PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert.

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1 PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. PROPRIETARY DRUG NAME / GENERIC DRUG NAME: Advil / Ibuprofen Sodium PROTOCOL NO.: AH (B ) PROTOCOL TITLE: Evaluation of the Efficacy of a Novel Ibuprofen Formulation in the Treatment of Post-Surgical Dental Pain Study Center: This was a single-center study conducted in the United States (US). Study Initiation and Final Completion Dates: 11 October 2010 to 14 January 2011 Phase of Development: Phase 3 Study Objective: The objective of this study was to evaluate the efficacy of a single dose of a novel ibuprofen (IBU) formulation, ibuprofen sodium tablets (; mg [equivalent to IBU 400 mg]) in the third molar extraction model of dental pain compared to a single dose of acetaminophen tablets (Extra strength Tylenol []; mg) and placebo. METHODS Study Design: This was a single-dose, double-blind (third-party dispenser-blind), randomized, placebo and active-controlled, single-center, inpatient study in subjects with dental pain after surgical extraction of 2 or more third molars. Eligible subjects were stratified by pain severity (moderate or severe) and gender, randomized (1:2:2 ratio) to receive placebo, IBU, or, respectively, and evaluated on-site for 6 hours following administration of a single dose of tablets (2 256 mg, equivalent to 400 mg IBU), (2 500 mg) or placebo. Subjective assessments of pain intensity and pain relief, using standardized categorical scales, were performed at regular intervals for up to 6 hours postdosing (Table 1). A flow chart of study procedure is provided in Table 1. Template version 1.1 Page 1

2 Table 1. Study Flow Chart Procedure Screening a Surgery Time (hours) Informed consent Medical history Urine pregnancy test a Surgical procedure Surgical trauma scale Vital signs (HR, BP, temperature, respiration) Randomization b Dosing Pain evaluation Categorical Pain Severity Rating Scale c Visual Analog Pain Severity Rating Scale d Categorical Pain Relief Rating Scale e Time to first perceptible relief f Time to meaningful relief g Subject global evaluation h Subjects taking a rescue medication during this time was Discontinued considered i : Adverse events Recorded at any time during the study as they occur. BP = blood pressure; HR = heart rate. a. Screening must be within 21 days of surgery; it may occur on the morning of surgery. Pregnancy test must be performed in the morning of surgery. b. Those subjects meeting all inclusion/exclusion criteria, including at least moderate baseline pain on the categorical pain severity rating scale confirmed by a score of at least 50 mm on a 100-mm visual analog pain severity rating scale. c. 4-point categorical pain severity rating scale: none =0, mild = 1, moderate = 2, and severe = 3. Completed at each time-point and immediately before rescue medication use (if it occurs before Hour 6). d. 100-mm visual analog pain severity rating scale: none = 0 to severe = 100. e. 5-point categorical pain relief rating scale: none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. Completed at each time point and immediately before rescue medication use (if it occurs before Hour 6). f. Subject stops the first stopwatch at any time you first begin to feel any pain relief. g. Subject stops the second stopwatch at any time the pain relief is meaningful to you. h. 6-point categorical scale ranging from very poor = 0, poor = 1, fair = 2, good = 3, very good = 4, and excellent = 5. Completed at the end of the study or immediately before rescue medication use (if it occurs before Hour 6). i. Subjects taking rescue medication within 1 hour after the first dose of study medication (ie, prior to 1-hour assessment) was considered discontinued and must be replaced. Template version 1.1 Page 2

