Toothache
Conditions
Keywords
Dental Pain, Analgesia
Brief summary
To evaluate the analgesic efficacy of a single, oral dose of a naproxen sodium extended-release tablet, compared to placebo in postsurgical dental pain.
Interventions
Analgesic efficacy in dental pain; per oral; 1 tablet extended release Naproxen Sodium; with a full glass of water within 4 hours post surgery
DRUGPlacebo
Inactive ingredient; per oral; 1 lactose based tablet; with a full glass of water within 4 hours post surgery
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy, ambulatory, male and female volunteers between 16 to 45 * Scheduled to undergo surgical removal of 1 - 2 impacted third molars, one of which must be at least a partial mandibular bony impaction * No use of any analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, any other pain reliever (Over The Counter or prescription), or herbal supplements within 5 days of surgery * Have moderate to severe postoperative pain on the Categorical Pain Intensity Scale (a score of at least 2 on a 4 point scale) and a score of \>/= 50 mm on the 100-mm visual analog Pain Severity Rating Scale
Exclusion criteria
* History of hypersensitivity to naproxen sodium, aspirin (ASA), other NSAIDs, opioid analgesics, and similar pharmacological agents or components of the investigational products, including the placebo * Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic diseases, or malignancies * Relevant concomitant disease such as asthma (exercise induced asthma is permitted), chronic sinusitis or nasal structural abnormalities causing greater than 50 percent obstruction (polyposis nasi, marked septal deviation) that can interfere with the conduct of the study * Current or past history of bleeding disorder(s) * History of gastrointestinal bleeding or perforation, related to previous NSAID therapy. Active, or history of recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity Difference (SPID) | 0 to 24 hours post dose | Categorical pain intensity scale - no pain (0), mild pain (1), moderate pain (2), or severe pain (3) was used for all pain intensity assessments postdose. Time-weighted Sum Pain Intensity Difference (SPID) was calculated by multiplying the Pain Intensity Difference (PID) score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values over 0-24 and 16-24 hours, respectively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Pain Relief (TOTPAR) | 0-24 hours post dose | Pain relief categorical rating scale - no relief (0), a little relief (1), some relief (2), a lot of relief (3), or complete relief (4) was used for all pain relief assessments postdose. Time weighted total pain relief (TOTPAR) was calculated by multiplying the pain relief score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values. |
| Summed Pain Intensity Difference at Specific Time Intervals | 0-16 hours post dose | Categorical pain intensity scale - no pain (0), mild pain (1), moderate pain (2), or severe pain (3) was used for all pain intensity assessments postdose. Time-weighted Sum Pain Intensity Difference (SPID) was calculated by multiplying the Pain Intensity Difference (PID) score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values for 0-6, 0-12, 0-16 hour intervals, respectively. |
| Time to First Use of Rescue Medication | postdose to first use of rescue medication | Time to first use of rescue medication was estimated using the Kaplan-Meier method and analyzed by a Log rank test stratified by trial site and baseline pain intensity (PI). The outcome measure is time to first use of rescue medication. The criteria are if adequate pain relief is not achieved, then subjects are permitted to take rescue medication. |
| Global Assessment of the Investigational Product as a Pain Reliever | at 24 hours postdose or immediately before first use of rescue medication | Categorical Scale: Poor (0), Fair (1), Good (2), Very Good (3), Excellent (4). |
| Time to Onset of Effect | from postdose to onset of first perceptible and meaningful pain relief for up to 6 hours | Time to onset of effect is defined as the time to meaningful pain relief, provided that the subjects experienced both perceptible and meaningful pain relief. Perceptible pain relief was defined as when the subject first began to feel any pain-relieving effect from the investigational product. Meaningful pain relief was defined as when the subject felt the degree of pain relief was meaningful to them. |
Countries
United States
Participant flow
Pre-assignment details
