BRAVE-DREAMS (BRAin VEnous DRainage Exploited Against Multiple Sclerosis) (BRAVE-DREAMS)

Randomized Multi-centered Study for Evaluating the Efficacy and Safety of Angioplastic Surgery of the Extracranial Veins in the Treatment of Multiple Sclerosis. Studio Randomizzato Multicentrico Per la Valutazione Dell'Efficacia e Sicurezza Dell'Intervento di Disostruzione Delle Vene Extracraniche Nel Trattamento Della Sclerosi Multipla

To assess in a double blinded randomized control trial (RCT) study design safety and effectiveness of balloon angioplasty of the main extracranial and extravertebral veins in multiple sclerosis (MS) associated to chronic cerebrospinal venous insufficiency (CCSVI). Mean follow-up 1 year. 5-8 Italian centres 360 relapsing remitting (RR) MS patients will be randomized, with expanded disability disease scale (EDSS) ranging 2-5.5, age 18-65.

Safety will be assessed by measuring serious and minor adverse effects related to treatment. Effectiveness will be assessed by measuring 2 primary endpoints: Clinical parameters will be expressed in an integrated functional measure leading to the score, respectively, of improved, stable, worsened. Functional assessment is performed by tools permitting a quantification and will be made by a team of independent assessors. Clinical instrumental evaluation will be performed at baseline, and subsequently on 3 months basis. The outcome parameters leading to the composite functional measure are instrumental parameters, less assessor dependent, singularly validated for measuring the disability in MS. They are the followings: A) Dynamic Balance Assessment: Balance Master Limits of Stability (LOS). In static platform, swinging to reach the set position of center of pressure. B) Walking Function: The subject walks spontaneously for 10 meters with chronometric measure of time counting the number of steps. The test calculates the walk ratio i.e. ratio between length and step frequency. C) Manual dexterity. Box & Block test, moving wooden cubes. D) Sphincter control: Post-voiding residual by ultrasounds. F) Visual acuity: Low-contrast visual acuity Sloan Letter Chart. Magnetic Resonance Imaging (MRI) outcome measures: T1Gad active lesion.T2 lesion volume MRI evaluation at baseline, 6, 12 months. Secondary endpoints are: EDSS, chronic fatigue, cognitive function, rate of restenosis, annualized relapse rate.

Multiple sclerosis, Chronic cerebrospinal venous insufficiency, Percutaneous Transluminal Angioplasty (PTA), Internal jugular vein, Azygous vein

Five neurological parameters will be measured by the means of proper validated tools along 1 year of follow-up. The evaluation leads to a score, respectively expressed as improved, stable, fluctuant, worsened.

Standard MRI parameters will be assessed by the means of a blinded centre of lecture. Outcome measurement will be performed at baseline, 6 months and at 1 year follow-up.

This highly disabling symptom completely orphan of effective therapy will be measured by M-FIS (Modified-Fatigue Impact Scale).

Overactive Bladder symptom will be measured by the means of validated Overactive Bladder Questionnaire-b.

Inclusion Criteria: patients affected by CCSVI associated with MS relapsing-remitting and\or secondary progressive 18-65 years old EDSS 2-5 disease duration < 10y No relapse in the 30 days preceding the procedure clinical stability in the last 6 months with disease mod. treatments Patients under the best available therapy Exclusion Criteria: patients previously treated for CCSVI or inserted in other clinical trials in the last 3 months under treatment with natalizumab pregnant or refusing to adopt contraception presence of significant comorbidities alcool-drug abuse thrombophilia contraindication to MR

Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Gianesini S, Bartolomei I, Mascoli F, Salvi F. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009 Dec;50(6):1348-58.e1-3. doi: 10.1016/j.jvs.2009.07.096. Erratum In: J Vasc Surg. 2010 Apr;51(4):1079.

Zamboni P, Galeotti R, Salvi F, Giaquinta A, Setacci C, Alborino S, Guzzardi G, Sclafani SJ, Maietti E, Veroux P; Brave Dreams Research Group. Effects of Venous Angioplasty on Cerebral Lesions in Multiple Sclerosis: Expanded Analysis of the Brave Dreams Double-Blind, Sham-Controlled Randomized Trial. J Endovasc Ther. 2020 Feb;27(1):1526602819890110. doi: 10.1177/1526602819890110. Epub 2019 Nov 17. Erratum In: J Endovasc Ther. 2020 Feb;27(1):NP1.

Zamboni P, Tesio L, Galimberti S, Massacesi L, Salvi F, D'Alessandro R, Cenni P, Galeotti R, Papini D, D'Amico R, Simi S, Valsecchi MG, Filippini G; Brave Dreams Research Group. Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2018 Jan 1;75(1):35-43. doi: 10.1001/jamaneurol.2017.3825.

Zamboni P, Bertolotto A, Boldrini P, Cenni P, D'Alessandro R, D'Amico R, Del Sette M, Galeotti R, Galimberti S, Liberati A, Massacesi L, Papini D, Salvi F, Simi S, Stella A, Tesio L, Valsecchi MG, Filippini G; Chair of the Steering Committee. Efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. Brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial. Trials. 2012 Oct 3;13:183. doi: 10.1186/1745-6215-13-183.