Study to Find Out the Optimal Dose of Caffeine in the Combination Tablet of Naproxen Sodium and Caffeine in Patients Experiencing Moderate to Severe Pain After Having Wisdom Teeth Removed

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04132336
• Collaborator: (none)
• Enrollment: 193
• Location: 1
• Arms: 7
• Actual Duration (Months): 3.7
• Patients Per Site Per Month: 52.5

Study Details

Study Description

Brief Summary

The researchers in this study wanted to find out the optimal dose of Caffeine in the combination tablet of Naproxen Sodium and Caffeine that works in patients experiencing moderate to severe pain after having wisdom teeth removed. 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 effectiveness of various pain relievers, and therefore is accepted as an additive to painkillers like aspirin and acetaminophen. Patients participating in this study underwent a surgery to remove 3 or 4 wisdom teeth. If the pain severity after the surgery met the study requirement, patients would receive oral tablet(s) of Naproxen Sodium and Caffeine, or Naproxen Sodium, or Caffeine, or placebo (drug with no active ingredient). Patients could also receive additional pain medication when needed. Researchers would also learn if the patients have any medical problems during the study.

Condition or Disease	Intervention/Treatment	Phase
Pain, Postoperative	Drug: Naproxen sodium/Caffeine (BAY2880376); Drug: Naproxen sodium (Aleve); Drug: Caffeine; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 193 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Single-Dose, Parallel, Placebo-Controlled Trial to Determine the Dose of Caffeine in a Fixed Dose Combination Tablet of Naproxen Sodium and Caffeine to Effectively Alleviate Postsurgical Dental Pain
• Actual Study Start Date: Nov 12, 2019
• Actual Primary Completion Date: Mar 2, 2020
• Actual Study Completion Date: Mar 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Naproxen sodium/caffeine - Dose 1 Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Drug: Naproxen sodium/Caffeine (BAY2880376); Tablet, oral, single dose
Experimental: Naproxen sodium/caffeine - Dose 2 Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Drug: Naproxen sodium/Caffeine (BAY2880376); Tablet, oral, single dose
Experimental: Naproxen sodium/caffeine - Dose 3 Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Drug: Naproxen sodium/Caffeine (BAY2880376); Tablet, oral, single dose
Experimental: Naproxen sodium/caffeine - Dose 4 Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Drug: Naproxen sodium/Caffeine (BAY2880376); Tablet, oral, single dose
Active Comparator: Naproxen sodium Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Drug: Naproxen sodium (Aleve); Tablet, oral, single dose
Active Comparator: Caffeine Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Drug: Caffeine; Tablet, oral, single dose
Placebo Comparator: Placebo Participants received a single dose of two tablets of matching placebo after extraction of third molars	Drug: Placebo; Tablet, oral, single dose

Outcome Measures

Primary Outcome Measures

1. Sum of Pain Intensity Difference (SPID) Over 8 Hours [Up to 8 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 over 8 hours ranges from -80 to 80. A higher value indicates a better pain reduction.

Secondary Outcome Measures

1. Sum of Pain Intensity Differences (SPIDs) From 0 to 2, 4 and 12 Hours Post-dose [Up to 2 hours, 4 hours and 12 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.

2. Total Pain Relief (TOTPAR) Over 8 Hours [Up to 8 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. TOTPAR over 8 hours ranges from 0 to 32, a higher value indicates more pain relief.

3. Total Pain Relief (TOTPAR) From 0 to 2, 4 and 12 Hours Post-dose [Up to 2 hours, 4 hours and 12 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. TOTPAR 0-2 ranges from 0 to 8, TOTPAR 0-4 ranges from 0 to 16, and TOTPAR 0-12 ranges from 0 to 48. A higher value indicates more pain relief

4. Time to First Use of Rescue Medication [Up to 12 hours post dose]

5. The Cumulative Percentage of Participants Taking Rescue Medication [Up to 12 hours post dose]

6. Pain Intensity Difference (PID) at Each Evaluation [Up to 12 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

7. Peak Pain Intensity Difference (PID) [Up to 12 hours post dose]

   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).

8. Pain Relief Score at Each Evaluation [Up to 12 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)

9. Peak Pain Relief Score [Up to 12 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). 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.

