Evaluate Efficacy and Safety of Extended Release (ER) Naproxen Sodium

Study Overview
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Brief Summary
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The objective is to evaluate pain relief of the extended release naproxen sodium 660 mg tablet compared to commercial naproxen sodium 220 mg tablet over 24 hours in patients with postsurgical dental pain.

Official Title
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A Randomized, Double-Blind, Placebo Controlled Trial to Assess the Analgesic Efficacy and Safety of Extended Release Naproxen Sodium Tablets in Postsurgical Dental Pain

Conditions
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Pain, Postoperative

Intervention / Treatment
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* Drug: Naproxen Sodium ER (BAYH6689)
* Drug: Naproxen Sodium IR (Aleve, BAYH6689)
* Drug: Naproxen Sodium ER Placebo
* Drug: Naproxen Sodium IR Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, ambulatory, male and female volunteers 15 years of age and above Scheduled to undergo surgical removal of up to two impacted third molars, one of which must be mandibular full or partial bony impaction and the other a maxillary impaction Female subjects of childbearing potential must be using a medically acceptable form of birth control for at least 1 month prior to screening (3 months on oral contraceptives), e.g., oral or patch contraceptives, intrauterine device, NuvaRing, Depo-Provera, or double-barrier and have a negative pregnancy test at Screening and prior to surgery Have not taken any form of medication or herbal supplements (ie, St. Johns Wort) within 5 days of admission (except for oral contraceptives, prophylactic antibiotics, or other routine medications to treat benign conditions, such as antibiotics to treat acne) and agree not to take any medication (other than that provided to them) throughout the study Have not consumed alcoholic beverages, or foods and beverages containing xanthines (examples, coffee, tea, chocolate, and colas) after midnight prior to surgery and agree not to consume any of these foods or beverages throughout the evaluation period Use of only short-acting local anesthetic (e.g., mepivacaine or lidocaine) preoperatively, with or without vasoconstrictor and nitrous oxide Have moderate to severe postoperative pain on the Categorical Pain Intensity Scale (a score of at least 2 on a 4 point scale) and a score of ≥ 50 mm on the 100 mm Visual Analog Scale (VAS) within 4 hours postsurgery, but no later than 1330 hours +/- 15 minutes Understand the pain rating scales (as judged by the study coordinator) Be willing and able to participate in all scheduled visits, treatment plan, tests and other trial procedures according to the protocol Provide a personally signed and dated informed consent form (ICF) indicating that the subject has been informed of all pertinent aspects of the trial, (subjects < 18 years of age must sign a written assent and have parental or guardian consent) Exclusion Criteria: History of hypersensitivity to naproxen sodium, acetaminophen, Non Steroidal Anti-inflammatory Drugs (NSAIDS), aspirin, hydrocodone, similar pharmacological agents or components of the investigational products Evidence or history of clinically significant (in the judgment of the investigator) hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic diseases, or malignancies within the last 5 years Relevant concomitant disease such as asthma (exercise induced asthma is permitted), chronic sinusitis or nasal structural abnormalities causing greater than 50 percent obstruction (polyposis nasi, marked septal deviation) that can interfere with the conduct of the study in the judgment of the investigator Current or past history of gastrointestinal bleeding or other bleeding disorder(s) Acute illness or local infection prior to surgery that can interfere with the conduct of the study in the judgment of the investigator Use of any Over-the-Counter (OTC) or prescription medications with which the administration of naproxen, acetaminophen, ibuprofen or any other NSAIDs, Lortab, is contraindicated or use of any medications within 5 days of surgery (except oral contraceptives, prophylactic antibiotics or medications to treat benign conditions such as antibiotics to treat acne) Females who are pregnant or lactating Habituation to analgesic drugs (i.e., routine use of oral analgesics 5 or more times per week for greater than 3 weeks) Alcoholism or drug abuse within 2 years prior to the Screening Visit or routine consumption of 3 or more alcohol containing beverages per day Positive urine, alcohol or nicotine test on day of surgery Smokers or using nicotine replacement therapies including transdermal patches, spray, lozenges or gum

