Oral Treatment for Gynaecological Post-operative Pain With Dexketoprofen Trometamol and Tramadol Hydrochloride (DAVID lap)

A Randomized, Double-blind, Placebo and Active-controlled, Parallel-group Study to Evaluate the Analgesic Efficacy and Safety of Dexketoprofen Trometamol and Tramadol Hydrochloride Oral Fixed Combination on Moderate to Severe Acute Pain Following Abdominal Hysterectomy

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.

Study Overview

• Status: Completed
• Conditions: Acute Pain
• Intervention / Treatment: Drug: Dexketoprofen/Tramadol-single dose; Drug: Dexketoprofen/Tramadol-multiple doses; Drug: Dexketoprofen-single dose; Drug: Dexketoprofen-multiple doses; Drug: Tramadol-single dose; Drug: Tramadol-multiple doses; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 606
• Phase: Phase 3

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary, 1106
    • Bajcsy-Zsilinszky Kórház
  • Debrecen, Hungary, H-4012
    • University Hospital of Debrecen
  • Szentes, Hungary, H-6600
    • Dr. Bugyi Istvan Korhaz
  • Székesfehérvár, Hungary, 8000
    • Fejer Megyei Szent Gyorgy Korhaz
• Latvia
  • Riga, Latvia, LV-1005
    • Juras Medicinas Centre
  • Riga, Latvia, LV-1038
    • Riga East University Hospital Gynecology Clinic
• Lithuania
  • Kaunas, Lithuania, LT-50009
    • Hospital of Lithuanian University of Health Sciences Kaunas
  • Vilnius, Lithuania, LT-02106
    • Vilniaus gimdymo namai
• Poland
  • Bialystok, Poland, 15-224
    • Prywatna Klinika Polozniczo-Ginekologiczna
  • Poznan, Poland, 60-535
    • Ginekologiczno-Polożniczy Szpital Kliniczny UM w Poznaniu
  • Przemyśl, Poland, 37-700
    • Wojewodzki Szpital
  • Tarnow, Poland, 33-100
    • Specjalistyczny Szpital im. E. Szczeklika
  • Warszawa, Poland, 02-507
    • Centralny Szpital Kliniczny MSW w Warszawie
  • Warszawa, Poland, 00-909
    • Wojskowy Instytut Medyczny, Centralny Szpital Kliniczny Mini
  • Lubelskie
    • Lublin, Lubelskie, Poland, 20-081
      • Samodzielny Publiczny Szpital Kliniczny Nr 1
    • Lublin, Lubelskie, Poland, 20-954
      • Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
• Romania
  • Bucharest, Romania, 050098
    • Spitalul Universitar de Urgenta Bucuresti
  • Bucharest, Romania, 011062
    • Institutul pentru Ocrotirea Mamei si Copilului (IOMC) "Prof. Dr. Alfred Rusescu"
  • Bucharest, Romania, 011475
    • Genesys Fertility Center
  • Bucharest, Romania, 020475
    • Spitalul Clinic "Dr. Ioan Cantacuzino" - Sectia Clinica Obstetrica Ginecologie II
  • Bucharest, Romania, 020475
    • Spitalul Clinic "Dr. Ioan Cantacuzino" - Sectia Clinica Obstetrica Ginecologie I
  • Bucuresti, Romania, 21623
    • Spitalul Clinic de Urgenta "Sfantul Pantelimon"
  • Targu-Mures, Romania, 540136
    • Spitalul Clinic Judetean de Urgenta Targu Mures - Sectia Obstretica Ginecologie I
• Russian Federation
  • Moscow, Russian Federation, 101000
    • Moscow Regional Research Institute of Obstetrics and Gynecol
  • Saint Petersburg, Russian Federation, 194291
    • FGUZ Clinical Hospital 122 n.a. L.G. Sokolova FMBA
• Slovakia
  • Sliac, Slovakia, 962-31
    • GYNPOR, s.r.o.
• Spain
  • Ferrol, Spain, 15405
    • Complejo Hospitalario Arquitecto Marcide
  • Lérida, Spain, 25198
    • Hospital Universitario Arnau de Vilanova

