Acute Pain
Conditions
Keywords
Moderate to severe acute pain, Postoperative pain, Hip arthroplasty, Analgesics, Dexketoprofen, Tramadol
Brief summary
This study aims to evaluate the analgesic efficacy of single and repeated doses of fixed combination of dexketoprofen trometamol (DKP) and tramadol hydrochloride (TRAM) in comparison to the single agents (and placebo for the single dose phase only) Approximately 600 male and female patients presenting moderate to severe pain after an elective primary hip arthroplasty are eligible to be randomised provided that they experience moderate to severe pain on the day after surgery.
Detailed description
In this clinical trial patients were randomized to the described 6 treatment arms, where each arm define the treatment to be received in the first single dose phase (lasting 8 hours after the 1st treatment intake) and in the subsequent multiple-dose phase (lasting from the second treatment intake up to the 8 hours after the last intake). Namely: * DKP/TRAM followed by DKP/TRAM; * DKP followed by DKP; * TRAM followed by TRAM; * placebo followed by DKP; * placebo followed by TRAM; * placebo followed by DKP/TRAM; The analyses of endpoints pertinent to the single dose phase were performed combining all the 3 treatment arms including placebo into one group, which resulted in the following 4 analysis groups: DKP/TRAM, DEXKETOPROFEN, TRAMADOL, and Placebo. The analysis of endpoints pertinent to the multiple dose phase were performed combining the treatment arms including the same active treatment, which resulted in the following 3 analysis groups: DKP/TRAM, DEXKETOPROFEN, and TRAMADOL.
Interventions
DRUGPlacebo
Placebo single oral dose (first 8 hours)
Tramadol single oral dose (first 8 hours)
Dexketoprofen single oral dose (first 8 hours)
Dexketoprofen/Tramadol oral single dose (first 8 hours)
Tramadol multiple oral doses t.i.d. for 5 days (total 12 doses)
Dexketoprofen multiple oral doses t.i.d. for 5 days (total 12 doses)
Dexketoprofen/Tramadol multiple oral doses t.i.d. for 5 days (total 12 doses)
Sponsors
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients aged 18 to 80 years. Females participating in the study must be either of non-childbearing potential, or willing to use a highly effective contraceptive method. * Scheduled to undergo standard primary (first-time) one-sided total hip replacement surgery due to primary osteoarthritis. * Patients experiencing pain at rest of at least moderate intensity the day after surgery.
Exclusion criteria
* Patients not suitable for study treatments and rescue medication (RM) or those for whom non-steroidal anti-inflammatory drugs (NSAIDs), opioids, acetyl salicylic acid, pyrazolones or pyrazolidines are contraindicated. * Patients with clinically significant abnormalities in vital signs, safety laboratory tests and 12-lead ECG at screening. * Patients with history of any illness or condition that might pose a risk to the patient or confound the efficacy and safety study results. * Patients using and not suitable to withdraw analgesics other than those specified in the protocol. * Patients using and not suitable for withdrawing any of the prohibited medication specified in the protocol. * Pregnant and breastfeeding women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | over 8 hours after the first dose | Sum of Pain Intensity Differences calculated as the weighted sum of the PI-VAS differences over 8 hour period. PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale (0=no pain to 100=worst pain imaginable) which was measured at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, and 8h after the first dose. A higher value in SPID indicates greater pain relief. The analysis was performed combining all randomization arms including placebo into one group, which resulted in the following 4 analysis groups: DKP/TRAM, DEXKETOPROFEN, TRAMADOL, and Placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SPID48 (Sum of Pain Intensity Differences Over First 48 Hours of the Multiple-dose Phase) | over 48 hours of the multiple-dose phase | Sum of Pain Intensity Differences calculated as the weighted sum of the PI-VAS differences over 48 hours of the multiple-dose phase. PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale (0=no pain to 100=worst pain imaginable) which was measured every two hours over the first 48 hours of the multiple-dose phase. A higher value in SPID indicates greater pain relief. The analysis was performed combining all randomization arms including the same active treatment, which resulted in the following 3 analysis groups: DKP/TRAM, DEXKETOPROFEN, and TRAMADOL. |
| Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale) | over 48 hours of the multiple-dose phase | Percentage of responders; response defined as achievement a mean pain intensity, PI-VAS \< 40 mm (PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale, 0=no pain to 100=worst pain imaginable),over 48 hours of the multiple-dose phase. The analysis was performed combining all randomization arms including the same active treatment, which resulted in the following 3 analysis groups: DKP/TRAM, DEXKETOPROFEN, and TRAMADOL. |
| Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | over 8 hours after the first dose | Percentage of responders over 8 hours after first dose, according to the 50% maximum total pain relief rule: maximum TOTPAR calculated as the theoretical maximum weighted sum of PAR-VRS (Pain Relief - Verbal Rating Scale: pain relief 0=none, 4=complete) scores. The analysis was performed combining all randomization arms including placebo into one group, which resulted in the following 4 analysis groups: DKP/TRAM, DEXKETOPROFEN, TRAMADOL, and Placebo. |
Countries
Czechia, Germany, Hungary, Latvia, Lithuania, Poland, Serbia, Spain, Taiwan, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DKP/TRAM Followed by DKP/TRAM Dexketoprofen/Tramadol-single dose followed by Dexketoprofen/Tramadol-multiple doses | 159 |
| DKP Followed by DKP Dexketoprofen-single dose followed by Dexketoprofen-multiple doses | 161 |
| TRAM Followed by TRAM Tramadol-single dose followed by Tramadol-multiple doses | 160 |
| Placebo Followed by DKP/TRAM Placebo single dose followed by Dexketoprofen/Tramadol-multiple doses | 54 |
| Placebo Followed by DKP Placebo single dose followed by Dexketoprofen-multiple doses | 53 |
| Placebo Followed by TRAM Placebo single dose followed by Tramadol-multiple doses | 54 |
| Total | 641 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 2 | 1 | 1 | 3 |
| Overall Study | Lack of Efficacy | 0 | 0 | 2 | 0 | 0 | 1 |
| Overall Study | no compliance | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 1 | 2 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 8 | 9 | 1 | 5 | 4 |
Baseline characteristics
| Characteristic | DKP/TRAM Followed by DKP/TRAM | DKP Followed by DKP | TRAM Followed by TRAM | Placebo Followed by DKP/TRAM | Placebo Followed by DKP | Placebo Followed by TRAM | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 10.43 | 63.3 years STANDARD_DEVIATION 9.01 | 61.3 years STANDARD_DEVIATION 9.68 | 63.9 years STANDARD_DEVIATION 9 | 61.0 years STANDARD_DEVIATION 11.1 | 59.8 years STANDARD_DEVIATION 11.3 | 61.9 years STANDARD_DEVIATION 9.96 |
| Height | 168.8 cm STANDARD_DEVIATION 8.99 | 167.9 cm STANDARD_DEVIATION 9.14 | 169.1 cm STANDARD_DEVIATION 9.2 | 166.1 cm STANDARD_DEVIATION 8.47 | 168.0 cm STANDARD_DEVIATION 9.49 | 169.9 cm STANDARD_DEVIATION 7.94 | 168.5 cm STANDARD_DEVIATION 9.01 |
| Race/Ethnicity, Customized Asian | 0 participants | 2 participants | 3 participants | 0 participants | 0 participants | 2 participants | 7 participants |
| Race/Ethnicity, Customized White | 159 participants | 159 participants | 157 participants | 54 participants | 53 participants | 52 participants | 634 participants |
| Region of Enrollment Czech Republic | 9 participants | 10 participants | 8 participants | 2 participants | 4 participants | 3 participants | 36 participants |
| Region of Enrollment Germany | 1 participants | 1 participants | 2 participants | 0 participants | 0 participants | 0 participants | 4 participants |
| Region of Enrollment Hungary | 49 participants | 57 participants | 54 participants | 17 participants | 16 participants | 11 participants | 204 participants |
| Region of Enrollment Latvia | 37 participants | 33 participants | 36 participants | 16 participants | 15 participants | 16 participants | 153 participants |
| Region of Enrollment Lithuania | 22 participants | 19 participants | 21 participants | 6 participants | 5 participants | 11 participants | 84 participants |
| Region of Enrollment Poland | 10 participants | 8 participants | 8 participants | 2 participants | 2 participants | 3 participants | 33 participants |
| Region of Enrollment Serbia | 15 participants | 18 participants | 14 participants | 5 participants | 5 participants | 5 participants | 62 participants |
| Region of Enrollment Spain | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment Taiwan | 0 participants | 2 participants | 3 participants | 0 participants | 0 participants | 2 participants | 7 participants |
| Region of Enrollment Ukraine | 15 participants | 13 participants | 13 participants | 6 participants | 6 participants | 3 participants | 56 participants |
| Sex: Female, Male Female | 86 Participants | 86 Participants | 80 Participants | 37 Participants | 33 Participants | 24 Participants | 346 Participants |
| Sex: Female, Male Male | 73 Participants | 75 Participants | 80 Participants | 17 Participants | 20 Participants | 30 Participants | 295 Participants |
