrolled in 116 centers, 2301 were randomized to
receive double-blind treatment with ximelagatran 24 mg (n=762),
ximelagatran 36 mg (n=775), or warfarin (n=764) at 114 centers located
throughout the United States, Canada, Israel, Mexico, and Brazil.

Sixteen randomized patients were excluded from the safety analysis
population because they did not receive study drug; 5 patients were
excluded from the ximelagatran 24 mg treatment group, 6 from the
ximelagatran 36 mg treatment group, and 5 from the warfarin treatment
group.

Approximately 92% of patients from each treatment group completed the
study. The proportion of early discontinuations from treatment for any
reason were not appreciably different among treatment groups; 5.4% (41)
patients discontinued from treatment with ximelagatran 24 mg, 6.8% (53)
patients from ximelagatran 36 mg, and 5.6% (43) patients

from warfarin. More patients discontinued treatment because of adverse
events in ximelagatran groups (23 patients in each group, 3%) than
warfarin group (13 patients, 1.7%).

**1.9 Demographic and other patient characteristics**

The demographic characteristics of study patients are summarized in
Table A2.

**Table A2: Summary of demographic characteristics of study patients**

![](media/image46.png){width="4.759027777777778in"
height="4.700694444444444in"}

![](media/image47.png){width="4.934027777777778in" height="3.8in"}

Of the 2285 patients included in the safety population, slightly more
than 60% were female in each treatment group (from 60.5% to 64.0%), 96%
of all patients were Caucasian in each treatment group. At baseline,
approximately 60% of patients were non-smokers in each treatment group
and slightly more than 60% of patients did not consume alcohol in each
treatment group (from 62.0% to 65.5%).

The mean age of patients in each treatment group was approximately 68
years and

approximately 56% were 70 years of age or younger in each treatment
group. Approximately 56% of patients had a maximum body weight of 85 kg
and approximately 52% had a maximum body mass index of 30 kg/m^2^. The
reasons for total knee replacement surgery are summarized in Table A3.

# Table A3: Summary of the reasons for knee surgery

![](media/image48.png){width="4.709027777777778in" height="1.525in"}

### 

Over 95% of patients in each treatment group had unilateral knee
surgery, predominately from a medial parapatellar approach (more than
88% in each treatment group). A total of 15% of patients (278 patients
out of a total 1851) underwent epidural catheter placement and
approximately one-third of this number (96 patients out of the total
278) had a catheter in place for more than 12 hours. No epidural
bleeding was reported. Prostheses were cemented in place in
approximately 90% of the patients in each treatment group and tibial
osteotomies were seldom performed. Mean tourniquet use approximated 75
minutes in each treatment group; mean operating times were approximately
95 minutes.

### 

In each treatment group, the mean time to the first dose of study drug
was approximately

20 hours, the mean time to ambulation was 1.6 days, and the mean
hospital stay was approximately 6 days. Approximately 60% of patients in
each treatment group were ambulatory within 1 day, and the majority of
patients in each treatment group were fully weight-bearing when
discharged from the hospital. Approximately 40% of patients in each
treatment group had maximum hospital stays of 4 days. More than 60% of
patients in each treatment group used passive embolism stockings
following surgery. More than 95% of patients in each treatment group
were discharged following surgery to their home (from 57.4% to 59.3%) or
to a rehabilitation center (from 36.6% to 38.2%).

**1.10 Efficacy Results**

### 

**1.10.1 Primary variable: Incidence of total venous thromboembolism
and/or all-cause mortality**

The frequency of total VTE and/or all-cause mortality among patients
undergoing knee replacement was 24.9% for patients randomized to
ximelagatran 24 mg, 20.3% for patients randomized to ximelagatran 36 mg,
and 27.6% for patients randomized to warfarin (see Table below).

**Table A4:** **Frequency of total VTE and/or all-cause mortality
(efficacy intention-to-**

**treat population)**

![](media/image49.png){width="5.950694444444444in" height="2.2in"}

Ximelagatran 36 mg was superior compared to warfarin (p=0.003) in
reducing total VTE and/or all-cause mortality among patients with TKR
according to blinded ICAC assessment. The reduction in the frequency of
total VTE and/or all-cause mortality in patients randomized to
ximelagatran 36 mg was 7.3% relative to patients randomized to warfarin
(p=0.003). The corresponding absolute reduction for patients in the
ximelagatran 24 mg treatment group was 2.7% (p=0.282).

According to blinded ICAC assessment, the absolute reduction in the
frequency of total VTE and/or all-cause mortality was 7.3% with
ximelagatran 36 mg compared to warfarin (27.6% warfarin vs 20.3%
ximelagatran 36 mg), providing a relative risk reduction of 26.4% and
the number needed to treat (1/ARR) was 14 (95% CI 8-39). In those
patients who received oral 24 mg ximelagatran twice daily, the rate of
total VTE and/or all-cause mortality was 24.9%; the relative risk
reduction was 9.8% and the absolute risk reduction was 2.7%. However,
the difference between the rate of 24.9% (ximelagatran 24 mg) and the
warfarin rate of 27.6% was not significant.

For patients with unilateral TKR, the reduction in total VTE and/or
all-cause mortality was 2.2% in the ximelagatran 24 mg treatment group
and 7.1% in the ximelagatran 36 mg treatment group relative to warfarin.
Corresponding reductions in total VTE and/or all-cause mortality for
patients with bilateral TKR were 15.7% and 12.6%, respectively. As
approximately 96% of patients in each treatment group had unilateral
surgery, the reductions in total VTE and/or all-cause mortality for the
combined surgeries approximate the reductions for patients with
unilateral surgery.

The reduction in the frequency of total VTE and/or all-cause mortality
among patients randomized to ximelagatran 36 mg was 4.6% relative to
patients randomized to ximelagatran 24 mg, but this difference was not
statistically significant (p=0.055).

**1.10.2 Secondary variables**

**Incidence of proximal deep vein thrombosis, pulmonary embolism, and/or
all-cause mortality (blinded ICAC assessment)**

The frequency of proximal DVT, PE, and/or all-cause mortality among
patients undergoing total knee replacement was 2.5% for patients
randomized to ximelagatran 24 mg, 2.7% for patients randomized to
ximelagatran 36 mg, and 4.1% for patients randomized to warfarin (Table
A5).

**Table A5 Frequency of proximal DVT, PE, and/or all-cause mortality
(efficacy intention-**

**to-treat population; blinded ICAC assessment)**

![](media/image50.png){width="4.934027777777778in"
height="1.7166666666666666in"}

Reductions in the frequency of proximal DVT, PE, and/or all-cause
mortality was

1.4% for patients randomized to ximelagatran 36 mg relative to patients
randomized to

warfarin (p=0.171) and 1.7% for patients randomized to ximelagatran 24
mg (p=0.104). There was no statistically significant difference between
the treatment groups for the frequency of composite endpoint of proximal
DVT, PE, and/or all-cause mortality that is a clinically meaningful
endpoint.

**Incidence of total venous thromboembolism and/or all-cause mortality
(local**

**assessment)**

The frequency of total VTE and/or all-cause mortality assessed locally
at study centers was approximately 10% higher than assessed centrally by
the ICAC. The locally assessed

frequency of total VTE and/or all-cause mortality among patients
undergoing knee

replacement was 33.4% for patients randomized to ximelagatran 24 mg,
29.6% for patients randomized to ximelagatran 36 mg, and 37.7% for
patients randomized to warfarin (Table A6).

**Table A6 Frequency of total VTE and/or all-cause mortality according
to local assessments**

**(safety population with evaluable local assessments)**

![](media/image51.png){width="5.0256944444444445in" height="1.95in"}

Corresponding frequencies according to central assessment were 24.9%,
20.3% and 27.6%. Ximelagatran 36 mg was superior to warfarin in reducing
total VTE and/or all-cause mortality among patients with TKR according
to local assessments. The absolute reduction in the frequency of total
VTE and/or all-cause mortality in patients randomized to ximelagatran 36
mg was 8.2% relative to patients randomized to warfarin (p=0.002)
according to local assessments versus 7.3% according to central
assessments. Corresponding reductions for patients in the ximelagatran
24 mg treatment group were 4.3% (p=0.108) according to local assessments
versus 2.7% according to central assessments.

### 

The reduction in the locally assessed frequency of total VTE and/or
all-cause mortality among patients randomized to ximelagatran 36 mg was
3.9% relative to patients randomized to ximelagatran 24 mg, according to
local assessments, but this difference was not statistically significant
(p=0.138).

Although the rates of total VTE and/or all-cause mortality assessed by
local study centers tended to be greater than those assessed centrally,
analyses based on the local assessments were consistent with central
assessments.

**Symptomatic and asymptomatic thromboembolic events**

There were 34 symptomatic thromboembolic events over the entire study
period, 10 (1.6%) in the ximelagatran 24 mg treatment group, 13 (2.1%)
in the ximelagatran 36 mg treatment group, and 11 (1.8%) in the warfarin
treatment group (Table A7).

# Table A7 Symptomatic and asymptomatic thromboembolic events over the entire

**study (efficacy intention-to-treat population)**

![](media/image52.png){width="4.967361111111111in"
height="2.7916666666666665in"}

There were no appreciable differences among treatment groups in the
incidences of syptomatic DVT, PE, or death. The main difference between
the treatment groups is the incidence of asyptomatic distal DVT which is
not clinically meaningful.

**1.10.3 Subgroup analyses**

The frequency of total VTE and/or all-cause mortality was examined by
subgroup factors

relating to prespecified demographic and other patient characteristics.
The results of the subgroup analysis were consistent with the overall
pattern of results seen for all patients, with the incidence of total
VTE and/or all-cause mortality consistently lower in the ximelagatran 36
mg group and comparable to or slightly lower in the ximelagatran 24 mg
group, in comparison to the warfarin group, for a majority of subgroups
examined.

**Table A8 Frequency of total VTE and/or all-cause mortality by selected
subgroup (efficacy**

**intention-to-treat population; blinded ICAC assessment)**

![](media/image53.png){width="4.967361111111111in"
height="4.675694444444445in"}

Results of the logistic regression analysis showed that the majority of
subgroups factors analyzed had no significant impact on the incidence of
total VTE and/or all-cause mortality. However, female patients, older
patients and patients enrolled at sites in Canada were associated with
higher rates of VTE (p = 0.043, 0.009 and \< 0.001, respectively). The
interaction of each subgroup factor with treatment was also analyzed and
indicated no statistically significant interactions between treatment
and any examined subgroup (p [\>]{.underline} 0.1).

### 

**1.10.4 INR in the warfarin treatment arm**

At the time of venography, only 58.3% of patients in the warfarin
treatment group had INR values within the therapeutic range of 1.8 to
3.0 (Table A9).

### 

Table A9 Proportion of patients in the warfarin treatment group with INR
within the

therapeutic range (efficacy intention-to-treat population)

### 

![](media/image54.png){width="5.000694444444444in"
height="1.9583333333333333in"}

There was no appreciable difference in mean INR between patients with
confirmed VTE and with no confirmed VTE at the postoperative Day 3 and
End of Treatment Period study visits, although the patients with
confirmed events had a mean INR slightly less than patients without
confirmed events (2.30 and 2.36, respectively for patients at
postoperative Day 3; 2.31 and 2.43, respectively for patient at the End
of Treatment Period study visit).

There were no appreciable differences between the distribution of INR
values in patients with and without confirmed VTE.

There are several major problems in this study using warfarin as a
comparator:

-   Warfarin is not suitable for short-term therapy for prevention of
    VTE in patients with TKR surgery. Warfarin is not approved for this
    indication.

-   The comparison is unfair, because warfarin will take about 3-5 days
    to reach therapeutic level, while Exanta reaches therapeutic levels
    within hours.

-   The results show that 35.2% of patients receiving warfarin had an
    INR less than 1.8 by postoperative day 3 and 24% by end of treatment
    (day 7 -- 12).

Therefore, it is unacceptable to claim that ximelagatran 36 mg bid is
superior to warfarin.

