Neuromodulating Cortical Regions Involved in Neurogenic Bladder in MS

NCT ID: NCT06072703

Last Updated: 2025-02-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

29 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-10-30

Study Completion Date

2027-12-31

Brief Summary

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Neurogenic overactive bladder (NOAB), characterized by urinary frequency, urgency or urgency incontinence symptoms occurring during the storage phase of the bladder, is the most common urinary complaint in multiple sclerosis (MS). Current management options for NOAB in MS have limited efficacy and considerable adverse effects, which underscores the significance of this study and highlights the need for better, less invasive therapies. This novel study investigates brain therapeutic targets that could shift the focus of NOAB management in MS from a bladder-centric focus to brain restoration; specifically modulating the brain regions identified in the prior functional magnetic resonance imagining studies. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation that can modulate neurons (excite or inhibit) to improve the connectivity of the regions of interest (ROI). The preliminary data demonstrate, for the first time, significant improvement in bladder symptoms in ten women with MS who have voiding dysfunction following multifocal transcranial magnetic stimulation without any treatment-related adverse effects.

This randomized double-blind, sham-controlled single center clinical trial with an optional open-label extension (OLE) phase is designed to evaluate the effects of targeted rTMS in women with MS and NOAB by investigating restorative reorganization of brain function The main purpose of this study is to determine the effects of individualized repetitive Transcranial Magnetic Stimulation (rTMS) for improving overactive bladder symptoms such as urinary frequency and urgency with or without incontinence in individuals with multiple sclerosis (MS). Patients will undergo initial screening that includes a demographics information, physical exam, past medical and surgical history, medication list, urine pregnancy test (female subjects with childbearing potential), and completion of questionnaires to confirm the eligibility of patients. All eligible patients will be required to complete a functional MRI scan followed by locating the regions of interest through neural navigation system and finally receiving 10 treatment sessions.

Since this is a randomized trial, some patients will receive active treatment/ therapy sessions while others will only receive sham or placebo treatments. The total duration to complete all treatment sessions and follow up visits is approximately 4-5 months.

Detailed Description

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Neurogenic overactive bladder (NOAB), characterized by urinary frequency, urgency or urgency incontinence symptoms occurring during the storage phase of the bladder, is the most common urinary complaint in multiple sclerosis (MS). Current management options for NOAB in MS have limited efficacy and considerable adverse effects, which underscores the significance of this study and highlights the need for better, less invasive therapies. This novel study investigates brain therapeutic targets that could shift the focus of NOAB management in MS from a bladder-centric focus to brain restoration; specifically modulating the brain regions identified in the prior functional magnetic resonance imagining studies. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation that can modulate neurons (excite or inhibit) to improve the connectivity of the regions of interest (ROI). The preliminary data demonstrate, for the first time, significant improvement in bladder symptoms in ten women with MS who have voiding dysfunction following multifocal transcranial magnetic stimulation without any treatment-related adverse effects.

This randomized double-blind, sham-controlled single center clinical trial with an optional open-label extension (OLE) phase is designed to evaluate the effects of targeted rTMS in women with MS and NOAB by investigating restorative reorganization of brain function and improvement of urinary frequency, urgency and incontinence.

Investigators hypothesize that cortical alterations in bladder volume sensing and their response to stimulation contribute to NOAB symptoms in MS, and that improving the response to bladder distention (ROI within circuits 1 and 2) with neuronavigated rTMS can restore brain activity and improve symptoms (frequency, urgency, and incontinence). Investigators will test this hypothesis with the following specific aims:

Aim 1: To determine the clinical effects of neuronavigated and multifocal active/sham rTMS in women with MS and NOAB Aim 2: To assess the neuroimaging restorative effects of neuronavigated active/sham rTMS in women with MS and NOAB Aim 3: To assess the long-term safety and therapeutic effects of repeated rTMS in women with MS and NOAB who participate in the OLE phase (which subjects from both groups will be invited to enter at the 3-month follow up).

Efforts to improve the current knowledge of brain contribution to lower urinary tract function and the development of an individualized, noninvasive, and effective treatment modality at the level of the brain will greatly impact the quality of life for individuals with MS and subsequently others with OAB, whether neurogenic or non-neurogenic

Conditions

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Neurogenic Bladder Multiple Sclerosis Overactive Bladder

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Intervention Model: 2:1 active: sham assignment, with an optional OLE phase
Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Investigators Outcome Assessors
Masking: Double (participants and principal investigator and co-investigator)

Study Groups

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Active rTMS

1 Hz (LF) and 10 Hz (HF) rTMS stimulation will be delivered at 90% of the resting motor threshold for 40 min each week day for two weeks.