10. Global Assessment of the Investigational Product [Up to 12 hours post dose]

    Global assessment is performed either at 12 hours post-dose or immediately prior to the first intake of rescue medication. 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.'

11. Number of Participants With Adverse Events [Up to 5 days post dose]

12. The Number of Participants With Clinically Significant Changes in Physical Examinations and Vital Signs [Up to 5 days post dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	JBR Clinical Research	Salt Lake City	Utah	United States	84107

Sponsors and Collaborators

• Bayer

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Aug 22, 2019
• Statistical Analysis Plan - May 13, 2020

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT04132336
• Other Study ID Numbers: 21069; 2019-003513-33
• First Posted: Oct 18, 2019
• Last Update Posted: Sep 1, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bayer: Dental pain
• Additional relevant MeSH terms: Pain, Postoperative; Naproxen; Caffeine

Study Results

Participant Flow

Recruitment Details	Study was conducted at a single center in United States with first participant first visit on 12-Nov-2019 and last participant last visit on 02-Mar-2020. Study was completed on 03-Mar-2020 (End of follow up, phone call).
Pre-assignment Detail	A total of 193 participants, including 32 in each of the naproxen sodium containing groups, 16 in the caffeine group, and 17 in the placebo group, underwent dental surgery and were randomized to study drug

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Period Title: Overall Study
STARTED	32	32	32	32	32	16	17
COMPLETED	32	31	32	32	32	16	17
NOT COMPLETED	0	1	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo	Total
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars	Total of all reporting groups
Overall Participants	32	32	32	32	32	16	17	193
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	17.0 (1.03)	17.4 (2.42)	17.1 (1.34)	17.3 (1.49)	17.9 (2.74)	17.3 (1.70)	17.7 (1.40)	17.4 (1.86)
Sex: Female, Male (Count of Participants)
Female	13 40.6%	14 43.8%	16 50%	10 31.3%	14 43.8%	5 31.3%	5 29.4%	77 39.9%
Male	19 59.4%	18 56.3%	16 50%	22 68.8%	18 56.3%	11 68.8%	12 70.6%	116 60.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.3%	0 0%	0 0%	3 9.4%	2 6.3%	3 18.8%	0 0%	10 5.2%
Not Hispanic or Latino	30 93.8%	32 100%	32 100%	29 90.6%	30 93.8%	13 81.3%	17 100%	183 94.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Baseline Pain Intensity Score (Count of Participants)
No Pain (0)	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Mild Pain (1)	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Moderate Pain (2)	15 46.9%	13 40.6%	12 37.5%	11 34.4%	11 34.4%	3 18.8%	5 29.4%	70 36.3%
Severe Pain (3)	17 53.1%	19 59.4%	20 62.5%	21 65.6%	21 65.6%	13 81.3%	12 70.6%	123 63.7%

Outcome Measures

1. Primary Outcome

Title	Sum of Pain Intensity Difference (SPID) Over 8 Hours
Description	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.
Time Frame	Up to 8 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
Mean (Standard Deviation) [Scores on a scale*hours]	35.45 (14.517)	37.87 (16.876)	30.70 (17.679)	36.02 (14.825)	29.95 (19.067)	8.75 (21.465)	6.03 (17.810)

2. Secondary Outcome

Title	Sum of Pain Intensity Differences (SPIDs) From 0 to 2, 4 and 12 Hours Post-dose
Description	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.
Time Frame	Up to 2 hours, 4 hours and 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
SPID 0-2	8.30 (3.141)	8.68 (3.789)	7.17 (3.721)	6.92 (3.501)	6.05 (3.511)	2.13 (4.060)	1.16 (2.925)
SPID 0-4	18.02 (6.387)	19.26 (8.019)	15.58 (7.697)	17.05 (7.232)	14.33 (8.391)	4.50 (9.604)	2.59 (7.625)
SPID 0-12	50.58 (24.237)	52.45 (27.305)	44.80 (28.929)	52.45 (23.022)	43.08 (30.034)	12.44 (32.059)	1.15 (2.833)

3. Secondary Outcome

Title	Total Pain Relief (TOTPAR) Over 8 Hours
Description	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. TOTPAR over 8 hours ranges from 0 to 32, a higher value indicates more pain relief.
Time Frame	Up to 8 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
Mean (Standard Deviation) [Scores on a scale*hours]	19.58 (7.007)	20.26 (7.673)	17.41 (8.063)	19.53 (6.448)	16.27 (8.514)	7.03 (9.283)	5.44 (7.709)