3 Number of Subjects (Planned and Analyzed): Approximately 237 subjects were planned to be enrolled to ensure that a minimum of approximately 215 subjects completing the study. A total of 218 subjects were randomized, received study medication, and were included in the intent-to-treat (ITT) and safety populations, with 45, 88, and 85 subjects in the placebo,, and groups, respectively. All subjects were enrolled at single-center in the US. Diagnosis and Main Criteria for Inclusion: Healthy male and female, years of age, outpatients with moderate to severe post-operative pain (confirmed by a Visual Analog Scale-Pain Severity Rating [VAS-PSR] Score of at least 50 mm on a 100 mm VAS PSR) following surgical extraction of 2 or more third molars, at least 1 of which had to be a partial or complete bony mandibular impaction. Permitted were the following pre-operative medication(s)/anesthetic(s): topical benzocaine, a short acting parenteral (local) anesthetic (mepivacaine or lidocaine) with or without vasoconstrictor and/or nitrous oxide. Study Treatment:,, and placebo tablets were provided by the Sponsor, in an unblinded fashion. To maintain the double-blind, the third party dispenser prepared the study drug for each subject in a designated dispensing room: after the study coordinator communicated the subjects stratification criteria (ie, baseline pain severity and gender) to the dispenser, who assigned the next available randomization number of the appropriate stratum to the subject, and dispensed the respective 2 tablets into an individual opaque plastic bottle for subject administration. Study treatments were as follows: Treatment A: 2 tablets. Treatment B: 2 tablets. Treatment C: 2 Placebo tablets. Efficacy Endpoints: Co-Primary Efficacy Endpoints: SPRID 0-6 (sum of Pain Intensity Difference (PID) scores and Pain Relief (PR) scores from 0-6 hours after dosing); Time to onset of meaningful relief. Secondary Efficacy Endpoints: Time to onset of first perceptible relief, confirmed by meaningful relief; Pain Relief Rating (PRR): scored on the 5-point Categorical Pain Relief Rating Scale (0 = No relief to 4 = Complete relief) at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours postdose; Template version 1.1 Page 3

4 Pain Intensity Difference (PID): scored on the 4-point Categorical Pain Severity Rating Scale (0 = None to 3 = Severe) at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours postdose; The sum of Pain Relief Rating and Pain Intensity Difference Scores (PRID) at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours postdose; Summary Efficacy Scores: Time-weighted sum of Pain Intensity Difference Scores over 2 hours (SPID2), over 3 hours (SPID3), and over 6 hours (SPID6) postdosing; Time-weighted sum of Pain Relief Rating Scores over 2 hours (TOTPAR2), over 3 hours (TOTPAR3), and over 6 hours (TOTPAR6) postdosing; Time-weighted sum of Pain Relief Rating Scores combined with pain intensity difference scores over 2 hours (SPRID2), and 3 hours (SPRID3) postdosing; The cumulative proportion of subjects achieving meaningful and first perceptible relief (confirmed by meaningful relief) by each postdosing time-point (ie, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours postdose); Duration of relief, as measured by the time to treatment failure; The cumulative proportion of treatment failures by each postdosing time point (ie, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours postdose); The cumulative proportion of subjects achieving complete relief by each post-dosing time-point (ie, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours postdose); Subject global evaluation of study medication. Safety Evaluations: Vital signs (ie, blood pressure, heart rate, temperature, and respiratory rate) were taken at Baseline and at the end of the study or at the time of rescue medication use, if needed. AEs (adverse event) were coded by the MedDRA (Medical Dictionary for Regulatory Activities) version (v)13.0 system organ class (SOC) and preferred term (PT), and classified by severity (mild, moderate, or severe) and relationship (related or not related) to study product. For the summary by severity, subjects who had multiple occurrences of the same AE were classified according to the worst reported severity of the AE. Similarly, for the summary by relationship to the study product, the AE was classified according to the closest relationship. Statistical Methods: The primary efficacy analysis was based on the ITT population, which included all randomized subjects who dosed with study product, and provided a baseline assessment. The efficacy parameters were also analyzed within each baseline pain stratum (moderate versus [vs] severe pain). Template version 1.1 Page 4

5 The safety population consisted of all subjects who took study product and had follow-up data. The summary scores of SPID, TOTPAR and SPRID from 0-2, 0-3, and 0-6 hours, as well as pain relief, PID and PRID scores at each postdosing time point were analyzed by analysis of variance with treatment, gender, baseline categorical pain severity, and treatment-by-baseline pain severity interaction (since it was significant for the majority of the pain intensity/relief measurements) terms in the model. Time to confirmed first perceptible relief, meaningful relief, and treatment failure were analyzed using the Proportional Hazards regression (PH) model, with terms for treatment, gender, and baseline pain severity terms in the model. Subject Global Evaluation of study medication was analyzed via the Cochran-Mantel-Haenzel row mean score test controlling for gender and baseline pain severity, using modified ridit scores. In order to protect the type 1 error due to multiple comparisons and multiple endpoints, the treatment comparisons of specific primary endpoints were performed as follows: 1. vs placebo for SPRID 0-6; 2. vs placebo for time to meaningful relief; 3. vs acetaminophen for SPRID 0-6; 4. vs acetaminophen for meaningful relief; 5. Acetaminophen vs placebo for SPRID 0-6; 6. Acetaminophen vs placebo for meaningful relief. Steps 1 through 6 were tested sequentially at the 5% level of significance (two-sided) to evaluate the alternate hypothesis that the first treatment was better than the second. If any comparison at the preceding step(s) was not statistically significant, the subsequent comparison was technically ineligible to be declared significant. To provide a complete picture, the results of all the pair-wise comparisons were presented regardless of any technical ineligibilities. The secondary endpoints were tested in a similar order, ie, vs placebo, followed by vs, followed by vs placebo. The incidence of treatment-emergent adverse events (TEAEs) among treatment groups was analyzed via Fisher s exact test. Template version 1.1 Page 5

