Tariquidar-ondansetron Combination in Neuropathic Pain

Overview

Prospective, randomized, double-blind, placebo controlled, cross-over proof of concept study. To determine the pharmacokinetics and tolerability of co-administration of 5-HT3R antagonist ondansetron with a P-glycoprotein inhibitor tariquidar, in patients with neuropathic pain.

Full Title of Study: “Administration of Ondansetron With P-glycoprotein Inhibitor Tariquidar in Patients With Neuropathic Pain”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 2023

Detailed Description

The investigators hypothesize that co-administration of a 5-HT3 receptor antagonist ondansetron (single 16mg dose) with p-glycoprotein inhibitor tariquidar (single 4mg/kg dose) vs placebo in a cross-over prospective randomized study, will: 1. Be tolerable in patients with neuropathic pain. 2. Increase the cerebrospinal fluid (CSF) to plasma ratio of ondansetron after intravenous administration, compare to ondansetron alone 3. Result in a greater reduction in pain intensity than with ondansetron alone.

Interventions

  • Drug: Ondansetron 16 mg with Tariquidar
    • In randomized order, each participant will receive two IV infusions of ondansetron, 3 weeks apart; one with placebo (D5W), and one with tariquidar (4mg/kg dose in D5W) administered IV over 60 minutes. Ondansetron will be diluted in 100mL 0.9% normal saline, and tariquidar will be diluted in 500mL D5W.
  • Drug: Ondansetron 16 mg with Placebo
    • In randomized order, each participant will receive two IV infusions of ondansetron, 3 weeks apart; one with placebo (D5W), and one with tariquidar (4mg/kg dose in D5W) administered IV over 60 minutes. Ondansetron will be diluted in 100mL 0.9% normal saline, and tariquidar will be diluted in 500mL D5W.

Arms, Groups and Cohorts

  • Experimental: Ondansetron + Tariquidar
  • Placebo Comparator: Ondansetron + Placebo

Clinical Trial Outcome Measures

Primary Measures

  • Concertation-time Profile of Ondansetron in Plasma
    • Time Frame: up to 8 weeks following consent
    • Venous blood sampling for plasma concentrations of ondansetron will be obtained: at 0, 15, 30, 60, 90, 120, 180, and 240 minutes from the beginning of ondansetron infusion, and compared between the two sessions (with placebo vs tariquidar)
  • Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron
    • Time Frame: up to 8 weeks following consent
    • Cerebrospinal fluid to plasma concentration ratio of ondansetron, compared between the two sessions, with placebo vs tariquidar
  • Cerebrospinal Fluid Penetration of Ondansetron – Area Under the Curve (AUC)
    • Time Frame: up to 8 weeks following consent
    • Cerebrospinal fluid penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with placebo vs tariquidar

Secondary Measures

  • Change in Pain Intensity
    • Time Frame: up to 8 weeks following consent
    • Change in spontaneous pain intensity (measured on 0-10 numerical rating scale; 0=no pain, 10=worst imaginable pain) from baseline to 60-120 minutes after ondansetron IV infusion, compared between two sessions with and without tariquidar.
  • Conditioned Pain Modulation (CPM) Magnitude (ΔCPM)
    • Time Frame: up to 8 weeks following consent
    • The difference between self-report intensity of pain (0-100 scale) as a response to a standard contact heat stimulus, compared to the same experiment performed with ice-water conditioning applied to the contralateral extremity. A larger negative value of CPM represents more efficient pain modulation.
  • Correlation between CPM Magnitude (ΔCPM) and Change in Pain Intensity
    • Time Frame: up to 8 weeks following consent
    • The association between baseline Conditioned Pain Modulation (CPM) magnitude (ΔCPM) and the % pain reduction from baseline will be determined by bivariate regression.
  • Change in Neuropathic Pain Symptom Score
    • Time Frame: up to 8 weeks following consent
    • Changes in Neuropathic Pain Symptom Inventory (NPSI) total score and sub-scores (burning pain, paroxysmal pain, paresthesia/dysesthesia score) will be compared between treatment sessions. Each subscore is scored on a 0-10 scale: 0=no symptom, 10=worst imaginable symptom

Participating in This Clinical Trial

Inclusion Criteria

1. Age 18-65; 2. Documented diagnosis of neuropathic pain due to damage or disease affecting the peripheral nervous system; 3. At least Probable neuropathic pain grading1; 4. Pain duration >3 months; 5. Average pain intensity ≥4 on 0-10 numerical rating scale (NRS). Exclusion Criteria:

1. Current pregnancy or lactation; 2. Moderate-severe kidney or liver dysfunction; 3. Active cardiac arrhythmias (non-sinus rhythm), Long QT syndrome, or QTc interval >450msec; 4. Congestive heart failure 5. Abnormal troponin values at screening visit; 6. Current treatment with MAO inhibitors, mirtazapine, SSRI antidepressants, or SNRI medications duloxetine or venlafaxine; 7. Current treatment with tapentadol, tramadol, or fentanyl; 8. Current treatment with P-glycoprotein substrate drugs with narrow therapeutic window, e.g. digoxin; 9. Current treatment with tricyclic antidepressant medications (e.g. amitriptyline, desipramine, imipramine) at a dose >25mg/day; 10. Ongoing use of any of the following medications with known effects on Pgp function: carbamazepine, phenytoin, phenobarbital, cyclosporine, clarithromycin, erythromycin, ritonavir, verapamil, rifampicin, St. John's wort; 11. Current treatment with QT-prolonging drugs, and drugs known to have a significant interaction with ondansetron or other P-glycoprotein substrates (see section 2.3.3.); 12. Current treatment with anticoagulant drugs;

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Washington University School of Medicine
  • Provider of Information About this Clinical Study
    • Principal Investigator: simon.haroutounian, Associate Professor – Washington University School of Medicine
  • Overall Official(s)
    • Simon Haroutounian, PhD, Principal Investigator, Washington University School of Medicine
  • Overall Contact(s)
    • Karen Frey, 314 454-5980, freyk@wustl.edu

References

Finnerup NB, Haroutounian S, Kamerman P, Baron R, Bennett DLH, Bouhassira D, Cruccu G, Freeman R, Hansson P, Nurmikko T, Raja SN, Rice ASC, Serra J, Smith BH, Treede RD, Jensen TS. Neuropathic pain: an updated grading system for research and clinical practice. Pain. 2016 Aug;157(8):1599-1606. doi: 10.1097/j.pain.0000000000000492.

Yawn BP, Wollan PC, Weingarten TN, Watson JC, Hooten WM, Melton LJ 3rd. The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population. Pain Med. 2009 Apr;10(3):586-93. doi: 10.1111/j.1526-4637.2009.00588.x. Epub 2009 Mar 17. Erratum In: Pain Med. 2011 Aug;12(8):1294.

Smith BH, Torrance N. Epidemiology of neuropathic pain and its impact on quality of life. Curr Pain Headache Rep. 2012 Jun;16(3):191-8. doi: 10.1007/s11916-012-0256-0.

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