Original Contribution
Desmoteplase 3 to 9 Hours After Major
Artery Occlusion Stroke
The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat
Acute Ischemic Stroke)
Rüdiger von Kummer, Prof Dr med; Etsuro Mori, MD; Thomas Truelsen, MD; Jens-Kristian S. Jensen, MSc;
Bjørn A. Grønning, MD; Jochen B. Fiebach, Prof Dr med; Karl-Olof Lovblad, Prof Dr med;
Salvador Pedraza, MD, PhD; Javier M. Romero, MD; Hugues Chabriat, MD, PhD; Ku-Chou Chang, MD;
Antoni Dávalos, MD, PhD; Gary A. Ford, FRCP; James Grotta, MD; Markku Kaste, MD, PhD;
Lee H. Schwamm, MD; Ashfaq Shuaib, MD, FRCPC; Gregory W. Albers, MD;
for the DIAS-4 Investigators
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke
[phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in
patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a
post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential
risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window.
Methods—Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to
intravenous treatment with desmoteplase (90 μg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS)
score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious
adverse events.
Results—In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an
mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of
symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis,
mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated
patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and
increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08–
2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0–2) at day 90 in both the treatment arms.
Conclusions—Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not
significantly improve functional outcome at 3 months.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661. (Stroke. 2016;47:00-00. DOI: 10.1161/STROKEAHA.116.013715.)
Key Words: brain ischemia ◼ cerebral arteries ◼ goals ◼ intracranial hemorrhage ◼ stroke
T
he efficacy of intravenous alteplase declines over
time, and clinical benefits have not been established
beyond 4.5 hours after stroke onset.1 It remains unclear
whether intravenous thrombolytics are beneficial in carefully selected patients with ischemic stroke presenting in
extended time windows.
Received April 9, 2016; final revision received July 30, 2016; accepted August 5, 2016.
From the Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Dresden, Germany (R.v.K.); Tohoku University Graduate School of
Medicine, Sendai, Japan (E.M.); H. Lundbeck A/S, Valby, Denmark (T.T., J.-K.S.J., B.A.G.); Center for Stroke Research Berlin, Charité-Universitätsmedizin
Berlin, Germany (J.B.F.); University of Geneva, Switzerland (K.-O.L.); c IDIBGI. Hospital Dr Josep Trueta, UDG. Girona, Spain (S.P.); Department of Radiology,
Harvard Medical School, Boston, MA (J.M.R.); Department of Neurology, Hopital Lariboisiere APHP, University Denis Diderot and INSERM U1161, DHU
NeuroVasc, Paris, France (H.C.); Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Taiwan (K.-C.C.); Department
of Neurosciences Hospital Germans Trias i Pujol, Universitat Autonoma, Barcelona, Spain (A.D.); Oxford University Hospitals and Medical Sciences Division,
University of Oxford, United Kingdom (G.A.F.); Memorial Hermann Hospital, Houston, TX (J.G.); Department of Neurology, Helsinki University Hospital,
Clinical Neurosciences, Neurology, University of Helsinki, Finland (M.K.); Department of Neurology and Stroke Service, Massachusetts General Hospital,
Harvard Medical School, Boston (L.H.S.); University of Alberta, Edmonton, Canada (A.S.); and Stanford University Medical Center, Palo Alto, CA (G.W.A.).
Guest Editor for this article was Seemant Chaturvedi, MD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
116.013715/-/DC1.
Correspondence to Rüdiger von Kummer, Prof Dr med, Institut für Diagnostische und Interventionelle Neuroradiologie, Universitätsklinikum Carl
Gustav Carus, Fetscherstr. 74, 01307 Dresden, Germany. E-mail [email protected]
© 2016 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.116.013715
1
2 Stroke December 2016
Preliminary evidence of safety and potential efficacy
in an extended time window was obtained in the DIAS
(Desmoteplase in Acute Ischemic Stroke) and DEDAS (Dose
Escalation of Desmoteplase in Acute Ischemic Stroke) trials.2,3 The DIAS-2 trial did not confirm efficacy, but supported
an excellent safety profile with the 90 µg/kg dose.4 Pooling
the data from DIAS, DEDAS, and DIAS-2 suggested that
desmoteplase was beneficial for patients with proximal arterial occlusion.5 These findings provided the rationale for the
concomitant DIAS-3, DIAS-4, and DIAS-J studies (Clinical
Study of Desmoteplase in Japanese Patients With Acute
Ischemic Stroke) of desmoteplase versus placebo in patients
treated 3 to 9 hours after stroke onset.6,7 DIAS-J was a randomized phase 2 study that evaluated the safety and tolerability of
desmoteplase in Japanese patients. DIAS-3 and DIAS-4 were
large multinational phase 3 sister trials assessing the efficacy
and safety of 90 µg/kg of desmoteplase in the 3- to 9-hour
window; a majority of patients in DIAS-3 were recruited in
Asia and Europe, whereas most patients in DIAS-4 were from
North and Latin America and Europe.
DIAS-3 reached the preplanned sample size of 492 patients
in November 2013 and showed that desmoteplase was as safe
as placebo, but without clinical benefit. On receiving the results
of DIAS-3, the sponsor terminated the DIAS-4 trial after the
enrollment of 270 of planned 400 patients, because the goal of
2 positive trials could not be met. Here, we present the results
of DIAS-4 and an exploratory analysis of the pooled DIAS-3,
DIAS-4, and DIAS-J patient data using the prespecified primary and secondary end points from DIAS-3 and DIAS-4.
The goal of the pooled analysis is to investigate efficacy and
safety of intravenous thrombolysis in the so far largest sample
of patients with major cerebral artery occlusions being treated
beyond 3 hours. In addition, we explored whether late arterial
recanalization may be associated with favorable clinical outcome.
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Figure. CONSORT flow diagram. A, DIAS-4.
B, DIAS-3/DIAS-4/DIAS-Japan pooled data.
CONSORT indicates Consolidated Standards
of Reporting Trials; DIAS, Efficacy and Safety
Study of Desmoteplase to Treat Acute Ischemic
Stroke (trial 3 or 4); and DIAS-Japan, Clinical
Study of Desmoteplase in Japanese Patients
With Acute Ischemic Stroke.
von Kummer et al Desmoteplase for Ischemic Stroke 3
Methods
injection. Computer-generated randomization lists with stratification
for baseline NIHSS (4–14 or 15–24) and for age (18–65, 66–75, and
76–85 years) were used (online-only Data Supplement).