4. Secondary Outcome

Title	Total Pain Relief (TOTPAR) From 0 to 2, 4 and 12 Hours Post-dose
Description	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. TOTPAR 0-2 ranges from 0 to 8, TOTPAR 0-4 ranges from 0 to 16, and TOTPAR 0-12 ranges from 0 to 48. A higher value indicates more pain relief
Time Frame	Up to 2 hours, 4 hours and 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
TOTPAR 0-2	4.83 (1.401)	4.77 (1.731)	4.22 (1.596)	3.97 (1.436)	3.52 (1.644)	1.66 (1.767)	1.06 (1.328)
TOTPAR 0-4	10.27 (2.750)	10.29 (3.449)	8.84 (3.286)	9.28 (2.842)	7.86 (3.813)	3.59 (4.148)	2.44 (3.281)
TOTPAR 0-12	28.20 (12.262)	28.26 (12.690)	25.13 (13.291)	28.72 (10.678)	22.95 (13.206)	10.28 (13.882)	8.44 (12.419)

5. Secondary Outcome

Title	Time to First Use of Rescue Medication
Time Frame	Up to 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
Median (Inter-Quartile Range) [hours]	NA	NA	NA	NA	NA	2.083	2.125

6. Secondary Outcome

Title	The Cumulative Percentage of Participants Taking Rescue Medication
Time Frame	Up to 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
0.5 Hours Post-Dose	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
1 Hour Post-Dose	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
1.5 Hours Post-Dose	0 0%	3.2 10%	3.1 9.7%	0 0%	0 0%	37.5 234.4%	25.0 147.1%
2 Hours Post-Dose	0 0%	3.2 10%	3.1 9.7%	0 0%	0 0%	50 312.5%	37.5 220.6%
3 Hours Post-Dose	0 0%	6.5 20.3%	6.3 19.7%	3.1 9.7%	15.6 48.8%	56.3 351.9%	56.3 331.2%
4 Hours Post-Dose	3.1 9.7%	6.5 20.3%	9.4 29.4%	3.1 9.7%	18.8 58.8%	56.3 351.9%	68.8 404.7%
5 Hours Post-Dose	9.4 29.4%	6.5 20.3%	15.6 48.8%	3.1 9.7%	18.8 58.8%	62.5 390.6%	68.8 404.7%
6 Hours Post-Dose	9.4 29.4%	9.7 30.3%	18.8 58.8%	6.3 19.7%	21.9 68.4%	68.8 430%	68.8 404.7%
7 Hours Post-Dose	12.5 39.1%	9.7 30.3%	21.9 68.4%	6.3 19.7%	21.9 68.4%	68.8 430%	68.8 404.7%
8 Hours Post-Dose	15.6 48.8%	9.7 30.3%	21.9 68.4%	9.4 29.4%	21.9 68.4%	68.8 430%	75.0 441.2%
9 Hours Post-Dose	21.9 68.4%	25.8 80.6%	25.0 78.1%	9.4 29.4%	28.1 87.8%	68.8 430%	75.0 441.2%
10 Hours Post-Dose	25.0 78.1%	25.8 80.6%	28.1 87.8%	15.6 48.8%	31.3 97.8%	68.8 430%	75.0 441.2%
11 Hours Post-Dose	25.0 78.1%	25.8 80.6%	28.1 87.8%	15.6 48.8%	34.4 107.5%	68.8 430%	75.0 441.2%
12 Hours Post-Dose	25.0 78.1%	29.0 90.6%	28.1 87.8%	18.8 58.8%	34.4 107.5%	75.0 468.8%	75.0 441.2%

