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Trial registered on ANZCTR


Registration number
ACTRN12618001998235
Ethics application status
Approved
Date submitted
23/11/2018
Date registered
13/12/2018
Date last updated
11/07/2019
Date data sharing statement initially provided
13/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to investigate the absorption and metabolism of Maxigesic Intravenous Infusion (1000 mg Acetaminophen + 300 mg Ibuprofen/100mL intravenous infusion) versus Ultracet® (325mg acetaminophen + 37.5mg tramadol hydrochloride) tablets and Dr. Reddy Laboratories Ibuprofen Tablets (800 mg Ibuprofen) in healthy volunteers under fasting conditions.
Scientific title
Randomized, Single Dose, Three-way Crossover Open Label Pharmacokinetic Parameters Study of AFT Maxigesic IV (Acetaminophen 1000mg + Ibuprofen 300mg/100 mL solution for infusion), Infusion over 15 minutes (One Dose Only), Ultracet (Acetaminophen 325mg + tramadol 37.5mg) Tablets and Dr. Reddy Laboratories Ibuprofen Tablets (Ibuprofen 800mg), after Oral administration to 30 healthy volunteers under fasting conditions
Secondary ID [1] 296696 0
AFT-MXIV-12
Universal Trial Number (UTN)
U1111-1224-4818
Trial acronym
Not applicable
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Pain Relief 310542 0
Condition category
Condition code
Anaesthesiology 309254 309254 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Test Product: Maxigesic® Intravenous Infusion (Acetaminophen 1000 mg + Ibuprofen 300 mg in 100mL solution infusion).
Each intravenous study formulation will be administered as a single, intravenous dose, infused over 15 minutes into an intravenous cannula.
There will a washout period of at least 3 days from the completion of dosing in one period to the start of dosing in the next period.
Healthy volunteers will be fasted for at least 10 hours overnight before dosing and for 4 hours after dosing at the study site. Water will be restricted for 1 hour pre dose and 1 hour post dose.
The test product will be administered under the site staff's supervision and the exact dosing time will be documented.

Intervention code [1] 313009 0
Treatment: Drugs
Comparator / control treatment
There will be two Reference Products:
1. ULTRACET® (325 mg Acetaminophen +37.5 mg Tramadol Hydrochloride), two tablets as single dose (total dose acetaminohpen 650mg + tramadol HCI 75mg) orally with 240 mL of water

2. Dr. Reddy’s Laboratories, Inc. IBU™ IBUPROFEN Tablets (Ibuprofen 800 mg), one tablet as single dose (total dose ibuprofen 800mg) orally with 240 mL of water

All the reference products will be administered under the site staff's supervision and the dosing time will be documented.


Control group
Active

Outcomes
Primary outcome [1] 308230 0
To evaluate and compare the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, Tmax, Kel and t1/2el) between test and reference products under fasting conditions
Timepoint [1] 308230 0
For Intravenous Formulation, blood samples will be collected in lithium-heparin tubes at pre-dose (0.00 hours), 5 minutes (0.083 hours), 10 minutes (0.167 hours), 15 minutes/immediately following infusion (0.25 hours), 20 minutes (0.33 hours), 25 minutes (0.42 hours), 30 minutes (0.50 hours), 45 minutes (0.75 hours) and 1.00, 1.25, 1.50, 2.00, 3.00, 6.00, 8.00, 10.00 and 12.00 hours post completion of infusion.

