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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.
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ondansetron/Placebo first, then Ondansetron/Tariquidar | Other | The study group where patients received Ondansetron with Placebo during Visit 1, and after a washout period of 3 weeks Ondansetron with Tariquidar at Visit 2 per the randomization schedule. Ondansetron 16 mg was administered IV over 60 minutes with placebo (D5W) or with tariquidar (4mg/kg dose in D5W). Ondansetron was diluted in 100mL 0.9% normal saline, and tariquidar was diluted in 500mL D5W. |
|
| Ondansetron/Tariquidar first, then Ondansetron/Placebo | Other | The study group where patients received Ondansetron with Tariquidar during Visit 1, and after 3 weeks of washout period Ondansetron with Placebo at Visit 2 per the randomization schedule. Ondansetron 16 mg was administered IV over 60 minutes with tariquidar (4mg/kg dose in D5W) or with placebo (D5W). Ondansetron was diluted in 100mL 0.9% normal saline, and tariquidar was diluted in 500mL D5W. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ondansetron 16 mg with Tariquidar | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Concertation-time Profile of Ondansetron in Plasma, Measured by the Area Under the Concentration-time Curve (AUC) | AUCinf for Ondansetron concentration in plasma based on venous blood sampling for plasma concentrations of ondansetron obtained at 0, 15, 30, 60, 90, 120, 180, and 240 minutes from the beginning of ondansetron infusion. | Measurements over 240 minutes, extrapolated to infinity |
| Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron | The level of ondansetron in plasma and CSF (cerebrospinal fluid) in samples, taken around the same time, was measured, and the ratio of the two values was calculated. This ratio (partition coefficient, Kp) of ondansetron, compared between the two sessions, with placebo vs tariquidar | anytime between 0-240 minutes |
| Measure | Description | Time Frame |
|---|---|---|
| % Change in Pain Intensity | Change in spontaneous pain intensity (measured on a 0-10 numerical rating scale; 0=no pain, 10=worst imaginable pain) from baseline to 90 minutes after ondansetron IV infusion, compared between two sessions with and without tariquidar. Values are presented as a percentage change from baseline. | baseline to 90 minutes after ondansetron IV infusion |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Simon Haroutounian, PhD | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine/Barnes-Jewish Hospital | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27115670 | Background | 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. | |
| 20849570 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Ondansetron/Placebo First, Then Ondasetron/Tariquidar | The study group where patients received Ondansetron with Placebo during Visit 1, and after a washout period of 3 weeks Ondansetron with Tariquidar at Visit 2 per the randomization schedule. Ondansetron 16 mg was administered IV over 60 minutes with placebo (D5W) or with tariquidar (4mg/kg dose in D5W). Ondansetron was diluted in 100mL 0.9% normal saline, and tariquidar was diluted in 500mL D5W. |
| FG001 | Ondansetron/Tariquidar First, Then Ondansetron/Placebo | The study group where patients received Ondansetron with Tariquidar during Visit 1, and after 3 weeks of washout period Ondansetron with Placebo at Visit 2 per the randomization schedule. Ondansetron 16 mg was administered IV over 60 minutes with tariquidar (4mg/kg dose in D5W) or with placebo (D5W). Ondansetron was diluted in 100mL 0.9% normal saline, and tariquidar was diluted in 500mL D5W. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Visit 1 |
| |||||||||||||
| Wash-out (3 Weeks) |
| |||||||||||||
| Visit 2 |
|
Data from 24 enrolled patients were used in baseline analysis.
