Trial Outcomes & Findings for Study Evaluating Dexketoprofen Trometamol/Tramadol Hydrochloride Analgesic Efficacy in Acute Low Back Pain (NCT NCT05170841)

Results Overview

Time to first achieve a Numeric Rating Scale-Pain Intensity (NRS-PI) score of \<4 or a pain intensity reduction ≥30% from drug intake till 8 hours after the first dose. Numeric Rate Scale-Pain Intensity is a Patients rated Pain Intensity scale using an 11-point Numeric Rate Scale (0 no pain; 10 worst pain).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

538 participants

Primary outcome timeframe

8 hours from first intake (referring to first 8 hours of Single Dose Phase)

Results posted on

2025-01-09

Participant Flow

Participant milestones

Participant milestones
Measure	Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (Both Phases) Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) (time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Tramadol Hydrochloride 100 mg Treatment (Both Phases) Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) (time 8h - Day 5) In this arm patients will receive during each phase (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) Two phase intervention. Single Dose Phase (SDP) (time 0 - time 8h) and Multiple Dose Phase (MDP) (time 8h - Day 5). SINGLE DOSE PHASE: Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE: Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single Dose Phase (SDP) (time 0 - time 8h) and Multiple Dose Phase (MDP) (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Single Dose Phase STARTED	211	207	59	61
Single Dose Phase COMPLETED	210	205	59	59
Single Dose Phase NOT COMPLETED	1	2	0	2
Multiple Dose Phase STARTED	210	205	59	59
Multiple Dose Phase COMPLETED	209	202	58	55
Multiple Dose Phase NOT COMPLETED	1	3	1	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (Both Phases) Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) (time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Tramadol Hydrochloride 100 mg Treatment (Both Phases) Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) (time 8h - Day 5) In this arm patients will receive during each phase (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) Two phase intervention. Single Dose Phase (SDP) (time 0 - time 8h) and Multiple Dose Phase (MDP) (time 8h - Day 5). SINGLE DOSE PHASE: Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE: Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single Dose Phase (SDP) (time 0 - time 8h) and Multiple Dose Phase (MDP) (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Single Dose Phase Adverse Event	1	2	0	2
Multiple Dose Phase Adverse Event	1	2	1	4
Multiple Dose Phase Withdrawal by Subject	0	1	0	0

Baseline Characteristics

Study Evaluating Dexketoprofen Trometamol/Tramadol Hydrochloride Analgesic Efficacy in Acute Low Back Pain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment n=211 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Tramadol Hydrochloride 100 mg Treatment n=207 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5) In this arm patients will receive during each phase (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours	Placebo Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment n=59 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE: Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo Then Tramadol Hydrochloride 100 mg n=61 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Total n=538 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	210 Participants n=5 Participants	205 Participants n=7 Participants	58 Participants n=5 Participants	61 Participants n=4 Participants	534 Participants n=21 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants
Sex: Female, Male Female	98 Participants n=5 Participants	101 Participants n=7 Participants	28 Participants n=5 Participants	28 Participants n=4 Participants	255 Participants n=21 Participants
Sex: Female, Male Male	113 Participants n=5 Participants	106 Participants n=7 Participants	31 Participants n=5 Participants	33 Participants n=4 Participants	283 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	211 Participants n=5 Participants	207 Participants n=7 Participants	58 Participants n=5 Participants	61 Participants n=4 Participants	537 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: 8 hours from first intake (referring to first 8 hours of Single Dose Phase)

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio. Tramadol Hydrochloride 100 mg is not applicable for primary outcome measure since the primary objective was "To evaluate the analgesic efficacy of Dexketo/Tram fixed combination versus placebo in moderate to severe acute low back pain after the first dose (first 8 hours)"

Time to first achieve a Numeric Rating Scale-Pain Intensity (NRS-PI) score of \<4 or a pain intensity reduction ≥30% from drug intake till 8 hours after the first dose. Numeric Rate Scale-Pain Intensity is a Patients rated Pain Intensity scale using an 11-point Numeric Rate Scale (0 no pain; 10 worst pain).

