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Randomized Controlled Trial
. 2021 Jun 1;78(6):687-698.
doi: 10.1001/jamaneurol.2021.0538.

Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients With Painful Diabetic Neuropathy: A Randomized Clinical Trial

Erika A Petersen  1 , Thomas G Stauss  2 , James A Scowcroft  3 , Elizabeth S Brooks  4 , Judith L White  5 , Shawn M Sills  6 , Kasra Amirdelfan  7 , Maged N Guirguis  8 , Jijun Xu  9 , Cong Yu  10 , Ali Nairizi  11 , Denis G Patterson  11 , Kostandinos C Tsoulfas  2 , Michael J Creamer  12 , Vincent Galan  13 , Richard H Bundschu  14 , Christopher A Paul  15 , Neel D Mehta  16 , Heejung Choi  15 , Dawood Sayed  17 , Shivanand P Lad  18 , David J DiBenedetto  19 , Khalid A Sethi  20 , Johnathan H Goree  15 , Matthew T Bennett  20 , Nathan J Harrison  8 , Atef F Israel  3 , Paul Chang  13 , Paul W Wu  21 , Gennady Gekht  14 , Charles E Argoff  22 , Christian E Nasr  23 , Rod S Taylor  24 , Jeyakumar Subbaroyan  25 , Bradford E Gliner  26 , David L Caraway  4 , Nagy A Mekhail  9
Affiliations
Randomized Controlled Trial

Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients With Painful Diabetic Neuropathy: A Randomized Clinical Trial

Erika A Petersen et al. JAMA Neurol. .

Abstract

Importance: Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments.

Objective: To determine whether 10-kHz spinal cord stimulation (SCS) improves outcomes for patients with refractory painful diabetic neuropathy (PDN).

Design, setting, and participants: The prospective, multicenter, open-label SENZA-PDN randomized clinical trial compared conventional medical management (CMM) with 10-kHz SCS plus CMM. Participants with PDN for 1 year or more refractory to gabapentinoids and at least 1 other analgesic class, lower limb pain intensity of 5 cm or more on a 10-cm visual analogue scale (VAS), body mass index (calculated as weight in kilograms divided by height in meters squared) of 45 or less, hemoglobin A1c (HbA1c) of 10% or less, daily morphine equivalents of 120 mg or less, and medically appropriate for the procedure were recruited from clinic patient populations and digital advertising. Participants were enrolled from multiple sites across the US, including academic centers and community pain clinics, between August 2017 and August 2019 with 6-month follow-up and optional crossover at 6 months. Screening 430 patients resulted in 214 who were excluded or declined participation and 216 who were randomized. At 6-month follow-up, 187 patients were evaluated.

Interventions: Implanted medical device delivering 10-kHz SCS.

Main outcomes and measures: The prespecified primary end point was percentage of participants with 50% pain relief or more on VAS without worsening of baseline neurological deficits at 3 months. Secondary end points were tested hierarchically, as prespecified in the analysis plan. Measures included pain VAS, neurological examination, health-related quality of life (EuroQol Five-Dimension questionnaire), and HbA1c over 6 months.

Results: Of 216 randomized patients, 136 (63.0%) were male, and the mean (SD) age was 60.8 (10.7) years. Additionally, the median (interquartile range) duration of diabetes and peripheral neuropathy were 10.9 (6.3-16.4) years and 5.6 (3.0-10.1) years, respectively. The primary end point assessed in the intention-to-treat population was met by 5 of 94 patients in the CMM group (5%) and 75 of 95 patients in the 10-kHz SCS plus CMM group (79%; difference, 73.6%; 95% CI, 64.2-83.0; P < .001). Infections requiring device explant occurred in 2 patients in the 10-kHz SCS plus CMM group (2%). For the CMM group, the mean pain VAS score was 7.0 cm (95% CI, 6.7-7.3) at baseline and 6.9 cm (95% CI, 6.5-7.3) at 6 months. For the 10-kHz SCS plus CMM group, the mean pain VAS score was 7.6 cm (95% CI, 7.3-7.9) at baseline and 1.7 cm (95% CI, 1.3-2.1) at 6 months. Investigators observed neurological examination improvements for 3 of 92 patients in the CMM group (3%) and 52 of 84 in the 10-kHz SCS plus CMM group (62%) at 6 months (difference, 58.6%; 95% CI, 47.6-69.6; P < .001).

