Transvenous Approach for the Treatment of cerebral Arteriovenous Malformations (TATAM): Study protocol of a randomised controlled trial

Abstract

Background

Transvenous embolisation is a promising technique but the benefits remain uncertain. We hypothesised that transvenous embolisation leads to a higher rate of arteriovenous malformation angiographic occlusion than transarterial embolisation.

Methods

The Transvenous Approach for the Treatment of cerebral Arteriovenous Malformations (TATAM) is an investigator initiated, multicentre, prospective, phase 2, randomised controlled clinical trial. To test the hypothesis that transvenous embolisation is superior to transarterial embolisation for arteriovenous malformation obliteration, 76 patients with arteriovenous malformations considered curable by up to two sessions of endovascular therapy will be randomly allocated 1:1 to treatment with either transvenous embolisation (with or without transarterial embolisation) (experimental arm) or transarterial embolisation alone (control arm). The primary endpoint of the trial is complete arteriovenous malformation occlusion, assessed by catheter cerebral angiography. Complete occlusions will be confirmed at 3 months, while incompletely occluded arteriovenous malformations, considered treatment failures, will then be eligible for complementary treatments by surgery, radiation therapy, or even transvenous embolisation. Standard procedural safety outcomes will also be assessed. Patient selection will be validated by a case selection committee, and participating centres with limited experience in transvenous embolisation will be proctored.

Discussion

The TATAM trial is a transparent research framework designed to offer a promising but still unvalidated treatment to selected arteriovenous malformation patients.

Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT03691870.

Introduction

Cerebral arteriovenous malformations (AVMs) are complex, heterogeneous lesions that can lead to significant neurological disability or death, most commonly from intracranial haemorrhage.¹ Three different modalities are currently used, alone or in combination, to treat brain AVMs: surgical resection, endovascular embolisation and radiotherapy. There is little agreement regarding the best treatment modality for individual patients,² and all approaches carry substantial risks of morbidity and mortality (ranging from 1% to 30%).^3–5 The management of unruptured brain AVMs remains controversial: a randomised controlled trial (RCT) comparing all three combined techniques with conservative management has shown that curative strategies can carry a higher short-term morbidity and mortality than medical treatment alone.⁶ Longer term trials assessing the potential benefits of therapy are ongoing.

A new endovascular route for the treatment of brain AVMs has recently been described:^7–10 transvenous embolisation (TVE). While transarterial embolisation (TAE) consists of navigating microcatheters into the feeding arteries supplying an AVM, TVE uses microcatheters to navigate through the draining veins of the AVM, to reach and fill the AVM nidus in a retrograde fashion with liquid embolic agents (LEAs). By occluding the vein, the method transgresses a long-held dogma in the surgical or endovascular treatment of AVMs: to preserve the draining vein until all afferent vessels have been occluded.⁵ When highly selected, initial case series have shown promising results, with high occlusion rates as compared to TAE, and few technical complications.^7–10 The method is increasingly used in a growing number of centres but there is currently no research protocol to guide the use of this promising treatment.

A most important research question will eventually concern the role of endovascular treatment (including TVE) in the management of brain AVMs. The modest but more immediate goal of the present phase 2 trial is to assess the safety and efficacy of TVE (with or without TAE) as compared to TAE alone in the treatment of selected brain AVMs.

Methods

Trial design at a glance

The Transvenous Approach for the Treatment of cerebral Arteriovenous Malformations (TATAM) trial is an investigator-initiated, multicentre, prospective, randomised controlled phase 2 clinical trial comparing TVE (with or without TAE) versus TAE for selected cerebral AVMs. The primary objective of the trial is to guide the introduction of an innovative procedure in the clinical management of brain AVM patients. The primary hypothesis is that TVE (with or without TAE) will increase angiographic occlusion rates as compared to TAE alone. Secondary objectives will assess the safety of TVE as compared with TAE.

All patients will be reviewed by a case selection committee (CSC). All patients will be randomly allocated (1:1) to TVE (with or without TAE) or TAE alone. Interventions will be performed in experienced centres (more than 20 patients treated with TVE). Centres without TVE experience can also participate, but the first five interventions will be performed with the proctoring of a TVE expert. The primary outcome is complete AVM obliteration assessed by catheter angiography (adjudicated by a central core lab blinded to treatment allocation). Complete occlusions will be confirmed at 3 months, while incompletely occluded AVMs, considered treatment failures, will then be eligible for complementary treatments by surgery, radiation therapy, or even TVE. The trial plans to recruit 76 patients over 2 years (Figure 1).

Figure 1.

Study flow chart.

Primary hypothesis

TVE (with or without TAE) will increase the rate of complete occlusion of the AVM at confirmatory 3-month catheter angiography from 40% to 80% as compared to TAE alone (90% power; two-sided alpha 0.05; n = 68; 76 patients to account for 10% losses).

