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Neuromodulation for Central Post-stroke Pain: Mechanism, Safety and Outcome

Primary Purpose

Central Post-stroke Pain, CPSP

Status
Recruiting
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
MCS surgery for CPSP
Vc-DBS surgery for CPSP
Sponsored by
Universitaire Ziekenhuizen KU Leuven
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Central Post-stroke Pain focused on measuring neuromodulation, DBS, rTMS, MCS

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Able to provide voluntary written informed consent of the participant prior to any screening procedures Male or female patients Aged 18-70 years Diagnosed with definite CPSP (Treede-Klit criteria) (1, 9), which is pharmacorefractory (i.e. amitriptyline 75mg/d 4w, lamotrigine 200mg/d 8w and pregabalin 600mg/d resulting in <50% VAS reduction and/or intolerable side-effects) Exclusion Criteria: Aphasia Pregnancy or intention to become pregnant in the following year Medical inoperability Impossibility to temporarily withhold anticoagulation or anti-platelet medication Impossibility to undergo MRI, fMRI and/or PET imaging Complete destruction of the stimulation target region (M1 or Vc) Uncontrolled seizures Expected relocation in the following year.

Sites / Locations

  • UZ LeuvenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Patients with CPSP which is pharmacorefractory and have a good analgesic response to M1-rTMS

Patients with CPSP which is pharmacorefractory with less analgesic M1-rTMS response

Arm Description

Diagnosed with definite CPSP (Treede-Klit criteria), which is pharmacorefractory (i.e. amitriptyline 75mg/d 4w, lamotrigine 200mg/d 8w and pregabalin 600mg/d resulting in <50% VAS reduction and/or intolerable side-effects). A good analgesic response to M1-rTMS is defined as: ≥50% mean 10-d VAS reduction immediately following vs. before active M1-rTMS minus mean 10-d VAS reduction immediately following vs. pre sham M1-rTMS. A good analgesic response gives a high positive predictive value for pain reduction by MCS.

Diagnosed with definite CPSP (Treede-Klit criteria), which is pharmacorefractory (i.e. amitriptyline 75mg/d 4w, lamotrigine 200mg/d 8w and pregabalin 600mg/d resulting in <50% VAS reduction and/or intolerable side-effects). Patients with less analgesic M1-rTMS response (n≈20) will be 1:1 randomized to either MCS (≈10) or Vc-DBS (n≈10).

Outcomes

Primary Outcome Measures

The relative difference in pain intensity (Visual Analogue Scale; VAS) immediately following 10 sessions of active vs. inactive rTMS;
The patients will receive 10 sessions (1/d) of active and 10 sessions (1/d) of sham M1-rTMS with a 8-week wash-out period in between.
The relative difference in pain intensity (Visual Analogue Scale; VAS) immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS.
Stimulation will be optimised for all patients up to 5 months post-surgery (Vc-DBS or MCS). After 2 weeks of wash-out, active and inactive stimulation will be offered in a double-blinded fashion for 4 weeks, with 2 weeks of wash-out in between.