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=51 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) n=50 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Time to First Achieve a Numeric Rating Scale-Pain Intensity Score <4 or a Pain Intensity Reduction of ≥30% From Drug Intake Till 8 Hours After the First Dose	105 score on a scale Interval 15.0 to 480.0	120 score on a scale Interval 15.0 to 360.0	120 score on a scale Interval 15.0 to 360.0	—

SECONDARY outcome

Timeframe: From t=o to T=4 hours

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio. This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen/Tramadol fixed combination versus Tramadol 100 mg after the first 4 h intake during Single Dose Phase. Placebo arms measurement are not applicable since, as per outcome measure title above, this outcome measure was compared only between active arms

TOTPAR was calculated as the time-weighted sum of the PAR- (VRS) scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at prespecified time point points in the single and the multiple-dose phases of the study. TOTPAR minimum and maximum values were 0 to 16 for Dexketoprofen/Tramadol group and 0 to 14 for Tramadol group. TOTPAR scale ranges from 0 with no upper limit.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Total Pain Relief (TOTPAR) at 4h After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	4.6 score on a scale Standard Deviation 3.60	3.8 score on a scale Standard Deviation 2.84	—	—

SECONDARY outcome

Timeframe: T=0 to T=6h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at prespecified time point points in the single and the multiple-dose phases of the study. TOTPAR minimum and maximum values were 0 to 24 for Dexketoprofen/Tramadol group and 0 to 19 for Tramadol group. TOTPAR scale ranges from 0 with no upper limit.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=203 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Total Pain Relief (TOTPAR) at 6h After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	7.4 score on a scale Standard Deviation 5.52	6.0 score on a scale Standard Deviation 4.41	—	—

SECONDARY outcome

Timeframe: From T=0 to T=8h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at prespecified time point points in the single and the multiple-dose phases of the study. TOTPAR minimum and maximum values were 0 to 31 for Dexketoprofen/Tramadol group and 0 to 26 for Tramadol group. TOTPAR scale ranges from 0 with no upper limit.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=204 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Total Pain Relief (TOTPAR) at 8h After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	10.1 score on a scale Standard Deviation 7.18	8.5 score on a scale Standard Deviation 5.92	—	—

SECONDARY outcome

Timeframe: From T=0 to T=6h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio. This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen/Tramadol fixed combination versus placebo after the first dose (first 6 h) in the Single Dose Phase. Tramadol 100 mg Arm measurement is not applicable since, as per outcome measure title above, this outcome measure was compared only between Dexketoprofen/Tramadol and Placebo

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at prespecified time point points in the single and the multiple-dose phases of the study. TOTPAR minimum and maximum values were 0 to 24 for Dexketoprofen/Tramadol group and 0 to 23 for Placebo group. TOTPAR scale ranges from 0 with no upper limit.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=101 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Total Pain Relief (TOTPAR) at 6h After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Placebo	7.4 score on a scale Standard Deviation 5.52	6.1 score on a scale Standard Deviation 4.37	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=8h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen/Tramadol fixed combination versus placebo after the first dose (first 8 h) in the Single Dose Phase. Tramadol 100 mg Arm measurement is not applicable since, as per outcome measure title above, this outcome measure was compared only between Dexketoprofen/Tramadol and Placebo

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at prespecified time point points in the single and the multiple-dose phases of the study. TOTPAR minimum and maximum values were 0 to 31 for Dexketoprofen/Tramadol group and 0 to 27 for Placebo group. TOTPAR scale ranges from 0 with no upper limit.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=101 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Total Pain Relief (TOTPAR) at 8h After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Placebo	10.1 score on a scale Standard Deviation 7.18	8.4 score on a scale Standard Deviation 5.81	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=4h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio. This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen/ Tramadol fixed combination versus Tramadol 100 mg after the first dose (first 4 h) in the Single Dose Phase. Placebo arms measurement are not applicable since, as per outcome measure title above, this outcome measure was compared only between active arms

Max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR), were calculated at prespecified time points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 97 and 0 to 84 respectively for Dexketoprofen/Tramadol and Tramadol group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 4 Hours After the First Dose- Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	29.1 percentage of score on a scale Standard Deviation 22.57	24.1 percentage of score on a scale Standard Deviation 17.92	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=6h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

Max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR) were calculated at prespecified time point points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 98 for Dexketoprofen/Tramadol group and 0 to 77 for Tramadol group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=203 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 6 Hours After the First Dose- Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	30.9 Percentage of score on a scale Standard Deviation 23.04	25.5 Percentage of score on a scale Standard Deviation 18.56	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=8h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