7. Secondary Outcome

Title	Pain Intensity Difference (PID) at Each Evaluation
Description	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
Time Frame	Up to 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	31	32	16	16
0.5 Hours Post-Dose	2.3 (2.07)	2.6 (1.82)	2.1 (2.23)	1.4 (1.56)	1.5 (1.34)	0.8 (0.98)	0.5 (0.89)
1 Hour Post-Dose	4.2 (1.88)	4.2 (2.44)	3.7 (1.95)	3.4 (2.39)	2.9 (1.88)	1.2 (2.26)	0.6 (1.71)
1.5 Hours Post-Dose	4.9 (1.67)	5.1 (2.26)	4.3 (1.98)	4.2 (2.32)	3.7 (2.16)	1.2 (2.79)	0.7 (1.74)
2 Hours Post-Dose	5.1 (1.76)	5.5 (2.20)	4.3 (2.23)	4.8 (2.23)	4.1 (2.22)	1.1 (2.67)	0.5 (1)
3 Hours Post-Dose	5.0 (1.82)	5.4 (2.27)	4.3 (2.33)	5.0 (2.29)	4.0 (2.83)	1.1 (2.85)	0.6 (2.42)
4 Hours Post-Dose	4.8 (2.17)	5.2 (2.59)	4.1 (2.62)	5.1 (2.27)	4.3 (2.82)	1.3 (3.11)	0.9 (2.78)
5 Hours Post-Dose	4.7 (2.28)	5.0 (2.42)	4.0 (2.72)	5.0 (2.25)	4.1 (2.83)	1.1 (3.14)	1.0 (2.92)
6 Hours Post-Dose	4.6 (2.24)	4.8 (2.42)	3.8 (2.87)	4.9 (2.40)	3.9 (2.88)	1.1 (3.19)	1.0 (3.06)
7 Hours Post-Dose	4.3 (2.55)	4.5 (2.45)	3.8 (3.07)	4.7 (2.31)	3.9 (3.08)	1.1 (3.36)	0.8 (2.49)
8 Hours Post-Dose	4.0 (2.53)	4.2 (2.65)	3.7 (3.12)	4.3 (2.29)	3.7 (2.96)	0.9 (2.95)	0.7 (2.65)
9 Hours Post-Dose	3.8 (2.71)	3.8 (3.12)	3.6 (3.00)	4.2 (2.45)	3.6 (3.14)	1.1 (3.09)	0.8 (2.74)
10 Hours Post-Dose	3.8 (2.88)	3.7 (3.04)	3.4 (3.15)	4.1 (2.60)	3.3 (3.07)	1.1 (3.07)	0.9 (2.99)
11 Hours Post-Dose	3.8 (2.92)	3.5 (3.02)	3.6 (3.17)	4.2 (2.79)	3.1 (3.02)	0.8 (2.99)	0.9 (2.96)
12 Hours Post-Dose	3.8 (2.97)	3.6 (3.06)	3.5 (3.38)	4.0 (2.92)	3.1 (2.97)	0.8 (3.00)	0.9 (2.96)

8. Secondary Outcome

Title	Peak Pain Intensity Difference (PID)
Description	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).
Time Frame	Up to 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
Mean (Standard Deviation) [Scores on a scale]	6.0 (1.53)	6.2 (1.97)	5.9 (2.01)	6.3 (1.72)	5.3 (2.57)	2.7 (2.94)	2.3 (2.98)

