A Safety And Efficacy Study of Ibuprofen 250 mg / Acetaminophen 500 mg In The Treatment Of Post-Surgical Dental Pain

Study Overview
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Brief Summary
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This is a randomized, double blind, placebo-controlled, parallel group, single-center study in approximately 560 subjects to determine the overall analgesic efficacy and safety of a fixed-dose ibuprofen 250 mg / acetaminophen 500 mg formulation compared to ibuprofen 250 mg alone, acetaminophen 650 mg alone, and to placebo. Subjects will be healthy males and females aged 18-40 years, inclusive, who are experiencing post-operative pain following surgical extraction of 3 or more third molar teeth. Following extraction, subjects must experience, within 5 hours, post-surgical pain of at least moderate severity (on a 4-point categorical scale), confirmed by a Visual Analog Pain Severity Rating Scale (VAS PSR) of at least 50 mm on a 100 mm VAS PSR scale. Eligible subjects will be randomized to receive a single oral dose of study medication under double-blind conditions and then evaluated on site for 12 hours following administration of study medication. Subjects will provide self-ratings of pain severity and pain relief at various time points using categorical and numerical scales. Additionally, subjects will also evaluate the time to first perceptible relief and time to meaningful relief using a double stopwatch method. Finally, at 12 hours, subjects will complete a categorical Global Evaluation of the study medication. A review of any reported adverse events will also be completed.

Detailed Description
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This is a 12-hour, 4-arm, randomized, double blind, placebo-controlled, parallel group, single-center study in approximately 560 subjects to determine the overall analgesic efficacy and safety of a fixed-dose ibuprofen 250 mg / acetaminophen 500 mg formulation (administered as two caplets of 125 mg/250 mg IBU/APAP) compared to ibuprofen 250 mg alone, acetaminophen 650 mg alone, and to placebo. Subjects will be healthy males and females aged 18-40 years, inclusive, otherwise healthy, who are experiencing post-operative pain following surgical extraction of 3 or more third molar teeth. Following extraction, subjects must experience, within 5 hours, post-surgical pain of at least moderate severity (on a 4-point categorical scale), confirmed by a Visual Analog Pain Severity Rating Scale (VAS PSR) of at least 50 mm on a 100 mm VAS PSR scale. Upon completion of the baseline scales, eligible subjects will be randomized to receive a single oral dose of study medication under double-blind conditions and then evaluated on site for 12 hours following administration of study medication. At 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours post dose time points, subjects will provide: self-ratings of pain severity using the numerical and categorical PSRs; and self-ratings of pain relief at each time point using a categorical pain relief rating scale. At 12 hours, subjects will also complete a 6-point categorical Global Evaluation of the study medication. Additionally, subjects will also evaluate the time to first perceptible relief and time to meaningful relief using a double stopwatch method up to 12 hours post-dose or until the time of first rescue medication use, whichever is sooner. A review of any reported adverse events will also be completed.

Official Title
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A Phase 3, Double-Blind, Randomized, Safety And Efficacy Study Comparing A Single Oral Dose Of Ibuprofen (IBU) 250 Mg/Acetaminophen (APAP) 500 Mg (Administered As Two Tablets Of IBU/APAP 125 Mg/250 Mg) To Each Active Drug Monocomponent Alone And To Placebo In The Treatment Of Post-Surgical Dental Pain

Conditions
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Post-surgical Pain Following Extraction of Molar Teeth

