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

NCT04622735 | Completed Phase 3 Results

• 1 other identifier: UP-CLI-2019-002
• Study Type: interventional
• Target: 321
• Locations: 5 countries
• Sites: 19

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.

Conditions

Acute Pain

Keywords

Moderate to severe acute pain; Postoperative pain; Third molar extraction; Analgesics; Nefopam; Paracetamol; Multimodal analgesia; Fixed drug combination

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (12)

• 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

• 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

• The Pain Intensity Differences (PID) Assessment

  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

Other Outcomes (1)

• Occurrence of Adverse Events (Serious and Non-serious Adverse Events).

  Up to 10 days after first dose

Study Arms (3)

FDC nefopam hydrochloride 30 mg / paracetamol 500 mg (X2)

EXPERIMENTAL

Each dose: 2 tablets (included in masking capsule)

Combination Product: nefopam hydrochloride 30mg / paracetamol 500mg X2

Paracetamol 500 mg (X2)

ACTIVE COMPARATOR

Each dose: 2 tablets (included in masking capsule)

Drug: Paracetamol 500 Mg Oral Tablet X2

Nefopam hydrochloride 30 mg (X2)

ACTIVE COMPARATOR

Each dose: 2 tablets (included in masking capsule)

Drug: Nefopam HCl 30 MG Oral Tablet X2

Interventions

nefopam hydrochloride 30mg / paracetamol 500mg X2 COMBINATION_PRODUCT

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.

FDC nefopam hydrochloride 30 mg / paracetamol 500 mg (X2)

Paracetamol 500 Mg Oral Tablet X2 DRUG

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.

Also known as: Acetaminophen

Paracetamol 500 mg (X2)

Nefopam HCl 30 MG Oral Tablet X2 DRUG

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.

Nefopam hydrochloride 30 mg (X2)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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)

You may not qualify if:

• 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),

Sponsors & Collaborators

• Unither Pharmaceuticals, France: lead
• Excelya: collaborator

Study Sites (19)

Hôpital Leuven

Leuven, Belgium

Location

CHU Angers

Angers, 49933, France

Location

CHU Marseille

Marseille, 13385, France

Location

Centre Hospitalier de Pontoise

Pontoise, 95300, France

Location

HIA Toulon

Toulon, 83800, France

Location

CHU de tours

Tours, 37170, France

Location

Clinexpert Kft.

Budapest, Hungary

Location

Óbudai Egészségügyi Centrum

Budapest, Hungary

Location

Swan-Med Kft.

Létavértes, Hungary

Location

Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház,

Nyíregyháza, Hungary

Location

Szent Borbála Kórház,

Tatabánya, Hungary

Location

Óbudai Egészségügyi Centrum

Zalaegerszeg, Hungary

Location

LLC Center for interdisciplinary dentistry & neuro

Moscow, 141207, Russia

Location

State Medico-stomato Univ., by A.I. Evdokimov

Moscow, Russia

Location

Regional clinical hospital

Yaroslavl, 150062, Russia

Location

Birmingham School of Dentistry

Birmingham, B5 7EG, United Kingdom

Location

University Dental Hospital

Cardiff, CF14 4XY, United Kingdom

Location

Edinburgh Dental Institute

Edinburgh, EH3 9HX, United Kingdom

Location

BARTS HEALTH NHS TRUST Royal London Hospital

London, E1 1FR, United Kingdom

Location

MeSH Terms

Conditions

Acute Pain; Pain, Postoperative

Interventions

Nefopam; Acetaminophen

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Postoperative Complications; Pathologic Processes

Intervention Hierarchy (Ancestors)

Oxazocines; Azocines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Results Point of Contact

• Title: Non Clinical & Clinical Project Manager
• Organization: Unither Pharmaceuticals

clinicaltrials@unither-pharma.com

+33 (0)1 44 63 51 78

Study Officials

• International Study Coordinator

  Birmingham School of Dentistry

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-blind. Participants, investigators, and all persons involved in the conduct, data management, and analysis of the study will be fully blinded to the participant's treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2020
• First Posted: November 10, 2020
• Study Start: February 22, 2020
• Primary Completion: October 12, 2022
• Study Completion: October 20, 2022
• Last Updated: November 27, 2024
• Results First Posted: November 27, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (5); BE (1); HU (6); RU (3); GB (4)