OPAL-1
Safety and Tolerability of YM150 in Subjects
with Non-valvular Atrial Fibrillation: a Phase II
Study
Alexander GG Turpie, Gregory YH Lip, Kazuo
Minematsu, Shinya Goto, Ronny W Renfurm and
KS Lawrence Wong
Profile of YM150
Direct factor Xa inhibitor
Rapid absorption
Active metabolite – YM222714
Peak YM222714 concentration at ~2 hours
Half-life 14−18 hours
Excretion route (renal/faeces: 50/50%)
Predictable PK/PD profile
Minimal food interaction
Iwatsuki Y, et al. Blood (ASH Annual Meeting Abstracts) 2006;108:Abstract 911; Turpie AG. Eur Heart J 2008;29(2):155-65; Kaku S, et al. Blood
(ASH Annual Meeting Abstracts) 2007;110:Abstract 3153; Saitoh M, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:Abstract 3155;
Turpie AG. Arterioscler Thromb Vasc Biol 2007;27(6):1238-47
YM150: Direct Factor Xa Inhibitor
Turpie AG. Arterioscler Thromb Vasc Biol 2007;27(6):1238-47
Study Design
12-week, prospective, multicentre, randomized, parallel-group, dosefinding study
Double-blind YM150 30, 60, 120 and 240 mg once-daily (qd), or
open-label warfarin
4-week follow-up period
Study sites:
 Japan, Singapore, Malaysia, Taiwan, Korea, Hong Kong, New
Zealand, Thailand and South Africa
Inclusion and Exclusion Criteria
Inclusion criteria
 Paroxysmal, permanent or persistent NVAF
 CHADS2 score 1–6
 INR ≤2.0
 aPTT ≤1.5 x ULN
Exclusion criteria
 Active bleeding
 Increased risk of bleeding
 Uncontrolled severe hypertension at screening (systolic and/or diastolic
blood pressure ≥180 and ≥110 mmHg, respectively)
 Haemoglobin values <10 g/dL and/or platelet count <100x109/L at screening
Randomized subjects
 N=448
NVAF=non-valvular atrial fibrillation; INR=internal normalization ratio aPTT=activated partial thromboplastin time; ULN=upper limit of normal
Study Flow
*14 days (7–28 days before baseline); †Group terminated early based on the Data and Safety Monitoring Board's recommendation regarding the
observed bleeding rate; ‡Stratified by warfarin use and region
Study Outcomes
Primary outcome
Major and clinically relevant non-major bleeding during the treatment
period
Secondary outcomes
Safety
Adverse events (AEs)
Laboratory tests (liver function [ALT and AST] and renal function
[serum creatinine])
Efficacy
Incidence of symptomatic stroke, transient ischaemic attack, systemic
thromboembolic events and all-cause death
ALT=alanine aminotransferase ;AST=aspartate aminotransferase
Subject Demographics
448 subjects randomized and treated
74 subjects stopped early
 AEs − 38%
 Withdrawal of consent − 8%
 Protocol deviation − 8%
 Discontinuation of 240 mg arm − 40%
 Other – 6%
Mean exposure was 80 days (range 77.0–80.6 days)
Mean treatment compliance was 95% (range 94.3–97.0%)
International Normalization Ratio Control
Proportion of subjects in target INR range in the warfarin group
Subjects aged <70 years
Subjects aged ≥70 years
Week 1
18.5
57.5
Week 2
31.5
44.7
Week 4
26.9
46.2
Week 8
45.3
43.2
Week 12
41.7
50.0
INR=international normalization ratio
Regional guidance in Asia-Pacific recommends that a lower INR (1.6−2.6) be used
in elderly subjects to reduce the risk of bleeding events1,2
1Yasaka
