Clinical trial protocols

Comment on ITAIS

Geoffrey Donnan

Editor-in-Chief

Editor’s comment:

The investigators of the ITAIS II Trial are to be congratulated

in publishing their protocol in this difficult area of stroke

research. They have designed a controlled trial with an

Assessor-Blinded outcomes to compare the safety and efficacy

of patients selected based on multiparametric CT parameters.

There will be considerable limitations to the study because of a

lack of randomization. To overcome these multiple adjust-

ments for baseline imbalances, entry biases may need to be

made.

However, very important practical information is likely to

be generated from this study about the safety of the use of

thrombolysis in CT perfusion selected patients for longer time

windows poststroke onset, and the provision of data to

strengthen the relationship between penumbra and penumbral

salvage and clinical outcome.

The organization of a large trial such this across a number of

centers with the technological challenge of CT perfusion

should not be underestimated. This trial in itself will be a

major organizational achievement.

Imaging-based thrombolysis trial in acute ischemicstroke-II (ITAIS-II)

Yilong Wang1w, Xiaoling Liao1w, Xingquan Zhao1, Chunxue Wang1, Liping Liu1,

Yong Zhou1, Chunjuan Wang1, Jing Xue2, Peiyi Gao2, Kehui Dong1, Xunming Ji3,

Yongjun Wang1�, for ITAIS-II investigators

Background Intravenous (i.v.) recombinant tissue plasmino-

gen activator (rtPA) remains the only approved therapy for

acute ischemic stroke. However, the use of i.v. thrombolysis is

restricted to a minority of patients by the rigid 3-h time

window. Modern imaging-based selection algorithms that

can identify penumbra have been proposed as methods

to extend the window and to select patients more likely to

respond favorably or unfavorably to i.v. thrombolysis.

Aims We aim to compare the safety and efficacy of multi-

parametric computed tomography (CT)-based i.v. thromboly-

sis after 3–9 h of symptom onset with standard CT-based

thrombolysis within 3 h and with CT-based thrombolysis or

placebo after 3–6 h from the pooled data of the large stroke

rtPA trials.

Design The imaging-based thrombolysis trial in acute is-

chemic stroke-II study is a prospective, multicenter and

wThese authors contribute equally to this article.

Correspondence: Yong-Jun Wang�, Department of Neurology, Beijing

Tiantan Hospital, Capital Medical University, No.6 Tiantanxili, Chongwen

District, Beijing 100050 China. Tel: 10086 010 67 098 350; Fax: 10086 010

67 013 383; e-mail: yongjunwang111@yahoo.com.cn1Department of Neurology, Beijing Tiantan Hospital, Capital Medical

University, Beijing, China2Department of Neuroradiology, Beijing Tiantan Hospital, Capital

Medical University, Beijing, China3Department of Neurosurgery, Xuanwu Hospital, Capital Medical

University, Beijing, China

& 2009 The Authors.Journal compilation & 2009 World Stroke Organization International Journal of Stroke Vol 4, February 2009, 49–53 49

assessor-blind controlled study. The primary efficacy outcome

will be a favorable outcome at 90 days defined as a modified

Rankin Scale and reperfusion improvement 24–36 h after

treatment; the primary safety end-point outcome will be

intracerebral hemorrhage 24–36 h after treatment. We aim

to include 200 patients by 2010. It is registered with IRCTN

number: ISRCTN12033002.

Key words: clinical protocols, controlled clinical trial, is-

chemic stroke, multiparametric CT, rtPA, thrombolysis

Introduction

Intravenous (i.v.) thrombolysis with recombinant tissue plas-

minogen activator (i.v. rtPA) within 3 h is the only approved

therapy for acute ischemic stroke (AIS). rtPA was licensed for

AIS in the China in 2004 based on NINDS trial criteria (1, 2).

However, the 3-h time window is too short for most patients;

there are still a number of burdens and failures in the optimal

accomplishment of thrombolytic treatment. rtPA is used only

in o4% of patients. The pooled analysis of three multicenter

randomized placebo-controlled trials of i.v. rtPA also suggests

that improved clinical outcomes extend beyond 3 h, which,

however, appeared not to extend to the full 6 h (3). In the last

few years, an increasing number of studies have suggested that

a preselection of patients with multiparametric magnetic

resonance imaging (MRI) or computed tomography (CT)

algorithms can identify patients with AIS who may benefit

from i.v. rtPA beyond 3 h after symptom onset without

increasing the risk (4–8).