Selection criteria

Patients with a brain AVM (previously ruptured or not) for whom TVE is considered a promising but yet unproved therapeutic option will be reviewed by the CSC prior to randomised allocation of treatment options. The CSC will review angiographic and brain imaging studies, in addition to past medical history and current neurological status of potential participants. The CSC will be composed of physicians experienced in TVE (more than 20 interventions each). Current indications may include (but are not restricted to) brain AVMs with a small (residual) nidus (<3 cm), with a single draining vein, and for which curative treatment can probably be attained with one or at most two treatment sessions. These indications are not formalised as selection criteria because: (a) indications are likely to change as the trial progresses; (b) the number of veins or venous collectors is often difficult to discern precisely even using cutting-edge imaging technologies.

Patients with incompletely treated brain AVMs (by any other modality) are eligible for participation. Patients included in the Treatment Of Brain Arteriovenous malformationS (TOBAS) RCT¹¹ can also participate in TATAM.

Exclusion criteria are an absolute contraindication to endovascular treatment or anaesthesia, and inability to obtain informed consent. Patients requiring urgent medical or surgical treatment (after a rupture for example) can be recruited once the patient can be scheduled for an elective or semi-elective curative procedure.

Randomisation and data storage

TATAM ensures concealment of treatment allocation by using a 1:1 web-based randomisation algorithm, including a minimisation algorithm to ensure a balanced number of ruptured AVMs between groups.

Number of patients

An increase in the obliteration rate from 40% to 80% would be clinically significant. Based on Fisher’s exact test, 76 patients (38 in each group) will be needed to detect an increase in the obliteration rate from 40% to 80% with an alpha error of 5% and a beta error of 10%, allowing 10% of losses at determination of the primary endpoint.

Data monitoring

The trial will be monitored by an independent data and safety monitoring committee (DSMC) and recommendations to interrupt or continue recruitment will be forwarded to the steering committee (SC), which is responsible for the final decision regarding continuation of the study.

Interventions

The experimental treatment (TVE) is an attempt to occlude the AVM completely using venous catheterisation and retrograde LAE injection. TAE can be performed to prepare for TVE during the same or one previous preparatory session, or TAE can be used to rescue an incomplete TVE. In some patients, balloon catheterisation is used transarterially to assist TVE.

The standard TAE, without TVE, is used in patients allocated to standard treatment.

Patients with a residual AVM at the end of the final embolisation procedure are adjudicated a failure to reach the primary outcome. Patients can then be further treated using alternative standard options (including surgery, radiation therapy) if deemed necessary. In addition, patients allocated to standard treatment can also be offered TVE, if still feasible, once the TAE has been adjudicated to have been a failure.

Participants and training

Any active endovascular centre treating more than 100 neurovascular patients a year can participate. Centres that have not a sufficient experience in TVE (fewer than 20 patients treated with TVE) must be assisted by an expert in TVE (more than 20 patients) for the first five patients.

Outcome measures

The primary outcome of TATAM is the complete occlusion of the AVM (i.e. no residual arteriovenous shunt) on confirmatory catheter angiography performed 3 months after the last embolisation session, adjudicated by an independent central core lab blinded to treatment allocation. Failures of catheterisation and incomplete embolisation at the end of the final procedure in either group are adjudicated failure to reach the primary outcome (Figure 1).

Secondary outcomes include standard safety outcomes: new neurological deficits, haemorrhagic/ischaemic procedural complications, modified Rankin scale (mRS) at discharge, discharge to location other than home, length of hospitalisation (days), new symptomatic ischaemia following treatment (seen on magnetic resonance imaging (MRI) with diffusion sequences prior to discharge), incidence of new admission to hospital during follow-up, any treatment of the AVM during follow-up, incidence of intracranial haemorrhage during follow-up, incidence of residual AVM on confirmatory catheter angiography at 3 months post-treatment, mRS at 3 months, and death from any cause.

Clinical follow-up and imaging protocol

Catheter angiography and brain MRI imaging are considered standard imaging studies prior to treatment decisions. Brain MRI with diffusion sequences (or computed tomography in case MRI is contraindicated) after the final embolisation session and before hospital discharge, to detect new but silent ischaemic lesions, are also considered standard of care. For the analysis of the primary outcome, all patients will undergo a confirmatory catheter angiogram 3 ± 1 months after the last embolisation session, unless the procedure was a technical failure (the last angiographic series of the failed embolisation session will then serve to adjudicate the primary outcome).

Planned analyses

Descriptive statistics will be performed on demographic variables and perioperative data to compare the two groups at baseline. Means, standard deviations and ranges will be presented for quantitative variables and frequency tables for categorical variables. Those statistics will be broken down by treatment arm.

