Pain
Conditions
Keywords
Analgesics, Dental Pain, Acetaminophen, Naproxen Sodium, Pain, Fixed-Dose
Brief summary
Study assessing the relative efficacy of five strengths of a fixed combination of acetaminophen and naproxen sodium is being investigated to help inform selection of dose(s) for further development and to evaluate the safety of a fixed combination of naproxen sodium and acetaminophen.
Detailed description
This is a randomized, double-blind, placebo-controlled study to evaluate the analgesic efficacy and safety profile of the following doses of a fixed combination of Acetaminophen (APAP)/Naproxen sodium (NPX) administered as a single two-tablet dose:\[Acetaminophen/Naproxen Sodium Dose A, Acetaminophen/Naproxen Sodium Dose B, Acetaminophen/Naproxen Sodium Dose C, Acetaminophen/Naproxen Sodium Dose D, Acetaminophen/Naproxen Sodium Dose E and Placebo\] following surgical extraction of four third molars.
Interventions
DRUGAcetaminophen/naproxen sodium Dose A
Acetaminophen/naproxen sodium Dose A administered as a single two-tablet dose.
DRUGAcetaminophen/naproxen sodium Dose B
Acetaminophen/naproxen sodium Dose B administered as a single two-tablet dose.
DRUGAcetaminophen/naproxen sodium Dose C
Acetaminophen/naproxen sodium Dose C administered as a single two-tablet dose.
DRUGAcetaminophen/naproxen sodium Dose D
Acetaminophen/naproxen sodium Dose D administered as a single two-tablet dose.
DRUGAcetaminophen/naproxen sodium Dose E
Acetaminophen/naproxen sodium Dose E administered as a single two-tablet dose.
DRUGPlacebo
Placebo tablets administered as a single two-tablet dose.
Sponsors
Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Post-operative dental pain following third molar extraction.
Eligibility
Sex/Gender
ALL
Age
17 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Males or females 17-50 years old 2. Weigh 100 pounds or greater and have a body mass index (BMI) of 17.5-35.4 (inclusive) at screening 3. Surgical removal of three or four third molars, of which, two must be mandibular impactions 4. Meets requirements for post-surgical pain level 5. Females of childbearing potential and males agree to contraceptive requirements of study 6. Have a negative urine drug screen at screening, and on day of surgical procedure
Exclusion criteria
1. Pregnant female, breastfeeding, trying to become pregnant or male with pregnant partner or partner currently trying to become pregnant 2. Have a known allergy or hypersensitivity to naproxen or other NSAIDs, including aspirin, or to acetaminophen, oxycodone or other opioids; 3. Not able to swallow whole large tablets or capsules 4. History of any condition (s) in investigator's opinion, may jeopardize subject safety, well-being and integrity of study 5. Use analgesics 5 or more times per week 6. History of chronic tranquilizer use, heavy drinking, or substance abuse, as judged by the investigator site staff, in the last 5 years 7. Use of any immunosuppressive drugs within 2 weeks of screening 8. History of endoscopically documented peptic ulcer disease or bleeding disorder in the last 2 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time Weighted Sum of Pain Intensity Difference Score From Baseline (0 Hour) to 12 Hours (SPID 0-12) | Baseline (0 hour) up to 12 hours post-dose on Day 1 | Time weighted sum of the pain intensity difference (SPID) score is derived from pain intensity difference (PID) score. Pain intensity-numerical rating scale (PI-NRS) was used to assess pain intensity on scale ranged from 0 (no pain) to 10 (very severe pain), higher score indicated severe pain intensity. PID score was the difference between baseline pain intensity and pain intensity at assessment timepoint (12 hours). The SPID scores were derived by first multiplying each PID score by the time from the previous time point and adding these time weighted PID scores together over the interval from 0 to 12 hours. The possible range of SPID for 0 to 12 hours was from -120 to 120. A higher value of SPID indicated greater pain relief. