You are here

  • Home
  • Archive
  • Volume 14, Issue 11
  • Differential target multiplexed spinal cord stimulation in patients with Persistent Spinal Pain Syndrome Type II: a study protocol for a 12-month multicentre cohort study (DETECT)

Article Text

Article menu

Download PDFPDF

Anaesthesia
Protocol
Differential target multiplexed spinal cord stimulation in patients with Persistent Spinal Pain Syndrome Type II: a study protocol for a 12-month multicentre cohort study (DETECT)
  1. Lisa Goudman1,2,3,4,5,
  2. Ann De Smedt1,3,6,
  3. Sam Eldabe7,
  4. Philippe Rigoard8,9,10,
  5. Maxime Billot8,
  6. Manuel Roulaud8,
  7. DETECT consortium,
  8. Maarten Moens1,2,3,4,5,11
    1. 1STIMULUS research group, Vrije Universiteit Brussel, Brussel, Belgium
    2. 2Department of Neurosurgery, Universitair Ziekenhuis Brussel, Brussel, Belgium
    3. 3Cluster Neurosciences, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussel, Belgium
    4. 4Pain in Motion (PAIN) Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Vrije Universiteit Brussel, Brussel, Belgium
    5. 5Research Foundation—Flanders (FWO), Brussel, Belgium
    6. 6Department of Physical Medicine and Rehabilitation, Universitair Ziekenhuis Brussel, Brussel, Belgium
    7. 7Pain Clinic, The James Cook University Hospital, Middlesbrough, UK
    8. 8PRISMATICS Lab (Predictive Research in Spine/Neuromodulation Management and Thoracic Innovation/Cardiac Surgery), CHU de Poitiers, Poitiers, France
    9. 9Service de neurochirurgie du rachis, chirurgie de la douleur et du handicap, CHU de Poitiers, Poitiers, France
    10. 10Pprime Institute UPR 3346, CNRS, ISAE-ENSMA, Université de Poitiers, Poitiers, France
    11. 11Department of Radiology, Universitair Ziekenhuis Brussel, Brussel, Belgium
    1. Correspondence to Dr Lisa Goudman; lisa.goudman{at}gmail.com

    Abstract

    Introduction Differential target multiplexed spinal cord stimulation (DTM SCS) is a new stimulation paradigm for chronic pain management with the aim of modulating glial cells and neurons in order to rebalance their interactions. Animal studies revealed positive effects of this type of stimulation; however, studies in humans are still scarce, pointing towards the need for an evaluation of the effectiveness and safety of DTM SCS in clinical settings. Furthermore, the differential target multiplexed (DTM) algorithm consists of a combination of several programmes, which will presumably consume more energy from the spinal cord stimulation (SCS) battery. Therefore, the objective of DETECT is to investigate the feasibility, effectiveness and safety of DTM SCS in patients with Persistent Spinal Pain Syndrome Type II through a longitudinal cohort study.

    Methods and analysis DETECT is a prospective multicentre cohort study (n≥250) with a follow-up until 12 months after receiving DTM SCS. The study initiated in October 2021 and is currently still recruiting patients. Self-reporting outcome variables were evaluated at baseline (before SCS) and at 1, 6 and 12 months of DTM SCS. The primary effectiveness endpoint is overall pain intensity, measured with the visual analogue scale. Secondary effectiveness outcome measures are back pain intensity, leg pain intensity, disability, health-related quality of life, pain medication use, functional disability, clinical holistic responder status, self-management, impression of change, work status, pain catastrophising, symptoms of central sensitisation, anxiety, depression and healthcare utilisation. Time spent in different body postures and SCS stimulation parameters will be read out from the pulse generator. The prevalence of technical issues, recharge frequency, (serious) adverse events and the proportion of successful DTM trials will be collected as well. Longitudinal mixed models will be calculated to evaluate the effectiveness of DTM SCS over time.

    Ethics and dissemination The study protocol was approved by the central Ethics Committee of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (B.U.N.1432021000563) and the Ethics Committees of each participating centre. Research findings will be disseminated to key stakeholders through peer-reviewed publications in scientific journals and presentations to clinical audiences.

    Trial registration number NCT05068011.

    • Chronic Pain
    • Pain management
    • Neurosurgery
    http://creativecommons.org/licenses/by-nc/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

    https://doi-org.ezproxy.u-pec.fr/10.1136/bmjopen-2023-083610

    Statistics from Altmetric.com

      Request Permissions

      If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

      STRENGTHS AND LIMITATIONS OF THIS STUDY

      • This study will reflect the effectiveness of differential target multiplexed spinal cord stimulation in standard clinical practice on different treatment outcomes in patients with Persistent Spinal Pain Syndrome Type II to provide complementary evidence to the available RCT data.

      • A broad range of outcome variables will be investigated with a rigorous follow-up until 12 months after implantation, even after reprogramming to another modality.

      • The results of this study will be collected in Belgium, potentially limiting the generalisability of the results towards other parts of the world.

