A Study Using Brain Stimulation and Behavioral Therapy to Increase Extent of Resection in Low-Grade Gliomas

Study Purpose

This study uses a cranial implant to deliver cortical stimulation that, when paired with physiotherapy, will remap the brain so that critical brain functions can be protected during brain tumor surgery. This pilot study will provide initial evidence for the safety and feasibility of such a protocol which will lead to future pivotal trials that could radically change eloquent area brain surgery. For patients with otherwise incompletely resectable brain tumors, this could mean a longer life expectancy and a better quality of life.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 65 Years
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

1. Age 18-65 years old. 2. Ability to understand a written informed consent document, and the willingness to sign it. 3. Radiographic evidence of likely low-grade glioma on MRI (i.e. non-enhancing) invading primary motor cortex in the non-dominant hemisphere. 4. Karnofsky performance status (KPS) ≥ 75. 5. Normal or near normal motor strength (i.e., at least 3/5 in relevant areas) 6. Normal or near normal speech (Can consistently name at least 4/5 cards) 7. No medical contraindication to surgery. 8. Free of other illness that may shorten life expectancy.

Exclusion Criteria:

1. Presence of other malignancy not in remission. 2. Evidence of bi-hemispheric or widespread tumor involvement. 3. Likely candidate to receive GTR on initial resection. 4. Medically high-risk surgical candidate. 5. History of recent scalp or systemic infection. 6. Presence of other implants or foreign bodies in the head. 7. Inability to receive an MRI for any reason. 8. Inability to receive cortical stimulation for any reason. 9. Coagulation disorders and/or use of anti-thrombotic therapies. 10. Platelet count < 50. 11. Diathermy procedures. 12. Electroconvulsive Therapy (ECT) 13. Transcranial Magnetic Stimulation (TMS) 14. Presence of implanted cardiac device (such as a pacemaker or defibrillator) 15. Pregnant women

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04745156
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	N/A
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Medical College of Wisconsin
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Max Krucoff, MD
Principal Investigator Affiliation	Medical College of Wisconsin
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioma, Glioma Intracranial, Gliomas Benign, Brain Tumor, Brain Cancer, Motor Cortex; Lesion

Additional Details

Study Protocol: Participants will undergo a standard-of-care craniotomy for resection of low-grade glioma. If part of the lesion cannot be removed due to involvement of functional cortex, RNS (Responsive Neurostimulation System [RNS; NeuroPace, Inc.]) electrodes will be implanted over the tumor-invaded area(s) in five participants. Stimulation will then be optimized for each individual to disrupt the function of the invaded cortical node (e.g., hand motor area -> hand dysfunction) (Aim 1). Over the next two months, outpatient physiotherapy will work to overcome the stim-induced deficits through gradual increases in stimulation amplitude as other, non-stimulated brain regions begin to assume its function (Aim 2). Once complete, participants will return to the OR for device explantation, repeated intraoperative mapping, and extended resection (if safe) (Aim 3). Aim 1: Optimize stimulation to maximize stim-induced deficits and minimize side effects Rationale: To induce plasticity, stimulation parameters must be individually tuned to maximize effect and minimize side effects. Approach: After device implantation and prior to hospital discharge, stimulus settings (frequency, pulse-width, and amplitude) will be optimized to the relevant clinical response while minimizing adverse effects (e.g., focal tonus, myoclonus, or seizures) while still in the safe, inpatient setting. Outcomes: Primary Endpoints: 1) stim-induced focal clinical deficit as measured on the relevant clinical scale (e.g., manual motor score [0-5], picture naming [x/10]), repetition [x/3]); 2) stim-induced side effects (e.g., seizures). Aim 2: Evaluate extent of remapping and safety of outpatient stimulation-physiotherapy protocol. Rationale: The ability to deliver chronic, outpatient stimulation is vital for practical clinical translation, yet neither its safety nor efficacy has been demonstrated. Approach: After Aim 1, a physiotherapist will assign a personalized, outpatient therapy regimen aimed at overcoming stim-induced deficits. Participants will have daily virtual sessions and return to clinic 2x/week for amplitude increases to re-induce deficits that therapy has overcome. This will continue until stimulation no longer can induce a deficit, suggesting successful functional remapping and enabling a return to the OR for further resection. Outcomes: Primary Endpoints: 1) absence of stim-related ER visits, readmissions, or serious adverse events (safety), 2) changes in intraop stimulation maps from surgery 1 to surgery 2 (induced remapping). Aim 3: Evaluate ability to extend surgical resections and associated neurological outcomes. Rationale: Any change in functional boundaries will only be useful if it results in a safe, extended resection. Approach: Each surgery will proceed with standard-of-care intraoperative functional mapping techniques and decision making. Neurological examinations will be performed preoperatively, daily while inpatient, then again at 2-weeks and 3-months postoperatively. Extent of resection will be evaluated as 3D residual tumor volume on postoperative MRI. Outcomes: Primary Endpoint: 1) Change in residual tumor volume after second versus first resection, 2) new neurological deficits 3-months after second resection compared to before second resection. Secondary Endpoint: 1) New, temporary neurological deficits after the second surgery

Arms & Interventions

Arms

Experimental: RNS System Implantation

This is a device feasibility study, therefore participants will only be enrolled into the investigational arm and will receive the RNS System Implantation.

Interventions

Device: - RNS System Implantation

Following resection consistent with SoC, if there is evidence of residual tumor which cannot be resected due to invasion of hand-M1 but which is small enough to be covered by two four-electrode strips, these strips will be placed on the functional cortex of interest and secured to the dura. The location of the leads will be registered into the navigation software (either Medtronic Stealth or Brainlab). The dura will then be closed as watertight as possible, and the RNS System will be incorporated into the craniotomy on closure Prior to closure, four bone screws will be placed and registered to the intraoperative navigation system as internal fiducials to be retrieved for future procedures.