M ,et al. Intern Med 2001;40(12):1183−88; 2Shinohara Y, et al. Int J Stroke 2008; 3(1):55−62
Baseline Characteristics
YM150, n (%)
Warfarin, n
30 mg
60 mg
120 mg
240 mg
(%)
(N=90)
(N=93)
(N=93)
(N=78)
(N=94)
Male, n (%)
77 (85.6)
71 (76.3)
74 (79.6)
60 (76.9)
72 (76.6)
Mean (SD) age, years
69.3 (8.4)
68.4 (9.4)
67.0 (9.6)
67.4 (9.0)
67.0 (9.4)
68 (75.6)
64 (68.8)
55 (59.1)
48 (61.5)
61 (64.9)
25.9 (3.9)
26.4 (4.8)
26.3 (4.8)
26.4 (4.8)
25.9 (5.0)
Paroxysmal
22 (24.4)
20 (21.5)
17 (18.3)
17 (21.8)
21 (22.3)
Persistent
22 (24.4)
37 (39.8)
26 (28.0)
22 (28.2)
24 (25.5)
Permanent
46 (51.1)
36 (38.7)
50 (53.8)
39 (50.0)
49 (52.1)
Previous use of warfarin, n (%)
59 (65.6)
59 (63.4)
59 (63.4)
49 (62.8)
60 (63.8)
Previous use of aspirin, n (%)
31 (34.4)
32 (34.4)
33 (35.5)
32 (41.0)
32 (34.0)
27 (30)
24 (26)
25 (27)
25 (32)
31 (33)
CHADS2 1 or 2, n (%)
69 (76.7)
74 (79.6)
69 (74.2)
60 (76.9)
77 (81.9)
CHADS2 ≥3, n (%)
21 (23.3)
19 (20.4)
24 (25.8)
18 (23.1)
17 (18.1)
Aged ≥65 years, n (%)
Mean (SD) BMI, kg/m2
NVAF status at baseline, n (%)
Use of concomitant aspirin during
the trial, n (%)
SD=standard deviation; BMI=body mass index; NVAF=non valvular atrial fibrillation
Subject Disposition
*These 30 subjects discontinued the trial due to termination of the YM150 240 mg dose group based on the Data and Safety Monitoring Board's
recommendation; AE=adverse event
Primary Outcome: Percentage of Patients
with Major and/or CRNM bleeding
0.3,7.8*
CRNM=clinically relevant non-major
0.3, 7.6*
0.7, 9.1*
9.2, 26.8*
0.3, 7.5*
Bleeding Events
YM150, n (%)
Major and CRNM
bleeding, n (%)
95% CI
Major bleeding
95% CI
CRNM bleeding
95% CI
Minor bleeding
95% CI
Any bleeding
95% CI
Warfarin, n
30 mg
60 mg
120 mg
240 mg
(%)
(N=90)
(N=93)
(N=93)
(N=78)
(N=94)
2 (2.2)
2 (2.2)
3 (3.2)
13 (16.7)
2 (2.1)
0.3, 7.8
0.3, 7.6
0.7, 9.1
9.2, 26.8
0.3, 7.5
0
0
0
1 (1.3)*
0
0.0, 4.0
0.0, 3.9
0.0, 3.9
0.0, 6.9
0.0, 3.8
2 (2.2)
2 (2.2)
3 (3.2)
12 (15.4)
2 (2.1)
0.3, 7.8
0.3, 7.6
0.7, 9.1
8.2, 25.3
0.3, 7.5
13 (14.4)
12 (12.9)
15 (16.1)
13 (16.7)
15 (16.0)
7.9, 23.4
6.8, 21.5
9.3, 25.2
9.2, 26.8
9.2, 25.0
14 (15.6)
14 (15.1)
17 (18.3)
23 (29.5)
17 (18.1)
8.8, 24.7
8.5, 24.0
11.0, 27.6
19.7, 40.9
10.9, 27.4
*Brainstem haemorrhage; CI=confidence interval CRNM=clinically relevant non-major
Bleeding Events: Concomitant Aspirin Use
YM150, n (%)
Warfarin, n (%)
30 mg (N=90)
60 mg (N=93)
120 mg (N=93)
240 mg (N=78)
(N=94)
0 (0/27)
8.3 (2/24)
4.0 (1/25)
24.0 (6/25)
6.5 (2/31)
3.2 (2/63)
0 (0/69)
2.9 (2/68)
13.2 (7/53)
0 (0/63)
Concomitant aspirin
14.8 (4/27)
4.2 (1/24)
24.0 (6/25)
20.0 (5/25)
12.9 (4/31)
No concomitant aspirin
14.3 (9/63)
15.9 (11/69)
13.2 (9/68)
15.1 (8/53)
17.5 (11/63)
Concomitant aspirin
14.8 (4/27)
12.5 (3/24)
24.0 (6/25)
40.0 (10/25)
19.4 (6/31)
No concomitant aspirin
15.9 (10/63)
15.9 (11/69)
16.2 (11/68)
24.5 (13/53)
17.5 (11/63)
Major* and CRNM bleeding, % (n/N)
Concomitant aspirin
No concomitant aspirin
Minor bleeding, % (n/N)
Any bleeding, % (n/N)
*Only one major bleeding event was recorded in the treatment period in a subject in the YM150 240 mg group who was not receiving
concomitant aspirin and who had previously received warfarin; CRNM=clinically relevant non-major
