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

Phase 3

Completed

Conditions: Acute Pain

Interventions: Combination Product: nefopam hydrochloride 30mg / paracetamol 500mg X2
Drug: Paracetamol 500 Mg Oral Tablet X2
Drug: Nefopam HCl 30 MG Oral Tablet X2

Registration Number: NCT04622735

Lead Sponsor: Unither Pharmaceuticals, France

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 321

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):

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,
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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
FDC nefopam hydrochloride 30 mg / paracetamol 500 mg (X2)	nefopam hydrochloride 30mg / paracetamol 500mg X2	Each dose: 2 tablets (included in masking capsule)
Paracetamol 500 mg (X2)	Paracetamol 500 Mg Oral Tablet X2	Each dose: 2 tablets (included in masking capsule)
Nefopam hydrochloride 30 mg (X2)	Nefopam HCl 30 MG Oral Tablet X2	Each dose: 2 tablets (included in masking capsule)

Primary Outcome Measures

Name	Time	Method
Ranked Endpoints : 1. Sum of Pain Intensity Differences at 6 Hours (SPID0-6h)	6 hours post-dose	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
Total Pain Relief at 6 Hours (TOTPAR0-6h)	6 hours post-dose	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
Proportion of Responder Patients	6 hours post-dose	A responder patient is a subject who achieves a reduction of 50% of pain intensity compared to baseline.
The Patient's Global Impression of Change (PGIC) Questionnaire	6 hours post-dose
The Onset of Pain Relief	during the first 6 hours	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.

Secondary Outcome Measures

Name	Time	Method
Total Pain Relief at 1 Hour (TOTPAR0-1h), 2 Hours (TOTPAR0-2h), 3 Hours (TOTPAR0-3h), and 4 Hours (TOTPAR0-4h)	At 1 hour, 2 hours, 3 hours, and 4 hours	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
Sum of Pain Intensity Differences at 1 Hour (SPID0-1h), 2 Hours (SPID0-2h), 3 Hours (SPID0-3h), and 4 Hours (SPID0-4h)	At 1 hour, 2 hours, 3 hours, and 4 hours	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
The Pain Intensity Differences (PID) Assessment	At each timepoint: 30min, At 45min, until at 360 min post-dose	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
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	At days 1, 2, 3, 4 and 5	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
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

Trial Locations

Locations (18): State Medico-stomato Univ., by A.I. Evdokimov
🇷🇺
Moscow, Russian Federation
University Dental Hospital
🇬🇧
Cardiff, United Kingdom
Regional clinical hospital
🇷🇺
Yaroslavl, Russian Federation
Birmingham School of Dentistry
🇬🇧
Birmingham, United Kingdom
Edinburgh Dental Institute
🇬🇧
Edinburgh, United Kingdom
BARTS HEALTH NHS TRUST Royal London Hospital
🇬🇧
London, United Kingdom
Hôpital Leuven
🇧🇪
Leuven, Belgium
Óbudai Egészségügyi Centrum
🇭🇺
Zalaegerszeg, Hungary
CHU Angers
🇫🇷
Angers, France
CHU de tours
🇫🇷
Tours, France
Centre Hospitalier de Pontoise
🇫🇷
Pontoise, France
HIA Toulon
🇫🇷
Toulon, France
CHU Marseille
🇫🇷
Marseille, France
Clinexpert Kft.
🇭🇺
Budapest, Hungary
Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház,
🇭🇺
Nyíregyháza, Hungary
LLC Center for interdisciplinary dentistry & neuro
🇷🇺
Moscow, Russian Federation
Szent Borbála Kórház,
🇭🇺
Tatabánya, Hungary
Swan-Med Kft.
🇭🇺
Letavertes, Hungary