An Open-label Clinical Trial to Compare the Safety and Effectiveness of Adaptive Versus Conventional Deep Brain Stimulation

Not Applicable

Withdrawn

• Conditions: Parkinson Disease
• Interventions: Device: adaptive DBS delivered through AlphaDBS IPG System; Device: conventional DBS delivered through AlphaDBS IPG System

• Registration Number: NCT05262348
• Lead Sponsor: Newronika

Brief Summary

The clinical trial aims to evaluate the safety and effectiveness of bilateral subthalamic nucleus (STN) and Globus Pallidus internus (GPi) deep brain stimulation (DBS) with the AlphaDBS IPG System when programmed in adaptive versus conventional stimulating modes. It includes an initial open-label, crossover phase and a long term follow-up phase, during which the patient is free to switch between stimulating modes.

Detailed Description

This is an international multi-center (North America and Europe) clinical trial to evaluate the safety and effectiveness of bilateral STN and GPi DBS with the AlphaDBS IPG System when programmed in adaptive (aDBS) versus conventional (cDBS) stimulating modes, in patients with advanced levodopa-responsive Parkinson's disease (PD).

The protocol is comprised of:

Phase 1: Initial Treatment Period: Cross-Over Design

* Phase 1a: All patients will start the study in cDBS mode. After a 1-month post-surgical stabilization, the AlphaDBS IPG System will be turned ON in cDBS mode. Participants will complete a 1-month period of programming optimization (to fine tune medical therapies and stimulation parameters) followed by a 3-month period of cDBS.

* Phase 1b: At the end of the 3-month follow up in cDBS, participants will be switched to the aDBS mode. Participants will then complete a 1-month period of optimization (to fine tune medical therapies and stimulation parameters) followed by a 3-month period of aDBS.

Phase 2: Long-term follow-up: Naturalistic Follow-up Design Patients completing Phase 1 are eligible to enter long-term follow-up for up to an additional 28 months. During this time, patients are free to change the DBS mode as preferred (with a maximum switches set by the physician). Visits at 6-month follow-ups will collect safety and efficacy data.

Study Timeline

• Study First Submitted: 2022-02-21
• Study First Submitted QC: 2022-02-21
• Study First Posted: 2022-03-02
• Study Start: 2022-08
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-08
• Last Update Posted: 2024-08-12
• Primary Completion: 2024-08-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Patient is ≥55 years old
2. Patient has been diagnosed with levodopa-responsive idiopathic Parkinson's disease for ≥5 years
3. The disease stage is II, III or IV according to the Hoehn and Yahr scale
4. Patient has history of improvement of Parkinson's symptoms as a direct result of administering levodopa
5. PD-related symptoms are not adequately controlled with medication, including motor complications of recent onset (>4 months duration)
6. Patient experiences persistent disabling PD-related symptoms or drug side effects (e.g., dyskinesia, motor fluctuations, or disabling "off periods") despite optimal medical therapy
7. Patient has been selected for bilateral STN or Gpi DBS, independently from this study, in accordance with local standard of care DBS screening
8. Patient has been selected to receive Medtronic leads model 3389 or 37086, independently from this study, in accordance with local standard of care DBS screening
9. Patient has DBS circuit integrity assessed and confirmed by impedance testing, before IPG implantation
10. ≥6 hours per day (waking hours) with poor motor symptoms control (time "OFF" plus time "ON" with dyskinesia) despite optimal medical therapy, as assessed by the 3-day diary
11. Montreal Cognitive Assessment (MoCA) >26 in MedON condition
12. Beck Depression Inventory II (BDI-II) score <17 in MedON condition
13. UPDRS-III improvement by ≥33% following intake of anti-parkinsonian medications
14. Patient is able to understand the study requirements and the treatment procedures and has provided written informed consent to participate
15. Patient is willing and capable of completing a 3-day diary and reaches a sufficient level of agreement (> 75%) with study personnel responses
16. Patient has a responsible caregiver who will help completing the 3-day diary, provide feedback on activities of daily living (ADL), and ensure the patient complies with visit schedule
17. Patient is willing to maintain a constant anti-PD medication treatment (best medical management) for at least one month prior to study enrollment
18. Patient is willing and able to attend all study-required visits, complete the study procedures and attend appropriate follow up visits

