Acute Pain
Conditions
Keywords
Acute pain, Acute moderate to severe pain, Postoperative pain, Dexketoprofen Tramadol, Dexketoprofen trometamol, Tramadol hydrochloride, Multimodal analgesia, Third molar extraction, Fixed drug combination, Paracetamol, Analgesics
Brief summary
The study is aimed to evaluate the analgesic efficacy of TRAM.HCl/DKP.TRIS 75mg/25mg oral fixed drug combination in comparison with TRAM.HCl /paracetamol 75mg/650mg in the treatment of moderate to severe acute pain.
Detailed description
The present phase IV study is a randomised, double-blind, placebo and active-controlled, parallel group study in moderate to severe acute pain after removal of impacted lower third molar. In this single-dose clinical trial patients are randomized to the following 3 treatment arms in a 2:2:1 ratio: * TRAM.HCL/DKP.TRIS * Paracetamol/TRAM.HCL * Placebo.
Interventions
DRUGTramadol Hydrochloride/Dexketoprofen Trometamol
DRUGTramadol Hydrochloride/Paracetamol
DRUGPlacebo
Sponsors
Menarini Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients aged more than 18 years. Females participating in the study must be either non-childbearing potential or routinely using an effective method of birth control resulting in a low failure rate. * Scheduled for outpatient surgical extraction -under local anaesthesia of lower third molar teeth, with at least one partially impacted in the mandible requiring bone manipulation. * Pain of at least moderate intensity in the first 4 hours after the end of surgery (NRS score ≥ 4).
Exclusion criteria
* History of allergy or hypersensitivity to the study treatments, RM or to any other NSAIDs, opioids and acetyl salicylic acid. * History of peptic ulcer, gastrointestinal disorders by NSAIDs or gastrointestinal bleeding or other active bleedings. * History of any illness or condition that, in the opinion of the Investigator might pose a risk to the patient or confound the efficacy and safety results of the study. * Patients using and not suitable for withdrawing the prohibited medications specified in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| TOTPAR6 (Total Pain Relief Over 6 Hours Post-dose) | 6 hours post-dose | TOTPAR calculated as the weighted sum of the PAR scores, measured according to a 5-point VRS (Verbal Rating Scale) from 0=no relief to 4=complete relief, over 6 hours post-dose (TOTPAR6). The TOTPAR6 ranges from a minimum of 0 to a maximum of 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| % of Patients Achieving 50% of Max TOTPAR | 8 hours post-dose | Percentage of patients who achieved at least 50% of the maximum TOTPAR at 8 hours. In the present trial the achievable TOTPAR over 8 hours ranges between 0 and 32. |
| % of Patients Achieving at Least 30% of PI (Pain Intensity) Reduction Over 8 Hours Post-dose | 8 hours post-dose | Percentage of patients who achieve at least 30% of PI Reduction versus baseline Over 8 Hours Post-dose. Percentage change of PI is calculated using the baseline value minus the PI assessed at 8 hours post-dose divided for the baseline value, then multiplied for 100. |
| Time to Confirmed FPPAR (First Perceptible Pain Relief) | 2 hours post-dose | Time to confirmed FPPAR (time to onset of analgesia) - i.e. time to FPPAR if confirmed by experiencing Meaningful Pain Relief (MPAR) FPPAR and MPAR assessed by using stopwatches: 1. 'first perceptible' PAR (FPPAR), i.e, at the moment they first felt any PAR whatsoever; 2. 'meaningful' PAR (MPAR, ie, when the relief from pain became meaningful to them) |
| % of Patients Requiring RM (Rescue Medication) | 8 hours post-dose | Percentage of patients who required RM within the first over 8 hours post-dose. |
| PGE (Patient Global Evaluation) | 8 hours postdose | PGE of the study medication (measured according to a five-point VRS from 1 = poor to 5 = excellent) at 8 hours post-dose or whenever the patient uses Rescue Medication (RM). |
Countries
Hungary, Italy, Poland, Spain, United Kingdom
Participant flow
Recruitment details
This study was conducted in 18 centers across 5 European countries: Hungary, Italy, Poland, Spain and the United Kingdom. The clinical phase of the study started on 28th April 2016 (first screened patient) and concluded on 14th February 2017 (last patient out).
Pre-assignment details
A total of 792 patients were screened, of which 654 patients were randomized. One randomized patient was excluded from all the analysis populations, because of being younger than 18 years old. Prior to randomization, enrolled patients underwent a Screening period lasting up 2 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Tramadol/Dexketoprofen Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose;
Placebo matching Tramadol Hydrochloride/Paracetamol 75 mg/650mg, as 2 x \[37.5mg/325mg\] film-coated tablets, oral single dose. | 260 |
| Tramadol/Paracetamol Tramadol Hydrochloride/Paracetamol 75 mg/650 mg, as 2 x \[37.5mg/325mg\] film-coated tablets, oral single dose;
Placebo matching Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose. | 262 |
| Placebo Placebo matching one film-coated tablet of Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg oral single dose;
Placebo matching two film-coated tablets of Tramadol Hydrochloride/Paracetamol 37.5mg/325mg oral single dose. | 131 |
| Total | 653 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Tramadol/Dexketoprofen | Tramadol/Paracetamol | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 26.8 years STANDARD_DEVIATION 7.48 | 27.1 years STANDARD_DEVIATION 8.13 | 26.5 years STANDARD_DEVIATION 7.67 | 26.9 years STANDARD_DEVIATION 7.78 |
| Pain Intensity at Qualification | 5.0 units on a scale STANDARD_DEVIATION 1.19 | 4.9 units on a scale STANDARD_DEVIATION 1.12 | 4.8 units on a scale STANDARD_DEVIATION 1.1 | 4.9 units on a scale STANDARD_DEVIATION 1.14 |
| Race/Ethnicity, Customized Asian | 14 Participants | 21 Participants | 6 Participants | 41 Participants |
| Race/Ethnicity, Customized Black or Afro-american | 7 Participants | 3 Participants | 6 Participants | 16 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 5 Participants | 1 Participants | 10 Participants |
| Race/Ethnicity, Customized White | 235 Participants | 233 Participants | 118 Participants | 586 Participants |
| Sex: Female, Male Female | 152 Participants | 104 Participants | 53 Participants | 309 Participants |
| Sex: Female, Male Male | 108 Participants | 158 Participants | 78 Participants | 344 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 260 | 0 / 262 | 0 / 131 |
| other Total, other adverse events | 35 / 260 | 40 / 262 | 13 / 131 |
| serious Total, serious adverse events | 1 / 260 | 0 / 262 | 0 / 131 |
Outcome results
Primary
TOTPAR6 (Total Pain Relief Over 6 Hours Post-dose)
TOTPAR calculated as the weighted sum of the PAR scores, measured according to a 5-point VRS (Verbal Rating Scale) from 0=no relief to 4=complete relief, over 6 hours post-dose (TOTPAR6). The TOTPAR6 ranges from a minimum of 0 to a maximum of 24.
