CPMT Journal

Introduction

Peripheral nerve stimulation (PNS) is a well-established treatment for chronic pain, typically used only after other therapies have been exhausted. The COMFORT Group previously reported results from the COMFORT RCT (Clinical Study of a Micro-Implantable Pulse Generator FOR the Treatment of Peripheral Neuropathic Pain), which showed strong and statistically significant improvement in pain, functionality, quality of life, pain interference, depression, global impression of change, and general satisfaction.

We now report the initial outcomes of COMFORT 2, a second RCT that uses an identical protocol to COMFORT, with the same non-integrated micro-IPG system (Nalu Neurostimulation System, Nalu Medical, Inc., Carlsbad, CA; FDA product code GZF) that was previously studied in COMFORT. This represents the first Level 1 evidence for a permanently implanted PNS device.

The use of identical protocols for COMFORT and COMFORT 2 was intentional to allow pooling of data from both studies. Each study incorporated a pragmatic design to mimic standard clinical practice as much as practical, to ensure applicability of the results outside of the study setting.

Materials and Methods

The COMFORT 2 Study was Institutional Review Board approved (April 5, 2023) and conducted in compliance with local regulations and standards for good clinical practice. The study is registered on ClinicalTrials.gov (NCT05870124).

COMFORT 2 (ongoing) is being conducted at 18 US clinical sites. Subjects were enrolled between April 27, 2023, and September 9, 2024. The COMFORT 2 protocol is identical to the previously published COMFORT protocol [1], with the exception that COMFORT 2 did not allow the introduction of any new Conventional Medical Management (CMM) to a subject’s regimen. Subjects could continue using their existing CMM regimen, representative of standard clinical practice, that they had when enrolled unless it was to avoid harm to the patient’s wellbeing or safety.

In brief, eligible patients were between the ages of 18 and 80 years and were diagnosed with chronic pain (≥6 months) of peripheral nerve origin, in the knee, shoulder, low back, or foot/ankle. Postsurgical/post-traumatic, peripheral neuralgia including pain due to nerve injury, postsurgical scar formation, nerve entrapment, mononeuropathy and osteoarthritic pain were the included etiologies of chronic pain. Patients needed to follow the prescribed CMM treatment prior to enrollment.

Major exclusion criteria included: diagnosis of complex regional pain syndrome; peripheral neuralgia of metabolic origin or postherpetic neuralgia; ≥ 90 morphine milligram equivalents (MME) per day; failure to pass psychological evaluation; and intolerance of, or inability to wear or use the micro-IPG system. Full inclusion/exclusion criteria are available on ClinicalTrials. gov.

The primary efficacy endpoint was measured using the Numeric Rating Scale (NRS) pain score recorded in the Brief Pain Inventory (question 5; BPI-Q5) from the target area of chronic pain. Secondary outcome measures included the following Patient Reported Outcomes (PRO): Patient Global Impression of Change

(PGIC), Brief Pain Inventory Short Form (BPI-SF), Quality-ofLife metric (EQ-5D-5L), Beck Depression Inventory (BDI), Oswestry Disability Index (ODI). Additional secondary outcomes included patient safety, satisfaction, device comfort, usability, and subject compliance with the therapy.

Eligible subjects were randomized to CMM + PNS (Active Arm) vs CMM alone (Control Arm) in a 2:1 ratio. Those randomized to the Control Arm could cross over to the Active Arm at 3 months following randomization. There were no experimental devices or off-label procedures as part of the study. Allocation was concealed prior to randomization, which was performed using a random permuted block design (block size of 3) with a 2:1 allocation ratio (Active vs Control). Randomization was stratified by investigational site and was assigned via a centralized electronic system. Randomization sequence was generated by SAS^TM (version 9.4, SAS Institute Inc, Cary, NC).

Subjects randomized to the Active Arm followed the standard clinical practice for PNS including a temporary trial lead placement at the target nerve. Subjects needed to demonstrate a ≥ 50% decrease in pain during the trial period to be eligible for a permanent implant; failure to do so was considered a trial failure and those subjects exited the study.

The micro-IPGs were programmed by qualified industry clinical specialists under the direction of the study physician following usual clinical practice. Advanced programming options included paresthesia and sub-paresthesia, multiple cathodes and/or anodes, multiple areas, current steering across leads, pulse widths of up to 1000 µs and frequencies of up to 1500 Hz.

