Disclosure Information … The following relationships exist related to this presentation:
description
Transcript of Disclosure Information … The following relationships exist related to this presentation:
Disclosure Information…The following relationships exist related to this presentation:
Michael R. Lassen Consulting Fees sanofi-aventis Modest Level
Dirk Zielske Employee sanofi-aventis 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 Modest level
SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip Replacement Surgery – DRIVE: a Dose Ranging Study
SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total
Hip Replacement Surgery – DRIVE: a Dose Ranging Study
Michael Rud LassenHørsholm Hospital, University of Copenhagen, Denmark
On behalf of Ola Dahl, Patrick Mismetti, Dirk Zielske, A.Graham Turpie, and the DRIVE Investigators
SR123781A
▲ Synthetic hexadecasaccharide
▲ Mixed profile of antithrombin-dependent anti-Factor Xa
and anti-factor IIa activities
▲ Completely absorbed after subcutaneous injection
▲ Half-life 11–16 h
▲ Dose-proportional and linear PK over doses studied,
0.8–18 mg
Antithrombin domainSpacerThrombin domain
OO
O
O O
O
O OO
O
OO
O
O
SO3-
SO3-
SO3-
SO3-
SO3-
-OOC
-OOC
SO3-
OMeO MeO
MeO
MeOOMe O OMe
OMe
MeOOO
O O
O
SO3-
SO3-
SO3-
OO
O
O O
O
SO3-
SO3-
SO3-
O
O O
O
SO3-
SO3-
SO3-
O
-O3SO
O
MeOMeO
OO
MeOMeO
OMe
O
OMeO
O
MeO MeO
OMe
MeO
OMe
-O3S 3
19 Na+
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
Sulphatedtetrasaccharide
PentasaccharideSulphated
tetrasaccharidePentasaccharide
SR123781ASynthetic Hexadecasaccharide
T domain =Tetrasaccharide
sequence
factor Xa
AT
ArgArgLys
A domain =Pentasaccharide
sequence
neutralspacer
Inhibition of activated Factor X
T domain =Tetrasaccharide
sequence
AT
ArgArgLys
A domain =Pentasaccharide
sequence
thrombin
neutralspacer
Inhibition of activated Factor II (Thrombin)
Study 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
DRIVE: graphical study design
Day 30 ±3
Patients 18 years
Undergoing elective
total hip replacement
surgery
End of treatment visit
Mandatory bilateral venography
Randomization (Day-1)
Surgery (Day1)
SR123781A 0.25 mg
enoxaparin 40 mg
Follow-up period
SR123781A 0.5 mg
SR123781A 1.0 mg
SR123781A 2.0 mg
SR123781A 4.0 mg
5 – 10 daysDouble blind, double dummy
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
Day 5 – 11
Main 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)
DRIVE populations
SR123781A Enox
0.25 mg 0.5 mg 1 mg 2 mg 4 mg 40 mg
All randomized 172 164 172 170 176 169
Safety population 171 163 170 168 171 166
Primary efficacy population
118 124 126 128 114 126
DRIVE demographics
BMI: body mass index; CrCL: creatinine clearance
SR123781A Enox
0.25 mg 0.5 mg 1 mg 2 mg 4 mg 40 mg
Median age, years 59 60 60 60 58 59
Age range, years 25–86 18–86 33–83 25–90 23–86 28–83
Age ≥75 years, % 9.9 11.7 8.2 8.9 7.0 9.0
Female, % 58.5 58.9 58.8 58.3 57.9 61.4
BMI ≥30 kg/m2, % 33.5 22.1 34.1 26.8 29.2 28.9
Baseline CrCL, %
<30 mL/min 1.2 0.6 1.2 0 0 1.2
≥30 – <50 mL/min 5.3 4.3 5.9 7.7 7.6 4.2
