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Trial registered on ANZCTR


Registration number
ACTRN12613001151729
Ethics application status
Approved
Date submitted
14/10/2013
Date registered
15/10/2013
Date last updated
26/05/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase I Pharmacokinetic study evaluating the pharmacokinetic profile of a fixed dose combination product (1000 mg paracetamol + 300 mg ibuprofen) under fasting and fed conditions
Scientific title
Single-centre, single-dose, open label, randomized, four-way cross-over study evaluating the pharmacokinetics of a fixed dose combination product containing paracetamol plus ibuprofen in 28 healthy volunteers under fasting and fed conditions
Secondary ID [1] 283396 0
Nil
Universal Trial Number (UTN)
Trial acronym
AFT-MX-11
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pharmacokinetic study 290294 0
Condition category
Condition code
Other 290690 290690 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a Phase I, single-center, single-dose, open-label, randomized, four way cross-over trial in 28 healthy adult participants. After an initial Screening Period, within 14 days of randomization, there will be four Study Periods each separated by a Washout Period of 7 days and a subsequent 7 days of final Follow-up Period, after the completion of the 4 study periods


The main objectives of the study are:
- to evaluate the pharmacokinetic parameters (Cmax, AUCtot, Tmax and t1/2) of 1000 mg paracetamol and 300 mg ibuprofen, when taken alone, or when taken in combination as 2 tablets of under fasting conditions
and
- to describe the effect of food on the pharmacokinetic profile of the combination when taken as two tablets (paracetamol 1000 mg + ibuprofen 300 mg).

All study medications (paracetamol 1000 mg, ibuprofen 300 mg and their combination) will be administered orally.

Participants will be fasted for at least 10 hours overnight before dosing and for 4 hours post dosing. Participants will be provided with standard meals from 4 hours post dose.
Drug assays will be carried out using validated chromatographic methods developed specifically for the determination of paracetamol and ibuprofen.
Participants allocated to receive the treatment under fed conditions will receive 30 minutes before the administration of the study drug a standardised high-fat, high-calorie meal. No additional food will be allowed for at least 4 hours after dosing


Intervention code [1] 288120 0
Treatment: Drugs
Comparator / control treatment
The control arms are the 2 study periods when participants are administered one active components (i.e paracetamol 1000 mg or ibuprofen 300 mg ) during a study period
Control group
Active

Outcomes
Primary outcome [1] 290704 0
- To define the pharmacokinetic parameters of 1000 mg paracetamol and 300 mg ibuprofen each one alone, or in combination as 2 tablets including:Cmax, Tmax, T1/2, AUC(0-t), AUC(0-inf)
Timepoint [1] 290704 0
Single dose study measuring plasma concentrations over 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 6, 8, 10 and 12 hours after study drug administration
Primary outcome [2] 290712 0
To compare the AUC(0-t) and AUC(0-inf) and Cmax values following fed and fasting administration of 2 tablets of a fixed dose combination of paracetamol 1000 mg + 300 mg ibuprofen to provide an estimate of food effect
Timepoint [2] 290712 0
Single dose study measuring plasma concentrations over 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 6, 8, 10 and 12 hours after study drug administration
Secondary outcome [1] 305071 0
Safety will be evaluated during each study period, and for 7 days following study drug administration.
An acute safety evaluation will be performed during each study period by recording spontaneously reported adverse events and by clinical assessments, including measurements of blood pressure and heart rate.
At screening and at the end of each study period an additional blood sample will be taken for haematology and biochemistry assessment.
Known NSAID adverse effects (i.e. GI ulceration, indigestion/stomach pain, GI bleeding, bronchospasm, water retention, renal failure, skin reactions and thromboembolic events), and known paracetamol adverse effects (i.e. clinical evidence of hepatotoxicity) will be compared between groups.
Adverse events will continue to be assessed up to 7 days after the last dose of the study medication by spontaneous reporting and at a final follow-up phone call.
Timepoint [1] 305071 0
Safety will be evaluated at screening and at the end of each study period and for 7 days following the last dose of the study drug administration.

