Intravenous Tapentadol in Post-Bunionectomy Pain

Study Overview
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Brief Summary
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The purpose of this trial is to established the safety and efficacy of multiple dose treatment with tapentadol IV in an adult population with moderate to severe pain following bunionectomy.

Official Title
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A Randomized, Double-blind, Placebo-controlled Parallel Group, Multicenter Trial to Evaluate the Efficacy and Safety of Multiple Dose Administration of an Intravenous Formulation of Tapentadol in the Treatment of Acute Pain Following Bunionectomy.

Conditions
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Bunion, Pain

Intervention / Treatment
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* Drug: Tapentadol
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled to undergo primary unilateral first metatarsal bunionectomy Female patients must be postmenopausal, surgically sterile, or practicing an effective method of birth control if they are sexually active Qualifying pain intensity (within a maximum of 5 hours after the last surgical stitch) and Baseline pain intensity (last pain score measured within 10 minutes before dosing) 5 on an 11-point (0 to 10) pain intensity numerical rating scale (NRS). Exclusion Criteria: History of malignancy within the past 2 years Current or history of alcohol or drug abuse. Clinically relevant pulmonary, gastrointestinal, endocrine, metabolic, neurological, psychiatric disorders (resulting in disorientation, memory impairment or inability to report accurately History of seizure disorder, epilepsy, or any condition that would put the subject at risk of seizures Severely impaired renal function Moderately or severely impaired hepatic function Contraindications, or a history of allergy or hypersensitivity, to tapentadol, ibuprofen, or excipients Use of prohibited concomitant medication, or not allowed use of restricted concomitant medication

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tapentadol intravenous<br>Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone. | Drug: Tapentadol<br>* 30 mg per administration, maximum 12 administrations over 48 hours<br>* Other names: Palexia, Nucynta;|
| Placebo Comparator: Matching placebo intravenous<br>Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain. | Drug: Matching Placebo<br>* Maximum 12 administrations over 48 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of Pain Intensity Differences (SPID 24) | Pain Intensity assessed at predefined time points (at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 20 and 24 hours after first drug administration) over a 24 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates no pain and a score of ten indicates pain as bad as you can imagine. Pain Intensity Differences at each predefined time point (calculated as post-baseline NRS values - baseline NRS values) were analyzed. Negative SPID24 values indicate a decrease in pain intensity and positive values indicate an increase in pain intensity since baseline. | Baseline value; up to 24 hours after first study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Pain Intensity Scores at Fixed Time Points | The mean pain intensity at fixed time points in the trial for all participants is listed. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. | Baseline; up to 48 hours | 
| Pain Intensity Differences at Fixed Time Points | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between baseline pain intensity (prior to the first dose) and the pain intensity at the time. A negative number indicates a decrease in pain in the whole treatment group. The greater the negative pain intensity difference value the greater the pain relief in the treatment arm. A score of 0 indicates that there has been no change in pain in a treatment group. A positive value indicates an increase in pain in the treatment group. | Starting at 15 minutes and up to 48 hours after first drug administration | 
| Patient Global Impression of Change After 12 Hours of Treatment | In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse). | Baseline value to 12 hours after first study drug administration | 
| Patients Global Impression of Change After 24 Hours of Treatment | In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse). | Baseline value to 24 hours after study drug administration | 
| Patient Global Impression of Change After 48 Hours of Treatment | In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse). | Baseline value to 48 hours after first study drug administration | 
| Sum of Pain Intensity Differences After 60 Minutes | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 60 minutes was calculated. If the value is negative then the baseline pain intensity was greater than the pain intensity measured after dosing. | Baseline value to 60 minutes after first study drug administration | 
| Sum of Pain Intensity Differences After 4 Hours | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 4 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing). | Baseline value to 4 hours after first study drug intake | 
| Sum of Pain Intensity Differences After 8 Hours | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 8 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing). | Baseline value to 8 hours after first study drug administration | 
| Sum of Pain Intensity Differences After 12 Hours | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 12 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing). | Baseline value to 12 hours after first study drug administration | 
| Sum of Pain Intensity Differences After 48 Hours | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 60 minutes was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing). | Baseline value to 48 hours after first study drug administration | 
| Number of Participants With 30% Response After 12 Hours, Based on Pain Intensity Scores | Individual participant response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 12 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value. | Baseline value to 12 hours after first study drug administration | 
| Number of Participants With 30% Response After 24 Hours, Based on Pain Intensity Scores | Individual participant response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 24 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value. | Baseline value to 24 hours after first study drug administration | 
| Number of Participants With 30% Response After 48 Hours, Based on Pain Intensity Scores | Individual participants response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 48 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value. | Baseline value to 48 hours after first study drug administration | 
| Number of Participants With 50% Response After 12 Hours, Based on Pain Intensity Scores | Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 12 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value. | Baseline value to 12 hours after first study drug administration | 
| Number of Participants With 50% Response After 24 Hours, Based on Pain Intensity Scores | Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 24 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value. | Baseline value to 24 hours after first study drug administration | 
| Number of Participants With 50% Response After 48 Hours, Based on Pain Intensity Scores | Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 48 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value. | Baseline value to 48 hours after first study drug administration | 
| Time to First Rescue Medication | The median time to first rescue medication intake (600 mg ibuprofen) in hours. | up to 48 hours | 
| Time to Perceptible Pain Relief | When the participant began to feel any pain-relieving effect after the administration of the first dose they were requested to stop the first stopwatch. The time was noted. This measured when the participant first felt any difference in the pain. | up to 48 hours | 
| Time to Meaningful Pain Relief | The participant was instructed to stop the stopwatch when they had meaningful pain relief. That is, when the pain relief made a real difference, after the first drug administration. | up to 48 hours | 
| Pharmacokinetic Concentrations of Tapentadol | Tapentadol concentrations were measured in participants in the tapentadol treatment arm. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL. | 15 minutes to 20 hours after first drug administration | 
| Pharmacokinetic Concentrations of Tapentadol-O-glucuronide | Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as breakdown products. The body alters the administered medication to a metabolite so that can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants in the tapentadol treatment arm. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL. | 15 minutes to 20 hours after first drug administration | 
| Mean Pain Intensity Scores at Relative Time- Tapentadol Randomized Participants | The pain intensity at the relative time points are the pain intensity before and one hour after study drug administration. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. | Baseline; for the first 6 administrations | 
| Mean Pain Intensity Scores at Relative Time - Matching Placebo Randomized Participants | The pain intensity at the relative time points are the pain intensity before and one hour after study drug administration. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. | Baseline; for the first 6 administrations | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bunionectomy, Postsurgical Pain, Acute Pain