6 RESULTS Subject Disposition and Demography: A total of 218 subjects were enrolled and received study medication, and were included in the primary ITT population and safety population: 45, 88, and 85 subjects were randomized to the placebo,, and groups, respectively. All except 2 subjects completed the study per-protocol and thus 216 subjects were included in the per-protocol analysis. The 2 subjects not completing the study had withdrawn their consent after completing the 5-hour efficacy assessment. The subject disposition and analysis sets are presented below in Table 2. Table 2. Subject Disposition and Analysis Sets Number of Subjects Placebo mg Screened 271 Enrolled (randomized) Received treatment (safety) ITT population Discontinued 1 1 Per-protocol population (completed) = acetaminophen; IBU = ibuprofen; ITT = intent to treat mg Overall, the treatment groups were comparable with respect to demographic characteristics. Basic demographic characteristics are summarized below in Table 3 Template version 1.1 Page 6

7 Table 3. Summary of Demographic Characteristics Total N=218 Placebo N= mg N= mg N=85 p-value a Gender Male 108 (49.5%) 22 (48.9%) 43 (48.9%) 43 (50.6%) Female 110 (50.5%) 23 (51.1%) 45 (51.1%) 42 (49.4%) Race White 202 (92.7%) 43 (95.6%) 79 (89.8%) 80 (94.1%) Black 2 (0.9%) 1 (2.2%) 0 (0%) 1 (1.2%) Asian 1 (0.5%) 0 (0%) 1 (1.1%) 0 (0%) Amer Indian/Alaskan 3 (1.4%) 0 (0%) 2 (2.3%) 1 (1.2%) Native Other 10 (4.6%) 1 (2.2%) 6 (6.8%) 3 (3.5%) Ethnicity Not Hispanic or Latino 200 (91.7%) 43 (95.6%) 79 (89.8%) 78 (91.8%) Hispanic or Latino 18 (8.3%) 2 (4.4%) 9 (10.2%) 7 (8.2%) Age (yr.) Mean SD Median Range (16, 31) (16, 24) (16, 31) (16, 29) ANOVA = analysis of variance; = acetaminophen; CMH = Cochran Mantel Haenzel; IBU = ibuprofen; ITT = intent to treat; PSR = pain severity rating; SD = standard deviation. a. p-value for gender, race, and ethnicity are from CMH test, controlling for baseline PSR and gender when appropriate, p-value for ages is from ANOVA model with treatment, baseline PSR, and gender terms. Efficacy Results: (2 256 mg, equivalent to IBU 400 mg) provided superior analgesic efficacy compared to over the 6 hour evaluation period as shown by SPRID 0-6 (co-primary parameter) and the summary efficacy parameters SPRID, SPID and TOTPAR over 2, 3, and 6 hours, while both active treatments were significantly better than placebo for all these parameters. In addition, was significantly better than and both treatments were better than placebo for the global evaluation of study medication as a pain reliever. Both and provided significantly faster onset of meaningful relief compared to placebo, although the 2 active treatments were not significantly different from each other. The duration of effect (time to treatment failure) for both active treatments in this study exceeded the 6 hours. Although, both active treatment groups were significantly better than placebo in terms of treatment failure, they were not significantly different from each other. Overall, and provided superior analgesic efficacy compared to placebo over 6 hours. also demonstrated significantly better overall analgesic efficacy compared to. The 2 active treatments provided significantly faster onset of pain relief compared to placebo, and were not statistically different from each other. See Table 4 below for a summary of primary and key secondary efficacy parameters. Template version 1.1 Page 7

