Parent artery reconstruction for large or giant cerebral aneurysms using a Tubridge flow diverter (PARAT): study protocol for a multicenter, randomized, controlled clinical trial
Equal contributors Department of Neurosurgery, Changhai Hospital, Second Military Medical University
168 Changhai Road, Shanghai 200433
Background: The treatment of large (10-25 mm) or giant (25 mm) cerebral aneurysms remains technically challenging, with a much higher complication and recanalization rate than that is observed for smaller aneurysms. The use of a flow diverter seems to facilitate the treatment of this special entity. In a previous single-center prospective study approved by the Ethics Committee and China Food and Drug Administration (CFDA), we obtained promising results, showing remarkable safety and effectiveness for the Tubridge flow diverter. Nevertheless, the previous study may have been limited by biases due to its single-center design and limited number of subjects. Furthermore, although various articles have reported durable results from treating aneurysms using flow diverters, increasing questions have arisen about this form of treatment. Thus, prospective, multiple-center, randomized trials containing more subjects are needed. Methods/Design: This study is a multicenter, randomized, controlled clinical trial comparing clinical outcomes for patients with unruptured large/giant intracranial aneurysms treated with either conventional stent-assisted coiling or flow diverter implantation. A total of 124 patients who fulfill the inclusion and exclusion criteria will be randomized into either a treatment group or a control group in the ratio of 1:1. The treatment group will receive Tubridge implantation alone or combined with bared coils, and the control group will be treated with stent-assisted coiling (bare coils). The primary endpoint will be the complete occlusion rate at 6-month follow-up. Secondary endpoints include the immediate technique success rate, overall mortality, adverse events (ischemic stroke or intracranial bleeding) within 30 days, 90 days and 1 year post-operation, and the rate of intra-stent stenosis and thrombosis 6 months post-operation. Discussion: This prospective trial may provide more information on the safety and efficacy of the Tubridge flow diverter and may potentially change the strategy for treatment of large or giant aneurysms. Trial registration: The trial is registered on the Chinese Clinical Trial Registry: ChiCTR-TRC-13003127
Intracranial aneurysms are pathological bulges of cerebral
arteries caused by various etiologies, such as inflammation
or hemodynamic stress. Their rupture often results in a
catastrophic outcome, and they are associated with high
rates of mortality and morbidity . Large (10-25 mm) or
giant (25 mm) aneurysms are a subtype of intracranial
aneurysm with a much higher rupture risk and poorer
outcomes compared with small aneurysms [2,3]. Despite
technical advances, the treatment of large or giant
aneurysms remains technically challenging, with a much higher
complication and/or recanalization rate [4-8].
In recent years, with better understanding of the
occurrence and development of intracranial aneurysms, the
concept of vessel reconstruction, especially flow diversion, has
attracted the interest of neurointerventionalists worldwide.
Accordingly, various flow diversion devices have emerged
around the world; the best known devices include the
Pipeline (ev3, Irvine, CA, USA) and the Silk (Balt Extrusion,
Montmorency, France), which gained the approval of the
FDA and the CE and have been used clinically in over 50
Compared with conventional endovascular treatment
such as stent-assisted coiling, the Flow Diverter (FD) can
alter the blood flow, reduce the hemodynamic stress in
the aneurysm neck, and promote intra-saccular thrombus
formation [17-20]. A series of studies have shown that
flow diverters can significantly improve the outcome of
intracranial aneurysms [9-11,13,14,16].
The Tubridge is a new type of flow diversion device
developed by MicroPort Medical Company (Shanghai, China)
based on our previous clinical experience of multiple
stenting in intracranial aneurysms and the hemodynamic study
of intracranial aneurysms. Referring to its structure, the
Tubridge FD is actually a braided, self-expanding
stentlike device with flared ends. Currently, Tubridge FDs are
available in many diameters (2.5-6.5 mm) and lengths
(1245 mm). A large Tubridge (diameter 3.5 mm) is
braided with 62 nickel- titanium microfilaments and 2
platinum-iridium radiopaque microfilaments, whereas a
smaller Tubridge (diameter <3.5 mm) is composed of 46
nitinol and 2 platinum-iridium microfilaments. All
Tubridge FDs were designed with a pore size of
0.0400.050 mm2 at a nominal diameter, aiming to provide a
high metal coverage (approximately 30.0%-35.0%) at the
aneurysmal neck after full opening. In addition to its
use of a nickel-titanium alloy (commonly known as
nitinol, which has the advantages of shape-holding
memory and super-elasticity) and flared ends, the Tubridge
FD offers some structural improvements compared
with the Pipeline and the Silk. The use of
platinumiridium material for the radiopaque microfilaments
allows for improved visualization of both diameter and
length during the procedure. More importantly, the
design, which includes more braided microfilaments
for large-size FDs, decreases the shortening rate of the
FD after its full opening.