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| ID | Title | Description |
|---|---|---|
| BG000 | Ondansetron With Tariquidar First, Then Ondansetron With Placebo | The study group where patients received Ondansetron with Tariquidar during Visit 1, and Ondansetron with Placebo at Visit 2 per the randomization schedule. The washout period between two visits was 3 weeks. Ondansetron 16 mg was administered IV over 60 minutes with tariquidar (4mg/kg dose in D5W) or with placebo (D5W). Ondansetron was diluted in 100mL 0.9% normal saline, and tariquidar was diluted in 500mL D5W. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Concertation-time Profile of Ondansetron in Plasma, Measured by the Area Under the Concentration-time Curve (AUC) | AUCinf for Ondansetron concentration in plasma based on venous blood sampling for plasma concentrations of ondansetron obtained at 0, 15, 30, 60, 90, 120, 180, and 240 minutes from the beginning of ondansetron infusion. | participants who completed both sessions | Posted | Mean | Standard Deviation | mg*hr/L | Measurements over 240 minutes, extrapolated to infinity |
|
6 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ondansetron + Tariquidar | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA | Systematic Assessment |
Due to ethical considerations, cerebrospinal fluid (CSF) sampling was optional in the study, therefore data on plasma/CSF ratio is not available for all patients.
A total of 24 patients were enrolled out of 28 participant planned.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Simon Haroutounian | Washington University in St Louis | 3132861715 | sharout@wustl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 21, 2022 | Nov 11, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D009437 | Neuralgia |
| ID | Term |
|---|---|
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D010146 | Pain |
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| ID | Term |
|---|---|
| D017294 | Ondansetron |
| C402343 | tariquidar |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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Prospective, randomized, double blind, crossover study
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|
|
| Ondansetron 16 mg with Placebo | Drug | 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. |
|
|
| Conditioned Pain Modulation (CPM) Magnitude (ΔCPM) | Conditioned Pain Modulation (CPM) is a psychophysical test to assess the efficiency of descending pain inhibition. CPM is calculated as difference in heat pain threshold with and without pain conditioning - i.e. immersion of a hand in cold water. Conditioned Pain Modulation (CPM) Negative CPM values represent efficient pain modulation/inhibition. This test was administered at baseline, and again 90-min after the end of ondansetron infusion. CPM values can range from -100 to 100, CPM<0 (i.e. decreased pain to heat stimulus following conditioning) implies descending pain inhibition. CPM Magnitude (ΔCPM) is the calculated by subtracting the measurement of CPM at baseline [possible range of CPM scores 0-100] from the measurement of CPM 90 min after the intervention [possible range of CPM scores 0-100]. A larger negative ΔCPM value indicates increased pain modulation efficiency following treatment, and therefore, a desired outcome. | Baseline and 90 minutes after the end of ondansetron infusion |
| 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. | 0-240 min from infusion |
| Change in Neuropathic Pain Symptom Inventory (NPSI) Score | Changes in the Neuropathic Pain Symptom Inventory (NPSI) total score will be compared between treatment sessions. NPSI is a questionnaire used to assess and quantify neuropathic pain by asking patients to rate the severity of different pain sensations on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. The version administered in the study consists of seven questions, each rated on a scale from 0 to 10, with the total score being the sum of all ratings. The possible range of the NPSI score of the version administered in the study is 70, and, since we measure the difference in scores, the changes in the NPSI score of the version administered in the study is -70 to 70. Higher NPSI scores indicate more severe neuropathic pain symptoms. Since the analysis is conducted on changes in NPSI scores from baseline, a more negative value corresponds to a greater reduction in neuropathic pain symptoms following treatment. | baseline to 70 min after infusion |
| 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. |
| 22395856 | Background | 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. |
| NOT COMPLETED |
|
|
| NOT COMPLETED |
|
| BG001 | Ondansetron With Placebo First, Then Ondansetron With Tariquidar | The study group where patients received Ondansetron with Placebo during Visit 1, and Ondansetron with Tariquidar at Visit 2 per the randomization schedule. The washout period between two visits was 3 weeks. Ondansetron 16 mg was administered IV over 60 minutes with placebo (D5W) or with tariquidar (4mg/kg dose in D5W). Ondansetron was diluted in 100mL 0.9% normal saline, and tariquidar was diluted in 500mL D5W. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Ondansetron + Placebo | 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. |
