Acute Pain
Conditions
Keywords
Moderate to severe acute pain, Postoperative pain, Abdominal hysterectomy, 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 female patients presenting moderate to severe pain after a total/subtotal abdominal hysterectomy 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)
Dexketoprofen single oral dose (first 8 hours)
Tramadol single oral dose (first 8 hours)
Dexketoprofen/Tramadol single oral dose (first 8 hours)
Dexketoprofen multiple oral doses t.i.d. for 3 days (total 6 doses)
Tramadol multiple oral doses t.i.d. for 3 days (total 6 doses)
Dexketoprofen/Tramadol multiple oral doses t.i.d. for 3 days (total 6 doses)
Sponsors
Menarini Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Female patients aged 18 to 75 years. * Scheduled to undergo a total or subtotal abdominal hysterectomy (with or without salpingo-oophorectomy) for benign conditions. * 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. * 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 |
|---|---|---|
| Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | over 8 hours after 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. |
| SPID48 (Sum of Pain Intensity Differences Over 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. |
Countries
Hungary, Latvia, Lithuania, Poland, Romania, Russia, Slovakia, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DKP/TRAM Followed by DKP/TRAM Dexketoprofen/Tramadol-single dose followed by Dexketoprofen/Tramadol-multiple doses | 152 |
| DKP Followed by DKP Dexketoprofen-single dose followed by Dexketoprofen-multiple doses | 151 |
| TRAM Followed by TRAM Tramadol-single dose followed by Tramadol-multiple doses | 150 |
| Placebo Followed by DKP/TRAM Placebo single dose followed by Dexketoprofen/Tramadol-multiple doses | 51 |
| Placebo Followed by DKP Placebo single dose followed by Dexketoprofen-multiple doses | 51 |
| Placebo Followed by TRAM Placebo single dose followed by Tramadol-multiple doses | 51 |
| Total | 606 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 | 0 | 1 | 1 | 2 |
| Overall Study | Lack of Efficacy | 0 | 3 | 1 | 3 | 3 | 1 |
| Overall Study | non compliance with study drug | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | DKP Followed by DKP | TRAM Followed by TRAM | Placebo Followed by DKP/TRAM | DKP/TRAM Followed by DKP/TRAM | Placebo Followed by DKP | Placebo Followed by TRAM | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 47.2 years STANDARD_DEVIATION 7.07 | 47.6 years STANDARD_DEVIATION 6.87 | 47.4 years STANDARD_DEVIATION 6.82 | 48.1 years STANDARD_DEVIATION 6.7 | 47.4 years STANDARD_DEVIATION 7.46 | 47.2 years STANDARD_DEVIATION 4.6 | 47.6 years STANDARD_DEVIATION 6.75 |
| Height | 163.7 cm STANDARD_DEVIATION 6.37 | 164.1 cm STANDARD_DEVIATION 6.1 | 164.5 cm STANDARD_DEVIATION 6.17 | 163.9 cm STANDARD_DEVIATION 5.4 | 163.5 cm STANDARD_DEVIATION 5.94 | 164.4 cm STANDARD_DEVIATION 5.59 | 164.0 cm STANDARD_DEVIATION 5.94 |
| Race/Ethnicity, Customized White | 151 participants | 150 participants | 51 participants | 152 participants | 51 participants | 51 participants | 606 participants |
| Region of Enrollment Hungary | 19 participants | 26 participants | 8 participants | 22 participants | 7 participants | 7 participants | 89 participants |
| Region of Enrollment Latvia | 17 participants | 17 participants | 7 participants | 22 participants | 4 participants | 5 participants | 72 participants |
| Region of Enrollment Lithuania | 4 participants | 3 participants | 1 participants | 2 participants | 1 participants | 3 participants | 14 participants |
| Region of Enrollment Poland | 53 participants | 60 participants | 18 participants | 63 participants | 23 participants | 17 participants | 234 participants |
| Region of Enrollment Romania | 40 participants | 32 participants | 10 participants | 32 participants | 12 participants | 12 participants | 138 participants |
| Region of Enrollment Russian Federation | 3 participants | 3 participants | 2 participants | 3 participants | 2 participants | 2 participants | 15 participants |
| Region of Enrollment Slovakia | 13 participants | 8 participants | 5 participants | 7 participants | 2 participants | 4 participants | 39 participants |
| Region of Enrollment Spain | 2 participants | 1 participants | 0 participants | 1 participants | 0 participants | 1 participants | 5 participants |
| Sex/Gender, Customized Females | 151 participants | 150 participants | 51 participants | 152 participants | 51 participants | 51 participants | 606 participants |
| Weight | 72.1 kg STANDARD_DEVIATION 13.54 | 71.3 kg STANDARD_DEVIATION 12.17 | 73.6 kg STANDARD_DEVIATION 13.74 | 75.2 kg STANDARD_DEVIATION 15.15 | 72.9 kg STANDARD_DEVIATION 14.6 | 72.6 kg STANDARD_DEVIATION 10.97 | 72.9 kg STANDARD_DEVIATION 13.58 |
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 | 22 / 151 | 22 / 152 | 33 / 150 | 3 / 52 | 10 / 50 | 10 / 51 |
| serious Total, serious adverse events | 7 / 151 | 2 / 152 | 1 / 150 | 0 / 52 | 0 / 50 | 0 / 51 |
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
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DKP/TRAM | SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | 241.8 units on a scale | Standard Deviation 139.06 |
| DEXKETOPROFEN | SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | 184.5 units on a scale | Standard Deviation 139.23 |
| TRAMADOL | SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | 157.3 units on a scale | Standard Deviation 150.89 |
| PLACEBO | SPID8 (Sum of Pain Intensity Differences Over 8 Hours) | 117.0 units on a scale | Standard Deviation 121.8 |
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 first dose
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DKP/TRAM | Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | 65.8 percentage of participants |
| DEXKETOPROFEN | Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | 47.7 percentage of participants |
| TRAMADOL | Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | 44.0 percentage of participants |
| PLACEBO | Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief) | 30.7 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
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DKP/TRAM | Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale) | 94.1 percentage of participants |
| DEXKETOPROFEN | Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale) | 82.7 percentage of participants |
| TRAMADOL | Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale) | 88.6 percentage of participants |
Secondary
SPID48 (Sum of Pain Intensity Differences 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.
Time frame: over 48 hours of the multiple-dose phase
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DKP/TRAM | SPID48 (Sum of Pain Intensity Differences Over 48 Hours of the Multiple-dose Phase) | 2273.0 units on a scale | Standard Deviation 864.03 |
| DEXKETOPROFEN | SPID48 (Sum of Pain Intensity Differences Over 48 Hours of the Multiple-dose Phase) | 1965.2 units on a scale | Standard Deviation 912.19 |
| TRAMADOL | SPID48 (Sum of Pain Intensity Differences Over 48 Hours of the Multiple-dose Phase) | 2035.0 units on a scale | Standard Deviation 919.49 |