At baseline and between 12 and 24 hours after study medication
administration, patients were imaged with CT or magnetic resonance
imaging depending on the preference of the study site. Magnetic resonance imaging included DWI, MRA, T2-fluid attenuation inversion
recovery, and gradient echo (T2*) sequences. CT included a nonenhanced CT and CTA, the latter being obligatory at baseline and
optional at follow-up. An imaging committee consisting of 4 experienced neuroradiologists (online-only Data Supplement) retrospectively assessed brain and vessel imaging for eligibility (occlusion/
high-grade stenosis) independently from the study sites and blinded
to all clinical information except the hemisphere affected. In addition,
the committee assessed the MRAs and CTAs using the TIMI scale
(Thrombolysis in Myocardial Infarction) with the scores: 0=complete
occlusion, 1=near complete occlusion, 2=mild-to-moderate stenosis,
and 3=normal open vascular segment. TIMI 0 and 1 was categorized
as arterial occlusion and TIMI 2 and 3 as arterial patency or recanalization. The committee also measured the volume (mL) of ischemic
injury at baseline and follow-up on CT or DWI using computerized
planimetry (Io software, Synarc, or Alice, Parexel).
Safety assessments included mortality at day 90, any ICH, symptomatic ICH (SICH) defined as ICH on imaging resulting in a worsening of ≥4 points on NIHSS, major bleeding other than SICH,
symptomatic ischemic edema (defined as brain edema with mass
effect on imaging resulting in a worsening of ≥4 points on NIHSS),
and other adverse events. An adjudication committee blinded to
Study Design
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The DIAS-4 study protocol was identical to that of DIAS-3 and has
been described in detail elsewhere.8 In brief, DIAS-4 was a multinational, randomized, double-blind, parallel-group placebo-controlled
phase III study designed and conducted in accordance with the principles of the Declaration of Helsinki.
Study sites recruited patients with ischemic stroke within 3 to 9
hours of witnessed symptom onset, between 18 and 85 years of age,
with a National Institute of Health Stroke Scale (NIHSS) score of
4 to 24 and occlusion or high-grade stenosis in proximal segments
of the middle, anterior, or posterior cerebral arteries (MCA-M1 and
MCA-M2, ACA, and PCA) as assessed with computed tomography
angiography (CTA) or magnetic resonance angiography (MRA) and
corresponding to the acute neurological deficit. Patients were excluded
if they had acute ischemic injury exceeding 1 of 3 of the MCA territory,
half of the ACA or PCA territory, or intracranial hemorrhage (ICH).
We defined acute ischemic injury (ischemic core volume) as x-ray
hypoattenuation (hypodensity) within the affected arterial territory on
computed tomography (CT) or restricted diffusion (increased signal)
on diffusion-weighted imaging (DWI). Patients with a prestroke modified Rankin Scale (mRS) score of >1 were excluded. Details of the
informed consent procedure and the inclusion/exclusion criteria are
presented in the online-only Data Supplement.
Like in DIAS-3, study sites randomized eligible patients 1:1 to desmoteplase 90 µg/kg or placebo, given as a single intravenous bolus
Table 1. Baseline Characteristics, Intent-to-Treat Data Set for Placebo- and DSPA-Treated Patients
DIAS-3
DIAS-4
DIAS-J
Pooled
Placebo
(n=245)
DSPA 90 µg/
kg (n=247)
Placebo
(n=135)
DSPA 90 µg/
kg (n=135)
Placebo
(n=17)
DSPA 90 µg/
kg (n=16)
Placebo
(n=397)
DSPA 90 µg/
kg (n=398)
Sex (female), n (%)
116 (47)
125 (51)
69 (51)
72 (53)
7 (41)
7 (44)
192 (48)
204 (51)
Age, mean (SD), y
67.8 (13.1)
67.0 (14.0)
68.2 (12.5)
69.1 (11.1)
74.9 (8.9)
72.9 (8.4)
68.2 (12.8)
67.9 (12.9)
148 (60)
141 (57)
6 (4)
7 (5)
17 (100)
16 (100)
171 (43)
164 (41)
Race, n (%)
Asian
Black
1 (<1)
2 (<1)
9 (7)
11 (8)
10 (3)
13 (3)
White
96 (39)
103 (42)
115 (85)
111 (82)
211 (53)
214 (54)
1 (<1)
5 (4)
6 (4)
5 (1)
7 (2)
11 (4–26)
12 (4–24)
10 (4–24)
11 (4–24)
13 (6–23)
8 (4–20)
11 (4–26)
12 (4–24)
6.9 (3.5–9.0)
7.0 (3.4–9.1)
7.3 (3.3–9.8)
7.3 (3.4–9.0)
6.1 (4.2–8.8)
6.9 (5.0–9.0)
7.1 (3.3–9.8)
7.1 (3.4–9.1)
mRS 0
209 (86)
219 (89)
112 (85)
107 (82)
14 (88)
13 (81)
335 (86)
339 (86)
mRS 1
29 (12)
27 (11)
19 (15)
24 (18)
2 (13)
3 (19)
50 (13)
54 (14)
CT
133 (56)
134 (55)
107 (82)
101 (80)
240 (62)
235 (61)
MRI
106 (44)
109 (45)
24 (18)
26 (20)
17 (100)
16 (100)
147 (38)
151 (39)
Asia
147 (60)
142 (57)
4 (3)
7 (5)
17 (100)
16 (100)
168 (42)
165 (41)
Europe
89 (36)
95 (38)
65 (48)
58 (43)
154 (39)
153 (38)
51 (38)
54 (40)
51 (13)
54 (14)
15 (11)
16 (12)
24 (6)
26 (7)
Other
NIHSS, median (range)
Symptom onset to treatment
time, median (range), h
Pre-stroke mRS, n (%)
Image modality, n (%)
Region, n (%)
North America
Rest of World
9 (4)
10 (4)
CT indicates computed tomography; DIAS, Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke (phase 3 or 4); DIAS-J, Clinical Study of
Desmoteplase in Japanese Patients With Acute Ischemic Stroke; DSPA, desmoteplase; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; and NIHSS,
National Institute of Health Stroke Scale.