8 Table 4. Summary of Results for Primary and Key Secondary Parameters Mean (SD) p-values Parameter Placebo (n=45) mg mg a vs PBO vs vs Placebo (n=88) (n=85) SPRID (9.9) 20.0 (11.6) 17.1 (11.9) <0.001 b b <0.001 c Median Time to >6hrs 58.0 min 53.4 min <0.001 b <0.001 c Meaningful relief SPRID (2.4) 6.9 (3.1) 6.0 (3.3) <0.001 b b <0.001 b SPRID (4.2) 10.6 (5.2) 9.1 (5.3) <0.001 b b <0.001 b SPID (1.1) 2.2 (1.4) 1.8 (1.4) <0.001 b b <0.001 b SPID (1.9) 3.4 (2.3) 2.8 (2.1) <0.001 b b <0.001 b SPID (4.4) 6.3 (5.0) 5.1 (4.6) <0.001 b b <0.001 b TOTPAR (1.4) 4.7 (1.9) 4.2 (2.0) <0.001 b b <0.001 b TOTPAR (2.5) 7.2 (3.1) 6.4 (3.4) <0.001 b b <0.001 b TOTPAR (5.9) 13.6 (7.0) 12.0 (7.6) <0.001 b b <0.001 b Median time to >6 hrs 18.0 min 23.7 min <0.001 b <0.001 b FPR d Confirmed by meaningful relief Median time to 1.6 hrs >6 hrs >6 hrs <0.001 b <0.001 b treatment failure Global evaluation 0.9 (1.3) 3.5 (1.3) 3.0 (1.5) <0.001 b b <0.001 b The two primary parameters are bolded. = acetaminophen; IBU = ibuprofen; ITT = intent to treat; PSR = pain severity rating; SD = standard deviation; SPID = time-weighted sum of pain intensity difference; SPRID = time-weighted sum of PRID Scores; TOTPAR = time-weighted sum of pain relief scores. a. Acetaminophen tablets (extra strength tylenol) b. p 0.05 in favor of the first treatment listed relative to the second (regardless of technical ineligibilities) c. p 0.05 in favor of the first treatment listed relative to the second but technically ineligible to be declared significant d. FPR First perceptible relief Co-Primary Efficacy Parameters SPRID 0-6 and Time to Onset of Meaningful Relief: was significantly better than placebo (p <0.001) and (p = 0.010) for SPRID 0-6. Subjects in the group reported meaningful relief significantly sooner (median = 58.0 minutes) compared to those in the placebo group (median >6 hours with less than 14% reporting meaningful relief). had a significantly faster onset of relief (median = 53.4 minutes) relative to placebo. The time to meaningful relief for was not significantly different from that for. By the end of the study, 13.3%, 79.5%, and 74.1% of subjects in the placebo,, and groups, respectively, had achieved meaningful relief. The onset of meaningful relief over time (Kaplan-Meier plot) for the overall population is illustrated in Figure 1. Template version 1.1 Page 8

9 Figure 1. Time to Meaningful Relief : Significantly better than placebo at level. Secondary Efficacy Parameters Summary parameters - SPRID, SPID and TOTPAR over 2, 3, and 6 hours: The results for the 2, 3, and 6-hours summary parameters SPRID, SPID and TOTPAR were consistent with those for SPRID 0-6, in that was significantly better than placebo and. Figure 2 graphically illustrates all summary efficacy measures, including the primary, SPRID 0-6. Template version 1.1 Page 9

10 Figure 2. : Summary Efficacy Measures Placebo (n=45) 2x256 mg (n=88) 2x500 mg (n=85) A Mean Score + std error 13 8 A 3-2 SPID 0-2 TOTPAR 0-2 SPRID 0-2 SPID 0-3 TOTPAR 0-3 SPRID 0-3 SPID 0-6 TOTPAR 0-6 SPRID 0-6 : Significantly better than placebo at level. A: Significantly better than at level; at 0.01 level; A- at 0.05 level PRID, PID, and Pain Relief Over Time: The mean PRID, PID and PR for both and groups were significantly better than placebo starting from the first evaluation time point (15 minutes) through the end of the study (6 hours). In addition, was significantly better than starting from the 15 minute (for PRID), 30 minute (for PID) time point through the end of the study at the majority of time points. For PR, trended better than at all time points with some achieving statistical significance (1-hour, 2-hour, 3-hour and 4-hour time points). The PRID scores over time are presented in Figure 3. Template version 1.1 Page 10