Adverse Events*
YM150, n (%)
Warfarin,
30 mg
60 mg
120 mg
240 mg
n (%)
(N=90)
(N=93)
(N=93)
(N=78)
(N=94)
Treatment period
51 (56.7)
59 (63.4)
62 (66.7)
52 (66.7)
55 (58.5)
Entire study period
54 (60.0)
62 (66.7)
62 (66.7)
52 (66.7)
62 (66.0)
Nasopharyngitis
7 (7.8)
7 (7.5)
9 (9.7)
7 (9.0)
9 (9.6)
Haematuria
8 (8.9)
6 (6.5)
4 (4.3)
6 (7.7)
8 (8.5)
Headache
3 (3.3)
6 (6.5)
3 (3.2)
3 (3.8)
2 (2.1)
Dizziness
2 (2.2)
6 (6.5)
2 (2.2)
3 (3.8)
2 (2.1)
Epistaxis
1 (1.1)
4 (4.3)
6 (6.5)
1 (1.3)
2 (2.1)
Gingival bleeding
1 (1.1)
2 (2.2)
4 (4.3)
4 (5.1)
0
Oedema, peripheral
2 (2.2)
4 (4.3)
1 (1.1)
2 (2.6)
1 (1.1)
Upper respiratory tract infection
1 (1.1)
2 (2.2)
3 (3.2)
0
4 (4.3)
All AEs, N (%)
Most common AEs, N (%)*
*Occurring in 10 or more subjects during the treatment period; AE=adverse event
Serious Adverse Events
YM150, n (%)
Warfarin,
30 mg
60 mg
120 mg
240 mg
n (%)
(N=90)
(N=93)
(N=93)
(N=78)
(N=94)
Treatment period
3 (3.3)
4 (4.3)
6 (6.5)
5 (6.4)
5 (5.3)
Entire study period
3 (3.3)
5 (5.4)
6 (6.5)
7 (9.0)
7 (7.4)
All serious adverse events, N (%)
Causal relationship to study drug was not ruled out for three serious
AEs
 Thromboembolic stroke (YM150 60 mg)
 Brain stem haemorrhage (YM150 240 mg)
 Vaginal haemorrhage (YM150 240 mg)
Laboratory Assessments
One subject had ALT >3-times the ULN (YM150 60 mg) and
two had AST >3-times the ULN (warfarin, n=2)
Bilirubin >2-times the ULN was 1.1%, 1.1%, 4.3% and 5.1% in
the YM150 30, 60, 120 and 240 mg dose groups, respectively,
and 2.1% in the warfarin group
One case of bilirubin >3-times the ULN was observed (YM150
120 mg)
Efficacy: 4 outcomes in 3 patients
1 symptomatic stroke (major bleeding event)
 Brain stem haemorrhage resulted in death (YM150 240 mg)
1 ischaemic colitis
 Adjudicated as a systemic thromboembolic event not related to study
medication; following hospitalization, event resolved (YM150 120
mg) > subsequently had TE stroke 7 days after discontinuation of
YM150, resolved
1 TE stroke (YM150 60 mg) – 1 day post final dose, resolved
Conclusions
YM150 30−120 mg once daily was safe and well tolerated
Higher incidence of bleeding observed with YM150 240 mg
AEs comparable across groups, mostly mild in severity
Serious AEs occurred rarely
No clinically relevant adverse effects on liver function
Results support further study of YM150 for stroke prevention in NVAF
YM150 Global Clinical Development
Programme
NVAF
OPAL-2 (EU/Japan/Asia): N=1280
(recruiting)
ACS
RUBY-1 (EU/Asia): N=1248
(recruiting)
 Phase IIb, double-blind, warfarin-
 Double-blind, placebo-controlled, Phase
controlled, dose-ranging in NVAF
 Data expected Q3/4, 2011
IIb dose ranging in ACS as add-on to
aspirin/clopidogrel
 Data expected Q3/4, 2011
VTE prevention
PEARL-2 (US): N=670 (enrolment completed)
 Phase IIb, warfarin-controlled, dose-ranging in TKR
 Data expected Q3/4, 2010
ONYX-3 (US/EU): N=2000 (enrolment completed)
 Phase IIb, double-blind, enoxaparin-controlled, dose-ranging in THR
 Data expected Q4, 2010
ACS=acute coronary syndrome; VTE=venous thromboembolism; TKR=total knee replacement; THR=total hip replacement
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