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Trial registered on ANZCTR


Registration number
ACTRN12611000952943
Ethics application status
Approved
Date submitted
5/09/2011
Date registered
5/09/2011
Date last updated
20/12/2018
Date data sharing statement initially provided
20/12/2018
Date results information initially provided
20/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study comparing the effects of a combination of paracetamol and ibuprofen with paracetamol alone or ibuprofen alone or placebo
Scientific title
Maxi-Analgesic Arthroscopy Study: A double-blind, placebo-controlled, randomised, parallel group comparison of the effects of Maxigesic (paracetamol 1000mg + ibuprofen 300mg per dose) versus its individual components in participants with moderate to severe pain from post arthrsocopy surgery of the knee.
Secondary ID [1] 262987 0
AFT-MX-6E
Universal Trial Number (UTN)
Trial acronym
Maxi-Analgesic Arthroscopy Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-operative pain from arthroscopy surgery of the knee 270713 0
Condition category
Condition code
Anaesthesiology 270889 270889 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A combination of Paracetamol 500mg + Ibuprofen 150mg per tablet, 2 tablets orally every 6 hours for 24 hours.
Intervention code [1] 269329 0
Treatment: Drugs
Comparator / control treatment
There will be 3 control groups as listed below:
Paracetamol 500mg per tablet, two tablets orally every 6 hours for 24 hours
Ibuprofen 150 mg per tablet, two tablets orally evey 6 hours for 24 hours
Placebo (lactose tablets with identical taste and apprearance), two tablets orally every 6 hours for 24 hours
Control group
Placebo