Modern imaging techniques that can identify penumbra

have been proposed as methods to extend the time window of

the treatment for i.v. thrombolysis and to select patients likely

to respond favorably or unfavorably to i.v. thrombolysis.

Currently, the most significant imaging for selecting patients

to implement rtPA thrombolysis is using multiparametric CT,

which includes nonenhanced CT (NECT), computed tomo-

graphy angiography (CTA) and computed tomography perfu-

sion (CTP), or multiparametric MR, which includes magnetic

resonance angiography (MRA), diffusion-weighted imaging

and perfusion-weighted imaging.

Both multiparametric CT and MRI are substantially more

accurate than NECT alone in diagnosing AIS, particularly in

their utility to distinguish between irreversible and reversible

ischemic tissue (9, 10). MRI may be more clear and accurate

than multiparametric CTwhen they are used to identify infarct

core, especially for acute brainstem ischemia. But when one is

considering patient selection for thrombolysis, there may well

be no major difference between multiparametric CT and MRI

(11, 12). Thus, when specifically considering the potential

thrombolytic patient, the choice of imaging modality may

relate more to availability and accessibility. And CT is not only

more universal but also cheaper and time saving than MR in

most centers in China. Hence, in this trial, multiparametric CT

is chosen for guiding to preselect patients suitable for i.v.

thrombolysis beyond 3 h.

The objective of this trial is to investigate:

1. For the preselected AIS patients with CTP/CTA-Source

Images (CTA-SI) mismatch after 3–9 h of symptom onset,

whether the efficacy and safety of i.v. thrombolysis are equiva-

lent to standard CT-based thrombolysis within 3 h in AIS.

2. We also aim to use multiparametric CT to select patients for

i.v. thrombolysis within an expanded time window of 9 h and

study the efficacy and safety in these patients in comparison

with CT-based thrombolysis or placebo after 3–6 h from the

pooled data of the large clinical trials of i.v. rtPA in AIS.

3. Whether using multiparametric CT in the super-early stage

of AIS can predict the outcome of the patient and the efficacy of

thrombolysis.

4. Whether the improvement of multiparametric CT imaging

can be a substitutive indication to evaluate the outcome, and

whether there is a significant correlation between the improve-

ment and the clinical outcome.

Design

The imaging-based Thrombolysis trial in acute ischemic

stroke-II (ITAIS-II) is a prospective, multicenter and asses-

sor-blind controlled study to assess the efficacy and safety of

i.v. thrombolysis in AIS patients after 3–9 h of symptom onset

mainly using multiparametric CT both for patient selection

and as a primary efficacy end-point measurement.

Subjects

Consecutive AIS patients within the 8-h time window, when

they get to the hospital, will be screened in all participating

centers. One hour will be left for delay in the emergency

department. i.v. rtPA thrombolysis was performed in patients

within 2 h of onset to door time window guided by NECT

according to NINDS criteria, and in those within the 2–8-h time

window the multiparametric CT algorithm including NECT,

CTA, CTA-SI and CTP must be conducted. All patients who

meet the multiparametric CT inclusion criteria will be enrolled

in this trial and will be treated by i.v. rtPA 0�9 mg/kg thrombo-

lysis after obtaining informed consent according to the Declara-

tion of Helsinki. For the inclusion and exclusion criteria for

patients within the 3–9-h time windows, see Table 1. Participants

included in the trial will be divided into a 3-h time-window

group and a 3–9-h time-window group according to imaging

examination and onset to needle time window. The study flow

chart was described in Fig. 1. Before beginning the study, the

ethics independent committee of the principal study center

(Beijing Tiantan Hospital) sought central ethical approval.

Multiparametric CT protocol

NECT was obtained with a 5 mm slice thickness for the

posterior fossa and a 9 mm slice thickness for the cerebral

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Clinical trial protocols Y. Wang et al.

hemispheres using imaging parameters of 120 kVp, 360 mAs,

1�5 mm section collimation and 1 s rotation. PCTwas obtained

with two contiguous 12-mm-thick axial sections centered at

the level of the basal ganglia and internal capsule. A 40 s cine

series was performed beginning 4 s after the i.v. administration

of 40 ml of iodinated contrast at 8 ml/s by a power injector into

an antecubital vein. PCT imaging parameters were 80 kVp,

209 mA s, 0�5 s rotation and 40 images per section.

