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

Phase 3

Completed

Conditions: Postoperative Dental Pain

Interventions: Drug: Naproxen sodium (Aleve)
Drug: Placebo
Drug: Naproxen sodium and caffeine (BAY2880376)
Drug: Caffeine

Registration Number: NCT05485805

Lead Sponsor: Bayer

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 541

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Naproxen sodium	Naproxen sodium (Aleve)	Participants will receive a single dose of one tablet of naproxen sodium plus one tablet of placebo after extraction of third molars.
Placebo	Placebo	Participants will receive a single dose of two tablets of matching placebo after extraction of third molars.
Naproxen sodium/caffeine - Dose 1	Naproxen sodium and caffeine (BAY2880376)	Participants will receive a single dose of one tablet of naproxen sodium/caffeine plus one tablet of placebo after extraction of third molars.
Naproxen sodium/caffeine - Dose 2	Naproxen sodium and caffeine (BAY2880376)	Participants will receive a single dose of two tablets of naproxen sodium/caffeine after extraction of third molars.
Caffeine	Caffeine	Participants will receive a single dose of two tablets of caffeine after extraction of third molars.

Primary Outcome Measures

Name	Time	Method
Sum of Pain Intensity Difference (SPID) Over 8 Hours Post-dose	Up to 8 hours post-dose	Pain intensity scale is the Numerical Rating Scale measured from 0 to 10, where 0 indicates no pain and 10 means the wors pain imaginable. Pain intensity Difference (PID) is calculated by subtracting the pain intensity at different time points in the post-dose time point from the pain intensity at baseline. The summed pain intensity difference (SPID) is to be 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 the values over the relevant time period. For SPID (0-8), eight PIDs are summed up, which is minimally 0, if there is no pain relief or maximally 80, if there is very strong pain and significant pain relief.

Secondary Outcome Measures

Name	Time	Method
Sum of Pain Intensity Differences From 0 to 2, 4, 6, 12 and 24 Hours Post-dose	from 0 to 2, 4, 6, 12 and 24 hours post-dose	Pain intensity scale is the Numerical Rating Scale measured from 0 to 10, where 0 indicates no pain and 10 means the wors pain imaginable. Pain intensity Difference (PID) is calculated by subtracting the pain intensity at different time points in the post-dose time point from the pain intensity at baseline. The summed pain intensity difference (SPID) is to be 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 the values over the relevant time period. For SPID(0-i), i PIDs are summed up, which minimally is 0, if there is no pain relief or maximally i\*10, if there is very strong pain and significant pain relief.
Total Pain Relief (TOTPAR) From 0 to 2, 4, 6, 8, 12 and 24 Hours Post-dose	up to 24 hours post-dose	Total Pain Relief (TOTPAR) is a cumulative measure that evaluates the overall pain relief over a specific time frame from 0-2,0-4,0-6,0-8,0-12 and 0-24 following drug administration. It is calculated by multiplying the pain relief score from the categorical pain relief scale at each time post-dose time by multiplying the duration (in hours) since the preceding time point and then adding these values. Categorical Pain Relief Scale measure the degree of pain relief using a scale from 0 to 4, in which 0 is no relief, 1 a little relief, 2 some relief, 3 a lot of relief and 4 complete relief. Higher values of TOTPAR indicates better pain relief and suggest that the investigational product provided consistence and meaningful pain relief over the period. Low TOTPAR values indicates minimal pain relief or short-lasting efficacy.
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	meaningful relief is the point when the participant perceives their pain as significant and meaningful to them using the double-stopwatched method that allows to differentiate between the onset of the analgesic effect (first perceptible pain relief) and the onset of meaningful pain relief
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)	up to 24 hours post-dose	Pain Intensity Difference (PID) is the change of pain intensity at a specific time point compared to baseline using the Numerical Rating Scale from 0 to 10. Value of 0 score means no pain and 10 score result means the worst possible pain. For each post-dose time point, pain intensity differences will be derived by subtracting the pain intensity at the post-dose time point from the baseline intensity score. Positive PID values indicate pain relief (reduction in pain intensity), while negative or small PID values suggest little or no reduction in pain intensity
Pain Relief Score	Up to 24 hours post-dose	Pain Relief Score (PRS): 0 = No Relief; 1 = A Little Relief; 2 = Some Relief; 3 = A Lot of Relief; 4 = Complete Relief.
Peak Pain Intensity Difference (PID)	Up to 24 hours post-dose	The Peak Pain Intensity (peak PID) refers to the maximum change in pain intensity from baseline observed at any post-dose time point using the Numerical Rating Scale from 0 to 10. Value of 0 score means no pain and 10 score result means the worst possible pain. Participants record their pain intensity assessment in the time frame points and the highest value is identified as the Peak Pain Intensity. A high peak pain intensuty (higher value on NRS) indicates severe pain and a less effective analgesic response, and a lower value signifies better pain control and a more effective response.
Number of Participants With Certain Peak Pain Relief Score	Up to 24 hours post-dose	Number of participants with pain relief score 4, 3, 2, 1. The Peak Pain Relief Score refers to the highest level of pain relief a participant reported at any time point during the study period. It provides an overview of the maximum effectiveness of the treatment at any given point during the observation period using the Categorical Pain Relief Scale which measure the degree of pain relief using a scale from 0 to 4, in which 0 is no relief, 1 a little relief, 2 some relief, 3 a lot of relief and 4 complete relief. A high socre closer indicates significant pain relief and reflects the effectiveness of the analgesic treatment. A score closer to 0 indicates little to no pain relief and suggests limited treatment efficacy.
Cumulative Percent of Participants With 'at Least a 2-point PID' Over Time	Up to 24 hours post-dose
Global Assessment of Pain Relief of the Investigational Product	24 hours post-dose	Number of participants with overall rating poor, fair, good, very good, excellent 24 hour post-dose
Number of Participants With Adverse Events	Up to 5 days post-dose	Number of participants with at least one treatment emergent adverse event
Number of Participants With Significant Changes in Vital Signs Since Baseline	Up to 5 days post-dose