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time Weighted Sum of Total Pain Relief Score From Baseline (0 Hour) to 12 Hours (TOTPAR 0-12) | Baseline (0 hour) up to 12 hours post-dose on Day 1 | Time weighted total pain relief (TOTPAR) was measured using a Pain Relief Numerical Rating Scale (PR-NRS) ranging from 0 to10 (0 = no relief, 10 = complete relief). A higher score indicated greater pain relief. Total pain relief scores (TOTPARs) were calculated by multiplying the pain relief score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values. The minimum value was 0, and the maximum value was 120. Higher scores were indicative of more pain relief. |
| Time Weighted Sum of Pain Intensity Difference Score From 6 Hours to 12 Hours (SPID 6-12) | From 6 hours up to 12 hours post-dose on Day 1 | Time weighted sum of the pain intensity difference (SPID) score is derived from PID score. PI-NRS was used to assess pain intensity on scale ranged from 0 (no pain) to 10 (very severe pain), higher score indicated severe pain intensity. PID was the difference between pain intensity at 6 hours and pain intensity at assessment timepoint (12 hours). The SPID scores were derived by first multiplying each PID score by the time from the previous time point and adding these time weighted PID scores together over the intervals from 6 to 12 hours (6 hours). The possible range of SPID for 6 to12 hours was from -60 to 60. A higher value of SPID indicated greater pain relief. |
| Time to First Use of Rescue Analgesic Medication | From 0 minute up to 1440 minutes post-dose (that is, up to 24 hours post-dose) on Day 1 | Time to first use of rescue analgesic medication was measured as the elapsed time (in minutes) from when the investigational product was given until the time rescue analgesic was first given. Participants who did not use rescue medication during the 24 hour study period had their time to rescue set to 24 hours and were censored at 24 hours. Kaplan-Meier method was used for the analysis. |
| Proportion of Participants Who Required Rescue Analgesic Medication | From 0 hour up to 24 hours post-dose on Day 1 | Proportion (cumulative data) of participants who used rescue analgesic medication through 24 hours post study drug administration on Day 1 which was assessed by using Kaplan-Meier estimates were reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants who underwent dental extraction of three or four third molars received a single oral dose of two placebo tablets on Day 1 post dental extraction. | 53 |
| Acetaminophen/Naproxen Sodium Dose A Participants who underwent dental extraction of three or four third molars received two tablets of fixed combination of acetaminophen and naproxen sodium Dose A orally on Day 1 post dental extraction. | 49 |
| Acetaminophen/Naproxen Sodium Dose B Participants who underwent dental extraction of three or four third molars received two tablets of fixed combination of acetaminophen and naproxen sodium Dose B orally on Day 1 post dental extraction. | 53 |
| Acetaminophen/Naproxen Sodium Dose C Participants who underwent dental extraction of three or four third molars received two tablets of fixed combination of acetaminophen and naproxen sodium Dose C orally on Day 1 post dental extraction. | 52 |
| Acetaminophen/Naproxen Sodium Dose D Participants who underwent dental extraction of three or four third molars received two tablets of fixed combination of acetaminophen and naproxen sodium Dose D orally on Day 1 post dental extraction. | 51 |
| Acetaminophen/Naproxen Sodium Dose E Participants who underwent dental extraction of three or four third molars received two tablets of fixed combination of acetaminophen and naproxen sodium Dose E orally on Day 1 post dental extraction. | 46 |