The max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR) were calculated at prespecified time point points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 98 for Dexketoprofen/Tramadol group and 0 to 83 for Tramadol group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=204 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 8 Hours After the First Dose- Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	32.1 Percentage of score on a scale Standard Deviation 22.75	27.1 Percentage of score on a scale Standard Deviation 18.59	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=6h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen/ Tramadol fixed combination versus placebo after the first dose (first 6 h) in the Single Dose Phase. Tramadol 100 mg Arm measurement is not applicable since, as per outcome measure title above, this outcome measure was compared only between Dexketoprofen/Tramadol and Placebo

The max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR) were calculated at prespecified time point points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 98 for Dexketoprofen/Tramadol group and 0 to 94 for Placebo group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=101 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 6 Hours After the First Dose- Single Dose Phase - Dexketoprofen/Tramadol vs Placebo	30.9 Percentage of score on a scale Standard Deviation 23.04	25.5 Percentage of score on a scale Standard Deviation 18.12	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=8h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen/Tramadol fixed combination versus placebo after the first dose (first 8 h) in the Single Dose Phase. Tramadol 100 mg Arm measurement is not applicable since, as per outcome measure title above, this outcome measure was compared only between Dexketoprofen/Tramadol and Placebo

The max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR) were calculated at prespecified time point points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 98 for Dexketoprofen/Tramadol group and 0 to 83 for Placebo group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=101 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 8 Hours After the First Dose- Single Dose Phase - Dexketoprofen/Tramadol vs Placebo	32.1 Percentage score on a scale Standard Deviation 22.75	26.4 Percentage score on a scale Standard Deviation 18.03	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=4h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=204 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Patients Achieving at Least 50% of Maximum TOTPAR at 4 Hours After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	20.6 percentage of patients	8.8 percentage of patients	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=6h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=204 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Patients Achieving at Least 50% of Maximum TOTPAR at 6 Hours After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	22.5 percentage of patients	9.8 percentage of patients	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=8h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=204 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Patients Achieving at Least 50% of Maximum TOTPAR at 8 Hours After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Tramadol	23.5 percentage of patients	11.3 percentage of patients	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=4h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg fixed combination versus placebo after the first dose (first 6 h) in the Single Dose Phase. Tramadol Hydrochloride 100 mg Arm is not reported since data of patients in that Arm are not analyzed for this Endpoint

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at pre-specified time point points in the single and the multiple-dose phases of the study.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=102 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Patients Achieving at Least 50% of Maximum TOTPAR at 4 Hours After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Placebo	20.6 percentage of patients	8.8 percentage of patients	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=6h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg fixed combination versus placebo after the first dose (first 6 h) in the Single Dose Phase. Tramadol Hydrochloride 100 mg Arm is not reported since data of patients in that Arm are not analyzed for this Endpoint

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at pre specified time point points in the single and the multiple-dose phases of the study.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=102 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Patients Achieving at Least 50% of Maximum TOTPAR at 6 Hours After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Placebo	22.5 percentage of patients	8.8 percentage of patients	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=8h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.This Secondary Endpoint is to evaluate the analgesic efficacy of Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg fixed combination versus placebo after the first dose (first 6 h) in the Single Dose Phase. Tramadol Hydrochloride 100 mg Arm is not reported since data of patients in that Arm are not analyzed for this Endpoint

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at pre specified time point points in the single and the multiple-dose phases of the study.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=204 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=102 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Patients Achieving at Least 50% of Maximum TOTPAR at 8 Hours After the First Dose - Single Dose Phase - Dexketoprofen/Tramadol vs Placebo	23.5 percentage of patients	11.8 percentage of patients	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=24h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at prespecified time point points in the single and the multiple-dose phases of the study. TOTPAR minimum and maximum values were 0 to 96 for Dexketoprofen/Tramadol group and 0 to 90 for Tramadol group. TOTPAR scale ranges from 0 with no upper limit.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=201 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) n=43 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg n=48 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Total Pain Relief (TOTPAR) at 24h After the First Dose - Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	44.6 score on a scale Standard Deviation 20.20	40.9 score on a scale Standard Deviation 19.85	44.6 score on a scale Standard Deviation 20.2	40.9 score on a scale Standard Deviation 19.85