11 Figure 3. PRID Scores Over Time A A Mean PRID Score A PP 0.50 P Time (hr) Placebo (n=45) 2x256 mg (n=88) 2x500 mg (n=85) : Significantly better than placebo at level; PP at 0.01 level; P- at 0.05 level : Significantly better than at 0.01 level; A- at 0.05 level. First Perceptible Relief: Confirmed FPR was achieved significantly sooner with (median = 18.0 minutes) compare to placebo (median >8 hours with ~14% of subjects experiencing confirmed FPR) but not compared to (median = 23.7 minutes). By the end of the study, 13.3%, 79.5%, 74.1% of subjects in the placebo,, and groups, respectively, had achieved FPR confirmed by meaningful relief. Global Evaluation: Both active treatment groups were significantly better than placebo. In addition, was significantly superior to (p = 0.02). Time to Treatment Failure: All treatment failures were due to taking rescue medication. The time to treatment failure was significantly (p <0.001) longer for and compared to placebo, with median times of more than 6 hours for the two active groups and 1.6 hours for placebo. was not significantly different compared to. By the end of the study 82.2%, 29.5% and 35.3% of subjects in the placebo,, and groups, respectively, required rescue medication. Figure 4 shows time to treatment failure (Kaplan-Meier plot) over time. Template version 1.1 Page 11

12 Figure 4. Time to Treatment Failure : Significantly better than placebo at level. Results of Subgroup Analyses: Per protocol, the efficacy parameters were analyzed within each baseline pain stratum, as it was of interest to evaluate the efficacy of the treatments among subjects with different levels of baseline pain. The subgroups were considered technically ineligible for being declared significant unless the corresponding analysis with all (ITT) subjects was significant. Results Of Subjects With Moderate Pain At Baseline: A total of 157/218 (72.0% of ITT) subjects entered the study with moderate pain at Baseline: 33/45 in the placebo group, 64/88 in the group, and 60/85 in the group. As with the ITT population, both active treatments were significantly better than placebo for all parameters within this subgroup. Although the differences between the 2 active treatments numerically favored the for most endpoints/time points, these differences were marginal. The results for the co-primary and key secondary parameters are summarized in Table 5. Template version 1.1 Page 12

13 Table 5. Summary of Results for Primary and Key Secondary Parameters for Subjects with Moderate Pain at Baseline Mean (SD) P-values Parameter Placebo (n=33) mg (n=64) mg a (n=60) vs PBO Vs vs Placebo SPRID (9.5) 18.4 (11.5) 18.2 (11.4) <0.001 b <0.001 c Median Time to Meaningful Relief >6hrs 59.1 min 52.8 min <0.001 b <0.001 c SPRID (2.4) 6.5 (3.2) 6.1 (3.2) <0.001 b <0.001 c SPRID (4.0) 9.9 (5.2) 9.4 (5.2) <0.001 b <0.001 c SPID (1.1) 1.9 (1.2) 1.6 (1.2) <0.001 b <0.001 c SPID (1.8) 2.8 (2.0) 2.5 (2.0) <0.001 b <0.001 c SPID (4.2) 5.0 (4.0) 4.8 (4.3) <0.001 b <0.001 c TOTPAR (1.4) 4.6 (2.1) 4.5 (2.0) <0.001 b <0.001 c TOTPAR (2.4) 7.1 (3.3) 6.9 (3.2) <0.001 b <0.001 c TOTPAR (5.8) 13.4 (7.3) 13.4 (7.2) <0.001 b <0.001 c Median time to FPR d Confirmed by Meaningful >6 hrs 17.4 min 22.2 min <0.001 b <0.001 c Relief Median Time to Treatment Failure 1.7 hrs >6 hrs >6 hrs <0.001 b <0.001 c Global Evaluation 0.8 (1.3) 3.5 (1.3) 3.2 (1.4) <0.001 b <0.001 c The two primary parameters are bolded. = acetaminophen; IBU = ibuprofen; ITT = intent to treat; PSR = pain severity rating; SD = standard deviation; SPID = time-weighted sum of pain intensity difference; SPRID = time-weighted sum of PRID Scores; TOTPAR = time-weighted sum of pain relief scores. a. -Acetaminophen tablets (extra strength tylenol) b. p 0.05 in favor of the first treatment listed relative to the second (regardless of technical ineligibilities) c. p 0.05 in favor of the first treatment listed relative to the second but technically ineligible to be declared significant d. FPR First perceptible relief Results Of Subjects With Severe Pain At Baseline: A total of 61 (28.0%) of ITT subjects entered the study with a severe pain at baseline: 12/45 in the placebo group, 24/88 in the group, and 25/85 in the group. The results for this subgroup were generally consistent with those observed for the entire ITT population in terms of the direction of the treatment differences. Relative to the ITT population, the magnitude of the differences favoring over were stronger in this subgroup. However, due to the decrease in the sample size for the subgroup, statistical significance was not always achieved even with the wider numerical separation. The results for SPRID 0-6 were consistent with those observed with the entire ITT population. As for the time to meaningful relief, compared to placebo (median >6 hours) both active groups had a faster onset (p 0.05) while had a marginally significantly faster onset compared to ( median:52.5 minutes vs median:79.0 minutes, p = 0.072). The results for the co-primary and key secondary parameters for this subgroup are summarized in Table 6. Template version 1.1 Page 13

