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Trial registered on ANZCTR


Registration number
ACTRN12618001465246
Ethics application status
Approved
Date submitted
21/08/2018
Date registered
31/08/2018
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
Retrospectively registered

Titles & IDs
Public title
A study to compare the bio-equivalence between single dose of ibuprofen tablet versus a combination of acetaminophen and ibuprofen.
Scientific title
Bioequivalence study of single dose of Ibuprofen Tablets 97.5 mg manufactured by Macleods Pharmaceuticals Ltd., India in comparison with fixed dose combination of Acetaminophen and
Ibuprofen Tablets 325 mg + 97.5 mg manufactured by Macleods Pharmaceuticals Ltd., India in healthy adult human subjects under fasting condition.
Secondary ID [1] 295852 0
AFT-MX-9
Universal Trial Number (UTN)
U1111-1219-1897
Trial acronym
Not applicable
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Pain Relief 309312 0
Condition category
Condition code
Anaesthesiology 308181 308181 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ibuprofen tablets 97.5mg (BN: BIC201A, Exp: Jun 2014)
Single Dose: Oral administration of one tablet with 240mL of water under fasting condition (fasted for at least 10 hours prior to administration of the study drug).
The product was administrated under the site staff's supervision with mouth check.
There was a washout period of at least 7 days from the completion of dosing between two periods.
Intervention code [1] 312192 0
Treatment: Drugs
Comparator / control treatment
Acetaminophen and ibuprofen tablets (325mg + 97.5mg) (BN: BAD 1201A, Exp: Jan 2014)
Single Dose: Oral administration of one tablet with 240mL of water under fasting condition (fasted for at least 10 hours prior to administration of the study drug).
The product was administrated under the site staff's supervision with mouth check.
There was a washout period of at least 7 days from the completion of dosing between two periods.
Control group
Active

Outcomes
Primary outcome [1] 307147 0
To evaluate the bio-equivalence of single dose of ibuprofen tablets 97.5mg with Acetaminophen and ibuprofen tablets 325mg + 97.5mg manufactured by Macleods Pharmaceuticals Ltd. in healthy adults under fasting condition.
The following PK parameters are the primary efficacy measurements:
Cmax : Maximum measured plasma concentration following each treatment.
AUCo_t : The area under the plasma concentration versus time curve from time zero to the last measurable concentration, as calculated by the linear trapezoidal method.
AUCo-inf: The area under the plasma concentration versus time curve, from zero to infinity
Timepoint [1] 307147 0
Blood samples were collected pre-dose and at 0.08,0.17,0.33,0.50,0.67,0.83,1.00,1.17,1.33, 1.50, 1.67, 1.83,2.00,2.25,2.50,2.75, 3.00, 3.33, 3.67,4.00,4.50, 5.00,6.00,8.00, 10.00 and 12.00 hours post dose.
Secondary outcome [1] 350902 0
The following PK parameters are the secondary efficacy measurements:
T max : Time of maximum measured plasma concentration. If maximum value occurs at more than one point, T max is defined as the first point with this value in each period.
Kel : Apparent first order elimination or terminal rate constant calculated from semi log plot of the plasma concentration versus time curve. The parameters were calculated by linear least square regression analysis using at least the last three non-zero plasma concentration.
T1/2 : Time required for the plasma drug concentration to decrease to one half.
npoints: No. of time points of the terminal log-linear phase used to estimate the terminal
disposition rate constant (Ke) with best fit regression method used.
Ke first : First time point of the terminal log-linear phase used to estimate the terminal disposition rate constant (Ke) with best fit regression method used
Ke_last: Last time point of the terminal log-linear phase used to estimate the terminal disposition rate constant (Ke) with best fit regression method used.
Timepoint [1] 350902 0
Blood samples were collected pre-dose and at 0.08,0.17,0.33,0.50,0.67,0.83,1.00,1.17,1.33, 1.50, 1.67, 1.83,2.00,2.25,2.50,2.75, 3.00, 3.33, 3.67,4.00,4.50, 5.00,6.00,8.00, 10.00 and 12.00 hours post dose.
Secondary outcome [2] 351025 0
To evaluate the safety and tolerability between the test product and reference product.
Timepoint [2] 351025 0
Safety was evaluated by monitoring clinical adverse events during study periods. Vital signs (Blood Pressure, Temperature and Pulse Rate) and subject questionnaire was done at the time of check-in, pre-dose and at 1.00, 3.00, 6.00, 9.00 and 12.00 hours post-dose (Time points being relative to the investigational product dosing).

