Simultaneous DBS of the GPi and the NBM in Patients With Parkinson's Disease and Mild Cognitive Impairment

Parkinson Disease Clinical Trial

Official title:

Simultaneous Deep Brain Stimulation of the Globus Pallidus Internus and the Nucleus Basalis of Meynert in Patients With Parkinson's Disease and Mild Cognitive Impairment

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05320523
• Other study ID #: 38865720.1.0000.0068
• Status: Recruiting
• Phase: N/A
• Start date: July 20, 2021
• Est. completion date: January 2024

Study information

• Verified date: October 2021
• Source: University of Sao Paulo General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase 1 study evaluating the safety of combined bilateral globus pallidus internus (GPi) and nucleus basalis of Meynert (NBM) stimulation in treating levodopa responsive motor symptoms of Parkinsonism and cognitive dysfunction, respectively, in patients with moderate to advanced Parkinson's disease having mild cognitive impairment.

Description:

This study aims to provide a proof of safety of combined bilateral Globus Pallidus internus (GPi) and Nucleus Basalis of Meynert (NBM) stimulation in patients with moderate to advanced Parkinson's disease having mild cognitive impairment.

GPi stimulation with high-frequency ameliorates the cardinal motor symptoms and motor complications in Parkinson's disease patients, and this present study also wants to determine if additional NBM stimulation, with low-frequency stimulation, improves or slows progression of cognitive decline in patients with moderate to advanced Parkinson's disease having mild cognitive impairment, and to evaluate the effect of NBM stimulation on gait and balance impairment.

Study Design: Prospective single center Phase 1 study with double-blind randomized delayed activation of basal nucleus of Meynert neurostimulation (staggered onset design).

Planned Number of Subjects: 10 patients.

Planned Number of Sites / Countries: Single center in Brazil.

Study schedule:

• Presurgical baseline evaluation (motor on and off medication state; cognitive testing in best motor on state).

• DBS Implant Procedure.

• Postsurgical baseline evaluation (motor off state; cognitive testing in best motor on state) at 3±1 weeks after surgery and activation of globus pallidus internus neurostimulation using individualized stimulation parameters after a standard monopolar review.

• Regular adjustments of the GPi stimulation parameters aiming at the best motor improvement.

• Visit 1 (16 weeks after activation of GPi neurostimulation): motor off medication + GPi stimulation state, cognitive testing in on medication + GPi stimulation state. Randomization and blinded activation of NBM neurostimulation according to a 1:1 scheme.

• Visit 2 (16 weeks after randomization): motor off and on medication + stimulation state (GPi stimulation ± NBM stimulation); cognitive testing in motor on medication + stimulation state (GPi stimulation ± NBM stimulation). Activation of NBM neurostimulation in all patients.

• Visit 3 (16 weeks after activation of NBM stimulation in all patients): motor off and on medication + GPi and NBM stimulation state; cognitive testing in motor on medication + GPi and NBM stimulation state.

• Annual follow-up visit for up to 5 years after activation of NBM stimulation.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: January 2024
• Est. primary completion date: August 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 75 Years

Eligibility

Inclusion Criteria:

• Age at the time of enrollment: 50 - 75 years.

• Diagnosis of idiopathic PD according to Movement Disorders Society (MDS) criteria (Albanese et al., 2017).

• Mild cognitive impairment (MCI) related to Parkinson's disease according to MDS criteria. (Livtan et al. 2012).

• Duration of bilateral idiopathic PD: = 5 years of motor symptoms.

• Modified Hoehn and Yahr stage = 2 on off medication state.

• UPDRS subset III (motor) = 30 points on off medication state.

• Levodopa must improve PD symptoms by = 30% in a levodopa challenge test, as measured by UPDRS subset III score.

• Presence of motor complications related to Parkinson's disease.

• Be willing and able to comply with all visits and study related procedures

• Able to understand the study requirements and the treatment procedures and to provide written informed consent before any study-specific tests or procedures are performed.

Exclusion Criteria:

• Alcohol or drug abuse.