In a previous single-center prospective study
approved by the Ethics Committee and China Food and
Drug Administration (CFDA), we obtained promising
results, showing remarkable safety and effectiveness
for the Tubridge FD. In that study(data in press), a
total of 33 Tubridge FDs were successfully implanted
for 28 large or giant aneurysms, with the exception of
one mid-stent with a poor opening, resulting in a
technical success rate of 97.0% (32/33). Follow-up
angiographies, taken at a mean follow-up of 9.9 m (524 m),
were available for 25 aneurysms. Of those, 18 (72.0%)
aneurysms were completely occluded, 6 (24.0%) were
improved, and 1 (4.0%) was unchanged. All visible
covered branches and the parent artery were patent, with
no stenosis or obliteration. During a follow-up period
of 6 to 30 months (mean 19.0 months), the symptoms
experienced were resolved in 13 patients, improved in
6, and showed no change in 4. No procedure-related
morbidity or mortality occurred. Nevertheless, biases
may exist in the study due to its single-center design
and limited number of subjects. Prospective,
multiplecenter, randomized trials that include more subjects
Furthermore, although various articles have reported
durable results from treating aneurysms with FDs,
increasing questions have arisen about this type of
treatment. For example, is the occurrence of peri-procedure
intra-parenchymal hemorrhage accidental or related to
the application of the device? Are ischemic
complications encountered more often with FDs than with
conventional therapy [21-25]? These questions need to be
answered through prospective trials, which have been
lacking to date.
Based on these considerations, we initiated this trial
with the aim of evaluating the safety and effectiveness of
the Tubridge FD for unruptured large or giant
aneurysms (10 mm).
This study is a multicenter, randomized, controlled clinical
trial comparing clinical outcomes for patients with
unruptured large/giant intracranial aneurysms treated with
either conventional stent-assisted coiling or with flow
diverter implantation. The study will be conducted in 13
centers, each of which have performed more than 30
stent-assisted coiling procedures per year in the past
5 years, after gaining approval from local ethics
committees. A total of 124 patients who fulfill the inclusion and
exclusion criteria will be randomized into either a
treatment group or a control group in the ratio of 1:1. The
treatment group will receive Tubridge FD implantation
alone or combined with bare coils, and the control group
will receive stent-assisted coiling (bare coils).
Procedurerelated complications, adverse events, and follow-up data
will be collected prospectively to evaluate the safety and
effectiveness of the Tubridge FDs.
Compared with conventional stent-assisted coiling, Tubridge
FD implantation does not enhance the risk of
procedurerelated complications and may lead to a higher complete
occlusion rate and a decreased recanalization rate.
Primary and secondary outcomes
The primary endpoint will be the complete occlusion
rate at 6-month follow-up.
Secondary endpoints will include:
1. Immediate technique success rate.
2. Overall morbidity or mortality (assessment time
point: 30 days, 90 days and 1 year post-operation).
3. Ischemic stroke or intracranial bleeding (assessment time point: 30 days, 90 days and 1 year post-operation)
4. The rate of intra-stent stenosis (assessment time point: 6 months post-operation)
5. The rate of intra-stent thrombosis (assessment time point: 6 months post-operation)
6. General adverse events (assessment time point: 30 days, 90 days and 1 year post-operation).
1. Age 18 years to 75 years, male or nonpregnant female.
2. Unruptured internal carotid artery or vertebral
artery saccular aneurysm (including recanalized
aneurysms), confirmed by CTA, MRA, or DSA.
3. Width of aneurysm neck 4 mm, and aneurysm size 10 mm.
4. Parent vessel with a diameter range of 2.0-6.5 mm.
5. Indications for Enterprise stent-assisted coiling and
Tubridge FD implantation with or without coiling.
6. Is willing to return to the investigational site for
follow-up according to our protocol.
7. Understands the nature of the procedure and provision of written informed consent.
1. No appropriate route to access the aneurysm via endovascular approach.
2. A non-treated arteriovenous malformation (AVM) in the territory of the target aneurysm.
3. Ruptured aneurysms.
4. Anatomy not appropriate for endovascular treatment due to severe intracranial vessel tortuosity or stenosis, or intracranial vasospasm not responsive to medical therapy.