Patient Reported Outcomes (PROs) were collected at 1, 3, 6 months. Subjects will be followed out to 36 months as part of this study. The study was initially designed out to 12 months and later amended to follow subjects out to 36-months to allow for long term data collection. In addition, the sample size (from up to 100 subjects to up to 200 subjects) was updated to allow for a larger study. The primary outcome was Numeric Rating Scale (NRS) as captured in the Brief Pain Inventory-Question 5 (BPI-Q5); secondary endpoints are listed in Table 2. This report focuses on the 3- and 6-month efficacy and safety data, while the study is ongoing. In addition to reporting outcomes from this ongoing study, data was pooled from the COMFORT [2] and COMFORT 2 RCTs and presented here. This includes pooled data from the Active Arm at 1, 3 and 6-months and from the Control Arm at 1 and 3-months.

Statistical Analysis

The modified-intention-to-treat (mITT) analysis was carried out as prespecified in the Statistical Analysis Plan. The mITT population was defined as “all randomized subjects, excluding subjects who failed the trial period”. The primary effectiveness endpoint was the percentage of responders (defined as ≥ 50% reduction in pain relative to baseline) at 3 months.

The sample size for the study is based on power requirements for the primary effectiveness endpoint. A sample size of up to 200 randomized subjects was calculated based on a two-sample exact binomial test with a two-sided 0.05 alpha level, providing 90% power for a difference in responder rate between the arms.

Comparisons were made between randomized arms. Missing data were assumed to be missing at random; no imputation for missing data was used. Results were reported as mean ± Standard Deviation (SD) for continuous variables and as a percentage (count) for categorical variables, unless otherwise noted. Comparisons of responder rates between the Active Arm and Control Arm were conducted by a two-sample t-test; within-arm comparisons were conducted using a two-sample t-test. For all outcomes, percent reduction is calculated as a paired analysis within each subject and reported as mean ± SD. An analysis was undertaken by a third party to confirm poolability of data from both studies.

Results

The number of subjects consented/enrolled in COMFORT 2 was 315. Of those, 121 were randomized to the Active Arm and 64 were randomized to the Control Arm. Of those, 12 exited the study due to failed trials and were excluded from the mITT population. The COMFORT 2 subject disposition is shown in Figure 1. The final COMFORT 2 mITT population included 109 active and 64 control subjects for a total of 173 subjects. The demographics of subject population are outlined in Table 1. The distribution of targeted areas of pain was as follows: low back (45.1%, 78/173), knee (22.5 %, 39/173), shoulder (14.5%, 25/173), foot/ankle (17.9%, 31/173).

Table 1: Subject demographics and baseline characteristics. Radio Frequency ablation (RFA), Trans-Cutaneous Nerve Stimulation (TENS).

COMFORT 2 Outcomes

At 3 months the COMFORT 2 Active Arm responder rate (those who achieved ≥50% pain reduction) was 80% (67/84) with an average pain reduction of 66%, compared to the Control Arm responder rate of 4% (2/55) and average pain reduction of 3% (p<0.001). The high responder rate (those who achieved ≥ 80% pain reduction) was 30% (25/84) in the Active Arm compared to 0% (0/55) in the Control Arm. At 6 months the Active Arm responder rate was 79% (64/81) with an average pain reduction of 64%; the high responder rate was 30% (24/81) (Figure 2). Likewise, statistically significant improvement was achieved for all of the secondary endpoints, which included psychological and functional outcomes (Table 2). The majority of Active Arm subjects achieved Minimal Clinically Important Differences (MCID) [3-6] at 3 and 6-months for the various PROs which assess overall improvements in a clinically meaningful way rather than relying only on pain scores (Table 2).

Figure 2 a. Mean NRS pain scores (BPI-Q5) and responder rates at 3 and 6 months. Pain scores captured in the office at baseline, 1, 3, and 6 months for COMFORT RCT, COMFORT 2 RCT, and pooled cohorts. Mean percent reduction in pain was statistically significant in the Active Arm compared to the Control Arm, at all timepoints in the 3 cohorts (p< 0.001). Responder rates (≥ 50% improvement) and high responder rates (≥ 80% improvement) were statistically better in the Active Arm versus the Control Arm, at p < 0.001. b. Individual subject pain relief at 6-months in the pooled cohort, Active Arm (n=123).