Eligibility
Key inclusion criteria
Healthy volunteers.
Participants must not have taken any prescription medications for at least 14 days or over-the-counter medications for at least 7 days before the start of each study phase, with the exception of oral contraceptives and the study medication.
Minimum age
18 Years
Maximum age
40 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Pregnancy, nursing, drug abuse, smoking > 10 cigarettes per day, excess alcohol intake, Rx drugs within 14 days of the study, participating in another trial within 80 days, clinically significant abnormal lab tests, have any history of allergy or hypersensitivity to ibuprofen, aspirin, paracetamol or other NSAID

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis
The pharmacokinetic parameters Cmax, AUC (0-t), AUC (0-8), Tmax and t1/2 will be derived from the plasma concentration vs. time data using non-compartmental methods. Plasma concentrations for each dose at each time and the pharmacokinetic parameters will be summarised using standard descriptive statistics, including means, medians, geometric means, ranges, inter-quartile ranges, standard deviations and standard errors.

The bioavailability of the fed vs. fasted pharmacokinetic parameters Cmax, AUC(0-t) and AUC(0-8) will be determined from the 90% confidence intervals for the ratios of the parameters calculated using the residual variance from an ANOVA of loge transformed values using Kinetica program. These differences and CIs will be transformed back to original scale to provide an estimate of the relative bioavailability under fed state.
The ANOVA model will include terms for participant, period and formulation.
Bioavailability for the fed vs. fasted estimates will be calculated using only those participants who complete both relevant periods of the study for each comparison.
The additional pharmacokinetic parameter t1/2 will be summarized as means with 90% confidence intervals and compared between the different treatment groupsdoses using ANOVA as described above. Tmax will be summarized as medians with inter-quartile ranges and compared between formulations using Wilcoxon signed rank tests.
Safety data will be summarized for each formulation using frequencies and percentages (% of participants with each specific AE).
The haematology and biochemistry data collected pre-study and after each period will be summarized descriptively using means, medians, standard deviations, ranges and frequencies and percentages as appropriate. Individual values outside normal ranges and considered clinically significant will be individually listed. Comparisons of the haematology and biochemistry measures associated with each formulation maybe compared between formulations by ANOVA test using Systat program.

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] 5497 0
Jordan
State/province [1] 5497 0
Amman

Funding & Sponsors
Funding source category [1] 288117 0
Commercial sector/Industry
Name [1] 288117 0
AFT Pharmaceuticals Ltd
Address [1] 288117 0
Level 1, 129 Hurstmere Rd, Takapuna, Auckland 0622
Country [1] 288117 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
AFT Pharmaceuticals Ltd
Address
Level 1, 129 Hurstmere Rd, Takapuna, Auckland 0622
Country
New Zealand
Secondary sponsor category [1] 286838 0
None
Name [1] 286838 0
Address [1] 286838 0
Country [1] 286838 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290040 0
IPRC Institutional Review Board
Ethics committee address [1] 290040 0
172 Queen Rania St
PO Box 963166
Amman 11942
Ethics committee country [1] 290040 0
Jordan
Date submitted for ethics approval [1] 290040 0
28/10/2013
Approval date [1] 290040 0
26/11/2013
Ethics approval number [1] 290040 0

Summary
Brief summary
To determine the pharmacokinetic parameters of a fixed dose combination of 1000 mg paracetamol and 300 mg ibuprofen and compare the pharmacokinetic (PK) parameters following fed and fasting administration to provide an estimate of food effect
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 43654 0
Prof Naji Najib
Address 43654 0
International Pharmaceutical Research Center Queen Rania St - Sport City Circle PO Box 963166 Amman 11196
Country 43654 0
Jordan
Phone 43654 0
+962562764/51
Fax 43654 0
Email 43654 0
iprc@iprc.com.jo
Contact person for public queries
Name 43655 0
Dr Hartley Atkinson
Address 43655 0
AFT Pharmaceuticals Ltd, Level 1, 129 Hurstmere Rd, Takapuna, Auckland 0622
Country 43655 0
New Zealand
Phone 43655 0
+6494880232
Fax 43655 0
Email 43655 0
hartley@aftpharm.com
Contact person for scientific queries
Name 43656 0
Dr Hartley Atkinson
Address 43656 0
AFT Pharmaceuticals Ltd, Level 1, 129 Hurstmere Rd, Takapuna, Auckland 0622
Country 43656 0
New Zealand
Phone 43656 0
+6494880232
Fax 43656 0
Email 43656 0
hartley@aftpharm.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary