Study design
This is a single-center, open-label, crossover, randomized trial.
Patient population
Patients will be selected based on inclusion and exclusion criteria as shown below. The main criterion for enrollment is intractable neuropathic pain without a history of spinal surgery at the site where the SCS lead will pass or be placed. Patients will be recruited from new patients treated according to standard clinical practice at Nagoya University Hospital.
Inclusion criteria
・Intractable neuropathic pain resistant to drug treatment using more than one drug
・Age ≥ 18 years
・Pain visual analog scale (VAS) score > 40
・Written, informed consent
Exclusion criteria
・Anti-cancer therapy
・History of drug abuse
・Histories of spine or spinal cord surgery at the site through which the spinal cord stimulation lead passes or will be placed
・Local and general anesthesia cannot be performed
・Conditions resulting in high surgical risk, such as unstable angina pectoris and end-stage liver disease presenting with hepatic encephalopathy
・Poorly controlled diabetes mellitus (HbA1c ≥ 9%)
・Serious concomitant diseases (liver disease, kidney disease, heart disease, lung disease, blood disease, brain disease, etc.)
・Pregnant or potentially pregnant
・Considered inappropriate by the head of research or researcher allocating patients
Who will take informed consent?
Potential participants will be identified from among patients visiting Nagoya University Hospital. After clinical research physicians assess potential participants for the inclusion and exclusion criteria, they will be given study information. Consent, both verbal and written, will then be obtained. The right of a participant to refuse to participate in this trial without giving reasons for the decision will be respected. This trial does not involve collecting biological specimens for storage.
Study Procedures
This trial consists of two steps. The first step is an SCS trial, and the second step is SCS system implantation. In the SCS trial, two cylinder-type leads (Model 977A190; Medtronic Inc.) will be inserted under local anesthesia and connected to an external stimulation device, and intraoperative stimulation will be performed to confirm the area of paresthesia induction. The leads will be placed at vertebral levels of the paresthesia covering the painful area, and then directly sutured to the skin at the puncture sites without a skin incision. During the SCS trial, three stimulation patterns, tonic, DTM, and FAST, will be applied. After the SCS trial ends, the inserted leads will be removed in all cases. If pain relief effects are obtained in the SCS trial, the cases will proceed to the second step. More than one month after the SCS trial, new cylinder-type leads and an implantable pulse generator (IPG) will be implanted under general anesthesia referring to the previous X-ray of the SCS trial lead placement. The type of implanted devices will be determined as follows: leads (Model 977A190; Medtronic Inc.) and IPG (Intellis; Medtronic Inc.) will be implanted if the DTM stimulation pattern is effective; leads (Linear ST lead; Boston Scientific) and IPG (WaveWriter Alpha 32; Boston Scientific) will be implanted if FAST or tonic stimulation patterns are effective.
Method of SCS trial
The SCS trial period will last 9 days and consist of 3 stimulation-on periods and 2 stimulation-off periods (Fig. 1). The initial stimulation will be started one day after SCS lead insertion. The pain relief effect will be assessed using a VAS scale 6 times: pre/post Stim-1, pre/post Stim-2, and pre/post Stim-3. After assessment of post Stim-3, the SCS leads will be removed. The order of stimulations will be set differently among 4 groups and the details are listed in Table 1. For example, the order of group 1 will be Tonic stimulation (Stim-1), DTM stimulation (Stim-2), and FAST stimulation (Stim-3). Each stimulation pattern will be performed for 2 days. There will be a one-day stimulation-off period between each stimulation (Stim-off). The participants will be randomly assigned to one of the 4 groups at the time of study registration.
Setting of each stimulation pattern
Tonic stimulation is a conventional stimulation pattern that delivers mild electrical pulses and elicits paresthesia. Stimulation parameters include frequency, pulse width, and voltage. Frequency (10–100 Hz) and pulse width (40–300 µs) will be set by clinical research physicians so that the patient feels the paresthesia as a comfortable sensation. After setting both frequency and pulse width, the voltage will be adjusted by the patient using a remote control.
DTM stimulation is one of the latest paresthesia-free stimulation patterns that delivers multiple electrical signals and stimulates multiple locations without paresthesia. DTM stimulation consists of one stimulation signal on the upper side of the leads, called the base program, and multiple stimulation signals on the lower side of the leads, called the prime program. The base program is set at a frequency of 50 Hz, pulse width of 200 µs, and voltage of approximately 70% of the paresthesia threshold. Three prime programs are set at the lower side of the base program. The prime program is set at a frequency of 300 Hz, pulse width of 170 µs, and voltage of approximately 65% of the paresthesia threshold. DTM stimulation delivers electrical signals from the base and three prime programs. Patients do not use a remote control during DTM stimulation.