Group Type ACTIVE_COMPARATOR

Magstim Rapid2 System

Intervention Type DEVICE

The Magstim Rapid2 system is the most commonly used magnetic stimulation system for rTMS clinical studies and therapeutic investigations, capable of selectively inducing, modulating or suppressing neuronal activity. This rTMS device will be used along with the D70 Alpha Coil package, which includes an active coil ideal for focal rTMS and a sham coil, The placebo coil looks identical to its active version and replicates pulse noise without producing the magnetic field necessary to modulate cortical neurons. Additionally, the investigators will be utilizing the StimGuide navigation system (currently available at the HMRI) to accurately target the proposed regions of interest.

The Magstim Rapid2 system is indicated to be used in Multiple Sclerosis patients as target users with lower urinary tract symptoms such as urinary frequency, urinary urgency, urinary incontinence and voiding dysfunction.

Sham rTMS

Low-frequency (1Hz) active rTMS stimulation will be delivered with an inert "sham" stimulation coil for 40 min each week day for two weeks.

Group Type SHAM_COMPARATOR

Magstim Rapid2 System

Intervention Type DEVICE

The Magstim Rapid2 system is the most commonly used magnetic stimulation system for rTMS clinical studies and therapeutic investigations, capable of selectively inducing, modulating or suppressing neuronal activity. This rTMS device will be used along with the D70 Alpha Coil package, which includes an active coil ideal for focal rTMS and a sham coil, The placebo coil looks identical to its active version and replicates pulse noise without producing the magnetic field necessary to modulate cortical neurons. Additionally, the investigators will be utilizing the StimGuide navigation system (currently available at the HMRI) to accurately target the proposed regions of interest.

The Magstim Rapid2 system is indicated to be used in Multiple Sclerosis patients as target users with lower urinary tract symptoms such as urinary frequency, urinary urgency, urinary incontinence and voiding dysfunction.

Interventions

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Magstim Rapid2 System

The Magstim Rapid2 system is the most commonly used magnetic stimulation system for rTMS clinical studies and therapeutic investigations, capable of selectively inducing, modulating or suppressing neuronal activity. This rTMS device will be used along with the D70 Alpha Coil package, which includes an active coil ideal for focal rTMS and a sham coil, The placebo coil looks identical to its active version and replicates pulse noise without producing the magnetic field necessary to modulate cortical neurons. Additionally, the investigators will be utilizing the StimGuide navigation system (currently available at the HMRI) to accurately target the proposed regions of interest.

The Magstim Rapid2 system is indicated to be used in Multiple Sclerosis patients as target users with lower urinary tract symptoms such as urinary frequency, urinary urgency, urinary incontinence and voiding dysfunction.

Intervention Type DEVICE

Other Intervention Names

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Repetitive Transcranial Magnetic Stimulation

Eligibility Criteria

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Inclusion Criteria

* Adult women (≥ 18 years of age)
* Clinically stable MS defined as ExpandedDisability Status Score (EDSS) ≤ 7.5without exacerbation worsening in the preceding 6 months prior to study entry
* Neurogenic Lower Urinary Tract Dysfunction symptoms ≥ 3 months with NBSS total ≥ 15
* Individuals with Montreal Cognitive Assessment (MoCA) score \>10 will be eligible
* At least one bladder storage symptoms (e.g., urinary frequency, urinary urgency, nocturia with or without incontinence) indicated by OAB -AT≥ 8
* Individuals with active urinary tract infection (UTI) will be treated and will be enrolled after negative urinalysis

Exclusion Criteria

* Pregnant/planning to become pregnant or nursing
* Urodynamic findings of bladder outlet obstruction
* Baclofen or other intrathecal pumps, Pacemakers.
* History of seizure disorder (SZ), immediate family of SZ disorder, in addition to individuals who are taking any medications such as (bupropion) Wellbutrin or substances (ex: heavy alcohol use) that would lower seizure threshold will be excluded.
* History of bipolar disorder, or individuals who are taking medications that can exacerbate the condition such as tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-nor-epinephrine reuptake inhibitors, anti-psychotics, lithium, bupropion (Wellbutrin) and antihistamines will be excluded.
* All intracranial lesions and hemorrhagic stroke will be excluded
* History of moderate to severe heart disease or unstable angina
* History of Autonomic Dysreflexia
* History of interstitial cystitis, pelvic radiation
* Intra-detrusor botulinumtoxinA (BTX-A) injection over the past 6 months
* Incarcerated patients will be excluded.
* Active sacral nerve stimulation (SNS) device or any other spinal stimulators
* Indwelling urethral or suprapubic catheter
Minimum Eligible Age

18 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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The Methodist Hospital Research Institute

OTHER

Sponsor Role lead

Responsible Party

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Rose Khavari, M.D.

