A Study to Learn How Well a Single Dose of the Study Treatment Naproxen Sodium and Caffeine Combined in One Tablet (Fixed-dose Combination) Works to Relieve Pain After Dental Surgeries Compared to the Single Ingredients and to Placebo

Study Overview
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Brief Summary
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Researchers are looking for a better way to relieve pain in people, such as after dental surgery. Participants in this study, have had 3 or 4 third molars (cheek teeth) removed and subsequently have moderate to severe tooth pain. The study treatment naproxen sodium suppresses inflammatory pain by reducing inflammation. In the US, naproxen has been marketed since 1976, and naproxen sodium has been approved for over-the-counter (OTC) use since 1994 for the temporary relief of minor aches and pains. Caffeine, which is generally consumed as coffee, tea, or cocoa, has been shown to enhance the effect of various painkillers, and therefore is accepted as an additive. The main purpose of this study is to learn how well a fixed-dose combination of naproxen sodium and caffeine relieves pain compared to each single ingredient as well as to placebo in participants after molar removal. A placebo is a treatment that looks like a medicine but does not have any medicine in it. To answer this, the researchers will compare the amount of pain decrease over 8 hours in participants who received a single dose of either: 1 fixed-dose tablet of naproxen sodium/caffeine 2 fixed-dose tablets of naproxen sodium/caffeine naproxen sodium only caffeine only or placebo The study participants will be randomly (by chance) assigned to one of the five treatment groups. They will take a single dose of two tablets by mouth within 4.5 hours after the surgery. If there is no pain relief within 2 hours after intake, other painkillers may be given.

Official Title
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A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-Controlled Pivotal Trial to Confirm the Efficacy of a Fixed Dose Combination Tablet of Naproxen Sodium and Caffeine to Effectively Alleviate Postsurgical Dental Pain

Conditions
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Postoperative Dental Pain

Intervention / Treatment
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* Drug: Naproxen sodium and caffeine (BAY2880376)
* Drug: Naproxen sodium (Aleve)
* Drug: Caffeine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, ambulatory, male or female volunteers 16 years of age or older; Body mass index (BMI) 18.5 to 35.0 kg/m^2 inclusive as measured by the National Institutes of Health (NIH) BMI Calculator; Participants will undergo surgical extraction of three or four third molars, two of which must be mandibular molars. Maxillary third molars may be removed regardless of impaction level. The mandibular extractions must have a trauma rating of mild or moderate and meet one of the following scenarios: two full bony impactions; two partial bony impactions; one full bony impaction in combination with one partial bony impaction. Supernumerary teeth present may also be removed at the discretion of the oral surgeon; Have not taken any form of medication, nutritional supplements with analgesic properties (e.g. gamma-Aminobutyric acid [GABA], turmeric) or herbal supplements (i.e., St. John's Wort) within 5 days of admission (except for oral contraceptives, prophylactic antibiotics, multivitamin supplements, 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; Use of only short-acting local anesthetic (e.g., mepivacaine or lidocaine) preoperatively, with or without a vasoconstrictor and nitrous oxide at the discretion of the Investigator; 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 ≥ 5 on the 0-10 pain intensity Numerical Rating Scale (NRS) within 4.5 hours post-surgery. Exclusion Criteria: History of hypersensitivity to naproxen sodium, caffeine, ibuprofen, nonsteroidal anti-inflammatory drug (NSAIDS), aspirin, similar pharmacological agents, local anesthetics, rescue medication or components of the investigational products; Evidence or history of clinically significant (in the judgment of the investigator) hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular (including hypertension and cardiac arrhythmia), hepatic, psychiatric, neurologic diseases, or malignancies within the last 5 years; Participants with the following medical conditions may be eligible at the discretion of the investigator: attention deficit hyperactivity disorder (ADHD) on a stable dose regimen of methylphenidate/(dextro) amphetamine for at least 6 months; participants with hypothyroidism on a stable dose of synthetic thyroid hormone for at least 6 months; Have received any form of treatment in the form of medication for depression in the past 6 months or any form of psychotropic agent (including selective serotonin uptake inhibitors [SSRI] but excluding ADHD medications described above) within the last 6 months; Relevant concomitant disease such as asthma (exercise induced asthma is permitted); Current or past history of gastrointestinal ulceration, gastrointestinal bleeding or other bleeding disorder(s); Acute illness or active 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, any other NSAID, (e.g., tramadol) or if a medication is contraindicated; Use of any medications within 5 days of surgery until discharge from the study site (except oral contraceptives, prophylactic antibiotics, synthetic thyroid hormones, methylphenidate or medications to treat benign conditions such as antibiotics to treat acne); Use of caffeine within 2 days prior to the study; Habits of high consumption of caffeine (>400 mg/day equivalent to about 3-4 cups of coffee per day); Habituation to analgesic drugs including opioids (i.e., routine use of oral analgesics 5 or more times per week for greater than 3 weeks within the past 2 years); Surgeon's trauma rating of severe following surgery.