Conclusions and relevance: Substantial pain relief and improved health-related quality of life sustained over 6 months demonstrates 10-kHz SCS can safely and effectively treat patients with refractory PDN.

Trial registration: ClincalTrials.gov Identifier: NCT03228420.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs Petersen, Scowcroft, White, Sills, Amirdelfan, Guirguis, Xu, Yu, Nairizi, Patterson, Galan, Mehta, Choi, Sayed, Lad, DiBenedetto, Goree, Wu, Argoff, Nasr, Taylor, and Mekhail have received personal fees from Nevro Corp. Dr Petersen has received research support from Medtronic, Neuros Medical, Nevro Corp, and ReNeuron as well as personal fees from Abbott Neuromodulation, Medtronic Neuromodulation, and Neuros Medical. Dr Scowcroft has received research support from Boston Scientific, Nevro Corp, Saluda Medical, and Vertiflex. Drs Brooks and Caraway are employees of Nevro Corp. Dr White has received consulting fees from Eli Lilly and Company and California Institute for Biomedical Research. Dr Amirdelfan has received research support from IPM Medical Group, Biotronik, Vivex Biologics, Saluda Medical, and SPR Therapeutics as well as personal fees from Nalu Medical, Saluda Medical, Biotronik, and Medtronic. Dr Guirguis has received personal fees from Avanos Medical and SPR Therapeutics as well as research support from Abbott Laboratories, Boston Scientific, Neuros Medical, and Avanos Medical. Dr Xu has received research support from the Cleveland Clinic MENTR Program and the National Institutes of Health. Dr Nairizi has received personal fees from Flowonix. Dr Patterson has received personal fees from Abbott Laboratories, AIS Healthcare, Allergan, Amgen, CornerLoc, Nuvectra Medical, and Saluda Medical as well as research support from Abbott Laboratories, Biotronik, Flowonix, Nuvectra Medical, and Vertiflex. Dr Galan has received research support from Medtronic, SPR Therapeutics, St Jude, Biotronik, and PainTEQ. Dr Mehta has received personal fees from Salix Pharmaceuticals, BioDelivery Sciences International, and Sollis Therapeutics as well as research support from Boston Scientific and Medtronic. Dr Sayed has received personal fees from Abbott Laboratories, Medtronic, Boston Scientific, Flowonix, Vertos Medical, and Vertiflex; research support from Abbott Laboratories, Biotronic, Vertos Medical, and Vertiflex; and owns equity in SPR Therapeutics. Dr DiBenedetto has received funding for serving as principal investigator of a study supported by SPR Therapeutics paid to his institution. Dr Goree has received personal fees from Abbott Laboratories and Stratus Medical. Dr Argoff has received research support from Allergan, Amgen, Daiichi Sankyo, Novartis, Teva Pharmaceutical, Eli Lilly and Company, and Vertex Pharmaceuticals as well as personal fees from AbbVie, Teva Pharmaceutical, Eli Lilly and Company, Novartis, Pfizer, Flowonix, Vertex Pharmaceuticals, Elsevier, and SK Life Science. Dr Nasr has received personal fees from Neurogastrx and Exelixis. Dr Taylor has received personal fees from Medtronic and Saluda Medical. Dr Subbaroyan and Mr Gliner were employees of Nevro Corp at the time this work was completed. Dr Subbaroyan has a patent for painful diabetic neuropathy and sensory modulation pending to Nevro Corp and owns stocks in Nevro Corp. Mr Gliner has a patent for HF10 therapy and related issued to Nevro Corp. Dr Mekhail has received personal fees from Boston Scientific, Sollis Therapeutics, Saluda Medical, Abbott Laboratories (formerly Spinal Modulation), Vertos Medical, Nuvectra Medical, and Relievant Medsystems; research support from Avanos Medical (previously Halyard Health), Mallinckrodt Pharmaceuticals, Mesoblast, and Neuros Medical; and was an independent medical monitor for this study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Disposition of All Patients Screened for Study Participation