1.10.5 Conclusions on efficacy results

In this study (EXULT 290A), ximelagatran 36 mg bid showed greater
efficacy than warfarin in preventing total VTE and/or all-cause
mortality in patients undergoing primary elective TKR. The absolute
reduction in the frequency of total VTE and/or all-cause mortality was
7.3% with warfarin (27.6% warfarin vs. 20.3% ximelagatran 36 mg),
providing a relative risk reduction of 26.4% and a number needed to
treat (1/ARR) of 14 (95% C.I. 8-39). The 36 mg dose was superior to
"warfarin group"(p=0.003). The benefit was mainly due to a reduction in
asymptomatic distal DVT diagnosed by venography which is not clinically
meaningful. There were no clinically or statistically significant
differences between ximelagatran and warfarin in reducing the frequency
of proximal DVT, PE, and/or all-cause mortality in this population.
Ximelagatran 24 mg bid was effective in achieving a rate of total VTE
and/or all-cause mortality numerically better than "warfarin" (27.6%
warfarin vs 24.9% ximelagatran 24 mg), but this difference did not reach
statistical significance. The female patients, older patients and
patients enrolled at sites in Canada were associated with higher rates
of VTE.

### 

There are several major problems for comparison of ximelagatran with
warfarin in this study. Warfarin is not suitable for short-term therapy
for prevention of VTE in patients with TKR surgery. Warfarin is not
approved for this indication. The comparison is unfair, because warfarin
will take about 3-5 days to reach therapeutic level, while Exanta
reaches therapeutic levels within hours. The results show that 35.2% of
patients receiving warfarin had an INR less than 1.8 by postoperative
day 3, and 24% by end of treatment (day 7 -- 12). Therefore, although
the study demonstrated that the 36 mg dose of ximelagatran was superior
to "warfarin group" (p=0.003) for primary endpoints, it is unacceptable
to claim that ximelagatran is better than warfarin for this indication.

### 

**1.11 Safety Results**

**1.11.1 Extent of exposure**

The duration of treatment received is summarized in Table A10. The mean
number of days on treatment was approximately 8 days for each treatment
group. There were no appreciable differences in exposure to study drug
among treatment groups from Day 10 onwards, although overall warfarin
administration may have been reduced relative to ximelagatran because
warfarin is often withheld if INR is elevated. The minimum number of
days on study drug was 1 day for patients in each treatment group; the
maximum was 13 days for patients in the ximelagatran 24 mg treatment
group and 14 days for patients in the ximelagatran 36 mg and warfarin
treatment groups.

# Table A10 Overview of exposure in the safety population

![](media/image55.png){width="5.309027777777778in"
height="1.9833333333333334in"}

**1.11.2 Adverse events**

A summary of adverse events in each category of seriousness is presented
in Table A11.

**Table A11 Number (%) of patients with treatment-emergent adverse
events (safety**

**population, follow-up included)**

![](media/image56.png){width="5.300694444444445in"
height="1.9166666666666667in"}

More than 60% of patients in each treatment group experienced at least
one adverse event. There were no appreciable differences among treatment
groups in the proportions of patients with at least one adverse event or
with drug-related adverse events. The incidence of serious adverse
events and discontinuations attributed to adverse events was higher in
the ximelagatran treatment groups than in the warfarin group. Eight
patients died who had undergone surgery and were randomized to study
drug; 4 received ximelagatran 36 mg and 2 each received ximelagatran 24
mg and warfarin.

The most common treatment-emergent adverse events experienced by at
least 5% of patients in any treatment group are shown in Table A12
listed by preferred term in order of decreasing total incidence.

**Table A12 Number (%) of patients with adverse events occurring with a
minimum**

**incidence of 5% of all patients (safety population)**

![](media/image57.png){width="5.4006944444444445in"
height="2.2083333333333335in"}

The most common adverse event was postoperative complications (for
events such as anemia; pain; wound infection; bleeding and delayed wound
healing) as experienced by 20.4% of all patients. The remaining common
adverse events experienced by at least 5% of the patients were fever
(7.0%), nausea (6.9%), increased serum levels of gamma glutamyl
transferase (6.4%) and constipation (5.0%). There were no appreciable
differences among treatment groups in the incidence of adverse events.

The common treatment-emergent adverse events attributed to study drug by
the investigator were increased serum levels of gamma glutamyl
transferase (4.3%), postoperative complications (3.1%), alkaline
phosphatase (2.8%), ALAT (2.6%) and ASAT (1.7%).

**Bleeding events**

Bleeding events were categorized as major/minor/no bleeding. The most
common treatment-emergent reported bleeding events were coded under
postoperative complications (5.1%). Treatment-emergent bleeding
complications reported by at least 1% of patients in any treatment group
are summarized in Table A13. Hemoptysis was experienced by 5 patients
(0.7%) randomized to ximelagatran, all on the 36 mg dose, and by 1
patient (0.1%) randomized to warfarin.

# Table A13 Number (%) of patients with reported bleeding events occurring with a

**minimum incidence of 1% of all patients (safety population)**

![](media/image58.png){width="5.375694444444444in" height="2.075in"}

The frequencies of adjudicated bleeding events on treatment are
summarized by event type in Table A14.

**Table A14 Frequency of ICAC adjudicated on-treatment bleeding events
by event**

**type (safety population)**

![](media/image59.png){width="5.350694444444445in"
height="3.7416666666666667in"}

Approximately 5% of patients in each treatment group had major or minor
bleeding events while receiving study medication; approximately 1% of
patients in each treatment group had major bleeding events, 0.8% in each
of the ximelagatran treatment groups and 0.7% in the warfarin treatment
group. Approximately 5% to 6% of patients in each treatment group had
major or minor bleeding events during the entire study, including the
period from the last administration of study medication until the
follow-up visit. Most bleeding events occurred while the patients were
receiving study medication. There were no statistically significant
differences between the ximelagatran and warfarin treatment groups in
the frequency of major, minor, or combined major or minor bleeding
events while receiving study medication (p[\>]{.underline}0.461).
Similarly, there were no statistically significant differences between
ximelagatran 24 mg and 36 mg in the frequencies of these bleeding events
while receiving study medication (p[\>]{.underline}0.490).

The frequency of on-treatment bleeding events for patients treated with
warfarin by INR range is summarized in Table A14.

Table A14 Frequency of on-treatment bleeding events for patients treated
with warfarin by

international normalized ratios (safety population)

![](media/image60.png){width="5.334027777777778in"
height="2.2666666666666666in"}

The frequency of bleeding events increased from postoperative Day 3 to
the End of Treatment Period Study Visit for patients within the
therapeutic INR range, from 36.4% to 60.6%, and decreased from
postoperative Day 3 to End of Treatment Period Study Visit for patients
below the therapeutic INR, from 57.6% to 30.3%.

For all warfarin treated patients with INR values within the therapeutic
range (1.8 to 3.0), 37.1% had confirmed bleeding events at postoperative
Day 3 versus 58.8% at End of Treatment Period Study Visit. Mean INRs of
warfarin treated patients with bleeding events were lower at
postoperative Day 3 and the day of the End of Treatment Period Study
Visit than for patients with no confirmed bleeding (1.9 versus 2.3, and
2.1 versus 2.4, respectively).

There were no appreciable differences in mean melagatran levels between
patients with confirmed on-treatment major/minor bleeding events and
with no confirmed bleeding at the postoperative Day 3 and End of
Treatment Period study visits suggesting that the bleeding events
occurred independently of melagatran plasma concentrations.

**Subgroup analyses of adjudicated bleeding events**

For the majority of subgroups examined, the pattern of results was
consistent with that of the overall population and the incidences of
bleeding events in the ximelagatran groups were comparable to or
slightly higher than those in the warfarin group. A logistic regression
analysis examining on-treatment bleeding events found that there was a
statistically significant effect of gender and location of the study
site on the incidence of major/minor bleeding events, with male patients
and patients enrolled at sites in Canada associated with an increased
risk of bleeding (p[\<]{.underline}0.001). The interaction of each
subgroup factor with treatment was also analyzed and indicated no
statistically significant interactions between treatment and any
examined subgroup (p[\>]{.underline}0.096). The frequency of
on-treatment major/minor bleeding events by selected subgroup factors is
summarized in Table A15.

# ![](media/image61.png){width="5.375694444444444in" height="4.392361111111111in"}Table A15 Frequency of on-treatment bleeding events by selected subgroup

**Deaths**

Eight patients died who had undergone surgery and were randomized to
treatment; 4 patients had received ximelagatran 36 mg, 2 patients had
received ximelagatran 24 mg, and 2 patients had received warfarin. Of
the eight deaths, 1 occurred in each treatment group during the study
treatment period; none of these was adjudicated as due to fatal PE or
fatal bleeding (2 MIs and 1 ischemic bowel with perforation). The other
five deaths occurred after study treatment was discontinued and up until
the end of the study.

The 2 warfarin treated patients died as a result of myocardial
infarction. Deaths of patients who received ximelagatran 36 mg resulted
from PE (Patients 93/144 and 217/3259), myocardial infarction (Patient
112/154), and hypotension, gastrointestinal bleeding, and multiorgan
failure (Patient 401/7037). Patient 46/2236, who received ximelagatran
24 mg, died as a result of intestinal perforation. The cause of death
for Patient 215/3776, who also received ximelagatran 24 mg, was unknown.

Narratives for patient 401/7037, Patient 46/2236 and Patient 215/3776
are listed below.

-   Patient 401/7037 was a 79 yeas old female Caucasian. The subject had
    a history of hypertension, deafness, congestive obstructive
    pulmonary disease, appendectomy, and renal lithotripsy. She
    underwent left TKR for osteoarthritis. Operative blood loss was 130
    mL, and postoperative drainage was 100 mL. The subject received the
    first dose of warfarin placebo approximately 10 hours after surgery.
    She received 1 day of treatment with ximelagatran 36 mg for a total
    of 2 doses. On postoperative day 1 at 17: 50 hour, the subject
    experienced paleness, nausea, and vomiting. She was found to have
    hypotension (80/ 50 mm Hg), a respiratory rate of 20/ min, and a
    temperature of 35.8 ^o^C. Therapy with the study drug was
    discontinued, and the patient was transferred to intensive care. She
    was evaluated again at 00: 30 hour and diagnosed with arrhythmia,
    seizures, disorientation, paleness, and hypotension (90/ 60 mm Hg).
    The subject's hemoglobin was low, and she had bleeding via her
    nasogastric tube. Hemodynamic instability, hydroelectrolytic and
    acid- base disorder, and upper gastrointestinal bleeding were
    diagnosed. She was intubated, and mechanical ventilation was
    necessary. Acute renal failure was diagnosed. The subject was
    treated with intravenous plasma, two units of blood, and potassium
    chloride. On postoperative day 3, the subject's upper
    gastrointestinal bleeding continued with hypotension and
    tachycardia. Her central venous pressure was 10.5 to 23 mm Hg. On
    postoperative day 5, the subject became unstable and underwent
    exploratory laparotomy for the upper gastrointestinal bleeding.
    During the procedure, multiple gastric ulcers were found. Her
    condition worsened, and she died on postoperative day 46. The
    probable cause of death was acquired hospital pneumonia and multiple
    organ failure. An autopsy was not performed. The mandatory
    venography was not performed for this subject because she was in
    intensive care. The study investigator assessed the acute renal
    failure as medically significant and assessed all of the events as
    not related to the study drug. The upper gastrointestinal bleeding
    was adjudicated as a major bleeding event.

