Intermittent Dosing of Dorsal Root Ganglion Stimulation As an Alternate Paradigm to Continuous Low-Frequency Therapy

This study seeks to evaluate the use of intermittent dosing as an alternative paradigm for patients with DRG stimulation in place for at least 1 year and minimum 50% pain relief in the targeted area.

Patients will be prospectively randomized to one of two stimulation paradigms both of which involve intermittent dosing at 30 seconds ON and 90 seconds OFF. Group 1 will have their frequency set at 20 Hz with amplitude levels adjusted in order to remain in the therapeutic window (subthreshold stimulation). Group 2 will have their frequency set at 5 Hz with amplitude levels adjusted in order to remain in the therapeutic window (subthreshold stimulation) This study will be performed in a crossover fashion, meaning patients will be changed to the alternate dosing regimen at the 13-week time period.

Patients will be seen and evaluated prior to randomization and reprogramming, and thereafter evaluated at 4, 8, and 12-weeks. At the 12-week time period, patients will begin a 1-week washout period of continuous stimulation. At the 13-week time period, patients will be evaluated, crossed over to the other study arm and thereafter evaluated at 17, 21, and 25-weeks.

Dorsal Root Ganglion (DRG) is a novel target of neuromodulation that's use has grown as a proven effective treatment in chronic painful conditions. Studies examining tonic, paresthesia-based dorsal column stimulation have demonstrated plateauing or diminishing effects after extended time periods. Although not yet studied in DRG stimulation due to its relative infancy, the possibility of decreased pain relief over time very much exists. In order to mitigate the potential for waning pain relief over time, other paradigms of stimulation within the framework of DRG therapy must be evaluated.

Intermittent dosing (ID) refers to the cycling of stimulation, in which there is a designated time period of stimulation being active (ON) and inactive (OFF). Previous studies have demonstrated the safe and effective use of intermittent dosing using spinal cord stimulation (SCS).9,10 In 2020, Deer et al. reported the efficacy of intermittent dosing of Burst stimulation with settings ranging from 30 seconds ON and 90 seconds OFF, to 30 seconds ON and 360 seconds OFF in SCS.10 However, no studies have examined the use of ID in DRG stimulation. Furthermore, a pre-clinical study by Chao et al. 2020 showed that DRG field stimulation delivered at 20 Hz continuously abated transmission of action potentials in most C-type fibers and 50% of Aδ fibers. Conversely, DRG field stimulation delivered at 5 Hz consistently evoked action potentials in Aβ, Aδ, and C type fibers, suggesting that this frequency may have greater potential to mitigate pain11. Nevertheless, translation of these results to clinical practice have yet to be studied.

Patients with chronic pain secondary to CRPS or other chronic neuropathic who have responded to DRG stimulation originally and have undergone permanent DRG stimulator implantation delivered by the Abbott PROCLAIM Dorsal Root Ganglion Neurostimulator System, have had the system in place for at least 1 year, utilizing continuous tonic therapy, reporting minimum 50% pain relief in the targeted area, will be randomized to 1 of 2 study arms, in a single-blinded, 1:1 fashion:

1. High ID Arm: DRG stimulation therapy at 20 Hz frequency for 30 seconds ON, 90 seconds OFF
2. Low ID Arm: DRG stimulation therapy at 5 Hz frequency for 30 seconds ON, 90 seconds OFF

Based on the stimulation frequency each patient receives the stimulation amplitude will be adjusted accordingly to remain in the therapeutic dosing window for each patient.

Patients will be seen and evaluated prior to randomization and reprogramming, and thereafter evaluated at 4, 8, and 12-weeks. At the 12-week time period, patients will begin a 1-week washout period of continuous stimulation at their pre-study stimulation settings. At the 13-week time period, patients will be evaluated, crossed over to the other study arm and thereafter evaluated at 17, 21, and 25-weeks.

As our primary endpoint, we hypothesize that intermittent dosing with either 20 Hz frequency (high) or 5 Hz frequency (low) ID will provide superior pain relief as measured by VAS scores when compared to continuous DRG stimulation therapy in this patient population. Other endpoints include: EQ-5D scores of wellbeing; PROMIS score for physical function, pain interference, sleep disturbance, and emotional distress; chronic pain acceptance questionnaire 8 (CPAQ-8), patient satisfaction scores, and patient global impression of change.

