Ibuprofen/Acetaminophen Versus Nurofen Plus® and Panadeine® Extra Dental Pain Study

Study Overview
=================
Brief Summary
-----------------
The objective is to assess the efficacy and tolerability of a combination of 400 mg ibuprofen plus 1000 mg acetaminophen, 200 mg ibuprofen plus 500 mg acetaminophen compared with Nurofen Plus® and Panadeine® Extra.

Detailed Description
-----------------
RB has developed a fixed-dose combination of ibuprofen and acetaminophen (paracetamol). Since the pharmacological actions of ibuprofen and acetaminophen (paracetamol) differ in their site and mode of action, the combination would be expected to be more effective than either active alone, given that pain is multi-factorial with different mediators. The purpose of this study was to compare the efficacy and tolerability of ibuprofen/acetaminophen (paracetamol) combination with leading market analgesics. The efficacy and tolerability was assessed in terms of total analgesic effect, peak analgesic effect, onset and duration of action and the subject's overall assessment of the study medication.

Official Title
-----------------
A Double-blind, 5 Parallel-group, Placebo-controlled, Randomised, Single Dose, 3-site Study to Compare the Analgesic Efficacy and Tolerability of a Combination of Ibuprofen 400 mg Plus Paracetamol 1000 mg; a Combination of Ibuprofen 200 mg Plus Paracetamol 500 mg; a Combination of Ibuprofen 400 mg Plus Codeine 25.6 mg (Nurofen Plus®); a Combination of Paracetamol 1000 mg Plus Codeine 30 mg (Panadeine® Extra) in Postoperative Adult Dental Pain Following Third Molar Extraction.

Conditions
-----------------
Post-operative Pain

Intervention / Treatment
-----------------
* Drug: Ibuprofen/acetaminophen
* Drug: Ibuprofen/acetaminophen (higher dose)
* Drug: Nurofen Plus®
* Drug: Panadeine® Extra
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: Experiencing moderate to severe pain after extraction of impacted third molars Main Exclusion Criteria: Any ongoing painful condition other than that associated with the current third molar surgery that could significantly interfere with the subject's suitability Any condition that would render the subject unsuitable to receive an NSAID, acetaminophen or codeine

