Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS)

Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS)

The purpose of this large comparative effectiveness study led by Richard J. Barohn, MD, of the University of Kansas Medical Center, is to learn about the safety and effectiveness of nortriptyline, duloxetine, pregabalin and mexiletine in treating cryptogenic sensory polyneuropathy (CSPN).

Study Overview

• Status: Completed
• Conditions: Cryptogenic Sensory Polyneuropathy
• Intervention / Treatment: Drug: Duloxetine; Drug: Pregabalin; Drug: Nortriptyline; Drug: Mexiletine

Detailed Description

The goal of this research project is to find the best drug for the treatment of pain in patients with CSPN. While the pharmaceutical industry has focused attention on drugs for treating diabetic sensory neuropathy (DSPN), and two drugs are now FDA approved, there have not been any prospective trials in CSPN. And, because there are no studies with CSPN patients, insurance carriers often reject authorizing prescriptions for some drugs for patients with CSPN.

There are four drugs that will be tested in this study: nortriptyline, duloxetine, pregabalin and mexiletine. These drugs are not approved by the FDA for the treatment of CSPN and are considered "investigational" in this study.

There are two periods in this study: Screening/Baseline and Study Drug. During the Screening/Baseline period the researchers will determine eligibility for potential subjects. During the second period, eligible patients who consented to participate will take the study drug. Participants will be randomized to receive one of the four drugs in this study. Participants will know which drug they are taking. Participants will not be allowed to switch groups and receive a different drug during the study.

This study uses an adaptive study design. This means the study can enroll less participants and provide better conclusions. The study design allows the researchers the ability to make changes to the approach of the study or to stop the study early if there are strong results.

• Study Type: Interventional
• Enrollment (Actual): 402
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
    • Phoenix, Arizona, United States, 85018
      • Phoenix Neurological Associates
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • San Francisco, California, United States, 94107
      • California Pacific Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver Anschutz Campus
    • Colorado Springs, Colorado, United States, 80907
      • Colorado Springs Neurological Associates
  • Florida
    • Gainesville, Florida, United States, 10236
      • University of Florida - Gainesville
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Science Center - Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
    • Orlando, Florida, United States, 32806
      • Neurological Services of Orlando Research
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Illinois
    • Glenview, Illinois, United States, 60026
      • NorthShore Neurological Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Mercy Medical Center - Des Moines
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kansas
    • Hutchinson, Kansas, United States, 67502
      • Hutchinson Clinic, Pa
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Neurology Services
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Grand Rapids, Michigan, United States, 49525
      • Spectrum Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63103
      • Saint Louis University
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • Buffalo, New York, United States, 14203
      • University of Buffalo School of Medicine and Biomedical Sciences
    • New York, New York, United States, 10029
      • Mount Sinai Beth Israel
  • Ohio
    • Cincinnati, Ohio, United States, 45221
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Medical Center
  • Texas
    • Austin, Texas, United States, 78703
      • Austin Neuromuscular Center
    • Austin, Texas, United States, 78705
      • Sara Austin, MD, PA
    • Austin, Texas, United States, 78705
      • Seton Brain and Spine Institute
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Dallas, Texas, United States, 75214
      • Texas Neurology
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houton
    • Katy, Texas, United States, 77494
      • Grand Medical Clinic
    • New Braunfels, Texas, United States, 78132
      • Neurology Clinic of Central Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center in San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Vermont
    • Burlington, Vermont, United States, 05403
      • University of Vermont Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of cryptogenic sensory polyneuropathy.
• Likert Pain Score of greater than or equal to 4.
• Must not currently be on nortriptyline, duloxetine, pregabalin or mexiletine or similar class of medication for at least 7 days from baseline study visit.

