Title: SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip R
1SR123781A, a New Synthetic Anticoagulant for the
Prevention of Venous Thromboembolism in Total Hip
Replacement Surgery DRIVE a Dose Ranging Study
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Michael R. Lassen Consulting Fees sanofi-aventis
Modest Level Dirk Zielske Employee sanofi-av
entis Significant Level Ola Dahl Consulting
Fees sanofi-aventis Modest Level Patrick Mismetti
Consulting Fees sanofi-aventis Modest Level A.
Graham Turpie Consulting Fees sanofi-aventis Modes
t level
2SR123781A, a New Synthetic Anticoagulant for the
Prevention of Venous Thromboembolism in Total Hip
Replacement Surgery DRIVE a Dose Ranging Study
- Michael Rud Lassen
- Hørsholm Hospital, University of Copenhagen,
Denmark - On behalf of Ola Dahl, Patrick Mismetti, Dirk
Zielske, A.Graham Turpie, and the DRIVE
Investigators
3SR123781A
- Synthetic hexadecasaccharide
- Mixed profile of antithrombin-dependent
anti-Factor Xa and anti-factor IIa activities - Completely absorbed after subcutaneous injection
- Half-life 1116 h
- Dose-proportional and linear PK over doses
studied, 0.818 mg
4SR123781ASynthetic Hexadecasaccharide
Antithrombin domain
Spacer
Thrombin domain
Sulphated tetrasaccharide
Pentasaccharide
Sulphated tetrasaccharide
Pentasaccharide
The 2 functional domains are separated by a
central, non sulphated, heptasaccharide This
"spacer" has been introduced to create charge
"clusters" to minimize non-specific interactions
5Inhibition of activated Factor X
neutral spacer
T domain Tetrasaccharidesequence
A domain Pentasaccharidesequence
factor Xa
Arg
Arg
Lys
AT
6Inhibition of activated Factor II (Thrombin)
T domain Tetrasaccharidesequence
neutral spacer
A domain Pentasaccharidesequence
thrombin
Arg
Arg
Lys
AT
7Study Aim
- The objective of this study was to assess the
dose-response of SR123781A for the prevention of
venous thromboembolism in patients undergoing
total hip replacement. - To investigate a 16-fold dose range of SR123781A
(0.25 mg 4.0 mg once daily) - To use 40 mg of enoxaparin once daily as
calibrator
8DRIVE graphical study design
Follow-up period
5 10 days
Double blind, double dummy
SR123781A 0.25 mg
SR123781A 0.5 mg
Patients ?18 years Undergoing elective total hip
replacement surgery
SR123781A 1.0 mg
SR123781A 2.0 mg
SR123781A 4.0 mg
enoxaparin 40 mg
Day 30 3
Day 5 11
End of treatment visit Mandatory bilateral
venography
Randomization (Day-1) Surgery (Day1)
All regimens injected subcutaneously once
daily SR123781A administration to be started 8 1
hours post-operatively, enoxaparin 12 1 hours
pre-operatively, or post-operatively in case of
loco-regional anesthesia
9Main endpoints
- Efficacy
- Composite of any deep-vein thrombosis (DVT),
non-fatal pulmonary embolism (PE), venous
thromboembolism (VTE)-related death up to Day11 - Safety Major bleeding
- Surgical site bleeding leading to intervention
- Non-surgical site bleeding retroperitoneal or
intracranial or into a critical organ, or leading
to intervention, or overt bleeding with a
bleeding index ? 2 - Fatal bleeding
- All outcomes were confirmed by an independent and
blinded Adjudication Committee (Hamilton, Canada)
10DRIVE populations
11DRIVE demographics
BMI body mass index CrCL creatinine clearance
12Surgical characteristics and treatment exposure
13Primary efficacy endpoint
Significant dose response p-value 0.0001
14Primary efficacy endpoint
15Secondary efficacy endpoints
Significant dose response in proximal DVT( p
0.0001)
No Symptomatic VTE were observed in any of the
groups
16Bleeding assessment
Significant dose response in major bleeding
p-value 0.0037
any bleeding p-value lt 0.0001
Fatal Surgical site leading to intervention
Non-surgical with bleeding index 2 5 and 5
17DRIVE summary of results
35
30
25
20
Any VTE ()
15
10
5
0
0.25
0.5
1
2
4
40
Enoxaparin (mg)
SR123781A (mg)
18DRIVE summary of results
35
30
25
20
Major bleeding ()
15
10
5
0
0.25
0.5
1
2
4
40
Enoxaparin (mg)
SR123781A (mg)
19DRIVE summary of results
20Safety evaluation
Fatal bleeding encephalopathic brain hypoxia
unrelated to bleeding or VTE
21DRIVE conclusions
- SR123781A displayed
- A highly significant dose-response in the
prevention of VTE over a 16-fold dose range - A significant dose-response for any bleeding and
major bleeding - SR123781A doses ranging 1.5 2.5 mg demonstrated
a reasonable risk-to benefit ratio for the
prevention of VTE in patients undergoing major
orthopedic surgery