An Observational study using Doppler Duplex ultrasound quantifying the occurrence of Jugular vein re-stenosis and complications following Angioplasty to treat Chronic Cerebral Spinal Venous Insufficiency (CCSVI)

BVI (Barrie Vascular Imaging) 001-2011

(Abbreviated title – post CCSVI angioplasty study)

An Observational study using Doppler Duplex ultrasound quantifying the occurrence of Jugular vein re-stenosis and complications following Angioplasty to treat Chronic Cerebral Spinal Venous Insufficiency (CCSVI)

BVI (Barrie Vascular Imaging) 001-2011

(Abbreviated title – post CCSVI angioplasty study)

An investigator Initiated Study with one clinical site.

Sponsor of the Study:

Dr. Sandy McDonald

50 Alliance Blvd.

Barrie, Ontario

705-722-8738

 Principle Investigator:

I agree to take responsibility for proper conduct of this study in compliance with this protocol and all applicable regulatory requirements.

Dr. Sandy McDonald: _____________________     Date: ________________

Registered Technologists:  Rose Mary Squires

Angela Lagace, Rachel Kaliyas

1.  INTRODUCTION

1.1                 Background

 Multiple Sclerosis is an inflammatory, demyelinating disease with an elusive origin, considered to have autoimmune determinants.   It is a potentially debilitating disease with symptoms varying, depending on the damage and affect on the nerves.  Multiple sclerosis symptoms may include:  Numbness or weakness in limbs, lack of coordination, partial or complete loss of vision, tingling or pain in body parts, shock sensations, fatigue and dizziness

In 1996 the United States National Multiple Sclerosis Society standardized four subtypes (1. 2.):

¦        Relapsing remitting - unpredictable relapses followed by periods of relative quiet (remission) with no new signs of disease activity.

¦        Secondary progressive – initial relapsing and then progressing into neurologic decline between acute attacks without any definite periods of remission.

¦        Primary progressive - progression of disability from onset, with no, or only occasional and miner, remissions and improvements.

¦        Progressive relapsing - from onset, have a steady neurologic decline but also suffer clear superimposed attacks.

The prevalence of MS is high in N. America impacting approx. 350,000 people in US and approx 75,000 in Canada with worldwide estimates to be approx. 2.5 million (2).

The etiology of the disorder is thought to be due to the narrowing of the veins which cause alterations in blood flow patterns within the brain that eventually causes injury to brain tissue and degeneration of neurons.  This has been identified as Chronic Cerebral Spinal Venous Insufficiency (CCSVI) by Dr. Zamboni and his colleagues (3. 4. 5. 6. 7. 8.). 

Presently there is no known cure for MS, though treatments can help in minimizing the progression of the disease and the symptoms (2). 

In a recent study, Dr. Zamboni et al studied the extracranial venous outflow routes using Doppler ultrasound in clinically defined multiple sclerosis (CDMS) compared to healthy subjects The result indicated that the risk of MS was dramatically increased by 43-fold with finding at least two parameters in CDMS patients (see appendix 1) vs. healthy subjects concluding that CDMS is strongly associated with CCSVI (3).   

Dr. Zamboni then went on to treat CCSVI patient’s abnormal restricted veins with angioplasty, which dilates these restricted veins, improving cerebral drainage, returning normal postural and respiratory mechanisms, and subsequently improving patient’s quality of life, with reduced symptoms, and improved mobility in some cases.  The patency rate of Azygous vein was 96% while the patency rate of the Internal Jugular Vein (IJV) was 53% and re-stenosis rate of the IJV was 47% (3).

This procedure remains controversial and experimental in Canada, though many clinics in Europe and the USA are providing this interventional angioplasty; however, this is not the case in Canada as yet.  Therefore, MS patients in Canada are travelling out of country for this treatment leaving them without a national comprehensive follow up medical care plan upon their return.  

