Tariquidar-ondansetron Combination in Neuropathic Pain

Administration of Ondansetron With P-glycoprotein Inhibitor Tariquidar in Patients With Neuropathic Pain

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.

Study Overview

• Status: Completed
• Conditions: Neuropathic Pain
• Intervention / Treatment: Drug: Ondansetron 16 mg with Tariquidar; Drug: Ondansetron 16 mg with Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Karen Frey; Phone Number: 314 454-5980; Email: freyk@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine/Barnes-Jewish Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ondansetron + Tariquidar	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.
Placebo Comparator: Ondansetron + Placebo	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concertation-time Profile of Ondansetron in Plasma	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)	up to 8 weeks following consent
Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron	Cerebrospinal fluid to plasma concentration ratio of ondansetron, compared between the two sessions, with placebo vs tariquidar	up to 8 weeks following consent
Cerebrospinal Fluid Penetration of Ondansetron - Area Under the Curve (AUC)	Cerebrospinal fluid penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with placebo vs tariquidar	up to 8 weeks following consent

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pain Intensity	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.	up to 8 weeks following consent
Conditioned Pain Modulation (CPM) Magnitude (ΔCPM)	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.	up to 8 weeks following consent
Correlation between CPM Magnitude (ΔCPM) and Change in Pain Intensity	The association between baseline Conditioned Pain Modulation (CPM) magnitude (ΔCPM) and the % pain reduction from baseline will be determined by bivariate regression.	up to 8 weeks following consent
Change in Neuropathic Pain Symptom Score	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	up to 8 weeks following consent

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Simon Haroutounian, PhD, Washington University School of Medicine

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2021
• Primary Completion (Actual): October 21, 2023
• Study Completion (Actual): November 3, 2023

Study Registration Dates

• First Submitted: September 21, 2020
• First Submitted That Met QC Criteria: October 22, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Estimated): November 8, 2023
• Last Update Submitted That Met QC Criteria: November 6, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Serotonin Agents; Serotonin Antagonists; Serotonin 5-HT3 Receptor Antagonists; Antipruritics; Ondansetron
• Other Study ID Numbers: 202008183

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No