Outcomes
Primary outcome [1] 279567 0
To compare the time-adusted SPIDs (Summed Pain Intensity Differences from baseline) of the VAS pain intensity scores up o 24 hours after the first dose of study medication among the 4 study groups to determine whether the combination is superior to the individual components and placebo
Timepoint [1] 279567 0
VAS pain scores will be collected from participants at the following time points:
Baseline (within 6 hours following completion of surgery)
During the hospital stay, VAS pain scores will be assessed at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, then 2, 3, 4, 5 and 6 hours after the first dose of study medication.
After discharge from hospital, VAS pain intensity scores will be assessed immediately before taking each dose and 2 hours after taking each dose while the subject is awake. In the event that subjects need to be woken for some doses during the night, the VAS pain intensity scores will be recorded immediately before each dose. To facilitate the subjects' compliance to the VAS pain score assessments at these scheduled time points, doses will be given with food approximately at breakfast, lunch, dinner and just before bedtime. It is anticipated that due to sleeping patterns the dose intervals will not be exactly the same during the day which is acceptable within this study design and mirrors the real world clinical situation.
If subjects need extra pain relief, the last VAS pain intensity score will be assessed immediately before taking the rescue medication.
At each time point, VAS pain intensity assessment will be done at rest.
Secondary outcome [1] 287908 0
To compare the time to onset of analgesia defined as time to perceptible pain relief and confirmed by meaningful pain relief among the four study groups using the two stop watch method.
Timepoint [1] 287908 0
Starts immediately after the first dose of study medication using two stopwatch method.
Secondary outcome [2] 287909 0
To compare the maximum VAS pain intensity scores up to 24 hours after the first dose of study medication among the four study groups.
Timepoint [2] 287909 0
VAS pain scores will be collected from participants at the following time points:
Baseline (within 6 hours following completion of surgery)
During the hospital stay, VAS pain scores will be assessed at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, then 2, 3, 4, 5 and 6 hours after the first dose of study medication.
After discharge from hospital, VAS pain intensity scores will be assessed immediately before taking each dose and 2 hours after taking each dose while the subject is awake. In the event that subjects need to be woken for some doses during the night, the VAS pain intensity scores will be recorded immediately before each dose. To facilitate the subjects' compliance to the VAS pain score assessments at these scheduled time points, doses will be given with food approximately at breakfast, lunch, dinner and just before bedtime. It is anticipated that due to sleeping patterns the dose intervals will not be exactly the same during the day which is acceptable within this study design and mirrors the real world clinical situation.
If subjects need extra pain relief, the last VAS pain intensity score will be assessed immediately before taking the rescue medication.
At each time point, VAS pain intensity assessment will be done at rest.
Secondary outcome [3] 287910 0
To compare the response rate (response rate defined as the percentage of participants who achieve at lease a 50% reduction in baseline within 6 hours i.e. the first doe period) among the four study groups.
Timepoint [3] 287910 0
VAS pain scores will be collected from participants at the following time points:
Baseline (within 6 hours following completion of surgery)
During the hospital stay, VAS pain scores will be assessed at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, then 2, 3, 4, 5 and 6 hours after the first dose of study medication.
After discharge from hospital, VAS pain intensity scores will be assessed immediately before taking each dose and 2 hours after taking each dose while the subject is awake. In the event that subjects need to be woken for some doses during the night, the VAS pain intensity scores will be recorded immediately before each dose. To facilitate the subjects' compliance to the VAS pain score assessments at these scheduled time points, doses will be given with food approximately at breakfast, lunch, dinner and just before bedtime. It is anticipated that due to sleeping patterns the dose intervals will not be exactly the same during the day which is acceptable within this study design and mirrors the real world clinical situation.
If subjects need extra pain relief, the last VAS pain intensity score will be assessed immediately before taking the rescue medication.
At each time point, VAS pain intensity assessment will be done at rest.
Secondary outcome [4] 287911 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 study groups.
Timepoint [4] 287911 0
VAS pain scores will be collected from participants at the following time points:
Baseline (within 6 hours following completion of surgery)
During the hospital stay, VAS pain scores will be assessed at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, then 2, 3, 4, 5 and 6 hours after the first dose of study medication.
After discharge from hospital, VAS pain intensity scores will be assessed immediately before taking each dose and 2 hours after taking each dose while the subject is awake. In the event that subjects need to be woken for some doses during the night, the VAS pain intensity scores will be recorded immediately before each dose. To facilitate the subjects' compliance to the VAS pain score assessments at these scheduled time points, doses will be given with food approximately at breakfast, lunch, dinner and just before bedtime. It is anticipated that due to sleeping patterns the dose intervals will not be exactly the same during the day which is acceptable within this study design and mirrors the real world clinical situation.
If subjects need extra pain relief, the last VAS pain intensity score will be assessed immediately before taking the rescue medication.
At each time point, VAS pain intensity assessment will be done at rest.
Secondary outcome [5] 287912 0
To compare the time to requirement of resuce medication among the four study groups.
Timepoint [5] 287912 0
Until the 24 hours after the first dose of study medication
Secondary outcome [6] 287913 0
To compare the amount of rescue medication used (defined as the number of tablets) among the four study groups over the 24-hour treatment period.
Timepoint [6] 287913 0
Until the 24 hours after the first dose of study medication
Secondary outcome [7] 287914 0
To compare the percentage of participant requiring rescue medication among the four study groups.
Timepoint [7] 287914 0
Until the 24 hours after the first dose of study medication
Secondary outcome [8] 287915 0
To compare the categorical global pain relief rating among the four study groups.
Timepoint [8] 287915 0
At the end of 24 hours after the first dose of study medication or immediately before taking the resuce medication where applicable (when resuce medication is required).