| Total | 304 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 | 3 | 3 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Acetaminophen/Naproxen Sodium Dose D | Total | Acetaminophen/Naproxen Sodium Dose E | Placebo | Acetaminophen/Naproxen Sodium Dose A | Acetaminophen/Naproxen Sodium Dose B | Acetaminophen/Naproxen Sodium Dose C |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 18.5 Years STANDARD_DEVIATION 1.82 | 18.5 Years STANDARD_DEVIATION 1.83 | 18.2 Years STANDARD_DEVIATION 1.5 | 18.5 Years STANDARD_DEVIATION 1.78 | 18.4 Years STANDARD_DEVIATION 1.83 | 18.6 Years STANDARD_DEVIATION 2.05 | 18.7 Years STANDARD_DEVIATION 1.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 36 Participants | 9 Participants | 12 Participants | 6 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 267 Participants | 37 Participants | 40 Participants | 43 Participants | 48 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 7 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 50 Participants | 292 Participants | 45 Participants | 50 Participants | 48 Participants | 51 Participants | 48 Participants |
| Sex: Female, Male Female | 27 Participants | 154 Participants | 24 Participants | 25 Participants | 27 Participants | 26 Participants | 25 Participants |
| Sex: Female, Male Male | 24 Participants | 150 Participants | 22 Participants | 28 Participants | 22 Participants | 27 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 49 | 0 / 53 | 0 / 52 | 0 / 51 | 0 / 46 |
| other Total, other adverse events | 12 / 53 | 7 / 49 | 6 / 53 | 5 / 52 | 3 / 51 | 3 / 46 |
| serious Total, serious adverse events | 0 / 53 | 0 / 49 | 0 / 53 | 0 / 52 | 0 / 51 | 0 / 46 |
Outcome results
Primary
Time Weighted Sum of Pain Intensity Difference Score From Baseline (0 Hour) to 12 Hours (SPID 0-12)
Time weighted sum of the pain intensity difference (SPID) score is derived from pain intensity difference (PID) score. Pain intensity-numerical rating scale (PI-NRS) was used to assess pain intensity on scale ranged from 0 (no pain) to 10 (very severe pain), higher score indicated severe pain intensity. PID score was the difference between baseline pain intensity and pain intensity at assessment timepoint (12 hours). The SPID scores were derived by first multiplying each PID score by the time from the previous time point and adding these time weighted PID scores together over the interval from 0 to 12 hours. The possible range of SPID for 0 to 12 hours was from -120 to 120. A higher value of SPID indicated greater pain relief.
Time frame: Baseline (0 hour) up to 12 hours post-dose on Day 1
Population: Intent-to-Treat (ITT) analysis set included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time Weighted Sum of Pain Intensity Difference Score From Baseline (0 Hour) to 12 Hours (SPID 0-12) | 5.59 Units on a scale | Standard Deviation 3.741 |
| Acetaminophen/Naproxen Sodium Dose A | Time Weighted Sum of Pain Intensity Difference Score From Baseline (0 Hour) to 12 Hours (SPID 0-12) | 37.08 Units on a scale | Standard Deviation 3.892 |
| Acetaminophen/Naproxen Sodium Dose B | Time Weighted Sum of Pain Intensity Difference Score From Baseline (0 Hour) to 12 Hours (SPID 0-12) | 46.98 Units on a scale | Standard Deviation 3.74 |
| Acetaminophen/Naproxen Sodium Dose C | Time Weighted Sum of Pain Intensity Difference Score From Baseline (0 Hour) to 12 Hours (SPID 0-12) | 52.45 Units on a scale | Standard Deviation 3.779 |
| Acetaminophen/Naproxen Sodium Dose D | Time Weighted Sum of Pain Intensity Difference Score From Baseline (0 Hour) to 12 Hours (SPID 0-12) | 59.63 Units on a scale | Standard Deviation 3.813 |
| Acetaminophen/Naproxen Sodium Dose E | Time Weighted Sum of Pain Intensity Difference Score From Baseline (0 Hour) to 12 Hours (SPID 0-12) | 65.52 Units on a scale | Standard Deviation 4.027 |
p-value: <0.00195% CI: [20.9, 42.07]ANOVA
p-value: <0.00195% CI: [31.02, 51.75]ANOVA
p-value: <0.00195% CI: [36.44, 57.27]ANOVA
p-value: <0.00195% CI: [43.57, 64.51]ANOVA
p-value: <0.00195% CI: [49.16, 70.68]ANOVA
Secondary
Proportion of Participants Who Required Rescue Analgesic Medication
Proportion (cumulative data) of participants who used rescue analgesic medication through 24 hours post study drug administration on Day 1 which was assessed by using Kaplan-Meier estimates were reported.