Eligibility
Key inclusion criteria
Healthy volunteers within the age range of 18 to 45 years
Presently non-tobacco users (smokers and chewers)
Willingness to provide written informed consent to participate in the study
Body-mass index (BMI) between 18.50 kg/m2 and 29.99 kg/m2 (both inclusive) with body weight not less than 50 kg (for males) and with body weight not less than 45 kg (for females)
Absence of significant disease or clinically significant abnormal laboratory values or laboratory evaluation, medical history or physical examination during the screening.
Have a normal 12-lead ECG or one with abnormality considered to be clinically insignificant.
Have a normal chest X-ray PA view or one with abnormality considered to be clinically insignificant.
Comprehension of the nature and purpose of the study and compliance with the requirement of the distributed ICF
Volunteer is regularly menstruating or Volunteer is in postmenopausal phase for at least 1 year or is surgically sterile (for females).
Volunteer of child bearing potential practicing an acceptable method of birth control for the duration of the study as judged by the investigator(s) such as condoms, foams, jellies, diaphragm, and intrauterine device (IUD) or abstinence etc. except hormonal contraceptives (for females).
Minimum age
18 Years
Maximum age
45 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Personal history of allergy or hypersensitivity to Ibuprofen or Acetominophen or allied drugs
Any major illness in the past 90 days or any clinically significant ongoing chronic medical illness e.g. Congestive Cardiac Failure (Heart failure), Hepatitis, Hypotensive episodes, Hyperglycemia etc.
Presence of any clinically significant abnormal laboratory values during screening e.g. Significant abnormality of liver function test, renal (kidney) function test etc
Severe cardiac, renal or liver impairment, gastro-intestinal disease or other conditions, any other organ or system impairment.
History of seizures, epilepsy or any kind of Neurological disorders
Past history of Anaphylaxis or Angioedema
Presence of disease markers of HIV or Hepatitis B or Hepatitis C virus.
History of chronic consumption of any kind of alcoholic beverages for more than 2 years or having consumed alcohol within 48 hours prior to dosing.
Consumption of products containing xanthine derivatives (chocolates, tea, coffee or cola drinks) or tobacco products within 48 hours prior to dosing.
Consumption of grapefruit or grapefruit containing products or any cruciferous vegetables (eg. broccoli, brussels sprouts, etc.) or char-broiled meat prior 7 days of investigational product administration.
Use of any recreational drug or a history of drug addiction
Participation in any clinical trial within the past 90 days.
History of difficulty with donating blood or difficulty in accessibility of veins in left or right arm
Donation of blood (one unit or 350 mL) within 90 days prior to receiving the first dose of study medication
Consumption of any other prescription drug or over the counter (OTC) drugs (including vitamins and medicinal products from natural origin) within two weeks prior to receiving the
first dose of study medication or repeated use of drugs within the last four weeks.
An unusual diet for whatever reason e.g. low sodium diet, for two weeks prior to receiving any medication and throughout subject's participation in the study
Recent history of dehydration from diarrhoea, vomiting or any other reason within a period of 48 hours prior to the study.
Known hypersensitivity to heparin
Use of oral contraceptive in last 90 days (for females)
Pregnant or Iactating volunteers (for females)