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Naproxen Sodium ER (BAYH6689)<br>1 naproxen sodium extended release (ER) 660 mg tablet and 1 naproxen sodium immediate release (IR) 220 mg placebo tablet initially followed by 1 naproxen sodium IR 220 mg matching placebo tablet at hour 8 (± 15 min), and 1 naproxen sodium IR 220 mg matching placebo tablet at hour 16 (± 15 min) | Drug: Naproxen Sodium ER (BAYH6689)<br>* 660 mg Naproxen Sodium extended release tablet, orally administered once daily for 24 hours<br>Drug: Naproxen Sodium IR Placebo<br>* Matching placebo of 220 mg Naproxen Sodium IR (Aleve) for 24 hours<br>|
| Active Comparator: Naproxen Sodium IR (Aleve, BAYH6689)<br>1 naproxen sodium ER 660 mg matching placebo tablet and 1 naproxen sodium IR 220 mg tablet initially followed by 1 naproxen sodium IR 220 mg tablet at hour 8 (± 15 min), and 1 naproxen sodium IR 220 mg tablet eight hours at hour 16 (± 15 min) | Drug: Naproxen Sodium IR (Aleve, BAYH6689)<br>* 220 mg Naproxen Sodium instant release tablet, orally administered 3 times daily (TID) for 24 hours<br>Drug: Naproxen Sodium ER Placebo<br>* Matching placebo of 660 mg Naproxen Sodium ER for 24 hours<br>|
| Placebo Comparator: Placebo<br>1 naproxen sodium ER 660 mg matching placebo tablet and 1 naproxen sodium IR 220 mg matching placebo tablet initially followed by 1 naproxen sodium IR 220 mg matching placebo tablet at hour 8 (± 15 min), and 1 naproxen sodium IR 220 mg matching placebo tablet at hour 16 (± 15 min) | Drug: Naproxen Sodium ER Placebo<br>* Matching placebo of 660 mg Naproxen Sodium ER for 24 hours<br>Drug: Naproxen Sodium IR Placebo<br>* Matching placebo of 220 mg Naproxen Sodium IR (Aleve) for 24 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed, Time-weighted Pain Intensity Difference From 0 to 24 Hours Postdose (SPID0-24) | SPID0-24 was calculated by multiplying the pain intensity difference score at each post-dose timepoint by the duration (in hours) since the preceding timepoint and then summing these values over 0 to 24 hours. Pain intensity was measured at baseline, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 20 and 24 hours using the 4-point categorical pain intensity scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe. SPID0-24 can vary from -24 to 72. The positive SPID value indicates improvement of pain relief. The higher the SPID value, the more improvement of pain relief. | From 0 to 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed, Time-weighted Pain Intensity Differences (SPID) | Pain intensity was measured at baseline, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 20 and 24 hours using the 4-point categorical pain intensity scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe. The total possible score ranges of SPIDs are SPID0-6: -6 to 18, SPID0-8: -8 to 24, SPID0-12: -12 to 36, SPID0-16: -16 to 48, SPID16-24: -8 to 24. The positive SPID value indicates improvement of pain relief. The higher the SPID value, the more improvement of pain relief. | 0-6, 0-8, 0-12, 0-16 and 16-24 hours postdose | 
| Summed, Time-weighted Total Pain Relief Scores (TOTPARs) | TOTPARs were derived by multiplying the pain relief score at each post-dose timepoint by the duration (in hours) since the preceding timepoint and then summing these values over the specified interval. Pain Relief was evaluated at 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 20 and 24 hours postdose, using the 5-point overall pain relief scale: 0 = No relief, 1 = A little relief, 2 = Some relief, 3 = A lot of relief, 4 = Complete relief. The possible total score ranges of TOTPARs are: TOTPAR0-6: 0 to 18, TOTPAR0-8: 0 to 24, TOTPAR0-12: 0 to 36, TOTPAR0-16: 0 to 48, TOTPAR0-24: 0 to 72, TOTPAR16-24: 0 to 24. | 0-6, 0-8, 0-12, 0-16, 0-24, and 16-24 hours postdose | 
| Pain Intensity Differences (PIDs) by Time From Initial Dose | Pain intensity was evaluated using a 4-point Categorical Pain Intensity Rating Scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe | At 0, 0.25, 0.5, 0.75, 1, 2, 3, 4 ,5 ,6, 8, 12, 16, 20 and 24 hours postdose | 
| Pain Relief From Initial Dose | Pain Relief was evaluated using the 5-point overall pain relief scale: 0 = No relief, 1 = A little relief, 2 = Some relief, 3 = A lot of relief, 4 = Complete relief | At 0.25, 0.5, 0.75, 1, 2, 3, 4 ,5 ,6, 8, 12, 16, 20 and 24 hours postdose | 
| Median Time to First Intake of Rescue Medication | Time to first use of rescue medication was estimated using Kaplan-Meier method and analyzed by a logrank test stratified by baseline pain intensity. If at least 50% of subjects in a treatment group took rescue medication, the median time to first rescue was determined for that treatment group. | Up to 24 hours postdose | 
| Cumulative Percentage of Participants Who Took Rescue Medication |  | At 0.25, 0.5, 0.75, 1, 2, 3, 4 ,5 ,6, 8, 12, 16, 20 and 24 hours postdose | 
| Number of Times the Participants Took Rescue Medication Over the 24-hour Period |  | 24 hours postdose | 
| Global Assessment of the Investigational Product as a Pain Reliever | Global assessment of investigational product as a pain reliever was rated on a 5-point categorical scale: 0 = poor, 1 = fair, 2 = good, 3 = very good, 4 = excellent | 24 hours postdose or immediately before the first intake of rescue medication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Naproxen Sodium,, dental pain