Pain
Conditions
Keywords
Moderate to severe pain, Postoperative pain, Analgesics, Dexketoprofen, Tramadol
Brief summary
The purpose of this study is to evaluate the analgesic efficacy of Dexketoprofen Trometamol and Tramadol Hydrochloride given in combinations and the analgesic efficacy of each single component in comparison to placebo on moderate to severe pain following impacted third mandibular molar tooth extraction. Ibuprofen will be used as an active control to validate the pain model.
Detailed description
The aim of this study is to develop a combination of Dexketoprofen Trometamol (DKP.TRIS) and Tramadol Hydrochloride (TRAM.HCl) for the treatment of acute moderate to severe pain, based on the rationale that more than one drug is necessary in most patients suffering of acute and chronic pain, particularly of moderate to severe intensity. DKP.TRIS and TRAM.HCl have different mechanisms of action, therefore their combination is expect to result in an additive or synergistic analgesia, thus allowing a decrease in the required doses of the individual agents, and consequently a reduced risk of adverse events In this study, patients who present moderate to severe pain after impacted third mandibular molar tooth extraction will be randomised to a total of 10 treatment arms including 4 combinations of DKP.TRIS + TRAM.HCl, the four corresponding single treatments, placebo and ibuprofen. Treatment administration will be followed by a 24-hour pain and analgesic effect assessment.
Interventions
Dexketoprofen Trometamol low dose, oral film-coated table, once
DRUGTramadol Hydrochloride
Tramadol Hydrochloride low dose, oral film-coated table, once
DRUGIbuprofen
Ibuprofen 400 mg, oral film-coated table, once
DRUGPlacebo
Placebo, oral film-coated table, once
DKP-TRIS low dose - TRAM.HCl low dose, oral film-coated table, once
Sponsors
PRA Health Sciences
Menarini Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Patients meeting ALL the following criteria will be eligible for entry into the study: * Male or female patients aged 18 to 70 years old. Females participating in the study must be either: of non-childbearing potential, or willing to use a highly effective contraceptive method. * Scheduled for outpatient surgical extraction -under local anaesthesia- of third mandibular molar teeth, with at least one of which is fully or partially impacted in the mandible requiring bone manipulation. * Normal physical examination or without clinically relevant abnormalities. At randomisation (after surgery): No intake of analgesics (including prescription and over the counter drugs) within 24h prior to the surgery. * No complication during the surgery, duration of surgery \< 1 hour and not requiring re-anaesthesia. * Patients experiencing pain of moderate or higher intensity in the first four hours after the end of surgery.
Exclusion criteria
* History of allergy or hypersensitivity to NSAIDs, opioids or acetyl salicylic acid. * History of asthma, bronchospasm, acute rhinitis, nasal polyps, urticaria or angioneurotic oedema. * History of peptic ulcer, gastrointestinal disorders by NSAIDs, gastrointestinal bleeding or other active bleedings.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 6 hours | Pain relief is measured by a verbal rating scale (ranging from 0=none to 4=complete). Theoretical maximum TOTPAR at 6 hours is calculated by summing up the maximum score of analgesia which the patient can attribute at defined time points along 6 hour (maxTOTPAR6h= 24). Unit of measure is % |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | 4, 8 and 12 hours | Pain relief is measured by a verbal rating scale (ranging from 0=none to 4=complete). Theoretical maximum TOTPAR at 6 hours is calculated by summing up the maximum score of analgesia which the patient can attribute at defined time points along 4, 8 and 12 hours(maxTOTPAR4h= 16, maxTOTPAR8h= 32 and maxTOTPAR12h= 48, respectively) Unit of measure is % |
| Percentage of Patients Using Rescue Medication at 6 Hours | Baseline to 6 hours | Percentage of patients using rescue medication at 6 hours post-dosing. |
Countries
Germany, Hungary, Italy, Poland, Spain, United Kingdom
Participant flow
Recruitment details
First patient in (screening) 23 Feb 2011, last patient out 14 Oct 2011. At 16 study centres in 6 European countries (Germany, Italy, Hungary, Poland, Spain and United Kingdom).
Pre-assignment details
The trial encompassed 3 visits: 1-Screening; 2-Dental surgery (patients who have moderate to severe pain afterwards were randomised and received study drug); 3-End of study. Overall, 745 patients were enrolled (screened), of them 611 were randomized to receive the study drug and therefore considered as started.
