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The study is aimed to evaluate the analgesic efficacy of TRAM.HCl/DKP.TRIS 75mg/25mg oral fixed drug combination in comparison with TRAM.HCl /paracetamol 75mg/650mg in the treatment of moderate to severe acute pain.
The present phase IV study is a randomised, double-blind, placebo and active-controlled, parallel group study in moderate to severe acute pain after removal of impacted lower third molar.
In this single-dose clinical trial patients are randomized to the following 3 treatment arms in a 2:2:1 ratio:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tramadol/Dexketoprofen | Experimental | Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose; Placebo matching Tramadol Hydrochloride/Paracetamol 75 mg/650mg, as 2 x [37.5mg/325mg] film-coated tablets, oral single dose. |
|
| Tramadol/Paracetamol | Active Comparator | Tramadol Hydrochloride/Paracetamol 75 mg/650 mg, as 2 x [37.5mg/325mg] film-coated tablets, oral single dose; Placebo matching Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose. . |
|
| Placebo | Placebo Comparator | Placebo matching one film-coated tablet of Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg oral single dose; Placebo matching two film-coated tablets of Tramadol Hydrochloride/Paracetamol 37.5mg/325mg oral single dose. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tramadol Hydrochloride/Dexketoprofen Trometamol | Drug |
| ||
| Tramadol Hydrochloride/Paracetamol |
| Measure | Description | Time Frame |
|---|---|---|
| TOTPAR6 (Total Pain Relief Over 6 Hours Post-dose) | TOTPAR calculated as the weighted sum of the PAR scores, measured according to a 5-point VRS (Verbal Rating Scale) from 0=no relief to 4=complete relief, over 6 hours post-dose (TOTPAR6). The TOTPAR6 ranges from a minimum of 0 to a maximum of 24. | 6 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| % of Patients Achieving 50% of Max TOTPAR | Percentage of patients who achieved at least 50% of the maximum TOTPAR at 8 hours. In the present trial the achievable TOTPAR over 8 hours ranges between 0 and 32." | 8 hours post-dose |
| % of Patients Achieving at Least 30% of PI (Pain Intensity) Reduction Over 8 Hours Post-dose |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dr. Tóth Bagi Zoltán Fogászati Rendeloje | Budapest | 1052 | Hungary | |||
| OralMed Studio Fogászati és Szájsebészeti Kft. |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30782886 | Derived | Gay-Escoda C, Hanna M, Montero A, Dietrich T, Milleri S, Giergiel E, Zoltan TB, Varrassi G. Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study). BMJ Open. 2019 Feb 19;9(2):e023715. doi: 10.1136/bmjopen-2018-023715. |
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A total of 792 patients were screened, of which 654 patients were randomized. One randomized patient was excluded from all the analysis populations, because of being younger than 18 years old. Prior to randomization, enrolled patients underwent a Screening period lasting up 2 weeks.
This study was conducted in 18 centers across 5 European countries: Hungary, Italy, Poland, Spain and the United Kingdom. The clinical phase of the study started on 28th April 2016 (first screened patient) and concluded on 14th February 2017 (last patient out).