9. Secondary Outcome

Title	Pain Relief Score at Each Evaluation
Description	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)
Time Frame	Up to 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
0.5 Hours Post-Dose	1.6 (1.08)	1.5 (0.89)	1.5 (1.02)	0.9 (0.80)	1.0 (0.74)	0.6 (0.62)	0.4 (0.63)
1 Hours Post-Dose	2.4 (0.84)	2.3 (1.22)	2.2 (0.91)	2.0 (1.14)	1.8 (0.91)	0.9 (1.00)	0.6 (0.81)
1.5 Hours Post-Dose	2.8 (0.64)	2.8 (0.99)	2.3 (0.87)	2.4 (0.91)	2.0 (1.05)	0.9 (1.24)	0.6 (0.73)
2 Hours Post-Dose	2.8 (0.85)	2.9 (1.01)	2.4 (1.01)	2.6 (0.79)	2.2 (1.01)	0.8 (1.05)	0.5 (0.82)
3 Hours Post-Dose	2.8 (0.79)	2.8 (0.97)	2.4 (1.04)	2.6 (0.91)	2.1 (1.21)	0.9 (1.24)	0.6 (1.09)
4 Hours Post-Dose	2.7 (1.07)	2.7 (1.19)	2.3 (1.16)	2.7 (0.96)	2.2 (1.26)	1.0 (1.37)	0.8 (1.18)
5 Hours Post-Dose	2.6 (1.16)	2.6 (1.15)	2.3 (1.27)	2.7 (1.00)	2.2 (1.24)	0.9 (1.36)	0.8 (1.18)
6 Hours Post-Dose	2.4 (1.16)	2.6 (1.18)	2.2 (1.35)	2.7 (1.10)	2.1 (1.30)	0.9 (1.45)	0.8 (1.24)
7 Hours Post-Dose	2.3 (1.34)	2.5 (1.15)	2.1 (1.38)	2.5 (1.08)	2.1 (1.29)	0.9 (1.50)	0.8 (1.28)
8 Hours Post-Dose	2.1 (1.33)	2.3 (1.28)	2.1 (1.46)	2.4 (1.19)	2.0 (1.28)	0.8 (1.33)	0.7 (1.25)
9 Hours Post-Dose	2.2 (1.40)	2.1 (1.48)	2.0 (1.45)	2.3 (1.12)	1.9 (1.41)	0.9 (1.36)	0.8 (1.34)
10 Hours Post-Dose	2.2 (1.51)	2.0 (1.43)	1.8 (1.42)	2.3 (1.28)	1.8 (1.41)	0.9 (1.36)	0.8 (1.34)
11 Hours Post-Dose	2.1 (1.52)	1.9 (1.40)	1.9 (1.48)	2.4 (1.34)	1.4 (1.32)	0.8 (1.34)	0.8 (1.34)
12 Hours Post-Dose	2.2 (1.55)	1.9 (1.46)	2.0 (1.51)	2.2 (1.45)	1.6 (1.39)	0.8 (1.34)	0.8 (1.34)

10. Secondary Outcome

Title	Peak Pain Relief Score
Description	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.
Time Frame	Up to 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
Mean (Standard Deviation) [Scores on a scale]	3.3 (0.62)	3.2 (0.78)	3.0 (0.82)	3.1 (0.66)	2.6 (1.01)	1.6 (1.55)	1.3 (1.39)

11. Secondary Outcome

Title	Global Assessment of the Investigational Product
Description	Global assessment is performed either at 12 hours post-dose or immediately prior to the first intake of rescue medication. 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.'
Time Frame	Up to 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	31	32	32	32	16	16
Poor (0)	1 3.1%	1 3.1%	1 3.1%	1 3.1%	4 12.5%	8 50%	10 58.8%
Fair (1)	2 6.3%	1 3.1%	4 12.5%	2 6.3%	5 15.6%	1 6.3%	2 11.8%
Good (2)	5 15.6%	6 18.8%	9 28.1%	7 21.9%	6 18.8%	4 25%	1 5.9%
Very Good (3)	18 56.3%	14 43.8%	13 40.6%	17 53.1%	14 43.8%	2 12.5%	3 17.6%
Excellent (4)	6 18.8%	9 28.1%	5 15.6%	5 15.6%	3 9.4%	1 6.3%	0 0%

12. Secondary Outcome

Title	Number of Participants With Adverse Events
Time Frame	Up to 5 days post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	32	32	32	32	16	17
Count of Participants [Participants]	6 18.8%	3 9.4%	1 3.1%	2 6.3%	3 9.4%	5 31.3%	4 23.5%