The patients underwent CTA of the whole brain. Another

90 ml of contrast medium was injected at a rate of 4 ml/s for

30 ml, followed by another 60 ml at 3 ml/s. After a delay of 17 s,

spiral scanning was performed with the following parameters:

beam collimation 0�75� 16 mm, slice width 0�75 mm, spiral

pitch 1�0, 140 kV and 100 mA s. For diagnosis, we used the

CTA-SI of 12 mm thickness and three-dimensional recon-

structions of the data sets.

In this study, PCT dynamic images were processed by the same

software. Dynamic raw dates were downloaded onto a PC in

DICOM 3�0 standard form. Then CT perfusion mapping and

quantitative measurement programs were used to analyze and

compute cerebral hemodynamic parameters, including cerebral

blood flow (CBF), cerebral blood volume (CBV), mean transit

time (MTT) and mapping of time-to-peak (TTP). Based on the

central volume principle, the mode of calculating the perfusion

Table 1 The inclusion and exclusion criteria for patients within 3–9-h time windows

Inclusion criteria

1. Female or male in patients

2. Age 18–80 years

3. Clinical diagnosis of ischemic stroke

4. Onset of symptoms within 3–9 h before initiation of thrombolysis treatment

5. Stroke symptoms present for at least 30 min and has not significantly improved before treatment

6. The National Institute of Health Stroke Scale (NIHSS) score of Z four

7. mCT screening to be started within 8�5 h after stroke onset

8. Perfusion abnormality of CT scan 42 cm in diameter involving hemisphere

9. CTP/CTA source image mismatch Z20%

10. CTA shows occlusion or significant stenosis of large vessels (Thrombolysis in Cerebral Ischemia grade is 0 or 1)

11. Patients are willing to receive thrombolysis treatment and to give informed consent

12. Patients are willing and able to comply with the study protocol

Exclusion criteria

1. Evidence of intracranial hemorrhage (ICH), brain tumors, vascular malformation, aneurysm and subarachnoid hemorrhage (SAH)

2. Major infarct involving 41/3 of MCA territory on the CTA-SI

3. Presenting obvious neurologic deficits because of past stroke [modified Rankin Scale (mRS) 42]

4. Severe stroke as assessed clinically (e.g. NIHSS425) and/or by appropriate, magnetic imaging techniques

5. Seizure at onset of stroke

6. Before stroke within the last 3 months

7. Patients with any history of prior stroke and concomitant diabetes

8. Administration of heparin within the previous 48 h and a thromboplastin time exceeding the upper limit of normal for laboratory

9. Platelet count of below 100 000 mm3

10. Uncompensated hypertension at study entry or hypertension requiring aggressive treatment to reduce blood pressure to nonhypertensive limits.

Uncompensated hypertension is defined as systolic blood pressure4185 mmHg or diastolic blood pressureZ110 mmHg on three repeated measures at

least 10 min apart

11. Blood glucose o50 or 4400 mg/dl

12. Known hemorrhagic diathesis within the last 6 months

13. Patients receiving oral anticoagulants, e.g. warfarin sodium, and coagulant response time (INR) 41�514. Known history of or suspected ICH including SAH

15. Pregnancy or lactation

16. Any history of severe central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)

17. Hemorrhagic retinopathy, e.g. in diabetes (vision disturbances may indicate hemorrhagic retinopathy)

18. Bacterial endocarditis, pericarditis

19. Prolonged traumatic external heart massage, or recent (o10 days) obstetrical delivery or recent puncture of a noncompressible blood vessel (e.g.

subclavian or jugular vein puncture)

20. Acute pancreatitis

21. Documented ulcerative gastrointestinal disease during the last 3 months

22. Esophageal varices, arterial aneurysm and arterial/venous malformation

23. Neoplasm with increased bleeding risk

24. Severe liver disease, including hepatic failure, cirrhosis, portal hypertension, esophageal varices and active hepatitis

25. Major surgery or significant trauma in past 10 days

26. Known serious sensitivity to alteplase

CT, computed tomography; CTA, computed tomography angiography; CTP, computed tomography perfusion; mCT, multimodal CT.

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Y. Wang et al. Clinical trial protocols

metrics of CBF, CBV, MTT and TTP for evaluation used the

maximal slope method as described previously (13, 14). In this

study, the abnormal volume on CTA-SI, the mismatch model of

CTP-MTT and CTA-SI and CTA were chosen to evaluate infarct

core, penumbra and vessel status, respectively.

Treatment

All patients who meet the inclusion criteria and included in

this trial will be treated by rtPA (alteplase) as an i.v. infusion:

0�9 mg/kg (maximum rt-PA dose 90 mg). Ten per cent of the

total dose will be given as a bolus in 1 min, and the remaining

will be given as an infusion over 1 h. Treatment must be started

within 9 h after symptom onset.

