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Trial registered on ANZCTR


Registration number
ACTRN12615000759594
Ethics application status
Approved
Date submitted
16/06/2015
Date registered
21/07/2015
Date last updated
21/07/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Angioplasty and Stenting versus medical treatment in patients with symptomatic intracranial artery stenosis: a randomized controlled trial and a preference cohort
Scientific title
Effect of angioplasty and stenting versus aggressive medical treatment on mortality and stroke in patients with symptomatic intracranial artery stenosis: a randomized controlled trial and a preference cohort
Secondary ID [1] 286918 0
FGHNC-2014-02
Universal Trial Number (UTN)
U1111-1171-2195
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
symptomatic intracranial artery stenosis 295338 0
Condition category
Condition code
Neurological 295756 295756 0 0
Other neurological disorders
Cardiovascular 295757 295757 0 0
Other cardiovascular diseases
Surgery 295758 295758 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Medical treatment will be given to all the participants. Basic drugs for the treatment are aspirin and clopidogrel. The aspirin and clopidogrel will be given orally at a dose of 100mg and 75mg per day respectively for 3 months. Patients in the PTAS group will receive the same dose of the aspirin and clopidogrel 5 days before operation, and continue for 3 months after the operation. When an emergency stenting operation is needed, a loading dose of 300 mg clopidogrel will be given. Additional medical treatment will be given to achieve a target systolic blood pressure of <140mmHg; hemoglobin A1c of <6.5% (in diabetes patients); low density lipoprotein of <2.58mmol/L. Interventions lowering the cardiovascular risk will also be used, such as lifestyle modification and smoking cessation. Participants who are allocated to PTAS will receive angioplasty and stenting within 5 days after randomization. A standard protocol of the PTAS procedure will be developed. The procedure will be performed by a cardiovascular surgeon. The participants will receive balloon-angioplasty with a balloon catheter, followed by stenting using the Wingspan stent system (manufactured by Stryker Neurovascular).
Intervention code [1] 292103 0
Treatment: Surgery
Intervention code [2] 292240 0
Treatment: Drugs
Comparator / control treatment
Agressive medical treatment (AMT) will be given to all the participants, both in the RCT and cohort. The basic drugs for AMT are aspirin and clopidogrel. The aspirin and clopidogrel will be given orally at a dose of 100mg and 75mg per day respectively for 3 months.
Control group
Active

Outcomes
Primary outcome [1] 295320 0
The primary outcome is a composite outcome, which is events of stroke or death assessed according to patient medical records.
Timepoint [1] 295320 0
within 30 days after enrolment
Secondary outcome [1] 315356 0
The incidence of recurrent ischaemic stroke in the territory of the stenosis arteries is assessed by CT or MRI images.
Timepoint [1] 315356 0
between 30 days and 2 years postoperatively
Secondary outcome [2] 315645 0
The restenosis rate is assessed with the Magnetic Resonance Angiography (MRA) scan in the territory of the stenosis arteries.
Timepoint [2] 315645 0
during the 2 years follow-up after surgery
Secondary outcome [3] 315650 0
The health-related quality of life is assessed by the MOS 36-item short-form health survey (SF-36).
Timepoint [3] 315650 0
1 and 2 years after surgery