SECONDARY outcome

Timeframe: Form T=0 to T=48h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at prespecified time point points in the single and the multiple-dose phases of the study. TOTPAR minimum and maximum values were 0 to 192 for Dexketoprofen/Tramadol group and 0 to 184 for Tramadol group. TOTPAR scale ranges from 0 with no upper limit.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=201 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) n=47 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg n=49 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Total Pain Relief (TOTPAR) at 48h After the First Dose - Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	97.8 score on a scale Standard Deviation 41.69	90.0 score on a scale Standard Deviation 41.88	97.8 score on a scale Standard Deviation 41.69	90.0 score on a scale Standard Deviation 41.88

SECONDARY outcome

Timeframe: Form T=0 to T=72h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at prespecified time point points in the single and the multiple-dose phases of the study. TOTPAR minimum and maximum values were 0 to 288 for Dexketoprofen/Tramadol group and 0 to 280 for Tramadol group. TOTPAR scale ranges from 0 with no upper limit.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=201 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) n=47 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg n=49 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Total Pain Relief (TOTPAR) at 72h After the First Dose - Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	156.9 score on a scale Standard Deviation 63.83	144.7 score on a scale Standard Deviation 64.14	156.9 score on a scale Standard Deviation 63.83	144.7 score on a scale Standard Deviation 64.14

SECONDARY outcome

Timeframe: Form T=0 to T=24h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

The max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR) were calculated at prespecified time point points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 100 for Dexketoprofen/Tramadol group and 0 to 94 for Tramadol group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=201 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) n=43 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg n=48 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 24 Hours After the First Dose- Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	46.6 Percentage of score on a scale Standard Deviation 21.07	42.7 Percentage of score on a scale Standard Deviation 20.66	46.6 Percentage of score on a scale Standard Deviation 21.07	42.7 Percentage of score on a scale Standard Deviation 20.66

SECONDARY outcome

Timeframe: Form T=0 to T=48h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

The max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR) were calculated at prespecified time point points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 100 for Dexketoprofen/Tramadol group and 0 to 96 for Tramadol group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=201 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) n=47 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg n=49 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 48 Hours After the First Dose- Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	51.2 Percentage of score on a scale Standard Deviation 21.69	46.9 Percentage of score on a scale Standard Deviation 21.79	51.2 Percentage of score on a scale Standard Deviation 21.69	46.9 Percentage of score on a scale Standard Deviation 21.79

SECONDARY outcome

Timeframe: Form T=0 to T=72h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

The max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR) were calculated at prespecified time point points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 100 for Dexketoprofen/Tramadol group and 0 to 97 for Tramadol group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=201 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) n=47 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg n=49 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 72 Hours After the First Dose- Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	54.7 Percentage of score on a scale Standard Deviation 22.15	50.3 Percentage of score on a scale Standard Deviation 22.24	54.7 Percentage of score on a scale Standard Deviation 22.15	50.3 Percentage of score on a scale Standard Deviation 22.24

SECONDARY outcome

Timeframe: Form T=0 to T=96h

Population: The modified intent-to-treat (mITT) population included the first cohort of patients randomized to the 4 treatment arms in a 4:4:1:1 ratio.

The max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), and percentage of maximum TOTPAR (%max TOTPAR) were calculated at prespecified time point points in the single and the multiple-dose phases of the study. Percentage of maximum TOTPAR minimum and maximum values were 0 to 100 for Dexketoprofen/Tramadol group and 0 to 98 for Tramadol group. %max TOTPAR scale ranges from 0 to 100.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=201 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=202 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) n=48 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg n=49 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Maximum TOTPAR (%Max TOTPAR) at 96 Hours After the First Dose- Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	57.7 Percentage of score on a scale Standard Deviation 22.7	53.3 Percentage of score on a scale Standard Deviation 22.82	57.7 Percentage of score on a scale Standard Deviation 22.7	53.3 Percentage of score on a scale Standard Deviation 22.82

SECONDARY outcome

Timeframe: Form T=0 to T=48h

Population: Per-protocol (PP) population included all patients in the ITT having major protocol violations that could affect the primary efficacy analysis. Protocol violations which had a major distorting influence on the primary endpoints resulted in patients being excluded from the PP population. Protocol Deviations identified during the the study conduct, as authorized in the final Protocol Deviation log, were taken into consideration in the final assignment of patients to the analysis sets.

