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Tariquidar-ondansetron Combination in Neuropathic Pain

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ClinicalTrials.gov Identifier: NCT04603066
Recruitment Status : Recruiting
First Posted : October 26, 2020
Last Update Posted : May 3, 2023
Sponsor:
Information provided by (Responsible Party):
simon.haroutounian, Washington University School of Medicine

Study Description
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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.


Condition or disease Intervention/treatment Phase
Neuropathic Pain Drug: Ondansetron 16 mg with Tariquidar Drug: Ondansetron 16 mg with Placebo Phase 1 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Prospective, randomized, double blind, crossover study
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Administration of Ondansetron With P-glycoprotein Inhibitor Tariquidar in Patients With Neuropathic Pain
Actual Study Start Date : January 31, 2021
Estimated Primary Completion Date : October 2023
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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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.


Outcome Measures
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Primary Outcome Measures :
  1. 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)

  2. 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

  3. 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 Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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;
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04603066


Contacts
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Contact: Karen Frey 314 454-5980 freyk@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine/Barnes-Jewish Hospital Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Karen Frey    314-454-5980    freyk@wustl.edu   
Principal Investigator: Simon Haroutounian, PhD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Simon Haroutounian, PhD Washington University School of Medicine
More Information
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Publications:

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Responsible Party: simon.haroutounian, Associate Professor, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT04603066    
Other Study ID Numbers: 202008183
First Posted: October 26, 2020    Key Record Dates
Last Update Posted: May 3, 2023
Last Verified: April 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neuralgia
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Pain
Neurologic Manifestations
Ondansetron
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
 Physiological Effects of Drugs
Gastrointestinal Agents
Antipruritics
Dermatologic Agents
Serotonin 5-HT3 Receptor Antagonists
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action