The Screening Period occurred up to 28 days prior to the day of dental surgery. A total of 447 subjects were screened, of which 135 were excluded (72 did not meet inclusion criteria, 19 refused to participate, 44 other reasons); 312 subjects were randomized and included in the intent-to-treat (ITT) population for efficacy and safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| Naproxen Sodium ER (BAYH6689) single dose (1 tablet) ER Naproxen sodium 660 mg with a full glass of water (240ml) within 1 - 4 hours post dental surgery. | 153 |
| Placebo single dose (1 tablet) of placebo with a full glass of water (240ml) within 1 - 4 hours post dental surgery. | 159 |
| Total | 312 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Naproxen Sodium ER (BAYH6689) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 20.8 years STANDARD_DEVIATION 4.03 | 20.4 years STANDARD_DEVIATION 4.31 | 20.6 years STANDARD_DEVIATION 4.17 |
| Baseline Pain Intensity by Categorical Scale Moderate | 99 participants | 103 participants | 202 participants |
| Baseline Pain Intensity by Categorical Scale Severe | 54 participants | 56 participants | 110 participants |
| Baseline Pain Intensity by Visual Analog Scale | 72.3 scores on a scale STANDARD_DEVIATION 13.13 | 72.6 scores on a scale STANDARD_DEVIATION 11.91 | 72.4 scores on a scale STANDARD_DEVIATION 12.51 |
| Sex: Female, Male Female | 89 Participants | 106 Participants | 195 Participants |
| Sex: Female, Male Male | 64 Participants | 53 Participants | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 153 | 36 / 159 |
| serious Total, serious adverse events | 0 / 153 | 0 / 159 |
Outcome results
Primary
Summed Pain Intensity Difference (SPID)
Categorical pain intensity scale - no pain (0), mild pain (1), moderate pain (2), or severe pain (3) was used for all pain intensity assessments postdose. Time-weighted Sum Pain Intensity Difference (SPID) was calculated by multiplying the Pain Intensity Difference (PID) score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values over 0-24 and 16-24 hours, respectively.
Time frame: 0 to 24 hours post dose
Population: Randomized population is defined as all subjects who signed informed consent form, completed the screening period, and were randomized. The ITT population is defined as all subjects who were randomized and received at least one dose of the study treatment. Efficacy analyses are based on the ITT population (n=312).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naproxen Sodium ER (BAYH6689) | Summed Pain Intensity Difference (SPID) | SPID 0-24 | 25.9 units on a scale | Standard Deviation 25.87 |
| Naproxen Sodium ER (BAYH6689) | Summed Pain Intensity Difference (SPID) | SPID16-24 | 8.8 units on a scale | Standard Deviation 9.3 |
| Placebo | Summed Pain Intensity Difference (SPID) | SPID 0-24 | -3.1 units on a scale | Standard Deviation 18.4 |
| Placebo | Summed Pain Intensity Difference (SPID) | SPID16-24 | -1.0 units on a scale | Standard Deviation 6.89 |
Comparison: The treatment differences between the two groups were tested each at the 5% two-sided significant level using a hierarchal testing procedure to control the overall type 1 error. SPID16-24 was eligible for testing only after a statistically significant difference between the two arms with respect to SPID0-24 was observed. The SPIDs were analyzed via ANCOVA model with treatment and trial site as fixed effects and baseline pain intensity score as the covariate.p-value: <0.001ANCOVA
Secondary
Global Assessment of the Investigational Product as a Pain Reliever
Categorical Scale: Poor (0), Fair (1), Good (2), Very Good (3), Excellent (4).
Time frame: at 24 hours postdose or immediately before first use of rescue medication
Population: Efficacy analyses are based on ITT population (n=312).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naproxen Sodium ER (BAYH6689) | Global Assessment of the Investigational Product as a Pain Reliever | 2.3 units on a scale | Standard Deviation 1.43 |
| Placebo | Global Assessment of the Investigational Product as a Pain Reliever | 0.6 units on a scale | Standard Deviation 1.04 |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Summed Pain Intensity Difference at Specific Time Intervals
Categorical pain intensity scale - no pain (0), mild pain (1), moderate pain (2), or severe pain (3) was used for all pain intensity assessments postdose. Time-weighted Sum Pain Intensity Difference (SPID) was calculated by multiplying the Pain Intensity Difference (PID) score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values for 0-6, 0-12, 0-16 hour intervals, respectively.