Primary outcomes

1. Favorable clinical outcome defined as a score of 0–1 on the

modified Rankin Scale (mRS) at 90 days.

2. Symptomatic intracerebral hemorrhage, which was defined

as any signs of hemorrhage on follow-up CT associated with

clinical deterioration of four or more points on the National

Institute of Health Stroke Scale (NIHSS) within 24–36 h after

thrombolysis.

3. Reperfusion improvement was assessed 24–48 h after treat-

ment and defined as either Z30% reduction of MTT volume

of abnormality or Ztwo-point improvement on the Throm-

bolysis in Cerebral Ischemia grading scheme.

Secondary outcomes

1. mRS 0–2 at 90 days.

2. Barthel index score 75–100 at 90 days.

3. NIHSS four-point improvement or 0–1 at 2 h after treat-

ment.

4. NIHSS four-point improvement or 0–1 at 24 h.

5. NIHSS four-point improvement or 0–1 at day 7.

Fig. 1 Study flowchart. NECT, nonenhanced computerized tomography; mCT, multimodal CT, including NECT, CTP (computerized tomography perfusion)

and CTA (computerized tomography angiography); NIHSS, National Institute of Health Stroke Scale; BI, Barthel index; mRS, modified Rankin Scale.

& 2009 The Authors.52 Journal compilation & 2009 International Journal of Stroke Vol 4, February 2009, 49–53

Clinical trial protocols Y. Wang et al.

Data quality control

Source data monitoring within ITAIS-II will be organized

by GIANT CRO (http://www.med-pharmachina.com/index

en.html) independently. Every center will be visited at least

three times and all source data of case report form for all

patients included in the trial must be verified.

Sample size

The primary outcome of this trial is a favorable clinical

outcome at 90 days defined as an mRS of 0–1. According to

the results of meta-analysis of the ATLANTIS, ECASS and

NINDS trials, 35�9% (32�1–39�4%) of patients in the placebo

group of 3–6-h time window have a favorable clinical outcome

(three). The ratio of good clinical outcome for the 3–9-h time-

window multiparametric CT-based rtPA thrombolysis group

in the ITAIS-II trial is supposed to be 45–55%. When the rate of

a favorable clinical outcome for the control group and the rtPA

thrombolysis group in the 3–9-h time window is 36% and

52%, respectively, 200 patients would be required in each

group (with a power of 80%) if calculations are based on

a5 0�025 for a one-sided test. We aim to include this number

of patients in 4 years; if necessary, we will extend the inclusion

period. Analysis of the results is planned at the end of 2011.

Statistical analyses

The study design is according to the ‘intention-to-treat’

principle. All values are presented as median (range) for

continuous variables and counts (percentage) for categorical

variables. The odds ratio of the primary outcome (good

clinical outcome at 90 days) in the 3–9-h multiparametric

CT-based rtPA thrombolysis group and the 0–3 h rtPA throm-

bolysis group will be compared by calculating the relative risk

with a corresponding 95% CI. If baseline incomparability

exists for gender, age, NIHSS score or clinical condition at

baseline, we will calculate the adjusted relative risks. The

statistical significance for intergroup differences was assessed

by the Pearson w2 or the Fisher exact test for categorical

variables, and the Student t-test and anova for continuous

variables. When indicated, nonparametric Mann–Whitney

U- and Spearman tests were used. Po0�05 was considered

statistically significant (SPSS 13�0; http://www.spss.com).

Study organization and funding

Steering committeeYongjun Wang, Lawrence Wong, Qiang Dong, Liying Cui,

Xunming Ji, Jinsheng Zeng, Suming Zhang, Peiyi Gao, Xing-

quan Zhao, Weijian Jiang, Chunxue Wang and Kehui Dong.

Study organization executive committeePrincipal investigator: Yongjun Wang; Xunming Ji.

Statistician: Yongzhou.

Study coordinator: Yilong Wang, Xiaoling Liao, Liping Liu.

Data monitoring committeeXingquan Zhao, Zhijiang Wang and Chunjuan Wang.

FundingThe ITAIS-II trial is funded by the Ministry of Science and

Technology and the Ministry of Health of the People’s Republic

of China. The name of the project is the key scientific research

program of the 11th National Five-Year Planning of China. The

grant no. is 2006BA101A11.

Current status

In June 2008, enrollments have taken place in 14 active

hospitals. So far, 27 patients have been included.

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