Trial Outcomes & Findings for Tramadol/Diclofenac Fixed-dose Combination Phase III Trial in Acute Pain After Third Molar Extraction (NCT NCT03714672)

Last Updated: 2019-07-24

Results Overview

Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point verbal rating scale (VRS) with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR4) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 4 hours after IMP intake. Minimum and maximum values for TOTPAR4 were 0=worst score and 16=best score, a higher score indicates more pain relief.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1151 participants

Primary outcome timeframe

Up to 4 hours after first dose

Results posted on

2019-07-24

Participant Flow

The first participant was enrolled on 26 August 2017.

A total of 1151 participants signed an informed consent form, 829 participants were allocated to treatment. Of the 829 allocated participants, 3 were not treated (1 each in the Diclofenac 50, Tramadol 50, and Tramadol/Diclofenac 25/25 treatment arms) and were not included in the Safety Set (N=826).

Participant milestones

Participant milestones
Measure	Tramadol/Diclofenac 50/50 Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Overall Study STARTED	209	206	206	208
Overall Study Safety Set	208	205	206	207
Overall Study COMPLETED	207	202	202	207
Overall Study NOT COMPLETED	2	4	4	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Tramadol/Diclofenac 50/50 Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Overall Study Adverse Event	0	0	3	0
Overall Study Physician Decision	0	1	0	0
Overall Study Other Reason	1	2	1	1
Overall Study Lost to Follow-up	1	1	0	0

