Tariquidar-ondansetron Combination in Neuropathic Pain

Neuropathic Pain Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04603066
• Other study ID #: 202008183
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 31, 2021
• Est. completion date: November 3, 2023

Study information

• Verified date: November 2023
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: November 3, 2023
• Est. primary completion date: October 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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;

Related Conditions & MeSH terms

• Neuralgia
• Neuropathic Pain

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Washington University School of Medicine/Barnes-Jewish Hospital	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Cerebrospinal Fluid Penetration of Ondansetron - Area Under the Curve (AUC)	Cerebrospinal fluid penetration of intravenous ondansetron will be determined as AUCCSF0-8 of ondansetron, and compared between the two sessions, with placebo vs tariquidar	up to 8 weeks following consent
Secondary	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
Secondary	Conditioned Pain Modulation (CPM) Magnitude (?CPM)	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
Secondary	Correlation between CPM Magnitude (?CPM) and Change in Pain Intensity	The association between baseline Conditioned Pain Modulation (CPM) magnitude (?CPM) and the % pain reduction from baseline will be determined by bivariate regression.	up to 8 weeks following consent
Secondary	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