Trial Information

Reperfusion of Pulmonary Arteriovenous Malformations After Embolotherapy. A Randomized Trial of Interlock™ Fibered IDC™ Occlusion System vs. Nester Coils

Introduction Pulmonary arteriovenous malformations (AVMs) can lead to life-threatening
complications. These complications can be prevented with pre-symptomatic embolization. The
Interlock™ Fibered IDC™ Occlusion System coil (IDC) is a new device which might be more
effective for embolizing pulmonary AVMs. This study will investigate the efficacy of the
Interlock™ Fibered IDC™ Occlusion System and compare rates of reperfusion using Nestor coils
(standard coils used at participating centre) versus Interlock™ Fibered IDC™ Occlusion,
randomizing by AVM.

Rationale Reperfused AVMs put the patient at risk of pulmonary AVM complications. As such,
these AVMs require repeat embolotherapy and therefore patients are subjected to further
radiation, contrast and hospitalization. A number of devices have been studied and are
currently being used for embolization of pulmonary AVMs including coils (stainless steel,
platinum) and plugs (Amplatzer plugs). The immediate technical success rate is nearly 100%,
but long-term reperfusion occurrence is approximately 15% of treated AVMs and up to 30% of
patients. The IDC coil characteristics may lead to reduced reperfusion rates. No studies
of IDC coils have been reported to date in the management of pulmonary AVMs. Safety of IDC
coils has been demonstrated in other organs. Embolization procedure with IDC coils is
similar to embolization with other devices, in terms of fluoroscopy time use and contrast
load, as are procedural complication rates.

Background Pulmonary AVMs are present in approximately 40% of patients with hereditary
hemorrhagic telangiectasia (HHT), with a mean of five pulmonary AVMs per patient. Pulmonary
AVMs can lead to life-threatening and debilitating complications, such as massive
haemoptysis, spontaneous haemothorax, stroke and cerebral abscess. Fortunately, these
complications are preventable, through screening of HHT patients and preventative treatment
of pulmonary AVMs, as summarized in a recent decision analysis. The International HHT
Guidelines recommends routine screening of all HHT patients for pulmonary AVMs, with
preventative transcatheter embolotherapy of all significant pulmonary AVMs.

Most published data have reported outcomes with stainless steel or platinum coils, and fewer
with detachable balloons or Amplatzer plugs. Even with good success rates, reperfusion has
generally been reported in the range of 15% of embolized AVMs with routine embolization
using stainless steel or platinum coils. To date, comparative studies between stainless
steel and platinum coils have not shown significant differences in outcomes.

PLAN OF INVESTIGATION Study Hypothesis The device of interest has local characteristics
including better positioning and controlled release, together with tighter packing, which
may lead to superior outcomes and reduce costs as well as radiation time. Therefore it is
hypothesized that the IDC coil will be associated with less reperfusion than standard Nestor
coils, and will present a therapeutic advantage over Nestor coils.

Objectives Primary Objective Reperfusion for each AVM will be assessed at 1-year follow-up
post-embolization. If there is insufficient involution (<70% by volume) of the lesion, then
the AVM will be considered to be reperfused and care will be according to best clinical
practice. Follow up imaging will be as per usual practice/guidelines. If the participant
develops complications suspected to be due to pulmonary AVMs during the first year follow-up
period, then reassessment will be arranged according to current clinical practice protocols.
If there is evidence at early follow-up of ongoing AVM perfusion or of lack of aneurismal
involution, the AVM will be considered to be "reperfused".

Secondary Objective Reported secondary outcomes include fluoroscopy time, contrast volume
required, procedural time and complication rates.

STUDY DESIGN Study Population All adult patients who attend the Hereditary Hemorrhagic
Telangiectasia (HHT) clinic, require embolization procedures for their pulmonary AVMs, who
meet the inclusion and exclusion criteria will be considered eligible for this study. The
Toronto HHT Centre has a large well-characterized HHT population (approximately 1000
patients), the largest such population in Canada, allowing for feasible recruitment. It is
estimated that approximately 30 new patients undergo embolization per year, comprising
approximately 150 AVMs.