5. Major surgery within the previous 30 days or planned within the next 90 days after the enrollment date.
6. Severe neurological deficit that renders the patient
incapable of living independently (modified Rankin
7. Co-morbid conditions that may limit survival to less than one year.
8. Enrollment in another trial.
9. Poor compliance (inability to complete the full study). 10. Allergy or contraindication for the use of nickeltitanium alloy.
11. Inability to receive anti-platelet or anticoagulant
12. History of life-threatening allergy to contrast dye.
Patients who have been included in this trial and have
given written informed consent but are not able to
complete the whole study for any reason will be
withdrawn, including circumstances as below:
1. The subjects voluntarily quit the trial for various reasons.
2. Occurrence of serious adverse events. The subjects, main researchers, ethics committee, supervisor or CFDA terminate the research based on the consideration of ethics.
3. Early termination of the process based on the
investigators judgment (to prevent development of
severe complications, and so on).
4. Significant deviation in implementation, or the
subject failed to comply with the protocol.
5. Lost of follow-up due to changes in working/liv
ing places, or fortuitous accident. When these
fortuitous accidents occurs, including traffic
accident, death,or bone fracture, et al., Close
follow-up should be conducted to determine their
relationship with the usage of Tubridge FD.
6. flawed or absence of informed consents.
When the subjects are withdrawn, the researcher would
try their best to contact the subjects via telephone call,
letter, clinic interview, et al., and document the reasons why
they are withdrawn in detail; of which, those experienced
adverse effects must be recorded in the CRF if the adverse
effects were thought related to the devices used in this
trial. All raw data of those enrolled and treated subjects
must be kept including subjects withdrawn.
Method of allocation and randomization
All recruited subjects will be randomly allocated to
either the flow diverter implantation group or the control
group using a web-based platform linked to a central
randomization database. According to existing research,
aneurysms larger than 15 mm with posterior circulation
are thought to carry a higher complication rate [26,27].
Stratification will be performed for aneurysm size (15 mm
versus >15 mm) and aneurysm location (anterior
circulation versus posterior circulation).
The sample size calculation is based on the study of
Mocco et al. , who reported the midterm results of
219 patients treated with Enterprise-assisted stent coiling.
In their research, the 6-month complete occlusion rate
was 40%; of these, 46.4% were cases of aneurisms smaller
than 7 mm. Because the aneurysmal complete occlusion
rate decreases with aneurysm size, we assume the
6month complete occlusion rate to be 35% following
Enterprise stent-assisted coiling for aneurysms larger than
10 mm. Furthermore, the 6-month complete occlusion
rate for the Tubridge FD implantation is predicted to be
65% according to our previous results and to those of
other studies using Silk or Pipeline implantation. Thus, at
least 98 patients will need to be randomized in the
ratio of 1:1 (49 in each group) to obtain a positive result
(two-tailed test, significance level of = 0.05, power
(1 ) = 0.80). Considering a withdrawn-patient
maximum of 20%, the sample size will increase to at least
124 (62 in each group).
For all recruited patients, dual antiplatelet drugs (300 mg/
day aspirin plus 75 mg/day clopidogrel) will be given for
at least 3 days before the procedure. All procedures will be
performed under general anesthesia and via the
transfemoral approach. After sheath placement, heparin will be
given to maintain the activated clotting time at 2 to 3
times the baseline throughout the procedure. Next, a
proper (7 F) guiding catheter will be placed in the distal
internal carotid artery or vertebral artery. Subsequently,
the aneurysms will be treated with conventional
stentassisted coiling or FD implantation with or without
coiling. All detailed data, such as the aneurysms actual size,
width of the aneurysmal neck, aneurysmal shape, diameter
of the parent artery, and treatment results, will be recorded.
The post-operative antiplatelet regimen will be
administered as follows: <6 w: 300 mg aspirin + 75 mg clopidogrel;
6 w-3 m: 100 mg aspirin + 75 mg clopidogrel; 3 m:
100 mg aspirin indefinitely.
Planned patient follow-up
Arrangements will be made for all patients to be evaluated
at discharge and 30 d (7 d), 90 d (15 d), and 1 year (30
d) post-treatment, either by clinic or telephone contact.
Postoperative DSA follow-up is required after 6 m (30 d).