Exclusion Criteria:

• Any medical condition or current medication that would prevent them from taking either nortriptyline, duloxetine, pregabalin or mexiletine.
• Unable to give consent.
• Unable or not willing to comply with the study.
• Other causes for polyneuropathy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nortriptyline; Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.	Drug: Nortriptyline
Experimental: Duloxetine; Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.	Drug: Duloxetine
Experimental: Pregabalin; Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.	Drug: Pregabalin
Experimental: Mexiletine; Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.	Drug: Mexiletine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit	The final outcome of the study is a combination of two endpoints, efficacy and quit or treatment discontinuation rates. The first endpoint was a patient responder-defined measure of efficacy. A patient was deemed efficacious if a 50% or more reduction was observed in the Likert pain-scale from the baseline visit to the 12 week visit (i.e. 6 at baseline to 3 or less at week 12). The second endpoint was the observed percentage of patients who discontinued treatment prior to the last follow up visit for any reason or were lost to follow up. The utility function, which combines efficacy and quit rates, was used to drive the adaptive randomization, stopping criteria, and final analysis conclusions.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SF12 Health Composite Scores	SF-12v2® Health Survey Standard The Optum™ SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses just 12 questions to measure functional health and well-being from the patient's point of view. Survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores. Scores are calibrated so that 50 is the average score or norm, standard deviation = 10. Higher scores indicate better health for both mental and physical component summary scores.	12 weeks
PROMIS Pain Interference Short Form v1.0 8a T Score	Higher scores for pain interference represents worse outcome (more pain interference) T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.	12 weeks
PROMIS Fatigue Short Form v1.0 8a	Higher scores for fatigue represents worse outcome (more fatigue). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.	12 Weeks
PROMIS Sleep Disturbance Short Form v1.0 8a	Higher scores for sleep disturbance represents worse outcome (more sleep disturbance). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population. Higher scores equals more of the concept being measured	12 weeks

Collaborators and Investigators

• Sponsor: University of Kansas Medical Center
• Collaborators: Patient-Centered Outcomes Research Institute

Publications and helpful links

General Publications

• Barohn RJ, Gajewski B, Pasnoor M, Brown A, Herbelin LL, Kimminau KS, Mudaranthakam DP, Jawdat O, Dimachkie MM; Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS) Study Team, Iyadurai S, Stino A, Kissel J, Pascuzzi R, Brannagan T, Wicklund M, Ahmed A, Walk D, Smith G, Quan D, Heitzman D, Tobon A, Ladha S, Wolfe G, Pulley M, Hayat G, Li Y, Thaisetthawatkul P, Lewis R, Biliciler S, Sharma K, Salajegheh K, Trivedi J, Mallonee W, Burns T, Jacoby M, Bril V, Vu T, Ramchandren S, Bazant M, Austin S, Karam C, Hussain Y, Kutz C, Twydell P, Scelsa S, Kushlaf H, Wymer J, Hehir M, Kolb N, Ralph J, Barboi A, Verma N, Ahmed M, Memon A, Saperstein D, Lou JS, Swenson A, Cash T. Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS): Bayesian Adaptive Comparative Effectiveness Randomized Trial. JAMA Neurol. 2021 Jan 1;78(1):68-76. doi: 10.1001/jamaneurol.2020.2590. Erratum In: JAMA Neurol. 2020 Nov 1;77(11):1453.
• Brown AR, Gajewski BJ, Aaronson LS, Mudaranthakam DP, Hunt SL, Berry SM, Quintana M, Pasnoor M, Dimachkie MM, Jawdat O, Herbelin L, Barohn RJ. A Bayesian comparative effectiveness trial in action: developing a platform for multisite study adaptive randomization. Trials. 2016 Aug 31;17(1):428. doi: 10.1186/s13063-016-1544-5.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): September 1, 2017

Study Registration Dates

• First Submitted: October 6, 2014
• First Submitted That Met QC Criteria: October 8, 2014
• First Posted (Estimate): October 9, 2014

Study Record Updates

• Last Update Posted (Actual): July 6, 2018
• Last Update Submitted That Met QC Criteria: June 6, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: pain; pain management; neuropathy; CSPN
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Polyneuropathies; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Anti-Anxiety Agents; Anticonvulsants; Serotonin and Noradrenaline Reuptake Inhibitors; Antidepressive Agents, Tricyclic; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Adrenergic Uptake Inhibitors; Duloxetine Hydrochloride; Pregabalin; Nortriptyline; Mexiletine
• Other Study ID Numbers: STUDY00001500; PCORI-1306-02496 (Other Grant/Funding Number: Patient-Centered Outcomes Research Institute)