Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12611000450910
Ethics application status
Approved
Date submitted
13/04/2011
Date registered
3/05/2011
Date last updated
20/12/2018
Date data sharing statement initially provided
19/12/2018
Date results information initially provided
19/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study comparing the effects of different paracetamol and ibuprofen combination doses and placebo
Scientific title
Maxi-Analgesic Dose Response Study: A double-blind, placebo-controlled, randomized, parallel group comparison of the effects of diferent paracetamol + ibuprofen combination doses and placebo in participants with pain from removal of 2-4 third molars.
Secondary ID [1] 259993 0
AFT-MX-3
Universal Trial Number (UTN)
U1111-1120-7300
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-operative pain from removal of 2-4 third molars 265644 0
Condition category
Condition code
Anaesthesiology 265774 265774 0 0
Anaesthetics
Oral and Gastrointestinal 265793 265793 0 0
Normal oral and gastrointestinal development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A combination of Paracetamol 500 mg + ibuprofen 150 mg per tablet, 2 tablets orally every 6 hours for 24 hours
Intervention code [1] 264408 0
Treatment: Drugs
Comparator / control treatment
Half dose of the Combination (paracetamol 250 mg + ibuprofen 75 mg per tablet)
Quarter dose of the Combination (paracetamol 125 mg + ibuprofen 27.5 mg per tablet)
Matching placebo tablets (identical in taste and appearance to the paracetamol and ibuprofen combination tablets but without active ingredient)
All the comparators will be administered as 2 tablets every 6 hours
Control group
Dose comparison

Outcomes
Primary outcome [1] 266528 0
To compare the time-adjusted SPIDs (Summed Pain Intensity Differences from baseline) of the VAS pain intensity scores up to 24 hours after the first dose of study medication among the 4 treatment groups to determine the form of the dose-response relationship.
Timepoint [1] 266528 0
VAS pain intensity scores will be collected from patients at the following time points:
Baseline (within 6 hours following completion of the surgery)
At 15 minutes, 30 minutes, 45 minutes, 60 minutes (1 hour), 90 minutes, then 2, 3, 4, 5, 6 hours after the first dose of study medication when participants are staying at the hospital.
At 8, 14, 20 and 24 hours after the first dose of study medication following discharge from the hospital while the participant is awake, and just prior to the dose of rescue medication (if applicable). As participants are being dosed every 6 hours they may need to be woken for some doses in which case the VAS will be recorded immediately before each dose
At each time point, VAS pain intensity assessment will be done at rest.
Secondary outcome [1] 273971 0
To compare the maximum VAS pain scores for the 24-hour period after the first dose of study medication among the four treatment groups to determine the form of the dose response relationship.
Timepoint [1] 273971 0
VAS pain intensity scores will be collected from patients at the following time points:
Baseline (within 6 hours following completion of the surgery)
At 15 minutes, 30 minutes, 45 minutes, 60 minutes (1 hour), 90 minutes, then 2, 3, 4, 5, 6 hours after the first dose of study medication when participants are staying at the hospital.
At 8, 14, 20 and 24 hours after the first dose of study medication following discharge from the hospital while the participant is awake, and just prior to the dose of rescue medication (if applicable). As participants are being dosed every 6 hours they may need to be woken for some doses in which case the VAS will be recorded immediately before each dose
At each time point, VAS pain intensity assessment will be done at rest.
Secondary outcome [2] 273972 0
To compare the response rates (response rate defined as the percentage of participants who achieve at least a 50% reduction in baseline pain within 6 hours i.e. the first dose period) among the four treatment groups to determine the form of the dose response relationship.
Timepoint [2] 273972 0
VAS pain intensity scores will be collected from patients at the following time points:
Baseline (within 6 hours following completion of the surgery)
At 15 minutes, 30 minutes, 45 minutes, 60 minutes (1 hour), 90 minutes, then 2, 3, 4, 5, 6 hours after the first dose of study medication when participants are staying at the hospital.
At 8, 14, 20 and 24 hours after the first dose of study medication following discharge from the hospital while the participant is awake, and just prior to the dose of rescue medication (if applicable). As participants are being dosed every 6 hours they may need to be woken for some doses in which case the VAS will be recorded immediately before each dose
At each time point, VAS pain intensity assessment will be done at rest.
Secondary outcome [3] 273973 0
To determine and compare the time to peak reduction in VAS pain intensity scores following the first dose of study medication among the four treatment groups to determine the form of the dose response relationship
Timepoint [3] 273973 0
VAS pain intensity scores will be collected from patients at the following time points:
Baseline (within 6 hours following completion of the surgery)
At 15 minutes, 30 minutes, 45 minutes, 60 minutes (1 hour), 90 minutes, then 2, 3, 4, 5, 6 hours after the first dose of study medication when participants are staying at the hospital.
At 8, 14, 20 and 24 hours after the first dose of study medication following discharge from the hospital while the participant is awake, and just prior to the dose of rescue medication (if applicable). As participants are being dosed every 6 hours they may need to be woken for some doses in which case the VAS will be recorded immediately before each dose
At each time point, VAS pain intensity assessment will be done at rest.
Secondary outcome [4] 273974 0
To compare time to perceptible and meaningful pain relief among the four treatment groups using the two stopwatch method.
Timepoint [4] 273974 0
Starts immediately after the first dose of study medication.
Secondary outcome [5] 273975 0
To compare the time to requirement for rescue medication among the four treatment groups. The time and doses of rescue medication taken during the 24 hours double blind treatment period will be recorded on the patient diary.
Timepoint [5] 273975 0
Until 24 hours after the first dose of study medication
Secondary outcome [6] 273976 0
To compare the amount of rescue medication used (defined as the number of tablets) among the four treatment groups over the 24-hour treatment period. The time and doses of rescue medication taken during the 24 hours double blind treatment period will be recorded on the patient diary.
Timepoint [6] 273976 0
Until 24 hours after the first dose of study medication
Secondary outcome [7] 273977 0
To compare the percentage of participants requiring rescue medication among the four treatment groups. The time and doses of rescue medication taken during the 24 hours double blind treatment period will be recorded on the patient diary.
Timepoint [7] 273977 0
Until 24 hours after the first dose of study medication
Secondary outcome [8] 273978 0
To compare the categorical global pain rating among the four treatment groups.
Timepoint [8] 273978 0
At the end of 24 hours after the first dose of study medication