Participants by arm
| Arm | Count |
|---|---|
| DKP-TRIS 12.5mg - TRAM.HCl 37.5mg DKP-TRIS 12.5mg - TRAM.HCl 37.5mg oral film-coated tablet, once | 61 |
| DKP-TRIS 12.5mg - TRAM.HCl 75mg DKP-TRIS 12.5mg - TRAM.HCl 75mg oral film-coated tablet, once | 63 |
| DKP-TRIS 25mg - TRAM.HCl 37.5mg DKP-TRIS 25mg - TRAM.HCl 37.5mg oral film-coated tablet, once | 63 |
| DKP-TRIS 25mg - TRAM.HCl 75mg DKP-TRIS 25mg - TRAM.HCl 75mg oral film-coated tablet, once | 61 |
| DKP-TRIS 12.5mg DKP-TRIS 12.5mg oral film-coated tablet, once | 60 |
| DKP-TRIS 25mg DKP-TRIS 25mg oral film-coated tablet, once | 61 |
| TRAM.HCl 37.5mg TRAM.HCl 37.5mg oral film-coated tablet, once | 59 |
| TRAM.HCl 75mg TRAM.HCl 75mg oral film-coated tablet, once | 60 |
| Ibuprofen 400mg Ibuprofen 400mg oral film-coated tablet, once | 61 |
| Placebo Placebo oral film-coated tablet, once | 62 |
| Total | 611 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Electronic data capture failure | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | DKP-TRIS 12.5mg - TRAM.HCl 37.5mg | DKP-TRIS 12.5mg - TRAM.HCl 75mg | DKP-TRIS 25mg - TRAM.HCl 37.5mg | DKP-TRIS 25mg - TRAM.HCl 75mg | DKP-TRIS 12.5mg | DKP-TRIS 25mg | TRAM.HCl 37.5mg | TRAM.HCl 75mg | Ibuprofen 400mg | Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | 28.6 years STANDARD_DEVIATION 7.64 | 26.9 years STANDARD_DEVIATION 7.62 | 26.3 years STANDARD_DEVIATION 7.33 | 27.3 years STANDARD_DEVIATION 7.55 | 27.0 years STANDARD_DEVIATION 9.85 | 26.9 years STANDARD_DEVIATION 6.94 | 25.5 years STANDARD_DEVIATION 7.15 | 27.8 years STANDARD_DEVIATION 7.99 | 26.6 years STANDARD_DEVIATION 6.48 | 26.1 years STANDARD_DEVIATION 6.64 | 26.9 years STANDARD_DEVIATION 7.56 |
| BMI | 23.7 kg/m^2 STANDARD_DEVIATION 3.39 | 24.1 kg/m^2 STANDARD_DEVIATION 3.69 | 23.0 kg/m^2 STANDARD_DEVIATION 2.87 | 23.2 kg/m^2 STANDARD_DEVIATION 3.19 | 23.6 kg/m^2 STANDARD_DEVIATION 3.2 | 23.5 kg/m^2 STANDARD_DEVIATION 3.3 | 23.0 kg/m^2 STANDARD_DEVIATION 3.19 | 24.2 kg/m^2 STANDARD_DEVIATION 3.08 | 22.4 kg/m^2 STANDARD_DEVIATION 3.04 | 22.7 kg/m^2 STANDARD_DEVIATION 2.8 | 23.3 kg/m^2 STANDARD_DEVIATION 3.21 |
| Sex: Female, Male Female | 35 Participants | 39 Participants | 36 Participants | 34 Participants | 36 Participants | 44 Participants | 38 Participants | 28 Participants | 41 Participants | 33 Participants | 364 Participants |
| Sex: Female, Male Male | 26 Participants | 24 Participants | 27 Participants | 27 Participants | 24 Participants | 17 Participants | 21 Participants | 32 Participants | 20 Participants | 29 Participants | 247 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 61 | 9 / 63 | 6 / 63 | 10 / 61 | 2 / 60 | 4 / 61 | 5 / 59 | 14 / 60 | 5 / 61 | 1 / 62 |
| serious Total, serious adverse events | 0 / 61 | 0 / 63 | 0 / 63 | 0 / 61 | 0 / 60 | 0 / 61 | 0 / 59 | 1 / 60 | 0 / 61 | 0 / 62 |
Outcome results
Primary
Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing.
Pain relief is measured by a verbal rating scale (ranging from 0=none to 4=complete). Theoretical maximum TOTPAR at 6 hours is calculated by summing up the maximum score of analgesia which the patient can attribute at defined time points along 6 hour (maxTOTPAR6h= 24). Unit of measure is %
Time frame: 6 hours
Population: ITT (intention to treat) population which was defined as all patients who have taken the study treatment and have at least 1 post-dose assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DKP-TRIS 12.5mg - TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 36.7 percentage of patients |
| DKP-TRIS 12.5mg - TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 59.7 percentage of patients |
| DKP-TRIS 25mg - TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 55.6 percentage of patients |
| DKP-TRIS 25mg - TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 72.1 percentage of patients |
| DKP-TRIS 12.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 26.7 percentage of patients |
| DKP-TRIS 25mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 55.0 percentage of patients |
| TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 10.2 percentage of patients |
| TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 25.4 percentage of patients |
| Ibuprofen 400mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 45.0 percentage of patients |
| Placebo | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | 9.7 percentage of patients |
Secondary
Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing.
