Nefopam/Paracetamol Fixed Dose Combination in Acute Pain After Impacted Third Molar Extraction

A Comparative, Randomized, Double-blind, 3-arm Parallel, Phase III Study to Evaluate the Efficacy and Safety of a Fixed Dose Combination of Nefopam/Paracetamol Taken Orally in Moderate to Severe Pain After Impacted Third Molar Extraction

This study aims to evaluate the analgesic efficacy of single and multiple doses of a new fixed dose combination of nefopam hydrochloride 30 mg and paracetamol 500mg taken orally in comparison to each single component.

Study Overview

• Status: Completed
• Conditions: Acute Pain
• Intervention / Treatment: Combination product: nefopam hydrochloride 30mg / paracetamol 500mg X2; Drug: Paracetamol 500 Mg Oral Tablet X2; Drug: Nefopam HCl 30 MG Oral Tablet X2

• Study Type: Interventional
• Enrollment (Actual): 321
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • Hôpital Leuven
• France
  • Angers, France, 49933
    • Chu Angers
  • Marseille, France, 13385
    • CHU Marseille
  • Pontoise, France, 95300
    • Centre Hospitalier de Pontoise
  • Toulon, France, 83800
    • HIA Toulon
  • Tours, France, 37170
    • CHU de Tours
• Hungary
  • Budapest, Hungary
    • Clinexpert Kft.
  • Budapest, Hungary
    • Óbudai Egészségügyi Centrum
  • Letavertes, Hungary
    • Swan-Med Kft.
  • Nyíregyháza, Hungary
    • Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház,
  • Tatabánya, Hungary
    • Szent Borbála Kórház,
  • Zalaegerszeg, Hungary
    • Óbudai Egészségügyi Centrum
• Russian Federation
  • Moscow, Russian Federation, 141207
    • LLC Center for interdisciplinary dentistry & neuro
  • Moscow, Russian Federation
    • State Medico-stomato Univ., by A.I. Evdokimov
  • Yaroslavl, Russian Federation, 150062
    • Regional Clinical Hospital
• United Kingdom
  • Birmingham, United Kingdom, B5 7EG
    • Birmingham School of Dentistry
  • Cardiff, United Kingdom, CF14 4XY
    • University Dental Hospital
  • Edinburgh, United Kingdom, EH3 9HX
    • Edinburgh Dental Institute
  • London, United Kingdom, E1 1FR
    • BARTS HEALTH NHS TRUST Royal London Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria:

• Male and female patient aged from 18 years up to 65 years,
• Patient scheduled to undergo the surgical removal of at least one fully or partially impacted third mandibular molar requiring bone removal under short-acting local anaesthetic (mepivacaine or lidocaine) with or without vasoconstrictor,
• Patient weighing > 50 kg,
• Patient who has signed a written informed consent prior to any study-related procedures.

Additional inclusion criteria after surgery (randomization):

1. Patient experiencing moderate to severe pain within 4 hours after the dental extraction, defined by a baseline pain intensity Visual Analogic Scale (VAS) score ≥ 50 mm,
2. Third molar extraction(s) completed without any immediate complication, that in the opinion of the investigator, would interfere with the study conduct and/or assessments (e.g., suspected neurosensory complication, incomplete removal of tooth)

Main Exclusion Criteria:

• Patient treated by analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) within 3 days preceding the day of randomization or within 5 times the elimination half-life whichever the longest,
• Woman with positive results on a urine pregnancy test or breastfeeding woman or woman of childbearing potential without an effective contraception,
• Patient with a history of convulsive disorders,
• Patient taking mono-amine-oxidase (MAO) inhibitors (including but not limited to selegiline, isocarboxazid, tranylcypromine, phenelzine…),
• Patient with an abnormal cardiac condition: medically significant disorders of cardiac rate and/or rhythm,
• Patient with known anaemia,
• Patient with known pulmonary disease,
• Patient with known active gastric or duodenal ulcer or a history of recurrent gastrointestinal ulcer/bleeding,
• Patient with known glaucoma,
• Patients with a prostatic hyperplasia or urinary retention,
• Patient with current or chronic history of liver disease, or known hepatic or biliary abnormalities,
• Patient with a current or chronic history of severe renal impairment (glomerular filtration below 30 mL/min),