|
|
|
| Primary | Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron | The level of ondansetron in plasma and CSF (cerebrospinal fluid) in samples, taken around the same time, was measured, and the ratio of the two values was calculated. This ratio (partition coefficient, Kp) of ondansetron, compared between the two sessions, with placebo vs tariquidar | Participant who had both CSF and plasma samples drawn at the same time, at both sessions. | Posted | Mean | Standard Error | ratio | anytime between 0-240 minutes |
|
|
|
|
| Secondary | % Change in Pain Intensity | Change in spontaneous pain intensity (measured on a 0-10 numerical rating scale; 0=no pain, 10=worst imaginable pain) from baseline to 90 minutes after ondansetron IV infusion, compared between two sessions with and without tariquidar. Values are presented as a percentage change from baseline. | All patients who received both treatments, excluding pharmacokinetic outlier (patient N 06) | Posted | Mean | Standard Deviation | % change from baseline | baseline to 90 minutes after ondansetron IV infusion |
|
|
|
| Secondary | Conditioned Pain Modulation (CPM) Magnitude (ΔCPM) | Conditioned Pain Modulation (CPM) is a psychophysical test to assess the efficiency of descending pain inhibition. CPM is calculated as difference in heat pain threshold with and without pain conditioning - i.e. immersion of a hand in cold water. Conditioned Pain Modulation (CPM) Negative CPM values represent efficient pain modulation/inhibition. This test was administered at baseline, and again 90-min after the end of ondansetron infusion. CPM values can range from -100 to 100, CPM<0 (i.e. decreased pain to heat stimulus following conditioning) implies descending pain inhibition. CPM Magnitude (ΔCPM) is the calculated by subtracting the measurement of CPM at baseline [possible range of CPM scores 0-100] from the measurement of CPM 90 min after the intervention [possible range of CPM scores 0-100]. A larger negative ΔCPM value indicates increased pain modulation efficiency following treatment, and therefore, a desired outcome. | All patients who completed both CPM procedures | Posted | Mean | Standard Error | score on a scale of 0-100 | Baseline and 90 minutes after the end of ondansetron infusion |
|
|
|
| Secondary | 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. | All patients who completed CPM and reported spontaneous pain intensity at corresponding time points | Posted | Number | r2 | 0-240 min from infusion |
|
|
|
| Secondary | Change in Neuropathic Pain Symptom Inventory (NPSI) Score | Changes in the Neuropathic Pain Symptom Inventory (NPSI) total score will be compared between treatment sessions. NPSI is a questionnaire used to assess and quantify neuropathic pain by asking patients to rate the severity of different pain sensations on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. The version administered in the study consists of seven questions, each rated on a scale from 0 to 10, with the total score being the sum of all ratings. The possible range of the NPSI score of the version administered in the study is 70, and, since we measure the difference in scores, the changes in the NPSI score of the version administered in the study is -70 to 70. Higher NPSI scores indicate more severe neuropathic pain symptoms. Since the analysis is conducted on changes in NPSI scores from baseline, a more negative value corresponds to a greater reduction in neuropathic pain symptoms following treatment. | Posted | Mean | Standard Error | units on a scale | baseline to 70 min after infusion |
|
|
|
| 0 |
| 23 |
| 0 |
| 23 |
| 12 |
| 23 |
| EG001 | Ondansetron + Placebo | 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. | 0 | 24 | 0 | 24 | 19 | 24 |
| Metallic Taste | Gastrointestinal disorders | MedDRA | Systematic Assessment | Dysgeusia (Change in taste) |
|
| Constipation | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Drowsiness | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Nausea | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Dry Mouth | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA | Systematic Assessment | specifically facial tingling |
|
| Dizziness | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA | Systematic Assessment | Vasovagal response (syncope) during needle placement |
|
| Infusion site bruising | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment | Pain/bruising/burning at infusion site |
|
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| D009461 |
| Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D002227 |
| Carbazoles |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006575 | Heterocyclic Compounds, 3-Ring |