FAST stimulation is a latest paresthesia-free stimulation pattern that delivers two symmetrical biphasic waveforms to the leads with frequency of 90 Hz and pulse width of 210 µs. Each wave is a rectangular phase of the charge-balanced stimulation cycle. During the first rectangular phase, a negative current is injected through negatively configured leads, and a positive current is injected through positively configured leads. During the second rectangular phase, the polarities are reversed to achieve charge balance. Then, positive and negative reversal stimulations are repeated. The stimulation power is lowered to approximately 30% of the paresthesia threshold. Patients do not use a remote control during FAST stimulation.
Criteria for discontinuing or modifying allocated interventions
Any patients requesting to end their participation in the study can be withdrawn from the study regardless of the stage they have reached in the study process. Patients found to be pregnant or those judged ineligible to continue participating in the study by the investigators will also be withdrawn from the study.
Strategies to improve adherence to interventions
All treatments will be administered to participants during their stay in the hospital by attending surgeons. Therefore, participants’ adherence to interventions is assured.
Relevant concomitant care permitted or prohibited during the trial
All other treatments will be allowed.
Provisions for post-trial care
Any patients who suffer harm from trial participation will be covered by the Japanese public healthcare system.
Clinical assessments
On enrollment in this trial, clinical research physicians will obtain information from the patients including age, sex, past history, current medication, causative disease of pain (central post-stroke pain, post–spinal cord injury pain, failed back surgery syndrome, complex regional pain syndrome, post-herpetic neuralgia, diabetic neuropathic pain, peripheral arterial disease, or others), lesion site causing pain (central or peripheral), location of pain (arm, leg, lower back, back, chest, face), laterality of pain (left, right, midline), degree of paralysis (none, mild, moderate, severe), sensory disturbance (hypoesthesia, allodynia, numbness), and duration of disease. During the SCS trial, the degree of pain will be evaluated using a VAS according to the plan (Fig. 1). After SCS system implantation, assessment items will be evaluated according to the plan, including the degree of improvement with respect to pain relief and mental state (Table 2).
Assessment items
Assessments of pain relief will be performed using the VAS and short-form McGill pain questionnaire-2 (SF-MPQ-2), and mental state will be assessed using the pain catastrophizing scale (PCS) and quick inventory of depressive symptomatology (QIDS-J).
Imaging evaluation
Before the SCS trial, whole-spine magnetic resonance imaging and X-ray examinations will be performed to rule out any abnormal findings. After the SCS trial and SCS system implantation, spinal X-ray and computed tomography examinations will be performed to confirm the location of the SCS leads and to rule out postoperative complications.
Primary outcome
Pain improvement is defined as more than 33% reduction in the pain VAS. The primary analysis will compare the pain improvement between the new stimulation patterns (DTM or FAST) and the conventional tonic stimulation in the SCS trial.
Secondary outcomes
The following evaluations of the secondary outcomes will be performed: 1) the relationship between causative disease and improvement rate by each stimulation pattern; 2) comparison of the improvement rates between DTM and FAST stimulation patterns in all cases and by causative disease; 3) changes in assessment items including the VAS, SF-MPQ-2, PCS, and QIDS-J preoperatively, and at 1, 3, 6, 12, 18, and 24 months after SCS system implantation; 4) preoperative factors associated with long-term effects defined as continuing for more than 12 months; and 5) adverse events related to this study 3 months after SCS system implantation.
Sample size
In the SCS trial, it is assumed that the percentage of patients achieving pain improvement will be 80% for the new stimulation patterns (DTM or FAST) and 50% for the conventional tonic stimulation pattern. The required sample size was calculated to be 78 cases with a significance level of 0.05, a power of 80%, and 1:1 allocation. Each group (A, B, C, and D) will enroll 20 cases (40 conventional tonic stimulation and 40 new stimulation patterns in Stim-1). Thus, it is possible to secure a power of 0.8 even with the analysis of Stim-1 alone. Considering dropout cases, the target number of cases is 23 in each group, for a total of 92 in all groups. Assuming, based on past performance, that there are 2–4 cases enrolled in the SCS trial per month, 24–48 patients are expected to be enrolled annually. Therefore, the target number is expected to be reached in 2 to 4 years.
Data management
Randomization will be performed centrally through the web-based system with a minimization procedure. The allocation sequence using the web-based system will be generated at the data center (Department of Advanced Medicine, Nagoya University Hospital). Enrolment of participants and assignment to interventions will be performed by TT. Registration, randomization, and data collection will be performed using an electronic data capture (EDC) system. Statistical analyses will be performed at the data center.
Concealment mechanism
The results of the allocation will be shown via the interactive web response system.