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-   Patient 46/2236 was a 79 years old female Caucasian. The subject's
    medical history included anemia, hypertension, depression, left
    bundle branch block, hyperlipidemia, colonic stricture and
    arteriovenous malformations of the cecum, and left eye cataract
    removal. The subject underwent left TKR for osteoarthritis.
    Operative blood loss was 250 mL, and postoperative drainage was 500
    mL. The subject received the first dose of warfarin placebo
    approximately 11 hours after surgery. She received 7 days of
    treatment with ximelagatran 24 mg for a total of 13 doses. On
    postoperative day 5, she complained of constipation. On
    postoperative day 6, a flat plate of the abdomen revealed a possible
    early ileus. The subject was put on enteral nutrition and started on
    Reglan (metoclopramide) therapy. On the morning of postoperative day
    7, she had cold clammy skin with gray pallor. The subject was
    tachypneic, and her abdomen was distended. A nasogastric tube was
    inserted. Study drug was discontinued. Laboratory results showed an
    increased white blood cell count. On postoperative day 8, abdominal
    obstruction series results were consistent with a bowel perforation.
    The subject was taken to surgery, and a subtotal colectomy was
    performed. She remained in critical condition following surgery and
    expired on postoperative day 9 due to multiple complications of
    sepsis. The mandatory venography was not performed for this subject.
    The study investigator assessed the event as not related to the
    study drug.

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-   Patient 215/3776 was a 70 years old male Caucasian. The subject had
    a history of asthma, cancer of the prostate, fractured wrist,
    influenza, and tonsillectomy. The subject underwent left TKR for
    osteoarthritis. Operative blood loss was not reported, and
    postoperative drainage was 365 mL. The subject received the first
    dose of warfarin placebo approximately 8 hours after surgery. He
    received 2 days of treatment with ximelagatran 24 mg for a total of
    4 doses. On postoperative day 2, the subject became diaphoretic,
    pale, and tachycardic. An EKG revealed atrial fibrillation, and a
    chest x- ray revealed pulmonary edema. Cardiac enzymes were
    subsequently negative. He was treated with digoxin, nitro- paste,
    and oxygen. At 02: 00 on postoperative day 3, the subject vomited
    coffee ground material and had bright red stools. The subject was
    transferred to the intensive care unit, and therapy with the study
    drug was discontinued and unblinded. He was diagnosed with a
    gastrointestinal bleed. He was treated with pantaloc, fresh frozen
    plasma, and packed red blood cells. On postoperative day 7, the
    subject was started on Fragmin (dalteparin). He was discharged to
    home recovered on postoperative day 12. The mandatory venography was
    not performed for this subject because he withdrew from the study
    due to the adverse event. The subject was re- hospitalized on
    postoperative day 18 with shortness of breath. On postoperative day
    21, he was transferred to another hospital and was lost to follow-
    up. The subject died secondary to an unknown cause on postoperative
    day 25. The study investigator assessed the upper and lower
    gastrointestinal bleed as related to the study drug and the
    shortness of breath and death as not related to the study drug. The
    Adjudication Committee classified this cause of death as pulmonary
    embolism, due to lack of information to the contrary and based on
    the pre- specified Adjudication Committee charter. The
    gastrointestinal bleed was adjudicated as a major bleeding event.

**Serious adverse events**

The frequency of serious adverse events experienced by at least two
patients who were treated with ximelagatran or with warfarin is
summarized in Table A16.

**Table A16 Number (%) of patients with serious adverse events occurring
in at least 2 patients treated with either ximelagatran or warfarin
(safety population)**

![](media/image62.png){width="5.925694444444445in"
height="6.159027777777778in"}

The most common serious adverse events experienced by at least 0.5% of
patients were postoperative complications (0.8%) and myocardial
infarction (0.6%).

Eleven randomized patients underwent surgery and dosing with study
medication (warfarin or placebo) on Day 0 but discontinued before dosing
with active study drug (ximelagatran or placebo) on Day 1. Of these 11
patients, 7 patients were randomized to warfarin, 3 patients to
ximelagatran 24 mg and one patient to ximelagatran 36 mg. Therefore,
four patients did not receive active study drug before discontinuing
from the study. All 11 patients have been included in the safety
analyses.

Serious postoperative complications were experienced by 18 patients, 13
(0.9%) randomized to ximelagatran and 5 (0.7%) to warfarin. Serious
myocardial infarctions were experienced by 13 patients, 11 (0.7%)
randomized to ximelagatran and 2 (0.3%) to warfarin.

Five patients experienced serious gastrointestinal hemorrhage; all five
were randomized to ximelagatran, 4 (0.5%) to the 24 mg dose and 1 (0.1%)
to the 36 mg dose. One patient in the ximelagatran 24 mg dose group,
experiencing a serious gastrointestinal hemorrhage, discontinued study
medication prior to receiving an active dose of study medication on
postoperative Day 1. This patient was one of the eleven patients
described in the previous paragraph. There were no other appreciable
differences in the incidence of serious adverse events among treatment
groups.

**1.11.3 Discontinuations due to adverse events**

The frequency of discontinuations of study drug attributed to adverse
events experienced by at least 0.2% patients is summarized in Table A17.

#### **Table A17 Number (%) of patients who discontinued from study drug because of**

**adverse events (greater than or equal to 0.2% of patients) (safety
population)**

![](media/image63.png){width="5.909027777777778in" height="2.7in"}

The two most common adverse events leading to discontinuation of study
drug were postoperative complications (7 patients \[0.3%\]) and
myocardial infarction (6 patients \[0.3%\]). Other adverse events that
led to discontinuation of study drug by at least 0.2% of all patients
were atrial fibrillation, nausea, gastrointestinal hemorrhage, and
vomiting. The incidence of discontinuations attributed to adverse events
was higher in the ximelagatran treatment groups than in the warfarin
group.

**1.11.4 Clinical laboratory evaluation**

**Hematology**

Changes from baseline in hemoglobin levels were greatest within the
first 3 days following surgery and returned to near baseline levels by
the end of the follow-up period. Changes from baseline in platelet
counts were greatest between baseline and End of Treatment Period Study
Visit and returned to above baseline levels by the end of the follow-up
period. There were no appreciable differences in changes from baseline
in hemoglobin levels or platelet counts among treatment groups at any
evaluation. Changes from baseline in other hematology parameters tended
to be smaller at follow-up than at End of Treatment Period Study Visit,
but no appreciable differences were seen over time or among treatment
groups.

**Clinical chemistry**

Changes from baseline in liver enzymes and total bilirubin were greater
at End of Treatment Period Study Visit than at follow-up. There were no
appreciable differences in mean baseline values or in changes from
baseline in liver enzymes and total bilirubin among treatment groups at
any evaluation.

**Changes in individual patients over time in selected liver function
parameters**

The frequencies of measures of liver function outside the extended
reference ranges for liver enzymes (ASAT, ALAT, and alkaline
phosphatase) and total bilirubin are summarized in Table A18. The only
hepatic parameter with values at least 3X ULN with an incidence
exceeding 1% in any treatment group was ALAT (ranging to 1.7%) at
venography. There were no appreciable differences in the frequency of
the measures of liver function at least 3X ULN among treatment groups
for any hepatic parameter. It should be noted that there were 5
additional patients with ALT elevation ([\>]{.underline} 3ULN) in the
ximelagatran groups (1 patient in 24 mg group and 4 patients in 36 mg
group) and none in the warfarin group during the following up period.
This may indicate that ximelagatran may cause late occurrence of liver
toxicity and 4-6 weeks of follow-up may not be adequate to assess the
safety for short-term use of ximelagatran.

**Table A18 Frequency of selected liver function test values elevated
above upper limits of**

**normal (safety population)**

![](media/image64.png){width="4.950694444444444in"
height="4.450694444444444in"}

Expected postoperative changes were observed: elevations were seen in
measures of hepatic function (ASAT, ALAT, GGT, alkaline phosphatase, and
LDH) and white blood cell counts, and reductions in RBCs, all at the
time of venography, which generally returned to near baseline values at
the follow-up visit. Hemoglobin levels diminished in all treatment
groups following surgery and returned to near baseline at the follow-up
visit. Platelet counts diminished in all treatment groups following
surgery and returned to above baseline at the follow-up visit. There
were few appreciable differences in clinical laboratory values among
treatment groups. These changes are consistent with surgical
intervention and postoperative recovery.

**1.11.5 Conclusions on safety results**

There were no statistically significant differences between either the
ximelagatran treatment group and warfarin in the frequency of major
bleeding events, the frequency of minor bleeding events, or the
frequency of any (major and minor) bleeding events on treatment or over
the entire study. Five patients experienced serious gastrointestinal
hemorrhage; all five were randomized to ximelagatran, 4 (0.5%) to the 24
mg dose and 1 (0.1%) to the 36 mg dose (One patient discontinued study
medication prior to receiving an active dose of study medication on
postoperative Day 1).

No appreciable differences were detected among the treated groups in
regard to adverse events. The incidences of serious adverse events
(5.7-5.9% vs. 4.3%), deaths (6 vs. 2) and discontinuations attributed to
adverse events (3% vs. 1.7%) were numerically higher in the ximelagatran
treatment groups than in the warfarin group. There was a statistically
significant effect of gender and location of the study site on the
incidence of major/minor bleeding events, with male patients and
patients enrolled at sites in Canada associated with an increased risk
of bleeding (p[\<]{.underline}0.001).

Serious myocardial infarctions were experienced by 13 patients, 11
(0.7%) randomized to ximelagatran and 2 (0.3%) to warfarin. Three
additional patients in ximelagatran group reported angina.

There were no appreciable differences in the frequency of the measures
of liver function at least 3X ULN among treatment groups for any hepatic
parameter. However, it should be noted that there were 5 additional
patients with ALT elevation ([\>]{.underline} 3ULN) in ximelagatran
groups and none in the warfarin group during the following up period.
This may indicate that ximelagatran may cause late occurrence of liver
toxicity and 4-6 weeks of follow-up may not be adequate to assess the
safety for short-term use of ximelagatran. A study incorporating at
least 6 months of follow-up will be needed to assess liver toxicity
following short-term use of ximelagatran.

**2**: **STUDY SH-TPO-0012 (EXULT B)**

Exult B was studied between June 2002 and April 2003. Title of the
protocol was "Safety and Efficacy of H 376/95 (Oral Direct Thrombin
Inhibitor) Compared to Warfarin (COUMADIN) for the Prevention of Venous
Thromboembolism Following Total Knee Arthroplasty.

2.1 Study objectives

Primary objectives

The purpose of this study was to confirm the superior efficacy of
ximelagatran compared to warfarin for the prevention of VTE in patients
after TKR. The primary analysis was to focus on the primary composite
endpoint of proximal and distal DVT and/or PE and/or all-cause
mortality, according to independent central adjudication.

Secondary objectives

The secondary objectives of this study were to compare ximelagatran with
warfarin for the incidence of:

-   the secondary composite endpoint of proximal DVT and/or PE and/or
    all-cause

mortality during the study drug treatment period

-   the secondary composite endpoint of total DVT and/or PE and/or
    all-cause

mortality according to local on-site evaluations during the study drug
treatment period

-   major and any bleeding during the study drug treatment period.

**2.2 Study design**

This (EXULT B) was a multi-center, randomized, double-blind,
double-dummy, parallel-group active comparator study in patients who had
undergone primary elective TKR. Patients were randomized to 1 of 2
treatment groups: ximelagatran 36 mg twice daily (bid) (initiated as
early as possible on the morning after surgery) or warfarin once daily
(initiated the evening of surgery), administered for 7 to 12 days.
Independent Central Adjudication Committee (ICAC) evaluation of
mandatory bilateral venography (performed at the End of Treatment Period
Study Visit) in conjunction with objectively confirmed, symptomatic VTE
events and/or all-cause mortality were used to determine the primary
endpoint. Symptomatic events or deaths occurring within 2 days following
mandatory venography or up to Day 12, if no mandatory venography was
done, were included in the primary analysis of efficacy.

**2.3 Selection of study population**

**Inclusion criteria**

For inclusion in the study, patients had to fulfill all of the following
criteria:

1\. Be scheduled for elective primary unilateral or bilateral TKR

2\. Be at least 18 years old

3\. Weigh between 88 lbs (40 kg) and 300 lbs (136 kg)

4\. Be a male, or a female that was either a) surgically sterile, b) at
least 2 years

postmenopausal, or c) using a reliable form of contraception.

5\. Provide written informed consent.