No Unanticipated Serious Adverse Device Effects (USADE) were reported in the study, to date. There were no Serious Adverse Events (SAE) related to the device or procedure. No reports of pocket pain have been reported to date. All non-serious adverse device effects (ADE) resolved with no sequelae. Lead migrations were reported in 3 subjects, all of which were addressed with reprogramming. Eight instances of IPG migrations, rotations, disconnections and placement issues resulted in revisions. Seven subjects reported minor infections which were resolved with antibiotics. Four additional subjects had infections that resulted in explants, with reimplantation of 1 subject upon resolution of infection. Two subjects had their devices explanted due to inefficacy and MRI compatibility issues.

Five non-device related SAEs were reported in the Active Arm at the 6-month timepoint, all resolving with no sequelae. In the Control Arm, 1 serious adverse event was reported, which was not related to the current CMM regimen. This safety profile is consistent with that reported for the COMFORT study and other studies involving the micro-IPG system [7,8].At baseline, 91% (158/173) of subjects reported the external wearable to be comfortable and easy to use. At 3-months, 79% (66/84) of Active Arm subjects reported the wearable was comfortable or very comfortable. Additionally, 90% (76/84) reported that the device was easy or very easy to use. 68% (57/84) reported typically using the device for a full day. At 6 months, 75% (61/81) of subjects continued to report the device to be very comfortable or comfortable. 88% (71/81) of subjects found the device to be very easy or easy to use and 70% (57/81) reported using it for a full day.

Pooled Analysis (COMFORT and COMFORT 2)

Pooling the COMFORT and COMFORT 2 data yielded a sample size of 250 (Active n=155; Control n=95). At 3 months the pooled Active Arm responder rate was 81% (103/127) with an average pain reduction of 66%, compared to the pooled Control Arm responder rate of 4% (3/84) and an average pain reduction of 4% (p<0.001); the high responder rate (those who achieved ≥ 80% pain reduction) was 30% (38/127) for the pooled Active Arm compared to  1% (1/84) in the pooled Control Arm. At 6 months the pooled Active responder rate was 82% (101/123) with an average pain reduction of 66%; the high responder rate was 33% (40/123). The pooled Active Arm was statistically better than the pooled Control Arm at reducing pain (p<0.001) at 3-months (Figure 2).

Figure 2a shows the outcomes for 3 cohorts, COMFORT RCT, COMFORT 2 RCT and the pooled results. The outcomes show excellent consistency across all time points between the 3 cohorts with the responder rate, average pain reduction and the high responder rate in alignment.

In the pooled Active Arm, a statistically significant improvement was observed for each PRO when the 3- and 6-month values were compared to baseline. In the control group, the difference between PROs at baseline and 3 months was not statistically significant except for one of the PROs (Table 2).

Table 2: Patient Reported Outcomes (PRxO). Brief Pain Inventory (BPI), Quality-of-Life metric (EQ-5D-5L), Beck Depression Inventory (BDI), Oswestry Disability Index (ODI).

Statistically significant improvements were seen for each of the four areas treated in the pooled cohort (Figure 3a). All NRS average pain scores were above 7/10 at baseline compared to scores less than 3/10 in each of the 4 targeted pain areas, at 3 and 6 months. The responder rates ranged from 96% to 74% at 3 and 6 months, and percentage pain relief ranged from 73% to 61% over the same periods. When compared to baseline, all responder rates and pain reductions were statistically significant (p<0.001).

For the pooled cohort, each subject’s overall impression of change following treatment was assessed using Patient Global Impression of Change (PGIC) (Figure 3b). At 3-months, 97% of subjects reported improvement (very much, much and minimally improved), 2% reported no change and 2% of subjects reported worsening. In the control arm, majority of subjects (65%) reported no change.

Subjects were asked to rate their overall satisfaction with the micro-IPG PNS system using a 5-point Likert scale, (Figure 3c). At 3 months, 91% (115/127) of Active Arm subjects were satisfied with the system. At 6 months, 92% (112/122) of Active Arm subjects were satisfied, and three subjects (2%) were dissatisfied.

Figure 3 a. Pain relief by area of pain with mean pain score at each timepoint, in the pooled cohort, Active Arm. The improvement in pain was statistically significant in each area at both 3- and 6-months, when compared to baseline. Responder rates and mean percent pain relief shown. b. Patient Global Impression of Change (PGIC) at 3 and 6 months in the pooled cohort, Active and Control Arms. c. Satisfaction with the PNS system reported by subjects in the pooled cohort, Active Arm at 3 and 6 months.