• Any significant psychiatric problems, including acute confusional state (delirium), ongoing psychosis, or clinically significant depression.

• Contraindications for deep brain stimulation (DBS) surgery.

• Heart failure, heart disease or any condition that contraindicates surgical procedures.

• Pacemaker or other active implanted stimulators.

• Clearly established Parkinson's disease dementia according to Movement Disorders Criteria.

• Participation in another drug, device, or biologics trial concurrently.

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Mild Cognitive Impairment
• Parkinson Disease

Intervention

Device:
• Deep brain stimulation implantation of a Vercise neurostimulation system in GPi and NBM.
Deep brain stimulation implantation of a Vercise neurostimulation system in GPi and NBM, at the same trajectory.
• GPi stimulation
Bilateral high-frequency neurostimulation of the GPi using a Vercise neurostimulation system
• NBM stimulation
Bilateral low-frequency neurostimulation of the NBM using a Vercise neurostimulation system
• Sham stimulation
Ineffective neurostimulation by setting 0mA output at the Vercise neurostimulation system

Locations

Country	Name	City	State
Brazil	University of São Paulo General Hospital	São Paulo

Sponsors (1)

Lead Sponsor	Collaborator
University of Sao Paulo General Hospital

Country where clinical trial is conducted

Brazil, 

References & Publications (10)

Dalrymple WA, Huss DS, Blair J, Flanigan JL, Patrie J, Sperling SA, Shah BB, Harrison MB, Druzgal TJ, Barrett MJ. Cholinergic nucleus 4 atrophy and gait impairment in Parkinson's disease. J Neurol. 2021 Jan;268(1):95-101. doi: 10.1007/s00415-020-10111-2. — View Citation

Freund HJ, Kuhn J, Lenartz D, Mai JK, Schnell T, Klosterkoetter J, Sturm V. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol. 2009 Jun;66(6):781-5. doi: 10.1001/archneurol.2009.102. Erratum i — View Citation

Gratwicke J, Zrinzo L, Kahan J, Peters A, Beigi M, Akram H, Hyam J, Oswal A, Day B, Mancini L, Thornton J, Yousry T, Limousin P, Hariz M, Jahanshahi M, Foltynie T. Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease De — View Citation

Gratwicke J, Zrinzo L, Kahan J, Peters A, Brechany U, McNichol A, Beigi M, Akram H, Hyam J, Oswal A, Day B, Mancini L, Thornton J, Yousry T, Crutch SJ, Taylor JP, McKeith I, Rochester L, Schott JM, Limousin P, Burn D, Rossor MN, Hariz M, Jahanshahi M, Fol — View Citation

Koulousakis P, Andrade P, Visser-Vandewalle V, Sesia T. The Nucleus Basalis of Meynert and Its Role in Deep Brain Stimulation for Cognitive Disorders: A Historical Perspective. J Alzheimers Dis. 2019;69(4):905-919. doi: 10.3233/JAD-180133. Review. — View Citation

Kuhn J, Hardenacke K, Lenartz D, Gruendler T, Ullsperger M, Bartsch C, Mai JK, Zilles K, Bauer A, Matusch A, Schulz RJ, Noreik M, Bührle CP, Maintz D, Woopen C, Häussermann P, Hellmich M, Klosterkötter J, Wiltfang J, Maarouf M, Freund HJ, Sturm V. Deep br — View Citation

Müller ML, Bohnen NI. Cholinergic dysfunction in Parkinson's disease. Curr Neurol Neurosci Rep. 2013 Sep;13(9):377. doi: 10.1007/s11910-013-0377-9. Review. — View Citation

Nombela C, Lozano A, Villanueva C, Barcia JA. Simultaneous Stimulation of the Globus Pallidus Interna and the Nucleus Basalis of Meynert in the Parkinson-Dementia Syndrome. Dement Geriatr Cogn Disord. 2019;47(1-2):19-28. doi: 10.1159/000493094. Epub 2019 — View Citation