      Introduction

      Spinal cord stimulation (SCS) is a well-established pain management technique with beneficial effects on different domains of life, among which disability and health-related quality of life.1 2 Specifically for patients with Persisting Spinal Pain Syndrome Type II, that is, chronic pain that is persisting after spine surgery, SCS is considered an efficient treatment option.3 Standard or so-called ‘conventional’ SCS typically involves electrical pulses delivered at a frequency of 50–60 Hz4 generating paraesthesias in the painful area which underpin the mechanism for pain reduction in this type of SCS. To optimise pain control and to minimise the side effects of conventional SCS (eg, uncomfortable SCS-induced paraesthesia, discomfort due to paraesthesia variability by postural changes),5 6 newer SCS algorithms have been introduced of which differential target multiplexed (DTM) stimulation is one of the latest developed stimulation paradigm.7

      Based on the hypothesis that different patterns of SCS activate unique pain-relieving mechanisms,8 potential ‘distinctive therapies’ may be offered that provide more choices for patients, offer improved pain relief with extended programming possibilities or target a specific mechanism underlying a pain syndrome. One option involves multiple electrical signals that can be different from each other in several aspects such as frequencies, pulse width and amplitudes, whereby electrical fields could differentially target neurons versus glial cells in the spinal cord.9 In a preclinical study with rats, multiplexed charge–balanced pulsed signals with frequencies ranging from 20 Hz to 1200 Hz and a maximum pulse width of 500 µS have shown significantly better results than stimulation at 50 Hz (150 µs pulse width) or stimulation at 1200 Hz (50 µs pulse width) for mechanical hypersensitivity using the spared nerve injury model of neuropathic pain.9 Moreover, gene expression levels of cell-specific transcriptomes were compared between different multiplexed signals, low frequencies and high frequencies versus no SCS versus healthy animals to further elucidate the specific targeting of neurons and glial cells.10 Differential target multiplexed programming yielded significant correlations to expression levels found in the healthy animals across every evaluated cell-specific transcriptome (ie, microglia, astrocyte, oligodendrocyte and neuron). High rate programming only yielded a strong correlation for the microglia-specific transcriptome, and low rate programming did not yield strong correlations with these cell types.10 In another experiment to exclusively evaluate microglia-specific activation transcriptomes, multiplexed stimulation revealed higher correlation values with expression levels found in healthy animals, higher than those found with low frequency and high frequency stimulation.11 Based on these animal studies, it is proposed that DTM stimulation uses multiple electrical signals with the aim of modulating glial cells and neurons in order to rebalance their interactions.12

      Studies with DTM SCS in humans are still scarce.13 Up until now, only a couple of studies are available in which the effect of DTM and conventional SCS was explored in patients with chronic intractable pain,14–16 besides a number of ongoing studies among which the ones of Tanei et al.17 18 Both SCS types were able to significantly reduce back pain intensity. However, a significantly stronger pain reduction was obtained with DTM compared with conventional SCS,14 suggesting superiority of DTM SCS compared with standard SCS.15 Moreover, in patients suffering from axial low back pain with or without leg pain and who are ineligible for spinal surgery, DTM SCS proved to be superior to conventional medical management.19 Additionally, in this population of patients who are non-surgical candidates, DTM SCS also proved to be superior to conventional SCS.16

      Objectives

      Despite the promising results of animal studies and the initial positive experiences from clinical practice, there still is a need for expanding the evidence on the benefits and safety profile of DTM SCS. Additionally, since DTM consists of interleaving of several programmes, the long-term impact of which on battery utilisation and patient acceptance has yet to be evaluated. DTM SCS includes therapy with a low rate (<200 Hz) and high rate (200–1200 Hz) waveform applied at two targets, with and without cycling. Presumably combining several programmes will consume more energy from the SCS battery, which may necessitate the use of rechargeable implantable pulse generators (IPG). However, depending on the specific parameters of the SCS programmes, energy consumption can be variable. The various combinations of DTM SCS that are currently used in clinical practice (ie, various frequencies combined with various configurations) need to be documented. Additionally, safety outcomes of this modality will be evaluated as well. Therefore, the objective of DETECT is to investigate the feasibility, effectiveness and safety of DTM SCS in patients with Persistent Spinal Pain Syndrome Type II (PSPS-T2) through a longitudinal cohort study up to 12 months after receiving DTM SCS. It is our hypothesis that DTM SCS is a safe and feasible pain management option for this patient population.

      Methods and analysis

      Study design

      This prospective multicentre cohort study is being conducted to evaluate DTM SCS for patients with PSPS-T2. Recruitment is ongoing in 14 centres in Belgium (both academic and regional hospitals), all with ample SCS experience, high standards of care and sufficient volume of PSPS-T2 patients for participation in DETECT. Details on study sites can be found at ClinicalTrials.gov with Identifier: NCT05068011, 5th of October, 2021.

      Recruitment has started in October 2021 and will be ongoing until 250 patients are included in the study. Randomisation and blinding are not applicable because all patients in this study will receive DTM SCS as part of Good Clinical Practice.

      Eligibility criteria

      This study is focusing on patients with chronic back and leg pain (due to PSPS-T2) who previously underwent spinal surgery and are scheduled for SCS implantation. In total, 250 patients will be enrolled in this study. This sample size should be sufficient to explore the feasibility, safety and effectiveness of DTM SCS. No formal sample size calculation has been conducted. A trial failure rate of 11.3% is expected.20 Inclusion criteria are:

      • Being diagnosed with PSPS-T2 (defined as the surgical end stage after one or several operative interventions on the lumbar neuroaxis, indicated to relieve lower back pain, radicular pain or the combination of both without positive effect21) with chronic back and leg pain and refractory to best medical treatment.

      • Having chronic pain as a result of PSPS-T2 that exists for at least 6 months with a pain intensity of 5 or higher measured on numeric rating scale, a tool mentioned in the Belgian legislation for reimbursement,22 for the dominant pain location.

      • Being offered treatment with DTM SCS as primary treatment option (ie, scheduled for SCS implantation with DTM stimulation).

      • Being at least 18 years old.

      Exclusion criteria are:

      • Expected inability of patients to properly operate the SCS system.

      • History of coagulation disorders, lupus erythematosus, diabetic neuropathy, rheumatoid arthritis or Morbus Bechterew.

      • Active malignancy.

      • Addiction to drugs, alcohol (more than 5 units/day) and/or medication.