Enrollment Potential study participants will be identified from the Toronto HHT Centre
Database, an IRB approved comprehensive database capturing clinical information of patients
who have expressed an interest to participate in HHT related research studies and/or from
the HHT Clinic. Potential participants will be pre- screened for eligibility and upon
determination be approached for study participation. The study will initially be presented
to the eligible patient by the treating physician or a member of the HHT clinic team, who
will then introduce study personnel to the patient in order to give any additional
information including obtaining informed consent.

Randomization

Each participant will receive a unique randomization list. The Investigators will first
determine the number of pulmonary AVMs for which embolotherapy is required per participant.
Each treatable AVM will be referenced anatomically and assigned a number starting from one
and continuing up in sequential order. The Study Coordinator will then match this list to a
pre determined randomization list. Each AVM will be randomized into one of the two
following treatment allocations:

1. AVM Allocation I: Standard embolization procedure with Nestor Coil

2. AVM Allocation II: Standard embolization procedure with The Interlock™ Fibered IDC™
Occlusion System coil Unused randomizations will be discarded and will not be carried
over to the subsequent enrolled participant. The Investigators will not have access to
the randomization lists but will be informed by the Study Coordinator as to which AVM
will acquire which allocated treatment device.

Blinding

Blinding of the Principal Investigator is not possible since the Primary Investigator is
also the treating Interventional Radiologist responsible for the embolotherapy procedure.
Participants will be blinded to the type of coil they receive (Group Allocation) for each
particular treatable aneurysm. Outcome ascertainment bias will be minimized by the
following:

1. Coil allocation will be performed by the Study Coordinator during randomization

2. Final analysis results are non-subjective and obtained from concrete values acquired
from imaging data such as reperfusion rate per coiled aneurysm

STUDY VISITS Visit I - Screening and Baseline The study will be explained in detail to the
eligible participant. They will be given as much time as needed to review the informed
consent form (ICF) and ask any questions they may have regarding the study. It will be
ensured that all questions regarding the study are answered to satisfaction of the eligible
participants.

Once satisfied and prior to commencement of any study related procedures, the participant
will be asked to sign the Research Ethics Board-approved written consent form for this
study. A copy of the informed consent form will be provided to the patient to take and look
over at their leisure.

After informed consent is obtained, the Study Coordinator will screen patients for study
eligibility using the inclusion/exclusion criteria defined in this protocol and will
document them on a screening log. Reasons for non-participation will be identified based on
inclusion and exclusion criteria.

Visit II - Procedure Pulmonary angiography and embolotherapy will be performed using
standard clinical technique. Using standard aseptic technique the right common femoral vein
is punctured under direct sonographic guidance. A 7 French sheath is placed and connected
to a continuous saline irrigation. The right heart and then pulmonary arteries cannulated
using a 7 French Van Aman catheter. Pulmonary artery pressures are obtained; followed by
pulmonary angiography, either unilateral or bilateral depending on the site of the PAVMs.
Once confirmed the feeding arteries are cannulated using the Lumax catheter. After
confirming position the coils are deployed until complete occlusion of the feeding artery is
achieved. Similar procedure repeated for the other PAVMs. The catheter and sheath are then
removed and haemostasis is obtained. The participant is sent to the ward for monitoring.

Visit III - Post Procedure Post procedure, the participant will follow standard clinical
practice recommendations. The participant will be admitted overnight and will undergo a
routine chest X-Ray 1-day post embolization, before discharge from the hospital. The
participant will be assessed for the presence of post-procedure complications.

Visit IV - Month 1-3 Follow-Up As per standard clinical practice, the participant will be
required to visit Dr. Faughnan at the HHT Clinic 1-3 months post-procedure. This visit will
also include a single view chest X-Ray and standard oxygen shunt test. If there is any
suspicion of reopening of the embolized artery, it will be managed as per usual clinical
practice.

Visit V - Month 10-14 Follow-Up As per usual clinical practice, the participant will be
re-assessed at 10-14 months post-procedure with an unenhanced low-dose CT scan of the chest.
If there is any suspicion of reopening of the embolized artery, this will be managed as per
usual clinical practice.