Secondary Outcome Measures

The relative difference in pain symptoms* immediately following 10 sessions of active vs. inactive rTMS;
* as measured through the Neuropathic Pain Symptom Inventory (NPSI) and Patient Global Impression of Change (PGIC)
The relative difference in use of analgesics* immediately following 10 sessions of active vs. inactive rTMS;
* as measured through the Medication Quantification Scale
The relative difference in functionality* immediately following 10 sessions of active vs. inactive rTMS;
* as measured through the Functional Independence Measure (FIM)
The relative difference in quality of life* immediately following 10 sessions of active vs. inactive rTMS;
* as measured through the 36-Item Short-Form Health Survey (SF-36 QoLS)
The relative difference in mood* immediately following 10 sessions of active vs. inactive rTMS;
* as measured through the Beck Depression Inventory (BDI)
The relative difference in pain symptoms* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
* as measured through the Neuropathic Pain Symptom Inventory (NPSI) and Patient Global Impression of Change (PGIC)
The relative difference in use of analgesics* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
* as measured through the Medication Quantification Scale
The relative difference in functionality* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
* as measured through the Functional Independence Measure (FIM)
The relative difference in quality of life* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
* as measured through the 36-Item Short-Form Health Survey (SF-36 QoLS)
The relative difference in mood* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
* as measured through the Beck Depression Inventory (BDI)
The relative difference in metabolic activity (as measured through FDG-PET) in pain matrix areas immediately following 10 sessions of active vs. inactive rTMS;
The relative difference in metabolic activity (as measured through rsMRI) in pain matrix areas immediately following 10 sessions of active vs. inactive rTMS;
The relative difference in metabolic activity (as measured through FDG-PET) in pain matrix areas immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
The relative difference in metabolic activity (as measured through rsMRI) in pain matrix areas immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
The spike rate in the presence or absence of noxious/innocuous sensory stimuli (selected through baseline QSM);
*as measured through the microelectrodes (Vc-DBS) and paddle electrodes (MCS)
The spectral power* in the presence or absence of noxious/innocuous sensory stimuli (selected through baseline QSM);
*as measured through the microelectrodes (Vc-DBS) and paddle electrodes (MCS)
Other neurophysiological parameters* in the presence or absence of noxious/innocuous sensory stimuli (selected through baseline QSM);
*as measured through the microelectrodes (Vc-DBS) and paddle electrodes (MCS)
The spike rate* in the presence and absence of noxious and innocuous sensory stimuli (selected through baseline QSM)
*as measured postoperatively through the implanted electrodes
The spectral power* in the presence and absence of noxious and innocuous sensory stimuli (selected through baseline QSM)
*as measured postoperatively through the implanted electrodes
Other neurophysiological parameters* in the presence and absence of noxious and innocuous sensory stimuli (selected through baseline QSM)
*as measured postoperatively through the implanted electrodes
The safety for every procedure and during active and inactive rTMS, MCS and/or Vc-DBS.
*as measured by the AEs and SAEs
The safety for every procedure
*as measured by the AEs and SAEs
The safety during active and inactive rTMS
*as measured by the AEs and SAEs
The safety during active and inactive MCS or Vc-DBS.
*as measured by the AEs and SAEs

Full Information

First Posted
January 9, 2023
Last Updated
February 16, 2023
Sponsor
Universitaire Ziekenhuizen KU Leuven
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1. Study Identification

Unique Protocol Identification Number
NCT05708729
Brief Title
Neuromodulation for Central Post-stroke Pain: Mechanism, Safety and Outcome
Official Title
Neuromodulation for Central Post-stroke Pain: Mechanism, Safety and Outcome
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 24, 2023 (Actual)
Primary Completion Date
April 2026 (Anticipated)
Study Completion Date
April 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Universitaire Ziekenhuizen KU Leuven

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
Central post-stroke pain (CPSP) is an often pharmacorefractory type of neuropathic pain that develops in 8% of stroke patients. CPSP has been treated with three distinct types of neuromodulation (deep brain stimulation of the sensory thalamus (Vc-DBS), motor cortex repetitive transcranial magnetic stimulation (M1-rTMS), and motor cortex stimulation (MCS)), but the level of evidence for these procedures is very low. Moreover, data on the changes in pain brain circuitry in CPSP, and the effect of neuromodulation on this circuitry is very limited.
Detailed Description
In this project, we propose a prospective double-blind randomized crossover on/off study in 32 CPSP patients. These patients will undergo M1-rTMS and either MCS or Vc-DBS. Before and after active and inactive stimulation they will be assessed with clinical scales for pain, function, quality of life and depression. Adverse events will be monitored. This allows to measure the outcome and safety of neuromodulation in CPSP. In addition, we will have functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) use. This will provide insight into the pathological changes in the pain circuitry, and the influence of neuromodulation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Central Post-stroke Pain, CPSP
Keywords
neuromodulation, DBS, rTMS, MCS

