Effect of Deep TMS on the Permeability of the BBB in Patients With Glioblastoma Multiforme: a Pilot Study

Glioblastoma Multiforme of Brain Clinical Trial

Official title:

Effects of Deep Transcranial Magnetic Stimulation on the Permeability of the Blood-brain Barrier in Patients With Glioblastoma Multiforme: a Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02474966
• Other study ID #: 3403/23.10.14
• Status: Completed
• Phase: Phase 2
• First received: June 11, 2015
• Last updated: June 17, 2015
• Start date: November 2014
• Est. completion date: May 2015

Study information

• Verified date: June 2015
• Source: University of Roma La Sapienza
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

The blood-brain barrier (BBB) is a specialized interface allowing a unique environment for neuro-glia networks. BBB dysfunction is common in brain disorders. The Transcranial Magnetic Stimulation (TMS) is a non-invasive method of stimulating cortical motor neurons with the use of rapidly changing electromagnetic fields generated by a coil placed over the scalp. The objective of this study is to evaluate the safety and effects of the deep TMS (dTMS) on barrier integrity in patients with malignant glial tumors. BBB permeability will be quantified using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Permeability change will be compared between two DCE-MRI scans performed immediately after "real" and "sham" rTMS, randomly assigned within one week of each other.

Description:

The blood-brain barrier (BBB) is a specialized interface allowing a unique environment for neuro-glia networks. BBB dysfunction is common in brain disorders. However, the mechanisms underlying BBB opening are poorly understood. The investigators suggest a novel mechanism modulating BBB integrity and therapeutic implications in patients with glioblastoma multiforme. The Transcranial Magnetic Stimulation (TMS) is a noninvasive method of stimulating cortical motor neurons through the scalp and skull capable of inducing electrical currents and depolarizing neurons in focal brain areas with the use of rapidly changing electromagnetic fields generated by a coil placed over the scalp. The objective of this study is to evaluate the safety and effects of the deep TMS (dTMS) on barrier integrity in 20 patients with malignant glial tumors (glioblastoma multiforme). BBB permeability will be quantified using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Permeability change will be compared between two DCE-MRI scans performed immediately after "real" and "sham" dTMS, randomly assigned within one week of each other.

Design of study: Randomized double-blind crossover study. Patients will present on two consecutive days in order to receive dTMS followed by DCE-MRI. Subjects will be randomized into two groups: the first group will be treated before with real-dTMS (the first day) and after with sham-dTMS (the second day); the second group will be treated before with sham-dTMS (the first day) and after with real-dTMS (the second day). At the end of each session of dTMS the patients will undergo by MRI exams.

Enrolled patients: twenty patients with glioblastoma multiforme treated with craniotomy and gross tumor resection or maximal debulking at least a year prior to the study and treated with standard post-operative radiotherapy and adjuvant chemotherapy.

dTMS will be delivered at 1 Hz, on the anterior periphery of the resected tumor bed using the Hesed-coil (H-coil) (Brainsway Ltd., Jerusalem, Israel). Sham stimulation will be delivered with a sham coil placed in the same helmet able to produce similar sounds and scalp sensations.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: May 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Histological diagnosis of glioblastoma multiforme (WHO grade IV)

• Craniotomy with resection of the tumor at least one year prior to the study

• Treatment with steroids or chemotherapy stable for at least four weeks prior to study enrollment

Exclusion Criteria:

• History of epilepsy

• Presence of cardiac pacemaker

• Presence of neurostimulators

• Presence of surgical clips or medical pumps

• Allergy to contrast medium for Magnetic Resonance Imaging

• History of head injuries

• Alcoholism or drugs abuse

• State of pregnant or breastfeeding

• Severe psychiatric disorders

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma Multiforme of Brain

Intervention

Device:
• Deep Transcranial Magnetic Stimulation (dTMS)
Patients will present on two consecutive days in order to receive dTMS followed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Subjects will be randomized into two groups: the first group will be treated before with real-dTMS (the first day) and after with sham-dTMS (the second day); the second group will be treated before with sham-dTMS (the first day) and after with realTMS (the second day). At the end of each session of dTMS the patients will undergo by MRI exams.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Roma La Sapienza