      • Evidence of an active disruptive psychiatric disorder or other known condition significant enough to impact perception of pain, compliance to intervention and/or ability to complete questionnaires, as determined by the investigator.

      • Immune deficiency (eg, HIV positive, immunosuppressive).

      • Life expectancy<1 year.

      • Local infection or other skin disorder at site of incision.

      • Pregnancy.

      • Other implanted active medical devices.

      Interventions

      The treating neurosurgeon or anaesthesiologist (local principal investigator or his/her designee) informs eligible patients of the project. Patients who wish to explore participation in the project are being screened for in- and exclusion criteria. Patients who are eligible for participation and are willing to participate receive detailed oral and written information about the study and have the opportunity to ask questions. Subsequently, they are asked to provide written informed consent before participation.

      After the baseline visit, patients undergo an SCS trial period (21 days in Belgium), followed by IPG implantation in case of a successful trial period (50% pain reduction and 50% reduction in pain medication use, according to the current Belgium reimbursement rules). All IPGs are allowed, as long as they are able to apply DTM settings. More concrete, the following types are used: Medtronic Inceptiv implantable neurostimulator or Intellis implantable neurostimulator with AdaptiveStim technology. With respect to the leads, both percutaneous (Vectris SureScan MRI 1×8 Compact lead) and surgical (Specify 5-6-5 SureScan MRI) leads are used. In humans, the DTM algorithm consists of two principles. Principle 1 is called ‘multiplexed frequencies’. A low-rate programme or ‘base’ is a programme with a frequency that varies between 20 Hz and 200 Hz. This base programme is combined with a high-rate component or ‘prime’, with a rate varying between 200 Hz and 1200 Hz. Principle 2 is called ‘multiple targets’ or the different configurations on the lead. The base and prime programmes use different cathode and anode configurations. So, DTM SCS includes therapy with a low-rate (200 Hz) and high-rate (200–1200 Hz) waveform applied at two targets, with and without cycling. Intensities are set according to a DTM SCS algorithm, starting at a percentage below the perception threshold and working them up at regular intervals until reaching therapeutic levels (merely subperception threshold). Patients can adjust intensity, and selected DTM SCS options are based on optimal pain relief.15

      Patients who after an adequate trial period prefer to discontinue DTM SCS can be programmed with another SCS modality. The reasons for changes in the therapeutic regime will be documented, and follow-up will take place according to the protocol, even if a different stimulation paradigm is provided.

      Outcomes

      Effectiveness outcomes

      The primary effectiveness outcome measure is overall pain during the last 7 days, defined as a combination of back and leg pain, but not pain from other body parts, measured with the visual analogue scale (VAS). The VAS (100 mm) pain score is believed to be reliable, valid and sensitive to change.23 24 The primary endpoint is the difference in pain intensity scores over time from baseline up to 12 months of DTM SCS.

      Several secondary effectiveness outcome measures are being collected (randomised order):

      • Pain intensity for the lower back and leg pain component is assessed separately with the VAS. In line with the primary effectiveness outcome, pain intensity for the last 7 days will be assessed on a 10-cm line.

      • Medication use, which entails the type of medication, dosage and frequency, is being recorded systematically at each visit. Medication will be converted to one score with the Medication Quantification Scale III (MQS III).

      • The Oswestry disability index (ODI) is used to measure functional disability due to abnormalities of the spine.25 26

      • Health-related quality of life is assessed with the EuroQol with five dimensions and five levels (EQ-5D-5L).27 The EQ-5D-5L index scores range from 0 to 1, with 0 and 1 corresponding respectively to death and full health, based on preference-weighted health state classification algorithms.28

      • The impression of change after DTM SCS is evaluated through the Patient Global Impression of Change Scale (PGIC). The PGIC consists of a 7-point Likert scale asking the respondent to rate the overall level of improvement since start of the treatment as ‘very much improved’, ‘much improved’, ‘minimally improved’, ‘no change’, ‘minimally worse’, ‘much worse’ and ‘very much worse’.29

      • The clinical holistic responder status30 will be determined after data collection and serves as composite measure for success, based on a combination of pain intensity, medication use, disability, quality of life and impression of change measurements.

      • Patient Activation Measure-13 (PAM-13) is a 13-item instrument to determine self-reported behaviour, knowledge and confidence for self-management of one’s health. PAM-13 has proven to be a reliable instrument to measure patient activation and self-management.31 32

      • A self-designed questionnaire is being used to evaluate return to work after spinal surgery.33 34 At baseline, current work status, job type, job description and work regime (eg, full time, part time) are asked. At the follow-up visits, patients fill in whether they already resumed professional activities, and if yes, since when and to what extent. Additionally, patients receive the opportunity to indicate whether a job change was needed or whether their job content needed to be changed to enable effective work resumption.

      • The Pain Catastrophizing Scale (PCS) is used to measure the level of pain catastrophising. The internal consistency, test-retest reliability and validity are acceptable for chronic pain patients.35 36

      • The Central Sensitization Inventory (CSI) consists of 25 symptom-related opinions that require a score on a 5-point Likert scale to evaluate the presence of central sensitisation–associated symptoms.37 The clinometric properties of the CSI are good in chronic pain patients.37 38

      • The Hospital Anxiety and Depression Scale (HADS) measures symptoms of anxiety and depression and consists of 14 items: seven items for the anxiety subscale (HADS Anxiety) and seven for the depression subscale (HADS Depression). The HADS was found to perform well in assessing the symptom severity of anxiety disorders and depression in both somatic, psychiatric and primary care patients and in the general population.39

      • Postoperative healthcare expenditure is investigated by self-reporting methods. Hence, postoperative healthcare expenditure includes the number of days spent in hospital following surgery, medical tests related to postoperative surgery and any kind of postsurgical treatments (eg, pain killers, physiotherapy, psychotherapy, programming sessions).