Ages Eligible for Study
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Minimum Age: 16 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naproxen sodium/caffeine - Dose 1<br>Participants will receive a single dose of one tablet of naproxen sodium/caffeine plus one tablet of placebo after extraction of third molars. | Drug: Naproxen sodium and caffeine (BAY2880376)<br>* Tablet, oral use, single dose<br>|
| Experimental: Naproxen sodium/caffeine - Dose 2<br>Participants will receive a single dose of two tablets of naproxen sodium/caffeine after extraction of third molars. | Drug: Naproxen sodium and caffeine (BAY2880376)<br>* Tablet, oral use, single dose<br>|
| Experimental: Naproxen sodium<br>Participants will receive a single dose of one tablet of naproxen sodium plus one tablet of placebo after extraction of third molars. | Drug: Naproxen sodium (Aleve)<br>* Tablet, oral use, single dose<br>|
| Experimental: Caffeine<br>Participants will receive a single dose of two tablets of caffeine after extraction of third molars. | Drug: Caffeine<br>* Tablet, oral use, single dose<br>|
| Placebo Comparator: Placebo<br>Participants will receive a single dose of two tablets of matching placebo after extraction of third molars. | Drug: Placebo<br>* Tablet, oral use, single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of pain intensity difference (SPID) over 8 hours | Pain intensity is measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = 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. Sum of Pain Intensity Differences (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 8 hours ranges from -80 to 80. A higher value indicates a better pain reduction. | Up to 8 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of pain intensity differences from 0 to 2, 4, 6, 12 and 24 hours post-dose | Pain intensity is measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = 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. Sum of Pain Intensity Differences (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 0-2 ranges from -20 to 20, SPID 0-4 ranges from -40 to 40 and SPID 0-12 ranges from -120 to 120. A higher value indicates a better pain reduction. | Up to 2 hours, 4 hours, 6 hours, 12 hours and 24 hours post-dose | 
| Total pain relief (TOTPAR) from 0 to 2, 4, 6, 8, 12 and 24 hours post-dose | Pain relief is measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, 4 = complete relief). Total Pain Relief is calculated as the area under the curve of pain relief score over time for the given time period by multiplying the pain relief score at each time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. TOTPAR0-2, TOTPAR0-4, TOTPAR0-6, TOTPAR 6-12, TOTPAR0-8 TOTPAR0-12, TOTPAR 12-24, and TOTPAR0-24. A higher value indicates more pain relief. | Up to 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours post-dose | 
| Time to first use of rescue medication |  | Up to 24 hours post-dose | 
| The cumulative proportion of participants taking rescue medication over the 24 hour period |  | Up to 24 hours post-dose | 
| Time to first perceptible relief measured by a stopwatch |  | Up to 24 hours post-dose | 
| Time to meaningful relief measured by a stopwatch |  | Up to 24 hours post-dose | 
| Time to first perceptible relief confirmed by meaningful relief defined as the time to perceptible pain relief |  | Up to 24 hours post-dose | 
| Pain intensity difference (PID) | Pain intensity is measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = 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. | Up to 24 hours post-dose | 
| Pain relief score | Pain relief is measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, 4 = complete relief). | Up to 24 hours post-dose | 
| Peak pain intensity difference (PID) | Pain intensity is measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). Participants circle a number (from 0 to 10) on the Numerical Rating Scale to indicate the severity the pain they are experiencing at baseline and at each post dose time point. 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). | Up to 24 hours post-dose | 
| Peak pain relief score | Pain relief is measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, 4 = complete relief). At each post-dose time point, participants check the appropriate box (from 0 to 4) on the Categorical Pain Relief Rating Scale to indicate the relief from starting pain at the post dose time points. | Up to 24 hours post-dose | 
| Cumulative percent of participants with 'at least a 2-point PID' over time |  | Up to 24 hours post-dose | 
| Global assessment of the investigational product | Global assessment will be completed immediately before first rescue medication is taken or at 24 hours post-dose. Global assessment is based on the question 'Overall, I would rate the study medication I received: 0=Poor, 1=Fair, 2=Good, 3=Very Good, 4=Excellent.' | Up to 24 hours post-dose | 
| Number of participants with adverse events |  | Up to 5 days post-dose | 
| The number of participants with clinically significant changes in physical examinations and vital signs |  | Up to 5 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dental pain