4 Stroke December 2016
Table 2. Efficacy Results for Placebo- and DSPA-Treated Patients in DIAS-4 Full-Analysis Data Set
Treatment
N
n (%)
Placebo
128
46 (35.9)
DSPA
124
52 (41.9)
Placebo
128
65 (50.8)
DSPA
124
61 (49.2)
Placebo
128
37 (28.9)
DSPA
124
40 (32.3)
OR (95% CI)
P Value
1.45 (0.79–32.64)
0.2290
0.98 (0.59–1.62)
0.9401
1.22 (0.68–2.18)
0.5076
1.12 (0.72–1.75)
0.6146
1.92 (0.94–3.95)
0.0749
0.28 (0.05–1.50)
0.1385
1.49 (0.57–3.85)
0.4144
1.43 (0.66–3.12)
0.3674
1.40 (0.73–2.66)
0.3090
2.66 (1.17–6.06)
0.0198
2.02 (0.79–5.18)
0.1447
Primary end point
mRS 0–2 response
Key secondary end points
NIHSS response
Composite response
mRS response (ordinal regression)
mRS 0–2 response in key subgroups
CT, ischemic injury volume <25 mL
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Placebo
84
32 (38.1)
DSPA
80
41 (51.3)
Placebo
16
10 (62.5)
DSPA
15
5 (33.3)
Symptom onset to treatment time
≤7 h
Placebo
50
20 (40.0)
DSPA
51
25 (49.0)
Symptom onset to treatment time
>7 h
Placebo
78
26 (33.3)
DSPA
73
27 (37.0)
Patients with confirmed occlusion/
high grade stenosis at baseline
Placebo
121
43 (35.5)
DSPA
109
44 (40.4)
Placebo
58
17 (29.3)
DSPA
48
25 (52.1)
Placebo
61
22 (36.1)
DSPA
57
27 (47.4)
MRI, ischemic injury volume <25 mL
Recanalization at 12–24 h
Patients with TIMI score 0–1 at
baseline who had a 12–24 h followup with CTA/MRA
Per-protocol analysis set
mRS 0–2 response
Responses: NIHSS response, NIHSS decrease=8 or NIHSS score=1 Composite response, mRS 0–2 response and NIHSS response. CI indicates
confidence interval; CT, computed tomography; CTA, computed tomography angiography; DIAS, Efficacy and Safety Study of Desmoteplase to
Treat Acute Ischemic Stroke (phase 4); DSPA, desmoteplase; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; mRS,
modified Rankin Scale; NIHSS, National Institute of Health Stroke Score; OR, odds ratio; and TIMI, Thrombolysis in Myocardial Infarction.
treatment, evaluated all deaths and neurological worsening by ≥4
NIHSS points and categorized their causes.
The primary efficacy end point for DIAS-4 was favorable outcome
(mRS, 0–2). Only certified raters assessed mRS ratings by direct
examination blinded to treatment allocation.
Key secondary efficacy end points (ordered hierarchically) were
decreased in NIHSS by ≥8 points from baseline or an NIHSS score
of ≤1 at day 90, and the combination of the dichotomized mRS and
the NIHSS response.
The mRS response at day 90 was also analyzed using the ordinal scale
(with scores 5 [severe disability] and 6 [death] merged into 1 category).
We also analyzed the primary efficacy end point in the following
key subgroups (prespecified for DIAS-4 and assessed by the imaging
committee):
1. Patients with core-lesion volume of <25 mL on DWI and <25
mL on CT.
2. Patients with time from stroke onset to treatment ≤7 hours and
>7 hours.
3. Patients with TIMI score of 0 to 1 at baseline according imaging committee judgment.
In addition, the recanalization rate was assessed at 12 to 24 hours
using CTA or MRA in the subgroup of patients with a baseline vessel
TIMI score of 0 or 1.
The DIAS-4 protocol prespecified the following data sets: all patientstreated set—comprising all randomized patients who received study
medication (all safety analyses); full-analysis set—all treated patients
with at least 1 postbaseline measurement of mRS, and the per-protocol
set—all full-analysis set patients fulfilling predefined inclusion/exclusion criteria in retrospect (Table I in the online-only Data Supplement).
Like in DIAS-3, we calculated the required sample size using a
power of 80% and a 2-sided significance level of 5%. The original
sample size was 302 patients (151 in each group), assuming an effect
size of 15 percentage points (40% responders with desmoteplase versus 25% with placebo) based on post hoc analyses of the DEDAS,
DIAS, and DIAS-2 trials.2–5 The protocol-specified analysis of the
primary efficacy end point was performed using a logistic regression model with treatment and geographical region as covariates, and
baseline NIHSS score, age, and time from stroke onset to treatment
as covariates. In case of missing data on outcome at day 90, the last
observation was carried forward when analyzing the full-analysis set
von Kummer et al Desmoteplase for Ischemic Stroke 5
Table 3. Efficacy Results for Placebo- and DSPA-Treated Patients: ITT for DIAS-3/4/J Pooled
Treatment
N
n (%)
OR (95% CI)
P Value
Placebo
397
167 (42.1)
DSPA
398
182 (45.7)
1.35 (0.97–1.87)
0.0786
Placebo
397
208 (52.4)
DSPA
398
219 (55.0)
1.16 (0.87–1.55)
0.3210
Placebo
397
140 (35.3)
DSPA
398
154 (38.7)
1.29 (0.94–1.77)
0.1204
1.19 (0.92–1.53)
0.1827
1.36 (0.86–2.17)
0.1912
1.84 (0.99–3.42)
0.0530
1.21 (0.76–1.94)
0.4244
1.49 (0.93–2.36)
0.0941
1.36 (0.96–1.92)
0.0857
Symptom onset to treatment time
≤7 h
1.07 (0.74–1.55)
0.7241
Symptom onset to treatment time
>7 h
1.31 (0.92–1.85)
0.1313
1.60 (1.09–2.36)
0.0168
Primary end point
mRS 0–2 response
Key secondary end points
NIHSS response
Composite response
mRS response (ordinal regression)
mRS 0–2 response
CT, ischemic injury volume <25 mL
Placebo
186
78 (41.9)
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DSPA
180
84 (46.7)
MRI, ischemic injury volume <25
mL
Placebo
107
57 (53.3)
DSPA
107
65 (60.7)
Symptom onset to treatment time
≤7 h
Placebo
188
81 (43.1)
DSPA
183
87 (47.5)
Symptom onset to treatment time
>7 h
Placebo
197
86 (43.7)
DSPA
199
95 (47.7)
Patients with occlusion/high grade
stenosis at baseline
Placebo
353
147 (41.6)
DSPA
356
166 (46.6)
mRS 0–2 response
Recanalization at 12–24 h
Placebo
224
86 (38.4)
Patients with TIMI score 0–1 at
baseline who had a 12–24 h followup with CTA/MRA
DSPA
220
109 (49.5)
mRS 0–1 response
Placebo
397
115 (29.0)
DSPA
398
117 (29.4)
1.14 (0.81–1.61)
0.4419
62 (56.9)
5.43 (2.76–10.69)
<0.0001
3.32 (1.71–6.48)
0.0004
1.24 (0.75–2.06)
0.4061
1.57 (0.92–2.68)
0.0981
Association between recanalization and favorable outcome (mRS 0–2 at 90 d)
DSPA
Placebo
Recanalized
109
Not recanalized
111
36 (32.4)
No 12–24 h angiography
103
42 (40.8)
86
50 (58.1)
Not recanalized
138
55 (39.9)
No 12–24 h angiography
112
31 (27.7)
Placebo
168
81 (48.2)
DSPA
165
85 (51.5)
Placebo
154
55 (35.7)
DSPA
153
67 (43.8)
Recanalized
mRS 0–2 response by region
Asia
Europe
(Continued )
6 Stroke December 2016
Table 3. Continued
Treatment
North America
Rest of World
N
n (%)
Placebo
51
17 (33.3)
DSPA
54
22 (40.7)
Placebo
24
14 (58.3)
DSPA
26
8 (30.8)
OR (95% CI)
P Value
2.13 (0.85–5.32)
0.1069
0.32 (0.08–1.29)
0.1104
Responses: NIHSS response, NIHSS decrease=8 or NIHSS score=1 Composite response, mRS 0–2 response and NIHSS response. CI
indicates confidence interval; CT, computed tomography; CTA, computed tomography angiography; DIAS, Efficacy and Safety Study of
Desmoteplase to Treat Acute Ischemic Stroke (phase 3 or 4); DIAS-J, Clinical Study of Desmoteplase in Japanese Patients With Acute
Ischemic Stroke; DSPA, desmoteplase; ITT, intent-to treat; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; mRS,
modified Rankin Scale; NIHSS, National Institute of Health Stroke Score; OR, odds ratio; and TIMI, Thrombolysis in Myocardial Infarction.
