NCT03714672

Tramadol/Diclofenac Fixed-dose Combination Phase III Trial in Acute Pain After Third Molar Extraction

Completed Phase 3 Results posted Last updated 24 July 2019

What this trial tests

Phase 3 trial testing Tramadol/Diclofenac 50/50 in Acute Pain in 1,151 participants. Completed in 22 March 2018.

Timeline

26 August 2017

Primary endpoint
9 March 2018

22 March 2018

Quick facts

Lead sponsor	Grünenthal GmbH
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	1,151
Start date	26 August 2017
Primary completion	9 March 2018
Estimated completion	22 March 2018
Sites	8 locations across Mexico

Drugs / interventions tested

• Tramadol/Diclofenac 50/50 — full drug profile →
• Tramadol/Diclofenac 25/25 — full drug profile →
• Tramadol 50 — full drug profile →
• Diclofenac 50 — full drug profile →

Conditions studied

• Acute Pain — all drugs for Acute Pain →

Sponsor

Grünenthal GmbH — full company profile →

Who can join

Adults 18 to 60, any sex, with Acute Pain. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4) Primary · Up to 4 hours after first dose

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

Group	Value	95% CI
Tramadol/Diclofenac 50/50	9.9	9.3 – 10.4
Tramadol/Diclofenac 25/25	8.6	8.0 – 9.1
Tramadol 50	5.4	4.9 – 5.9
Diclofenac 50	5.8	5.3 – 6.3

Total Pain Relief at 6 Hours Post-dose (TOTPAR6) Secondary · Up to 6 hours after first dose

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

Group	Value	95% CI
Tramadol/Diclofenac 50/50	15.2	14.4 – 16.0
Tramadol/Diclofenac 25/25	13.3	12.5 – 14.2
Tramadol 50	9.3	8.4 – 10.1
Diclofenac 50	9.8	9.0 – 10.6

Total Pain Relief at 8 Hours Post-dose (TOTPAR8) Secondary · Up to 8 hours after first dose

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

Group	Value	95% CI
Tramadol/Diclofenac 50/50	20.1	19.0 – 21.2
Tramadol/Diclofenac 25/25	17.8	16.7 – 18.9
Tramadol 50	13.1	12.0 – 14.2
Diclofenac 50	13.7	12.6 – 14.8

Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose Secondary · Baseline; up to 24 hours after first dose

Pain intensity was assessed by the participant before and at defined time points after the first IMP dose using an 11-point NRS with anchors at 0 for "no pain" and 10 for "pain as bad as you can imagine". Pain Intensity Difference (PIDt) was defined as the difference between baseline pain intensity and pain intensity at time point t, and SPID defined as summed PIDt x \[time (hours) elapsed since previous observation\]. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pai

4 Hours

Group	Value	95% CI
Tramadol/Diclofenac 50/50	16.24	± 0.564
Tramadol/Diclofenac 25/25	13.67	± 0.576
Tramadol 50	6.43	± 0.570
Diclofenac 50	7.72	± 0.568

6 Hours

Group	Value	95% CI
Tramadol/Diclofenac 50/50	25.54	± 0.836
Tramadol/Diclofenac 25/25	21.86	± 0.855
Tramadol 50	12.89	± 0.845
Diclofenac 50	14.36	± 0.843

8 Hours

Group	Value	95% CI
Tramadol/Diclofenac 50/50	33.70	± 1.121
Tramadol/Diclofenac 25/25	28.90	± 1.146
Tramadol 50	19.10	± 1.133
Diclofenac 50	20.54	± 1.129

24 Hours

Group	Value	95% CI
Tramadol/Diclofenac 50/50	107.15	± 3.787
Tramadol/Diclofenac 25/25	91.99	± 3.873
Tramadol 50	71.41	± 3.828
Diclofenac 50	72.08	± 3.816

Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone) Secondary · Up to 24 hours after first dose

