Efficacy and Safety of IV Diclofenac (DIV075V)for Pain After Elective Orthopedic Surgery

Study Overview
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Brief Summary
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This study will compare repeated intermittent IV dosing of diclofenac in patient with moderate to severe post-surgical pain from elective orthopedic surgery.

Detailed Description
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The primary objective is to evaluate the analgesic efficacy and safety of three dosage levels of parenteral diclofenac in providing pain relief as compared to placebo or Ketorolac tromethamine.

Official Title
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Randomized, Double-Blind, Active-and Placebo-Controlled Study of the Analgesic Efficacy and Safety of Repeated Dosing of DIC075V Versus Parenteral Ketorolac and Placebo in Acute Post-Operative Pain After Elective Orthopedic Surgery

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: IV Diclofenac
* Drug: IV ketorolac
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled within three weeks of the screening visit to undergo elective orthopedic surgery. Moderate to severe pain within 6 hours following completion of the required surgery. Exclusion Criteria: Chronic pain conditions. Chronic disease or recent cardiovascular events. Known allergy or hypersensitivity to the active compounds or any of the excipients used in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>DIC075V (IV diclofenac) | Drug: IV Diclofenac<br>* IV Diclofenac q6h<br>|
| Active Comparator: B<br>IV Ketorolac | Drug: IV ketorolac<br>* IV ketorolac q6h<br>|
| Placebo Comparator: C<br>Placebo | Drug: Placebo<br>* Placebo q6h<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of the Pain Intensity Differences (SPID) Over 24 Hours | Pain intensity was measured on VAS (from 0 mm to 100 mm: 0 = no pain, 100 = worst possible pain). For each post dose time point, pain intensity difference (PID) is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. SPIDs was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 24 hours ranges from -2400 to 2400. A higher value indicates a better pain reduction. | Over 24 hours post first dose | 
| Sum of the Pain Intensity Differences (SPID) Over 48 Hours | Pain intensity was measured on VAS (from 0 mm to 100 mm: 0 = no pain, 100 = worst possible pain). For each post dose time point, PID is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. SPIDs was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 48 hours ranges from -4800 to 4800. A higher value indicates a better pain reduction. | Over 48 hours post first dose | 
| Sum of the Pain Intensity Differences (SPID) Over 72 Hours | Pain intensity was measured on VAS (from 0 mm to 100 mm: 0 = no pain, 100 = worst possible pain). For each post dose time point, PID is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. SPIDs was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 72 hours ranges from -7200 to 7200. A higher value indicates a better pain reduction. | Over 72 hours post first dose | 
| Sum of the Pain Intensity Differences (SPID) Over 96 Hours | Pain intensity was measured on VAS (from 0 mm to 100 mm: 0 = no pain, 100 = worst possible pain). For each post dose time point, PID is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. SPIDs was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 96 hours ranges from -9600 to 9600. A higher value indicates a better pain reduction. | Over 96 hours post first dose | 
| Sum of the Pain Intensity Differences (SPID) Over 120 Hours | Pain intensity was measured on VAS (from 0 mm to 100 mm: 0 = no pain, 100 = worst possible pain). For each post dose time point, PID is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. SPIDs was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 120 hours ranges from -12000 to 12000. A higher value indicates a better pain reduction. | Over 120 hours post first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Intensity Differences (PID) Over Time | Pain intensity was measured on VAS (from 0 mm to 100 mm: 0 = no pain, 100 = worst possible pain). For each post dose time point, PID is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). PID score range at any post dose (post baseline) evaluation time point was -100 to 100. A positive difference score is indicative of improvement. | Baseline (0 hour), 5, 10, 15, 30, 45 minutes post first dose, 1, 2, 3, 5, 6, 9, 12, 15, 18, 21, 24, 48, 72, 96, 120 hours post first dose | 
| Percentage of Participants Attaining Greater Than or Equal to (>=) 30 Percent (%) Reduction From Baseline in Pain Intensity | Pain intensity was measured on a 0 to 100 mm VAS, larger values indicate greater pain intensity. In this outcome measure, percentage of participants attaining >= 30 % reduction in pain intensity from baseline to specified time points was reported. | Baseline (0 hour), 5, 30 minutes post first dose, 1, 24, 48, 72, 90, 120 hours post first dose | 
| Total Pain Relief (TOTPAR) | Pain relief values at specified time points were measured on a 0 to 100 mm VAS, where higher values indicate greater pain relief. TOTPAR over specified time interval was calculated as area under pain relief curve over specified time intervals using trapezoidal approximation. For 0-24 hours score range was 0-2400, for 0-48 hours score range was 0- 4800, for 0-96 hours score range was 0-9600 and for 0-120 hours score range was 0-12000. Higher TOTPAR values indicated more relief. | 0-24, 0-48, 0-72, 0-96 and 0-120 hours post first dose | 
| Visual Analog Pain Relief Values Over the Time | Pain relief values at specified time points were measured on a 0 to 100 mm VAS, where higher values indicate greater pain relief. | 5, 10, 15, 30, 45 minutes post first dose, 1, 2, 3, 5, 6, 9, 12, 15, 18, 21, 24, 48, 72, 96, 120 hours post first dose | 
| Time From Administration of Study Drug to Administration of Rescue Medication | Time from administration of study drug to administration of rescue medication were censored at time of last pain assessment for participants who did not receive rescue medication. Rescue medication was additional pain medication, available to participants if they did not receive pain relief from the study drug. Rescue medication available during this study was IV morphine. | Maximum up to 5 days | 
| Cumulative Amount of Rescue Medication | In this outcome measure, cumulative amount of rescue medication used over 0-24, 0-48, 0-72, 0-96, and 0-120 hours were reported. Rescue medication was additional pain medication, available to participants if they did not receive pain relief from the study drug. Rescue medication available during this study was IV morphine. | 0-24, 0-48, 0-72, 0-96 and 0-120 hours | 
| Number of Participants According to Frequency of Use of Rescue Medication | In this outcome measure, number of participants are reported according to number of times they received rescue medication. Rescue medication was additional pain medication, available to participants if they did not receive pain relief from the study drug. Rescue medication available during this study was IV morphine. Only those categories with at least one nonzero value are reported. | 0-24, 0-48, 0-72, 0-96 and 0-120 hours post first dose | 
| Participant Global Evaluation Over Time | Participants global evaluation of study medication was accessed on a scale ranging from scale 0 to 4 where 0= poor, 1= fair, 2= good, 3= very good, 4= excellent where higher score represented better outcome. | 0-24, 0-48, 0-120 hours post-dose | 
| Time to Perceptible Relief | Participants were instructed to stop the first stopwatch at the onset of perceptible pain relief after first dose. Event times of participants not reporting perceptible relief were censored at 6 hours; event times of participants who withdrew or were administered rescue medication were censored at time of withdrawal or rescue. Kaplan-Meier estimate was used for analysis. | Within 6 hours of first dose on Day 1 | 
| Time to Meaningful Relief | Participants were instructed to stop the second stopwatch at the onset of meaningful pain relief after first dose. Event times of participants not reporting meaningful relief were censored at 6 hours; event times of participants who withdrew or were administered rescue medication were censored at time of withdrawal or rescue. Kaplan-Meier estimate was used for analysis. | Within 6 hours of first dose on Day 1 |