Results
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and per-protocol set. For the primary efficacy end point in prespecified key subgroups of patients with core-lesion volume of <25 mL
on DWI or <25 mL on CT and patients with time from stroke onset
to treatment ≤7 hours and >7 hours, we used a logistic regression
model similar to the primary analysis, including a treatment by imaging modality and treatment by time from stroke interaction factor,
respectively.
DIAS-J was a phase II dose-escalation study designed to test the
safety and tolerability of 2 doses (70 and 90 µg/kg) of desmoteplase
in Japanese patients.7 Only data from patients treated with 90 µg/
kg of desmoteplase or placebo are included in the pooled analyses.
The DIAS-J study protocol was identical to those of DIAS-3 and
DIAS-4 except that only magnetic resonance imaging at baseline was
used and only patients with occlusion/severe stenosis in the proximal
MCA (M1 and M2 of MCA) were included in DIAS-J.
The analysis of pooled data from DIAS-3, DIAS-4, and DIAS-J
was not prespecified, but followed the statistical analysis plan of
DIAS-3 and DIAS-4. We performed all pooled analyses on the intentto-treat (ITT) analysis set. The worst case was used in case of missing
data on outcome at day 90. Tests for heterogeneity between studies
were performed in separate models with interaction between study
and treatment (and interaction variable if relevant, see below).
Table 4. Efficacy and Safety Study of Desmoteplase
to Treat Acute Ischemic Stroke-4
The study was conducted between February 7, 2009 and
October 7, 2014. A total of 270 patients were randomized from
81 hospitals in 17 countries from Europe, North America, Latin
and South America, South Africa, and Asia (listed in the onlineonly Data Supplement). Patients were randomly assigned to
desmoteplase (n=135) or placebo (n=135). Figure (A) shows
the CONSORT (Consolidated Standards of Reporting Trials)
diagram, and Table 1 presents the baseline characteristics.
Thirteen patients were randomized, but not treated, five patients
were treated, but had no valid functional assessment done, leaving 252 for the efficacy analysis. In each of the treatment arms,
67 patients were retrospectively found not to fulfill all inclusion/exclusion criteria leaving 57 patients in the desmoteplase
group and 61 patients in the placebo group for the per protocol
data set (Table I in the online-only Data Supplement).
Safety: All Patients Treated with Placebo or DSPA in DIAS-3, DIAS-4, DIAS-J, and Pooled
Study
DIAS-3
Placebo
(N=238)
DIAS-4
DSPA 90 µg/
kg (N=240)
Placebo
(N=131)
DIAS-J
DSPA 90 µg/
kg (N=126)
Placebo
(N=16)
Pooled
DSPA 90 µg/
kg (N=16)
Placebo
(N=385)
n
(%)
n
(%)
n
(%)
n
(%)
n
(%)
n
(%)
n
Death
23
9.7
24
10.0
18
13.7
15
11.9
1
6.3
1
6.3
0–24 h
1
0.4
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
24–72 h
2
0.8
1
0.4
3
2.3
1
0.8
0
0.0
0
3–7 d
5
2.1
3
1.3
3
2.3
1
0.8
0
0.0
>7 d
DSPA 90 µg/
kg (N=382)
(%)
n
(%)
42
10.9
40
10.5
1
0.3
0
0.0
0.0
5
1.3
2
0.5
0
0.0
8
2.1
4
1.0
1
6.3
28
7.6
34
9.1
15
6.6
20
8.5
12
9.7
13
10.5
1
6.3
Symptomatic intracranial
hemorrhage (1)
5
2.1
6
2.5
3
2.3
6
4.8
2
12.5
10
2.6
12
3.1
Symptomatic cerebral edema (2)
4
1.7
5
2.1
12
9.2
8
6.3
1
6.3
17
4.4
13
3.4
Major hemorrhage
15
6.3
10
4.2
7
5.3
8
6.3
22
5.7
18
4.7
Asymptomatic intracranial
hemorrhage within 24 h (3)
73
30.7
96
40.0
55
42.0
48
38.1
5
31.3
8
50.0
133
34.5
152
39.8
Any serious adverse events
69
29.0
64
26.7
56
42.7
61
48.4
4
25.0
3
18.8
129
33.5
128
33.5
(1) Adjudicated intracranial hemorrhage resulting in a worsening of =4 points on NIHSS, (2) adjudicated cerebral edema resulting in a worsening of =4 points on
NIHSS, (3) intracranial hemorrhage as assessed by the imaging committee in patients without a worsening of =4 points on the NIHSS. DIAS indicates Efficacy and Safety
Study of Desmoteplase to Treat Acute Ischemic Stroke (phase 3 or 4); DIAS-J, Clinical Study of Desmoteplase in Japanese Patients With Acute Ischemic Stroke; DSPA,
desmoteplase; and NIHSS, National Institute of Health Stroke Score.
von Kummer et al Desmoteplase for Ischemic Stroke 7
Table 2 presents the outcomes on the primary and secondary efficacy end points.
Desmoteplase did not significantly increase the proportion
of patients with mRS score of 0 to 2 at day 90 by (absolute
difference: 6%, P=0.2290) but increased the recanalization
rate at 12 to 24 hours by and absolute difference of 22.8%
(P=0.0198).