TOTPAR was calculated as the time-weighted sum of the PAR-VRS scores. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some (meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at pre-specified time point points in the single and the multiple-dose phases of the study.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=235 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=230 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Patients Achieving at Least 50% of Maximum TOTPAR at 48 Hours After the First Dose - Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	60 Percentage of patients	46.5 Percentage of patients	—	—

SECONDARY outcome

Timeframe: Form T=0 to T=72h

Population: Per-protocol (PP) population included all patients in the ITT having major protocol violations that could affect the primary efficacy analysis. Protocol violations which had a major distorting influence on the primary endpoints resulted in patients being excluded from the PP population. Protocol Deviations identified during the the study conduct, as authorized in the final Protocol Deviation log, were taken into consideration in the final assignment of patients to the analysis sets.

The max TOTPAR was calculated as the theoretical maximum time-weighted sum of the PAR values for each patient. The maximum possible TOTPAR was the value of TOTPAR that would have been obtained if the patient had a complete pain relief for that observation period. The Verbal Rating Scale (VRS) is a 5-point scale to assess the pain relief. The patients were asked to answer the question 'How do you rate your pain relief?' where 0 = 'no relief', 1 = 'a little (perceptible) relief', 2 = 'some(meaningful) relief', 3 = 'lot of relief', 4 = 'complete relief'. Based on VRS, pain relief (PAR) scores, total pain relief (TOTPAR),percentage of maximum TOTPAR (%max TOTPAR), and percentage of patients achieving at least 50% of maximum TOTPAR were calculated at pre specified time point points in the single and the multiple-dose phases of the study.

Outcome measures

Outcome measures
Measure	Dexketoprofen Trometamol 25 mg/ Tramadol Hydrochloride 75 mg Treatment (Both Phases) n=147 Participants Two phase intervention. Single dose phase (SDP) (time 0 - time 8h) and Multiple dose phase (MDP) time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Placebo (SDP) Then Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment (MDP) n=123 Participants Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE (MDP): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo (Single Dose Phase) Then Tramadol Hydrochloride 100 mg (Multiple Dose Phase) Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE (SDP): Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE (MDP): Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg	Placebo and Tramadol Hydrochloride 100 mg Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple dose phase (time 8h - Day 5). SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg) Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours Placebo: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg
Percentage of Patients Achieving at Least 50% of Maximum TOTPAR at 72 Hours After the First Dose - Multiple Dose Phase - Dexketoprofen/Tramadol vs Tramadol	62.6 Percentage of patients	53.5 Percentage of patients	—	—

Adverse Events

Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment - MULTIPLE DOSE PHASE

Serious events: 0 serious events

Other events: 68 other events

Deaths: 0 deaths

Tramadol Hydrochloride 100 mg Treatment - MULTIPLE DOSE PHASE

Serious events: 1 serious events

Other events: 73 other events

Deaths: 0 deaths

Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment - SINGLE DOSE PHASE

Serious events: 1 serious events

Other events: 28 other events

Deaths: 0 deaths

Tramadol Hydrochloride 100 mg Treatment - SINGLE DOSE PHASE

Serious events: 0 serious events

Other events: 31 other events

Deaths: 0 deaths

Placebo - SINGLE DOSE PHASE

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment - MULTIPLE DOSE PHASE n=270 participants at risk Multiple dose phase (time 8h - Day 5) In this arm patients will receive during this phase film coated tablets (administered as one tablet): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Tramadol Hydrochloride 100 mg Treatment - MULTIPLE DOSE PHASE n=268 participants at risk Multiple dose phase (time 8h - Day 5) In this arm patients will receive during this phase (administered as 2 capsules of Tramadol 50 mg): Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours	Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment - SINGLE DOSE PHASE n=211 participants at risk Single dose phase (time 0 - time 8h) In this arm patients will receive during this phase film coated tablets (administered as one tablet): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Tramadol Hydrochloride 100 mg Treatment - SINGLE DOSE PHASE n=207 participants at risk Single dose phase (time 0 - time 8h) In this arm patients will receive during this phase (administered as 2 capsules of Tramadol 50 mg): Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours	Placebo - SINGLE DOSE PHASE n=119 participants at risk Single dose phase (time 0 - time 8h) Placebo administered as one film-coated tablets if matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg treatment or 2 capsules if matching Tramadol Hydrochloride 100 mg Treatment (as 2 capsules of Tramadol 50 mg).
Renal and urinary disorders Calculus Urinary	0.00% 0/270 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.00% 0/268 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.47% 1/211 • Number of events 1 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.00% 0/207 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.00% 0/119 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term
Nervous system disorders Monoparesis	0.00% 0/270 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.37% 1/268 • Number of events 1 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.00% 0/211 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.00% 0/207 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.00% 0/119 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term