Eligibility
Key inclusion criteria
1)Provide written informed consent before initiation of any study-related procedures (including the willingness of staying at the hospital up to 6 hours after the surgery).
2)Males and females aged at least 16 years and not more than 80 years old on the day of consent.
3)Undergoing arthroscopy for removal of meniscus around the knee under standardized general anaesthesia (see section 5.7).
4)A resting VAS pain intensity score at baseline (within 6 hours following completion of surgery) of = 40mm on a 100mm VAS scale with 0 = no pain and 100 = worst pain imaginable.
Minimum age
16 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 anaesthetics within 24 hours prior to surgery
3)Hypersensitivity to oxycodone
4)Administration of any intra-articular drug during the surgery including morphine, bupivacain, lidocaine or tramadol etc.
5)Known hypersensitivity to oxycodone
6)Known history of drug or alcohol abuse
7)Known to be pregnant or possibly pregnant.
8)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.
9)Women of childbearing potential who are unwilling to undergo a urine pregnancy test
10)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.
11)In the opinion of the investigator, unable to understand the visual analogue pain score or comply with the protocol requirements.
12)Currently or in the last 30 days, has been in a clinical trial involving another study drug.
13)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.
14)Participant weight < 50kg or > 120 Kg.
15)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
16)Hypersensitivity to aspirin or other NSAID.
17)Hypersensitivity to paracetamol.
18)Severe known haemopoetic, renal or hepatic disease, or immunosuppressed.
19)History of gastric ulceration and bleeding 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.).
20)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)
Randomisation will occur at the study site, once participant eligibility for the study is confirmed post-operatively. The randomisation will be stratified based on baseline VAS pain intensity score measured at rest (moderate pain [VAS 40-69 mm] and severe pain [VAS greater than or equal to 70mm])
Randomisation number for each participant consists of a-two digits stratum number (i.e. 01 and 02) and a-three digits participant number (e.g. 01_012, 01_013 etc.) According to the baseline VAS pain score, each eligible participant will be assigned to the appropriate stratum and then randomised in a sequential order in each stratum.
The site will receive a set of sealed blinding envelopes for each stratum. Each successive participant will be assigned a unique randomisation number. Participants will be enrolled into the study until a minimum of 220 participants meeting the criteria for the ITT population are in the study.
The randomisation sequence will be generated prior to any enrolment by computer, by the study statistician. The sequence will include stratification for baseline pain. The statistician will maintain a confidential schedule of participant numbers and drug allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be generated prior to any enrolment by computer, by the study statistician. The sequence will include stratification for baseline pain. The statistician will maintain a confidential schedule of participant 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 1:1:1:1 ratio (73 per group)
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 3825 0
New Zealand
State/province [1] 3825 0
Hamilton
Country [2] 5151 0
New Zealand
State/province [2] 5151 0
Christchurch

Funding & Sponsors
Funding source category [1] 269797 0
Commercial sector/Industry
Name [1] 269797 0
AFT Pharmaceuticals Ltd.
Address [1] 269797 0
Level 1, 129 Hurstmere Road, Takapuna, Auckland, 0622, New Zealand.
Country [1] 269797 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] 268830 0
None
Name [1] 268830 0
Address [1] 268830 0
Country [1] 268830 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 271749 0
Northern Y Regional Ethics Committee
Ethics committee address [1] 271749 0
Level 3, Bridgewater Building,
130 Grantham Street,
Hamilton 3204
Ethics committee country [1] 271749 0
New Zealand
Date submitted for ethics approval [1] 271749 0
23/08/2011
Approval date [1] 271749 0
05/10/2011
Ethics approval number [1] 271749 0
NTY/11/08/088

Summary
Brief summary
A Phase 3 study in dental pain has demonstrated efficacy for the fixed-dose combination compared with the individual components(Merry et al. 2010). However an additional model of acute pain is required to demonstrate consistent efficacy in acute pain as per EMEA guidelines required (EMEA/CPMP/EWP/612/00 21 November, 2002).
The fixed dose combination has already been approved in New Zealand and is on the market for OTC use. Periodic Safety Update data from the NZ market and also the open –label phase of the Phase II Osteoarthritis study 12 month continuation phase data are available.
Trial website
Trial related presentations / publications
No publications available yet
Public notes

Contacts
Principal investigator
Name 33116 0
Dr John Moodie
Address 33116 0
Waikato Clinical Research (2008)Ltd.
PO Box 12278, Chartwell, Hamilton 3248
Country 33116 0
New Zealand
Phone 33116 0
+ 64 7 843 0105
Fax 33116 0
Email 33116 0
jmoodie@waikatoclinicalresearch.com
Contact person for public queries
Name 16363 0
Ms Jennifer Zhang
Address 16363 0
Level 1, 129 Hurstmere Road, PO Box 33-203, Takapuna, Auckland, 0622, New Zealand
Country 16363 0
New Zealand
Phone 16363 0
+ 64 9 488 0232
Fax 16363 0
+ 64 9 488 0234
Email 16363 0
jenniferz@aftpharm.com
Contact person for scientific queries
Name 7291 0
Ms Jennifer Zhang
Address 7291 0
Level 1, 129 Hurstmere Road, PO Box 33-203, Takapuna, Auckland, 0622, New Zealand
Country 7291 0
New Zealand
Phone 7291 0
+ 64 9 488 0232
Fax 7291 0
Email 7291 0
+ 64 9 488 0234

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 other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary
This study confirmed that Maxigesic Tablets (acetaminophen 500mg + ibuprofen 150mg) provides superior pain relief than placebo in adults for post-operative pain relief. Maxigesic tablets was safe and well tolerated and did not result in a higher risk of experiencing side effects comparing to placebo.