Eligibility
Key inclusion criteria
1) Provide written informed consent before initiation of any study-related procedures (including the willingness to stay at the hospital up to 6 hours after the surgery).
2) Males and females aged at least 16 years and not more than 60 years old on the day of consent.
3) Undergoing oral surgery for the extraction of 2-4 impacted 3rd molar teeth, one of which must be mandibular and require bone removal. The molars removed, are either bilateral or ipsilateral.
4) A resting VAS pain intensity score at baseline (within 6 hours following completion of surgery) of greater than or equal to 50mm on a 100mm VAS scale with 0 ( no pain) and 100 (worst pain imaginable).
Minimum age
16 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Study contra-indications
1) Has taken any NSAID or paracetamol within 12 hours prior to the start of surgery other than aspirin less than or equal to 150mg/day.
2) Subjects who have received any anesthetics from midnight the night prior to surgery, except for lidocaine with epinephrine, nitrous oxide, diazepam (Valium [Registered Trademark]), methohexitol (Brevital[Registered Trademark]).
3) Hypersensitivity to opioids
4) Known to be pregnant or possibly pregnant.
5) Women of childbearing potential who are unwilling to take adequate contraceptive precautions, i.e., a hormonal contraceptive, an intrauterine device, double-barrier method, or abstinence (should the subject become sexually active, she must agree to use a double-barrier method of contraception). A woman of childbearing potential is defined as any female who is less than 2 years post-menopausal or has not undergone a partial or total hysterectomy or surgical sterilization, e.g., bilateral tubal ligation, bilateral oophorectomy.
6) Women of childbearing potential who are unwilling to undergo a urine pregnancy test
7) Suffering from a neurological disorder relating to pain perception or any acute or chronic condition that, in the opinion of the investigator, makes the subject unsuitable from an efficacy or safety perspective.
8) In the opinion of the investigator, unable to understand the visual analogue pain score or comply with the protocol requirements.
9) Currently or in the last 30 days, has been in a clinical trial involving another study drug.
10) Currently treated with an ACE inhibitor, warfarin, steroid (other than nasal steroids or topical steroids with the approval of the investigator), cyclosporin, tacrolimus or methotrexate, or any other medication felt by the investigator to interfere with safety or efficacy evaluations.
11) Participant weight < 50kg.
12) Suffering from any other diseases or condition which, in the opinion of the investigator, means that it would not be in the participant’s best interests to participate in this study.
NSAID and/or paracetamol contra-indications
13) Hypersensitivity to aspirin or other NSAID.
14) Hypersensitivity to paracetamol.
15) Severe known haemopoetic, renal or hepatic disease, or immunosuppressed.
16) History of gastric ulceration or other GI disorders that, in the opinion of the investigator make the subject unsuitable (e.g., frequent treatment of GERD, inflammatory bowel disease, etc.).
17) History of severe asthma defined as asthma requiring frequent or ongoing treatment to control symptoms. Exercise-induced asthma or mild asthma not requiring ongoing treatment may not be exclusionary at the discretion of the investigator.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomization will occur at the study site, once participant eligibility for the study is confirmed post-operatively. The randomization will be stratified based on baseline VAS pain intensity score measured at rest (moderate pain [VAS 50-69 mm]; severe pain [VAS greater than or equal to 70mm]) and anaesthesia used for the surgery (general anaesthesia or local anaesthesia). Each eligible participant will be assigned to one of the four strata as listed below:
Moderate pain at baseline and general anaesthesia was used for the surgery
Moderate pain at baseline and local anaesthesia was used for the surgery
Severe pain at baseline and general anaesthesia was used for the surgery
Severe pain at baseline and local anaesthesia was used for the surgery
The randomization number for each participant consists of a-two digit stratum number (i.e. 01, 02, 03 and 04) and a-three digit participant number (e.g. 01001, 01002) According to the baseline VAS pain score and the anaesthesia used for the surgery, each eligible participant will be assigned to the appropriate stratum as listed above and then randomized in a sequential order within each stratum.
The site will receive a set of sealed blinding envelopes for each stratum. Each successive participant will be assigned a unique randomization number. Participants will be enrolled into the study until a minimum of 140 participants meeting the criteria for the mITT population are in the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization sequence will be generated prior to any enrolment by computer, by the study statistician. The sequence will include stratification for baseline pain and anaesthesia used for the surgery and will be arranged within permuted blocks. The statistician will maintain a confidential schedule of randomization numbers and drug allocation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Participants will be randomized in a 3:3:4:4 ratio (40 per group for placebo and the combination quarter dose and 30 per group for the combination half dose and full dose)
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
12/06/2011
Actual
1/09/2011
Date of last participant enrolment
Anticipated
Actual
4/10/2012
Date of last data collection
Anticipated
Actual
31/10/2012
Sample size
Target
140
Accrual to date
Final
159
Recruitment outside Australia
Country [1] 3382 0
New Zealand
State/province [1] 3382 0
Hamilton
Country [2] 6077 0
New Zealand
State/province [2] 6077 0
Christchurch