**Exclusion criteria**

Any of the following was regarded as a criterion for exclusion from the
study:

1\. Be scheduled for hemiarthroplasty or surface repair or revisionary
surgery

2\. Have had a traumatic epidural/spinal puncture for this surgery (\> 3
attempts or gross bleeding)

3\. Have any condition resulting in immobilization for [\>]{.underline}
days within the 30 days prior to surgery

4\. Have treatment with anticoagulant or antiplatelet drugs within 7
days prior to surgery. Acetylsalicylic acid up to 500 mg daily and
non-steroidal anti-inflammatory drugs (NSAIDs) were allowed.

5\. Have a known disorder associated with an increased risk of bleeding

6\. Have had an ischemic stroke or MI within the 30 days prior to
surgery

7\. Have had any major surgical procedure within 30 days prior to
surgery

8\. Have significant renal impairment (CrCL\<30 mL/min)

9\. Have abused drugs and/or alcohol within the last 6 months

10\. Have malignancy currently under active cytotoxic treatment, or
being the reason for joint replacement surgery

11\. Have a known clinically significant liver disorder, or ASAT and/or
ALAT \> 2 times ULN.

12\. Have thrombocytopenia (platelet count \<100 x 10^9^ /L)

13\. Have a known allergy to contrast media or iodine

14\. Have any condition that would preclude venography

15\. Have been previously randomized into this study or any other study
of melagatran or ximelagatran

16\. Be mentally or legally incapacitated

17\. Be in a situation or condition that, in the opinion of the
investigator, may interfere with full participation in the study or
produce a significant risk to the patient

18\. Have received any investigational agent (drug or device) for any
therapeutic reason within 30 days prior to surgery

19\. Have planned use of intermittent pneumatic compression or foot pump
device (Passive anti-embolism stockings and continuous passive motion
devices are acceptable.)

20\. Have a contraindication to warfarin.

**2.4 Doses and treatment regimens**

Patients were randomized in a double-dummy fashion to 1 of 2 treatment
groups:

-   Ximelagatran 36-mg tablet given twice daily in the morning and
    evening with doses taken at intervals as close to 12 hours as
    possible and placebo capsule(s) matching warfarin given in the
    evening,

**or**

-   Warfarin 2.5 mg capsule(s) given once daily in the evening and
    titrated to a target INR of 2.5 (range: 1.8 to 3.0) and 1 placebo
    tablet matching ximelagatran 36 mg given twice daily in the morning
    and evening.

**2.5 Criteria for evaluation (main variables)**

**Efficacy**

-   Primary endpoint: The number of patients with verified distal and/or
    proximal DVT, and/or symptomatic PE with objective confirmation,
    and/or all-cause mortality during the treatment period according to
    central evaluations.

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```
-   Secondary endpoints: The number of patients with proximal DVT/PE
    (venographic assessment of the proximal veins + symptomatic,
    objectively confirmed proximal DVT and/or PE during the treatment
    period) + all-cause mortality during the treatment period.

> And
>
> The number of patients with verified distal and/or proximal DVT,
> and/or symptomatic PE with objective confirmation, and/or all-cause
> mortality during the treatment period according to local on-site
> evaluations.

**Safety**

Safety assessments included bleeding complications occurring after TKR;
surgical site evaluations; adverse event (AE) reports; clinical
laboratory data (hematology and clinical

chemistry) and vital signs. An independent Data Safety Monitoring Board
was in place during the performance of the study.

**2.6 Statistical methods**

The presence or absence of DVT, PE, and all-cause mortality was assessed
locally at each

investigative site and by the ICAC. The primary statistical analysis was
performed using central evaluations. To address the primary objective of
this study, ximelagatran 36 mg was compared to warfarin. Treatment
differences were tested using the Cochran-Mantel-Haenszel (CMH)
chi-square test, stratified by type of surgery (unilateral and
bilateral). All objectives were assessed at a significance level of
0.05. A secondary analysis, in which the local venography assessments
were substituted for the central venography assessments and analyzed,
was also performed. Sub-group analyses were also performed on the
frequency of thromboembolic events (total VTE and proximal VTE). The
main analysis of efficacy was performed on the efficacy
intention-to-treat (ITT) population, ie, all randomized and treated
patients with a venogram adequate for evaluation or objectively
confirmed, symptomatic DVT/PE and/or all-cause mortality while on
treatment.

The frequency of adjudicated bleeding events (major and/or minor) was
determined for each treatment group by the type of surgery performed.
Differences among treatment groups were tested using the CMH chi-square
test, stratified by type of surgery (unilateral/bilateral). Liver
function test results (alanine aminotransferase \[ALAT\], aspartate
aminotransferase \[ASAT\], alkaline phosphatase, total bilirubin) were
summarized according to the proportion of patients with results greater
than 2, 3, 5, and 7 times the upper limit of normal (ULN). Analyses of
AEs, laboratory parameters (including hemoglobin and platelet count),
and vital signs were summarized descriptively.

**2.7 Summary of patients**

Of 2813 patients enrolled in 115 centers, 2303 were randomized to study
drug at 113 centers. Four randomized patients were excluded from the
safety analysis population because they did not receive study drug. Of
the 2299 patients included in the safety population, data from 982 and
967 patients in the ximelagatran and warfarin groups, respectively, were
analyzed for efficacy in the ITT population while data from 941 and 883
patients, respectively, were included in the PP population. The
discrepancy in the number of patients in each treatment group evaluable
for the PP population was primarily due to a higher proportion of
patients in the warfarin group compared with the ximelagatran group who
were noncompliant (did not have a minimum INR of 1.5) with study drug or
who did not receive their first dose of study drug on schedule.

Approximately 94% of patients in each treatment group completed the
study (ie, completed the 4- to 6-week follow-up visit). The proportion
of patients who discontinued study drug early for any reason was
comparable in the ximelagatran group (n=53, 4.6%) and the warfarin group
(n=52, 4.5%). The most common reason for early discontinuation of study
drug in the ximelagatran and warfarin groups was AEs (29 and 34
patients, respectively). Other reasons for discontinuation of treatment
across both treatment groups included consent withdrawn (17 patients),
confirmed VTE event (14 patients), other (10 patients), and eligibility
criteria not fulfilled (1 patient).

An additional 19 patients (9 ximelagatran; 10 warfarin) discontinued the
study during the 4- to 6-week follow-up period. The reason for
discontinuation of the study following completion of treatment was
consent withdrawn (6 patients in each treatment group), AE (2
ximelagatran; 1 warfarin), and other (1 ximelagatran; 3 warfarin).

2.8 Protocol deviations

The numbers of patients with protocol deviations that resulted in data
being excluded from the analyses are provided in Table B1.

**Table B1 Number (%) of patients with protocol deviations (randomized
population)**

![](media/image65.png){width="5.142361111111111in"
height="4.467361111111111in"}

Three primary patient populations were analyzed in this study, the
safety population, the efficacy ITT population, and the PP population.

More patients (44, 3.8%) in warfarin group than ximelagatran group (11,
1.0%) did not receive first dose of study drug on schedule.

**2.9 Summary of demographic and baseline characteristics**

The demographic and key baseline characteristics of patients included in
the safety population are summarized in Table B2.

**Table B2 Demographic and baseline characteristics (safety
population)**

![](media/image66.png){width="5.142361111111111in" height="2.675in"}

![](media/image67.png){width="5.209027777777778in" height="1.675in"}

![](media/image68.png){width="5.217361111111111in"
height="6.325694444444444in"}

The 2 treatment groups were well matched with respect to demographic and
baseline characteristics. Of the 2299 patients included in the safety
population, slightly more than 60% in each treatment group were female,
approximately 94% in each treatment group were Caucasian, and
approximately two-thirds of the patients were enrolled at centers in the
United States or Canada. At baseline, slightly more than 60% of patients
in the ximelagatran and warfarin groups were non-smokers and
approximately 67% of patients in each treatment group did not consume
alcohol.

The mean age of patients in the ximelagatran and warfarin groups was
approximately 67 years and between 41% and 44% of patients in both
groups were between 65 and 74 years of age. The estimated creatinine
clearance was normal ([\>]{.underline}80 mL/min) for comparable
proportions of patients in the ximelagatran (65.4%) and warfarin (62.8%)
groups.

### 

The proportions of patients included in the efficacy ITT population who
entered the study

with risk factors for DVT were generally comparable in the 2 treatment
groups. More patients in the ximelagatran group (n=11, 1.1%) compared
with the warfarin group (n=6, 0.6%) entered the study with a known
history of PE, while comparable proportions of patients in the 2 groups
had a history of DVT (n=35, 3.6% and n=29, 3.0%, respectively).
Approximately one-quarter of patients in both the ximelagatran and
warfarin groups (24.2% and 25.9%, respectively) had a history of
varicose veins. No patient in either treatment group was reported to
have known APC resistance, protein-C, protein-S, or antithrombin III
deficiencies. Three patients (2 ximelagatran, 1 warfarin) entered the
study with another known coagulation disorder.

### 

In the efficacy ITT population, the most common reason for TKR was
osteoarthrosis, with comparable percentages of patients in the
ximelagatran and warfarin groups (94.2% and 95.4%, respectively)
presenting with this reason.

### 

Approximately 95% of patients in each treatment group underwent
unilateral knee surgery, most (\>94%) for osteoarthrosis. Prostheses
were cemented in place in approximately 90% of the patients in each
treatment group. There were no appreciable differences between treatment
groups in the use of prior, concomitant, or follow-up therapies or in
the proportion of patients using an anticoagulant for extended
prophylaxis. The population of patients studied was suitable for the
purpose of this study and representative of the general TKR population.

### 

### 

**2.10 Efficacy results**

**2.10.1 Primary variable: Incidence of total venous thromboembolism
and/or all-cause mortality (blinded ICAC assessment)**

In this study, frequency rates of total VTE included patients with a
confirmed DVT of the

distal or proximal veins by mandatory venography as well as any patient
who had clinical

signs/symptoms of DVT or PE that were objectively confirmed and
centrally adjudicated by the ICAC. Frequency rates of proximal VTE
included patients with a confirmed DVT of the proximal veins by
mandatory venography as well as any patient with objectively confirmed
and adjudicated signs/symptoms of proximal DVT or PE. All-cause
mortality included all deaths occurring during treatment or within 2
days following venography or up to postoperative Day 12, if mandatory
venography was not performed. Symptomatic events occurring within 2 days
following mandatory venography or up to Day 12, if no mandatory
venography was done, were included in this analysis. Patients adequate
for evaluation for the presence of total VTE may not have been adequate
for evaluation for the presence of proximal DVT/PE.

The frequency of total VTE and/or all-cause mortality among patients
undergoing TKR was 22.5% for patients in the ximelagatran group and
31.9% for patients in the warfarin group (Table B3).

**Table B3 Frequency of total venous thromboembolism and/or all-cause
mortality (efficacy ITT population; blinded ICAC assessment)**

![](media/image69.png){width="5.192361111111111in"
height="1.8916666666666666in"}

Ximelagatran 36 mg was superior to warfarin group (p\<0.001) in reducing
total VTE and/or all-cause mortality among patients with TKR according
to blinded ICAC assessment. The absolute reduction in the frequency of
total VTE and/or all-cause mortality was 9.3% with ximelagatran (31.9%
warfarin vs 22.5% ximelagatran 36 mg) (p\<0.001); the number needed to
treat to obtain benefit (1/ARR) was 11 (95% CI: 8 to 19).

Results obtained from data in the efficacy ITT population were confirmed
by analyses of data from patients in the PP population. The frequency
rates of total VTE and/or all-cause

mortality in the PP population were 22.6% and 33.3% among patients in
the ximelagatran and warfarin groups, respectively (p\<0.001).

**2.10.2 Secondary variables**

**Incidence of proximal deep vein thrombosis, pulmonary embolism, and/or
all-cause mortality (blinded ICAC assessment)**

The frequency of proximal DVT, PE, and/or all-cause mortality using
blinded ICAC

assessments among patients undergoing TKR was 3.9% for patients
randomized to

ximelagatran 36 mg and 4.1% for patients randomized to warfarin (Table
B4).