      • Based on the AdaptiveStim technology, the time spent in seven body postures can be recorded from the IPG. If this feature is activated, the data are being extracted from SCS implantation up to 1 month of SCS, from 1 month of SCS up to 6 months and from 6 months up to 12 months.

      Safety-related outcome

      The primary safety outcome variables are the number of serious adverse events (SAEs) and adverse events (AEs). Any adverse change in health or the appearance or worsening of any undesirable sign, symptom or medical condition occurring after enrolment into the trial is documented as AE (whether or not it is considered to be related to the intervention). Afterwards, AEs will be categorised according to severity and relationship to device and procedure.

      An SAE is considered any untoward medical occurrence (whether considered to be related to the investigational intervention or not) that is fatal or life-threatening, requires or prolongs hospitalisation, results in persistent or significant disability or incapacity, constitutes a congenital anomaly or birth defect, requires intervention to prevent permanent impairment or damage, or is an important medical event. An unexpected SAE is an AE of which the nature or severity is not consistent with the expected side effects or risks of the intervention (suspected unexpected adverse reaction, SUSAR). Hospitalisations which are the result of elective or previously scheduled surgery for pre-existing conditions which have not worsened after initiation of treatment will not be classed as SAEs.

      SAEs and SUSARs will be reported to relevant Competent Authorities and to the Ethics Committee, in accordance with the European Union Clinical Trial Directive. The investigator is responsible for the evaluation and report of these events during the study. AEs are recorded in the AE form in Qualtrics; however, SAEs require reporting to the sponsor and principal investigator within 24 hours.

      Feasibility-related outcome

      Feasibility is being evaluated by determining the proportion of successful DTM trials. As a technical feasibility, the prevalence of technical issues with regard to DTM SCS and battery consumption/recharge frequency is questioned and programming parameters for the different programmes that are provided within DTM SCS are recorded. Identification of clinical effective parameters concerning frequency, pulse duration and amplitude occurs at each visit after implantation.

      Table 1 provides an overview of the outcome measurements at each visit.

      View this table:
      Table 1

      Overview of the outcome measurements at each study visit for DETECT

      At baseline, demographic data are recorded. All effectiveness outcomes are being evaluated, except for impression of change, postoperative healthcare utilisation and the time spent in body postures. One month after IPG implantation, the second assessment takes place during which all outcome measures are being evaluated except for work status. Six months and 12 months after IPG implantation, all outcomes are evaluated. Unscheduled visits can be conducted according to daily clinical routines of the participating centres and will be documented through healthcare expenditures. The project flowchart is presented in figure 1.

      Figure 1
      Figure 1

      Patient flow chart. DTM, differential target multiplexed; IPG, implantable pulse generator; n, number; SCS, spinal cord stimulation.

      In case a patient is lost to follow-up at the outpatient clinic, attempts are made to contact the patient by phone to perform any possible assessments, if the patient agrees.

      Patient and public involvement

      The selection of questionnaires was performed after identifying goalsetting in patients before SCS implantation through qualitative interviews with independent researchers40 and exploring factors that chronic pain patients aim to achieve.41 Patient support groups (not including study participants) will be offered opportunity to discuss the findings on completion of the study. The outcomes of the study will help in enhancing patient and public involvement.

      Data management

      A web-based data collection tool called Qualtrics is being used for this study to store data from all participants. Patients can complete the self-reported outcome measurements through accessing the URL towards Qualtrics or by scanning the QR code which will direct them immediately towards the data collection tool. The physician can complete the safety and feasibility-related outcome measures through the same system. Each patient is uniquely identified in the trial by the centre identification and the patient number assigned by the investigator. Patient numbers start with number 001, and subsequent patients are assigned consecutive numbers.

      The following source data are being generated:

      • Medical history of the participants from their patient’s medical file to evaluate eligibility.

      • Informed consent forms (paper format).

      • Questionnaire results (Qualtrics, exported as .csv files).

      • Personal data concerning health status (Qualtrics, exported as .csv files).

      • Safety reporting and SCS parameters (Qualtrics, exported as .csv files).

      The source documents are to be completed at the time of the participant’s visit. The participating sites will keep copies of relevant documents, as well as essential centre-specific documents in their Investigator Site File.

      The investigator is archiving all study related documents and trial data in a safe and secure location according to Good Clinical Practice guidelines and takes measures to prevent accidental or premature destruction of these documents. No trial data should be destroyed without the sponsor’s agreement. Any source data are archived according to the archiving regulations of the investigational sites following national regulations. The investigator is required to arrange for the retention of the patient identification codes for at least 25 years after the completion or discontinuation of the trial. The investigator will permit trial-related monitoring, audits from the sponsor, Ethics Committee (EC) review and regulatory inspection(s), providing direct access to source data/documents.

      Data analysis plan

      Data processing and statistical analyses will be performed on pseudonymised data. The analyses will be performed after last patient completed the study, after monitoring and cleaning of data gathered from all patients. Analysis will be performed by the biostatistician involved in this project, using statistical software packages R studio and SAS 9.2 (or later versions). The flow of participants will be illustrated in a flow diagram. A description will be given of key patient characteristics recorded at the baseline visit.

      To respect the design of this study, the longitudinal aspect will be taken into account in all analyses. Therefore, the inferential statistical analysis for the primary outcome, namely an expected reduction in overall pain up to 12 months, will be evaluated with longitudinal mixed models.42

      In case a statistical significant effect is found for the primary outcome measurement, secondary outcome measurements can be evaluated as well with claims of statistical significance. In case of a non-significant effect for the primary outcome measure, no claims of statistical inference will be made about the secondary outcome measurements. Secondary outcome variables will be evaluated with longitudinal mixed models, Tweedie generalised linear models (in case of a discrete mass at zero43) or generalised mixed model to determine differences in scores over time. Analyses will be performed on the data as observed. Sensitivity analyses regarding missing data policy will be performed to evaluate robustness of the obtained results.