Sankar T, Lipsman N, Lozano AM. Deep brain stimulation for disorders of memory and cognition. Neurotherapeutics. 2014 Jul;11(3):527-34. doi: 10.1007/s13311-014-0275-0. Review. — View Citation

Wilson J, Yarnall AJ, Craig CE, Galna B, Lord S, Morris R, Lawson RA, Alcock L, Duncan GW, Khoo TK, O'Brien JT, Burn DJ, Taylor JP, Ray NJ, Rochester L. Cholinergic Basal Forebrain Volumes Predict Gait Decline in Parkinson's Disease. Mov Disord. 2021 Mar; — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety of combined bilateral Globus Pallidus internus (GPi) and Nucleus Basalis of Meynert (NBM) stimulation in patients with moderate to advanced Parkinson's disease with mild cognitive impairment as determined by reported adverse events.	Safety of combined bilateral GPi and NBM stimulation in patients with moderate to advanced Parkinson's disease having mild cognitive impairment as determined by reported adverse events.	36 weeks
Secondary	Change in Parkinson's Disease - Cognitive Rating Scale (PD-CRS).	This scale can range from 0 to 134, and higher scores mean a better outcome.	36 weeks
Secondary	Change in Mattis Dementia Rating Scale.	This scale can range from 0 to 144, and higher scores mean a better outcome.	36 weeks
Secondary	Change in Verbal Fluency Battery.	FAS and animals	36 weeks
Secondary	Change in Trail Making Task.	Trail Making Task Part A + B.	36 weeks
Secondary	Change in Stroop Test.	Stroop Test (Victoria Version).	36 weeks
Secondary	Change in Symbol Digit Modalities Test.	Digit symbol coding - WAIS.	36 weeks
Secondary	Change in Parkinson's Disease Questionnaire for quality of life (PDQ-39).	This questionnaire can range from 0 to 100%, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Questionnaire of the EuroQol-group (EQ-5D-5L).	This questionnaire can range from 0 to 25, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Unified Parkinson's Disease Rating Scale section I (UPDRS I).	This scale can range from 0 to 52, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Unified Parkinson's Disease Rating Scale section II (UPDRS II).	This scale can range from 0 to 52, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Unified Parkinson's Disease Rating Scale section III (UPDRS III).	This scale can range from 0 to 132, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Unified Parkinson's Disease Rating Scale section IV (UPDRS IV).	This scale can range from 0 to 24, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in objective assessment of gait measured by a sensor (MobilityLab) that assess step speed.		36 weeks
Secondary	Change in objective assessment of gait measured by a sensor (MobilityLab) that assess number of steps per minute.		36 weeks
Secondary	Change in objective assessment of gait measured by a sensor (MobilityLab) that assess distance between heels.		36 weeks
Secondary	Change in objective assessment of gait measured by a sensor (MobilityLab) that assess balance.		36 weeks
Secondary	Change in objective assessment of gait measured by Time Up and Go - Test 3 meters (TUG test 3M).		36 weeks
Secondary	Change in objective assessment of gait measured by Time Up and Go dual task - Test 3 meters (TUG dual task - test 3M).		36 weeks
Secondary	Change in objective assessment of gait measured by freezing of gait score (FOG score).		36 weeks
Secondary	Change in New Freezing of Gait Questionnaire (N-FOG).	This questionnaire can range from 0 to 28, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Falls Efficacy Scale International (FES-I).	This questionnaire can range from 0 to 64, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Activities-Specific Balance Confidence Scale (ABC scale).	This scale can range from 0 to 100%, and higher scores mean a better outcome.	36 weeks
Secondary	Change in Beck Depression Inventory (BDI).	This inventory can range from 0 to 63, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Beck Anxiety Inventory (BAI).	This inventory can range from 0 to 63, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Starkstein Apathy Scale.	This scale can range from 0 to 42, and higher scores mean a worse outcome.	36 weeks
Secondary	Change in Neuropsychiatric Inventory (NPI).		36 weeks
Secondary	Change in Ardouin Scale of Behavior in Parkinson's Disease.	This scale can range from 0 to 84, and higher scores mean a worse outcome.	36 weeks