**Table B4 Frequency of proximal DVT, pulmonary embolism, and/or
all-cause mortality (efficacy ITT population; blinded ICAC assessment)**

![](media/image70.png){width="5.167361111111111in"
height="1.5666666666666667in"}

There was no difference for reduction in the frequency of proximal DVT,
PE, and/or all-cause mortality between the patients in ximelagatran 36
mg group and warfarin group (p=0.802).

**Incidence of total VTE and/or all-cause mortality (local assessment)**

The frequency of total VTE and/or all-cause mortality assessed locally
at study centers was slightly higher in both treatment groups (\<10%
difference) than when assessed centrally by the ICAC. The locally
assessed frequency of total VTE and/or all-cause mortality among
patients undergoing TKR was 30.1% in the ximelagatran group and 35.8% in
the warfarin group (Table B5).

**Table B5 Frequency of total venous thromboembolism and/or all-cause
mortality**

**according to local assessments (safety population with evaluable local
assessments)**

![](media/image71.png){width="5.200694444444444in"
height="1.8166666666666667in"}

Ximelagatran 36 mg was superior compared to warfarin in reducing total
VTE and/or all-cause mortality among patients with TKR according to
local assessments (p=0.007). Using local assessments, the absolute
reduction in the frequency of total VTE and/or all-cause mortality in
the ximelagatran group was 5.7% in relation to patients in the warfarin
group, providing a relative risk reduction of 15.9 (95% CI: 4.6 to
2.58).

The rate of proximal VTE and/or all-cause mortality was numerically
higher using local versus central assessments, 6.8% in the ximelagatran
group compared with 5.7% in the warfarin group (p=0.298; 95% CI of -1.0
to 3.3 surrounding the between-group difference of 1.1%).

**2.10.3 Subgroup analysis**

The results of the subgroup analysis were generally consistent with the
overall pattern of results seen the total efficacy ITT population, with
the incidence of total VTE and/or all-cause mortality consistently lower
in the ximelagatran group compared with the warfarin group. The
frequency of total VTE and/or all-cause mortality is shown for selected
subgroups in Table B6.

**Table B6 Impact of selected subgroups on the frequency of total VTE
and/or all-cause mortality (efficacy ITT population; blinded ICAC
assessment)**

![](media/image72.png){width="5.159027777777778in"
height="5.142361111111111in"}

A higher frequency of total VTE and/or all-cause mortality was observed
across both treatment groups for female patients (relative to males),
older patients (relative to younger patients), patients enrolled at
sites in Canada (relative to those in the United States and the rest of
the world), patients with bilateral surgery (relative to unilateral
surgery), patients with a history of VTE (relative to no VTE history),
and patients with earlier scheduled venograms (relative to later
venograms) (p‹0.016 across all factors).

**2.10.4 Symptomatic and asymptomatic thromboembolic events**

Over the entire study period (treatment and follow-up), there were 45
objectively confirmed, symptomatic thromboembolic events in the efficacy
ITT population occurring in 20 (2.0%) patients in the ximelagatran 36 mg
group and 24 (2.5%) patients in the warfarin group (Table B7).

**Table B7 Objectively confirmed symptomatic and asymptomatic
thromboembolic events over the entire study (efficacy ITT population)**

![](media/image73.png){width="5.175694444444445in"
height="3.033333333333333in"}

The proportions of patients with objectively confirmed, symptomatic
total DVT and proximal DVT were low in both treatment groups (1.1% and
0.4% in the ximelagatran group, respectively; and 1.7% and 0.2% in the
warfarin group, respectively). During the treatment period, the
incidence of any confirmed thromboembolic event was lower in the
ximelagatran group (n=14, 1.4%) compared with the warfarin group (n=22,
2.3%).

Among patients included in the efficacy ITT population, 21.8% of
ximelagatran-treated and 31.1% of warfarin-treated patients had
asymptomatic DVTs detected at mandatory venography. Corresponding
proportions of patients with proximal DVTs at mandatory venography were
3.1% and 3.4%. Venograms were not evaluable for 15.2% of all patients.
The most common reasons provided by the sites for not performing the
venogram included failed venous access and withdrawal of patient
consent. There was no appreciable difference in the number of patients
without central venogram assessments between the ximelagatran and
warfarin groups (14.7% and 15.8%, respectively).

**2.10.5 International normalized prothrombin time ratios (INR) in the
warfarin treatment arm**

At the End of Treatment Period Study Visit, 54.6% of patients in the
warfarin treatment group had INR values within the therapeutic range of
1.8 to 3.0 (Table B8).

**Table B8 Proportion of patients in the warfarin treatment group with
INR within 1.8 and 3.0 (efficacy ITT population)**

![](media/image74.png){width="5.134027777777778in" height="2.0in"}

On postoperative Day 3 and at the End of Treatment Period Study Visit,
66.9% and 73.1% of warfarin patients, respectively, had INR values of
1.8 or greater.

There was no appreciable difference in mean INR between patients in the
warfarin group with confirmed VTE or no confirmed VTE at the
postoperative Day 3 and End of Treatment Period Study visits. The mean
INR for patients with confirmed vs no confirmed VTE was 2.319 and 2.393,
respectively at postoperative Day 3 and 2.342 and 2.445, respectively,
at the End of Treatment Period Study Visit.

There were no appreciable differences between the distribution of INR
values in patients with and without confirmed VTE, with approximately
one-third of patients with a confirmed event within the therapeutic
range of 1.8 to 3.0 on both postoperative Day 3 and at the End of
Treatment Period Study Visit.

There are several major problems in this study using warfarin as a
comparator. Warfarin is not suitable for short-term therapy for
prevention of VTE in patients with TKR surgery. Warfarin is not approved
for this indication. The comparison is unfair, because warfarin will
take about 3-5 days to reach therapeutic level, while Exanta reaches
therapeutic levels within hours. The results show that 33.1% of patients
receiving warfarin had an INR less than 1.8 by postoperative day 3, and
26.9% by end of treatment (day 7 -- 12). Therefore, although the study
demonstrated that the 36 mg dose of ximelagatran was superior to
"warfarin group" (p\<0.001) for primary endpoints, it is unacceptable to
claim that ximelagatran is better than warfarin for this indication.

**2.10.6 Conclusions on efficacy results**

In this study (EXULT B), an oral treatment regimen of ximelagatran 36 mg
bid begun at least 12 hours following TKR and continued for 7 to 12 days
was associated with a low rate of VTE (22.5%) in comparison with
warfarin (31.9%). According to blinded ICAC assessment, the absolute
reduction in the frequency of total VTE and/or all-cause mortality was
9.3% with ximelagatran (31.9% warfarin vs 22.5% ximelagatran 36 mg,
p\<0.001), providing a relative risk reduction of 29.3% (95% CI: 18.1 to
39.1) and a number needed to treat to obtain benefit (1/ARR) of 11(95%
CI: 8 to 19). The benefit was mainly due to a reduction in asymptomatic
distal DVT diagnosed by venography which is not clinically meaningful.
There were no clinically or statistically significant differences
between ximelagatran and warfarin in reducing the frequency of proximal
DVT, PE, and/or all-cause mortality in this population. The incidence of
proximal DVT, PE, and/or all-cause mortality was low in both treatment
groups, 3.9% for ximelagatran and 4.1% for warfarin (p=0.802).

The reduction in total VTE and/or all-cause mortality observed for the
efficacy ITT population was confirmed by analyses of data from patients
in the PP population (p\<0.001) and using local assessments (p=0.007).
The locally assessed frequency of total VTE and/or all-cause mortality
among patients undergoing TKR was 30.1% for ximelagatran and 35.8% for
warfarin (absolute reduction of 5.7%).

A higher frequency of total VTE and/or all-cause mortality was observed
across both treatment groups for female patients (relative to males),
older patients (relative to younger patients), patients enrolled at
sites in Canada (relative to those in the United States and the rest of
the world), patients with bilateral surgery (relative to unilateral
surgery), patients with a history of VTE (relative to no VTE history),
and patients with earlier scheduled venograms (relative to later
venograms) (p‹0.016 across all factors).

There are several major problems for comparison of ximelagatran with
warfarin in this study. Warfarin is not suitable for short-term therapy
for prevention of VTE in patients with TKR surgery. Warfarin is not
approved for this indication and has not been used for this purpose in
medical practice. The comparison is unfair, because warfarin will take
about 3-5 days to reach therapeutic level, while Exanta reaches
therapeutic levels within hours. The results show that 33.1% of patients
receiving warfarin had an INR less than 1.8 by postoperative day 3, and
26.9% by end of treatment (day 7 -- 12). More patients (44, 3.8%) in the
warfarin group than the ximelagatran group (11, 1.0%) did not receive
first dose of study drug on schedule. Therefore, although the study
demonstrated that the 36 mg dose of ximelagatran was superior to
warfarin group (p\<0.001) for the primary endpoint efficacy analysis, it
is unacceptable to claim that ximelagatran is better than warfarin.

### 

### 2.11 Safety results

### 

**2.11.1 Extent of exposure**

Of the 2303 patients randomized to study drug in this study, 4 patients
(1 ximelagatran, 3 warfarin) never received study drug following surgery
and were therefore excluded from the safety population.

The duration of exposure to study drug is summarized in Table B9 for the
safety population.

**Table B9 Overview of exposure in the safety population**

![](media/image75.png){width="5.467361111111111in"
height="2.0416666666666665in"}

The mean number of days on treatment was 8.2 days in the ximelagatran
group and 7.6 days in the warfarin group. There was a disparity between
the 2 treatment groups, with a higher percentage of patients in the
warfarin group treated for only 1 to 6 days (19.0%) compared with
patients in the ximelagatran group (4.9%). Of the 218 patients recorded
as receiving 1 to 6 days of warfarin treatment, most (n=171) were
reported to have completed therapy. The remaining 47 patients
discontinued study drug prematurely, most commonly due to AEs (n=30) and
a confirmed VTE event (n=6). The above discrepancy resulted in a higher
proportion of patients in the ximelagatran group (71.7%) compared with
the warfarin group (58.7%) who were treated for 7 to 9 days; there were
no appreciable differences in exposure to study drug between the
treatment groups from postoperative Day 10 onwards.

**2.11.2 Adverse events**

A summary of treatment-emergent AEs in each category of seriousness is
presented for the safety population in Table B10.

**Table B10 Number (%) of patients with treatment-emergent adverse
events (safety population, follow-up included)**

![](media/image76.png){width="5.4840277777777775in"
height="3.7916666666666665in"}

The overall tolerability profiles for ximelagatran and warfarin were
similar, with approximately 61% of patients in each treatment group
reporting at least 1 treatment-emergent AE and approximately 14% of
patients reporting drug-related AEs. There were no appreciable
differences between treatment groups in the proportions of patients with
bleeding-related and non-bleeding-related AEs. In addition, the
proportions of patients who experienced an SAE or who discontinued
treatment prematurely for an AE were similarin the ximelagatran and
warfarin groups. Ten patients, 7 in the ximelagatran group and 3 in the
warfarin group, died during treatment or within the study-defined 4- to
6-week follow-up visit.

**2.11.2.1 Most common treatment-emergent adverse events (safety
population)**

The most frequently reported AE in both treatment groups was
postoperative complications (preferred term coding for events such as
anemia, pain, wound infection, and bleeding) which was reported by 18.6%
of patients in the ximelagatran group and 17.0% of patients in the
warfarin group. The remaining common AEs experienced by at least 5% of
the patients in either treatment group were fever, nausea, and increased
levels of GGT. The types and incidence rates of common AEs in the study
were generally comparable in the ximelagatran and warfarin groups.

Among the less commonly reported AEs, there was at least a 2-fold higher
incidence of chest pain in the ximelagatran group (1.9%) compared with
the warfarin group (0.8%). None of the episodes of chest pain were
considered related to study drug. No additional AEs occurred with at
least a 2-fold higher incidence in the ximelagatran group compared with
the warfarin group.

