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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Pain

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


Participation Criteria
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Eligibility Criteria
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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): 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),

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FDC nefopam hydrochloride 30 mg / paracetamol 500 mg (X2)<br>Each dose: 2 tablets (included in masking capsule) | Combination Product: nefopam hydrochloride 30mg / paracetamol 500mg X2<br>* 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.<br>|
| Active Comparator: Paracetamol 500 mg (X2)<br>Each dose: 2 tablets (included in masking capsule) | Drug: Paracetamol 500 Mg Oral Tablet X2<br>* 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.<br>* Other names: Acetaminophen;|
| Active Comparator: Nefopam hydrochloride 30 mg (X2)<br>Each dose: 2 tablets (included in masking capsule) | Drug: Nefopam HCl 30 MG Oral Tablet X2<br>* 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.<br>|

What is the study measuring?
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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 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 IMP intake and/or right before first intake of rescue medication using a 100-mm Visual Analogic Scale (VAS) compared to baseline. | 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). | 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 | 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. | 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. | 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 IMP intake |  | Up to 5 days after first dose | 
| Time to rescue medication intake |  | Up to 10 days after first dose | 
| Sum of Pain Intensity Differences (SPID) | 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. | 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 IMP intakes |  | Up to 5 days after first dose | 
| Patient's Global Impression of Change (PGIC) score |  | Up to 10 days after first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate to severe acute pain, Postoperative pain, Third molar extraction, Analgesics, Nefopam, Paracetamol, Multimodal analgesia, Fixed drug combination