Pain
Conditions
Keywords
Ibuprofen, acetaminophen, pain, molar extraction
Brief summary
This study is being conducted to determine the overall analgesic efficacy and safety of a fixed-dose ibuprofen 250 mg / acetaminophen 500 mg formulation compared to placebo in subjects who are experiencing post operative pain following surgical extraction of 3 or more third molar teeth. A review of any reported adverse events will also be completed.
Interventions
DRUGFDC IBU/APAP 250 mg/500 mg
FDC IBU/APAP 250 mg/500 mg
DRUGPlacebo
Placebo
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
1. Males and females 18 years to 40 years of age (inclusive). 2. Outpatients who have undergone surgical extraction of 3 or more third molars, of which at least 2 must be a partial or complete bony mandibular impaction. 3. Subject must have at least moderate pain on the 4 point categorical scale, confirmed by at least 50 mm on the 100 mm VAS PSR scale within approximately 5 hours (ie, less than or equal to 5 hours, 15 minutes) after surgery is completed. 4. In general good health and have no contraindications to the study or rescue medication.
Exclusion criteria
1. Presence or history of any significant hepatic, renal, endocrine, cardiovascular, neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic disorder determined by the Investigator to place the subject at increased risk, including the presence or history within 2 years of screening of the following medical conditions/disorders: * Gastrointestinal ulcer or gastrointestinal bleeding; * Paralytic ileus or other gastrointestinal obstructive disorders; * Bleeding disorder. 2. Hypersensitivity to ibuprofen, naproxen, aspirin, or any other NSAID; or to APAP, tramadol, other opioids, or to their combinations. 3. Prior use of any type of analgesic or NSAID within five half lives of that drug or less before taking the first dose of investigational product, except for pre anesthetic medication and anesthesia for the procedure. .
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-weighted Sum of Pain Intensity Difference Scores on 11-Point Numerical Scale From 0 to 24 Hours Post-dose (SPID11 [0-24]) | 0 to 24 hours post dose | Pain intensity was assessed on an 11-point numerical pain severity rating scale. SPID11 \[0-24\]: Time-weighted sum of Pain Intensity Difference (PID) scores over 24 hours. SPID11 score range was -120 (worst score) to 240 (best score) for SPID 0-24. PID was calculated by subtracting the pain intensity score at given post-dose time points (pain severity score range: 0 =no pain to 10 =worst possible pain) from the baseline pain intensity scores (score range: 5 =moderate pain to 10 =worst possible pain; as participants with baseline pain score of at least moderate were included in study). Total possible score range for PID: -5 (worst score) to 10 (best score). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 0 to 8 hours, 6 to 8 hours, 0 to 16 hours, 8 to 16 hours and 0 to 48 hours post dose | Pain intensity was assessed on an 11-point numerical pain severity rating scale. SPID11 for various time intervals: Time-weighted sum of PID scores over time intervals of 0-8 hours, 6-8 hours, 0-16 hours, 8-16 hours and 0-48 hours. SPID11 score range was -40 (worst score) to 80 (best score) for (SPID11 \[0-8\]), -15 (worst score) to 30 (best score) for (SPID11 \[6-8\]), -80 (worst score) to 160 (best score) for (SPID11 \[0-16\]), -45 (worst score) to 90 (best score) for (SPID11 \[8-16\]), -240 (worst score) to 480 (best score) for (SPID11 \[0-48\]). PID was calculated by subtracting the pain intensity score at given post-dose time points (pain severity score range: 0 =no pain to 10 =worst possible pain) from the baseline pain intensity scores (score range: 5 =moderate pain to 10 =worst possible pain; as participants with baseline pain score of at least moderate were included in study). Total possible score range for PID: -5 (worst score) to 10 (best score). |
| Duration of Relief After First Dose | Up to 8 hours after first dose | Duration of relief (in minutes) was defined as the time interval from the administration of first dose of study drug up to the administration of a rescue medication or discontinuation of the participant from the study due to lack of efficacy or administration of second dose of study drug, whichever occurred first. If prior to taking rescue medication or secondary dose, a participant discontinued early from the study due to other reasons, the time was censored at time when the participant last performed a study evaluation prior to the discontinuation. |
| Time to Onset of Meaningful Pain Relief After First Dose | Up to 8 hours after first dose | Using the double stopwatch method, participants started two stopwatches soon after dosing. Participants evaluated time to meaningful relief after first dose by stopping the second stopwatch labelled as meaningful relief at the moment they first began to experience meaningful relief after the administration of first dose and prior to the administration of second dose of study drug. The stopwatch was active for up to 8 hours after dosing or until stopped by the participant, or until second dose or a rescue medication whichever is administered first. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to fixed dose combination of ibuprofen (IBU) / acetaminophen (APAP) (administered as 2 tablets) within 7 minutes of the completion of Baseline (0 hours on Day 1) pain assessments and, thereafter, every 8 hours up to 40 hours during the study duration of 48 hours. Participants were followed up to 28 days after the last dose of study drug (up to Day 30). | 41 |