Drug-related treatment-emergent AEs were reported for comparable
percentages of patients in the ximelagatran (13.6%) and warfarin (14.7%)
groups. The types and incidence rates of treatment-emergent drug-related
AEs were generally comparable between treatment groups. The most
frequently reported treatment-emergent, drug-related AEs in the
ximelagatran and warfarin groups were increased serum levels of GGT
(4.8% and 3.6% for ximelagatran and warfarin, respectively),
postoperative complications (3.7% and 2.9%, respectively), increased
SGPT (2.6% and 2.3%, respectively), and increased alkaline phosphatase
(2.6% and 2.5%, respectively).

**2.11.2.2 Treatment-emergent adverse events (modified safety
population)**

The modified safety population included patients who had TKR performed
and received at least 1 dose of active study medication at any point on
or after postoperative Day 1.

Seven patients (4 ximelagatran, 3 warfarin) were excluded from the
modified safety

population. Each of the 4 ximelagatran-treated patients received
warfarin placebo on the day of surgery but were discontinued from the
study prior to receiving the morning dose of ximelagatran on Day 1.
Similarly, the 3 warfarin-treated patients received a single dose of
warfarin on the day of surgery but were discontinued prior to receipt of
study medication on Day 1 (ximelagatran placebo or warfarin).

The percentage of patients included in this population who reported at
least 1 treatment-emergent AE (60.8% and 61.5% for the ximelagatran and
warfarin groups, respectively) was almost identical to that of the
overall safety population (60.7% and 61.6%, respectively).

Of the 4 patients in the ximelagatran group who were excluded from the
modified safety

population, 1(6/10829) died as the result of ventricular fibrillation
and cardiomyopathy on postoperative Day 1. One additional patient in the
ximelagatran group (29/10944) and the 3 patients in the warfarin group
(105/10382, 207/12335, and 210/12327) discontinued treatment prematurely
as the result of AEs that began on postoperative Day 1.

**2.11.2.3 Bleeding events**

As seen in Table B11, the majority of bleeding-related AEs in the
ximelagatran and warfarin groups were assessed by the ICAC as a minor
bleeding event or no bleeding event. A higher incidence of major
bleeding events was found in the ximelagatran group than warfarin group,
1.1% and 0.5% of patients, respectively.

**Table B11 Number (%) of patients with treatment-emergent
bleeding-related AEs**

**by ICAC adjudication (safety population)**

![](media/image77.png){width="5.442361111111111in"
height="1.5666666666666667in"}

Five patients (0.4%) in each treatment group had GI hemorrhage reported
as a bleeding-related AE. For 3 of these patients (2 ximelagatran, 1
warfarin), the ICAC assessed the GI hemorrhage as a major bleeding
event. One patient in the ximelagatran group (227/12588) died as a
result of the GI hemorrhage following attempted cardiopulmonary
resuscitation due to loss of melenic stool, sudden volume depletion, and
peripheral shut down.

**Incidence of adjudicated bleeding events**

The frequencies of adjudicated bleeding events on treatment are
summarized by event type in Table B12.

**Table B12 Frequency of ICAC adjudicated on-treatment bleeding events
by event**

**type (safety population)**

![](media/image78.png){width="5.450694444444444in" height="3.175in"}

Major bleeding events were uncommon during the treatment period and were
reported for only 12 of the 1151 (1.0%) patients treated with
ximelagatran 36 mg and 5 of the 1148 (0.4%) of the patients treated with
warfarin. Minor bleeding events were reported during treatment for 4.2%
and 3.4% of patients in the ximelagatran and warfarin groups,
respectively, while 5.0% and 3.8% of patients, respectively, were
reported to have any bleeding event (major or minor). Only 7 additional
patients (3 ximelagatran, 4 warfarin) experienced adjudicated major or
minor bleeding events between administration of the last dose of study
medication and the follow-up visit. Although there were no statistically
significant differences between the 2 treatment groups in the frequency
of major, minor, or combined major or minor bleeding events while
receiving study medication (p[\>]{.underline}0.087) or during the entire
study (p[\>]{.underline}0.105), a numerically higher incidence of major
bleeding events in the ximelagatran group was found.

The frequency of on-treatment bleeding events for patients treated with
warfarin by INR range is summarized in Table B13.

**Table B13 Frequency of on-treatment bleeding events for patients
treated with warfarin by international normalized ratios (safety
population)**

![](media/image79.png){width="5.317361111111111in" height="2.175in"}

There were no appreciable differences between the distribution of INR
values in patients without a confirmed bleeding event at postoperative
Day 3 or the End of Treatment Period Study Visit or with a confirmed
bleeding event at the End of Treatment Period Study Visit. On
postoperative Day 3, however, most patients with a confirmed bleeding
event had an INR value of \<3.0.

**Subgroup analyses of adjudicated bleeding events**

The frequency of adjudicated on-treatment major/minor bleeding events
was examined by subgroup factors relating to pre-specified demographic
and other patient characteristics (Table B14). For the majority of
subgroups examined, the pattern of results was consistent with that of
the overall population, with the incidence of bleeding events in the
ximelagatran group comparable to or slightly higher than that in the
warfarin group. A logistic regression analysis examining on-treatment
bleeding events found that across both treatment groups there was a
statistically significant effect of age and gender on the incidence of
major/minor bleeding events, with male patients and older patients
associated with an increased risk of bleeding (p‹0.02 for both factors).
The interaction of each subgroup factor with treatment was also analyzed
and indicated a statistically significant interaction between treatment
and age and treatment and body mass index (p‹0.048). In the warfarin
group, the rate of on-treatment bleeding events was highest in patients
aged \>75 years and those with a body mass index of \<30 kg/m^2^. By
comparison, rates of on-treatment adjudicated major/minor bleeding
events in the ximelagatran group were similar across all 3 age and body
mass index subcategories.

**Table B14 Impact of selected subgroups on the frequency of
on-treatment bleeding events (combined major and minor) (safety
population)**

![](media/image80.png){width="5.475694444444445in"
height="5.325694444444444in"}

**2.11.2.4 Deaths, serious adverse events, discontinuation due to
adverse events, and other significant adverse events**

**Deaths**

Among all randomized patients, 10 died, including 7 in the ximelagatran
group and 3 in the warfarin group. One death was considered by the
investigator to be related to study drug: Patient 227/12588 in the
ximelagatran group died as the result of a GI hemorrhage on
postoperative Day 8 while receiving study medication. Six of the 10
deaths occurred while patients were receiving treatment, including 4 in
the ximelagatran group and 2 in the warfarin group. Deaths while on
treatment with ximelagatran included ventricular fibrillation with
cardiomyopathy, MI, sudden death, and GI hemorrhage, while those
occurring on treatment with warfarin included cardiac arrest with AV
block and MI. The remaining 4 deaths occurred during the 4- to 6-week
follow-up period.

Of the 7 patients in the ximelagatran group who died, the ICAC could not
rule out that the death was associated with a PE for 3 patients; 2 had
experienced a MI (401/15134 and

507/14091) and 1 died suddenly and the exact cause of death was unknown
(510/14366). One of these deaths occurred on treatment (507/14091),
while the other 2 deaths occurred during follow-up. None of these 3
patients had an objectively confirmed clinical PE. The ICAC assessed 1
death to be the result of a major bleeding event; Patient 227/12588 in
the ximelagatran group died as the result of a GI hemorrhage on
postoperative Day 8 following his morning dose of study drug. The
remaining 3 deaths in the ximelagatran group were not associated with a
VTE or bleeding event as assessed by the ICAC. Of the 3 deaths occurring
in the warfarin group, none were associated with a VTE or bleeding event
as assessed by the ICAC. All patients who died are listed in Table B15.

**Table B15 Listing of all patients who died**

![](media/image81.png){width="5.7756944444444445in"
height="3.7333333333333334in"}

![](media/image82.png){width="5.742361111111111in"
height="1.6916666666666667in"}

Narratives for patients 6/10829, 227/12588, 235/12122 and 510/14366 are
presented below:

-   Patient 6/10829 was a 43 year old male Caucasian. The subject had a
    history of hyperlipidemia, coronary angiogram, type II diabetes
    mellitus, ischemic colitis, obstructive sleep apnea, ear
    infection, H. pylori, right knee arthroscopy, laminectomy and
    fusion, adenoidectomy and septoplasty. He underwent right total knee
    replacement for osteoarthritis. Operative blood loss was 400 mL, and
    no postoperative drainage volume was reported. The subject received
    the first dose of warfarin placebo approximately 8 hours after
    surgery but did not receive any doses of ximelagatran. On
    postoperative day 1, the subject died suddenly. Based on an autopsy
    performed the next day, cardiac arrhythmia (ventricular
    fibrillation) due to hypertrophic cardiomyopathy was the primary
    cause of death, and hepatomegaly and obesity were secondary causes
    of death. No embolism, infarction, or hemorrhage was reported as
    contributing to death. The mandatory venography was not performed
    for this subject because he died before venography was performed.
    The study investigator assessed these events of cardiac arrhythmia
    (ventricular fibrillation) and hypertrophic cardiomyopathy as not
    related to the study drug.

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-   Patient 227/12588 was an 80 year old male Caucasian. The subject had
    a history of cardiomegaly, abnormal electrocardiogram (EKG),
    bifascicular block, right bundle branch block with left axis
    deviation, benign microhematuria, rotator cuff tear, hiatal hernia,
    right hand tremors, bilateral glaucoma, and umbilical hernia repair.
    He underwent right total knee replacement for osteoarthritis.
    Operative blood loss was 50 mL, and postoperative drainage was 400
    mL. The subject received the first dose of warfarin placebo
    approximately 10 hours after surgery. He received 8 days of
    treatment with ximelagatran 36 mg for a total of 13 doses.
    Postoperatively, the subject had agitation and intermittent
    confusion. On postoperative day 2, the subject developed a decreased
    level of consciousness. Study drug was withheld until the
    neurologist assessed the subject. A computed tomography (CT) scan
    was negative for bleed, lesion, or cerebrovascular accident. Study
    drug continued to be withheld due to drowsiness. Hemoglobin and
    hematocrit were 85 g/ L and 24.1%, respectively. Lasix (furosemide)
    was given intravenously per blood transfusion protocol. On
    postoperative day 7, some non- progressive bruising on the subject's
    thigh was noted. Hemoglobin and hematocrit were 98 g/ L and 28.6%,
    respectively. PT and PTT were elevated above normal reference
    ranges. Cardiac enzymes were within normal range. Red blood cell
    count was below normal limits at 3.24x10^9^/ L. That same day, the
    subject became diaphoretic, pale, and weak, and a large amount of
    melenic stool was found in the bed. He became unresponsive, and his
    blood pressure dropped significantly. Thirty minutes later,
    hemoglobin was decreased to 84 g/ L; red blood cells and hematocrit
    decreased to 2.74x10^9^/ L and 24.9%, respectively. PT, PTT, and BUN
    were above normal limits at 1.4, 40 seconds, and 10.2 mmol/ L,
    respectively. Cardiac enzymes were within normal range. The
    subject's condition continued to deteriorate. Cardiopulmonary
    resuscitation was performed, but the subject expired one hour after
    onset of symptoms. The study investigator and hospital physician
    thought that a massive gastrointestinal bleed had occurred due to
    symptoms of the large melena stool immediately before the event, the
    sudden volume depletion, and peripheral shut down. The autopsy
    assessment note and a review with the coroner concluded the cause of
    death to be a massive upper gastrointestinal bleed due to a chronic
    duodenal ulcer perforation due to anticoagulation. The mortality
    classification status was fatal bleed. The upper gastrointestinal
    bleed was centrally adjudicated as a major bleeding event. The study
    investigator assessed the upper gastrointestinal bleed as related to
    the study drug.