Time frame: From 0 hour up to 24 hours post-dose on Day 1
Population: ITT analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Participants Who Required Rescue Analgesic Medication | 0.792 Proportion of participants |
| Acetaminophen/Naproxen Sodium Dose A | Proportion of Participants Who Required Rescue Analgesic Medication | 0.571 Proportion of participants |
| Acetaminophen/Naproxen Sodium Dose B | Proportion of Participants Who Required Rescue Analgesic Medication | 0.519 Proportion of participants |
| Acetaminophen/Naproxen Sodium Dose C | Proportion of Participants Who Required Rescue Analgesic Medication | 0.353 Proportion of participants |
| Acetaminophen/Naproxen Sodium Dose D | Proportion of Participants Who Required Rescue Analgesic Medication | 0.353 Proportion of participants |
| Acetaminophen/Naproxen Sodium Dose E | Proportion of Participants Who Required Rescue Analgesic Medication | 0.152 Proportion of participants |
p-value: 0.014Wald method
p-value: 0.002Wald method
p-value: <0.001Wald method
p-value: <0.001Wald method
p-value: <0.001Wald method
Secondary
Time to First Use of Rescue Analgesic Medication
Time to first use of rescue analgesic medication was measured as the elapsed time (in minutes) from when the investigational product was given until the time rescue analgesic was first given. Participants who did not use rescue medication during the 24 hour study period had their time to rescue set to 24 hours and were censored at 24 hours. Kaplan-Meier method was used for the analysis.
Time frame: From 0 minute up to 1440 minutes post-dose (that is, up to 24 hours post-dose) on Day 1
Population: ITT analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Use of Rescue Analgesic Medication | 90.0 Minutes |
| Acetaminophen/Naproxen Sodium Dose A | Time to First Use of Rescue Analgesic Medication | 898.0 Minutes |
| Acetaminophen/Naproxen Sodium Dose B | Time to First Use of Rescue Analgesic Medication | 1195.0 Minutes |
| Acetaminophen/Naproxen Sodium Dose C | Time to First Use of Rescue Analgesic Medication | NA Minutes |
| Acetaminophen/Naproxen Sodium Dose D | Time to First Use of Rescue Analgesic Medication | NA Minutes |
| Acetaminophen/Naproxen Sodium Dose E | Time to First Use of Rescue Analgesic Medication | NA Minutes |
p-value: <0.001Wilcoxon test
p-value: <0.001Wilcoxon test
p-value: <0.001Wilcoxon test
p-value: <0.001Wilcoxon test
p-value: <0.001Wilcoxon test
Secondary
Time Weighted Sum of Pain Intensity Difference Score From 6 Hours to 12 Hours (SPID 6-12)
Time weighted sum of the pain intensity difference (SPID) score is derived from PID score. PI-NRS was used to assess pain intensity on scale ranged from 0 (no pain) to 10 (very severe pain), higher score indicated severe pain intensity. PID was the difference between pain intensity at 6 hours and pain intensity at assessment timepoint (12 hours). The SPID scores were derived by first multiplying each PID score by the time from the previous time point and adding these time weighted PID scores together over the intervals from 6 to 12 hours (6 hours). The possible range of SPID for 6 to12 hours was from -60 to 60. A higher value of SPID indicated greater pain relief.