After evaluation, all eligible and consented subjects will be randomized into one of two treatment groups. Randomization will be performed using a computer-generated random sequence generator with equal selection probabilities to all groups. Subjects will be blinded to their randomization.

After randomization, each consented subject will present to clinic at which time will first be seen by a team of investigators, sub-investigators, and/or study staff. Patients will be sent for x-ray at initial presentation to evaluate for real-time DRG lead position. Patients will be excluded from study if there is significant migration, at the discretion of clinician. Patients will have had at least one prior attempted reprogramming in standard fashion (increasing amplitude firing in tonic stimulation to document stimulation is targeting dermatome of initial placement) before enrollment in this study. Otherwise, after evaluation and collection of baseline data, a clinical specialist for the Abbott PROCLAIM Dorsal Root Ganglion Neurostimulator System will program the subject's DRG system according to the treatment group to which they have been randomized, under direct physician supervision and with use of the radiographic films.

Patient will be subsequently evaluated at 4, 8 and 12 weeks. At the 12-week time interval, the patient will begin a 1-week washout period of continuous stimulation. At the 13-week time interval, the patient will be crossed over to the alternative study arm. Thereafter, they will be evaluated again at the 17-week, 21-week, and 25-week time interval. At each interval, the patient will be evaluated by a team of investigators, sub-investigators, and/or study staff to administer questionnaires and collect data.

Patient specific data to be collected prior to first allocated dosing stimulation will include:

* Age
* Height
* Weight
* BMI
* Gender
* Primary diagnosis
* Current daily morphine milligram equivalent usage

Data to be collected at baseline and at 12, 13 and 25 weeks of stimulation only:

* Patient Health Questionnaire (PHQ-8)
* PROMIS Health questionnaires

  * Global Health 10 item questionnaire
  * Physical Function 8b questionnaire
  * Emotional Distress-8a Anxiety questionnaire
  * Sleep Disturbance 4a questionnaire
  * Fatigue 8 item questionnaire
* CPAQ-8 score (Chronic Pain Acceptance Questionnaire 8)
* Patient Global Impression of Change (see fig. 2)
* Patient Satisfaction Score (7-point Likert-type scale; see fig. 2)

Data to be collected at each study visit:

* NRS pain scores (22-point scale, 0-10 in 0.5 increments)
* Current dorsal root ganglion stimulation parameters (i.e. mode of stimulation-continuous vs. ID, frequency, amplitude, pulse width)
* Average charging frequency over last week

Risks \& Benefits:

As with all clinical research, there exists a potential for loss of confidentiality. Measure to protect the confidentiality of study participants will be implemented as described in the Data Collection \& Management Section Below.

Further loss of therapeutic pain relief is another potential risk that could occur following reprogramming to ID parameters. If at any point a subject reports diminishing pain relief and wishes to return to baseline mode of stimulation, they will be allowed to do so and considered a study failure. Patients would be encouraged to proceed with randomization process and if pain relief diminished, would be allowed to return to whichever desired mode of stimulation.

Subjects may experience benefit in the form of pain relief and improved functionality following reprogramming to ID parameters. However, if the patient chooses to no longer participate in the study, they may still receive treatment from the treating physician, which may include the ID parameters, administered separately, being investigated in this study.

Eligibility Criteria:
Inclusion Criteria:

* Age between 18 and 99
* 1-year or more use of continuous DRG therapy as delivered a permanently implanted Abbott PROCLAIM XR Dorsal Root Ganglion Neurostimulator System for chronic back and/or leg pain
* Endorse at least 50% pain relief in the targeted area over the last year
* Must have been seen for routine follow-up within last 4 months
* Must have been reprogrammed in standard fashion at least once prior to randomization
* Willing and able to complete protocol requirements, including:

  * Complete health questionnaires and pain scales as specified in the protocol
  * Sign the study-specific informed consent form
  * Complete follow-ups at the designated time periods

Exclusion Criteria:

* Significant lead migration, as determined by clinician
* Other concurrent neuromodulation system in place
* Corticosteroid injection in previous 30 days prior to enrollment
* Intermittent dosing and/or failure within last 6m
* Changing or unstable pain medications within 30 days