Intervention / Treatment
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* Drug: Ibuprofen 250 mg / Acetaminophen 500 mg
* Drug: Ibuprofen 250 mg
* Drug: Acetaminophen 650 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatients who have undergone surgical extraction of 3 or more third molars, of which at least 2 must be a partial or complete bony mandibular impaction. Subject must have at least moderate pain on the 4-point categorical scale, confirmed by at least 50 mm on the 100 mm VAS PSR scale within approximately 5 hours (i.e., less than or equal to 5 hours, 15 minutes) after surgery is completed. Female subjects are not pregnant or breast feeding. Informed consent. Exclusion Criteria: Presence or history of any significant hepatic, renal, endocrine, cardiovascular, neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic disorder determined by the Investigator to place the subject at increased risk, including the presence or history within 2 years of screening. Acute localized dental alveolar infection at the time of surgery that could confound the post-surgical evaluation. Hypersensitivity to ibuprofen, naproxen, aspirin, or any other NSAID; or to APAP, tramadol, other opioids, or to their combinations.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Ibuprofen 250 mg / Acetaminophen 500 mg<br>2 caplets of Ibuprofen 125 mg / Acetaminophen 250 mg | Drug: Ibuprofen 250 mg / Acetaminophen 500 mg<br>* 2 caplets of Ibuprofen 250 mg / Acetaminophen 500 mg<br>* Other names: IBU 250 / APAP 500;|
| Active Comparator: Ibuprofen 250 mg<br>2 caplets of IBU 125 mg | Drug: Ibuprofen 250 mg<br>* 2 caplets of Ibuprofen 125 mg<br>* Other names: IBU 250;|
| Active Comparator: Acetaminophen 650 mg<br>2 tablets of APAP 325 mg | Drug: Acetaminophen 650 mg<br>* 2 tablets of Acetaminophen 325 mg<br>* Other names: APAP 650;|
| Active Comparator: Placebo<br>2 caplets of Placebo | Drug: Placebo<br>* 2 caplets of Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Sum of Pain Intensity Difference Scores on 11-Point Numerical Scale From 0 to 8 Hours Post-dose (SPID11 [0-8]) | Pain intensity was assessed on an 11-point numerical pain severity rating scale. SPID11 (0-8): Time-weighted sum of pain intensity difference (PID) scores over 8 hours. SPID11 score range was -40 (worst score) to 80 (best score) for SPID 0-8. PID was calculated by subtracting the pain intensity score at given post-dose time points (pain severity score range: 0 =no pain to 10 =worst possible pain) from the baseline pain intensity scores (score range: 5 =moderate pain to 10 =worst possible pain; as participants with baseline pain score of at least moderate were included in study). Total possible score range for PID: -5 (worst score) to 10 (best score). | 0 to 8 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Sum of Pain Intensity Difference Scores on 11-Point Numerical Scale From 6 to 8 Hours Post-dose (SPID11 [6-8]) | Pain intensity was assessed on an 11-point numerical pain severity rating scale. SPID11 (6-8): Time-weighted sum of PID scores over 6 to 8 hours. SPID11 score range was -15 (worst score) to 30 (best score) for SPID 6-8. PID was calculated by subtracting the pain intensity score at given post-dose time points (pain severity score range: 0 =no pain to 10 =worst possible pain) from the baseline pain intensity scores (score range: 5 =moderate pain to 10 =worst possible pain; as participants with baseline pain score of at least moderate were included in study). Total possible score range for PID: -5 (worst score) to 10 (best score). | 6 to 8 hours post-dose | 
| Time-weighted Sum of Pain Relief Rating (TOTPAR) From 0 to 8 Hours and 6 to 8 Hours Post-dose | TOTPAR: Time-weighted sum of Pain Relief Rating (PRR) scores over 0 to 8 and 6 to 8 hours. TOTPAR total score range: 0 (worst score) to 32 (best score) for TOTPAR 0-8 and 0 (worst score) to 12 (best score) for TOTPAR 6-8 hours. PRR was assessed on a 5-point categorical pain relief rating scale which ranges from 0 =no relief to 4 =complete relief. | 0 to 8 hours, 6 to 8 hours post-dose | 
| Time to Treatment Failure | Time to treatment failure was defined as the time interval from the study drug administration up to the first documentation of treatment failure. Treatment failure was defined as taking the rescue medication or discontinuation of the participants from the study due to lack of efficacy, whichever came first. Participants were censored at 12 hours or at their final assessment time, whichever came first. | 0 to 12 hours post-dose | 
| Cumulative Percentage of Participants With Treatment Failure at 6 and 8 Hours | Treatment failure was defined as taking the rescue medication or discontinuation of the participants from the study due to lack of efficacy, whichever came first. Participants were censored at 12 hours or at their final assessment time, whichever came first. Percentage of participants who had treatment failure were reported. | 6 hours, 8 hours post-dose | 
| Time to Onset of Meaningful Pain Relief | Participants evaluated time to meaningful relief by stopping a second stopwatch labelled as meaningful relief at the moment they first began to experience meaningful relief. Stopwatch was active up to 12 hours after dosing or until stopped by participant, or participant became treatment failure prior to depressing the second stopwatch. Treatment failure was defined as participant taking rescue medication, or discontinuing due to lack of efficacy. | 0 to 12 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ibuprofen, acetaminophen, pain, molar extraction