Time frame: 0-16 hours post dose
Population: Efficacy analyses were based on ITT population (n=312).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naproxen Sodium ER (BAYH6689) | Summed Pain Intensity Difference at Specific Time Intervals | SIPD 0 - 16 | 17.1 units on a scale | Standard Deviation 16.85 |
| Naproxen Sodium ER (BAYH6689) | Summed Pain Intensity Difference at Specific Time Intervals | SPID 0 - 6 | 6.2 units on a scale | Standard Deviation 5.7 |
| Naproxen Sodium ER (BAYH6689) | Summed Pain Intensity Difference at Specific Time Intervals | SIPD 0 - 12 | 12.7 units on a scale | Standard Deviation 12.3 |
| Placebo | Summed Pain Intensity Difference at Specific Time Intervals | SPID 0 - 6 | -0.4 units on a scale | Standard Deviation 4.2 |
| Placebo | Summed Pain Intensity Difference at Specific Time Intervals | SIPD 0 - 12 | -1.4 units on a scale | Standard Deviation 8.54 |
| Placebo | Summed Pain Intensity Difference at Specific Time Intervals | SIPD 0 - 16 | -2.0 units on a scale | Standard Deviation 11.68 |
p-value: <0.001ANCOVA
Secondary
Time to First Use of Rescue Medication
Time to first use of rescue medication was estimated using the Kaplan-Meier method and analyzed by a Log rank test stratified by trial site and baseline pain intensity (PI). The outcome measure is time to first use of rescue medication. The criteria are if adequate pain relief is not achieved, then subjects are permitted to take rescue medication.
Time frame: postdose to first use of rescue medication
Population: Efficacy analyses are based on ITT population (n=312).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Naproxen Sodium ER (BAYH6689) | Time to First Use of Rescue Medication | 22.27 hours |
| Placebo | Time to First Use of Rescue Medication | 1.90 hours |
Comparison: The statistics are from the Kaplan-Meier method. The median for naproxen treatment arm was not estimable from Kaplan-Meier method, therefore it is presented as the maximum value from the full range.p-value: <0.001Log Rank
Secondary
Time to Onset of Effect
Time to onset of effect is defined as the time to meaningful pain relief, provided that the subjects experienced both perceptible and meaningful pain relief. Perceptible pain relief was defined as when the subject first began to feel any pain-relieving effect from the investigational product. Meaningful pain relief was defined as when the subject felt the degree of pain relief was meaningful to them.
Time frame: from postdose to onset of first perceptible and meaningful pain relief for up to 6 hours
Population: Efficacy analyses are based on ITT population (n=312).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Naproxen Sodium ER (BAYH6689) | Time to Onset of Effect | 1.37 hours |
| Placebo | Time to Onset of Effect | 4.13 hours |
p-value: <0.001Log Rank
Secondary
Total Pain Relief (TOTPAR)
Pain relief categorical rating scale - no relief (0), a little relief (1), some relief (2), a lot of relief (3), or complete relief (4) was used for all pain relief assessments postdose. Time weighted total pain relief (TOTPAR) was calculated by multiplying the pain relief score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values.
Time frame: 0-24 hours post dose
Population: Efficacy analyses were based on ITT population (n=312).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naproxen Sodium ER (BAYH6689) | Total Pain Relief (TOTPAR) | TOTPAR 0 - 12 hours | 25.5 units on a scale | Standard Deviation 17.06 |
| Naproxen Sodium ER (BAYH6689) | Total Pain Relief (TOTPAR) | TOTPAR 0 - 24 hours | 51.3 units on a scale | Standard Deviation 36.41 |
| Naproxen Sodium ER (BAYH6689) | Total Pain Relief (TOTPAR) | TOTPAR 0 - 16 hours | 34.1 units on a scale | Standard Deviation 23.49 |
| Naproxen Sodium ER (BAYH6689) | Total Pain Relief (TOTPAR) | TOTPAR 16 - 24 hours | 17.2 units on a scale | Standard Deviation 13.37 |
| Naproxen Sodium ER (BAYH6689) | Total Pain Relief (TOTPAR) | TOTPAR 0 - 6 hours | 12.7 units on a scale | Standard Deviation 7.81 |
| Placebo | Total Pain Relief (TOTPAR) | TOTPAR 16 - 24 hours | 3.7 units on a scale | Standard Deviation 9.4 |
| Placebo | Total Pain Relief (TOTPAR) | TOTPAR 0 - 6 hours | 3.1 units on a scale | Standard Deviation 5.07 |
| Placebo | Total Pain Relief (TOTPAR) | TOTPAR 0 - 12 hours | 5.5 units on a scale | Standard Deviation 10.7 |
| Placebo | Total Pain Relief (TOTPAR) | TOTPAR 0 - 16 hours | 7.2 units on a scale | Standard Deviation 14.83 |
| Placebo | Total Pain Relief (TOTPAR) | TOTPAR 0 - 24 hours | 10.9 units on a scale | Standard Deviation 23.95 |
p-value: <0.001ANCOVA