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-   Patient 235/12122 was an 81 years old male Caucasian. The subject
    had a history of coronary artery disease, hyperlipidemia, prostate
    cancer, non- insulin dependent diabetes, hiatal hernia, alcoholism
    (21 drinks/ week), and right total knee replacement. He underwent
    left total knee replacement for osteoarthritis. Operative blood loss
    was 75 mL, and no postoperative drain was used. The subject received
    the first dose of warfarin placebo approximately 4 hours after
    surgery. He received 3 days of treatment with ximelagatran 36 mg for
    a total of 5 doses. On postoperative day 1, the subject received a
    blood transfusion for decreased hemoglobin of 83 g/ L. The subject
    developed confusion after the transfusion (approximately 24 hours
    postoperatively), which the study investigator attributed to alcohol
    withdrawal. The subject was treated with a benzodiazepine
    medication. On postoperative day 2, the subject became aggressive
    and violent, assaulted one of the nurses, and had to be restrained.
    On postoperative day 3, his confusion was still fairly significant.
    The study investigator noted the subject to be improved, fairly
    lucid, and denying any problems in regard to the knee replacement.
    On postoperative day 4, the subject was discovered unresponsive with
    absent vital signs. Resuscitation was attempted but was
    unsuccessful, and the subject expired. An autopsy was performed. The
    coroner stated the subject's death was due to cardiac arrhythmia, on
    the basis of extensive coronary artery disease with no evidence of
    any thromboembolic events. Cardiac arrhythmia was therefore the
    cause of death recorded on the death certificate. The study
    investigator assessed the sudden death as not related to the study
    drug. The mandatory venography was not performed for this subject
    due to his death.

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-   Patient 510/14366 was an 80 years old female Caucasian. The subject
    had a history of hypertension, gastritis, varicose veins,
    perineoplasty, and removal of dorsal sebaceous cyst. She underwent
    right total knee replacement for osteoarthritis. Operative blood
    loss was 300 mL, and postoperative drainage was 1340 mL. The subject
    received the first dose of warfarin placebo approximately 5 hours
    after surgery. She received 7 days of treatment with ximelagatran 36
    mg for a total of 13 doses. The subject was discharged to home on
    postoperative day 4. On postoperative day 7, the subject had a
    mandatory bilateral venogram assessed as positive for intraluminal-
    filling defects in the left muscular and right fibular veins. Both
    legs were classified as having any deep vein thrombosis (DVT)
    distally. The subject received Clexane (heparin- fraction, sodium
    salt) and open- label warfarin sodium for treatment of the DVT. On
    postoperative day 19, the subject's family reported to the study
    investigator that the subject had died at home on postoperative
    day 15. The cause of death was unknown. No autopsy was performed.
    Based on central adjudication, the mortality classification status
    was fatal pulmonary embolism (PE), as PE could not be excluded as
    the cause of the unexplained, undescribed death at home two weeks
    after surgery. The study investigator assessed the death (unknown
    reason) as not related to the study drug.

**Serious adverse events other than deaths**

Of the 2299 patients included in the safety population, 158 patients had
a treatment-emergent SAE, and the proportion of patients with an SAE was
identical in the ximelagatran and warfarin groups (n=79, 6.9% for each).
A summary of the SAEs (including death) experienced by at least 2
patients in either treatment group is provided in Table B16 by preferred
term.

**Table B16 Number (%) of patients with SAEs occurring in at least 2
patients**

![](media/image83.png){width="5.392361111111111in"
height="4.134027777777778in"}

In both treatment groups, the most common SAE was postoperative
complications, occurring in 2.1% of ximelagatran patients and 1.4% of
warfarin patients. Pneumonia and MI were considered serious for more
patients in the ximelagatran group (n=6, 0.5% for both) compared with
the warfarin group (n=1, 0.1% and n=3, 0.3%, respectively). Serious
postoperative complications were experienced by 18 patients, 13 (0.9%)
randomized to ximelagatran and 5 (0.7%) to warfarin. In contrast, atrial
fibrillation and increased INR were considered serious for more patients
in the warfarin group (n=6, 0.5% and n=5, 0.4%, respectively) compared
with the ximelagatran group (n=2, 0.2% for each).

The proportion of patients with SAEs considered related to study
medication by the investigator was similar in the ximelagatran (n=13,
1.1%) and warfarin (n=19, 1.7%) groups. Few patients had serious
postoperative complications that were assessed by the investigator as
related to study drug (5 in the ximelagatran group; 4 in the warfarin
group). Seventeen patients in the ximelagatran group (including 3 who
died) and 19 in the warfarin group (including 2 who died) had treatment
discontinued prematurely as the result of a SAE(s).

Treatment-emergent SAEs were assessed by the ICAC as a major bleeding
event for 8 patients in the ximelagatran group and included GI
hemorrhage (2), postoperative complications (2), hemorrhoids (1),
hemarthrosis (1), purpura (1), and intracranial hemorrhage (1). In the
warfarin group, treatment-emergent SAEs were assessed by the ICAC as
major bleeding events for 4 patients, including hemarthrosis (1),
purpura (1), GI hemorrhage (1), and postoperative complications (1).

**Discontinuations due to adverse events**

A summary of the treatment-emergent AEs leading to discontinuation of
study drug by at least 2 patients in either treatment group is provided
in Table B17 by preferred term in decreasing order of frequency in the
ximelagatran group.

The proportion of patients for whom the investigator coded the AE as
having caused premature discontinuation of study drug was comparable in
the ximelagatran group (n=28, 2.4%) and the warfarin group (n=34, 3.0%).

**Table B17 Number (%) of patients who discontinued from treatment due
to a treatment-emergent adverse event (safety population)**

![](media/image84.png){width="5.425694444444445in"
height="4.334027777777778in"}

**2.11.3 Clinical laboratory evaluation**

At baseline, mean hemoglobin levels and platelet counts were comparable
in the ximelagatran and warfarin groups. There was a steady decline in
hemoglobin levels and platelet counts during the first 3 days
postoperatively in both treatment groups, with the largest mean decrease
in both parameters observed on postoperative Day 3 (mean percent
reduction of 25% to 26% in both groups). By the End of Treatment Period
Study Visit, hemoglobin levels had increased slightly and had returned
to near baseline levels by the end of the follow-up period in both the
ximelagatran and warfarin groups. Mean platelet counts at the End of
Treatment Period Study Visit were elevated above baseline values, likely
due to the receipt of transfusions. Mean platelet count had returned to
near baseline levels during follow-up.

Each of the liver function parameters and total bilirubin were increased
relative to baseline in both treatment groups at the End of Treatment
Period Study Visit and there was no difference between treatment groups
in the magnitude of the increase. In both treatment groups, the largest
mean increase from baseline was observed for ALAT (mean percent increase
of approximately 55%). At follow-up, ALAT, ASAT, and total bilirubin
values were at or near baseline values while alkaline phosphatase values
remained elevated.

The frequencies in measures of liver function outside the extended
reference ranges for liver enzymes (ASAT, ALAT, and alkaline
phosphatase) and total bilirubin are summarized in Table B18.

**Table B18 Frequency of selected liver function test values elevated
above upper limits of normal (safety population)**

![](media/image85.png){width="5.309027777777778in"
height="4.392361111111111in"}

Few patients (\<3%) in the ximelagatran or warfarin groups had
abnormalities outside the extended range at any time point for any of
the liver function parameters. Less than 1% of patients in either
treatment group had increases of \>3x ULN for any liver function
parameter during the study. All patients in both treatment groups with
an elevation in ALAT of \>3x ULN at the end of treatment or at follow-up
(ie, more than 2 days after the last dose of study medication), had
normalized values within 4 weeks of onset. It should be noted that there
were more patients with ALT elevation ([\>]{.underline} 3ULN) in
ximelagatran group (n=7) than in the warfarin group (n=2) during the
following up period. This may indicate that ximelagatran may cause late
occurrence of liver toxicity and 4-6 weeks of follow-up may not be
adequate to assess the safety for short-term use of ximelagatran.

**2.11.4 Conclusions on safety results**

There were no statistically significant differences between ximelagatran
and warfarin in the frequency of major bleeding events, the frequency of
minor bleeding events, or the frequency of any (major and minor)
bleeding events on-treatment or over the entire study
(p[\>]{.underline}0.087). With the exception of a significantly higher
incidence of unusual bruising or hematoma on postoperative Day 3 in the
ximelagatran group compared with the warfarin group (p=0.015), there
were no significant differences between treatment groups at any other
time point in the incidence of any other wound assessments
(p[\>]{.underline}0.245).

No appreciable differences were detected between treatment groups in the
incidence of treatment-emergent AEs, SAEs, or discontinuations due to
study drug. However, a larger number of patients in the ximelagatran
group died (n=7) compared with the warfarin group (n=3). MI was
considered serious for more patients in the ximelagatran group (n=6,
0.5%) compared with the warfarin group (n=3, 0.3%, respectively). It
should be noted that there were more patients with ALT elevation
([\>]{.underline} 3ULN) in ximelagatran group (n=7) than in the warfarin
group (n=2) during the following up period. This may indicate that
ximelagatran may cause late occurrence of liver toxicity and 4-6 weeks
of follow-up may not be adequate to assess the safety for short-term use
of ximelagatran.

**3 Study SH-TPV-0003 (THRIVE III)** **for the** **Indication of
Prolonged prophylaxis VTE after a six-month anticoagulation treatment
for VTE**

The sponsor provided only one study, SH-TPV-0003 (THRIVE III) to support
this indication. This was a multicentre, double-blind, parallel-group,
placebo control study.

Title: Oral Thrombin Inhibitor Ximelagatran given to Patients as
Prolonged Prophylaxis after a Six-month Anticoagulation Treatment for
Venous Thromboembolism. An International Multicentre Double-blind
Placebo Controlled Study (THRIVE III)

**3.1 Study objectives**

**Primary objectives**

To assess whether the oral thrombin inhibitor ximelagatran given as
prolonged prophylaxis after a six-month anticoagulation treatment for
VTE reduces the recurrence rate of symptomatic objectively confirmed VTE
event compared to placebo (time to event).

**Secondary objectives**

To estimate all-cause mortality, the safety of treatment with
ximelagatran with special regard to bleeding and the pharmacokinetics of
melagatran during long term treatment with ximelagatran.

**3.2 Overall study design**

This was a double-blind, randomized, placebo-controlled, parallel-group
multi-center study comparing the efficacy and safety of ximelagatran 24
mg twice daily with placebo when given orally as long term secondary
prevention for 18 months to patients after a six-month anticoagulation
treatment for VTE.

The clinical endpoints were symptomatic objectively confirmed VTE,
non-fatal or fatal, and all-cause mortality and major bleeding. The
primary variable was time to symptomatic objectively confirmed VTE event
during 18 months of treatment.

A total of 1,200 patients at approximately 150 centers in 18 countries,
with roughly 10 (6-20) patients per center, were planned to be
randomized into the study.

The study comprised the following 4 periods:

**Anticoagulant and wash-out periods**

Patients who had received anticoagulation treatment for six (five to
seven) months after an objectively verified, symptomatic VTE were to be
included. Dates for the bilateral ultrasonography of the legs and the
perfusion scan of the lungs (baseline) were to be scheduled shortly
before randomization. The patients were instructed to stop treatment
with vitamin K antagonist (VKA) two to seven days before the scheduled
randomization visit.

### 

**Randomization**

The randomization was stratified on the basis of the presence or absence
of known active malignancy during the past five years. The patients were
randomized in equal proportions to receive either ximelagatran tablets
24 mg or placebo tablets orally twice daily for 18 months.

**18-month randomized treatment period**

Study visits were scheduled at two weeks and four weeks and then every
month (three to five weeks) during the first six months after the
randomization and thereafter every three months (10-14 weeks).

**Follow-up period**

A follow-up visit was to be planned two weeks after completing the
randomized treatment period.

### 

**3.3 Selection of study population**

The first exclusion criterion (patients with a need of continuous
treatment with anticoagulants) implies that patients considered to be at
high risk of recurrence were not to be included in the study. This
criterion was set for ethical reasons, since it would not have been
appropriate to randomize this type of patient to treatment with placebo.

