Efficacy of 300 mg Ibuprofen Prolonged-Release Tablets for the Treatment of Pain After Surgical Removal of Impacted Third Molars

SPID12 was used to compare the test product (2 × 300 mg ibuprofen PR tablets) and comparator product (2 × 200 mg ibuprofen IR tablets three times a day [TID]) against the placebo product. An 11-point (0-10) numeric rating scale (NRS) for pain was used to assess pain intensity, where a higher score indicates a greater amount of pain. SPID12 was calculated using the summed pain intensity difference (change from Time 0) under the NRS-time curve from 15 minutes through 12 hours calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of SPID12 is 0 (no change in pain intensity from Time 0 to 12 hours); the theoretical maximum is 120 (if a patient had a score of 10 [worst pain intensity] at baseline, which decreased to 0 [no pain] at the next time point and remained at 0 after); a higher SPID12 score indicates a better outcome.

SPID24 was used to compare the test product (2 × 300 mg ibuprofen PR tablets BID) and comparator product (2 × 200 mg ibuprofen IR tablets TID) against the placebo product. An 11-point (0-10) numeric rating scale (NRS) for pain was used to assess pain intensity, where a higher score indicates a greater amount of pain. SPID24 was calculated using the summed pain intensity difference (change from Time 0) under the NRS-time curve from 15 minutes through 24 hours calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of SPID24 is 0 (no change in pain intensity from Time 0 to 24 hours); the theoretical maximum is 240 (if a patient had a score of 10 [worst pain intensity] at baseline, which decreased to 0 [no pain] at the next time point and remained at 0 after).

SPID4 was used to compare the test product (2 × 300 mg ibuprofen PR tablets BID) and comparator product (2 × 200 mg ibuprofen IR tablets TID) against the placebo product. An 11-point (0-10) numeric rating scale (NRS) for pain was used to assess pain intensity, where a higher score indicates a greater amount of pain. SPID4 was calculated using the summed pain intensity difference (change from Time 0) under the NRS-time curve from 15 minutes through 4 hours calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of SPID4 is 0 (no change in pain intensity from Time 0 to 4 hours); the theoretical maximum is 40 (if a patient had a score of 10 [worst pain intensity] at baseline, which decreased to 0 [no pain] at the next time point and remained at 0 after).

SPID8 was used to compare the test product (2 × 300 mg ibuprofen PR tablets BID) and comparator product (2 × 200 mg ibuprofen IR tablets TID) against the placebo product. An 11-point (0-10) numeric rating scale (NRS) for pain was used to assess pain intensity, where a higher score indicates a greater amount of pain. SPID8 was calculated using the summed pain intensity difference (change from Time 0) under the NRS-time curve from 15 minutes through 8 hours calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of SPID8 is 0 (no change in pain intensity from Time 0 to 8 hours); the theoretical maximum is 80 (if a patient had a score of 10 [worst pain intensity] at baseline, which decreased to 0 [no pain] at the next time point and remained at 0 after).

A 5-point categorical Pain Relief Scale (PRS) with choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 was completed in response to the question "How much relief have you had since your starting pain?". Higher scores indicate a better outcome. TOTPAR4 is the total pain relief measured by the PRS from 15 minutes through 4 hours, calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of TOTPAR4 is 0 (no pain relief from Time 0 to 4 hours); the theoretical maximum is 16 (if a patient experiences maximum pain relief at all time points after baseline).

A 5-point categorical Pain Relief Scale (PRS) with choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 was completed in response to the question "How much relief have you had since your starting pain?". Higher scores indicate a better outcome. TOTPAR8 is the total pain relief measured by the PRS from 15 minutes through 8 hours, calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of TOTPAR8 is 0 (no pain relief from Time 0 to 8 hours); the theoretical maximum is 32 (if a patient experiences maximum pain relief at all time points after baseline).