      In addition to the mixed-effect modelling, which takes into account within-individual correlations for longitudinal data, latent class trajectory modelling (LCTM) will be applied.44 45 LCTM simplifies heterogeneous populations into more homogeneous clusters, with respect to an unobserved latent variable.46 One can include random effects to allow for individual variation within these clusters.47 As such, this data-driven technique will allow to create trajectories to identify clusters in this patient sample based on shared parameters, rather than a priori determination of categories based on patient or clinical characteristics.

      Based on the EQ-5D-5L index scores, patient-level quality-adjusted life-years (QALYs) will be calculated. QALYs are estimated by applying the area under the curve method, by summing the areas of the geometrical shapes obtained by linearly interpolating between utility scores over the study period.48 The same calculation will be performed with a baseline index value that is extrapolated up to 12 months.34 This value is representing the QALY of a patient who is not receiving an additional treatment. The incremental QALY is calculated by subtracting the QALY without additional treatment from the QALY during DTM SCS, over a period of 12 months.

      Data monitoring and oversight

      The trial management group (MM, LG and ADS) is the main decision-making and steering body of the project. The trial management group organised a kick-off meeting at the start of the project to establish common working procedures. The main tasks of the trial management group are: (1) agree on common working procedures and management policies, (2) monitor overall progress and follow-up of deliverables, (3) decisions on major changes to the work programme, (4) conflict handling and (5) budget decisions. The Steering Board is assembling meetings at least every year. Additional teleconferences can be organised ad hoc in case of urgent issues. The trial management group is responsible for assuring the quality of the workflow and project implementation, considering the available resources. The principal investigators in the recruiting centres are responsible for patient recruitment and data collection in their own centre. The study coordinator at Vrije Universiteit Brussel will regularly monitor data that are entered in Qualtrics in the participating centres. The study is also monitored by the Clinical Trials Center of UZ Brussel, Vrije Universiteit Brussel. The trial management group is also responsible for scientific communication, dissemination of data and results exploitation. The trial management group will closely interact with all partners involved and will review the scientific and organisational suggestions from the Scientific Advisory Board. The Scientific Advisory Board represents key opinion leaders in the field of neuromodulation research. The composition of this board assembling renowned independent experts will guarantee a sound methodological approach. Ad hoc meetings with the Scientific Advisory Board are organised based on the needs of the project. During the design of the study, the Scientific Advisory Board was asked for advice on the selection of specific questionnaires to avoid questionnaires that are partly evaluating a similar underlying concept.

      Ethics and dissemination

      Ethics considerations

      The study protocol was approved by the central Ethics Committee of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (B.U.N.1432021000563) and the Ethics Committees of each participating centre (AZ Sint-Lucas Brugge, UZ KULeuven, AZ Delta, AZ Turnhout, Vitaz, Jessa Ziekenhuis, CHR La Citadelle, AZ Sint-Maarten, ZNA Antwerpen, GZA Antwerpen, Heilig Hart Lier, AZ Sint-Jan Brugge and AZ Groeninge). The trial will be conducted according to:

      • The current version of the principles laid down in the Declaration of Helsinki.

      • Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

      • The ‘Note for guidance on Good Clinical Practice’ (CPMP/ICH/135/95 of 17 January 1997).

      • The current version of the Good Clinical Practice regulation.

      Confidentiality

      All data are handled, and all records are kept in accordance with the European Union General Data Protection Regulation (EU GDPR) applicable from 25 May 2018 (Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data and repealing Directive 95/46/EC (General Data Protection Regulation)). The EU GDPR was designed to harmonise data privacy laws across Europe, to protect and empower all citizens of the EU data privacy and to reshape the way organisations across the region approach data privacy.

      Participant identification codes are being used to link data to patients. On screening forms, digital or other documents submitted to the coordinating centre, sponsor or principal investigator, patients are only identified by the code number. The file containing the link between participant numbers and personal data (ie, key) is managed by the researchers at each site individually and is being locked for access by others. The name and any other identifying details are not included in the study database.

      Dissemination plan

      Regular updates concerning the study are provided to all stakeholders to keep everyone informed, involved and motivated for this project. Further, we will communicate findings of this project via the publication of scientific manuscripts and presentations on national and international symposia, as well as through social media. The results of the trial will be reported to the Belgian regulatory authorities and Ethics Committee. Publication of the main study results and any information derived from the study or study data will be in accordance with the accepted scientific practice, academic standards and customs. Publication will be on behalf of the DETECT consortium, whereby the investigators of each participating site will be included in the DETECT consortium. DETECT consortium will be included as an author on publications, whereby individual investigators will be named (a) in acknowledgements and (b) as collaborators, depending on the Journal guidelines. Authorship on publication(s) will be according to the scientific guidelines for which guidelines of the International Committee of Medical Journal Editors will be followed.

      After finalising the project, access restrictions will be applied to the pseudonymised data and will be specified in a data use agreement containing the following elements: evaluation of the re-use request by ethical committee, non-disclosure agreement and warranties for safely storage of data.

      Ethics statements

      Patient consent for publication

      Acknowledgments

      We would like to thank the scientific advisory board for the help during the design of this study.