Assignment of interventions: blinding
Who will be blinded
Trial participants will be blinded to their group assignment.
Procedure for unblinding if needed
Not applicable.
Plans to promote participant retention and complete follow-up
Medical interviews and adjustments of the SCS parameters will be booked for all patients.
Confidentiality
The form used to code patients will be stored in a locked cabinet with logged access only available to the researchers and administrators responsible for the study.
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use
Not applicable.
Statistical analysis
The primary analysis will be performed after completion of the SCS trial of the final registered participant. An analysis of the 12-month follow-up period data will be performed at the completion of the 12-month follow-up after the implantation of the final registered participant. Analyses of the 18- and 24-month follow-up period data will be performed at the completion of 24-month follow-up from the implantation of the final registered participant.
The primary outcome analysis will be as follows. Pain improvement will be compared between each stimulation using logistic regression analysis with explanatory variables of stimulation timing (Stim-1, Stim-2), treatment group (new stimulation patterns, conventional tonic stimulation), pre-VAS score for each stimulation pattern, and interaction between stimulation timing and treatment group. The carryover effect will be examined by testing the interaction terms with a significance level of 10%. If there is no carry-over effect, treatment groups will be compared with a significance level of 5%. If a carryover effect is observed, analysis will be performed with data from Stim-1 only.
The secondary outcome will be analyzed as follows:
-
Similar analyses of the primary outcome analysis will be performed for each causative disease.
-
Comparison of DTM and FAST stimulation patterns for pain improvement in Stim-3. Pain improvements will be compared between DTM and FAST stimulations using logistic regression analysis adjusted for treatment group (DTM stimulation, FAST stimulation) and pre-VAS value. Similar analyses will be performed by causative disease.
-
Adjusted mean values and 95% confidence intervals of changes in assessment items including the VAS, SF-MPQ-2, PCS, and QIDS-J preoperatively, and at 1, 3, 6, 12, 18, and 24 months after SCS system implantation at each time point will be calculated using a linear mixed model with the interaction between treatment group and time point as a fixed effect. Analysis will be performed using a linear mixed model with the change rate and change amount of each indicator as outcome variables. The rate and amount of changes in each index at each evaluation time point will be compared between groups using fixed effects such as pretreatment value of each index, treatment group, evaluation time point, and interaction between treatment group and evaluation time point. The 12-month analysis will be performed at preoperative, 1, 3, 6, and 12 months, and the 24-month analysis will be performed at 18 months and the final follow-up (24 months).
-
In participants with no missing VAS values preoperatively to 12 months after implantation, analyses of the prognostic factors related to the long-term effect of continuing 33% reduction in the pain VAS over 12 months will be performed using logistic analysis with the following explanatory variables: treatment group, pre-implantation VAS value, sex, age, causative disease, site of pain, degree of paralysis, degree of sensory disturbance, and disease duration.
Interim analyses
Interim analyses are not planned.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data
No statistical methods will be used to compensate for missing data.
Plans to give access to the full protocol, participant-level data, and statistical code
Details of the full protocol, participant-level data, and statistical code will not be publicly available. Unpublished data will be made available upon reasonable request to the corresponding author of the publication.
Oversight and monitoring
Composition of the coordinating center and trial screening committee
Nagoya University will serve as the coordinating center. Only the investigators and members of the data center will have access to the anonymized data in the electronic data capture system (REDCap).
Composition of the data monitoring committee, its role and reporting structure
Two participating researchers at Nagoya University Hospital will monitor the data. They have the responsibility of verifying patients’ eligibility, written, informed consent, compliance with the protocol, and accuracy of the data in REDCap.
Adverse event reporting and harms
Researchers will immediately report serious adverse events associated with the trial to the chief investigator. The chief investigator will then report serious adverse events to the director of the hospital and the principal investigator. Data about all serious adverse events will also be collected in REDCap.
Frequency and plans for auditing trial conduct
During the study period, monitoring will be carried out by the monitoring staff to ensure that the study is conducted properly. SM and YN are the monitoring staff, and they are members of the trial team. The monitoring will be conducted by visits, e-mail, etc. at an appropriate frequency, checking the following items: 1) consent acquisition; 2) eligibility assessment; 3) observance of the study protocol; 4) presence or absence of diseases; 5) consistency between source documents and case reports; 6) confirmation of serious illnesses; 7) clinical study procedures; and 8) storage status of documents.
Plans for communicating important protocol amendments to relevant parties
Any protocol modifications will be reviewed by the Certified Review Board of Nagoya University Hospital and then registered at jRCT. All relevant information will be shared among the researchers.
Dissemination plans
The results of this study will be published in a peer-reviewed journal and presented at national and international medical congresses.