| Weight | 83.3 kg STANDARD_DEVIATION 15.37 | 81.4 kg STANDARD_DEVIATION 15.63 | 83.5 kg STANDARD_DEVIATION 17.25 | 82.4 kg STANDARD_DEVIATION 15.91 | 81.7 kg STANDARD_DEVIATION 13.77 | 82.1 kg STANDARD_DEVIATION 15.27 | 82.6 kg STANDARD_DEVIATION 15.8 |
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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 159 | 18 / 161 | 24 / 160 | 9 / 54 | 2 / 53 | 5 / 54 |
| serious Total, serious adverse events | 2 / 159 | 3 / 161 | 1 / 160 | 1 / 54 | 0 / 53 | 0 / 54 |
Outcome results
Primary
SPID8 (Sum of Pain Intensity Differences Over 8 Hours)
Sum of Pain Intensity Differences calculated as the weighted sum of the PI-VAS differences over 8 hour period. PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale (0=no pain to 100=worst pain imaginable) which was measured at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, and 8h after the first dose. A higher value in SPID indicates greater pain relief. The analysis was performed combining all randomization arms including placebo into one group, which resulted in the following 4 analysis groups: DKP/TRAM, DEXKETOPROFEN, TRAMADOL, and Placebo.
Time frame: over 8 hours after the first dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DKP/TRAM | SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | 246.9 units on a scale | Standard Deviation 156.5 |
| DEXKETOPROFEN | SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | 208.8 units on a scale | Standard Deviation 154.69 |
| TRAMADOL | SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | 204.6 units on a scale | Standard Deviation 145.79 |
| PLACEBO | SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | 151.1 units on a scale | Standard Deviation 158.51 |
Secondary
Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief)
Percentage of responders over 8 hours after first dose, according to the 50% maximum total pain relief rule: maximum TOTPAR calculated as the theoretical maximum weighted sum of PAR-VRS (Pain Relief - Verbal Rating Scale: pain relief 0=none, 4=complete) scores. The analysis was performed combining all randomization arms including placebo into one group, which resulted in the following 4 analysis groups: DKP/TRAM, DEXKETOPROFEN, TRAMADOL, and Placebo.
Time frame: over 8 hours after the first dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DKP/TRAM | Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | 57.9 percentage of participants |
| DEXKETOPROFEN | Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | 56.5 percentage of participants |
| TRAMADOL | Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | 51.9 percentage of participants |
| PLACEBO | Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | 37.9 percentage of participants |
Secondary
Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale)
Percentage of responders; response defined as achievement a mean pain intensity, PI-VAS \< 40 mm (PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale, 0=no pain to 100=worst pain imaginable),over 48 hours of the multiple-dose phase. The analysis was performed combining all randomization arms including the same active treatment, which resulted in the following 3 analysis groups: DKP/TRAM, DEXKETOPROFEN, and TRAMADOL.
Time frame: over 48 hours of the multiple-dose phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DKP/TRAM | Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale) | 90.1 percentage of participants |
| DEXKETOPROFEN | Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale) | 76.6 percentage of participants |
| TRAMADOL | Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale) | 82.2 percentage of participants |
Secondary
SPID48 (Sum of Pain Intensity Differences Over First 48 Hours of the Multiple-dose Phase)
Sum of Pain Intensity Differences calculated as the weighted sum of the PI-VAS differences over 48 hours of the multiple-dose phase. PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale (0=no pain to 100=worst pain imaginable) which was measured every two hours over the first 48 hours of the multiple-dose phase. A higher value in SPID indicates greater pain relief. The analysis was performed combining all randomization arms including the same active treatment, which resulted in the following 3 analysis groups: DKP/TRAM, DEXKETOPROFEN, and TRAMADOL.
Time frame: over 48 hours of the multiple-dose phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DKP/TRAM | SPID48 (Sum of Pain Intensity Differences Over First 48 Hours of the Multiple-dose Phase) | 1943.7 units on a scale | Standard Deviation 1000.51 |
| DEXKETOPROFEN | SPID48 (Sum of Pain Intensity Differences Over First 48 Hours of the Multiple-dose Phase) | 1677.5 units on a scale | Standard Deviation 1070.91 |
| TRAMADOL | SPID48 (Sum of Pain Intensity Differences Over First 48 Hours of the Multiple-dose Phase) | 1765.6 units on a scale | Standard Deviation 963.49 |