Baseline Characteristics

One participant (Tramadol/Diclofenac 25/25) from the Safety Set had no efficacy assessments and was not included in the Full Analysis Set.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tramadol/Diclofenac 50/50 n=208 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=205 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=206 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were be taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were be taken 8 hours apart.	Total n=826 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=208 Participants	0 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	0 Participants n=826 Participants
Age, Categorical Between 18 and 65 years	208 Participants n=208 Participants	205 Participants n=205 Participants	206 Participants n=206 Participants	207 Participants n=207 Participants	826 Participants n=826 Participants
Age, Categorical >=65 years	0 Participants n=208 Participants	0 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	0 Participants n=826 Participants
Age, Continuous	22.9 years n=208 Participants	24.0 years n=205 Participants	23.8 years n=206 Participants	23.6 years n=207 Participants	23.6 years n=826 Participants
Sex: Female, Male Female	126 Participants n=208 Participants	136 Participants n=205 Participants	132 Participants n=206 Participants	135 Participants n=207 Participants	529 Participants n=826 Participants
Sex: Female, Male Male	82 Participants n=208 Participants	69 Participants n=205 Participants	74 Participants n=206 Participants	72 Participants n=207 Participants	297 Participants n=826 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	208 Participants n=208 Participants	204 Participants n=205 Participants	206 Participants n=206 Participants	206 Participants n=207 Participants	824 Participants n=826 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants n=208 Participants	1 Participants n=205 Participants	0 Participants n=206 Participants	1 Participants n=207 Participants	2 Participants n=826 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=208 Participants	0 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	0 Participants n=826 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=208 Participants	2 Participants n=205 Participants	0 Participants n=206 Participants	1 Participants n=207 Participants	3 Participants n=826 Participants
Race (NIH/OMB) Asian	0 Participants n=208 Participants	0 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	0 Participants n=826 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=208 Participants	0 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	0 Participants n=826 Participants
Race (NIH/OMB) Black or African American	0 Participants n=208 Participants	0 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	0 Participants n=826 Participants
Race (NIH/OMB) White	0 Participants n=208 Participants	4 Participants n=205 Participants	4 Participants n=206 Participants	2 Participants n=207 Participants	10 Participants n=826 Participants
Race (NIH/OMB) More than one race	202 Participants n=208 Participants	198 Participants n=205 Participants	200 Participants n=206 Participants	203 Participants n=207 Participants	803 Participants n=826 Participants
Race (NIH/OMB) Unknown or Not Reported	6 Participants n=208 Participants	1 Participants n=205 Participants	2 Participants n=206 Participants	1 Participants n=207 Participants	10 Participants n=826 Participants
Region of Enrollment Mexico	208 participants n=208 Participants	205 participants n=205 Participants	206 participants n=206 Participants	207 participants n=207 Participants	826 participants n=826 Participants
Body mass index (BMI)	24.5 kg/m^2 STANDARD_DEVIATION 4.08 • n=208 Participants	25.0 kg/m^2 STANDARD_DEVIATION 4.39 • n=205 Participants	25.1 kg/m^2 STANDARD_DEVIATION 4.25 • n=206 Participants	24.5 kg/m^2 STANDARD_DEVIATION 4.51 • n=207 Participants	24.8 kg/m^2 STANDARD_DEVIATION 4.31 • n=826 Participants
Baseline pain intensity categorized Moderate	88 Participants n=208 Participants	87 Participants n=205 Participants	86 Participants n=206 Participants	81 Participants n=207 Participants	342 Participants n=826 Participants
Baseline pain intensity categorized Severe	120 Participants n=208 Participants	117 Participants n=205 Participants	120 Participants n=206 Participants	126 Participants n=207 Participants	483 Participants n=826 Participants
Baseline pain intensity categorized None	0 Participants n=208 Participants	0 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	0 Participants n=826 Participants
Baseline pain intensity categorized Mild	0 Participants n=208 Participants	0 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	0 Participants n=826 Participants
Baseline pain intensity categorized Missing	0 Participants n=208 Participants	1 Participants n=205 Participants	0 Participants n=206 Participants	0 Participants n=207 Participants	1 Participants n=826 Participants
Baseline pain intensity 11-point NRS	7.0 units on a scale STANDARD_DEVIATION 1.51 • n=208 Participants • One participant (Tramadol/Diclofenac 25/25) from the Safety Set had no efficacy assessments and was not included in the Full Analysis Set.	7.0 units on a scale STANDARD_DEVIATION 1.45 • n=204 Participants • One participant (Tramadol/Diclofenac 25/25) from the Safety Set had no efficacy assessments and was not included in the Full Analysis Set.	7.0 units on a scale STANDARD_DEVIATION 1.45 • n=206 Participants • One participant (Tramadol/Diclofenac 25/25) from the Safety Set had no efficacy assessments and was not included in the Full Analysis Set.	7.0 units on a scale STANDARD_DEVIATION 1.40 • n=207 Participants • One participant (Tramadol/Diclofenac 25/25) from the Safety Set had no efficacy assessments and was not included in the Full Analysis Set.	7.0 units on a scale STANDARD_DEVIATION 1.45 • n=825 Participants • One participant (Tramadol/Diclofenac 25/25) from the Safety Set had no efficacy assessments and was not included in the Full Analysis Set.
Number of molars extracted Number of molars extracted 3	37 Participants n=208 Participants	41 Participants n=205 Participants	42 Participants n=206 Participants	43 Participants n=207 Participants	163 Participants n=826 Participants
Number of molars extracted Number of molars extracted 4	171 Participants n=208 Participants	164 Participants n=205 Participants	164 Participants n=206 Participants	164 Participants n=207 Participants	663 Participants n=826 Participants
Duration of surgery, minutes	33.0 minutes STANDARD_DEVIATION 21.90 • n=208 Participants	35.0 minutes STANDARD_DEVIATION 21.56 • n=205 Participants	34.2 minutes STANDARD_DEVIATION 20.25 • n=206 Participants	32.9 minutes STANDARD_DEVIATION 19.21 • n=207 Participants	33.8 minutes STANDARD_DEVIATION 20.74 • n=826 Participants
Lidocaine used during surgery, mg	211.1 mg STANDARD_DEVIATION 44.18 • n=208 Participants	211.4 mg STANDARD_DEVIATION 41.13 • n=205 Participants	211.3 mg STANDARD_DEVIATION 43.36 • n=206 Participants	207.7 mg STANDARD_DEVIATION 42.13 • n=207 Participants	210.4 mg STANDARD_DEVIATION 42.67 • n=826 Participants
End of surgery to first dose of IMP, hours	2.2 hours STANDARD_DEVIATION 0.89 • n=208 Participants	2.2 hours STANDARD_DEVIATION 0.83 • n=205 Participants	2.1 hours STANDARD_DEVIATION 0.90 • n=206 Participants	2.1 hours STANDARD_DEVIATION 0.85 • n=207 Participants	2.2 hours STANDARD_DEVIATION 0.87 • n=826 Participants

PRIMARY outcome

Timeframe: Up to 4 hours after first dose

Population: Full Analysis Set

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4)	9.9 units on a scale Interval 9.3 to 10.4	8.6 units on a scale Interval 8.0 to 9.1	5.4 units on a scale Interval 4.9 to 5.9	5.8 units on a scale Interval 5.3 to 6.3

SECONDARY outcome

Timeframe: Up to 6 hours after first dose

Population: Full Analysis Set

Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point VRS with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR6) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 6 hours after IMP intake. Minimum and maximum values for TOTPAR6 were 0=worst score and 24=best score, a higher score indicates more pain relief.