Safety and efficacy assessment
During the procedure and at each follow-up time point,
information about the patients will be documented in
detail. All data will be collected and analyzed by an
independent central laboratory to compare the complication rate,
morbidity, mortality, as well as initial and follow-up
angiographic results between the two groups. If any adverse
event has occurred, the detailed symptoms, duration,
severity, possible reasons, actions taken, results and other
relevant information will be reported. In addition, researchers
must fill out a serious adverse event (SAE) form and notify
the principal investigator, institutional review board (IRB),
China Food and Drug Administration (CFDA), Clinical
Research Associate (CRA), and other regulatory authorities
within 24 hours.
Immediate angiographic results will be classified
according to Raymonds classification for those treated with
stentassisted coiling or FD implantation combined with coils
. For aneurysms treated with the Tubridge FD alone,
flow modifications will be defined as disrupted inflow jet,
slow flow (if the contrast circulation within the aneurysm is
slowed), or reduced contrast filling (if increased contrast
stagnation is observed within the aneurysm at the late
venous phase of the angiographic series) .
The angiographic results will be classified into four
categories when compared with the immediate degree
of embolization: 1) Occluded, defined as no contrast
filling into the aneurysm sac; 2) Improved, defined as
decreased contrast filling into the aneurysm sac; 3)
Stable, defined as unchanged contrast filling into the
aneurysm sac; 4) Recanalized, defined as increased
contrast filling into the aneurysm sac. The intra-stent
stenosis will also be documented.
Table 1 shows a summary of the intervention and
Statistical analyses will be conducted based on an
intention-to-treat (ITT) population. Participants who are
recruited and treated will be considered the full analysis
set (FAS), those who complete treatment and the entire
Table 1 Summary of measurement items and point of data capture
Medical history/demographic information
Point of data capture
Informed consent form
Physical examination (1)
Routine urine and blood test
Blood biochemistry test (3)
Blood lipid test (4)
CTA, MRA or DSA
1. Physical examination: height, weight, and neurological presentation.
2. Vital signs: systolic pressure, diastolic pressure and heart rate.
3. Blood biochemistry tests: fasting blood glucose, blood urea nitrogen, TBIL, and serum creatine.
4. Blood lipid tests: total cholesterol, triglycerides, and low density lipoprotein.
5. Pregnancy tests: restricted to women with suspected pregnancy. 6. DSA examination: angiographic images will be sent to an independent laboratory for data analysis.
follow-up protocol will be considered the per-protocol set
(PPS), and those who are treated and have at least one
safety evaluation will be considered the safety set (SS).
Last observation carried forward (LOCF) method will
be implemented to handle the missing data from
withdrawn subjects, who would be included in FAS.
Comparisons of demographic information will first be
conducted to measure the balance between the two groups.
Then evaluation of primary and secondary outcome will
conducted as below:
The comparison of the treatment groups with regard
to the primary endpoint will be performed with the
data of the Full Analysis Set as well as of the Per
Protocol Set. In case the two analyses will lead to
different conclusions the result of the analysis of the
Per Protocol Set is deciding.
Use superiority test for analysis of primary outcome.
The formal test problem is as follows:
Test problem for the complete occlusion rate at
Let T be the rate of complete occlusion rate of
treatment group at 6-month follow-up.
Let c be the rate of complete occlusion rate of control
group at 6-month follow-up.
Immediate occlusion rate will be conducted in FAS
group, while other safety evaluation will be be
conducted in SS group. For quantitative data, t-test (for
equal variances and normal distribution) or Wilcoxon
rank sum test could be applied according to the
distribution of the data. The categorical variables will be
compared between study arms using Chi-square tests
or Fisher's exact tests (if Chi-square test is not valid).
Besides, for immediate technique success rate, 95%
confidence interval of each groups and difference
between groups will be estimated.
The statistical analysis process will be conducted by a
statistician at the Institute of Clinical Evaluation affiliated
with Beijing University, and the data will be analyzed
using Statistical Analysis System (SAS) software version
9.2 (SAS Institute Inc., Cary, NC, USA).
Thirteen institutes will take part in this trial, and the trial
has been approved by all relevant local ethics boards
including Shanghai changhai hospital ethics committee,
Huashan hospital ethics committee, Xuanwu hospital
ethics committee, Tiantan hospital ethics committee, ethics
committee of the second affiliated hospital of Zhejiang
university, Henan Peoples hospital ethics committee,
ethics committee of the first affiliated hospital of the third
military medical college of PLA, ethics committee of
the first affiliated hospital of China Medical University,
ethics committee of General Hospital of Shenyang military
Region, Renji hospital ethics committee, ethics committee
of the second affiliated hospital of Guangzhou medical
college, ethics committee of General Hospital of Guangzhou
military Region. Written informed consent will be obtained
from each participant prior to enrollment. The trial is
registered on the Chinese Clinical Trial Registry:
Monitor and supervise of the trial
The whole process of the trial will be supervised by a
Trial Steering Committee and a data and safety
monitoring committee. The Trial Steering Committee consists of
3 independent members, they will guide and supervise
the trial from the beginning, and provide expert advice
to the investigators on all aspects of the trial, including
decisions about continuation or termination of the trial
or amendments to the protocol.