1.2          Study Rationale:

With no formal guidelines available for follow up care for CCSVI MS patients post angioplasty, there is a need for an established formal protocol to identify and quantify re-stensosis rates and or life threatening thrombosis to maintain the long term health of these patients.

2.            STUDY OBJECTIVES AND END POINTS

2.1          Study Objectives:  

¦        To quantify re-stenosis rates post angioplasty within the follow-up time interval

¦        To determine whether there is regression of patients quality of life and the time interval 

¦        To determine the occurrence of internal jugular venous thrombosis  post angioplasty and the time interval for occurrence

¦        To establish Guidelines for appropriate and effective medical care plan post angioplasty.

2.2          Study Endpoints: 

The data collected in the study will be used to define a Doppler Duplex Ultrasound follow up medical care plan for CCSVI MS patient post Angioplasty intervention.  The following endpoints will be examined.

¦        2 out of 5 CCSVI criteria established by Dr. Zamboni will be utilized to identify        

the presence of re-stenosis (CCSVI). 

¦        Change in patient’s Quality of life (noted from MS QOL 54 form)

¦        Abnormal ultrasound finding defined by internal vessel echoes with the reduction of wall movement and color  Doppler filling to determine the presence of thrombosis

3.            STUDY PLAN

3.1          Study Design

This will be an observational study conducted with 250 participants that meet the CCSVI criteria and have undergone angioplasty.   This is a single center study conducted at the Barrie Vascular imaging center.    A baseline duplex ultrasound will be obtained prior to CCSVI angioplasty procedure.   Post CCSVI angioplasty, the participants will be observed with duplex ultrasound over a period of 18 months at 3 time points (between 1-3 months, 6-12 months and 12 -18 months) post CCSVI angioplasty.  In all cases, the CCSVI Zamboni criteria will be used for the ultrasound assessment (3).  Two out of five markers described previously would be considered evidence of re-stenosis (Appendix 1). The study will be conducted according to this protocol.

3.2          Study Population

The study start date will commence September 1, 2011 and end on September 30, 2014.

3.2.1.                Inclusion Criteria 

The following participant will be included in the study:

•         Have signed an Informed Consent

•         CCSVI MS patients that have had/will have one or more angioplasty.

3.2.2                Exclusion Criteria

Participants that have any of the following will be excluded from qualifying in the study, but would not be denied follow up ultrasound surveillance.

• Bechcet disease


• Vasculitis


• Cerebral vascular malformations


• Congential vascular malformations ( Klippel-Trenaunray, Parkes-Weber, Servelle-Martorell and Budd-Chiari syndromes)


• Participants that do not meet the required time interval ultrasounds pre and post CCSVI angioplasty.

4                TREATMENT DURING STUDY  

This is an observational study.  There are no study drugs or invasive medical devices being used in the study.

5                MEASUREMENTS AND EVALUATION

There will be potentially 4 visits conducted by participant to the Barrie vascular imaging center with the following procedures:

Visit 1 (pre CCSVI angioplasty)

Written and signed informed consent will be obtained from the participant.

Participant demographics will be collected (Gender, DOB, classification of MS)

Screening assessment will be conducted to determine if patient qualify for the study.   The following will be applied to all qualified participants:

A baseline duplex ultrasound will be conducted by the registered vascular technologist, trained with CCSVI protocol, who will record images as per their standard operating procedure.  

If participant have conducted the baseline ultrasound at another institution with a qualified CCSVI trained registered vascular technologists, then the participant will be asked to provide the pre op ultrasound findings.

The participant will be asked to fill out a MS QOL54 assessment to obtain a base line score.

Participants that have had ultrasound and angioplasty completed prior to their first visit to BVI, may already progress to visit 2 if they fall within the visit range.

Visit 2 to 4  (1- 3 months, 6 to 12 months, 12 to 18months post angioplasty)

A duplex ultrasound will be conducted.