Time frame: From 6 hours up to 12 hours post-dose on Day 1
Population: ITT analysis set included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time Weighted Sum of Pain Intensity Difference Score From 6 Hours to 12 Hours (SPID 6-12) | 2.58 Units on a scale | Standard Deviation 2.154 |
| Acetaminophen/Naproxen Sodium Dose A | Time Weighted Sum of Pain Intensity Difference Score From 6 Hours to 12 Hours (SPID 6-12) | 15.12 Units on a scale | Standard Deviation 2.241 |
| Acetaminophen/Naproxen Sodium Dose B | Time Weighted Sum of Pain Intensity Difference Score From 6 Hours to 12 Hours (SPID 6-12) | 20.31 Units on a scale | Standard Deviation 2.153 |
| Acetaminophen/Naproxen Sodium Dose C | Time Weighted Sum of Pain Intensity Difference Score From 6 Hours to 12 Hours (SPID 6-12) | 24.47 Units on a scale | Standard Deviation 2.176 |
| Acetaminophen/Naproxen Sodium Dose D | Time Weighted Sum of Pain Intensity Difference Score From 6 Hours to 12 Hours (SPID 6-12) | 27.59 Units on a scale | Standard Deviation 2.195 |
| Acetaminophen/Naproxen Sodium Dose E | Time Weighted Sum of Pain Intensity Difference Score From 6 Hours to 12 Hours (SPID 6-12) | 31.89 Units on a scale | Standard Deviation 2.318 |
p-value: <0.00195% CI: [6.44, 18.63]ANOVA
p-value: <0.00195% CI: [11.76, 23.7]ANOVA
p-value: <0.00195% CI: [15.89, 27.88]ANOVA
p-value: <0.00195% CI: [18.98, 31.03]ANOVA
p-value: <0.00195% CI: [23.11, 35.5]ANOVA
Secondary
Time Weighted Sum of Total Pain Relief Score From Baseline (0 Hour) to 12 Hours (TOTPAR 0-12)
Time weighted total pain relief (TOTPAR) was measured using a Pain Relief Numerical Rating Scale (PR-NRS) ranging from 0 to10 (0 = no relief, 10 = complete relief). A higher score indicated greater pain relief. Total pain relief scores (TOTPARs) were calculated by multiplying the pain relief score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values. The minimum value was 0, and the maximum value was 120. Higher scores were indicative of more pain relief.
Time frame: Baseline (0 hour) up to 12 hours post-dose on Day 1
Population: ITT analysis set included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time Weighted Sum of Total Pain Relief Score From Baseline (0 Hour) to 12 Hours (TOTPAR 0-12) | 18.40 Units on a scale | Standard Deviation 4.55 |
| Acetaminophen/Naproxen Sodium Dose A | Time Weighted Sum of Total Pain Relief Score From Baseline (0 Hour) to 12 Hours (TOTPAR 0-12) | 54.06 Units on a scale | Standard Deviation 4.734 |
| Acetaminophen/Naproxen Sodium Dose B | Time Weighted Sum of Total Pain Relief Score From Baseline (0 Hour) to 12 Hours (TOTPAR 0-12) | 67.45 Units on a scale | Standard Deviation 4.548 |
| Acetaminophen/Naproxen Sodium Dose C | Time Weighted Sum of Total Pain Relief Score From Baseline (0 Hour) to 12 Hours (TOTPAR 0-12) | 72.04 Units on a scale | Standard Deviation 4.597 |
| Acetaminophen/Naproxen Sodium Dose D | Time Weighted Sum of Total Pain Relief Score From Baseline (0 Hour) to 12 Hours (TOTPAR 0-12) | 79.33 Units on a scale | Standard Deviation 4.637 |
| Acetaminophen/Naproxen Sodium Dose E | Time Weighted Sum of Total Pain Relief Score From Baseline (0 Hour) to 12 Hours (TOTPAR 0-12) | 85.98 Units on a scale | Standard Deviation 4.898 |
p-value: <0.00195% CI: [22.79, 48.54]ANOVA
p-value: <0.00195% CI: [36.44, 61.65]ANOVA
p-value: <0.00195% CI: [40.97, 66.31]ANOVA
p-value: <0.00195% CI: [48.19, 73.67]ANOVA
p-value: <0.00195% CI: [54.49, 80.67]ANOVA