Pooled Analysis
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Table 1 presents the baseline characteristics of 795 ITT
patients (397 placebo and 398 desmoteplase treated), and
Figure (B) shows the CONSORT diagram.
Desmoteplase tended to increase the proportion of patients
with mRS score of 0 to 2 at day 90 by an absolute difference of 3.6% (P=0.0786; Table 3). There was no statistically
significant heterogeneity between the 3 studies for the primary end point (P=0.10 for study×treatment interaction).
The treatment effect was similar in patients with ischemic
injury volume of <25 mL at baseline and for patients with
treatment initiation before and after 7 hours. Treatment with
desmoteplase was associated with a higher recanalization rate
at 12 to 24 hours (11.1% absolute increase, P=0.0168). The
ordinal analysis of the primary end point did not show a treatment response.
Recanalization was associated with favorable outcomes
at day 90 (mRS, 0–2) in both the desmoteplase-treated
(P<0.0001) and placebo-treated patients (P=0.0004).
Recanalization was associated with better outcomes for
patients in the desmoteplase group, regardless of whether the
patients were treated before or after 7 hours. There was no
difference in treatment effect by region or by affected vessel.
Table 4 presents the safety analysis showing no significant
differences between the treatment groups of all 3 trials and
the pooled analysis. In DIAS-4, 15 of 126 (11.9%) of the desmoteplase patients died compared with 18 of 131 (13.7%)
placebo patients (hazard ratio, 0.82; 95% confidence interval,
0.41: 1.63; P=0.57). Of these 33 patients, 2 of 126 (1.6%)
patients died within the first 7 days in the desmoteplase group
and 6 of 131 (4.6%) in the placebo group. The SICH rates in
DIAS-4 were 3 of 131 (2.3%) in the placebo group and 6 of
126 (4.8%) in the desmoteplase group. In the pooled population, these rates were 10 of 385 (2.6%) and 12 of 382 (3.1%),
respectively.
Discussion
Because of early termination, DIAS-4 was underpowered with
only 270 patients randomized and did not meet its primary
efficacy end point; outcomes in the desmoteplase group were
similar to the anticipated outcomes based on the study design
projections. Favorable clinical outcomes in the placebo group
were, however, more frequent than anticipated (36% versus
25%). In contrast to DIAS-3, patients with small ischemic
injury volume on CT, but not on DWI, tended to benefit from
desmoteplase. DIAS-4 confirmed that treatment with intravenous 90 µg/kg desmoteplase is safe, despite a median time
to the treatment of 7.3 hours. Desmoteplase increased the
recanalization rate in the subgroup of patients with confirmed
arterial occlusions at baseline and vessel imaging at 24 to 48
hours after randomization.
DIAS-4 failed to show a significant effect on clinical
outcome, we suspect the primary reasons for this were (1)
DIAS-4 was terminated early and, therefore, was underpowered to detect the projected effect of desmoteplase on the
primary outcome, (2) the dose of 90 µg/kg was too low to
achieve sufficient brain tissue reperfusion in enough subjects
to allow significantly better functional recovery, and (3) tissue reperfusion did not result in functional recovery in some
patients because of irreversible injury (disappearance of
penumbra).
The pooled sample of DIAS-3, DIAS-4, and DIAS-J
patients represents the largest pool of ischemic stroke patients
with proven major cerebral artery occlusions treated with
intravenous thrombolytics between 3 and 9 hours after stroke
onset. We did not include the 86 patients treated with 90 µg/
kg of desmoteplase in the earlier DIAS, DEDAS, and DIAS-2
because they had been selected with inclusion/exclusion criteria that differed from the more recent larger studies.
With almost 800 patients, an ITT analysis of the pooled
data showed a nonsignificant trend toward a small beneficial
effect of desmoteplase on functional outcome. Desmoteplase
increased significantly the recanalization rate by absolute difference of 11% in the subgroup described above for DIAS4, suggesting that 90 µg/kg of desmoteplase had a biological
effect on obstructing thrombi leading to reperfusion and potentially improved functional recovery. Interestingly, we observed
excellent functional outcomes (mRS, 0–1) in 29% after placebo
treatment similar to the 30.6% (357/1166) excellent outcome
rate in placebo-treated patients who were randomized after 4.5
hours in the alteplase randomized trials.1 This confirms that ≈1
of 3 of ischemic stroke patients with small ischemic cores and
presumably good collaterals presenting late after stroke onset
have excellent long-term outcomes without thrombolysis even
if vessel imaging shows a major intracranial artery occlusion.
The challenge will remain to identify the 2 of 3 patients who
likely will have persistent neurological deficits without treatment. Moreover, our data suggest that late recanalization even
beyond 7 hours after stroke onset is closely associated with
favorable functional outcome and not with an increased rate of
SICH. These results are in line with the recent 5 successful trials of endovascular therapy, where thrombectomy was initiated
beyond 3 hours after stroke onset.9–13
The statistically significant increase in recanalization rates
from an unexpected 38.4% after placebo to 49.5% (desmoteplase) was apparently too small to achieve statistically
significant clinical benefits in the late time window. One can
speculate that thrombolytic therapy in this type of patient—
treatment beyond 3 hours, major artery occlusion, but small–
moderate ischemic lesion—might be beneficial if higher rates
of arterial recanalization are achieved compared with the considerable placebo effect, for example, in combination with
thrombectomy or by a more potent thrombolytic agent.
In summary, treatment with intravenous 90 µg/kg desmoteplase administered 3 to 9 hours after stroke onset in patients
with proven cerebral artery occlusions did not significantly
increase favorable clinical outcomes, although it modestly
increased arterial recanalization with no increased rate of SICH.
Identification of patients with major cerebral artery occlusions
8 Stroke December 2016
and a small ischemic core seems to be a relevant target for more
effective means for arterial recanalization beyond 3 hours.
Source of Funding
This study was supported by H. Lundbeck A/S.
Disclosures
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
R. von Kummer reports personal fees from H. Lundbeck A/S,
Boehringer Ingelheim, Covidien, and Brainsgate, Penumbra, Inc;
Drs Mori, Truelsen, J.-K.S. Jensen, Dr Grønning, K.-O. Lovblad, Drs
Romero, Chabriat, Dávalos, and Shuaib report personal fees from H.
Lundbeck A/S; J.B. Fiebach reports personal fees from H. Lundbeck
A/S, Boehringer Ingelheim, Cerevast, BioClinica, Synarc, and
Perceptive; Dr Pedraza reports personal fees from H. Lundbeck A/S
and Synarc; Dr Chang reports compensation from H. Lundbeck A/S
and grants from Ministry of Science and Technology, Taiwan; G.A.