      References

      1. ↵
        1. Zheng Y,
        2. Liu CW,
        3. Hui Chan DX, et al
        . Neurostimulation for Chronic Pain: A Systematic Review of High-Quality Randomized Controlled Trials With Long-Term Follow-Up. Neuromodulation 2023;26:1276–94. doi:10.1016/j.neurom.2023.05.003
        OpenUrlPubMed
      2. ↵
        1. Kurt E,
        2. Noordhof RK,
        3. Dongen R, et al
        . Spinal Cord Stimulation in Failed Back Surgery Syndrome. An Integr Rev of Quant and Qual Stud Neuromodul 2022;25:657–70. doi:10.1016/j.neurom.2021.11.013
        OpenUrl
      3. ↵
        1. van de Minkelis J,
        2. Peene L,
        3. Cohen SP, et al
        . 6. Persistent spinal pain syndrome type 2. Pain Pract 2024. doi:10.1111/papr.13379
      4. ↵
        1. Linderoth B,
        2. Foreman RD
        . Conventional and Novel Spinal Stimulation Algorithms: Hypothetical Mechanisms of Action and Comments on Outcomes. Neuromodulation 2017;20:525–33. doi:10.1111/ner.12624
        OpenUrlCrossRefPubMed
      5. ↵
        1. Schultz DM,
        2. Webster L,
        3. Kosek P, et al
        . Sensor-driven position-adaptive spinal cord stimulation for chronic pain. Pain Physician 2012;15:1–12.
        OpenUrlPubMed
      6. ↵
        1. Russo M,
        2. Van Buyten J-P
        . 10-kHz High-Frequency SCS Therapy: A Clinical Summary. Pain Med 2015;16:934–42. doi:10.1111/pme.12617
        OpenUrlPubMed
      7. ↵
        1. Provenzano DA,
        2. Heller JA,
        3. Hanes MC
        . Current Perspectives on Neurostimulation for the Management of Chronic Low Back Pain: A Narrative Review. J Pain Res 2021;14:463–79. doi:10.2147/JPR.S249580
        OpenUrlPubMed
      8. ↵
        1. Guzzi G,
        2. Della Torre A,
        3. La Torre D, et al
        . Spinal Cord Stimulation in Chronic Low Back Pain Syndrome: Mechanisms of Modulation, Technical Features and Clinical Application. Healthcare (Basel) -> Healthc (Basel) 2022;10:1953. doi:10.3390/healthcare10101953
      9. ↵
        1. Vallejo R,
        2. Kelley CA,
        3. Gupta A, et al
        . Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain. Mol Pain 2020;16:1744806920918057. doi:10.1177/1744806920918057
      10. ↵
        1. Cedeño DL,
        2. Smith WJ,
        3. Kelley CA, et al
        . Spinal cord stimulation using differential target multiplexed programming modulates neural cell-specific transcriptomes in an animal model of neuropathic pain. Mol Pain 2020;16:1744806920964360. doi:10.1177/1744806920964360
      11. ↵
        1. Smith WJ,
        2. Cedeño DL,
        3. Thomas SM, et al
        . Modulation of microglial activation states by spinal cord stimulation in an animal model of neuropathic pain: Comparing high rate, low rate, and differential target multiplexed programming. Mol Pain 2021;17:1744806921999013. doi:10.1177/1744806921999013
      12. ↵
        1. Cedeño DL,
        2. Kelley CA,
        3. Chakravarthy K, et al
        . Modulation of Glia-Mediated Processes by Spinal Cord Stimulation in Animal Models of Neuropathic Pain. Front Pain Res (Lausanne) 2021;2:702906. doi:10.3389/fpain.2021.702906
      13. ↵
        1. Murphy MZ,
        2. Fishman MA
        . Differential target multiplexed spinal cord stimulator: a review of preclinical/clinical data and hardware advancement. Pain Manag 2023;13:233–42. doi:10.2217/pmt-2022-0052
        OpenUrlPubMed
      14. ↵
        1. Fishman MA,
        2. Calodney A,
        3. Kim P, et al
        . Prospective, Multicenter Feasibility Study to Evaluate Differential Target Multiplexed Spinal Cord Stimulation Programming in Subjects With Chronic Intractable Back Pain With or Without Leg Pain. Pain Pract 2020;20:761–8. doi:10.1111/papr.12908
        OpenUrlPubMed
      15. ↵
        1. Fishman M,
        2. Cordner H,
        3. Justiz R, et al
        . Twelve-Month results from multicenter, open-label, randomized controlled clinical trial comparing differential target multiplexed spinal cord stimulation and traditional spinal cord stimulation in subjects with chronic intractable back pain and leg pain. Pain Pract 2021;21:912–23. doi:10.1111/papr.13066
        OpenUrlPubMed
      16. ↵
        1. White T,
        2. Justiz R,
        3. Almonte W, et al
        . Twelve-month results from a randomized controlled trial comparing differential target multiplexed spinal cord stimulation and conventional spinal cord stimulation in subjects with chronic refractory axial low back pain not eligible for spine surgery. N Am Spine Soc J 2024;19:100528. doi:10.1016/j.xnsj.2024.100528
      17. ↵
        1. Tanei T,
        2. Maesawa S,
        3. Nishimura Y, et al
        . Efficacy of the latest new stimulation patterns of spinal cord stimulation for intractable neuropathic pain compared to conventional stimulation: study protocol for a clinical trial. Trials 2023;24:604. doi:10.1186/s13063-023-07637-x
      18. ↵
        1. Tanei T,
        2. Maesawa S,
        3. Nishimura Y, et al
        . Differential target multiplexed spinal cord stimulation using a paddle-type lead placed at the appropriate site for neuropathic pain after spinal cord injury in patients with past spinal surgical histories: study protocol for an exploratory clinical trial. Trials 2023;24:395. doi:10.1186/s13063-023-07433-7
      19. ↵
        1. Kallewaard JW,
        2. Billet B,
        3. Van Paesschen R, et al
        . European randomized controlled trial evaluating differential target multiplexed spinal cord stimulation and conventional medical management in subjects with persistent back pain ineligible for spine surgery: 24‐month results. Eur J Pain 2024;28:1745–61. doi:10.1002/ejp.2306
        OpenUrlPubMed
      20. ↵
        1. Goudman L,
        2. De Smedt A,
        3. Eldabe S, et al
        . High-dose spinal cord stimulation for patients with failed back surgery syndrome: a multicenter effectiveness and prediction study. Pain 2021;162:582–90. doi:10.1097/j.pain.0000000000002035
        OpenUrlPubMed
      21. ↵
        1. Follet K,
        2. Dirks B
        . Etiology and evaluation of the failed back surgery syndrome. Neurosurg Q 1993;3:40–59.
        OpenUrl
      22. ↵
        1. Bernaerts L,
        2. Roelant E,
        3. Lecomte F, et al
        . Large-scale real-world data on a multidisciplinary approach to spinal cord stimulation for persistent spinal pain syndromes: first evaluation of the Neuro-Pain nationwide screening and follow-up interactive register. Front Neurosci 2024;18:1322105. doi:10.3389/fnins.2024.1322105
      23. ↵
        1. Jensen MP,
        2. Karoly P,
        3. Braver S
        . The measurement of clinical pain intensity: a comparison of six methods. Pain 1986;27:117–26. doi:10.1016/0304-3959(86)90228-9
