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

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

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.

Study Overview

• Status: Completed
• Conditions: Postoperative Dental Pain
• Intervention / Treatment: Drug: Naproxen sodium and caffeine (BAY2880376); Drug: Naproxen sodium (Aleve); Drug: Caffeine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 541
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • JBR Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sum of Pain Intensity Difference (SPID) Over 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.	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 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.	from 0 to 2, 4, 6, 12 and 24 hours post-dose
Total Pain Relief (TOTPAR) From 0 to 2, 4, 6, 8, 12 and 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.	up to 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	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	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 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	up to 24 hours post-dose
Pain Relief Score	Pain Relief Score (PRS): 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)	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.	Up to 24 hours post-dose
Number of Participants With Certain Peak Pain Relief Score	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.	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 Pain Relief of the Investigational Product	Number of participants with overall rating poor, fair, good, very good, excellent 24 hour post-dose	24 hours post-dose
Number of Participants With Adverse Events	Number of participants with at least one treatment emergent adverse event	Up to 5 days post-dose
Number of Participants With Significant Changes in Vital Signs Since Baseline		Up to 5 days post-dose

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

Helpful Links

• Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials.gov identifier (NCT) number or Bayer Study Identifier (ID) in the search field.

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2022
• Primary Completion (Actual): January 25, 2024
• Study Completion (Actual): January 29, 2024

Study Registration Dates

• First Submitted: July 28, 2022
• First Submitted That Met QC Criteria: August 1, 2022
• First Posted (Actual): August 3, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 7, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Dental pain
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Stomatognathic Diseases; Tooth Diseases; Facial Pain; Toothache; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Gout Suppressants; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Neurotransmitter Agents; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Purinergic Antagonists; Purinergic Agents; Central Nervous System Stimulants; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Caffeine; Naproxen
• Other Study ID Numbers: 22093; 2022-003274-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No