Ford reports personal fees from AstraZeneca, Cerevast, Medtronic
and Pfizer, and grants from Boehringer Ingelheim; Dr Grotta reports
grants and personal fees from H. Lundbeck A/S, personal fees from
Genentech, Frazer, and Stryker; Dr Kaste reports personal fees from
H. Lundbeck A/S and Siemens AG; Dr Schwamm reports personal
fees from Mass Department of Public Health, H. Lundbeck A/S,
Penumbra, and grants from NINDS-NIH and Genentech; Dr Albers
reports grants and personal fees from H. Lundbeck A/S, iSchemaView,
and Covidien.
References
1. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al;
Stroke Thrombolysis Trialists’ Collaborative Group. Effect of treatment
delay, age, and stroke severity on the effects of intravenous thrombolysis
with alteplase for acute ischaemic stroke: a meta-analysis of individual
patient data from randomised trials. Lancet. 2014;384:1929–1935. doi:
10.1016/S0140-6736(14)60584-5.
2. Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw
M, et al; DIAS Study Group. The Desmoteplase in Acute Ischemic
Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke
thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66–
73. doi: 10.1161/01.STR.0000149938.08731.2c.
3. Furlan AJ, Eyding D, Albers GW, Al-Rawi Y, Lees KR, Rowley HA,
et al; DEDAS Investigators. Dose Escalation of Desmoteplase for
Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to
9 hours after stroke onset. Stroke. 2006;37:1227–1231. doi: 10.1161/01.
STR.0000217403.66996.6d.
4. Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, et al.
Intravenous desmoteplase in patients with acute ischaemic stroke selected
by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS2): a prospective, randomised, double-blind, placebo-controlled study.
Lancet Neurol. 2009;8:141–150. doi: 10.1016/S1474-4422(08)70267-9.
5. Fiebach JB, Al-Rawi Y, Wintermark M, Furlan AJ, Rowley HA, Lindstén
A, et al. Vascular occlusion enables selecting acute ischemic stroke
patients for treatment with desmoteplase. Stroke. 2012;43:1561–1566.
doi: 10.1161/STROKEAHA.111.642322.
6. Albers GW, von Kummer R, Truelsen T, Jensen JK, Ravn GM, Grønning
BA, et al; DIAS-3 Investigators. Safety and efficacy of desmoteplase
given 3-9 h after ischaemic stroke in patients with occlusion or high-grade
stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised,
placebo-controlled phase 3 trial. Lancet Neurol. 2015;14:575–584. doi:
10.1016/S1474-4422(15)00047-2.
7. Mori E, Minematsu K, Nakagawara J, Hasegawa Y, Nagahiro S, Okada
Y, et al; DIAS-J Investigators. Safety and Tolerability of Desmoteplase
Within 3 to 9 Hours After Symptoms Onset in Japanese Patients
With Ischemic Stroke. Stroke. 2015;46:2549–2554. doi: 10.1161/
STROKEAHA.115.009917.
8. von Kummer R, Albers GW, Mori E; DIAS Steering Committees. The
Desmoteplase in Acute Ischemic Stroke (DIAS) clinical trial program.
Int J Stroke. 2012;7:589–596. doi: 10.1111/j.1747-4949.2012.00910.x.
9. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF,
Yoo AJ, et al; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11–20.
doi: 10.1056/NEJMoa1411587.
10. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi
N, et al; EXTEND-IA Investigators. Endovascular therapy for ischemic
stroke with perfusion-imaging selection. N Engl J Med. 2015;372:1009–
1018. doi: 10.1056/NEJMoa1414792.
11. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et
al; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–
1030. doi: 10.1056/NEJMoa1414905.
12. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira
A, et al; REVASCAT Trial Investigators. Thrombectomy within 8 hours
after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296–
2306. doi: 10.1056/NEJMoa1503780.
13. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al;
SWIFT PRIME Investigators. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285–
2295. doi: 10.1056/NEJMoa1415061.
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial
(Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke)
Rüdiger von Kummer, Etsuro Mori, Thomas Truelsen, Jens-Kristian S. Jensen, Bjørn A.
Grønning, Jochen B. Fiebach, Karl-Olof Lovblad, Salvador Pedraza, Javier M. Romero, Hugues
Chabriat, Ku-Chou Chang, Antoni Dávalos, Gary A. Ford, James Grotta, Markku Kaste, Lee H.
Schwamm, Ashfaq Shuaib, Gregory W. Albers and for the DIAS-4 Investigators
Stroke. published online November 1, 2016;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/early/2016/11/01/STROKEAHA.116.013715
Data Supplement (unedited) at:
http://stroke.ahajournals.org/content/suppl/2016/11/01/STROKEAHA.116.013715.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
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1
Online-only Supplement R2
Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The Desmoteplase in Acute Ischemic Stroke (DIAS)-4 Trial
1. List of study committee members, principal investigators and participating countries
Steering Committee
Rüdiger von Kummer, MD (Co-chair; neuroradiologist and neurologist)
Gregory Albers, MD (Co-chair; neurologist)
Hugues Chabriat, MD
Antoni Dávalos, MD
Gary Ford, MD
James Grotta, MD
Markku Kaste, MD
Ashfaq Shuaib, MD
Lee Schwamm, MD
Ku-Chou Chang, MD
Imaging Committee
Jochen B. Fiebach, MD
Salvador Pedraza, MD
Larl-Olof Lovblad, MD
Javier Romero, MD
Rüdiger von Kummer, MD
Adjudication Committee
Rüdiger von Kummer, MD (Chair)
Geoffrey Donnan, MD (neurologist)
Howard Rowley, MD (neuroradiologist and neurologist)
Mark Alberts, MD (neurologist)
Data Monitoring Committee
Kennedy R. Lees, BSc (hons) MB ChB MD FRCP FESO FRSE (Chair)
Lawrence R. Wechsler, MD
Misha Eliasziw, PhD (biostatistics)
Prinicipal investigators DIAS-4
2
Belgium: Nina De Klippel; Brazil: Mauricio Andre Gheller Friedrich, Sheila Cristina Ouriques Martins, Gabriel Rodriguez de Freitas, Daniel da Cruz Bezerra,
Li Li Min; Canada: Andrew M. Demchuk, Cheryl Jaigobin, Ashfaq Shuaib, Brian Buck, Andrew Penn, Grant Stotts, David Gladstone; Chile: Roberto Maturana,
Daniel Galdames; Denmark: Grethe Andersen, Derk W. Krieger; Estonia: Janika Kõrv; Finland: Turgut Tatlisumak, Risto Roine; Ireland: Joseph Harbison;
Italy: Danilo Toni, Mauro Furlan, Maurizia Rasura, Paolo Bovi, Andrea Zini, Carlo Serrati; Mexico: Juan Manuel Calleja, Carlos Gerardo Cantu Brito, Juan
Fernando Góngora Rivera; South Africa: John Gardiner; Spain: Jaime Masjuan Vallejo; Taiwan, Province of China: Helen L. Po, Lee Tsong-Hai; Thailand:
Nijasri C. Suwanwela, Sombat Muengtaweepongsa;; United Kingdom: Anthony Hemsley, Damian Jenkinson, Christine Roffe, Lalit Kalra, Keith Muir, Matthew
Walters, Aravindakshan Manoj, Paul Guyler, Philip Bath, Robert Simister, Mary-Joan Macleod, Hugh Marcus, Barry Moynihan; United States: Carlos Kase,