Participants will complete a second MS QOL 54 assessment to compare score findings to the pre angioplasty score.

All participants will be asked to provide their angioplasty procedural notes including the specific veins that intervention was carried out on along with the size of angioplasty balloon sizes and if stents were also performed.

See attached flow chart for study procedures (Appendix 2).

6.            Safety Considerations

The ultrasound findings of a re-stenosis (2 out of 5 Zamboni criteria) will be communicated to the participant.  If patient does not have access for medical follow up care in Canada for this re-stenosis, the patient will take the responsibility to make their own decision on seeking further care outside of Canada.

Patients that present with findings of a venous thrombosis will need emergency follow up anti-coagulation.   The investigator or his designee will let the patient know of this outcome and contact the family physician to inform him/her.  If the family physician is not available then the patient will be directed to an emergency facility.

The study investigator may end a subject’s participation in the study if it is judged to be in the patient's best interest, if the participant does not meet the inclusion criteria, or if the participant is unable to comply with study protocol.  In addition, the study investigator may end the participation in the study at any time without the participants consent.  All withdrawals will be logged along with explanation why the participant was withdrawn.

7.                 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS

There are no known serious adverse event untoward patients having ultrasound known to date. 

The American Institute of Ultrasound in Medicine has a Bioeffects Committee that meets regularly to consider safety issues and evaluate reports dealing with bioeffects and the safety of ultrasound. The AIUM has adopted the following official statement: "There are no known harmful effects associated with the medical use of sonography (ultrasound). Widespread clinical use of diagnostic ultrasound for many years has not revealed any harmful effects. Studies in humans have revealed no direct link between the use of diagnostic ultrasound and any adverse outcome. Although the possibility exists that biological effects may be identified in the future, current information indicates that the benefits to patients far outweigh the risks, if any."

There could be a possible allergic reaction to ultrasound gel, though incidence is quite rare.  Non latex gloves and probe covers are utilized in the facility to avoid adverse reactions for participants having this allergy.

8.            DATA ANALYSIS METHOD 

The following will be identified for each subject:

•         Time interval at which re-stenosis was identified post angioplasty

•         Time interval at which thrombosis was identified post angioplasty

•         Time interval at which there was change in patient’s overall improvement in symptoms (per MS QOL54)

•         Type of Change in patient’s symptoms (per MS QOL54)

The total occurrence of re-stenosis and thrombosis will be stratified according to demographics, MS classification, country origin of angioplasty and balloon size used in angioplasty and stents.

The change in participants overall improvement in symptoms (per MS QOL 54) will be summarized.

9              STUDY ADMINISTRATION

9.2.1      Data collection

All potential participants who are screened for entry into the study will be listed on the Screening Log which will be placed in the Study Files.  Reason for exclusion will be clearly documented.

Data will be recorded on electronic data collection forms:

•         The participant demographics and baseline angioplasty data will be completed by BVI staff.  

•         The patient questionnaire form MS QOL54 will be completed by the participant.

The investigator will sign and date the forms attesting to his responsibility for the quality of the data recorded and that the data represents a complete and accurate record of each subjects’ participation. This data will be entered into an onsite database which will be retained at BVI.

Technologists will create ultrasound studies digitally using the participant’s identification name and OHIP number, and correlate all information gathered from the participant without their identification name under the study identification number file.  Under each file a spread sheet for recording ultrasound findings and MS QOL scores is the responsibility of the technologist performing the ultrasound.

9.2.2                Regulatory and Ethical Considerations (Ethical Approval) 

The investigator will ensure that this protocol is reviewed and approved by the appropriate IRB.

The IRB must also review and approve the site’s informed consent form (ICF) and any other written information provided to the subject prior to any enrolment of subjects and any advertisement that will be used for subject recruitment. 

If during the study, it is necessary to amend either the protocol or the informed consent form, the investigator will be responsible for ensuring the IRB reviews and approves these amended documents.  The IRB approval of the amended ICF will be obtained before the new subjects consent to the part in the study using this new version. 