aPatients who missed the 3-month primary end point assessment (2 patients in the conventional medical management group, 1 in the 10-kHz spinal cord stimulation plus conventional medical management group) were considered part of the safety population but excluded from the per-protocol population for other outcome assessments even though they completed the 6-month visit.
Figure 2.
Figure 2.. Pain Relief Over Time Measured by a 10-cm Visual Analogue Scale (VAS)
A, Proportion of patients with at least 50% pain relief on a VAS from baseline or lower limb pain of 3 cm or less using the VAS at 1, 3, and 6 months for conventional medical management (CMM) and 10-kHz spinal cord stimulation (SCS) plus CMM. B, Mean lower limb pain scores on the VAS over time for 93 patients in the CMM group and 87 patients in the 10-kHz SCS plus CMM group. Error bars indicate 95% CIs. C, Individual pain response. Each line represents the change in a single patient’s lower limb pain VAS score at 6 months relative to baseline for 93 patients in the CMM group and 87 in the 10-kHz SCS plus CMM group. The dotted blue line represents the threshold for treatment responders of at least 50% pain relief. In the CMM group, 5% of patients were responders compared with 85% of patients in the 10-kHz SCS plus CMM group (orange boxes).
Figure 3.
Figure 3.. Changes in Neurological Assessment and Quality of Pain
A, Proportion of patients with clinically meaningful improvement in motor, sensory, or reflex neurological examination scores and without a clinically meaningful deficit in any category as determined by the investigator at 6 months compared with baseline for 92 patients in the conventional medical management (CMM) group and 84 in the 10-kHz spinal cord stimulation (SCS) plus CMM group. B, Distribution of patients over time with Douleur Neuropathique (DN4) score of less than 3 and 3 or more for 91 patients in the CMM group and 84 in the 10-kHz SCS plus CMM group. DN4 score measures the severity of neuropathic pain. C, Mean Short-Form McGill Pain Questionnaire (SF-MPQ-2) scores for each subscale at baseline and 6 months for 93 patients in the CMM group and 87 in the 10-kHz SCS plus CMM group. SF-MPQ-2 is a patient-reported measure of the intensity of pain descriptors. Error bars indicate 95% CIs.
Figure 4.
Figure 4.. Health-Related Quality of Life Outcomes and Patient Satisfaction
A, Mean EuroQol 5-Dimension Questionnaire (EQ-5D-5L) overall health visual analogue scale (VAS) score (left) and index score (right) for 92 patients in the conventional medical management (CMM) group and 87 in the 10-kHz spinal cord stimulation (SCS) plus CMM group from baseline to 6 months. The minimally important difference in index scores is estimated between 0.03 to 0.05. B, Mean scores for the Pain and Sleep Questionnaire assessing how often pain disturbs sleep. A score of 0 indicates never and a score of 10 indicates always. Scores are shown for 93 patients in the CMM group and 87 in the 10-kHz SCS plus CMM group. C, Mean scores on Global Assessment of Functioning at baseline and at 1, 3, and 6 months for 91 patients in the CMM group and 86 in the 10-kHz SCS plus CMM group. The Global Assessment of Functioning represents the physician’s evaluation of how much a patient’s symptoms affect psychological, social, and occupational functioning. D, Patient satisfaction with treatment at 6 months. Scores are shown for 93 patients in the CMM group and 87 in the 10-kHz SCS plus CMM group. Error bars indicate 95% CIs.
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