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DKP/TRAM followed by DKP/TRAM; Dexketoprofen/Tramadol-single dose followed by Dexketoprofen/Tramadol-multiple doses	Drug: Dexketoprofen/Tramadol-single dose; Dexketoprofen/Tramadol single oral dose (first 8 hours); Drug: Dexketoprofen/Tramadol-multiple doses; Dexketoprofen/Tramadol multiple oral doses t.i.d. for 3 days (total 6 doses)
Active Comparator: DKP followed by DKP; Dexketoprofen-single dose followed by Dexketoprofen-multiple doses	Drug: Dexketoprofen-single dose; Dexketoprofen single oral dose (first 8 hours); Drug: Dexketoprofen-multiple doses; Dexketoprofen multiple oral doses t.i.d. for 3 days (total 6 doses)
Active Comparator: TRAM followed by TRAM; Tramadol-single dose followed by Tramadol-multiple doses	Drug: Tramadol-single dose; Tramadol single oral dose (first 8 hours); Drug: Tramadol-multiple doses; Tramadol multiple oral doses t.i.d. for 3 days (total 6 doses)
Other: Placebo followed by DKP/TRAM; Placebo single dose followed by Dexketoprofen/Tramadol-multiple doses	Drug: Dexketoprofen/Tramadol-multiple doses; Dexketoprofen/Tramadol multiple oral doses t.i.d. for 3 days (total 6 doses); Drug: Placebo; Placebo single oral dose (first 8 hours)
Other: Placebo followed by DKP; Placebo single dose followed by Dexketoprofen-multiple doses	Drug: Dexketoprofen-multiple doses; Dexketoprofen multiple oral doses t.i.d. for 3 days (total 6 doses); Drug: Placebo; Placebo single oral dose (first 8 hours)
Other: Placebo followed by TRAM; Placebo single dose followed by Tramadol-multiple doses	Drug: Tramadol-multiple doses; Tramadol multiple oral doses t.i.d. for 3 days (total 6 doses); Drug: Placebo; Placebo single oral dose (first 8 hours)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	over 8 hours after the first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	over 8 hours after first dose
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.	over 48 hours of the multiple-dose phase
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.	over 48 hours of the multiple-dose phase

Collaborators and Investigators

• Sponsor: Menarini Group
• Investigators: Study Chair: Henry J McQuay, Professor, Balliol College Oxford; Study Chair: Andrew Moore, Professor, Pain Research & Nuffield Department of Anaesthetics - University of Oxford

Publications and helpful links

General Publications

• Moore RA, McQuay HJ, Tomaszewski J, Raba G, Tutunaru D, Lietuviete N, Galad J, Hagymasy L, Melka D, Kotarski J, Rechberger T, Fulesdi B, Nizzardo A, Guerrero-Bayon C, Cuadripani S, Piza-Vallespir B, Bertolotti M. Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy. BMC Anesthesiol. 2016 Jan 22;16:9. doi: 10.1186/s12871-016-0174-5. Erratum In: BMC Anesthesiol. 2017 Nov 30;17 (1):159.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: July 17, 2013
• First Submitted That Met QC Criteria: July 17, 2013
• First Posted (Estimate): July 22, 2013

Study Record Updates

• Last Update Posted (Estimate): April 1, 2016
• Last Update Submitted That Met QC Criteria: March 4, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Postoperative pain; Analgesics; Tramadol; Dexketoprofen; Moderate to severe acute pain; Abdominal hysterectomy
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Analgesics, Opioid; Narcotics; Tramadol; Dexketoprofen trometamol
• Other Study ID Numbers: DEX-TRA-04; 2012-004545-32 (EudraCT Number)