Tramadol/Diclofenac Fixed-dose Combination Phase III Trial in Acute Pain After Third Molar Extraction

A Randomized, Double-blind, Multi-site, Comparator-controlled, Phase III Trial to Evaluate the Efficacy and Safety of a Fixed-dose Combination of Tramadol Hydrochloride and Diclofenac Sodium in Acute Moderate to Severe Pain After Third Molar Extraction

This study evaluated a new drug fixed-dose combination tablet (FDC) called tramadol/diclofenac at two different strengths (fixed doses of 25 milligrams [mg] of tramadol and of diclofenac or of 50 mg each). Tramadol and diclofenac each relieve pain, but they do so by different mechanisms. They were used alone as comparator drug in this study. Both are marketed drugs and are standard treatment for acute pain, including wisdom tooth removal.

Study Overview

• Status: Completed
• Conditions: Acute Pain
• Intervention / Treatment: Drug: Tramadol/Diclofenac 50/50; Drug: Tramadol/Diclofenac 25/25; Drug: Tramadol 50; Drug: Diclofenac 50

Detailed Description

The purpose of this study was to demonstrate that the FDC of Tramadol and Diclofenac 50/50 has superior analgesic effect than the monotherapies and that the FDC of Tramadol and Diclofenac 25/25 has non-inferior analgesic effect than the monotherapies. There was an Enrollment Period, a blinded Treatment Period, and a Follow-up Period. Previously used analgesic medication was washed out for at least 24 hours before surgery. The Treatment Period starts on Day 1 with dental surgery and treatment allocation. Treatment was started within 4 hours after the end of surgery if the participant's pain intensity had reached at least 5 points on the 11-point numerical rating scale (NRS). Each participant received 3 doses of one of the four treatments within 24 hours. One fourth of the participants received the fixed-dose combination tablet at a low dose, one fourth at the higher dose, one fourth received 50 mg of the comparator tramadol alone, and one fourth 50 mg of the comparator diclofenac alone.

The first 2 doses of the investigational medicinal product (IMP) were taken at the site, the last dose in an out-patient setting. Participants returned to the site at 24 hours after the first dose. A Follow-up Period included a final visit at the site or a phone call on Day 14 to assess the participant's safety.

• Study Type: Interventional
• Enrollment (Actual): 1151
• Phase: Phase 3

Contacts and Locations

Study Locations

• Mexico
  • Aguascalientes, Mexico, CP 20230
    • Private Clinic
  • Chihuahua, Mexico, CP 31203
    • Private Clinic
  • Leon Guanajuato, Mexico, CP 37160
    • Private Clinic
  • Puebla, Mexico, CP 72160
    • Private Clinic
  • San Luis Potosí, Mexico, CP 78290
    • University
  • Jalisco
    • Zapopan, Jalisco, Mexico, CP 45030
      • Private Clinic
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, CP 64000
      • Private Clinic
    • Monterrey, Nuevo León, Mexico, CP 64718
      • Private Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The participant has read the informed consent form, has understood the relevant aspects of the clinical study, and grants his/her authorization to participate by signing the informed consent form prior to the inclusion in the clinical study and the performance of any procedure.
2. Male and female participants above 18 years up to 60 years.
3. Female participants of childbearing potential must be practicing an acceptable method of birth control and must have a negative urine pregnancy test at enrollment with confirmation at the Allocation Visit.
4. Participants are in good health, i.e., the medical record, vital signs, physical examination, and laboratory parameter assessments do not show any abnormal deviations impeding the participation in the clinical study.
5. Participants requiring extraction of 3 or more third molars with 2 mandibular impacted third molars.
6. Clinical and radiological diagnosis of impacted lower third molars.
7. Class I and Class II molars according to Pell and Gregory's classification (Gay Escoda et al. 2004).
8. Participants must be able to swallow the IMPs.

Exclusion Criteria at Enrollment:

1. Findings in the medical record, vital signs, and/or physical examination demonstrating abnormal conditions of participant's general state of health preventing his/her participation in the clinical study according to the investigator's opinion.
2. Participant unable to speak, read, or write in Spanish language.
3. Clinical laboratory parameters exceed the pre-defined alert ranges (i.e., 1 standard deviation above or below the upper/lower limit of the normal ranges).
4. Known hypersensitivity to the IMPs, the anesthetic to be used during surgery, or to the rescue medication (ibuprofen, ketorolac).
5. Known alcohol or drug abuse in the last 6 months or any history of seizures. Alcohol abuse is defined as the consumption of more than 3 ounces (about 90 milliliters) of liquor or spirits or 18 ounces (about 530 milliliters) of beer per day, for 5 consecutive days during the 6-month period. Drug abuse is defined as the use of any recreational drug for 5 consecutive days during the 6 month period.
6. Participants who take analgesic medication for chronic pain, monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or other drugs that reduce the seizure threshold within 4 weeks of enrollment.
7. Pregnant or lactating women.
8. Participants who received systemic corticosteroids or opioid analgesics less than 2 weeks before surgery.
9. Participants with molars linked to the mandibular canal.

