Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS): Bayesian Adaptive Comparative Effectiveness Randomized Trial

Richard J. Barohn, Byron Gajewski, Mamatha Pasnoor, Alexandra Brown, Laura L. Herbelin, Kim S. Kimminau, Dinesh Pal Mudaranthakam, Omar Jawdat, Mazen M. Dimachkie, Stanley Iyadurai, Amro Stino, John Kissel, Robert Pascuzzi, Thomas Brannagan, Matthew Wicklund, Aiesha Ahmed, David Walk, Gordon Smith, Dianna Quan, Darryl HeitzmanAlejandro Tobon, Shafeeq Ladha, Gil Wolfe, Michael Pulley, Ghazala Hayat, Yuebing Li, Pariwat Thaisetthawatkul, Richard Lewis, Suur Biliciler, Khema Sharma, Kian Salajegheh, Jaya Trivedi, William Mallonee, Ted Burns, Mark Jacoby, Vera Bril, Tuan Vu, Sindhu Ramchandren, Mark Bazant, Sara Austin, Chafic Karam, Yessar Hussain, Christen Kutz, Paul Twydell, Stephen Scelsa, Hani Kushlaf, James Wymer, Michael Hehir, Noah Kolb, Jeffrey Ralph, Alexandru Barboi, Navin Verma, Moiz Ahmed, Anza Memon, David Saperstein, Jau Shin Lou, Andrea Swenson, Tiyonnoh Cash

Research output: Contribution to journalArticlepeer-review

Abstract

Importance: Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective: To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants: From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment's sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions: Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures: The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results: Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance: This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration: ClinicalTrials.gov Identifier: NCT02260388.

Original languageEnglish (US)
Pages (from-to)68-76
Number of pages9
JournalJAMA Neurology
Volume78
Issue number1
DOIs
StatePublished - Jan 1 2021

Bibliographical note

Funding Information:
reported receiving grants from Patient-Centered Outcomes Research Institute (PCORI) during the conduct of the study. Dr Gajewski reported receiving grants from PCORI during the conduct of the study; and grants from the National Institutes of Health (NIH) outside the submitted work. Dr Pasnoor reported receiving grants from PCORI during the conduct of the study; and personal fees from CSL Behring, Argenx, catalyst, and Momenta outside the submitted work. Ms Brown reported receiving grants from PCORI and the NIH during the conduct of the study. Dr Herbelin reported a patent issued. Dr Dimachkie reported receiving grants from PCORI during the conduct of the study. Dr A. Ahmed reported other from Biogen and other from Sanofi outside the submitted work. Dr Walk reported other from University of Kansas during the conduct of the study. Dr Quan reported receiving grants from PCORI during the conduct of the study; and grants from Pfizer outside the submitted work. Dr Pulley reported receiving personal fees from CSL Behring, Grifols, Stealth Biotherapeutcs, Bio Products Laboratory, Catalyst Pharmaceuticals, and Argenx outside the submitted work. Dr Lewis reported receiving personal fees from CSL Behring, Akcea, Alnylam, Annexon, Argenx, Biotest, Momenta, Pfizer, Sanofi, and Takeda outside the submitted work. Dr Salajegheh reported receiving grants from PCORI during the conduct of the study. Dr Bril reported receiving grants from PCORI during the conduct of the study. Dr Vu reported participating as the site principal investigator for clinical trials for CIDP, serving on the speaker bureau for CSL Behring, and serving as a consultant for BPL, Physicians Education Resource LLC, and Pharmacy Times. Dr Kushlaf reported receiving personal fees from Akcea, Sanofi Genzyme, Alexion, Catalyst Pharmaceuticals, and PTC Therapeutics outside the submitted work. Dr Wymer reported receiving grants from PCORI during the conduct of the study. Dr Hehir reported receiving grants from PCORI during the conduct of the study; and personal fees from Alexion Pharma, Argenx Pharma, and CSL Behring outside the submitted work. Dr Kolb reported receiving personal fees from Disarm Therapeutics outside the submitted work. No other disclosures were reported.

Funding Information:
Funding/Support: This study was supported by PCORI award: University of Kansas Medical Center CER-1306-02496 and NIH Clinical and Translational Science Award UL1TR002366.

Publisher Copyright:
© 2020 American Medical Association. All rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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