Surgical characteristics and treatment exposure
SR123781A Enox0.25 mgN=171
0.5 mgN=163
1 mgN=170
2 mgN=168
4 mgN=171
40 mgN=166
Mean duration of surgery ± SD, min 92 ± 44 87 ± 34 89 ± 36 91 ± 39 95 ± 44 89 ± 36
Use of cement, % 39.8 39.3 42.4 36.5 36.8 37.3
Anesthesia type, %
General only 19.9 17.2 15.9 13.8 15.8 15.7
Regional only 77.8 81.6 82.4 83.8 81.3 82.5Post-op treatment exposure, median (range), days
9 (1–11) 9 (4–11) 9 (4–11) 9 (4–11) 8 (1–11) 9 (2–11)
Primary efficacy endpoint
SR123781A Enox
0.25 mg
N=118
0.5 mg
N=124
1 mg
N=126
2 mg
N=128
4 mg
N=114
40 mg
N=126
Any VTE
n
%
95% CI
25
21.2
14.2–29.7
22
17.7
11.5–25.6
17
13.5
8.1–20.7
9
7.0
3.3–12.9
5
4.4
1.4–9.9
11
8.7
4.4–15.1
Significant dose response: p-value = 0.0001
Primary efficacy endpoint
SR123781A
0.25 mg 0.5 mg
61% RRR [33–84] p=0.0015
79% RRR [50–92] p=0.0001
0
10
20
30
40
1 mg 2 mg 4 mgenoxaparin
40 mg
Any
VT
E (
%)
Secondary efficacy endpoints
SR123781A Enox0.25 mg 0.5mg 1mg 2mg 4 mg 40 mg
Proximal DVT n/N % 95% CI
9/1356.7
3.1–12.3
9/1436.3
2.9–11.6
2/1471.4
0.2–4.8
1/1490.7
0.0–3.7
0/1300.0
0.0–2.8
2/1361.5
0.2–5.2
Distal DVT n/N % 95% CI
16/11713.7
8.0–21.3
14/12511.2
6.3–18.1
15/12512.0
6.9–19.0
8/1316.1
2.7–11.7
5/1154.3
1.4–9.9
10/1277.9
3.8–14.0
Significant dose response in proximal DVT( p = 0.0001)
No Symptomatic VTE were observed in any of the groups
Bleeding assessment
SR123781A Enox
0.25 mg
N=171
0.5 mg
N=163
1 mg
N=170
2 mg
N=168
4 mg
N=171
40 mg
N=166
Major, n (%)
95% CI
2*‡ (1.2)
0.1–4.2
1** (0.6)
0.0–3.4
1** (0.6)
0.0–3.2
1‡ (0.6)
0.0–3.3
10§ (5.8)
2.8-10.5
1‡ (0.6)
0.0–3.3
Minor, n (%)
95% CI
5 (2.9)
1.0–6.7
8 (4.9)
2.1–9.4
4 (2.4)
0.6–5.9
10 (6.0)
2.9–10.7
32 (18.7)
13.2–25.4
5 (3.0)
1.0–6.9
Any, n (%)
95% CI
7 (4.1)
1.7–8.3
9 (5.5)
2.6–10.2
5 (2.9)
1.0–6.7
11 (6.5)
3.3–11.4
42 (24.6)
18.3–31.7
6 (3.6)
1.3–7.7
Significant dose response in major bleeding: p-value = 0.0037 any bleeding: p-value < 0.0001
*Fatal; **Surgical site leading to intervention; ‡ Non-surgical with bleeding index ≥2; §5** and 5‡
0.25 0.5 1 2 4 40
SR123781A (mg) Enoxaparin (mg)
An
y V
TE
(%
)
0
5
10
15
20
25
30
35
DRIVE summary of results
0.25 0.5 1 2 4 40
SR123781A (mg) Enoxaparin (mg)
Maj
or
ble
edin
g (
%)
0
5
10
15
20
25
30
35
DRIVE summary of results
0.25 0.5 1 2 4 40
SR123781A (mg) Enoxaparin (mg)
An
y V
TE
(%
)
0
5
10
15
20
25
30
35
Maj
or
ble
edin
g (
%)
0
5
10
15
20
25
30
35
DRIVE summary of results
Safety evaluation
SR123781A Enox0.25 mg
N=1710.5 mgN=163
1 mgN=170
2 mgN=168
4 mgN=171
40 mgN=166
Any averse event, n (%)
58 (33.9) 68 (41.7) 54 (31.8) 55 (32.7) 103 (60.2) 60 (36.1)
Drug-related 13 (7.6) 12 (7.4) 9 (5.3) 17 (10.1) 51 (29.8) 7 (4.2)
Serious 4 (2.3) 3 (1.8) 5 (2.9) 1 (0.6) 20 (11.7) 3 (1.8)
Leading to study discontinuation
2 (1.2) 0 2 (1.2) 1 (0.6) 12 (7.0) 3 (1.8)
Severe Intensity 4 (2.3) 2 (1.2) 3 (1.8) 1 (0.6) 16 (9.4) 2 (1.2)
Leading to death 1*(0.6) 0 0 0 1**(0.6) 0
*Fatal bleeding; **encephalopathic brain hypoxia unrelated to bleeding or VTE
DRIVE 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