The data and safety monitoring committee consists of
2 biostatisticians, 2 professor expertise in the treatment
of intracranial aneurysms, and an independent company.
They will work together to make sure that monitor and
supervise the whole process of the trial to ensure that 1)
the trial is being conducted in accordance with the
principles of Good Clinical Practice and the relevant
regulations of China. 2) any adverse events during the study
are promptly reported to the sponsor, the Clinical Trials
Units, and related agency. 3) any variances from the
clinical trial program to the sponsor. 4) the devices are used
as suggested by the protocol. 5) all subjects are fully
informed, and informed consent are achieved. 6) the clinical
report forms are promptly and clearly completed. And
they will review the progress of the trial and accruing trial
data, including updated figures on recruitment, data
quality and safety data, and provide expert advice to the
investigators on all aspects of the trial, including decisions
about continuation or termination of the trial or
amendments to the protocol.
Large and giant aneurysms carry the risk of a
significantly worse outcome compared with small aneurysms
. The ISUIA study showed that the risks of rupture
within 6 years for large and giant aneurysms are as
high as 13% and 27%, respectively . The treatment
of this entity, whether with conventional endovascular
treatment or surgery, imposes a great challenge for
both neurosurgeons and neurointerventionalists. A
deconstructive approach such as internal carotid artery
(ICA) occlusion requires sufficient compensation from
other vessels; even so, rates of ischemia as high as
4%15% have been recorded . In addition, there are also
concerns about de novo aneurysm following ICA
occlusion . Bypass surgery, especially high-flow bypass,
preceding ICA occlusion may help reduce ischemic
complications, but operative complications are not
uncommon, though reports in different manuscripts vary
. In contrast, reconstructive approaches such as
stentassisted coiling aiming to preserve the parent artery are
associated with much higher recanalization rates, ranging
from 19.2% to 50%. However, the use of FDs, including
Pipeline, Silk, and Tubridge, have recently shown excellent
and promising results [9-14,16]. Because of this, we began
this prospective trial, which may provide more
information on the safety and efficacy of the Tubridge flow
diverter and may change the treatment strategy for large or
giant aneurysms if the hypotheses are confirmed.
A similar trial, MARCO POLO, which was designed to
compare the results of coiling (with balloon remodeling
and/or stents when necessary) to those of Silk FD
implantation, is being conducted in 7 countries around the world
. However, there are apparent differences between our
trial and MARCO POLO, such as the target aneurysms
and the different active comparators used.
Although sporadic studies have reported FD application
in ruptured intracranial aneurysms, basilar trunk
aneurysms, and aneurysms beyond the circle of Willis, its
safety is not confirmed yet [34-37]. Anti-platelet therapy
may enhance the aneurysm rupture risk. Furthermore,
ischemic events may also be encountered more often when
FDs are implanted at the basilar trunk or in parent arteries
beyond the circle of Willis due to the involvement of small
perforators. To ensure the maximum safety of all subjects
and to obtain results more efficiently, we restricted our
target to unruptured Internal carotid artery or vertebral
The Enterprise is a type of intracranial self-expansion
stent with a closed-cell design. It is one of the most widely
used stents in clinics around the world [28,38,39], and
sufficient data has also demonstrated its safety. In this trial,
therefore, we choose to use Enterprise-assisted coiling in
the comparative arm of the study to evaluate the safety
and efficacy of the Tubridge FD.
During the development, Prof. Liu had given some advice about the design
of this device, and offered some data about our previous hemodynamic
studies. The other authors declare they have no competing interests.
QHH and JML conceived of the study. YX, BH, WYZ, and YBF designed the
study. PFY and YZ contributed to the draft of the manuscript. QL and RZ
contributed to the revision of the manuscript. All authors read and approved
the final manuscript.
This work was supported by subject of National Science and Technology
Supporting Program (2011BAI08B14), and project of Shanghai Science and
Technology Commission (11DZ1921603).