Clinical trial NCT06072703: Neuromodulating Cortical Regions Involved in Neurogenic Bladder in MS
Official title: A Randomized, Sham-Controlled Clinical Trial Evaluating Individualized Neuromodulation of Cortical Regions Involved in Neurogenic Overactive Bladder in Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Neurogenic Bladder
Multiple Sclerosis
Overactive Bladder
Keywords: Neurogenic bladder
Functional Neuroimaging
repetitive Transcranial Magnetic Stimulation (rTMS)
Neuromodulation
Lead sponsor: The Methodist Hospital Research Institute
Sponsor class: OTHER
First posted: 2023-10-10
Enrollment: 29
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Intervention Model: 2:1 active: sham assignment, with an optional OLE phase
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: 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

Primary outcomes:
measure: Changes in subjective clinical outcomes following treatment - Neurogenic Bladder Symptom Score (NBSS) Questionnaire
timeFrame: Baseline, 1 week after, 1 month after and 3 months after rTMS treatment
measure: Changes on patient reported outcomes following treatment - 2 day bladder diary
timeFrame: Baseline, 1 week after, 1 month after and 3 months after rTMS treatment
Secondary outcomes:
measure: Changes in brain activation patterns following rTMS treatment - functional MRI imaging
timeFrame: Baseline and 1 week after rTMS treatment
measure: Changes in objective clinical outcomes following treatment - Bladder Capacity
timeFrame: Baseline, 1 week after, 1 month after and 3 months after rTMS treatment
measure: Changes in %Post-Void Residual/Bladder Capacity (PVR/BC) following treatment
timeFrame: Baseline, 1 week after, 1 month after and 3 months after rTMS treatment
Other outcomes:
measure: Changes in subjective clinical outcomes following treatment - American Urological Association Symptom Score (AUASS) Questionnaire
timeFrame: Baseline, 1 week after, 1 month after and 3 months after rTMS treatment
measure: Changes in subjective clinical outcomes following treatment - Incontinence Impact Questionnaire Short Form (IIQ-7)
timeFrame: Baseline, 1 week after, 1 month after and 3 months after rTMS treatment
measure: Changes in subjective clinical outcomes following treatment - Overactive Bladder (OAB) Awareness Tool
timeFrame: Baseline, 1 week after, 1 month after and 3 months after rTMS treatment
Locations:
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
Study officials:
affiliation: The Methodist Hospital Research Institute
name: Rose Khavari, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.