Funding & Sponsors
Funding source category [1] 264878 0
Commercial sector/Industry
Name [1] 264878 0
AFT Pharmaceuticals Ltd.
Country [1] 264878 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
AFT Pharmaceuticals Ltd.
Address
Level 1, 129 Hurstmere Road, Takapuna, Auckland, 0622, New Zealand
Country
New Zealand
Secondary sponsor category [1] 263978 0
None
Name [1] 263978 0
Address [1] 263978 0
Country [1] 263978 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 266834 0
Northern Y Regional Ethics Committee
Ethics committee address [1] 266834 0
Level 3, Bridgewater Building, 130 Grantham Street, Hamilton
Ethics committee country [1] 266834 0
New Zealand
Date submitted for ethics approval [1] 266834 0
12/04/2011
Approval date [1] 266834 0
14/06/2011
Ethics approval number [1] 266834 0
NTY /11/04/042

Summary
Brief summary
The test product Maxigesic (a combination of paracetamol 500 mg and ibuprofen 150 mg per tablet) has been on the market since Oct 2009 with Medsafe’s approval. The unit dose determined in each tablet is compliant with the maximum OTC dose for each ingredient as per New Zealand regulatory requirements. However, the side effects of each ingredient are dose related which means taking a higher dose may increase the chance of experiencing adverse effects. Recent regulatory reassessments of NSAIDs in some areas have encouraged treatment to be at the lowest effective dose and as short as possible because of the twin risks of GI bleeding and newly identified thromboembolic events. Therefore, it is important to determine the dose response relationship of this combination to allow more definitive dosing recommendations to be made and limit the risk of experiencing adverse effects.
The primary study hypothesis is the pain relief effects of these three different combination doses and placebo administered will form a dose response curve.
Trial website
Trial related presentations / publications
Combination paracetamol and ibuprofen for pain relief after oral
surgery: a dose ranging study
Atkinson HC, Currie J, Moodie J, Carson S, Evans S, Worthington JP, Steenberg LJ, Bisley E, Frampton C
Eur J Clin Pharmacol. 2015 May;71(5):579-87
Public notes

Contacts
Principal investigator
Name 32483 0
Dr John Currie
Address 32483 0
Waikato Clinical Research (2008) Ltd.
PO Box 12278, Chartwell Hamilton 3248, New Zealand
Country 32483 0
New Zealand
Phone 32483 0
+ 64 7 843 0105
Fax 32483 0
Email 32483 0
[email protected]
Contact person for public queries
Name 15730 0
Ms Jennifer Zhang
Address 15730 0
Level 1, 129 Hurstmere Road, PO Box 33-203, Takapuna, Auckland, 0622, New Zealand
Country 15730 0
New Zealand
Phone 15730 0
+ 64 9 488 0232 ext 710
Fax 15730 0
+ 64 9 488 0234
Email 15730 0
[email protected]
Contact person for scientific queries
Name 6658 0
Ms Jennifer Zhang
Address 6658 0
Level 1, 129 Hurstmere Road, PO Box 33-203, Takapuna, Auckland, 0622, New Zealand
Country 6658 0
New Zealand
Phone 6658 0
+ 64 9 488 0232 ext 710
Fax 6658 0
+ 64 9 488 0234
Email 6658 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Combination paracetamol and ibuprofen for pain rel... [More Details]
Plain language summaryNo All the doses (full dose, half dose and quarter do... [More Details]

Documents added automatically
No additional documents have been identified.