A 5-point categorical Pain Relief Scale (PRS) with choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 was completed in response to the question "How much relief have you had since your starting pain?". Higher scores indicate a better outcome. TOTPAR12 is the total pain relief measured by the PRS from 15 minutes through 12 hours, calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of TOTPAR12 is 0 (no pain relief from Time 0 to 12 hours); the theoretical maximum is 48 (if a patient experiences maximum pain relief at all time points after baseline).

A 5-point categorical Pain Relief Scale (PRS) with choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 was completed in response to the question "How much relief have you had since your starting pain?". Higher scores indicate a better outcome. TOTPAR24 is the total pain relief measured by the PRS from 15 minutes through 24 hours, calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of TOTPAR24 is 0 (no pain relief from Time 0 to 24 hours); the theoretical maximum is 96 (if a patient experiences maximum pain relief at all time points after baseline).

The summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 0 to 4 hours (SPRID4) was determined by calculating the difference in the PRS at the 4-hour time point and the 0-hour time point (TOTPAR4) and adding this value to the difference in the NRS for pain at the 4-hour time point and the 0-hour time point (SPID4). The minimum value of SPRID4 is 0; the theoretical maximum is 56; a higher SPRID4 score indicates a better outcome.

The summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 0 to 8 hours (SPRID8) was determined by calculating the difference in the PRS at the 8-hour time point and the 0-hour time point (TOTPAR8) and adding this value to the difference in the NRS for pain at the 8-hour time point and the 0-hour time point (SPID8). The minimum value of SPRID8 is 0; the theoretical maximum is 112; a higher SPRID8 score indicates a better outcome.

The summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 0 to 12 hours (SPRID12) was determined by calculating the difference in the PRS at the 12-hour time point and the 0-hour time point (TOTPAR12) and adding this value to the difference in the NRS for pain at the 12-hour time point and the 0-hour time point (SPID12). The minimum value of SPRID12 is 0; the theoretical maximum 168; a higher SPRID12 score indicates a better outcome.

The summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 0 to 24 hours (SPRID24) was determined by calculating the difference in the PRS at the 24-hour time point and the 0-hour time point (TOTPAR24) and adding this value to the difference in the NRS for pain at the 24-hour time point and the 0-hour time point (SPID24). The minimum value of SPRID24 is 0; the theoretical maximum is 336; a higher SPRID24 score indicates a better outcome.

A responder was defined as a subject with ≥30% improvement in pain intensity at the 8-hour assessment without rescue medication during the first 8 hours. An 11-point (0-10) numeric rating scale (NRS) for pain was used to assess pain intensity, where a higher score indicates a greater amount of pain.

An 11-point (0-10) numeric rating scale (NRS) for pain was used to assess pain intensity, where a higher score indicates a greater amount of pain, and the PID (the difference in NRS pain intensity between each time point and Time 0) at each time point was calculated.

Pain intensity score at each scheduled time point will be assessed using a numeric rating scale (NRS) for pain. An 11-point (0-10) numeric rating scale (NRS) for pain was used to assess pain intensity, where a higher score indicates a greater amount of pain.

Pain relief score at each scheduled time point after Time 0 was measured using the Pain Relief Scale (PRS). The PRS was used to measure pain relief and is a 5-point categorical scale, with response choices of: none = 0; a little = 1; some = 2; a lot = 3; and complete = 4 to be completed in response to the question "How much relief have you had since your starting pain?". Higher scores indicate a better outcome.

Peak pain relief at each time point was measured using the Pain Relief Scale (PRS). The PRS was used to measure pain relief and is a 5-point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question "How much relief have you had since your starting pain?". Higher scores indicate a better outcome. For each subject, peak pain relief was calculated as the maximum pain relief over all PRS assessments, and summarised by counts (and percentages) for each PRS score. Peak pain relief was calculated from PRS scores that were adjusted for rescue medication usage using windowed worst observation carried forward (WOCF).

