Primary 3-Month Outcomes of a Double-Blind Randomized Prospective Study (The QUEST Study) Assessing Effectiveness and Safety of Novel High-Frequency Electric Nerve Block System for Treatment of Post-Amputation Pain

Abstract

Purpose: This multicenter, randomized, double-blinded, active sham-controlled pivotal study was designed to assess the efficacy and safety of high-frequency nerve block treatment for chronic post-amputation and phantom limb pain.

Patients and methods: QUEST enrolled 180 unilateral lower-limb amputees with severe post-amputation pain, 170 of whom were implanted with the Altius device, were randomized 1:1 to active-sham or treatment groups and reached the primary endpoint. Responders were those subjects who received ≥50% pain relief 30 min after treatment in ≥50% of their self-initiated treatment sessions within the 3-month randomized period. Differences between the active treatment and sham control groups as well as numerous secondary outcomes were determined.

Results: At 30-min, (primary outcome), 24.7% of the treatment group were responders compared to 7.1% of the control group (p=0.002). At 120-minutes following treatment, responder rates were 46.8% in the Treatment group and 22.2% in the Control group (p=0.001). Improvement in Brief Pain Inventory interference score of 2.3 ± 0.29 was significantly greater in treatment group than the 1.3 ± 0.26-point change in the Control group (p = 0.01). Opioid usage, although not significantly different, trended towards a greater reduction in the treatment group than in the control group. The incidence of adverse events did not differ significantly between the treatment and control groups.

Conclusion: The primary outcomes of the study were met, and the majority of Treatment patients experienced a substantial improvement in PAP (regardless of meeting the study definition of a responder). The significant in PAP was associated with significantly improved QOL metrics, and a trend towards reduced opioid utilization compared to Control. These data indicate that Altius treatment represents a significant therapeutic advancement for lower-limb amputees suffering from chronic PAP.

Keywords: high-frequency nerve block; neuromodulation; peripheral nerve stimulation; phantom limb pain; post-amputation pain.

Figure 1

The Altius Bioelectric Nerve Block System and Implantation schematic. (A) The Altius Bioelectric Nerve Block System is designed to deliver high frequency nerve block (HFNB) to relieve chronic PAP. Implantable Pulse Generator (IPG) shown in the foreground connected to a single nerve cuff electrode (1). Implanted system components shown in the background: Physician Programming Wand (2), IPG Battery Charger (3), Patient Controller (4). (B) Increased magnification of the IPG and nerve cuff electrode. (C) Surgical implantation schematic showing the cuff electrode wrapped around the distal end of the target nerve and connected to the IPG which is typically implanted in a subcutaneous pocket in the abdomen. Adapted with permission from Dove Medical Press. Kapural L, Syed Shah N, Fang Z-P, Mekhail N. Multicenter, Double-Blinded, Randomized, Active-Sham Controlled Clinical Study Design to Assess the Safety and Effectiveness of a Novel High Frequency Electric Nerve Block System in the Treatment of Post-Amputation Pain (The QUEST Study). J Pain Res. 2022;15:1623–1631.

Figure 2

QUEST subject study schedule and subject flow chart. (A) QUEST study schedule. (B) QUEST subject flow chart. ^1 Subject failed eligibility but proceeded to implant; *Subject Withdrew/Other Exits included voluntary, investigator withdrawing subject, subject failing to keep in contact with site, exit post-enrollment, or exit after an unsuccessful implant of the study device. (A) is adapted with permission from Dove Medical Press. Kapural L, Syed Shah N, Fang Z-P, Mekhail N. Multicenter, Double-Blinded, Randomized, Active-Sham Controlled Clinical Study Design to Assess the Safety and Effectiveness of a Novel High Frequency Electric Nerve Block System in the Treatment of Post-Amputation Pain (The QUEST Study). J Pain Res. 2022;15:1623–1631.

Figure 3

Examples of self-initiated treatment sessions demonstrate meaningful pain reduction in both Responders and Non-Responders. (A) Pain scores prior to device activation (baseline) and directly after treatment (30-min) throughout the randomized period for an example QUEST Responder. (B) Same as in A, only for an example QUEST Non-Responder. Green lines represent a single session with ≥50% pain reduction; black lines represent a single session with 30–50% pain reduction. The box-plot diagram represents the 75th percentile (top bar), 25th percentile (bottom bar), and median (middle dark bar).

Figure 4

Cumulative percent pain reduction across all Altius treatment sessions. (A) Percent pain reduction as a function of total treatment sessions in the Treatment group (solid blue; N=3013 total sessions) and Control group (dashed; N=5003 total sessions) 30-min post-treatment demonstrating a robust treatment effect across all possible pain reduction thresholds. (B) Same as A, only at 120-min post-treatment. Treatment Group (solid blue; N=1858 total sessions) and Control Group (dashed; N=3022 total sessions).

Figure 5

Group- and Subject-level Average Daily Morphine Equivalent Dose (MED) Percent Change at 3-Month relative to Baseline – (A) Mean Percent Change of Average Daily MED for Treatment (blue) and Control (gray) groups. Data is presented as Mean Percent Change of Average Daily MED ± SEM for subjects that reported using opioids for 2 Weeks at Baseline and 2 Weeks immediately before 3-Month visit. (B) Tornado Plots of the Mean Percent Change of Average Daily MED for each Treatment and Control subjects used to generate (A). Colors on each figure indicate degree of reduction or increase: Complete Reduction = 100% from baseline; Profound Reduction = ≥90% to <100% from baseline; Significant Reduction = ≥50% to <90% from baseline; Noticeable Reduction = ≥20% to <50% from baseline; Reduction = <20% from baseline. Reduction is indicated as negative (-) percent change, an increase as a positive percent change. N= 35 subjects in Treatment Group and N=24 subjects in Control Group.

Figure 6

Change in Brief Pain Inventory (BPI) Pain Interference Score. (A). Average BPI Pain Interference scores at Baseline and 3-Month in Treatment (blue) and Control (gray) groups. Data is presented as Mean ± SEM. (B) Average BPI Interference change from Baseline to 3-Month in Treatment (blue) and Control (gray) groups. *Represents p=0.01.