| Ibuprofen 250 mg / Acetaminophen 500 mg Participants received fixed dose combination of IBU 250 mg/ APAP 500 mg (administered as 2 tablets of IBU 125 mg/APAP 250 mg) within 7 minutes of the completion of baseline (0 hours on Day 1) pain assessments and, thereafter, every 8 hours up to 40 hours during the study duration of 48 hours. Participants were followed up to 28 days after the last dose of study drug (up to Day 30). | 82 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Medication Error | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 5 |
Baseline characteristics
| Characteristic | Placebo | Ibuprofen 250 mg / Acetaminophen 500 mg | Total |
|---|---|---|---|
| Age, Continuous | 21.8 Years STANDARD_DEVIATION 4.09 | 21.8 Years STANDARD_DEVIATION 3.73 | 21.8 Years STANDARD_DEVIATION 3.84 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 5 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 35 Participants | 77 Participants | 112 Participants |
| Sex: Female, Male Female | 22 Participants | 45 Participants | 67 Participants |
| Sex: Female, Male Male | 19 Participants | 37 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 82 |
| other Total, other adverse events | 14 / 41 | 11 / 82 |
| serious Total, serious adverse events | 0 / 41 | 0 / 82 |
Outcome results
Primary
Time-weighted Sum of Pain Intensity Difference Scores on 11-Point Numerical Scale From 0 to 24 Hours Post-dose (SPID11 [0-24])
Pain intensity was assessed on an 11-point numerical pain severity rating scale. SPID11 \[0-24\]: Time-weighted sum of Pain Intensity Difference (PID) scores over 24 hours. SPID11 score range was -120 (worst score) to 240 (best score) for SPID 0-24. PID was calculated by subtracting the pain intensity score at given post-dose time points (pain severity score range: 0 =no pain to 10 =worst possible pain) from the baseline pain intensity scores (score range: 5 =moderate pain to 10 =worst possible pain; as participants with baseline pain score of at least moderate were included in study). Total possible score range for PID: -5 (worst score) to 10 (best score).
Time frame: 0 to 24 hours post dose
Population: The full analysis set (FAS) included all randomized participants who were dosed with the study medication and provided a baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time-weighted Sum of Pain Intensity Difference Scores on 11-Point Numerical Scale From 0 to 24 Hours Post-dose (SPID11 [0-24]) | -8.13 units on a Scale | Standard Error 9.426 |
| Ibuprofen 250 mg / Acetaminophen 500 | Time-weighted Sum of Pain Intensity Difference Scores on 11-Point Numerical Scale From 0 to 24 Hours Post-dose (SPID11 [0-24]) | 64.76 units on a Scale | Standard Error 6.676 |
Comparison: Treatment difference and 95 percent (%) confidence interval (CI) were based on LS Mean from analysis of covariance (ANCOVA) with treatment, gender, baseline categorical pain severity rating (PSR) as classification variables and baseline numerical PSR used as a continuous covariate.p-value: <0.00195% CI: [50.075, 95.707]ANCOVA
Secondary
Duration of Relief After First Dose
Duration of relief (in minutes) was defined as the time interval from the administration of first dose of study drug up to the administration of a rescue medication or discontinuation of the participant from the study due to lack of efficacy or administration of second dose of study drug, whichever occurred first. If prior to taking rescue medication or secondary dose, a participant discontinued early from the study due to other reasons, the time was censored at time when the participant last performed a study evaluation prior to the discontinuation.
Time frame: Up to 8 hours after first dose
Population: The FAS included all randomized participants who were dosed with the study medication and provided a baseline assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Duration of Relief After First Dose | 82.0 minutes |
| Ibuprofen 250 mg / Acetaminophen 500 | Duration of Relief After First Dose | NA minutes |
p-value: <0.001Gehan-Wilcoxon test
Secondary
Time to Onset of Meaningful Pain Relief After First Dose
Using the double stopwatch method, participants started two stopwatches soon after dosing. Participants evaluated time to meaningful relief after first dose by stopping the second stopwatch labelled as meaningful relief at the moment they first began to experience meaningful relief after the administration of first dose and prior to the administration of second dose of study drug. The stopwatch was active for up to 8 hours after dosing or until stopped by the participant, or until second dose or a rescue medication whichever is administered first.
