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

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 After Elective Unilateral Total Hip Arthroplasty

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.

Study Overview

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

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): 641
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czech Republic
  • Brno, Czech Republic, 625 00
    • Fakultní Nemocnice Brno
  • Brno, Czech Republic, 662 50
    • Urazova nemocnice v Brne
  • Jihlava, Czech Republic, 586 33
    • Nemocnice Jihlava, p.o.
  • Kladno, Czech Republic, 272 59
    • Oblastní nemocnice Kladno
  • Mlada Boleslav, Czech Republic, 293 50
    • Oblastni nemocnice Mlada Boleslav a.s.
• Germany
  • Frankfurt am Main, Germany, 65929
    • Klinikum Frankfurt Höchst GmbH
• Hungary
  • Budapest, Hungary, 1145
    • Uzsoki Hospital, Department of Orthopaedics
  • Debrecen, Hungary, H-4012
    • University of Debrecen
  • Pécs, Hungary, 7632
    • PTE KK Trauma Központ-Balesetsebészeti és Kézsebésze
  • Szolnok, Hungary, 5000
    • MÁV Kórház és Rendelőintézet, Ortopédiai osztály
  • Székesfehérvár, Hungary, 8000
    • Fejer Megyei Szent Gyorgy Korhaz
• Latvia
  • Liepaja, Latvia, LV-3414
    • Liepaja Regional Hospital
  • Riga, Latvia, LV-1005
    • Hospital of Traumatology and Orthopaedics
  • Riga, Latvia, LV-1004
    • Riga's 2nd Hospital
  • Valmiera, Latvia, LV-4201
    • Vidzemes Hospital
• Lithuania
  • Kaunas, Lithuania, LT-50009
    • Hospital of Lithuanian University of Health Sciences Kaunas
  • Kaunas, Lithuania, LT-44320
    • Kaunas Clinical Hospital
  • Klaipeda, Lithuania, 92288
    • Klaipedos Universitetine Ligonine
  • Vilnius, Lithuania, LT-04130
    • Respublikine Vilniaus universitetine ligonine
• Poland
  • Bialystok, Poland, 15-276
    • Uniwersytecki Szpital Klioniczny w Bialymstoku
  • Elblag, Poland, 82-300
    • Warminskie Centrum Ortopedyczne
  • Lublin, Poland, 20-718
    • Wojewodzki Szpital Specjalistyczny
  • Tarnow, Poland, 33-100
    • Specjalistyczny Szpital im. E. Szczeklika
  • Wroclaw, Poland, 51-128
    • Urazowo - Ortopedycznej Wojewodzkiego Szpitala Specjalistycznego we Wrocławiu
  • Łódzkie
    • Lodz, Łódzkie, Poland, 91-002
      • Medical University of Lodz
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Center of Serbia
  • Belgrade, Serbia, 11000
    • Institute for orthopedic Surgery Banjica [Ortopedic Surgery
  • Kragujevac, Serbia, 34000
    • Clinical Center Kragujevac
  • Nis, Serbia, 18000
    • Clinic for Orthopedic Surgery and Trauma Bul. Dr Zorana Djindjica
• Spain
  • Barcelona, Spain, 08024
    • Hospital L'Esperança. Parc de Salut Mar.
  • Cadiz, Spain, 11009
    • Hospital Universitario Puerta del Mar
• Taiwan
  • Taichung, Taiwan, 433
    • Kuang Tien General Hospital
  • Taichung, Taiwan, 404
    • China Medical University Hospital [Orthopedic]
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Cherkaska Oblasna likarnia
  • Kharkiv, Ukraine, 61024
    • Instytut patologii khrebta ta suglobiv im. prof. M.I. Sytenka NAMN Ukraine
  • Kyiv, Ukraine, 04107
    • Kyivska oblasna klinichna likarnia
  • Sevastopol, Ukraine, 99018
    • Sevastopolska miska likarnia №9

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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 oral single dose (first 8 hours); Drug: Dexketoprofen/Tramadol-multiple doses; Dexketoprofen/Tramadol multiple oral doses t.i.d. for 5 days (total 12 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 5 days (total 12 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 5 days (total 12 doses)
Other: Placebo followed by DKP/TRAM; Placebo single dose followed by Dexketoprofen/Tramadol-multiple doses	Drug: Placebo; Placebo single oral dose (first 8 hours); Drug: Dexketoprofen/Tramadol-multiple doses; Dexketoprofen/Tramadol multiple oral doses t.i.d. for 5 days (total 12 doses)
Other: Placebo followed by DKP; Placebo single dose followed by Dexketoprofen-multiple doses	Drug: Placebo; Placebo single oral dose (first 8 hours); Drug: Dexketoprofen-multiple doses; Dexketoprofen multiple oral doses t.i.d. for 5 days (total 12 doses)
Other: Placebo followed by TRAM; Placebo single dose followed by Tramadol-multiple doses	Drug: Placebo; Placebo single oral dose (first 8 hours); Drug: Tramadol-multiple doses; Tramadol multiple oral doses t.i.d. for 5 days (total 12 doses)

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
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.	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
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 the first dose

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

• McQuay HJ, Moore RA, Berta A, Gainutdinovs O, Fulesdi B, Porvaneckas N, Petronis S, Mitkovic M, Bucsi L, Samson L, Zegunis V, Ankin ML, Bertolotti M, Piza-Vallespir B, Cuadripani S, Contini MP, Nizzardo A. Randomized clinical trial of dexketoprofen/tramadol 25 mg/75 mg in moderate-to-severe pain after total hip arthroplasty. Br J Anaesth. 2016 Feb;116(2):269-76. doi: 10.1093/bja/aev457.

Helpful Links

• Related Info

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: July 15, 2013
• First Submitted That Met QC Criteria: July 15, 2013
• First Posted (Estimate): July 18, 2013

Study Record Updates

• Last Update Posted (Estimate): March 7, 2016
• Last Update Submitted That Met QC Criteria: February 4, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Postoperative pain; Hip arthroplasty; Analgesics; Tramadol; Dexketoprofen; Moderate to severe acute pain
• 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-05; 2012-004548-31 (EudraCT Number)