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

Erika A. Petersen; Thomas G. Stauss; James A. Scowcroft; Elizabeth S. Brooks; Judith L. White; Shawn M. Sills; Kasra Amirdelfan; Maged N. Guirguis; Jijun Xu; Cong Yu; Ali Nairizi; Denis G. Patterson; Kostandinos C. Tsoulfas; Michael J. Creamer; Vincent Galan; Richard H. Bundschu; Christopher A. Paul; Neel D. Mehta; Heejung Choi; Dawood Sayed; Shivanand P. Lad; David J. Dibenedetto; Khalid A. Sethi; Johnathan H. Goree; Matthew T. Bennett; Nathan J. Harrison; Atef F. Israel; Paul Chang; Paul W. Wu; Gennady Gekht; Charles E. Argoff; Christian E. Nasr; Rod S. Taylor; Jeyakumar Subbaroyan; Bradford E. Gliner; David L. Caraway; Nagy A. Mekhail

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^*, Thomas G. Stauss, James A. Scowcroft, Elizabeth S. Brooks, Judith L. White, Shawn M. Sills, Kasra Amirdelfan, Maged N. Guirguis, Jijun Xu, Cong Yu, Ali Nairizi, Denis G. Patterson, Kostandinos C. Tsoulfas, Michael J. Creamer, Vincent Galan, Richard H. Bundschu, Christopher A. Paul, Neel D. Mehta, Heejung Choi, Dawood SayedShivanand P. Lad, David J. Dibenedetto, Khalid A. Sethi, Johnathan H. Goree, Matthew T. Bennett, Nathan J. Harrison, Atef F. Israel, Paul Chang, Paul W. Wu, Gennady Gekht, Charles E. Argoff, Christian E. Nasr, Rod S. Taylor, Jeyakumar Subbaroyan, Bradford E. Gliner, David L. Caraway, Nagy A. Mekhail

^*Corresponding author for this work

Anesthesiology

Research output: Contribution to journal › Article › peer-review

163 Scopus citations

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 A_1c(HbA_1c) 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 HbA_1cover 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.

Original language	English (US)
Pages (from-to)	687-698
Number of pages	12
Journal	JAMA Neurology
Volume	78
Issue number	6
DOIs	https://doi.org/10.1001/jamaneurol.2021.0538
State	Published - Jun 2021

Funding

Funding/Support: This study was funded by Nevro Corp. 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

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Clinical Neurology

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10.1001/jamaneurol.2021.0538

Cite this

Petersen, E. A., Stauss, T. G., Scowcroft, J. A., Brooks, E. S., White, J. L., Sills, S. M., Amirdelfan, K., Guirguis, M. N., Xu, J., Yu, C., Nairizi, A., Patterson, D. G., Tsoulfas, K. C., Creamer, M. J., Galan, V., Bundschu, R. H., Paul, C. A., Mehta, N. D., Choi, H., ... Mekhail, N. A. (2021). Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients with Painful Diabetic Neuropathy: A Randomized Clinical Trial. JAMA Neurology, 78(6), 687-698. https://doi.org/10.1001/jamaneurol.2021.0538

@article{827d4b4383f14dd090da97b892769627,

title = "Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients with Painful Diabetic Neuropathy: A Randomized Clinical Trial",

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 HbA1cover 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.",

author = "Petersen, {Erika A.} and Stauss, {Thomas G.} and Scowcroft, {James A.} and Brooks, {Elizabeth S.} and White, {Judith L.} and Sills, {Shawn M.} and Kasra Amirdelfan and Guirguis, {Maged N.} and Jijun Xu and Cong Yu and Ali Nairizi and Patterson, {Denis G.} and Tsoulfas, {Kostandinos C.} and Creamer, {Michael J.} and Vincent Galan and Bundschu, {Richard H.} and Paul, {Christopher A.} and Mehta, {Neel D.} and Heejung Choi and Dawood Sayed and Lad, {Shivanand P.} and Dibenedetto, {David J.} and Sethi, {Khalid A.} and Goree, {Johnathan H.} and Bennett, {Matthew T.} and Harrison, {Nathan J.} and Israel, {Atef F.} and Paul Chang and Wu, {Paul W.} and Gennady Gekht and Argoff, {Charles E.} and Nasr, {Christian E.} and Taylor, {Rod S.} and Jeyakumar Subbaroyan and Gliner, {Bradford E.} and Caraway, {David L.} and Mekhail, {Nagy A.}",

note = "Funding Information: Funding/Support: This study was funded by Nevro Corp. Funding Information: 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 Publisher Copyright: {\textcopyright} 2021 American Medical Association. All rights reserved.",

year = "2021",

month = jun,

doi = "10.1001/jamaneurol.2021.0538",

language = "English (US)",

volume = "78",

pages = "687--698",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "6",

}

Petersen, EA, Stauss, TG, Scowcroft, JA, Brooks, ES, White, JL, Sills, SM, Amirdelfan, K, Guirguis, MN, Xu, J, Yu, C, Nairizi, A, Patterson, DG, Tsoulfas, KC, Creamer, MJ, Galan, V, Bundschu, RH, Paul, CA, Mehta, ND, Choi, H, Sayed, D, Lad, SP, Dibenedetto, DJ, Sethi, KA, Goree, JH, Bennett, MT, Harrison, NJ, Israel, AF, Chang, P, Wu, PW, Gekht, G, Argoff, CE, Nasr, CE, Taylor, RS, Subbaroyan, J, Gliner, BE, Caraway, DL & Mekhail, NA 2021, 'Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients with Painful Diabetic Neuropathy: A Randomized Clinical Trial', JAMA Neurology, vol. 78, no. 6, pp. 687-698. https://doi.org/10.1001/jamaneurol.2021.0538

TY - JOUR

T1 - Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients with Painful Diabetic Neuropathy

T2 - A Randomized Clinical Trial

AU - Petersen, Erika A.

AU - Stauss, Thomas G.

AU - Scowcroft, James A.

AU - Brooks, Elizabeth S.

AU - White, Judith L.

AU - Sills, Shawn M.

AU - Amirdelfan, Kasra

AU - Guirguis, Maged N.

AU - Xu, Jijun

AU - Yu, Cong

AU - Nairizi, Ali

AU - Patterson, Denis G.

AU - Tsoulfas, Kostandinos C.

AU - Creamer, Michael J.

AU - Galan, Vincent

AU - Bundschu, Richard H.

AU - Paul, Christopher A.

AU - Mehta, Neel D.

AU - Choi, Heejung

AU - Sayed, Dawood

AU - Lad, Shivanand P.

AU - Dibenedetto, David J.

AU - Sethi, Khalid A.

AU - Goree, Johnathan H.

AU - Bennett, Matthew T.

AU - Harrison, Nathan J.

AU - Israel, Atef F.

AU - Chang, Paul

AU - Wu, Paul W.

AU - Gekht, Gennady

AU - Argoff, Charles E.

AU - Nasr, Christian E.

AU - Taylor, Rod S.

AU - Subbaroyan, Jeyakumar

AU - Gliner, Bradford E.

AU - Caraway, David L.

AU - Mekhail, Nagy A.

N1 - Funding Information: Funding/Support: This study was funded by Nevro Corp. Funding Information: 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 Publisher Copyright: © 2021 American Medical Association. All rights reserved.

PY - 2021/6

Y1 - 2021/6

N2 - 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 HbA1cover 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.

AB - 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 HbA1cover 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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ER -

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

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