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Masking Description
Blinding for rTMS (active stimulation vs sham stimulation)
Allocation
Randomized
Enrollment
32 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Patients with CPSP which is pharmacorefractory and have a good analgesic response to M1-rTMS
Arm Type
Experimental
Arm Description
Diagnosed with definite CPSP (Treede-Klit criteria), which is pharmacorefractory (i.e. amitriptyline 75mg/d 4w, lamotrigine 200mg/d 8w and pregabalin 600mg/d resulting in <50% VAS reduction and/or intolerable side-effects). A good analgesic response to M1-rTMS is defined as: ≥50% mean 10-d VAS reduction immediately following vs. before active M1-rTMS minus mean 10-d VAS reduction immediately following vs. pre sham M1-rTMS. A good analgesic response gives a high positive predictive value for pain reduction by MCS.
Arm Title
Patients with CPSP which is pharmacorefractory with less analgesic M1-rTMS response
Arm Type
Experimental
Arm Description
Diagnosed with definite CPSP (Treede-Klit criteria), which is pharmacorefractory (i.e. amitriptyline 75mg/d 4w, lamotrigine 200mg/d 8w and pregabalin 600mg/d resulting in <50% VAS reduction and/or intolerable side-effects). Patients with less analgesic M1-rTMS response (n≈20) will be 1:1 randomized to either MCS (≈10) or Vc-DBS (n≈10).
Intervention Type
Device
Intervention Name(s)
MCS surgery for CPSP
Intervention Description
The investigational devices that will be used for the MCS surgeries are the following: the Vanta with AdaptiveStim Technology Primary cell neurostimulator or the Intellis Implantable Neurostimulator with AdaptiveStim Technology from Medtronic, Inc. (MN, USA). These implantable neurostimulators are intended to generate electrical pulses and to deliver stimulation trough one or more leads as part of a neurostimulation system for pain therapy in adults.
Intervention Type
Device
Intervention Name(s)
Vc-DBS surgery for CPSP
Intervention Description
For the deep brain stimulation procedure, we will use Vercise stimulators from Boston Scientific together with the Cartesia Directional Leads or the Percept PC stimulator from Medtronic.
Primary Outcome Measure Information:
Title
The relative difference in pain intensity (Visual Analogue Scale; VAS) immediately following 10 sessions of active vs. inactive rTMS;
Description
The patients will receive 10 sessions (1/d) of active and 10 sessions (1/d) of sham M1-rTMS with a 8-week wash-out period in between.
Time Frame
After completion of all rTMS sessions (approximately one month before surgery)
Title
The relative difference in pain intensity (Visual Analogue Scale; VAS) immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS.
Description
Stimulation will be optimised for all patients up to 5 months post-surgery (Vc-DBS or MCS). After 2 weeks of wash-out, active and inactive stimulation will be offered in a double-blinded fashion for 4 weeks, with 2 weeks of wash-out in between.
Time Frame
After completion of the 4 weeks of active vs. inactive MCS or Vc-DBS (approximately at 9 months after surgery)
Secondary Outcome Measure Information:
Title
The relative difference in pain symptoms* immediately following 10 sessions of active vs. inactive rTMS;
Description
* as measured through the Neuropathic Pain Symptom Inventory (NPSI) and Patient Global Impression of Change (PGIC)
Time Frame
Immediately after completion of the 10 sessions of active (1 per day, on 10 consecutive days) and 10 sessions of sham (1 per day, on 10 consecutive days) M1-rTMS with a 8 weeks washout period inbetween
Title
The relative difference in use of analgesics* immediately following 10 sessions of active vs. inactive rTMS;
Description
* as measured through the Medication Quantification Scale
Time Frame
Immediately after completion of the 10 sessions of active (1 per day, on 10 consecutive days) and 10 sessions of sham (1 per day, on 10 consecutive days) M1-rTMS with a 8 weeks washout period inbetween
Title
The relative difference in functionality* immediately following 10 sessions of active vs. inactive rTMS;
Description
* as measured through the Functional Independence Measure (FIM)
Time Frame
Immediately after completion of the 10 sessions of active (1 per day, on 10 consecutive days) and 10 sessions of sham (1 per day, on 10 consecutive days) M1-rTMS with a 8 weeks washout period inbetween
Title
The relative difference in quality of life* immediately following 10 sessions of active vs. inactive rTMS;
Description
* as measured through the 36-Item Short-Form Health Survey (SF-36 QoLS)
Time Frame
Immediately after completion of the 10 sessions of active (1 per day, on 10 consecutive days) and 10 sessions of sham (1 per day, on 10 consecutive days) M1-rTMS with a 8 weeks washout period inbetween
Title
The relative difference in mood* immediately following 10 sessions of active vs. inactive rTMS;
Description
* as measured through the Beck Depression Inventory (BDI)
Time Frame
Immediately after completion of the 10 sessions of active (1 per day, on 10 consecutive days) and 10 sessions of sham (1 per day, on 10 consecutive days) M1-rTMS with a 8 weeks washout period inbetween
Title
The relative difference in pain symptoms* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Description
* as measured through the Neuropathic Pain Symptom Inventory (NPSI) and Patient Global Impression of Change (PGIC)
Time Frame
immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The relative difference in use of analgesics* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Description
* as measured through the Medication Quantification Scale
Time Frame
immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The relative difference in functionality* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Description
* as measured through the Functional Independence Measure (FIM)
Time Frame
immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The relative difference in quality of life* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Description
* as measured through the 36-Item Short-Form Health Survey (SF-36 QoLS)
Time Frame
immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The relative difference in mood* immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Description
* as measured through the Beck Depression Inventory (BDI)
Time Frame
immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The relative difference in metabolic activity (as measured through FDG-PET) in pain matrix areas immediately following 10 sessions of active vs. inactive rTMS;
Time Frame
Immediately after completion of the 10 sessions of active (1 per day, on 10 consecutive days) and 10 sessions of sham (1 per day, on 10 consecutive days) M1-rTMS with a 8 weeks washout period inbetween
Title
The relative difference in metabolic activity (as measured through rsMRI) in pain matrix areas immediately following 10 sessions of active vs. inactive rTMS;
Time Frame
Immediately after completion of the 10 sessions of active (1 per day, on 10 consecutive days) and 10 sessions of sham (1 per day, on 10 consecutive days) M1-rTMS with a 8 weeks washout period inbetween
Title
The relative difference in metabolic activity (as measured through FDG-PET) in pain matrix areas immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Time Frame
immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The relative difference in metabolic activity (as measured through rsMRI) in pain matrix areas immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Time Frame
immediately following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The spike rate in the presence or absence of noxious/innocuous sensory stimuli (selected through baseline QSM);
Description
*as measured through the microelectrodes (Vc-DBS) and paddle electrodes (MCS)
Time Frame
Intraoperative
Title
The spectral power* in the presence or absence of noxious/innocuous sensory stimuli (selected through baseline QSM);
Description
*as measured through the microelectrodes (Vc-DBS) and paddle electrodes (MCS)
Time Frame
Intraoperative
Title
Other neurophysiological parameters* in the presence or absence of noxious/innocuous sensory stimuli (selected through baseline QSM);
Description
*as measured through the microelectrodes (Vc-DBS) and paddle electrodes (MCS)
Time Frame
Intraoperative
Title
The spike rate* in the presence and absence of noxious and innocuous sensory stimuli (selected through baseline QSM)
Description
*as measured postoperatively through the implanted electrodes
Time Frame
following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The spectral power* in the presence and absence of noxious and innocuous sensory stimuli (selected through baseline QSM)
Description
*as measured postoperatively through the implanted electrodes
Time Frame
following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
Other neurophysiological parameters* in the presence and absence of noxious and innocuous sensory stimuli (selected through baseline QSM)
Description
*as measured postoperatively through the implanted electrodes
Time Frame
following 4 weeks of active (with optimized stimulation parameters) vs. inactive MCS or Vc-DBS;
Title
The safety for every procedure and during active and inactive rTMS, MCS and/or Vc-DBS.
Description
*as measured by the AEs and SAEs
Time Frame
during procedure and during active and inactive rTMS, MCS and/or Vc-DBS.
Title
The safety for every procedure
Description
*as measured by the AEs and SAEs
Time Frame
during procedure
Title
The safety during active and inactive rTMS
Description
*as measured by the AEs and SAEs
Time Frame
during active and inactive rTMS
Title
The safety during active and inactive MCS or Vc-DBS.
Description
*as measured by the AEs and SAEs
Time Frame
during active and inactive MCS or Vc-DBS.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Able to provide voluntary written informed consent of the participant prior to any screening procedures Male or female patients Aged 18-70 years Diagnosed with definite CPSP (Treede-Klit criteria) (1, 9), which is pharmacorefractory (i.e. amitriptyline 75mg/d 4w, lamotrigine 200mg/d 8w and pregabalin 600mg/d resulting in <50% VAS reduction and/or intolerable side-effects) Exclusion Criteria: Aphasia Pregnancy or intention to become pregnant in the following year Medical inoperability Impossibility to temporarily withhold anticoagulation or anti-platelet medication Impossibility to undergo MRI, fMRI and/or PET imaging Complete destruction of the stimulation target region (M1 or Vc) Uncontrolled seizures Expected relocation in the following year.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Philippe De Vloo, prof. dr.
Phone
016 344290
Email
neurochirurgie@uzleuven.be
First Name & Middle Initial & Last Name or Official Title & Degree
Daan Remans
Phone
016 344290
Email
neurochirurgie@uzleuven.be
Facility Information:
Facility Name
UZ Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Philippe De Vloo, prof.dr.
Phone
016 344290
Email
neurochirurgie@uzleuven.be

12. IPD Sharing Statement

Plan to Share IPD
No

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Neuromodulation for Central Post-stroke Pain: Mechanism, Safety and Outcome

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