Eligibility
Key inclusion criteria
1. Patients aged from 18 to 70 years.
2. Complaints of a Symptomatic ICAS: a history of recurrent transient ischemic attacks or an ischemic stroke within 1 year owing to a stenosis from 70% to 99% in an internal carotid artery, middle cerebral artery, vertebral artery, or basilar artery.
3. A length less than or equal to 15mm of a stenosis in the target vessel and a vessel size greater than or equal to 2mm.
4. Hypoperfusion in the territory of the target vessels, which is determined by CT or MRI in 14 days before stenting.
5. CT or MRI scans show no massive cerebral infarction (beyond half of the MCA territory), intracranial hemorrhage, epidural or sub-dural hemorrhage, and intracranial brain tumor.
6. Patients who understand the purpose of the study and have provided informed consent.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Not able to receive general anesthesia.
2. Not able to receive angiographic assessment.
3. A stenosis >50% in an extracranial carotid or vertebral artery on the ipsilateral side.
4. Infarctions due to the perforators occlusion (determined by MRI scan), which is defined as basal ganglia or brainstem/thalamus infarction related with middle cerebral artery or basilar artery stenosis.
5. A high risk (leading to a stroke or death) to deliver the stent to the lesion.
6. A previous stent or angioplasty in the target lesion.
7. Progressive neurological signs within 24 hours before enrolment
8. Any haemorrhagic infarct within 14 days before enrolment
9. The presence of a cardiac source of embolus
10. Thrombolytic therapy within 24 hours before enrollment
11. Presence of intraluminal thrombus proximal to or at the target lesion
12. Myocardial infarction within previous 30 days
13. Non-atherosclerotic lesions: arterial dissection, moya-moya disease; vasculitic disease; herpes zoster, varicella zoster or other viral vasculopathy; neurosyphilis; any other intracranial infection; any intracranial stenosis associated with cerebrospinal fluid pleocytosis; radiation-induced vasculopathy; fibromuscular dysplasia; sickle cell disease; neurofibromatosis; benign angiopathy of central nervous system; postpartum angiopathy; suspected vasospastic process, and suspected recanalized embolus.
14. Known contraindications for aspirin and clopidogrel treatment.
15. An modified Rankin score greater than or equal to 3.
16. With a childbearing potential or a positive pregnancy test in 1 week before enrolment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Symptomatic ICAS patients who are eligible to enter the RCT will be randomly allocated to receive AMT or PTAS plus AMT (allocation ratio, 1:1). The randomization sequence will be concealed in the evaluation center by an anonymous staff.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization sequence will be generated by a third party, with a permuting block generated by a computer software.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
We also perform a preference cohort simultaneously. In this cohort, patients will choose the intervention of surgery plus aggressive medical treatment (AMT) or AMT alone. We choose the same outcome assessments as the randomized trial. We will incorporate the cohort to the trial using the propensity score matching.
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size is estimated on the following considerations. Among the ICAS patients with symptomatic severe stenosis (70%–99%), one-year risk in medication arm is 18% for WASID study and one-year risk in stent arm is 6%. That produces a 12% difference between the two arms. Power calculation (80%) for sample size was performed based on a two-sided test at the 5% level of significance. The sample size per group is estimated to be 90. If the rate of lost follow-up or early withdrawal is set at 10%, a total of 198 participants will be needed in the RCT. The preference will not be applied sample size limitations, we include as many participants as possible. In the primary analysis, we used propensity score adjustment to control for potential selection bias due to nonrandom treatment assignment in the preference cohort. The propensity-score derivation model was constructed with the use of multivariable logistic regression, with the primary outcome as the dependent variable. We made an a priori decision to include the baseline parameters along with a variable indicating whether the patient had undergone randomization. Additional variables, with no missing values, that will be unbalanced between the study groups at a significance level of 0.05 will also be considered for inclusion. The treatment effect is defined as the odds of the primary outcome as a function of the treatment received, with adjustment for the duration of follow-up and quintiles of the propensity score.
The log-rank test will be used to compare the treatment groups for the primary and secondary endpoints. Cumulative probabilities based on estimates of the primary endpoint from the Kaplan-Meier curves at specific time points (years 1 and 2) will be compared between the treatment groups with a Z test. We will investigate longitudinal differences in risk factors between the treatment groups using generalized estimating equation regression models with an exchangeable correlation structure. Subgroup analyses for pre-specified baseline factors will be done by fitting a Cox proportional hazards regression model that included treatment, a treatment by time interaction (because the proportional hazards assumption for the treatment was not met), the factor, and the treatment by factor interaction (the p value for which is reported in this paper). All analyses will be performed by intention to treat. All reported p values are two-sided without adjustment for multiple testing.
Three pre-specified sensitivity analyses will be used to generate data for patients withdrawing or becoming lost to follow-up. First, all patients lost to follow-up or withdrawn will be considered to have had a primary endpoint at last contact. Second, only patients in the PTAS group will be considered to have had a primary endpoint at last contact. Third, only patients in the medical group will be considered to have had a primary endpoint at last contact. Additionally, we will use a simulation approach in which a hazard rate per month for the primary endpoint is estimated for each treatment group from available data for all patients with patients lost to follow-up or withdrawn censored at their last study visit. For each patient lost to follow-up or withdrawn, we will randomly determine whether a primary endpoint occur for each study month according to the hazard rate. If a simulated primary endpoint does occur in any month, the patient is censored at the longest possible follow-up time. The simulated data for patients lost to follow-up or withdrawn will be combined with the actual data for the remaining patients and the p value for the log-rank test comparing the treatment groups and the probabilities of a primary endpoint by 2 years were computed. We will used SPSS (version 20.0) and R project (version3.1.0) for all statistical analyses.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2015
Actual
6/06/2015
Date of last participant enrolment
Anticipated
1/06/2019
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
198
Accrual to date
Final
Recruitment outside Australia
Country [1] 6979 0
China
State/province [1] 6979 0
Fujian