13. Secondary Outcome

Title	The Number of Participants With Clinically Significant Changes in Physical Examinations and Vital Signs
Time Frame	Up to 5 days post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1	Naproxen Sodium/Caffeine-Dose 2	Naproxen Sodium/Caffeine-Dose 3	Naproxen Sodium/Caffeine-Dose 4	Naproxen Sodium	Caffeine	Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars	Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars	Participants received a single dose of two tablets of matching placebo after extraction of third molars
Measure Participants	32	32	32	32	32	16	17
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Up to 5 days post-dose
Arm/Group Title	Naproxen Sodium/Caffeine-Dose 1		Naproxen Sodium/Caffeine-Dose 2		Naproxen Sodium/Caffeine-Dose 3		Naproxen Sodium/Caffeine-Dose 4		Naproxen Sodium		Caffeine		Placebo
Arm/Group Description	Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/medium low dose) after extraction of third molars		Participants received a single dose of two tablets of naproxen sodium/caffeine (low dose/low dose) after extraction of third molars		Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ medium low dose) plus one tablet of placebo after extraction of third molars		Participants received a single dose of one tablet of naproxen sodium/caffeine (low dose/ low dose) plus one tablet of placebo after extraction of third molars		Participants received a single dose of one tablet of naproxen sodium (low dose) plus one tablet of placebo after extraction of third molars		Participants received a single dose of two tablets of caffeine (medium low dose) after extraction of third molars		Participants received a single dose of two tablets of matching placebo after extraction of third molars
All Cause Mortality
	Naproxen Sodium/Caffeine-Dose 1		Naproxen Sodium/Caffeine-Dose 2		Naproxen Sodium/Caffeine-Dose 3		Naproxen Sodium/Caffeine-Dose 4		Naproxen Sodium		Caffeine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/32 (0%)		0/32 (0%)		0/32 (0%)		0/32 (0%)		0/16 (0%)		0/17 (0%)
Serious Adverse Events
	Naproxen Sodium/Caffeine-Dose 1		Naproxen Sodium/Caffeine-Dose 2		Naproxen Sodium/Caffeine-Dose 3		Naproxen Sodium/Caffeine-Dose 4		Naproxen Sodium		Caffeine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/32 (0%)		0/32 (0%)		0/32 (0%)		0/32 (0%)		0/16 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Naproxen Sodium/Caffeine-Dose 1		Naproxen Sodium/Caffeine-Dose 2		Naproxen Sodium/Caffeine-Dose 3		Naproxen Sodium/Caffeine-Dose 4		Naproxen Sodium		Caffeine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/32 (18.8%)		3/32 (9.4%)		1/32 (3.1%)		2/32 (6.3%)		3/32 (9.4%)		5/16 (31.3%)		4/17 (23.5%)
Cardiac disorders
Tachycardia	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1	0/16 (0%)	0	0/17 (0%)	0
Ear and labyrinth disorders
Ear pain	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	1/16 (6.3%)	1	0/17 (0%)	0
Gastrointestinal disorders
Nausea	1/32 (3.1%)	1	1/32 (3.1%)	1	0/32 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	3	4/16 (25%)	5	0/17 (0%)	0
Vomiting	2/32 (6.3%)	2	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	1/16 (6.3%)	1	2/17 (11.8%)	2
General disorders
Chest discomfort	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/16 (0%)	0	1/17 (5.9%)	1
Feeling hot	0/32 (0%)	0	1/32 (3.1%)	1	0/32 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1	0/16 (0%)	0	0/17 (0%)	0
Pyrexia	1/32 (3.1%)	1	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/16 (0%)	0	0/17 (0%)	0
Infections and infestations
Alveolar osteitis	0/32 (0%)	0	1/32 (3.1%)	1	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/16 (0%)	0	0/17 (0%)	0
Cellulitis	1/32 (3.1%)	1	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/16 (0%)	0	0/17 (0%)	0
Nervous system disorders
Dizziness	1/32 (3.1%)	1	1/32 (3.1%)	1	0/32 (0%)	0	1/32 (3.1%)	1	0/32 (0%)	0	0/16 (0%)	0	1/17 (5.9%)	1
Headache	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	2/16 (12.5%)	2	0/17 (0%)	0
Syncope	1/32 (3.1%)	1	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/16 (0%)	0	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	2/32 (6.3%)	5	0/32 (0%)	0	1/32 (3.1%)	1	0/32 (0%)	0	0/32 (0%)	0	0/16 (0%)	0	0/17 (0%)	0
Paranasal sinus discomfort	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/16 (0%)	0	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Cold sweat	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	1/16 (6.3%)	1	0/17 (0%)	0
Hyperhidrosis	0/32 (0%)	0	1/32 (3.1%)	1	0/32 (0%)	0	0/32 (0%)	0	0/32 (0%)	0	0/16 (0%)	0	0/17 (0%)	0

Limitations/Caveats

Other pre-specified outcomes (non-key secondary) "Time to first perceptible relief/meaningful relief/perceptible relief confirmed by meaningful relief" and "Cumulative percentage of subjects with at least '2-point PID' over time" were also analyzed

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.