Exclusion Criteria

1. Patient has contraindications for DBS surgery, including any intracranial abnormality (e.g., generalized atrophy, vascular malformation, hydrocephalus, hematoma, cavernous or venous angioma, tumor or metastases, midline shift, etc.) or metallic implant (e.g., aneurysm clip, cochlear implant, etc.)
2. Patient has a history of suicide attempt or current active suicidal ideation as determined by a positive response to Item 2-5 of suicide ideation sub-scale of the Columbia Suicide Severity Rating Scale (CSSR-S)
3. Patient has dementia, major depression, seizures, congestive heart failure, uncontrolled diabetes, dialysis, substance use disorders as described in DSM-V, or any other severe medical condition
4. Patient has any medical condition that could interfere with study procedures, confound the assessment of study endpoints, or prevent a proper data collection
5. Patient had confirmation of diagnosis of a terminal illness associated with survival <12 months
6. Patient needs repeated MRI scans
7. Patient requires diathermy, transcranial magnetic stimulation (TMS), or electroconvulsive therapy (ECT)
8. Patient carries an electrical or electromagnetic implant (e.g., cochlear prosthesis, pacemaker, neurostimulator, etc.)
9. Patient has, or plans to obtain, an implanted electrical stimulation medical device and/or an implanted medication pump (e.g., DUOPATM infusion pump) and/or is treated with a portable infusion pump
10. Patient is on anticoagulant therapy which cannot be paused for >5 days before IPG implant surgery
11. Patient with a history of cranial surgery including ablation procedure or any other previous neurosurgical procedure for the treatment of PD symptoms on either side of the brain
12. Patient is currently participating in another clinical study (excluding any sub-study of the present study)
13. Patient is a female who is breastfeeding or of child-bearing potential with a positive urine pregnancy test or not using adequate contraception.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Phase 1b - adaptive stimulation	adaptive DBS delivered through AlphaDBS IPG System	Stimulation will be delivered bilaterally to the STN or the GPi, with the neurologist-set therapeutic window (which corresponds to the upper and lower limits for aDBS amplitude). The stimulation will be automatically adapted according to the personalized algorithm based on real time LFP analysis.
Phase 1a - conventional stimulation	conventional DBS delivered through AlphaDBS IPG System	Stimulation will be delivered bilaterally to the STN or the GPi. The stimulation parameters will be based upon standard practice by the neurologist.

Primary Outcome Measures

Name	Time	Method
To assess Treatment-Emergent Adverse Events	9 months	To identify Treatment-Emergent Adverse Events (TEAEs) (including serious, device-related, stimulation-related, and/or procedure related TEAEs), discontinuations of aDBS and study discontinuation and physical or neurological findings as categorized by the Data and Safety Monitoring Board.
To compare change in Good on time (GOT) when the patient receives aDBS versus change in GOT when the patient receives cDBS.	9 months	The expected treatment effectiveness of AlphaDBS IPG System with aDBS mode (∆GOTaDBS = GOTaDBS@3-Months - GOT@Baseline) and with cDBS mode (∆GOTcDBS = GOTcDBS@3-Months - GOT@Baseline) will not differ more than two hours.

Secondary Outcome Measures

Name	Time	Method
Success rate, number of patients with at least 2 hours improvement in each treatment mode	9 months	Treatement success is defined as number of patients with \>2 hours ∆GOTaDBS and ∆GOTcDBS
Percentage of time in which the system is used in aDBS mode	28 months	During the long term follow up, when the patient will be able to switch between programming modes, the patient preference will be assessed considering the percentage of time in which the system is used in aDBS.
UPDRS III	9 months and 36 months	UPDRS III score, in MedOFF-StimON and MedON-StimON conditions
Patient fluctuations	9 months and 36 months	Number of ON/OFF transitions based on the 3-day diary
UdysRS	9 months and 36 months	Score of the Unified Dyskinesia Rating Scale (UdysRS) in MedOFF-StimON and MedON-StimON condition.