Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12610000598088
Ethics application status
Not yet submitted
Date submitted
22/07/2010
Date registered
23/07/2010
Date last updated
6/10/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Tolerability study of Maxigesic in patients with Mild to Severe Pain
Scientific title
Maxi-Analgesic Tolerability Study:
Open-Label, Phase IV, Multi-Centre Clinical Trial to Evaluate the Safety and Tolerability of Maxigesic in Patients with Mild to Severe
Pain.
Secondary ID [1] 252265 0
AFT-MX-5

AFT Pharmaceuticals Ltd
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Pain 257781 0
Chronic Pain 257782 0
Condition category
Condition code
Anaesthesiology 257954 257954 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Interventions:
The combination of paracetamol and ibuprofen (paracetamol 500 mg + ibuprofen 150 mg per tablet)

Treatment Period:
Acute Pain Treatment group: 2 tablets every 6 hours for a minimum of 48 hours to 14 days
Chronic Pain Treatment group:
Fixed dosing group: 2 tablets every 6 hours between 15 days and 3 months
Flexible dosing group: 1-2 tablets every 4 or 6 hours up to a maximum of 8 tablets per day between 15 days and 3 months
Intervention code [1] 256851 0
Treatment: Drugs
Comparator / control treatment
All participants received Maxigesic. No comparators will be used in the study.

Safety data observed in the current study will be compared with previously published safety data of paracetamol alone or ibuprofen alone

The dose response relationship between the number of tablets taken and the pain intensity will be compared in the flexible dosing group with the fixed dosing group.
Control group
Dose comparison

Outcomes
Primary outcome [1] 258824 0
To compare the safety profile of the combination of paracetamol and ibuprofen with the estabilished safety profile of paracetamol and ibuprofen when administered alone.

The incidence of known Non-steriod Anti-inflammatory Drugs (NSAID) and paracetamol side effects will be specifically evaluated (gastrointestinal side effects such as stomach pain/ulceration and bleeding; and effects on liver such as clinical hepatotoxicity).

All adverse events reported in the patient diary and from the site visit notes recorded by investigators will be collected and assessed at the end of the study. The rate oberseved in the study will be grouped using Medical Dictionary for Regulatory Activities (MedDRA) categories and compared with published data for combination therapies (NSAID + paracetamol) and individual therapies.
Timepoint [1] 258824 0
Acute pain group: from 48 hours to 14 days following administration of the first study drug. Data will be collected at 21-28 days after the last dose of study drug.
Chronic pain group: from 15 days to 3 months following administration of the first study drug. Data will be collected at 21-28 days after the last dose of study drug
Secondary outcome [1] 264923 0
The tolerability of the combination of paracetamol and ibuprofen will be evaluated by assessing the number of participants who stop taking the study drug due to side effects.

Data will be recorded on the patient diary and site visit notes.
Timepoint [1] 264923 0
Acute pain group: from 48 hours to 14 days following administration of the first dose of study drug. Data will be collected after the last dose of study drug.
Chronic pain group: from 15 days to 3 months following administration of the first dose of study drug. Data will be collected after the last dose of study drug.
Secondary outcome [2] 264924 0
The number of participants who stop taking study drug due to a lack of efficacy will be counted in the chronic pain treatment group to evaluate the proportion of patients achieving adequate pain relief.

Data will be recorded on the patient diary and site visit notes.
Timepoint [2] 264924 0
Chronic pain group only: from 15 days to 3 months following administration of the first dose of study drug. Data will be collected after the last dose of study drug.
Secondary outcome [3] 264925 0
The relationship between the number of tablets taken and the visual analogue scale (VAS) pain intensity score among those with chronic pain allocated to the flexibel dosing group will be evaluated.

The number of tablets taken and the VAS pain score will be recorded on the patient diary daily. The Pain VAS is to be completed in the participant?s diary immediately prior to a dose of Maxigesic and should be completed at the same time each day. Participants in the Chronic Pain Treatment Group are required to complete the Pain VAS every day until completion of treatment.
Timepoint [3] 264925 0
Chronic pain group only: from 15 days to 3 months following administration of the first study drug. Data will be collected after the last dose of study drug.
Secondary outcome [4] 264926 0
The pain level over the duration of the study will be evaluated by daily single measurements of 24 hour pain level using a visual analogue scale (VAS).

The Pain VAS is to be completed in the participant?s diary immediately prior to a dose of Maxigesic and should be completed at the same time each day. Participants in the Acute Pain Treatment Group complete the Pain VAS every 24 hours after their first dose of Maxigesic until they no longer require treatment. Participants in the Chronic Pain Treatment Group also complete the Pain VAS every day until completion of treatment.
Timepoint [4] 264926 0
Acute pain group: from 48 hours to 14 days following administration of the first study drug. VAS pain score will be assessed daily on the patient diary and data will be collected after the last dose of study drug.
Chronic pain group: from 15 days to 3 months following administration of the first study drug. VAS pain score will be assessed daily on the patient diary and data will be collected after the last dose of study drug.
Secondary outcome [5] 264927 0
The calculated pharmacokinetic parameters from a subset of patients with acute pain (N=25-30) will be compared with published population pharmacokinetic parameters.