Copies of the IRB approval and the IRB approved ICFs will be filed in the study files.

9.2.3                Notification of Primary Care Physician

See section 6.

9.2.4      Subject Informed Consent

The investigator or his designee will inform the subject or, where required, the participant’s legally authorized representative (e.g. a parent, guardian, next of kin, or other individual with appropriate jurisdiction) of all aspects regarding the subject’s participation in the study.

The informed consent will be obtained in accordance with all applicable regulatory requirements.  The investigator or his designee and the participant (or participant’s legally authorized representative) must both sign and date the informed consent before the participant can participant in the study.  A copy of the signed informed consent will be provided to the participant.  The investigator will emphasize that participation in the study is completely voluntary and that consent may be withdrawn at any time without penalty or loss of benefits to which the participant is otherwise entitled.

9.2.7                Records Retention

In accordance with applicable regulatory requirements, following closure of the study the investigator will maintain all study records in a safe and secure location.  Raw and electronic data will be retained for seven years.

9.2.8                Confidentiality

The Investigator will maintain patient confidentiality in accordance with applicable regulatory requirements (PIPEDA).

All data collected during the study will be held in strict confidence.  Participants will be identified with a study number in the study document with the exception of the ultrasound which is required to have their full name for proper identification.  No names or identifying information will be used in any publication or presentations.  No information identifying the participants will be transferred outside the investigator in this study unless required by health Canada, IRB or other regulatory agencies.

10     References 

1.            Adams, CW.  Vascular aspects of multiple sclerosis.  A colour atlas of multiple sclerosis

and other myelin disorders. London: Wolfe Medical Publication; 1989:184–7.

2.            www.bing.com/health/article/mayo-125502  what is Multiple Sclerosis?

3.                Zamboni, P.  Iron-dependent inflammation in venous disease and proposed parallels in

multiple sclerosis. J R Soc Med 2006; 99:589–93.

4.                Zamboni, P, Menegatti, E, Bartolomei, I, Galeotti, R, Malagoni, AM, Tacconi, G, et al.

Intracranial venous hemodynamics in multiple sclerosis.  Curr Neurovasc Res 2007;4:252-8.

5.                Zamboni, P, et al.  The value of cerebral Doppler venous hemodynamics in the assessment of multiple sclerosis.  J Neurol Sci 2009; 282(1-2):21-7.

6.            Simka, et al.  Extracranial Doppler sonographic criteria of chronic cerebrospinal venous

insufficiency in patients with MS.  Int Angiol 29(2):109-114.

7.            Simka, M, - Abstract: Euromedic Specialist Clinics, 31/08/10.

8.            Simka, M, et al.  Correlation of localization and severity of extracranial venous lesions with clinical status of multiple sclerosis.  Aug 30, 2010; Abstract.

Appendix 1                CCSVI Criteria by Zamboni et al

COLOR DUPLEX-TRANSCRANIAL DUPLEX CRITERIA

2 of 5 need criteria are to be fulfilled to determine cerebral venous outflow and need for venographic assessment. 

1.                   B-mode abnormalities.

2.                   Reflux of IJV and VV > 1.5 seconds

3.                   Reflux of Deep cervical veins

4.                   No flow detected in IJV or VV despite deep inspiration with head at zero degrees and 90 degrees complete and or lack of flow for 1.5 seconds.

5.                   Reverted postural control of main cerebral venous outflow

Subtract CSA of IJV supine and sitting, if the difference is a positive value cerebral venous outflow is normal, a negative value is consistent with CVO, or if the delta is <7mm2.

Full Ultrasound Barrie Vascular Imaging Procedure Protocol attached.

Appendix 2:

Study Flow Chart

BVI (Barrie Vascular Imaging) 001-2011

(Abbreviated title – post CCSVI angioplasty study)