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| ID | Title | Description |
|---|---|---|
| FG000 | Tramadol/Dexketoprofen | Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose; Placebo matching Tramadol Hydrochloride/Paracetamol 75 mg/650mg, as 2 x [37.5mg/325mg] film-coated tablets, oral single dose. |
| FG001 | Tramadol/Paracetamol |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Nov 24, 2015 | Dec 10, 2020 |
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| Drug |
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| Placebo | Drug |
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Percentage of patients who achieve at least 30% of PI Reduction versus baseline Over 8 Hours Post-dose. Percentage change of PI is calculated using the baseline value minus the PI assessed at 8 hours post-dose divided for the baseline value, then multiplied for 100. |
| 8 hours post-dose |
| Time to Confirmed FPPAR (First Perceptible Pain Relief) | Time to confirmed FPPAR (time to onset of analgesia) - i.e. time to FPPAR if confirmed by experiencing Meaningful Pain Relief (MPAR) FPPAR and MPAR assessed by using stopwatches:
| 2 hours post-dose |
| % of Patients Requiring RM (Rescue Medication) | Percentage of patients who required RM within the first over 8 hours post-dose. | 8 hours post-dose |
| PGE (Patient Global Evaluation) | PGE of the study medication (measured according to a five-point VRS from 1 = poor to 5 = excellent) at 8 hours post-dose or whenever the patient uses Rescue Medication (RM). | 8 hours postdose |
| Budapest |
| 1126 |
| Hungary |
| Szegedi Tudományegyetem | Szeged | 6725 | Hungary |
| Ospedale Civile San Salvatore di L'Aquila | L’Aquila | 67100 | Italy |
| Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico | Milan | 20122 | Italy |
| Azienda Ospedaliero-Universitaria Pisana | Pisa | 56126 | Italy |
| Azienda Ospedaliera Universitaria Integrata | Verona | 37134 | Italy |
| Ars-Dent | Bialystok | 15-078 | Poland |
| Gabinet Stomatologiczny Andrzej Wojtowicz AW Clinic | Warsaw | 00-852 | Poland |
| Charme Clinique Klinika Stomatologii | Warsaw | 02-670 | Poland |
| Hospital Médico Quirúrgico de Conxo | A Coruña | 15702 | Spain |
| Centro Medico Teknon | Barcelona | 08022 | Spain |
| Hospital Universitario Virgen del Rocío | Seville | 41009 | Spain |
| Universidad de Valencia | Valencia | 46010 | Spain |
| Birmingham Community Healthcare NHS Foundation Trust | Birmingham | B4 6NN | United Kingdom |
| University Hospital of Wales | Cardiff | CF14 4XT | United Kingdom |
| University of Manchester | Manchester | M15 6FH | United Kingdom |
| University Hospitals of North Midlands NHS Trust | Stoke-on-Trent | ST4 6QG | United Kingdom |
Tramadol Hydrochloride/Paracetamol 75 mg/650 mg, as 2 x [37.5mg/325mg] film-coated tablets, oral single dose; Placebo matching Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose. |
| FG002 | Placebo | Placebo matching one film-coated tablet of Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg oral single dose; Placebo matching two film-coated tablets of Tramadol Hydrochloride/Paracetamol 37.5mg/325mg oral single dose. |
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| NOT COMPLETED |
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Intention-to-treat (ITT) population: all patients randomized.
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| ID | Title | Description |
|---|---|---|
| BG000 | Tramadol/Dexketoprofen | Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose; Placebo matching Tramadol Hydrochloride/Paracetamol 75 mg/650mg, as 2 x [37.5mg/325mg] film-coated tablets, oral single dose. |
| BG001 | Tramadol/Paracetamol | Tramadol Hydrochloride/Paracetamol 75 mg/650 mg, as 2 x [37.5mg/325mg] film-coated tablets, oral single dose; Placebo matching Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose. |
| BG002 | Placebo | Placebo matching one film-coated tablet of Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg oral single dose; Placebo matching two film-coated tablets of Tramadol Hydrochloride/Paracetamol 37.5mg/325mg oral single dose. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Pain Intensity at Qualification | Patients rate their pain intensity (PI) on e-Diary using an 11-point Numerical Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst pain). This PI-NRS does not include subscales. | Mean | Standard Deviation | units on a scale |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | TOTPAR6 (Total Pain Relief Over 6 Hours Post-dose) | TOTPAR calculated as the weighted sum of the PAR scores, measured according to a 5-point VRS (Verbal Rating Scale) from 0=no relief to 4=complete relief, over 6 hours post-dose (TOTPAR6). The TOTPAR6 ranges from a minimum of 0 to a maximum of 24. | A total of 654 patients were randomized and received the study treatments, of these one underage patient, erroneously enrolled in the study, was excluded from all the analysis populations, therefore 653 patients constituted ITT population. | Posted | Mean | Standard Deviation | 5-point Verbal Rating Scale | 6 hours post-dose |