Sidney Starkman, Matthew Jensen, Marilou Ching, Victor Urrutia, Jeffrey Hilburn, Majaz Moonis, Thomas Devlin, Andrew Barreto,,Pramod Sethi, Lee
Schwamm, Jeff Switzer, Sarah Uffindell, Nojan Valadi, Martin Gizzi, Souvik Sen, Michael Kaminski, Robert Schwendimann, Michael Jacoby, Rima Dafer,
Gary Bernardini, Timothy Lukovits, Mohamed Umar Farooq, Vivek Reddy, Eugene LaFranchise, Panayiotis Mitsias, Ann Helms, Dorothea Altschul, Vivien
Lee, Raul Nogueira, Carol Lynn Clark, Rishi Gupta, Robert Swor.; Vietnam: Nguyen Thang Huy, Anh Dat Nguyen
2. Informed consent procedure
The nature of the illness often implies impairment to understand and /or consent to participate in a study in the acute setting. Hence, consenting procedures,
normally done by the patient and /or his / her legal representative, were extended to include consent by an impartial witness, a proxy (a relative), or a studyindependent physician. However, this was only allowed under the conditions listed below and if allowed by local law and regulations and approved by the
relevant ethics committee or IRB:
The patient was able to understand the nature and potential consequences of the interventions and was able to give consent but not in writing. In such a case, an
impartial person was allowed to sign the Informed Consent Form as witness in addition to the informing physician (principal or sub-investigator).
The patient was not able to understand the nature and potential consequences of the interventions, but a proxy was available to express the assumed will of the
patient. In such a case, the proxy was allowed to sign the Informed Consent Form on behalf of the patient in addition to the informing physician.
The patient was not able to understand the nature and potential consequences of the interventions and no proxy was available to express the assumed will of the
patient. In such a case, the informing physician and a study-independent physician were allowed to include the patient.
In all the above-listed cases, re-consent was to be requested once the patient became capable of doing so.
3. Selection criteria
Inclusion Criteria
• Clinical diagnosis of acute ischemic stroke
• Informed consent has been obtained according to a procedure approved by the ethics committee responsible
for approval of the study at this site.
• Male or female between 18 and 85 years of age inclusive.
• Treatment of the subject can be initiated within 3-9 hours after the onset of stroke symptoms. If the actual
time of onset of stroke is unclear then the onset will be considered the time that the subject was last known to be well. All measures are to be taken, so
treatment with alteplase within 3 hours of symptom onset is not
delayed in subjects who qualified for receiving alteplase
• The subject has a score of 4-24 inclusive on the NIHSS with clinical signs of hemispheric infarction (for
example, hemiparesis)
• The subject shows occlusion or high-grade stenosis as assessed by MRA or CTA in proximal cerebral arteries that correspond to the acute clinical
deficit. Eligible vessels are the Middle Cerebral Artery (MCA) M1, MCA, M2, anterior cerebral artery (ACA) or posterior cerebral artery (PCA)
3
The subject must receive IMP within 60 minutes after completion of diagnostic imaging screening. The time stamp on the last imaging sequence is the
reference for calculating the time elapsing.
Main Exclusion Criteria
• The subject has a pre-stroke mRS > 1 indicating previous disability
• The subject has previously been exposed to desmoteplase
• The subject shows signs of extensive early infarction on MRI or CT in any affected area, that is an infarcted core involving > 1/3 of MCA territory or >
1/2 of the ACA or PCA territories
• The subject has imaging evidence of ICH or SAH (regardless of age of the bleeding); AV malformation; cerebral aneurysm; or cerebral neoplasm
(incidental meningioma and microbleeds per se are not exclusion criterion. An incidental intracranial aneurysm that is small (< 5 mm), not thrombosed,
and not visibly bleeding is not an exclusion criterion
• The subject has an internal carotid artery occlusion on the side of the stroke lesion
• The subject has been treated with heparin in the past 48 hours and has a prolonged partial thromboplastin time exceeding the upper limit of the local
laboratory normal range. Preventive low doses of LMWH (for
example, for deep vein thrombosis (DVT) prophylaxis) do not disqualify the subject from the study
• The subject is on oral anticoagulants and has a prolonged prothrombin time (INR > 1.6)
• The subject has been treated with glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single agent oral platelet inhibitors (e.g. low-dose
clopidogrel 75 mg or low-dose aspirin ≤325 mg) or the combination of low-dose-aspirin (e.g. 50 mg) and dipyridamole (e.g. 400 mg) prior to study
entry is permitted.
Withdrawal Criteria
• A subject must be withdrawn from the study if:
• the subject withdraws his/her consent
• the investigator considers it, for safety reasons, in the best interests of the subject that he/she be withdrawn
•
the subject is lost to follow-up
•
The date and reason for withdrawal should be noted in the Withdrawal Form in the electronic case report form (eCRF). All subjects who withdraw from the study
should, if at all possible, be seen for a Withdrawal Visit scheduled as soon as possible after the subjects withdraw from the study. Subjects, who withdraw from
the study, will not be replaced.
4. Randomization procedures
Patients were randomized in blocks of two. All study personnel and patients were blinded to treatment assignment. In order to be able to allocate patients to
study medication in the case of unavailability of the standard randomization procedure (via an interactive voice response system), forced randomization was
used.
4.1. Details on forced randomization procedures
In order to be able to allocate patients to study medication in the case of unavailability of standard interactive voice response system (IVRS) randomization
procedure or delays in the refill of study medication stocks at the sites, forced randomization was used in DIAS-3 and DIAS-4.
4
If only one type of study medication was available at a site when randomizing a patient, this type of study medication and the corresponding randomization
number was automatically allocated to the patient. Consequently, one or more study medication numbers were skipped on the randomization list. These numbers
were ‘back-filled’ and used for the next patient(s) to be randomized (occurred for 17 patients in DIAS-3 and five patients in DIAS-4).