Approximately three blood samples will be requested from study participants who are using Maxigesic for the relief of post-operative pain (i.e. in the acute pain treatment group). It is intended that the samples are obtained at a range of times across the dosing interval of six hours and the actual times of dosing and blood sample collection will be recorded so that the pharmacokinetic modelling can be conducted. Population estimates of pharmacokinetic parameters (volume of distribution, absorption rate half-time and clearance) obtained using non-linear mixed effects modelling will be compared with published population pharmacokinetic parameters. It is expected that approximately 25-30 study participants requiring post-operative pain relief will provide blood samples for this analysis.
Timepoint [5] 264927 0
Acute pain group only: approximately 3 blood samples will be taken at various time during the dosing intervals of 6 hours.

Eligibility
Key inclusion criteria
Provide written informed consent before initiation of any study-related procedures
Be aged at least 18 years and not more than 80 years old on the day of consent
Require treatment of mild to severe pain due to either acute or chronic pain
Acute pain includes: Dental pain including tooth/teeth extraction; Post-operative pain after minor surgery e.g. cutaneous surgery, hernia; Post-operative pain after moderate surgery e.g. orthopaedic surgery, abdominal surgery, episiotomy; Muscle and ligament sprain; Skeletal trauma;Dysmenorrhoea

Chronic pain includes: Osteoarthritis;Rheumatoid arthritis; Low back pain
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Has taken any NSAID or paracetamol within 12 hours prior to study initiation other than aspirin less than or equal to 150mg/day for prevention of cardiovascular disease.
Has taken another analgesic other than paracetamol or an NSAID within 3 days prior to study initiation.
Known to be pregnant or possibly pregnant.
Has been in a clinical trial involving another study drug in last 30 days prior to baseline.
Currently treated with an angiotensin-converting enzyme (ACE) inhibitor, warfarin, steroid (other than dexamethasone intra-operatively), cyclosporin, tacrolimus or methotrexate.
Patient weight < 50kg at baseline.
Is suffering from any other disease or condition which, in the opinion of the investigator, means that it would not be in the patient’s best interest to participate in this study.
Has any of the following NSAID and/or paracetamol contra-indications:
Hypersensitivity to aspirin or other NSAID
Hypersensitivity to paracetamol
Severe known haemopoetic, renal or hepatic disease, immunosuppressant
History of gastric ulceration, indigestion, stomach pain or bleeding
Currently suffering from dehydration through diarrhoea and/or vomiting
History of severe asthma defined as previous steroid treatment or hospital admission

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)
Participants will be allocated to acute pain treatment group or chronic pain treatment group depending on their disease conditions whether acute pain or chronic pain treatment is required. Investigators will decide whether a patient shall be allocated to an acute pain treatment group or a chronic pain treatment group. Participants' study number for acute pain treatment group and chronic pain treatment group will be generated separately.


In the chronic pain treatment group, participants will be randomized into either fixed dosing group (2 tablets every 6 hours) or flexible dosing group (1-2 tablets every 4-6 hours up to a maximum of 8 tablets per day). A set of sealed opaque envelopes will be used for the randomization allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
For the chronic pain treatment group, the randomization code will be generated by an independent statistician through computer.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Not applicable
Phase
Phase 4
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
The study was withdrawn due to administrative reason
Date of first participant enrolment
Anticipated
1/10/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
600
Accrual to date
Final
Recruitment outside Australia
Country [1] 2774 0
New Zealand
State/province [1] 2774 0

Funding & Sponsors
Funding source category [1] 257311 0
Commercial sector/Industry
Name [1] 257311 0
AFT Pharmaceuticals Ltd
Country [1] 257311 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
AFT Pharmaceuticals Ltd
Address
Level 2, 9 Anzac Street, Takapuna, Auckland, 0622
Country
New Zealand
Secondary sponsor category [1] 256556 0
None
Name [1] 256556 0
Address [1] 256556 0
Country [1] 256556 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 259338 0
Northern X Regional Ethics Committee
Ethics committee address [1] 259338 0
3rd Floor, Unisys Building, 650 Great South Road, Penrose, Auckland, 1061
Ethics committee country [1] 259338 0
New Zealand
Date submitted for ethics approval [1] 259338 0
11/08/2010
Approval date [1] 259338 0
Ethics approval number [1] 259338 0

Summary
Brief summary
Both paracetamol and ibuprofen are relatively safe when administered at over the counter (OTC) dose and their safety profile has been well-estabilished for many years.

A combination of paracetamol and ibuprofen has been proved to be more effective than each individual component in a phase 3 clinical trial in an acute pain model (ACTRN:12606000291583). However, the safety observation in the same trial is only for 48 hours. In many clinical circumstances, the pain relief period is required to be up to 14 days such as post-operative pain relief for some moderate surgery.

At the same time, it is proposed to observe the safety profile for long term use (up to 3 months) in patients with chronic pain.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31416 0
Dr Hartley Atkinson
Address 31416 0
Level 1, 129 Hurstmere Road, Takapuna, Auckland
Country 31416 0
New Zealand
Phone 31416 0
+ 64 9 488 0232
Fax 31416 0
Email 31416 0
[email protected]
Contact person for public queries
Name 14663 0
Dr Hartley Atkinson
Address 14663 0
Level 2, 9 Anzac Street, Takapuna, Auckland, 0622
Country 14663 0
New Zealand
Phone 14663 0
+ 64 9 488 0232
Fax 14663 0
Email 14663 0
[email protected]
Contact person for scientific queries
Name 5591 0
Ms Jennifer Zhang
Address 5591 0
Level 2, 9 Anzac Street, Takapuna, Auckland, 0622
Country 5591 0
New Zealand
Phone 5591 0
+ 64 9 488 0232
Fax 5591 0
Email 5591 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.