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using a randomization table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Not applicable
Phase
Phase 1
Type of endpoint(s)
Bio-equivalence
Statistical methods / analysis
PK analysis:
Primary parameters: Cmax. AUC0-1 and AUCo_inf
Secondary parameters: T1I2. Ke, Tmax. npoints, Ke_first and Ke_last.
For estimation of PK parameters, concentrations that were below level of quantification (BLQ) were assigned a value of zero if they preceded quantifiable samples in the initial portion of the profile. A BlQ that occurred at the end of the profile will be set to zero. A BlQ or zero concentration that is embedded between two quantifiable points will be assigned a value of missing. If consecutive BlQs in the terminal portion of the profile are followed by quantifiable determinations, these quantified values were excluded from PK analysis by assigning them a value of missing. In the calculations of PK parameters, missing values were ignored. Plasma concentrations used to determine PK parameters were listed.
The log-transformed pharmacokinetic parameters (Cmax. AUCo_t and AUCo_inf,) of Ibuprofen were analysed using an ANOVA model. Calculated 90% confidence interval for the ratio of both the products averages (geometric means) of Cmax, AUCo_t and AUCo_oo ' Ratios of mean AUCO-t to mean AUCo_.inf for test and reference are expressed in percentage and power test is performed using SAS® version 9.2.
The calculations of the individual pharmacokinetic parameters were carried out as follows:
Cmax : Maximum measured plasma concentration following each treatment
AUCo_t : The area under the plasma concentration versus time curve from time zero to the last measurable concentration, as calculated by the linear trapezoidal method.
AUCo-inf: The area under the plasma concentration versus time curve, from zero to infinity. it was calculated as the sum of the AUC0-t plus the ratio of the last measurable concentration to the elimination rate constant.
T max : Time of maximum measured plasma concentration. If maximum value occurs at more than one point, T max is defined as the first point with this value in each period.
Kel : Apparent first order elimination or terminal rate constant calculated from semi log plot of the plasma concentration versus time curve. The parameters were calculated by linear least square regression analysis using at least the last three non-zero plasma oncentration.
T1/2 : Time required for the plasma drug concentration to decrease to one half.
npoints: No. of time points of the terminal log-linear phase used to estimate the terminal disposition rate constant (Ke) with bestfit regression method used.
Ke)irst : First time point of the terminal log-linear phase used to estimate the terminal disposition rate constant (Ke) with bestfit regression method used.
Ke_last: Last time point of the terminal log-linear phase used to estimate the terminal disposition rate constant (Ke) with bestfit regression method used.
Descriptive statistics (number of subjects, mean, SO, CV, minimum and maximum) was used to summarize the plasma concentrations at each time of measurement.
For purposes of descriptive summary, plasma concentrations below level of quantification (BLQ) were set to zero.
Linear and semi-logarithmic plots of the mean and individual plasma concentration-by scheduled sampling-time were provided.
The summary statistics for all pharmacokinetic parameters were reported for both the test and reference products. The reported parameters were the minimum, maximum, median, arithmetic means, standard deviation and the coefficient of variation for un-transformed data and relevant pharmacokinetic parameters were the arithmetic means and the standard deviation for the log-transformed data.

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] 20793 0
India
State/province [1] 20793 0
Mumbai

Funding & Sponsors
Funding source category [1] 300452 0
Commercial sector/Industry
Name [1] 300452 0
AFT Pharmaceuticals Ltd
Address [1] 300452 0
Level 1, 129 Hurstmere Road, Takapuna, Auckland, 0622 New Zealand
Country [1] 300452 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
MACLEODS PHARMACEUTICALS LTD.
Address
G-2, Mahakali Caves Road,Shanti Nagar, Andheri - (East),Mumbai - 400 093. India
Country
India
Secondary sponsor category [1] 299924 0
None
Name [1] 299924 0
Address [1] 299924 0
Country [1] 299924 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301255 0
Independent Ethics Committee.
Ethics committee address [1] 301255 0
Snehal Hospital, Naupada, Gokhale Road,
Thane (West) - 400602, Mumbai, India
Ethics committee country [1] 301255 0
India
Date submitted for ethics approval [1] 301255 0
26/11/2012
Approval date [1] 301255 0
14/01/2013
Ethics approval number [1] 301255 0
IORG0006104

Summary
Brief summary
This study is designed as a phase 1 study to evaluate the bio-equivalence measured by the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, Tmax, Kel and T1/2) between the test and reference products under fasting conditions.
Trial website
Not applicable
Trial related presentations / publications
Not applicable
Public notes
Not applicable

Contacts
Principal investigator
Name 86378 0
Dr Ashish Mungantiwar
Address 86378 0
Macleods Pharmaceuticals Limited
Bioequivalence Department
G-2, Mahakali Caves Road, Shanti Nagar,
Aildheri - (East), Mumbai 400 093, India
Country 86378 0
India
Phone 86378 0
+ 91-22-28306435/28314611
Fax 86378 0
+ 91-22-28304641
Email 86378 0
drashish@macleodspharma.com
Contact person for public queries
Name 86379 0
Dr Jennifer Zhang
Address 86379 0
AFT Pharmaceuticals. Ltd.
Level 1, 129 Hurstmere Road, Takapuna, Auckland, 0622, New Zealand
Country 86379 0
New Zealand
Phone 86379 0
+ 64 9 488 0232
Fax 86379 0
+ 64 9 488 0234
Email 86379 0
jenniferz@aftpharm.com
Contact person for scientific queries
Name 86380 0
Dr Jennifer Zhang
Address 86380 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road, Takapuna, Auckland, 0622, New Zealand
Country 86380 0
New Zealand
Phone 86380 0
+ 64 9 488 0232
Fax 86380 0
+ 64 9 488 0234
Email 86380 0
jenniferz@aftpharm.com

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
The study confirmed that the test product (ibuprofen tablets 97.5mg manufactured by Macleods Pharmaceuticals Ltd. India) produces similar maximum blood levels and the time profile of the drugs in the body to the individual ingredient of ibuprofen in a fixed dose combination 325 (acetaminophen 325mg + ibuprofen 97.5mg).
Both formulations are well tolerated following single dose administration in healthy adults under fasting conditions.