14 Table 6. Summary of Results for Primary and Key Secondary Parameters for Subjects with Severe Pain at Baseline Parameter Mean (SD) P-values Placebo (n=12) mg (n=24) mg a (n=25) vs PBO vs vs Placebo Co-Primary SPRID (10.8) 24.0 (11.3) 14.3 (12.7) <0.001 b b c Median Time to >6hrs 52.5 min 79.0 min b c Meaningful Relief Key Secondary SPRID (2.4) 8.0 (2.6) 5.8 (3.6) <0.001 b b <0.001 b SPRID (4.7) 12.6 (4.7) 8.4 (5.7) <0.001 b b b SPID (0.9) 3.2 (1.2) 2.3 (1.5) <0.001 b b <0.001 b SPID (1.9) 5.1 (2.1) 3.4 (2.4) <0.001 b b b SPID (4.5) 9.7 (4.9) 5.8 (5.3) <0.001 b b b TOTPAR (1.5) 4.8 (1.4) 3.5 (2.1) <0.001 b b <0.001 b TOTPAR (2.8) 7.5 (2.6) 5.1 (3.4) <0.001 b b <0.001 b TOTPAR (6.2) 14.3 (6.4) 8.5 (7.4) <0.001 b b b Median time to FPR d confirmed by meaningful relief >6 hrs 19.9 min 30.3 min <0.001 b b b Median time to treatment failure 1.5 hrs >6 hrs 4.3 hrs <0.001 b b b Global evaluation 0.9 (1.6) 3.6 (1.1) 2.4 (1.5) <0.001 b b b = acetaminophen; IBU = ibuprofen; ITT = intent to treat; PSR = pain severity rating; SD = standard deviation; SPID = time-weighted sum of pain intensity difference; SPRID = time-weighted sum of PRID Scores; TOTPAR = time-weighted sum of pain relief scores. a. -Acetaminophen tablets (Extra Strength Tylenol) b. p 0.05 in favor of the first treatment listed relative to the second (regardless of technical ineligibilities). c. p 0.05 in favor of the first treatment listed relative to the second but technically ineligible to be declared significant. d. FPR First perceptible relief. Safety Results: A total of 47 TEAEs were reported by 26 (11.9%) subjects, with 10 (22.2%) in the placebo group, 5 (5.7%) in the group, and 11 (12.9%) in the group reporting events. There was a significant treatment difference in the overall incidence of AEs (p = 0.019), likely due to the higher incidence rate seen with the placebo group. No significant treatment differences were observed in any of the system organ classes (SOCs). The incidence of nausea within the gastrointestinal disorder SOC was significantly (p = 0.038) different among the 3 treatment groups, where 6 (13.3%) in the placebo group, 2 (2.3%) in the group, and 6 (7.1%) in the group reported this event. The AE rates were not significantly different among the treatment groups for any other individual AE. The majority of AEs were rated as mild or moderate in severity, and none were determined to be related to the study medication. There were no serious adverse event (SAEs) reported in this study, and no subject discontinued due to an AE. Overall, there were no safety concerns and both active treatments were well tolerated. See Table 7 below for an overall summary of AEs and frequent (incidence rate 2%) TEAEs by SOC and PT. Template version 1.1 Page 14