Two stopwatches were started immediately after the subject swallowed the study drug. Subjects were instructed to, "Stop the first stopwatch when you first feel any pain relief whatsoever. This does not mean you feel completely better, although you might, but when you first feel any relief in the pain you have now" (perceptible pain relief), and then, "Stop the second stopwatch when you feel the pain relief is meaningful to you" (meaningful pain relief). If the stopwatches were not stopped within 8 hours after Time 0 use of the stopwatches was discontinued. If the subject had meaningful pain relief (i.e., pressed both stopwatches) then time to onset of analgesia was date/time of perceptible pain relief - date/time of the first dose of study drug. Values presented are from Kaplan-Meier estimates.

Two stopwatches were started immediately after the subject swallowed the study drug. Subjects were instructed to, "Stop the first stopwatch when you first feel any pain relief whatsoever. This does not mean you feel completely better, although you might, but when you first feel any relief in the pain you have now" (perceptible pain relief). Time to first perceptible pain relief was date/time of the first reported pain relief (any) as assessed by the subject (i.e., when the subject stopped the first stopwatch, irrespective of the second) - date/time of the first dose of study drug. If the stopwatch were not stopped within 8 hours after Time 0, use of the stopwatches was discontinued. Values presented are from Kaplan-Meier estimates.

Two stopwatches were started immediately after the subject swallowed the study drug. Each subject was instructed, "Stop the second stopwatch when you feel the pain relief is meaningful to you" (meaningful pain relief). Time to meaningful pain relief was the date/time of the first reported meaningful (subjective) pain relief as assessed by the subject (i.e., when the subject stopped the second stopwatch) - date/time of the first dose of study drug. If the stopwatches were not stopped within 8 hours after Time 0 use of the stopwatches was discontinued. Values presented are from Kaplan-Meier estimates.

The PRS was used to measure pain relief and is a 5-point categorical scale, with response choices of: none = 0; a little = 1; some = 2; a lot = 3; and complete = 4 to be completed in response to the question "How much relief have you had since your starting pain?". A higher score indicates greater pain. Time to peak pain relief was the time when peak pain relief (PPR) first occurred. Values presented are from Kaplan-Meier estimates.

After randomisation and administration of study drug, paracetamol/acetaminophen (1000 mg) was permitted as the initial rescue medication. Subjects were encouraged to wait at least 60 minutes after receiving study drug before taking rescue medication. If acetaminophen rescue medication was not effective in relieving the subject's pain, 5 mg oxycodone rescue medication was administered at the discretion of the investigator. At the investigator's discretion, repeat doses of rescue medication were also administered as required.

Time to first use of rescue medication, in hours.

Time to first use of rescue medication, in hours. Values presented are the hazard ratios, calculated from Cox proportional hazards model with treatment group as a categorical factor and baseline pain as a continuous covariate. A hazard ratio of <1 means that when subjects did take rescue medication, subjects in the ibuprofen groups refrained from taking rescue medication for longer than subjects in the placebo group. A hazard ratio of >1 means that when subjects did take rescue medication, subjects in the placebo group refrained from taking rescue medication for longer than subjects in the ibuprofen groups.

Incidence of treatment emergent adverse events (TEAEs). Data listings will be provided for protocol specified safety data.

Incidence of changes in vital sign measurements. Descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from Baseline for vital signs will be calculated for each subject.

Incidence of changes in vital sign measurements. Descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from Baseline for vital signs will be calculated for each subject.

Incidence of changes in vital sign measurements. Descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from Baseline for vital signs will be calculated for each subject.

Incidence of changes in vital sign measurements. Descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from Baseline for vital signs will be calculated for each subject.

Patient's global evaluation of study drug using 5 point categorical scale, response choices of 0 = poor, 1 = fair, 2 = good, 3 = very good, or 4 = excellent to be completed by the patient in response to the question "How effective do you think the study drug is as a treatment for pain?". Subjects will complete the global evaluation of study drug 24 hours after Time 0 or immediately before the first dose of rescue medication (whichever occurs first).