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

Group	Value	95% CI
Tramadol/Diclofenac 50/50	1.27	± 1.216
Tramadol/Diclofenac 25/25	1.73	± 2.778
Tramadol 50	3.01	± 3.731
Diclofenac 50	2.53	± 2.865

Time to Onset of First Perceptible Pain Relief Secondary · Up to 8 hours after first dose

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

Group	Value	95% CI
Tramadol/Diclofenac 50/50	0.57	± 0.483
Tramadol/Diclofenac 25/25	0.67	± 0.875
Tramadol 50	1.07	± 1.000
Diclofenac 50	1.12	± 1.151

Time to Onset of Meaningful Pain Relief Secondary · Up to 8 hours after first dose

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

Group	Value	95% CI
Tramadol/Diclofenac 50/50	1.47	± 1.149
Tramadol/Diclofenac 25/25	2.04	± 1.810
Tramadol 50	2.93	± 1.895
Diclofenac 50	2.75	± 1.882

Time to Intake of First Rescue Medication Dose Secondary · First dose to 24 hours after first dose

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

Group	Value	95% CI
Tramadol/Diclofenac 50/50	21.84	± 6.222
Tramadol/Diclofenac 25/25	20.99	± 7.450
Tramadol 50	17.37	± 9.745
Diclofenac 50	17.38	± 9.646

Subject's Global Evaluation of the Treatment Secondary · 8 hours after the first dose of IMP or before first intake of rescue medication (whatever the first) and 24 hours after the first dose of IMPs

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

8-Hours

Group	Value	95% CI
Tramadol/Diclofenac 50/50	4
Tramadol/Diclofenac 25/25	7
Tramadol 50	28
Diclofenac 50	23
Tramadol/Diclofenac 50/50	10
Tramadol/Diclofenac 25/25	12
Tramadol 50	30
Diclofenac 50	25
Tramadol/Diclofenac 50/50	17
Tramadol/Diclofenac 25/25	33
Tramadol 50	36
Diclofenac 50	35
Tramadol/Diclofenac 50/50	73
Tramadol/Diclofenac 25/25	64
Tramadol 50	52
Diclofenac 50	67

24-Hours

Group	Value	95% CI
Tramadol/Diclofenac 50/50	3
Tramadol/Diclofenac 25/25	4
Tramadol 50	7
Diclofenac 50	7
Tramadol/Diclofenac 50/50	4
Tramadol/Diclofenac 25/25	5
Tramadol 50	23
Diclofenac 50	13
Tramadol/Diclofenac 50/50	12
Tramadol/Diclofenac 25/25	18
Tramadol 50	34
Diclofenac 50	39
Tramadol/Diclofenac 50/50	57
Tramadol/Diclofenac 25/25	65
Tramadol 50	59
Diclofenac 50	67

Incidence and Type of Adverse Events Secondary · Day 1 to Day 14

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

TEAE

Group	Value	95% CI
Tramadol/Diclofenac 50/50	96
Tramadol/Diclofenac 25/25	62
Tramadol 50	105
Diclofenac 50	48

Severe TEAE

Group	Value	95% CI
Tramadol/Diclofenac 50/50	6
Tramadol/Diclofenac 25/25	1
Tramadol 50	3
Diclofenac 50	2

TEAE related to IMP or rescue medication

Group	Value	95% CI
Tramadol/Diclofenac 50/50	49
Tramadol/Diclofenac 25/25	23
Tramadol 50	64
Diclofenac 50	10

Serious TEAE

Group	Value	95% CI
Tramadol/Diclofenac 50/50	0
Tramadol/Diclofenac 25/25	1
Tramadol 50	0
Diclofenac 50	0

TEAE with outcome of death

Group	Value	95% CI
Tramadol/Diclofenac 50/50	0
Tramadol/Diclofenac 25/25	0
Tramadol 50	0
Diclofenac 50	0