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Total Pain Relief at 6 Hours Post-dose (TOTPAR6)	15.2 units on a scale Interval 14.4 to 16.0	13.3 units on a scale Interval 12.5 to 14.2	9.3 units on a scale Interval 8.4 to 10.1	9.8 units on a scale Interval 9.0 to 10.6

SECONDARY outcome

Timeframe: Up to 8 hours after first dose

Population: Full Analysis Set

Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point VRS with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR8) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 8 hours after IMP intake. Minimum and maximum values for TOTPAR8 were 0=worst score and 32=best score, a higher score indicates more pain relief.

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Total Pain Relief at 8 Hours Post-dose (TOTPAR8)	20.1 units on a scale Interval 19.0 to 21.2	17.8 units on a scale Interval 16.7 to 18.9	13.1 units on a scale Interval 12.0 to 14.2	13.7 units on a scale Interval 12.6 to 14.8

SECONDARY outcome

Timeframe: Baseline; up to 24 hours after first dose

Population: Full Analysis Set

Pain intensity was assessed by the participant before and at defined time points after the first IMP dose using an 11-point NRS with anchors at 0 for "no pain" and 10 for "pain as bad as you can imagine". Pain Intensity Difference (PIDt) was defined as the difference between baseline pain intensity and pain intensity at time point t, and SPID defined as summed PIDt x \[time (hours) elapsed since previous observation\]. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain \[maximum=10 at each time point\], and negative numbers indicate an increase in pain \[minimum=-10 at each time point\]. The overall minimum and maximum are -10 and 10 times the number of hours specified (SPID-4=\[-40 to 40\], SPID-6=\[-60 to 60\], SPID-8=\[-80 to 80\], and SPID-24=\[-240 to 240\]).

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose 4 Hours	16.24 units on a scale Standard Error 0.564	13.67 units on a scale Standard Error 0.576	6.43 units on a scale Standard Error 0.570	7.72 units on a scale Standard Error 0.568
Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose 6 Hours	25.54 units on a scale Standard Error 0.836	21.86 units on a scale Standard Error 0.855	12.89 units on a scale Standard Error 0.845	14.36 units on a scale Standard Error 0.843
Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose 8 Hours	33.70 units on a scale Standard Error 1.121	28.90 units on a scale Standard Error 1.146	19.10 units on a scale Standard Error 1.133	20.54 units on a scale Standard Error 1.129
Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose 24 Hours	107.15 units on a scale Standard Error 3.787	91.99 units on a scale Standard Error 3.873	71.41 units on a scale Standard Error 3.828	72.08 units on a scale Standard Error 3.816

SECONDARY outcome

Timeframe: Up to 24 hours after first dose

Population: Full Analysis Set

Time (hours) when the participant achieved a 50 percent reduction of baseline (starting) pain. It was assessed at defined time points after the first IMP dose using a YES or NO question for pain half gone.

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone)	1.27 hours Standard Deviation 1.216	1.73 hours Standard Deviation 2.778	3.01 hours Standard Deviation 3.731	2.53 hours Standard Deviation 2.865

SECONDARY outcome

Timeframe: Up to 8 hours after first dose

Population: Full Analysis Set

Participants used one stopwatch to document the time between first IMP dose and when they begin to feel any pain-relieving effect from the IMP.

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Time to Onset of First Perceptible Pain Relief	0.57 hours Standard Deviation 0.483	0.67 hours Standard Deviation 0.875	1.07 hours Standard Deviation 1.000	1.12 hours Standard Deviation 1.151

SECONDARY outcome

Timeframe: Up to 8 hours after first dose

Population: Full Analysis Set

Participants used a second stopwatch to document the time between first IMP dose and when they felt their pain relief was meaningful to them.

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Time to Onset of Meaningful Pain Relief	1.47 hours Standard Deviation 1.149	2.04 hours Standard Deviation 1.810	2.93 hours Standard Deviation 1.895	2.75 hours Standard Deviation 1.882

SECONDARY outcome

Timeframe: First dose to 24 hours after first dose

Population: Full Analysis Set

The time from first IMP dose to first dose of rescue medication (ibuprofen or ketorolac), if needed, within 24 hours post-dose was calculated.

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Time to Intake of First Rescue Medication Dose	21.84 hours Standard Deviation 6.222	20.99 hours Standard Deviation 7.450	17.37 hours Standard Deviation 9.745	17.38 hours Standard Deviation 9.646

SECONDARY outcome

Timeframe: 8 hours after the first dose of IMP or before first intake of rescue medication (whatever the first) and 24 hours after the first dose of IMPs

Population: Full Analysis Set

Participants documented their overall impression of the analgesic efficacy of the IMPs on a 5-point Likert scale from Excellent (4) to Poor (0).