**Inclusion criteria**

For inclusion in the study, patients had to fulfill all of the following
criteria:

1\. Patients with symptomatic objectively confirmed VTE treated with
anticoagulants for six months (no recurrent VTE was allowed during this
period)

2\. Age [\>]{.underline}18 years

3\. Signed informed consent

**Exclusion criteria**

Any of the following was regarded as a criterion for exclusion from the
study:

> 1\. Patients with a need of continuous treatment with anticoagulants

2\. Conditions associated with an increased risk of bleeding

3\. Anemia (Hb \< 90 g/L)

4\. Platelet count \< 90x10 ^9^ /L

5\. Renal impairment (calculated creatinine clearance \< 30 mL/min)

6\. Known clinically significant liver disease (as judged by the
investigator) or persistent ASAT and/or ALAT [\>]{.underline} 3 x ULN
(defined by central laboratory)

7\. Pregnancy and/or lactation

8\. Childbearing potential without reliable contraception

9\. Concomitant treatment with other anticoagulant, antiplatelet or
fibrinolytic agents; continuous treatment with acetylsalicylic acid
(ASA) \>500 mg per day or continuous treatment with NSAID.

10\. Participation in an interventional clinical study during the last
three months

11\. Planned surgery

12\. Involvement in the planning and conducting of the study

13\. Previous randomization in the present study

14\. Known drug addiction and/or alcohol abuse

15\. Mental condition preventing understanding of the study

16\. Poor compliance, as evidenced during the six months of
anticoagulation treatment before randomization, as judged by the
investigator

17\. Serious illness, with survival for 18 months being unlikely ie,
terminally ill patients

**3.4 Criteria for discontinuation**

1\. Patients for whom the treatment code was prematurely broken were
withdrawn from further study treatment and assessments.

2\. Major bleeding.

3\. Objectively confirmed venous thromboembolic event.

4\. Other AEs severe enough to necessitate discontinuation of study drug
administration.

5\. If a pregnant woman was included by mistake or a woman became
pregnant.

Discontinuation of the study drug should also have been considered if:

-   S-ALAT was \>7 times the ULN

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-   Repeated measurements showed that S-ALAT was 3-7 times the ULN
    during a 2- month period without showing any tendency to decrease.

**3.5 Doses and treatment regimens**

The patients were randomized to treatment with either one 24-mg
ximelagatran tablet twice daily or one tablet of placebo twice daily,
taken orally in the morning and in the evening for 18 months.

**3.6 Efficacy variable**

**Primary variable**

The primary variable was time to symptomatic objectively confirmed VTE
event during the 18 months of treatment or until premature
discontinuation of the study.

**Secondary variable**

Time to death from any cause and time to major bleeding event, during 18
months of treatment or until premature discontinuation of the study (ITT
population).

**3.7 Statistical analysis methods**

In the primary analysis, only centrally adjudicated events are
considered as events. Because of the long treatment period, the number
of drop-outs in the study was expected to be substantial. Therefore, the
equality of time until event between ximelagatran and placebo is tested
with a log rank test. Due to the independent Safety Committee monitoring
for a positive trend of the pre-planned interim analyses, the
significance level for the primary analysis is 4.76%. For all other
analyses a significance level of 5% is used. Survival curves for the
time to event, based on Kaplan-Meier estimates, are presented, as is the
estimated risk for an event by 3, 6, 9, 12, 15 and 18 months. The hazard
ratio between treatments is estimated together with 95% confidence
intervals using a Cox-regression model assuming a proportional hazard.

Data from the 18-month follow-up of prematurely discontinued patients
will be presented together with the original study data. The combined
data will be analyzed as a complementary ITT analysis using the same
methods as described above. The events collected at the 18-month
follow-up will not be centrally adjudicated, however.

Time until death by any cause, locally confirmed VTE events, the
composite of VTE event and death of any cause, major and major and/or
minor bleedings are analyzed and presented using the same methods as for
the primary variable.

Descriptive statistics and frequency tables on pertinent variables are
calculated for baseline demographics, days on study medication,
compliance, laboratory variables, ECG, physical examinations and vital
signs. In addition, time to elevated ALAT is presented using Kaplan-
Meier estimates. The influence of the potential prognostic factors
mentioned above on the risk for ALAT \>3 x ULN is investigated using
logistic regression. Logistic regression is used in these analyses since
an assumption of proportional hazard is unrealistic. Adverse events are
presented using frequency tables.

**3.8 Disposition**

Of the 1356 patients enrolled, 1233 were randomized at 142 centers and
903 completed the study. The most common reason for premature
termination the study was adverse event. Patient disposition and reason
for premature study discontinuation are summarized in Figure 1. In the
placebo group locally confirmed VTE recurrence was the most common
reason for premature discontinuation of the study. In general,
discontinuations for other reasons than VTE were slightly more common in
the ximelagatran group.

![](media/image86.png){width="4.934027777777778in"
height="4.959027777777778in"}

There were no major differences between treatment groups in the number
of patients who had protocol deviations that were considered serious
enough to warrant exclusion of data from the PP analyses. Overall, the
treatment groups were comparable for demographic characteristics,
baseline parameters, treatment compliance and use of concomitant
medication. The major part of the patients (93%) were Caucasians.

**Patient populations analyzed**

Three patient populations were analyzed:

-   An ITT efficacy population, which included all randomized patients
    who had taken at least one dose of the study treatment and had at
    least one data point after randomization. This population was the
    primary population for analysis.

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-   A PP efficacy population, which included all patients in the ITT
    population who had no deviations from the protocol judged to affect
    the treatment effect. However, some patients who had a major
    deviation are included in the analyses up to the time of that
    deviation.

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```
-   A safety population, which included the same patients as in the ITT
    population.

The patient populations analyzed and the number of patients in each
population are summarized in Figure 2.

![](media/image87.png){width="5.959027777777778in"
height="7.075694444444444in"}

Of the 1233 randomized patients, 10 patients had no data after
randomization, 5 of them randomized to ximelagatran and 5 to placebo. Of
the 5 patients on ximelagatran, 3 patients were also confirmed not to
have received any study medication, as can be seen in Figure 2.

Consequently, 1223 patients were analyzed for safety and efficacy in an
ITT population. Among 1015 of the patients, all or a portion of the data
was included in the PP analysis. Among 725 of the patients, all
available data were included in a complete PP analysis. The most common
reason for the exclusion of data was non-compliance as regarded the
study drug.

**3.9 Demographic and other patient characteristics**

Overall, the demographic and other patient characteristics were
comparable between the treatment groups. The demographic and baseline
characteristics for the ITT population are summarised in Table C1.

**Table C1 Demographics and baseline characteristics, ITT population**

![](media/image88.png){width="5.250694444444444in"
height="1.3416666666666666in"}

### 

### 

### 

### ![](media/image89.png){width="5.334027777777778in" height="7.100694444444445in"}

Information on the initial VTE event in the ITT population is summarized
in Table C2.

### 

### Table C2: Information on initial VTE, ITT population

![](media/image90.png){width="5.309027777777778in"
height="4.992361111111111in"}

![](media/image91.png){width="5.300694444444445in"
height="1.0666666666666667in"}

The majority of the patients (97%) in both groups started the study
medication within 3 days after randomization, and the number of days
between randomization and the first dose of medication was comparable
between the treatment groups.

The median time on study medication was slightly above 500 days, which
is shorter than the anticipated 18 months (approximately 540 days). This
might be explained by the flexibility in the time interval between
visits allowed according to the protocol.

The use of concomitant medication at study entry was similar in the two
treatment groups.

**Conclusions on study patients**

The study population, as demonstrated by baseline characteristics,
includes important

subgroups of a general population of patients with previous VTE.
Different age groups were adequately represented and the balance between
the sexes was appropriate. Patient weights were widely distributed and
obese patients were well-represented. Fourteen percent of the patients
had a history of more than one previous VTE event.

A total of 5% of patients with known malignancy at entry was enrolled in
this study.

A limitation of the study population is the exclusion of patients with
known liver disease and/or elevations in liver enzymes (ASAT and/or
ALAT) at entry, and of patients with severely impaired renal function,
as specified in the exclusion criteria. Consequently, the results of
this study cannot safely be extended to these subgroups of the VTE
population.

3.10 Efficacy results

**3.10.1 Primary variable: symptomatic objectively-confirmed VTE, ITT
population**

The estimated cumulative risk of symptomatic objectively-confirmed VTE
during 18 months of treatment was 2.8% and 12.6% for patients on
ximelagatran and placebo, respectively, see Table C3.

**Table C3 Estimated cumulative risk (%) of a VTE event, ITT
population**

![](media/image92.png){width="5.425694444444445in"
height="2.183333333333333in"}

The estimated hazard ratio between treatments is 0.16 (95% CI 0.09; 0.30
and p\< 0.0001). According to the outcome of the primary analysis,
ximelagatran significantly reduced the recurrence rate of symptomatic,
objectively confirmed VTE events as compared to placebo (p\<0.0001).

The number of patients with a VTE event was 12 in the ximelagatran group
and 71 in the placebo group. The number of patients with a PE event was
lower in the ximelagatran group compared to the placebo group, 2 and 23,
respectively. Number of patients with a VTE event is summarized in Table
C4.

**Table C4 Number of patients with a VTE event, ITT population**

![](media/image7.png){width="5.3590277777777775in"
height="0.9416666666666667in"}

Of the VTE events described in Table C4, 3 occurred during the follow-up
period i.e., after

cessation of study medication (2 patients in the ximelagatran group and
1 in the placebo

group).

### 

The location of DVT is summarized in Table C5, the total numbers of
proximal DVT were fewer in the ximelagatran group than in the placebo
group, 6 and 41 respectively.

#### **Table C5 Location of DVT events, ITT population**

### 

### ![](media/image93.png){width="5.3590277777777775in" height="0.9166666666666666in"}

### 

**3.10.2 Secondary variables**

**All cause mortality, ITT population**

There were few deaths and they were evenly distributed, 6 in the
ximelagatran group and 7 in the placebo group. The estimated cumulative
risk of a death (all-cause mortality) during 18 months of treatment was
1.1% and 1.4% for patients on ximelagatran and placebo, respectively.
The estimated hazard ratio between treatments is 0.83 (95% CI 0.28;
2.46, p=0.7289). According to the outcome of the secondary analysis,
there was no significant difference in all-cause mortality between the
treatment groups during the 18 months.

**All-cause mortality and/or VTE events, ITT population**

The total number of patients who died and/or experienced a VTE event was
18 in the ximelagatran group and 75 in the placebo group. The estimated
hazard ratio between treatments is 0.23, p\< 0.0001. Ximelagatran
significantly reduced the recurrence rate of the combined endpoint,
all-cause mortality and/or VTE events, compared to placebo (p\<0.0001).
The magnitude is similar to the difference seen with VTE event only.

**Locally confirmed VTE events, ITT population**

The agreement between the local investigator's judgement and the central
adjudication by the independent Endpoint Committee was generally good,
with few discrepancies. Consequently, the analysis of locally judged VTE
events gave results similar to those for the centrally adjudicated
events. Patients with suspected VTE events with local assessment versus
central adjudication are summarized in Table C6.

**Table C6 Patients with suspected VTE events. Local assessment versus
central adjudication, ITT population**

![](media/image94.png){width="4.959027777777778in"
height="1.3583333333333334in"}

By local assessment, the total number of patients who experienced a VTE
event was 13 in the ximelagatran group and 75 in the placebo group. The
estimated hazard ratio between treatments is 0.17, p\< 0.0001. The
difference between the treatments was statistically significant and of
the same magnitude as in the case of the centrally confirmed events used
in the primary efficacy analysis.

**3.10.3 Summary of efficacy results**

Ximelagatran significantly reduced the recurrence rate of symptomatic,
objectively confirmed VTE (the primary variable of the study) as
compared to placebo over 18 months of treatment (cumulative risk of 2.8%
versus 12.6%; hazard ratio 0.16; p\<0.0001). The results for the
secondary variable, all-cause mortality, showed no significant
difference between the treatment groups during the 18 months.
Ximelagatran also reduced the recurrence rate of the composite endpoint,
VTE and all-cause mortality, thereby supporting the results obtained for
the primary objective. Complementary intention-to-treat analyses in
randomized patients followed for the full intended 18 months period,
regardless of any premature study medication discontinuation, did not
change the aforementioned conclusions.

**3.11** **Safety results**

See integrated review of safety for details.