Selected TEAE

Group	Value	95% CI
Tramadol/Diclofenac 50/50	68
Tramadol/Diclofenac 25/25	26
Tramadol 50	77
Diclofenac 50	13

TEAE leading to dose reduction

Group	Value	95% CI
Tramadol/Diclofenac 50/50	0
Tramadol/Diclofenac 25/25	0
Tramadol 50	0
Diclofenac 50	0

TEAE leading to dose interruption

Group	Value	95% CI
Tramadol/Diclofenac 50/50	1
Tramadol/Diclofenac 25/25	2
Tramadol 50	1
Diclofenac 50	0

Adverse events — posted to ClinicalTrials.gov

Time frame: Day 1 to Day 14. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Tramadol/Diclofenac 50/50

Serious: 0/208 (0%)

Deaths: 0/208

Tramadol/Diclofenac 25/25

Serious: 1/205 (0%)

Deaths: 0/205

Tramadol 50

Serious: 0/206 (0%)

Deaths: 0/206

Diclofenac 50

Serious: 0/207 (0%)

Deaths: 0/207

Serious adverse events (1 terms)

Reaction	System	Tramadol/Diclofenac 50/50	Tramadol/Diclofenac 25/25	Tramadol 50	Diclofenac 50
Seizure	Nervous system disorders	—	—	—	—

Other adverse events (57 terms — click to expand)

Reaction	System	Tramadol/Diclofenac 50/50	Tramadol/Diclofenac 25/25	Tramadol 50	Diclofenac 50
Nausea	Gastrointestinal disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Procedural pain	Injury, poisoning and procedural complications	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Post procedural inflammation	Injury, poisoning and procedural complications	—	—	—	—
Oral pain	Gastrointestinal disorders	—	—	—	—
Chills	General disorders	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—
Somnolence	Nervous system disorders	—	—	—	—
Hyperhidrosis	Skin and subcutaneous tissue disorders	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—
Gastritis	Gastrointestinal disorders	—	—	—	—
Inflammation	General disorders	—	—	—	—
Pain	General disorders	—	—	—	—
Tooth abscess	Infections and infestations	—	—	—	—
Post procedural haemorrhage	Injury, poisoning and procedural complications	—	—	—	—
Post procedural swelling	Injury, poisoning and procedural complications	—	—	—	—
Hypoaesthesia	Nervous system disorders	—	—	—	—
Paraesthesia	Nervous system disorders	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—
Palpitations	Cardiac disorders	—	—	—	—
Ear pain	Ear and labyrinth disorders	—	—	—	—
Tinnitus	Ear and labyrinth disorders	—	—	—	—
Vertigo	Ear and labyrinth disorders	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—
Gingival pain	Gastrointestinal disorders	—	—	—	—
Hypoaesthesia oral	Gastrointestinal disorders	—	—	—	—
Face oedema	General disorders	—	—	—	—
Malaise	General disorders	—	—	—	—
Alveolar osteitis	Infections and infestations	—	—	—	—
Gingivitis	Infections and infestations	—	—	—	—
Infection	Infections and infestations	—	—	—	—
Post procedural infection	Infections and infestations	—	—	—	—
Tonsillitis	Infections and infestations	—	—	—	—

Most-reported serious reactions: Seizure.

Data from ClinicalTrials.gov NCT03714672 adverse events section.

Sponsor's own description

This study evaluated a new drug fixed-dose combination tablet (FDC) called tramadol/diclofenac at two different strengths (fixed doses of 25 milligrams \[mg\] of tramadol and of diclofenac or of 50 mg each). Tramadol and diclofenac each relieve pain, but they do so by different mechanisms. They were used alone as comparator drug in this study. Both are marketed drugs and are standard treatment for acute pain, including wisdom tooth removal.

Publications & conference data

No peer-reviewed publications indexed yet for this trial. Completed trials usually publish results within 12-18 months.