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibuprofen/acetaminophen (lower dose)<br>One tablet of ibuprofen 200 mg plus acetaminophen 500 mg and one placebo tablet | Drug: Ibuprofen/acetaminophen<br>* One tablet of ibuprofen 200 mg plus acetaminophen 500 mg and one placebo tablet, single dose taken orally with 300 ml water<br>* Other names: Ibuprofen/paracetamol (lower dose);|
| Experimental: Ibuprofen/acetaminophen (higher dose)<br>Two tablets of ibuprofen 200 mg plus acetaminophen 500 mg | Drug: Ibuprofen/acetaminophen (higher dose)<br>* Two tablets of ibuprofen 200 mg plus acetaminophen 500 mg, single dose taken orally with 300 ml water<br>* Other names: Ibuprofen/Paracetamol;|
| Active Comparator: Nurofen Plus®<br>Two tablets ibuprofen 200mg plus codeine 12.8mg (Nurofen Plus®) | Drug: Nurofen Plus®<br>* Two tablets ibuprofen 200mg plus codeine 12.8mg (Nurofen Plus®), single dose taken orally with 300 ml water<br>* Other names: Ibuprofen/Codeine;|
| Active Comparator: Panadeine® Extra<br>Two tablets acetaminophen 500 mg plus codeine 15 mg (Panadeine® Extra) | Drug: Panadeine® Extra<br>* Two tablets acetaminophen 500 mg plus codeine 15 mg (Panadeine® Extra), single dose taken orally with 300 ml water<br>* Other names: Paracetamol/codeine;|
| Placebo Comparator: Placebo<br>Two placebo tablets | Drug: Placebo<br>* Two placebo tablets, single dose taken orally with 300 ml water<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Area Under the Curve (AUC) of Pain Intensity and Relief Scores (SPRID) | SPRID 0-12h: Sum of pain intensity difference (PID) and the pain relief (PR) score over the twelve-hour follow-up period. Score range: 0mm = No pain and 100mm = Worst pain. This was calculated as the area under the curve (AUC) using the method of linear trapezoids assuming that the baseline assessment took place at time zero. Pain intensity (PI) was measured by pain assessment questionnaire, where subject tick the appropriate box in a 4-point ordinal scale ranging from 0 = No pain, 1 = Mild pain, 2 = Moderate pain, and 3 = Severe pain, in response to the question 'What is your pain level at this time?' Total Pain Relief (TOTPAR) was measured using pain assessment diary, where subject tick the appropriate box on a 5-point Ordinal Rating Scale: 0 = None, 1 = A Little, 2 = Some, 3 = A Lot, and 4 = Complete, in response to the question 'How much relief have you had from your starting pain?' | 0 (baseline), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in AUC (0-8h) of SPRID | SPRID 0-8h: Sum of pain intensity difference (PID) and the pain relief (PR) score over the twelve-hour follow-up period. Score range: 0 mm = No pain and 100 mm = Worst pain. This was calculated as the area under the curve (AUC) using the method of linear trapezoids assuming that the baseline assessment took place at time zero. Pain intensity (PI) was measured by pain assessment questionnaire, where subject tick the appropriate box in a 4-point ordinal scale ranging from 0 = No pain, 1 = Mild pain, 2 = Moderate pain, and 3 = Severe pain, in response to the question 'What is your pain level at this time?' Total Pain Relief (TOTPAR) was measured using pain assessment diary, where subject tick the appropriate box on a 5-point Ordinal Rating Scale: 0 = None, 1 = A Little, 2 = Some, 3 = A Lot, and 4 = Complete, in response to the question 'How much relief have you had from your starting pain?' | 0 (baseline), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours post-dose | 
| Change From Baseline in AUC for Pain Intensity Difference Scores (SPID) | Sum of Pain Intensity Difference (SPID) was calculated as the area under the curve (AUC) using the method of linear trapezoids assuming that the baseline assessment took place at time zero. Score range: 0mm = No pain and 100mm = Worst pain. Pain intensity (PI) was measured by pain assessment questionnaire, where subject tick the appropriate box in a 4-point ordinal scale ranging from 0 = No pain, 1 = Mild pain, 2 = Moderate pain, and 3 = Severe pain, in response to the question 'What is your pain level at this time?' | 0-4, 0-6, 0-8 and 0-12 hours | 
| Change From Baseline in AUC of Pain Relief Scores (TOTPAR) | Total pain relief (TOTPAR) was measured using pain assessment diary where subject tick the appropriate box in response to the question 'How much relief have you had from your starting pain?' Pain Relief (PR) was rated on a 5-point Ordinal Rating Scale: 0 = None, 1 = A Little, 2 = Some, 3 = A Lot, and 4 = Complete. | 0-4, 0-6, 0-8 and 0-12 hours | 
| Change From Baseline in AUC of Individual Reading Pain Intensity and Relief Scores (SPRID) | SPRID 0-12h: Sum of pain intensity difference (PID) and the pain relief (PR) score over the twelve-hour follow-up period. Score range: 0mm = No pain and 100mm = Worst pain. This was calculated as the area under the curve (AUC) using the method of linear trapezoids assuming that the baseline assessment took place at time zero. Pain intensity (PI) was measured by pain assessment questionnaire, where subject tick the appropriate box in a 4-point ordinal scale ranging from 0 = No pain, 1 = Mild pain, 2 = Moderate pain, and 3 = Severe pain, in response to the question 'What is your pain level at this time?' Total Pain Relief (TOTPAR) was measured using pain assessment diary, where subject tick the appropriate box on a 5-point Ordinal Rating Scale: 0 = None, 1 = A Little, 2 = Some, 3 = A Lot, and 4 = Complete, in response to the question 'How much relief have you had from your starting pain?' | 15, 30, 45, 60, 90 minutes and 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours | 
| Individual Pain Intensity Differences (Ordinal) | Pain intensity (PI) was measured by pain assessment questionnaire where subject tick the appropriate box in response to the question 'What is your pain level at this time?' PI measured using a 4-point ordinal scale: 0 = No pain, 1 = Mild pain, 2 = Moderate pain, and 3 = Severe pain. | 15, 30, 45, 60, 90 minutes and 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours | 
| Individual Pain Intensity Differences Visual Analogue Scale (VAS) | Pain Intensity (PI) VAS was measured using a horizontal 100-mm VAS ranging 0 mm = 'No Pain' as the left anchor and 100 mm = 'Worst Pain' as the right anchor, labelled by the subject marking the VAS line in the pain assessment questionnaire in response to the instruction 'Please indicate with a line on the scale below your pain at this time.' | 15, 30, 45, 60, 90 minutes and 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours | 
| Change From Baseline in Peak Pain Intensity Difference (Peak PID - Ordinal) | Pain intensity (PI) was measured by pain assessment questionnaire where subject tick the appropriate box in response to the question 'What is your pain level at this time?' PI measured using a 4-point ordinal scale: 0 = No pain, 1 = Mild pain, 2 = Moderate pain, and 3 = Severe pain. | 0 (baseline), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours post-dose | 
| Change From Baseline in Peak Pain Relief (PR) | Total pain relief (TOTPAR) was measured using pain assessment diary where subject tick the appropriate box in response to the question 'How much relief have you had from your starting pain?' Pain Relief (PR) was rated on a 5-point Ordinal Rating Scale: 0 = None, 1 = A Little, 2 = Some, 3 = A Lot, and 4 = Complete. | 0 (baseline), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours post-dose | 
| Subjects' Overall Assessment of the Study Medication Assessed at 12 Hours or Just Before Administration of Rescue Medication | Subject's Overall Assessment measured by subject ticking the appropriate box in response to the question 'How effective do you think the study medication is as a treatment for pain?' Subject's Overall Assessment rated on a five-point ordinal scale: 1 = Poor, 2 = Fair, 3 = Good, 4 = Very good, and 5 = Excellent. | At 12 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dental pain, Ibuprofen, Acetaminophen, Nurofen Plus®, Panadeine® Extra, Paracetamol