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=209 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=204 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=205 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Subject's Global Evaluation of the Treatment 24-Hours · Very Good	57 Participants	65 Participants	59 Participants	67 Participants
Subject's Global Evaluation of the Treatment 8-Hours · Poor	4 Participants	7 Participants	28 Participants	23 Participants
Subject's Global Evaluation of the Treatment 8-Hours · Fair	10 Participants	12 Participants	30 Participants	25 Participants
Subject's Global Evaluation of the Treatment 8-Hours · Good	17 Participants	33 Participants	36 Participants	35 Participants
Subject's Global Evaluation of the Treatment 8-Hours · Very Good	73 Participants	64 Participants	52 Participants	67 Participants
Subject's Global Evaluation of the Treatment 8-Hours · Excellent	103 Participants	83 Participants	51 Participants	51 Participants
Subject's Global Evaluation of the Treatment 24-Hours · Poor	3 Participants	4 Participants	7 Participants	7 Participants
Subject's Global Evaluation of the Treatment 24-Hours · Fair	4 Participants	5 Participants	23 Participants	13 Participants
Subject's Global Evaluation of the Treatment 24-Hours · Good	12 Participants	18 Participants	34 Participants	39 Participants
Subject's Global Evaluation of the Treatment 24-Hours · Excellent	132 Participants	109 Participants	82 Participants	80 Participants

SECONDARY outcome

Timeframe: Day 1 to Day 14

Population: Safety Set

The incidence of treatment emergent adverse events (TEAE) reported from first dose (Day 1) to last scheduled contact with the participant on Day 14 was descriptively summarized. Selected TEAEs were events with preferred terms of nausea, vomiting, abdominal pain, gastrointestinal bleeding, dizziness, or hypotension.

Outcome measures

Outcome measures
Measure	Tramadol/Diclofenac 50/50 n=208 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=205 Participants Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=206 Participants Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 Participants Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Incidence and Type of Adverse Events TEAE leading to dose reduction	0 participants	0 participants	0 participants	0 participants
Incidence and Type of Adverse Events TEAE	96 participants	62 participants	105 participants	48 participants
Incidence and Type of Adverse Events Severe TEAE	6 participants	1 participants	3 participants	2 participants
Incidence and Type of Adverse Events TEAE related to IMP or rescue medication	49 participants	23 participants	64 participants	10 participants
Incidence and Type of Adverse Events Serious TEAE	0 participants	1 participants	0 participants	0 participants
Incidence and Type of Adverse Events TEAE with outcome of death	0 participants	0 participants	0 participants	0 participants
Incidence and Type of Adverse Events Selected TEAE	68 participants	26 participants	77 participants	13 participants
Incidence and Type of Adverse Events TEAE leading to dose interruption	1 participants	2 participants	1 participants	0 participants
Incidence and Type of Adverse Events TEAE leading to IMP withdrawal	2 participants	1 participants	1 participants	0 participants
Incidence and Type of Adverse Events Dose reduction, interruption, or withdrawal	3 participants	3 participants	2 participants	0 participants

Adverse Events

Tramadol/Diclofenac 50/50

Serious events: 0 serious events

Other events: 96 other events

Deaths: 0 deaths

Tramadol/Diclofenac 25/25

Serious events: 1 serious events

Other events: 62 other events

Deaths: 0 deaths

Tramadol 50

Serious events: 0 serious events

Other events: 105 other events

Deaths: 0 deaths

Diclofenac 50

Serious events: 0 serious events

Other events: 48 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tramadol/Diclofenac 50/50 n=208 participants at risk Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol/Diclofenac 25/25 n=205 participants at risk Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.	Tramadol 50 n=206 participants at risk Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.	Diclofenac 50 n=207 participants at risk Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction. Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Nervous system disorders Seizure	0.00% 0/208 • Day 1 to Day 14 Sites were instructed not to report dental pain as an AE until 24 hours after the first dose of IMP.	0.49% 1/205 • Number of events 1 • Day 1 to Day 14 Sites were instructed not to report dental pain as an AE until 24 hours after the first dose of IMP.	0.00% 0/206 • Day 1 to Day 14 Sites were instructed not to report dental pain as an AE until 24 hours after the first dose of IMP.	0.00% 0/207 • Day 1 to Day 14 Sites were instructed not to report dental pain as an AE until 24 hours after the first dose of IMP.

Other adverse events

Additional Information

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