MD/PI

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Rose Khavari, MD

Role: PRINCIPAL_INVESTIGATOR

The Methodist Hospital Research Institute

Locations

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Houston Methodist Hospital

Houston, Texas, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Rose Khavari, MD

Role: CONTACT

7137030660

Betsy Salazar, PhD

Role: CONTACT

Facility Contacts

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Betsy Salazar, PhD

Role: primary

713-363-9911

Hamida Rajab, BS

Role: backup

713-363-9154

References

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Khavari R, Elias SN, Boone T, Karmonik C. Similarity of functional connectivity patterns in patients with multiple sclerosis who void spontaneously versus patients with voiding dysfunction. Neurourol Urodyn. 2019 Jan;38(1):239-247. doi: 10.1002/nau.23837. Epub 2018 Oct 12.

Reference Type BACKGROUND
PMID: 30311665 (View on PubMed)

Khavari R, Elias SN, Pande R, Wu KM, Boone TB, Karmonik C. Higher Neural Correlates in Patients with Multiple Sclerosis and Neurogenic Overactive Bladder Following Treatment with Intradetrusor Injection of OnabotulinumtoxinA. J Urol. 2019 Jan;201(1):135-140. doi: 10.1016/j.juro.2018.07.066.

Reference Type BACKGROUND
PMID: 30076906 (View on PubMed)

Khavari R, Tran K, Helekar SA, Shi Z, Karmonik C, Rajab H, John B, Jalali A, Boone T. Noninvasive, Individualized Cortical Modulation Using Transcranial Rotating Permanent Magnet Stimulator for Voiding Dysfunction in Women with Multiple Sclerosis: A Pilot Trial. J Urol. 2022 Mar;207(3):657-668. doi: 10.1097/JU.0000000000002297. Epub 2021 Oct 25.

Reference Type BACKGROUND
PMID: 34694911 (View on PubMed)

Khavari R, Karmonik C, Shy M, Fletcher S, Boone T. Functional Magnetic Resonance Imaging with Concurrent Urodynamic Testing Identifies Brain Structures Involved in Micturition Cycle in Patients with Multiple Sclerosis. J Urol. 2017 Feb;197(2):438-444. doi: 10.1016/j.juro.2016.09.077. Epub 2016 Sep 21.

Reference Type BACKGROUND
PMID: 27664581 (View on PubMed)

Shi Z, Tran K, Karmonik C, Boone T, Khavari R. High spatial correlation in brain connectivity between micturition and resting states within bladder-related networks using 7 T MRI in multiple sclerosis women with voiding dysfunction. World J Urol. 2021 Sep;39(9):3525-3531. doi: 10.1007/s00345-021-03599-4. Epub 2021 Jan 29.

Reference Type BACKGROUND
PMID: 33512570 (View on PubMed)

Tran K, Karmonik C, Boone TB, Khavari R. Are White Matter Tract Integrities Different in Multiple Sclerosis Women With Voiding Dysfunction? Female Pelvic Med Reconstr Surg. 2021 Jan 1;27(1):e101-e105. doi: 10.1097/SPV.0000000000000830.

Reference Type BACKGROUND
PMID: 32265400 (View on PubMed)

Tran K, Shi Z, Karmonik C, John B, Rajab H, Helekar SA, Boone T, Khavari R. Therapeutic effects of non-invasive, individualized, transcranial neuromodulation treatment for voiding dysfunction in multiple sclerosis patients: study protocol for a pilot clinical trial. Pilot Feasibility Stud. 2021 Mar 24;7(1):83. doi: 10.1186/s40814-021-00825-z.

Reference Type BACKGROUND
PMID: 33757581 (View on PubMed)

Salazar BH, Hoffman KA, Lincoln JA, Karmonik C, Rajab H, Helekar SA, Khavari R. Evaluating noninvasive brain stimulation to treat overactive bladder in individuals with multiple sclerosis: a randomized controlled trial protocol. BMC Urol. 2024 Jan 25;24(1):20. doi: 10.1186/s12894-023-01358-8.

Reference Type DERIVED
PMID: 38273296 (View on PubMed)

Other Identifiers

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PRO00035884

Identifier Type: -

Identifier Source: org_study_id

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