Pain relief is measured by a verbal rating scale (ranging from 0=none to 4=complete). Theoretical maximum TOTPAR at 6 hours is calculated by summing up the maximum score of analgesia which the patient can attribute at defined time points along 4, 8 and 12 hours(maxTOTPAR4h= 16, maxTOTPAR8h= 32 and maxTOTPAR12h= 48, respectively) Unit of measure is %
Time frame: 4, 8 and 12 hours
Population: ITT (intention to treat) population which was defined as all patients who have taken the study treatment and have at least 1 post-dose assessment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DKP-TRIS 12.5mg - TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 63.3 percentage of patient |
| DKP-TRIS 12.5mg - TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 11.7 percentage of patient |
| DKP-TRIS 12.5mg - TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 21.7 percentage of patient |
| DKP-TRIS 12.5mg - TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 48.4 percentage of patient |
| DKP-TRIS 12.5mg - TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 35.5 percentage of patient |
| DKP-TRIS 12.5mg - TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 72.6 percentage of patient |
| DKP-TRIS 25mg - TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 28.6 percentage of patient |
| DKP-TRIS 25mg - TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 65.1 percentage of patient |
| DKP-TRIS 25mg - TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 44.4 percentage of patient |
| DKP-TRIS 25mg - TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 37.7 percentage of patient |
| DKP-TRIS 25mg - TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 78.7 percentage of patient |
| DKP-TRIS 25mg - TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 54.1 percentage of patient |
| DKP-TRIS 12.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 40.0 percentage of patient |
| DKP-TRIS 12.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 16.7 percentage of patient |
| DKP-TRIS 12.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 10.0 percentage of patient |
| DKP-TRIS 25mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 31.7 percentage of patient |
| DKP-TRIS 25mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 65.0 percentage of patient |
| DKP-TRIS 25mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 13.3 percentage of patient |
| TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 11.9 percentage of patient |
| TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 5.1 percentage of patient |
| TRAM.HCl 37.5mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 6.8 percentage of patient |
| TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 20.3 percentage of patient |
| TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 23.7 percentage of patient |
| TRAM.HCl 75mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 15.3 percentage of patient |
| Ibuprofen 400mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 33.3 percentage of patient |
| Ibuprofen 400mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 56.7 percentage of patient |
| Ibuprofen 400mg | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 25.0 percentage of patient |
| Placebo | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 4 hours post-dose | 6.5 percentage of patient |
| Placebo | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 12 hours post-dose | 6.5 percentage of patient |
| Placebo | Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | at 8 hours post-dose | 6.5 percentage of patient |
Secondary
Percentage of Patients Using Rescue Medication at 6 Hours
Percentage of patients using rescue medication at 6 hours post-dosing.
Time frame: Baseline to 6 hours
Population: ITT (intention to treat) population which was defined as all patients who have taken the study treatment and have at least 1 post-dose assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DKP-TRIS 12.5mg - TRAM.HCl 37.5mg | Percentage of Patients Using Rescue Medication at 6 Hours | 66.7 percentage of patients |
| DKP-TRIS 12.5mg - TRAM.HCl 75mg | Percentage of Patients Using Rescue Medication at 6 Hours | 46.8 percentage of patients |
| DKP-TRIS 25mg - TRAM.HCl 37.5mg | Percentage of Patients Using Rescue Medication at 6 Hours | 39.7 percentage of patients |
| DKP-TRIS 25mg - TRAM.HCl 75mg | Percentage of Patients Using Rescue Medication at 6 Hours | 37.7 percentage of patients |
| DKP-TRIS 12.5mg | Percentage of Patients Using Rescue Medication at 6 Hours | 65.0 percentage of patients |
| DKP-TRIS 25mg | Percentage of Patients Using Rescue Medication at 6 Hours | 53.3 percentage of patients |
| TRAM.HCl 37.5mg | Percentage of Patients Using Rescue Medication at 6 Hours | 69.5 percentage of patients |
| TRAM.HCl 75mg | Percentage of Patients Using Rescue Medication at 6 Hours | 64.4 percentage of patients |
| Ibuprofen 400mg | Percentage of Patients Using Rescue Medication at 6 Hours | 48.3 percentage of patients |
| Placebo | Percentage of Patients Using Rescue Medication at 6 Hours | 72.6 percentage of patients |