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FDC nefopam hydrochloride 30 mg / paracetamol 500 mg (X2); Each dose: 2 tablets (included in masking capsule)	Combination product: nefopam hydrochloride 30mg / paracetamol 500mg X2; The first intake is taken right after randomization. Then on-demand period (5 days maximum) respecting a 6-hour interval between intakes, and up to 3 intakes per day.
Active Comparator: Paracetamol 500 mg (X2); Each dose: 2 tablets (included in masking capsule)	Drug: Paracetamol 500 Mg Oral Tablet X2; The first intake is taken right after randomization. Then on-demand period (5 days maximum) respecting a 6-hour interval between intakes, and up to 3 intakes per day.; Other Names: Acetaminophen
Active Comparator: Nefopam hydrochloride 30 mg (X2); Each dose: 2 tablets (included in masking capsule)	Drug: Nefopam HCl 30 MG Oral Tablet X2; The first intake is taken right after randomization. Then on-demand period (5 days maximum) respecting a 6-hour interval between intakes, and up to 3 intakes per day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ranked Endpoints : 1. Sum of Pain Intensity Differences at 6 Hours (SPID0-6h)	Pain intensity difference (PID) will be calculated using the score of pain intensity assessed by the patient at defined time points (T30, T45, T60, T90, T120, T150, T180, T240, T300, T360 min,) after the first Investigational Medicinal Product (IMP) intake and/or right before first intake of rescue medication using a 100-mm Visual Analogic Scale (VAS) compared to baseline. Calculation: Sum of Pain intensity difference (SPID) is the time-weighted summary measure of the total area under the pain intensity difference (PID) curve that integrates serial assessments of pain during x times after the first Investigational Medicinal Product SPID0-6h= SPID0-30min+SPID30min-45min+SPID45min-1h+SPID1h-1h30+SPID1h30-2h+SPID2h-2h30+SPID2h30-3h+SPID3h-4h+SPID4h-5h+SPID5h-6h With: SPIDTime1-Time2 = (PID Theoretical Time1 + PID Theoretical Time2) * (Theoretical Time2- Theoretical Time1) / 2 SPID min 0-6h = 0 SPID max 0-6h = 36000 The lower score mean a better score	6 hours post-dose
Total Pain Relief at 6 Hours (TOTPAR0-6h)	Pain Relief will be assessed by the patient at defined time points (T30, T45, T60, T90, T120, T150, T180, T240, T300, T360 min) after the first IMP intake and/or right before first intake of rescue medication using a 5-point verbal rating scale (VRS). Calculation: TOTPAR is the time-weighted summary measure of the total area under the pain release difference curve that integrates serial assessments of pain release during x times after the first Investigational Medicinal Product TOTPAR0-6h=TOTPAR0-30min+TOTPAR30min-45min+TOTPAR45min-1h+TOTPAR1h-1h30+TOTPAR1h30-2h+TOTPAR2h-2h30+TOTPAR2h30-3h+ TOTPAR 3h-4h+ TOTPAR 4h-5h+ TOTPAR 5h-6h With: TOTPARTime1-Time2 = (PAR Time1 + PAR Time2) * (Time2-Time1) / 2 And with the score of pain relief at T0 = 0 ("none") TOTPAR min 0-6h = 0 TOTPAR max 0-6h = 1800 The higher score mean a better outcome	6 hours post-dose
Proportion of Responder Patients	A responder patient is a subject who achieves a reduction of 50% of pain intensity compared to baseline.	6 hours post-dose
The Patient's Global Impression of Change (PGIC) Questionnaire		6 hours post-dose
The Onset of Pain Relief	Score of pain intensity will be assessed by the patient at defined time points (T30, T45, T60, T90, T120, T150, T180, T240, T300, T360 min). The time point of the first assessment obtaining a score ≤ 30 mm will be retained as time score of onset of pain relief.	during the first 6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Pain Relief at 1 Hour (TOTPAR0-1h), 2 Hours (TOTPAR0-2h), 3 Hours (TOTPAR0-3h), and 4 Hours (TOTPAR0-4h)	Pain relief (PAR) will be assessed by the patient at defined time points (T30, T45, T60, T90, T120, T150, T180, T240 min) after the first IMP intake and/or right before first intake of rescue medication using a 5-point verbal rating scale Calculation: TOTPAR is the time-weighted summary measure of the total area under the pain release difference curve that integrates serial assessments of pain release during x times after the first Investigational Medicinal Product TOTPAR0-6h=TOTPAR0-30min+TOTPAR30min-45min+TOTPAR45min-1h+TOTPAR1h-1h30+TOTPAR1h30-2h+TOTPAR2h-2h30+TOTPAR2h30-3h+ TOTPAR 3h-4h+ TOTPAR 4h-5h+ TOTPAR 5h-6h With: TOTPARTime1-Time2 = (PAR Time1 + PAR Time2) * (Time2-Time1) / 2 And with the score of pain relief at T0 = 0 ("none") TOTPAR min 0-any time = 0 TOTPAR max 0-1h = 300 ; TOTPAR max 0-2h = 600 ;TOTPAR max 0-3h = 900 ;TOTPAR max 0-4h = 1200 ; The higher score mean a better outcome	At 1 hour, 2 hours, 3 hours, and 4 hours