10. Participants requiring immediate dental procedures other than third and fourth molars extraction,

    Exclusion Criteria at the Allocation Visit:

11. Participant received a long-acting non-steroidal anti-inflammatory drug within 24 hours or 5 times the elimination half-life of that drug prior to surgery, whatever the longer.
12. Participant received any analgesic medication other than short-acting pre-operative or intra-operative anesthetic agents within 24 hours before taking IMPs.
13. Participant received more than 300 mg of lidocaine in total.
14. Participant received any analgesic medication other than the IMPs immediately after the oral surgical procedure was completed.
15. Baseline pain intensity of the participant after oral surgical procedure remains below 5 points on the 11-point NRS.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tramadol/Diclofenac 50/50; Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.	Drug: Tramadol/Diclofenac 50/50; Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.; Other Names: Adorlan Forte (Registered Trademark)
Experimental: Tramadol/Diclofenac 25/25; Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.	Drug: Tramadol/Diclofenac 25/25; Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.; Other Names: Adorlan (Registered Trademark)
Active Comparator: Tramadol 50; Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.	Drug: Tramadol 50; Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.; Other Names: Tramadol immediate-release capsule; Tradol (Registered Trademark)
Active Comparator: Diclofenac 50; Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction	Drug: Diclofenac 50; Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.; Other Names: Voltaren (Registered Trademark) (diclofenac enteric-coated tablet)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4)	Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point verbal rating scale (VRS) with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR4) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 4 hours after IMP intake. Minimum and maximum values for TOTPAR4 were 0=worst score and 16=best score, a higher score indicates more pain relief.	Up to 4 hours after first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Pain Relief at 6 Hours Post-dose (TOTPAR6)	Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point VRS with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR6) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 6 hours after IMP intake. Minimum and maximum values for TOTPAR6 were 0=worst score and 24=best score, a higher score indicates more pain relief.	Up to 6 hours after first dose
Total Pain Relief at 8 Hours Post-dose (TOTPAR8)	Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point VRS with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR8) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 8 hours after IMP intake. Minimum and maximum values for TOTPAR8 were 0=worst score and 32=best score, a higher score indicates more pain relief.	Up to 8 hours after first dose
Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose	Pain intensity was assessed by the participant before and at defined time points after the first IMP dose using an 11-point NRS with anchors at 0 for "no pain" and 10 for "pain as bad as you can imagine". Pain Intensity Difference (PIDt) was defined as the difference between baseline pain intensity and pain intensity at time point t, and SPID defined as summed PIDt x [time (hours) elapsed since previous observation]. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum=10 at each time point], and negative numbers indicate an increase in pain [minimum=-10 at each time point]. The overall minimum and maximum are -10 and 10 times the number of hours specified (SPID-4=[-40 to 40], SPID-6=[-60 to 60], SPID-8=[-80 to 80], and SPID-24=[-240 to 240]).	Baseline; up to 24 hours after first dose
Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone)	Time (hours) when the participant achieved a 50 percent reduction of baseline (starting) pain. It was assessed at defined time points after the first IMP dose using a YES or NO question for pain half gone.	Up to 24 hours after first dose
Time to Onset of First Perceptible Pain Relief	Participants used one stopwatch to document the time between first IMP dose and when they begin to feel any pain-relieving effect from the IMP.	Up to 8 hours after first dose
Time to Onset of Meaningful Pain Relief	Participants used a second stopwatch to document the time between first IMP dose and when they felt their pain relief was meaningful to them.	Up to 8 hours after first dose
Time to Intake of First Rescue Medication Dose	The time from first IMP dose to first dose of rescue medication (ibuprofen or ketorolac), if needed, within 24 hours post-dose was calculated.	First dose to 24 hours after first dose
Subject's Global Evaluation of the Treatment	Participants documented their overall impression of the analgesic efficacy of the IMPs on a 5-point Likert scale from Excellent (4) to Poor (0).	8 hours after the first dose of IMP or before first intake of rescue medication (whatever the first) and 24 hours after the first dose of IMPs
Incidence and Type of Adverse Events	The incidence of treatment emergent adverse events (TEAE) reported from first dose (Day 1) to last scheduled contact with the participant on Day 14 was descriptively summarized. Selected TEAEs were events with preferred terms of nausea, vomiting, abdominal pain, gastrointestinal bleeding, dizziness, or hypotension.	Day 1 to Day 14

Collaborators and Investigators

• Sponsor: Grünenthal GmbH
• Collaborators: Grünenthal, S.A.

Publications and helpful links

General Publications

• Gay Escoda C, Piñera Penalva M, Velasco Vivancos V, Berini Aytés L. Cordales incluidos. Patología, clínica y tratamiento del tercer molar incluído. In: Gay Escoda C, Berini Aytés L. (eds.). Tratado de Cirugía Bucal. Tomo I. Madrid: Ergón; 2004. p. 355-85

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2017
• Primary Completion (Actual): March 9, 2018
• Study Completion (Actual): March 22, 2018

Study Registration Dates

• First Submitted: October 19, 2018
• First Submitted That Met QC Criteria: October 19, 2018
• First Posted (Actual): October 22, 2018

Study Record Updates

• Last Update Posted (Actual): July 24, 2019
• Last Update Submitted That Met QC Criteria: July 23, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Dental pain; Wisdom tooth removal
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Analgesics, Opioid; Narcotics; Diclofenac; Tramadol
• Other Study ID Numbers: KF8001-01 (Registry Identifier: RNEC (Mexico)); U1111-1179-2333 (Other Identifier: World Health Organization)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Information available on the Grünenthal Group Web Site (see URL below for details).
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No