Tariquidar-ondansetron Combination in Neuropathic Pain

Phase 1

Completed

• Conditions: Neuropathic Pain
• Interventions: Drug: Ondansetron 16 mg with Placebo; Drug: Ondansetron 16 mg with Tariquidar

• Registration Number: NCT04603066
• Lead Sponsor: Washington University School of Medicine

Brief 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.

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 Timeline

• Study First Submitted: 2020-09-21
• Study First Submitted QC: 2020-10-22
• Study First Posted: 2020-10-26
• Study Start: 2021-01-31
• Primary Completion: 2023-10-21
• Status Verified: 2023-11
• Study Completion: 2023-11-03
• Last Update Submitted: 2023-11-06
• Last Update Posted: 2023-11-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Ondansetron + Placebo	Ondansetron 16 mg with Placebo	-
Ondansetron + Tariquidar	Ondansetron 16 mg with Tariquidar	-

Primary Outcome Measures

Name	Time	Method
Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron	up to 8 weeks following consent	Cerebrospinal fluid to plasma concentration ratio of ondansetron, compared between the two sessions, with placebo vs tariquidar
Concertation-time Profile of Ondansetron in Plasma	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 Penetration of Ondansetron - Area Under the Curve (AUC)	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 Outcome Measures

Name	Time	Method
Correlation between CPM Magnitude (ΔCPM) and Change in Pain Intensity	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 Pain Intensity	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.
Change in Neuropathic Pain Symptom Score	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
Conditioned Pain Modulation (CPM) Magnitude (ΔCPM)	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.

Trial Locations

Locations (1)

Washington University School of Medicine/Barnes-Jewish Hospital; 🇺🇸 Saint Louis, Missouri, United States