In case the sites experienced problems that precluded them from the usual randomization through the IVRS system, they called a hotline where the site could be
instructed to use the study medication with the lowest number available at the site (3 patients in DIAS-3 and 6 patients in DIAS-4).
Both types of forced randomization were considered unbiased by the sponsor, prior to unblinding. As the allocation of treatment still was performed fully
blinded, this would not lead to selection bias; the statistical efficacy evaluation (on the FAS) for forced randomized patients was based on the treatment actually
received.
5. Supplemental Table I. Pre-defined criteria to exclude patients from the per-protocol-population (Full Analysis
Set)
DIAS-4
DSPA 90
Placebo
µg/kg
(N=124)
(N=128)
Pooled
DSPA 90
Placebo
µg/kg
(N=376)
(N=381)
Imaging Evaluation Discrepancies (IC versus Investigator) Leading to exclusion from the Per Protocol Set, n (%)
Hyperintensity on FLAIR (MRI), or marked hypodensity (CT)
7 (5%)
5 (4%)
19 (5%)
Internal carotid artery occlusion on the side of the stroke lesion
6 (5%)
6 (5%)
19 (5%)
Lesion ≥ 1/3 of middle cerebral artery territory or ≥ 1/2 of anterior/posterior cerebral
13 (10%)
14 (11%)
40 (10%)
artery territory
No Occlusion/High-grade stenosis
7 (5%)
15 (12%)
33 (9%)
Presence of intra cranial haemorrhage/subarachnoid haemorrhage
6 (5%)
6 (5%)
13 (3%)
Total number of patients with at least 1 imaging evaluation discrepancy
22 (17%)
30 (24%)
89 (23%)
Protocol Deviations Leading to Exclusion from the Per Protocol Set, n (%)
Another stroke or a serious head injury in the past 6 weeks
Baseline NIHS not in(4-24)
Code break during study
Direct Factor Xa and thrombin inhibitors in past 72 hrs
Glucose not in(50-200 mg/dL) (3-11 mmol/L)
Haematocrit < 0.25
Heparin in past 48 hours, APTT > ULN
History or clinical presentation of ICH, subarachnoid hemorrhage (SAH), arteriovenous malformation, aneurysm, or cerebral neoplasm
More than 60 min from image completion (eCRF) to IMP (or image timestamp
14 (4%)
12 (3%)
29 (8%)
29 (8%)
13 (3%)
72 (19%)
2 (<1%)
1 (<1%)
2 (<1%)
2 (2%)
8 (6%)
1 (<1%)
1 (<1%)
11 (9%)
2 (2%)
1 (<1%)
26 (20%)
19 (5%)
1 (<1%)
1 (<1%)
30 (8%)
3 (<1%)
1 (<1%)
2 (<1%)
31 (25%)
46 (12%)
52 (14%)
5
missing)
Platelet count < 100,000/mm3
Potential Dosing errors
Pre-stoke mRS > 1
Prohibited medication or endovascular/mechanical treatment of stroke
Protocol violations extracted from IPD log
The subject has symptomatic acute vertebral or basilar artery occlusion
Thrombolytic agent within the past 72 hours
Time since stroke to treatment not within 3-9 hrs
Uncontrolled hypertension ... (SysBP > 185 or DiaBP > 110 immidiately prior to
IMP)
Total number of patients with at least 1 protocol deviation
1 (<1%)
1 (<1%)
20 (16%)
20 (16%)
1 (<1%)
1 (<1%)
4 (1%)
45 (12%)
2 (<1%)
1 (<1%)
43 (11%)
1 (<1%)
1 (<1%)
8 (6%)
4 (3%)
1 (<1%)
1 (<1%)
2 (<1%)
16 (4%)
54 (42%)
53 (43%)
112 (29%)
112 (30%)
67 (52%)
67 (54%)
177 (46%)
155 (41%)
1 (<1%)
3 (<1%)
9 (2%)
Total number of patients excluded from the Per Protocol Set
DSPA, desmoteplase; SD, standard deviation; NIHSS, National Institute of Health Stroke Scale; mRS: Modified Rankin Scale; CT, computerized
tomography; MRI, magnetic resonance imaging; IC, imaging committee
6. Full list of protocol pre-specified endpoints/variables (from SAP)
Primary endpoint:
•
mRS response (score 0-2) at Day 90
Key secondary endpoints
•
•
Outcome at Day 90 defined as achieving a decrease of ≥ 8 points on NIHSS from baseline or NIHSS ≤1
Outcome at Day 90 defined as achieving mRS score of 0-2 and a decrease of ≥8 points from baseline on NIHSS or NIHSS ≤1
Secondary endpoint:
•
mRS response at Day 90 using the ordinal scale (with scores 5 and 6 collapsed into one category)
Exploratory endpoints:
•
•
•
mRS response (score 0 to 2) at Day 30
mRS response at Day 30 using the ordinal scale
NIHSS response at Day 7 and at Day 30
6
Imaging endpoints:
•
•
•
•
•
•
Recanalisation defined as achieving a TIMI grade of 2 or 3 (assessed in the subgroup of patients with follow up angiography at 12-24 hours)
Change in infarct size from baseline to 12-24 hours (mL)
Change from baseline in PI-DWI absolute mismatch (mL) to 12-24 hours
Change from baseline in PI-DWI relative mismatch (% units) to 12-24 hours
Change from baseline in Perfusion (mL) to 12-24 hours
Reperfusion at 12-24 hours (50% change or more from baseline to 12-24 hours in PI volume)
7. Exploratory Analyses
Analyses of mRS 0-1 were done with a logistic regression model identical to that for the primary endpoint. Analysis of the association between recanalization
and a favorable mRS 0-2 was done with a logistic regression model similar to that for the primary endpoint, including interaction between treatment and
recanalization in order to derive the within-group estimates.
The ordinal logistic regression analyses were performed including the same factors and covariates. Tests for homogeneity of the proportional odds ratios were
tested with a score test in a regression model only including treatment as factor. We analyzed time to death by a proportional hazards model with study, treatment
and geographical region as factors, and baseline NIHSS score, age and time from stroke onset to treatment as covariates. The incidence of SICHs was analyzed
by a Fisher’s Exact test. The DIAS-4 power calculations were performed using a power of 80% and a two-sided significance level of 5%. The original sample
size was 302 patients (151 in each arm) assuming an effect size of 15% (40% responders with desmoteplase and 25% with placebo). The scientific steering
committee recommended a more conservative treatment effect (e.g.; closer to 10%), and reduced the assumption of treatment effect from 15% to 13% (38%
responders with desmoteplase and 25% with placebo), leading to an increase in sample size from 302 to 400 in October 2009. The principal statistical software
used was SAS®, Version 9·4.