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| Secondary | % of Patients Achieving 50% of Max TOTPAR | Percentage of patients who achieved at least 50% of the maximum TOTPAR at 8 hours. In the present trial the achievable TOTPAR over 8 hours ranges between 0 and 32." | ITT population | Posted | Number | percentage of patients | 8 hours post-dose |
| ||||||||||||||||||||||||||||||||||
| Secondary | % of Patients Achieving at Least 30% of PI (Pain Intensity) Reduction Over 8 Hours Post-dose | Percentage of patients who achieve at least 30% of PI Reduction versus baseline Over 8 Hours Post-dose. Percentage change of PI is calculated using the baseline value minus the PI assessed at 8 hours post-dose divided for the baseline value, then multiplied for 100. | ITT population | Posted | Number | percentage of patients | 8 hours post-dose |
| ||||||||||||||||||||||||||||||||||
| Secondary | Time to Confirmed FPPAR (First Perceptible Pain Relief) | Time to confirmed FPPAR (time to onset of analgesia) - i.e. time to FPPAR if confirmed by experiencing Meaningful Pain Relief (MPAR) FPPAR and MPAR assessed by using stopwatches:
| The analysis is conducted only on active treatment arms. | Posted | Median | 95% Confidence Interval | minutes | 2 hours post-dose |
|
| ||||||||||||||||||||||||||||||||
| Secondary | % of Patients Requiring RM (Rescue Medication) | Percentage of patients who required RM within the first over 8 hours post-dose. | ITT population | Posted | Number | percentage of patients | 8 hours post-dose |
| ||||||||||||||||||||||||||||||||||
| Secondary | PGE (Patient Global Evaluation) | PGE of the study medication (measured according to a five-point VRS from 1 = poor to 5 = excellent) at 8 hours post-dose or whenever the patient uses Rescue Medication (RM). | ITT population | Posted | Mean | Standard Deviation | units on a scale | 8 hours postdose |
|
Reported treatment emergent AEs (TEAEs) include events starting after administration of study drug on or after Day 1 and on or before end of study visit Day 6+/- 1.
If an AE occurs for the first time or if it worsens after study drug intake it is classified as TEAE. If a subject experienced more than 1 of a given TEAE, the subject is counted only once for that TEAE.
Overall 654 patients received the treatment, however one patient was excluded from all the analysis populations, because of being younger than 18 years old. Thus, the safety population accounts for 653 patients.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tramadol/Dexketoprofen | Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose; Placebo matching Tramadol Hydrochloride/Paracetamol 75 mg/650mg, as 2 x [37.5mg/325mg] film-coated tablets, oral single dose. | 0 | 260 | 1 | 260 | 35 | 260 |
| EG001 | Tramadol/Paracetamol | Tramadol Hydrochloride/Paracetamol 75 mg/650 mg, as 2 x [37.5mg/325mg] film-coated tablets, oral single dose; Placebo matching Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose. | 0 | 262 | 0 | 262 | 40 | 262 |
| EG002 | Placebo | Placebo matching one film-coated tablet of Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg oral single dose; Placebo matching two film-coated tablets of Tramadol Hydrochloride/Paracetamol 37.5mg/325mg oral single dose. | 0 | 131 | 0 | 131 | 13 | 131 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Syncope | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
| |
| Face oedema | General disorders | MedDRA (Unspecified) | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
| |
| Postoperative wound infection | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
| |
| Procedural pain | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
| |
| Haematoma | Vascular disorders | MedDRA (Unspecified) | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Angela Capriati (Clinical Sciences Director) | Menarini Ricerche | +39 055 5680 | 9933 | acapriati@menarini-ricerche.it |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 14, 2017 | Dec 10, 2020 | SAP_001.pdf |
| ID | Term |
|---|---|
| D059787 | Acute Pain |
| D010149 | Pain, Postoperative |
| ID | Term |
|---|---|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D014147 | Tramadol |
| C118296 | dexketoprofen trometamol |
| D000082 | Acetaminophen |
| ID | Term |
|---|---|
| D003511 | Cyclohexanols |
| D000441 | Hexanols |
| D005233 | Fatty Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D004123 | Dimethylamines |
| D008744 | Methylamines |
| D000588 | Amines |
| D008055 | Lipids |
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D000814 | Aniline Compounds |
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| Asian |
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| Black or Afro-american |
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| Other |
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