Other adverse events

Other adverse events
Measure	Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment - MULTIPLE DOSE PHASE n=270 participants at risk Multiple dose phase (time 8h - Day 5) In this arm patients will receive during this phase film coated tablets (administered as one tablet): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Tramadol Hydrochloride 100 mg Treatment - MULTIPLE DOSE PHASE n=268 participants at risk Multiple dose phase (time 8h - Day 5) In this arm patients will receive during this phase (administered as 2 capsules of Tramadol 50 mg): Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours	Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg Treatment - SINGLE DOSE PHASE n=211 participants at risk Single dose phase (time 0 - time 8h) In this arm patients will receive during this phase film coated tablets (administered as one tablet): Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg: Administered as one single tablet to be taken every 8 hours	Tramadol Hydrochloride 100 mg Treatment - SINGLE DOSE PHASE n=207 participants at risk Single dose phase (time 0 - time 8h) In this arm patients will receive during this phase (administered as 2 capsules of Tramadol 50 mg): Tramadol Hydrochloride 100 mg: Administered as two capsules with 50 mg each to be taken every 8 hours	Placebo - SINGLE DOSE PHASE n=119 participants at risk Single dose phase (time 0 - time 8h) Placebo administered as one film-coated tablets if matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg treatment or 2 capsules if matching Tramadol Hydrochloride 100 mg Treatment (as 2 capsules of Tramadol 50 mg).
Gastrointestinal disorders Nausea	6.7% 18/270 • Number of events 18 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	9.3% 25/268 • Number of events 25 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	3.8% 8/211 • Number of events 8 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	2.9% 6/207 • Number of events 6 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	4.2% 5/119 • Number of events 5 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term
Gastrointestinal disorders Vomiting	4.8% 13/270 • Number of events 15 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	8.2% 22/268 • Number of events 23 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	1.4% 3/211 • Number of events 3 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.97% 2/207 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	2.5% 3/119 • Number of events 3 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term
Nervous system disorders Dizziness	6.3% 17/270 • Number of events 17 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	6.0% 16/268 • Number of events 16 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	5.7% 12/211 • Number of events 12 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	5.8% 12/207 • Number of events 12 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	1.7% 2/119 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term
Nervous system disorders Somnolence	4.4% 12/270 • Number of events 12 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	2.6% 7/268 • Number of events 7 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.95% 2/211 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	3.4% 7/207 • Number of events 7 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	1.7% 2/119 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term
Nervous system disorders Headache	3.0% 8/270 • Number of events 9 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	1.9% 5/268 • Number of events 5 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.47% 1/211 • Number of events 1 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.97% 2/207 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	1.7% 2/119 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term
General disorders Asthenia	1.9% 5/270 • Number of events 5 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.75% 2/268 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.47% 1/211 • Number of events 1 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.48% 1/207 • Number of events 1 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.84% 1/119 • Number of events 1 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term
Ear and labyrinth disorders Vertigo	0.74% 2/270 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	1.5% 4/268 • Number of events 4 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.47% 1/211 • Number of events 1 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.97% 2/207 • Number of events 2 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term	0.00% 0/119 • Adverse events were collected starting from informed consent signature till the end of the study at Visit 2 (Day 6+2 Days). For the purpose of the study, in accordance to study Protocol, the AEs have been divided by study phases (i.e Single Dose Phase and Multiple Dose Phase) If a patient reports the same Adverse Event (AE) more than once within that System Organ Class/Preferred Term, then that patient will be counted only once for that System Organ Class or Preferred Term

Additional Information

Corporate Medical Affair and Clinical Operation Director

A Menarini Industrie Farmaceutiche Riunite SrL

Phone: +39 055 5680459

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60