The number of patients reaching the primary outcome (i.e. complete angiographic occlusion) will be compared with a Fisher’s exact test. Secondary safety outcomes will be compared with Student’s t-tests (for continuous variables) or Fisher’s exact tests (for categorical variables).

All outcomes will be analysed in an intention-to-treat fashion, with as-treated analyses as appropriate.

Duration of the trial

Each patient will be followed for at least 3 months after the final endovascular procedure. We plan a 2-year recruitment phase. The trial should be completed within 3 years, including data analysis.

Protection against bias

Classic biases such as selection bias or information bias will be dealt with by randomly assigning patients and blinding in the assessment of the primary outcome. Random allocation of treatment is best for ensuring internal validity and is the best approach to control for confounding and selection bias.

Regulatory and ethical considerations

The institutional review board of the Centre Hospitalier de l’Université de Montréal (CHUM) approved the protocol on 2 August 2018 (study ID: 18.118). The trial is currently before other institutional review boards at other centres. Participants will be made fully aware of the study purposes, the procedure and the risks of each intervention. When signing the study consent form, they will be informed that participation is voluntary and they can request to be withdrawn from the study at any time. Patient enrollment in this trial will comply with the principles enunciated in the Declaration of Helsinki. All the information collected with the questionnaires will be kept confidential and will be anonymised. Trial management is transparent, fully independent and aims to preserve the scientific integrity of the research enterprise and the welfare of the participants. The industry has no control over the design or conduct of the trial, and no access to the data will be granted until publication; the results will be published whether they are favourable or not, and publications will be fully independent and autonomous. The SC has full responsibility regarding the conduct and progress of the trial, as well as reporting of results. The SC will not have access to the unmasked data before completion or interruption of the trial. The clinical events committee, the endpoint review committee and the adverse event committee, once nominated, will work independently from the SC. These committees regularly send progress reports, notices and warnings (when appropriate) to the independent DSMC. The committees that would have access to unmasked data are limited to the adverse event committee (responsible for reviewing each adverse event) and the DSMC (whenever members judge that unmasking of groups is mandatory to protect the safety of participants, or once they are convinced that significantly different results have occurred). The DSMC will follow the progress of the trial, with masked results and events (tagged as groups A and B) at all times, but with the possibility of unmasking if necessary. The DSMC will inform the SC that the trial should be interrupted if any concerns arise during the trial. The SC will act according to the DSMC recommendations.

Discussion

Innovations in neurovascular care have most often been introduced through case series of selected patients. In that respect, TVE has been no exception, at least so far.^7–10 Results have been promising: a meta-analysis of eight case series of TVE in 66 patients found complete angiographic AVM exclusion in 96% (91–100%) of patients, with technical complications in 8% (2–14%), a good functional outcome in 89% (82–96%) and no treatment-related mortality.¹²

The problem with case series is that participating patients are not truly given a chance to escape the enthusiasm associated with the novelty. No one really knows if patients could not have been better served with standard treatment options (such as TAE, with or without radiation therapy or surgery). In addition, the results of case series of innovative treatments are barely generalisable, for they cannot be validly compared: we are left with historical or matched controls, and no one knows whether the innovation represents real progress in terms of patient outcomes.

TATAM is a randomised clinical trial designed to assist the introduction of a promising but yet unproved treatment, in the best medical interest of participating patients. In that respect, it was designed in the spirit of care trials.¹³ In line with the care trial philosophy, the study is carried out using routine care personnel who collect data on simple web-based case report forms according to normal routine clinical practice and there is no additional test required by protocol in addition to what is considered standard care.

Some ‘explanatory’ features were added to the trial design to ensure patients’ safety in the context of an innovative treatment. These included case selection by the CSC composed of experts in TVE, and the proctoring of inexperienced operators, even though these features may affect the generalisability of the results. In addition, because TVE is rapidly evolving, a surrogate angiographic primary outcome was chosen for this phase 2 trial to provide short-term feedback and address the ‘moving target’ problem.¹⁴

As compared to case series, TATAM will allow a rigorous scientific assessment of TVE risks and benefits as compared with TAE. After the completion of this phase 2 trial, we plan to launch a phase 3 care trial with a more pragmatic design, a longer term angiographic confirmation of obliteration and a stronger and more meaningful primary clinical outcome.

TATAM is now recruiting interested centres for participation in the study.

ClinicalTrials.gov Identifier: NCT03691870.

Full protocol can be found at http://www.clinical-care-trials.org/home.

Author contribution

RF was responsible for the figure and the writing of the paper; TED and CM were responsible for the study design and writing of the paper. RC, MP, RB, VMP, DGA, DI, AW, DR and LN contributed to the writing of the paper; SN, RK and GG assisted with the figure, data collection and data acquisition; JR contributed to the study design and writing of the paper.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics

The patients (or their parents or guardians) have given their written informed consent. The study protocol has been approved by the research institute’s committee on human research.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.