Sum of Pain Intensity Differences at 1 Hour (SPID0-1h), 2 Hours (SPID0-2h), 3 Hours (SPID0-3h), and 4 Hours (SPID0-4h)	PID will be calculated using the score of pain intensity assessed by the patient at defined time points (T30, T45, T60, T90, T120, T150, T180, T240 min) after the first IMP intake and/or right before first intake of rescue medication using a 100-mm VAS compared to baseline. Calculation: SPID is the time-weighted summary measure of the total area under the pain intensity difference curve that integrates serial assessments of pain during x times after the first IMP SPID0-4h= SPID0-30min+SPID30min-45min+SPID45min-1h+SPID1h-1h30+SPID1h30-2h+SPID2h-2h30+SPID2h30-3h+SPID3h-4h With: SPIDTime1-Time2 = (PID Theoretical Time1 + PID Theoretical Time2) * (Theoretical Time2- Theoretical Time1) / 2 SPID min 0-any time = 0 SPID max 0-1h = 6000 ; SPID max 0-2h = 12000; SPID max 0-3h = 18000; SPID max 0-4h = 24000 The lower score mean a better score	At 1 hour, 2 hours, 3 hours, and 4 hours
The Pain Intensity Differences (PID) Assessment	PID will be calculated using the scores of pain intensity (VAS) at each time point compared to baseline. PID30min = VAS of pain intensity 30min - VAS of pain intensity baseline PID min = 0 / PID max = 100 A higher PID is a better outcome	At each timepoint: 30min, At 45min, until at 360 min post-dose
Proportion of Responder Patients.		At 1 hour, 2 hours, 3 hours and 4 hours.
Time to the Second Investigational Medicinal Product (IMP) Intake		Up to 5 days after first dose
Participant Having Taken a Rescue Analgesic Treatment		Up to 10 days after first dose
Sum of Pain Intensity Differences	Pain Intensity Difference (PID) will be calculated using the score of pain intensity assessed by the patient at defined time points using a 100-mm visual Analog Scale (VAS) compared to baseline. Calculation: Sum of Pain Intensity Difference (SPID) is the time-weighted summary measure of the total area under the pain intensity difference curve that integrates serial assessments of pain during x times after the first Investigational Medicinal Product With: SPIDTime1-Time2 = (VAS Theoretical Time1 + VAS Theoretical Time2) * (Theoretical Time2- Theoretical Time1) / 2 SPID min 0-any time = 0 SPID max 0-day 1 = 144000 ; SPID max 0-day 2 = 288000 ; SPID max 0-day 3 = 432000 ; SPID max 0-day 4 = 576000 ; SPID max 0-day 5 = 720000 ; The lower score means a better outcome	At days 1, 2, 3, 4 and 5
Proportion of Patients Having Taken a Rescue Analgesic Treatment Throughout the Study.		Up to 10 days after first dose
The Total Dose of Rescue Medication Taken.		Up to 10 days after first dose
Mean Duration Under Rescue Medication Over the 5 Days.		Up to 5 days after first dose
Number of Investigational Medicinal Product (IMP) Intakes		Up to 5 days after first dose
Patient's Global Impression of Change (PGIC) Score		Up to 10 days after first dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Adverse Events (Serious and Non-serious Adverse Events).	= Number of Events	Up to 10 days after first dose

Collaborators and Investigators

• Sponsor: Unither Pharmaceuticals, France
• Collaborators: EXCELYA Bordeaux
• Investigators: Principal Investigator: International Study Coordinator, Birmingham School of Dentistry

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2020
• Primary Completion (Actual): October 12, 2022
• Study Completion (Actual): October 20, 2022

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: November 3, 2020
• First Posted (Actual): November 10, 2020

Study Record Updates

• Last Update Posted (Estimated): November 27, 2024
• Last Update Submitted That Met QC Criteria: November 20, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Postoperative pain; Paracetamol; Analgesics; Multimodal analgesia; Moderate to severe acute pain; Third molar extraction; Fixed drug combination; Nefopam
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Antipyretics; Acetaminophen; Nefopam
• Other Study ID Numbers: UP-CLI-2019-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No