        OpenUrlCrossRefPubMedWeb of Science
      24. ↵
        1. Ogon M,
        2. Krismer M,
        3. Söllner W, et al
        . Chronic low back pain measurement with visual analogue scales in different settings. Pain 1996;64:425–8. doi:10.1016/0304-3959(95)00208-1
        OpenUrlCrossRefPubMedWeb of Science
      25. ↵
        1. Chapman JR,
        2. Norvell DC,
        3. Hermsmeyer JT, et al
        . Evaluating Common Outcomes for Measuring Treatment Success for Chronic Low Back Pain. Spine (Phila Pa 1986) 2011;36:S54–68. doi:10.1097/BRS.0b013e31822ef74d
        OpenUrl
      26. ↵
        1. Fairbank JC,
        2. Pynsent PB
        . The Oswestry Disability Index. Spine (Phila Pa 1976) 2000;25:2940–52. doi:10.1097/00007632-200011150-00017
        OpenUrl
      27. ↵
        1. Garratt AM,
        2. Furunes H,
        3. Hellum C, et al
        . Evaluation of the EQ-5D-3L and 5L versions in low back pain patients. Health Qual Life Outcomes 2021;19:155. doi:10.1186/s12955-021-01792-y
      28. ↵
        1. Bilbao A,
        2. García-Pérez L,
        3. Arenaza JC, et al
        . Psychometric properties of the EQ-5D-5L in patients with hip or knee osteoarthritis: reliability, validity and responsiveness. Qual Life Res 2018;27:2897–908. doi:10.1007/s11136-018-1929-x
        OpenUrlCrossRefPubMed
      29. ↵
        1. Poulsen DM,
        2. Sørensen JCH,
        3. Blichfeldt-Eckhardt MR, et al
        . Pain Catastrophizing Does Not Predict Spinal Cord Stimulation Outcomes: A Cohort Study of 259 Patients With Long-Term Follow-Up. Neuromodulation 2021;24:76–85. doi:10.1111/ner.13213
        OpenUrlPubMed
      30. ↵
        1. Goudman L,
        2. Billot M,
        3. Duarte RV, et al
        . Gradation of Clinical Holistic Response as New Composite Outcome to Evaluate Success in Spinal Cord Stimulation Studies for Pain. Neuromodulation 2023;26:139–46. doi:10.1016/j.neurom.2021.10.020
        OpenUrlPubMed
      31. ↵
        1. Rademakers J,
        2. Maindal HT,
        3. Steinsbekk A, et al
        . Patient activation in Europe: an international comparison of psychometric properties and patients’ scores on the short form Patient Activation Measure (PAM-13). BMC Health Serv Res 2016;16:570. doi:10.1186/s12913-016-1828-1
      32. ↵
        1. Rademakers J,
        2. Nijman J,
        3. van der Hoek L, et al
        . Measuring patient activation in The Netherlands: translation and validation of the American short form Patient Activation Measure (PAM13). BMC Public Health 2012;12:577. doi:10.1186/1471-2458-12-577
      33. ↵
        1. Ickmans K,
        2. Moens M,
        3. Putman K, et al
        . Back school or brain school for patients undergoing surgery for lumbar radiculopathy? Protocol for a randomised, controlled trial. J Physiother 2016;62:165. doi:10.1016/j.jphys.2016.05.009
        OpenUrlPubMed
      34. ↵
        1. Goudman L,
        2. De Smedt A,
        3. Putman K, et al
        . Long-term quality of life and work status after high-dose spinal cord stimulation in patients with failed back surgery syndrome: a secondary analysis of real-world data. J Neurosurg Spine 2021;34:440–8. doi:10.3171/2020.7.SPINE20764
        OpenUrlPubMed
      35. ↵
        1. Lamé IE,
        2. Peters ML,
        3. Kessels AG, et al
        . Test--retest stability of the Pain Catastrophizing Scale and the Tampa Scale for Kinesiophobia in chronic pain over a longer period of time. J Health Psychol 2008;13:820–6. doi:10.1177/1359105308093866
        OpenUrlCrossRefPubMedWeb of Science
      36. ↵
        1. Osman A,
        2. Barrios FX,
        3. Kopper BA, et al
        . Factor structure, reliability, and validity of the Pain Catastrophizing Scale. J Behav Med 1997;20:589–605. doi:10.1023/a:1025570508954
        OpenUrlCrossRefPubMed
      37. ↵
        1. Mayer TG,
        2. Neblett R,
        3. Cohen H, et al
        . The development and psychometric validation of the central sensitization inventory. Pain Pract 2012;12:276–85. doi:10.1111/j.1533-2500.2011.00493.x
        OpenUrlCrossRefPubMedWeb of Science
      38. ↵
        1. Kregel J,
        2. Vuijk PJ,
        3. Descheemaeker F, et al
        . The Dutch Central Sensitization Inventory (CSI): Factor Analysis, Discriminative Power, and Test-Retest Reliability. Clin J Pain 2016;32:624–30. doi:10.1097/AJP.0000000000000306
        OpenUrlPubMed
      39. ↵
        1. Bjelland I,
        2. Dahl AA,
        3. Haug TT, et al
        . The validity of the Hospital Anxiety and Depression Scale. J Psychosom Res 2002;52:69–77. doi:10.1016/S0022-3999(01)00296-3
        OpenUrlCrossRefPubMedWeb of Science
      40. ↵
        1. Goudman L,
        2. Bruzzo A,
        3. van de Sande J, et al
        . Goal Identification Before Spinal Cord Stimulation: A Qualitative Exploration in Potential Candidates. Pain Pract 2020;20:247–54. doi:10.1111/papr.12845
        OpenUrlPubMed
      41. ↵
        1. Goudman L,
        2. De Smedt A,
        3. Linderoth B, et al
        . Identifying goals in patients with chronic pain: A European survey. Eur J Pain 2021;25:1959–70. doi:10.1002/ejp.1814
        OpenUrlPubMed
      42. ↵
        1. Verbeke G,
        2. Molenberghs G
        . Linear mixed models for longitudinal data. 2010.
      43. ↵
        1. Jorgensen B,
        2. Tsao M
        . Dispersion models and longitudinal data analysis. Stat Med 1999;18:2257–70. doi:10.1002/(sici)1097-0258(19990915/30)18:17/18<2257::aid-sim253>3.0.co;2-m
        OpenUrlPubMed
      44. ↵
        1. Lemoine M,
        2. Gmel G,
        3. Foster S, et al
        . Multiple trajectories of alcohol use and the development of alcohol use disorder: Do Swiss men mature-out of problematic alcohol use during emerging adulthood? PLoS One 2020;15:e0220232. doi:10.1371/journal.pone.0220232
      45. ↵
        1. Bennett KM,
        2. Morselli D,
        3. Spahni S, et al
        . Trajectories of resilience among widows: a latent transition model. Aging Ment Health 2020;24:2014–21. doi:10.1080/13607863.2019.1647129
        OpenUrlPubMed
      46. ↵
        1. Watson C,
        2. Geifman N,
        3. Renehan AG
        . Latent class trajectory modelling: impact of changes in model specification. Am J Transl Res 2022;14:7593–606.
        OpenUrlPubMed
      47. ↵
        1. Lennon H,
        2. Kelly S,
        3. Sperrin M, et al
        . Framework to construct and interpret latent class trajectory modelling. BMJ Open 2018;8:e020683. doi:10.1136/bmjopen-2017-020683
      48. ↵
        1. Manca A,
        2. Hawkins N,
        3. Sculpher MJ
        . Estimating mean QALYs in trial-based cost-effectiveness analysis: the importance of controlling for baseline utility. Health Econ 2005;14:487–96. doi:10.1002/hec.944
        OpenUrlCrossRefPubMedWeb of Science