Time frame: 6 hours post-dose
Population: A total of 654 patients were randomized and received the study treatments, of these one underage patient, erroneously enrolled in the study, was excluded from all the analysis populations, therefore 653 patients constituted ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol/Dexketoprofen | TOTPAR6 (Total Pain Relief Over 6 Hours Post-dose) | 13.0 5-point Verbal Rating Scale | Standard Deviation 6.97 |
| Tramadol/Paracetamol | TOTPAR6 (Total Pain Relief Over 6 Hours Post-dose) | 9.2 5-point Verbal Rating Scale | Standard Deviation 7.65 |
| Placebo | TOTPAR6 (Total Pain Relief Over 6 Hours Post-dose) | 1.9 5-point Verbal Rating Scale | Standard Deviation 3.89 |
Secondary
% of Patients Achieving 50% of Max TOTPAR
Percentage of patients who achieved at least 50% of the maximum TOTPAR at 8 hours. In the present trial the achievable TOTPAR over 8 hours ranges between 0 and 32.
Time frame: 8 hours post-dose
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tramadol/Dexketoprofen | % of Patients Achieving 50% of Max TOTPAR | 47.7 percentage of patients |
| Tramadol/Paracetamol | % of Patients Achieving 50% of Max TOTPAR | 35.5 percentage of patients |
| Placebo | % of Patients Achieving 50% of Max TOTPAR | 5.3 percentage of patients |
Secondary
% of Patients Achieving at Least 30% of PI (Pain Intensity) Reduction Over 8 Hours Post-dose
Percentage of patients who achieve at least 30% of PI Reduction versus baseline Over 8 Hours Post-dose. Percentage change of PI is calculated using the baseline value minus the PI assessed at 8 hours post-dose divided for the baseline value, then multiplied for 100.
Time frame: 8 hours post-dose
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tramadol/Dexketoprofen | % of Patients Achieving at Least 30% of PI (Pain Intensity) Reduction Over 8 Hours Post-dose | 40.0 percentage of patients |
| Tramadol/Paracetamol | % of Patients Achieving at Least 30% of PI (Pain Intensity) Reduction Over 8 Hours Post-dose | 35.5 percentage of patients |
| Placebo | % of Patients Achieving at Least 30% of PI (Pain Intensity) Reduction Over 8 Hours Post-dose | 9.9 percentage of patients |
Secondary
% of Patients Requiring RM (Rescue Medication)
Percentage of patients who required RM within the first over 8 hours post-dose.
Time frame: 8 hours post-dose
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tramadol/Dexketoprofen | % of Patients Requiring RM (Rescue Medication) | 51.2 percentage of patients |
| Tramadol/Paracetamol | % of Patients Requiring RM (Rescue Medication) | 55.0 percentage of patients |
| Placebo | % of Patients Requiring RM (Rescue Medication) | 88.5 percentage of patients |
Secondary
PGE (Patient Global Evaluation)
PGE of the study medication (measured according to a five-point VRS from 1 = poor to 5 = excellent) at 8 hours post-dose or whenever the patient uses Rescue Medication (RM).
Time frame: 8 hours postdose
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol/Dexketoprofen | PGE (Patient Global Evaluation) | 3.6 units on a scale | Standard Deviation 1.1 |
| Tramadol/Paracetamol | PGE (Patient Global Evaluation) | 2.8 units on a scale | Standard Deviation 1.4 |
| Placebo | PGE (Patient Global Evaluation) | 1.5 units on a scale | Standard Deviation 0.9 |
Secondary
Time to Confirmed FPPAR (First Perceptible Pain Relief)
Time to confirmed FPPAR (time to onset of analgesia) - i.e. time to FPPAR if confirmed by experiencing Meaningful Pain Relief (MPAR) FPPAR and MPAR assessed by using stopwatches: 1. 'first perceptible' PAR (FPPAR), i.e, at the moment they first felt any PAR whatsoever; 2. 'meaningful' PAR (MPAR, ie, when the relief from pain became meaningful to them)
Time frame: 2 hours post-dose
Population: The analysis is conducted only on active treatment arms.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tramadol/Dexketoprofen | Time to Confirmed FPPAR (First Perceptible Pain Relief) | 21 minutes |
| Tramadol/Paracetamol | Time to Confirmed FPPAR (First Perceptible Pain Relief) | 24 minutes |