15 Table 7. Overall Summary of Adverse Events and Most Frequent Adverse Events (Incidence Rate 2%) Placebo N= mg N= mg N=85 Number of subjects n(%) reporting any AE N (%) 10 (22.2) 5 (5.7) 11 (12.9) Number of subjects n(%) reporting 0 event 35 (77.8) 83 (94.3) 74 (87.1) 1 event 6 (13.3) 3 (3.4) 4 (4.7) >1 event 4 (8.9) 2 (2.3) 7 (8.2) Number of events reported Severity n (%) Mild 7 (46.7) 3 (37.5) 11 (45.8) Moderate 8 (53.3) 5 (62.5) 11 (45.8) Severe 0 (0.0) 0 (0.0) 2 (8.3) Relation to study drug n (%) Not Related 15 (100.0) 8 (100.0) 24 (100.0) Related Incidence rates by SOC a Nervous system disorders Total n (%) 5 (11.1) 3 (3.4) 9 (10.6) Dizziness 1 (2.2) 2 (2.3) 5 (5.9) Headache 1 (2.2) 1 (1.1) 3 (3.5) Somnolence 1 (2.2) 0 (0.0) 2 (2.4) Paraesthesia 1 (2.2) 0 (0.0) 0 (0.0) Tremor 1 (2.2) 0 (0.0) 0 (0.0) Gastrointestinal disorders Total n (%) 6 (13.3) 3 (3.4) 6 (7.1) Nausea 6 (13.3) 2 (2.3) 6 (7.1) Vomiting 1 (2.2) 1 (1.1) 2 (2.4) General disorders and administration site conditions Total n (%) 1 (2.2) 0 (0.0) 1 (1.2) Hyperhidrosis 1 (2.2) 0 (0.0) 1 (1.2) Musculoskeletal and connective Total n (%) 1 (2.2) 0 (0.0) 0 (0.0) Muscular weakness 1 (2.2) 0 (0.0) 0 (0.0) Respiratory, thoracic and mediastinal disorders Total n (%) 1 (2.2) 0 (0.0) 0 (0.0) Epistaxis 1 (2.2) 0 (0.0) 0 (0.0) = acetaminophen; AE = adverse events; IBU = ibuprofen; N = total number of subjects; n = number of subjects in sub group; SOC = system organ class a. Those with incidence rate 2% in any treatment group Summary of AEs by relationship to study product (incidence rate 2%) is shown in Table 8. Template version 1.1 Page 15

16 Table 8. Summary of Adverse Events by Relationship to Study Product (Incidence Rate 2%) SOC Preferred Term Placebo N= mg N= mg N=85 Any SOC: Number of AEs a Gastrointestinal disorders Nausea 6 (13.3) 2 (2.3) 6 (7.1) Vomiting 1 (2.2) 1 (1.1) 2 (2.4) General disorders and administration site conditions Hyperhidrosis 1 (2.2) 0 (0.0) 1 (1.2) Musculoskeletal and connective tissue disorders Muscular weakness 1 (2.2) 0 (0.0) 0 (0.0) Nervous system disorders Dizziness 1 (2.2) 2 (2.3) 5 (5.9) Headache 1 (2.2) 1 (1.1) 3 (3.5) Somnolence 1 (2.2) 0 (0.0) 2 (2.4) Paraesthesia 1 (2.2) 0 (0.0) 0 (0.0) Respiratory, thoracic and mediastinal disorders 1 (2.2) 0 (0.0) 0 (0.0) Epistaxis 1 (2.2) 0 (0.0) 0 (0.0) = Acetaminophen tablets (Extra Strength Tylenol); IBU = ibuprofen; N = total number of subjects. a. A subject may have multiple AEs for each system organ class (SOC). The number of AEs includes all events. The number of subjects, however, counts a subject only once within each SOC. No deaths, SAEs or other clinically important AEs occurred during the study. No subject discontinued due to safety related reasons. CONCLUSIONS: Both and demonstrated overall analgesic superiority compared to placebo. also provided significantly better overall analgesic efficacy compared to as demonstrated for both the primary (SPRID 0-6) and secondary summary efficacy endpoints (SPRID, SPID, and TOTPAR over 2, 3, and 6 hours). There were no statistically significant differences between the 2 active treatments for onset of analgesic effect and duration of action. In general, both active treatments were well tolerated. Template version 1.1 Page 16