References & Publications (15)

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Bolwig TG, Hertz MM, Paulson OB, Spotoft H, Rafaelsen OJ. The permeability of the blood-brain barrier during electrically induced seizures in man. Eur J Clin Invest. 1977 Apr;7(2):87-93. — View Citation

Chassidim Y, Veksler R, Lublinsky S, Pell GS, Friedman A, Shelef I. Quantitative imaging assessment of blood-brain barrier permeability in humans. Fluids Barriers CNS. 2013 Feb 7;10(1):9. doi: 10.1186/2045-8118-10-9. — View Citation

Côté J, Bovenzi V, Savard M, Dubuc C, Fortier A, Neugebauer W, Tremblay L, Müller-Esterl W, Tsanaclis AM, Lepage M, Fortin D, Gobeil F Jr. Induction of selective blood-tumor barrier permeability and macromolecular transport by a biostable kinin B1 recepto — View Citation

Hirschberg H, Uzal FA, Chighvinadze D, Zhang MJ, Peng Q, Madsen SJ. Disruption of the blood-brain barrier following ALA-mediated photodynamic therapy. Lasers Surg Med. 2008 Oct;40(8):535-42. doi: 10.1002/lsm.20670. — View Citation

Mottaghy FM, Gangitano M, Horkan C, Chen Y, Pascual-Leone A, Schlaug G. Repetitive TMS temporarily alters brain diffusion. Neurology. 2003 May 13;60(9):1539-41. — View Citation

Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005 Jan;2(1):3-14. Review. — View Citation

Prager O, Chassidim Y, Klein C, Levi H, Shelef I, Friedman A. Dynamic in vivo imaging of cerebral blood flow and blood-brain barrier permeability. Neuroimage. 2010 Jan 1;49(1):337-44. doi: 10.1016/j.neuroimage.2009.08.009. Epub 2009 Aug 12. — View Citation

Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120( — View Citation

Roth Y, Zangen A, Hallett M. A coil design for transcranial magnetic stimulation of deep brain regions. J Clin Neurophysiol. 2002 Aug;19(4):361-70. — View Citation

Sharp CD, Hines I, Houghton J, Warren A, Jackson TH 4th, Jawahar A, Nanda A, Elrod JW, Long A, Chi A, Minagar A, Alexander JS. Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol Heart — View Citation

Wassermann EM, Zimmermann T. Transcranial magnetic brain stimulation: therapeutic promises and scientific gaps. Pharmacol Ther. 2012 Jan;133(1):98-107. doi: 10.1016/j.pharmthera.2011.09.003. Epub 2011 Sep 7. Review. — View Citation

Zangen A, Roth Y, Voller B, Hallett M. Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil. Clin Neurophysiol. 2005 Apr;116(4):775-9. Epub 2004 Dec 16. — View Citation

Zimmermann R, Schmitt H, Rotter A, Sperling W, Kornhuber J, Lewczuk P. Transient increase of plasma concentrations of amyloid ß peptides after electroconvulsive therapy. Brain Stimul. 2012 Jan;5(1):25-9. doi: 10.1016/j.brs.2011.01.007. Epub 2011 Mar 12. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in blood-brain barrier permeability	The efficacy of the deep Transcranial Magnetic Stimulation (dTMS) in modulating blood-brain barrier permeability in patients with glioblastoma multiforme through the measurement of the average value of the slope-value distribution function (CDF) evidenced with dynamic contrast-enhanced magnetic resonance imaging	Six months	No
Secondary	Number of patients with adverse events as a measure of safety and tolerability	To evaluate the safety of the deep Transcranial Magnetic Stimulation (dTMS) applied in patients with glioblastoma multiforme	Six months	Yes