Funding & Sponsors
Funding source category [1] 291476 0
Government body
Name [1] 291476 0
Military medical and health research fund
Country [1] 291476 0
China
Primary sponsor type
Hospital
Name
Fuzhou General Hospital of Nanjing Command, PLA and clinical medical college of Fujian medical university
Address
No. 156 West Er-huan-xi road, Fuzhou, Fujian
Country
China
Secondary sponsor category [1] 290155 0
Hospital
Name [1] 290155 0
Fujian medical university union hospital
Address [1] 290155 0
NO.29,Xinquan Road,Fuzhou City,Fujian Province,China
Country [1] 290155 0
China

Ethics approval
Ethics application status
Approved

Summary
Brief summary
Introduction: Recent studies indicated that endovascular stenting is inferior to aggressive medication for reducing cerebrovascular events in patients with symptomatic intracranial stenosis(ICAS). However, a high rate of postprocedure complications and a biased selection of patients raised concerns about the accuracy and stability of the results. Hence, we designed a randomized controlled trial and a preference cohort to examine the effectiveness and safety of an improved protocol of angioplasty and stenting for patients with ICAS.
Methods and analysis: This study will be performed in 2 parts, a randomized controlled trial and a preference cohort. In the randomized controlled trial, ICAS patients will be randomized assigned to an angioplasty and stenting group (PTAS) and an aggressive medical treatment group (AMT), after screened by a strict selection criteria. The ICAS patients who are ineligible to the trial will be suggested for a preference to PTAS or AMT, and therefore be included in a preference cohort study. The PTAS will be performed in 3 to 5 days after enrolment, while the AMT will be initiated at the enrolment day. The primary outcome of this study is events of stroke or death within 30 days after enrolment. The secondary outcomes included the incidence of recurrent ischaemic stroke in the territory of the stenosis arteries between 30 days and 2 years postoperatively, the restenosis rate and health-related quality of life during the 2-years follow-up period.
Ethics and dissemination: The protocol of this study is approved by the institutional review boards of the participating centers. The results will be disseminated to patients, clinical practitioners and policymakers through publications in journals or conference papers. It is anticipated that the results will improve current PTAS quality and guide clinical decisions for choosing treatments for ICAS patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58122 0
Dr Hang Lin
Address 58122 0
Fuzhou General Hospital of Nanjing Command, PLA and clinical medical college of Fujian medical university. Address: 156 West er-huan-xi Road, Fuzhou 350025, China
Country 58122 0
China
Phone 58122 0
+86 591-22859529
Fax 58122 0
Email 58122 0
[email protected]
Contact person for public queries
Name 58123 0
Dr Xiao-Ping Cui
Address 58123 0
Fuzhou General Hospital of Nanjing Command, PLA and clinical medical college of Fujian medical university. Address: 156 West er-huan-xi Road, Fuzhou 350025, China
Country 58123 0
China
Phone 58123 0
+86 591-22859529
Fax 58123 0
Email 58123 0
[email protected]
Contact person for scientific queries
Name 58124 0
Dr Min Lin
Address 58124 0
Fuzhou General Hospital of Nanjing Command, PLA and clinical medical college of Fujian medical university. Address: 156 West er-huan-xi Road, Fuzhou 350025, China
Country 58124 0
China
Phone 58124 0
+86 591-22859529
Fax 58124 0
Email 58124 0
[email protected]

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