      Footnotes

      • Collaborators Group authorship: DETECT consortium consists of the following members: Bart Billet, Dimitri Vanhauwaert, Pieter-Jan Germonpre, Jeroen Ceuppens, Christ Declerck, Hannie Braems, Johan Vangeneugden, Bart Bryon, Thibault Remacle, Raf Van Paesschen, Sofie Denkens, Laura Verschueren, Mark Plazier, Vincent Raymaekers, Tom Theys, Anaïs Van Hoylandt, Philippe De Vloo, Jean-Pierre Van Buyten, Iris Smet, Ali Jerjir, Michel Turlot, Stefaan Goossens, Patricia Da Silva, Ella Ver Donck, Mayken Gorissen, in addition to the Steering Board.

      • Contributors MM, LG and ADS conceived the study. LG, ADS, SE, PR, MB, MR, DETECT consortium and MM contributed to the design of the study. LG and MM developed the methodology of DETECT. LG wrote the first draft version of the manuscript with critical input from ADS, SE, PR, MB, MR, DETECT consortium and MM. LG, ADS, SE, PR, MB, MR, DETECT consortium and MM read and approved the final version of the manuscript.

      • Funding DETECT is an investigator initiated trial which is financially supported by a research grant from Medtronic Inc (Medtronic External Research Program). Medtronic Inc is not involved in the study design and has no influence on the analysis, interpretation, or publication of the data.

      • Competing interests The principal investigator (MM) has no financial or competing interests that might influence the design, conduct or reporting of the trial. He has no ownership interest related to the medical device. He has received speaker fees from Medtronic. SE has received consulting fees from Medtronic, Mainstay Medical and Saluda Medical. His department has received research funding from Medtronic, Nevro and Boston Scientific. MB reported grants from Medtronic, Abbott and Boston Scientific. MR reported grants from Medtronic, Abbott and Boston Scientific. PR reports grants from Medtronic, Abbott and Boston Scientific and consultant fees and payments for lectures from Medtronic and Boston Scientific, outside the submitted work. LG is a postdoctoral research fellow funded by the Research Foundation Flanders (FWO), Belgium (project number 12ZF622N). STIMULUS has received independent research grants from Medtronic.

      • Patient and public involvement Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research. Refer to the Methods section for further details.

      • Provenance and peer review Not commissioned; externally peer reviewed.