Time frame: Up to 8 hours after first dose
Population: The FAS included all randomized participants who were dosed with the study medication and provided a baseline assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset of Meaningful Pain Relief After First Dose | 165.9 minutes |
| Ibuprofen 250 mg / Acetaminophen 500 | Time to Onset of Meaningful Pain Relief After First Dose | 59.2 minutes |
p-value: <0.001Gehan-Wilcoxon test
Secondary
Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose
Pain intensity was assessed on an 11-point numerical pain severity rating scale. SPID11 for various time intervals: Time-weighted sum of PID scores over time intervals of 0-8 hours, 6-8 hours, 0-16 hours, 8-16 hours and 0-48 hours. SPID11 score range was -40 (worst score) to 80 (best score) for (SPID11 \[0-8\]), -15 (worst score) to 30 (best score) for (SPID11 \[6-8\]), -80 (worst score) to 160 (best score) for (SPID11 \[0-16\]), -45 (worst score) to 90 (best score) for (SPID11 \[8-16\]), -240 (worst score) to 480 (best score) for (SPID11 \[0-48\]). PID was calculated by subtracting the pain intensity score at given post-dose time points (pain severity score range: 0 =no pain to 10 =worst possible pain) from the baseline pain intensity scores (score range: 5 =moderate pain to 10 =worst possible pain; as participants with baseline pain score of at least moderate were included in study). Total possible score range for PID: -5 (worst score) to 10 (best score).
Time frame: 0 to 8 hours, 6 to 8 hours, 0 to 16 hours, 8 to 16 hours and 0 to 48 hours post dose
Population: The FAS included all randomized participants who were dosed with the study medication and provided a baseline assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 6 to 8 hours | -1.46 units on a scale | Standard Error 1.123 |
| Placebo | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 8 to 16 hours | -3.68 units on a scale | Standard Error 3.794 |
| Placebo | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 0 to 8 hours | -3.12 units on a scale | Standard Error 2.708 |
| Placebo | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 0 to 48 hours | -14.97 units on a scale | Standard Error 19.668 |
| Placebo | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 0 to 16 hours | -6.24 units on a scale | Standard Error 6.028 |
| Ibuprofen 250 mg / Acetaminophen 500 | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 0 to 48 hours | 123.69 units on a scale | Standard Error 13.93 |
| Ibuprofen 250 mg / Acetaminophen 500 | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 6 to 8 hours | 6.45 units on a scale | Standard Error 0.795 |
| Ibuprofen 250 mg / Acetaminophen 500 | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 0 to 16 hours | 45.43 units on a scale | Standard Error 4.27 |
| Ibuprofen 250 mg / Acetaminophen 500 | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 8 to 16 hours | 23.64 units on a scale | Standard Error 2.687 |
| Ibuprofen 250 mg / Acetaminophen 500 | Time-weighted Sum of Pain Intensity Difference Score on 11-Point Numerical Scale (SPID11) From 0 to 8, 6 to 8, 0 to 16, 8 to 16 and 0 to 48 Hours Post-dose | 0 to 8 hours | 23.33 units on a scale | Standard Error 1.918 |
Comparison: 0 to 8 hours: Treatment difference and 95% CI were based on least square (LS) mean from analysis of covariance (ANCOVA) with treatment, gender, baseline categorical PSR as classification variables and baseline numerical PSR used as a continuous covariate.p-value: <0.00195% CI: [19.895, 33.005]ANCOVA
Comparison: 6 to 8 hours: Treatment difference and 95% CI were based on LS mean from ANCOVA with treatment, gender, baseline categorical PSR as classification variables and baseline numerical PSR used as a continuous covariate.p-value: <0.00195% CI: [5.196, 10.632]ANCOVA
Comparison: 0 to 16 hours: Treatment difference and 95% CI were based on LS mean from ANCOVA with treatment, gender, baseline categorical PSR as classification variables and baseline numerical PSR used as a continuous covariate.p-value: <0.00195% CI: [37.075, 66.258]ANCOVA
Comparison: 8 to 16 hours: Treatment difference and 95% CI were based on LS mean from ANCOVA with treatment, gender, baseline categorical PSR as classification variables and baseline numerical PSR used as a continuous covariate.p-value: <0.00195% CI: [18.139, 36.508]ANCOVA
Comparison: 0 to 48 hours: Treatment difference and 95% CI were based on LS mean from ANCOVA with treatment, gender, baseline categorical PSR as classification variables and baseline numerical PSR used as a continuous covariate.p-value: <0.00195% CI: [91.045, 186.261]ANCOVA