For Oral Tablets Formulation, blood samples collected in lithium-heparin tubes at pre-dose (0.00 hours) and at 5 minutes (0.083 hours), 10 minutes (0.167 hours), 15 minutes (0.25 hours), 20 minutes (0.33 hours), 25 minutes (0.42 hours), 30 minutes (0.50 hours), 45 minutes (0.75 hours) and 1.00, 1.25, 1.50, 2.00, 3.00, 6.00, 8.00, 10.00 and 12.00 hours after study drug administration.
Secondary outcome [1] 354316 0
To compare the safety and tolerability of test and reference products under fasting conditions.
An acute safety evaluation will be performed during each study period by recording spontaneously reported adverse events and by clinical assessments, including measurements of vital signs (blood pressure, heart rate, respiratory rate) and body temperature.
These measurements will be done at screening as well as prior, during and after each dosing period.
Vital signs will be measured pre-dose and approximately at 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 6.00 and 12.00 hours after study drug administration. Body temperature will be measured before dosing and approximately at the following times after dosing: 4th and 12th hour. Vital signs may be taken at other times if deemed necessary.
At screening and at the end of each study period an additional blood sample will be taken for haematology, biochemistry and serological assessment (only in screening).
Known NSAID adverse effects (i.e. GI ulceration, indigestion/stomach pain, GI bleeding, bronchospasm, water retention, renal failure, skin reactions and thromboembolic events), known acetaminophen adverse effects (i.e. clinical evidence of hepatotoxicity) and known IV administration adverse effects (pain at injection site) will be summarized by treatment 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] 354316 0
Safety will be evaluated during each study period and for 7 days following study drug administration

Eligibility
Key inclusion criteria
Healthy male and female volunteers aged 18 to 50 years of age. Females must be sterile or using adequate contraception. Participants must not have taken any prescription medications for at least 14 days or over-the-counter medications and herbal remedies for at least 7 days before the start of each study phase and for the duration of the study, with the exception of oral contraceptives and the study medication.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Female who are pregnant or nursing (not applicable for male subjects).
• Female of childbearing potential who are unwilling to take adequate contraceptive precautions, i.e., a hormonal contraceptive, an intrauterine device, double-barrier method, or abstinence. 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 sterilisation, e.g. bilateral tubal ligation, bilateral oophorectomy (not applicable for male subjects).
• Female of childbearing potential who are unwilling to undergo a urine pregnancy test (not applicable for male subjects).
• Have an alcohol intake in excess of 14 units per week for females and 21 units per week for males.
• Have a history of drug abuse or positive test results for drug abuse during screening.
• Unwilling to abstain from smoking throughout the whole duration of the study
• Unable and refuse to abstain the used prescription drugs (not including oral contraceptives and the study medication) within 14 days prior to study drug administration or have used over-the-counter drugs or herbal products within 7 days prior to study drug administration and during the study.
• Unable and refuse to abstain the use of vitamins for nutritional purposes within
2 days prior to study drug administration until the last study sample is collected in each period.
• Unable and refuse to abstain to consume grapefruit containing foods or beverages within 7 days or caffeine containing foods or beverages within 24 hours prior to study drug administration until the last study sample is collected in each period.
• Currently, or in last 80 days, participating in a clinical trial involving another study drug.
• Have donated blood or blood products within 60 days prior to study drug administration.
• Have a clinically significant abnormal laboratory test (as determined by the Principal Investigator), Hb, PCV and RBC indices (MCV, MCH and MCHC) tests which deviated outside the 5% of reference range or laboratory results of liver or kidney function tests (creatinine, urea and ALP will be accepted if below reference range, total protein and albumin accepted if above reference range) are outside the reference range.
• Be on a special diet (for example is vegetarian).
• Unable and refuse to abstain to engage in strenuous exercise within 24 hours prior to study drug administration until the last sample is collected in each study period.
• Have at screening examination a pulse outside the normal range of (60-100 beat per minute) or a body temperature outside the normal range of (35.0-37.2 Degrees Celsius ) or a respiratory rate outside the normal range of (14-20 breath per minute) or a sitting blood pressure less than 100/60 mm Hg or more than or equal to 140/90 mm Hg.
• Unable and refuse to abstain to consume any beverages or food containing alcohol for at least 24 hours prior to study drug administration until the last study sample is collected in each period.
• Have a history of difficulties in swallowing or any gastrointestinal disease which could affect the drug absorption.
• 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.
• Subject is a heavy smoker (more than 10 cigarettes per day).
• Acute infection within one week preceding study drug administration.
• Have any history of allergy or hypersensitivity to ibuprofen, aspirin or other NSAID.
• Have any history of allergy or hypersensitivity to acetaminophen.
• Have severe known haemopoetic, renal or hepatic disease, immunosuppression.
• Have a history of gastric ulceration, indigestion, stomach pain or GI bleeding or bleeding disorders.
• Currently suffering from dehydration through diarrhoea and/or vomiting.
• Have a history of severe asthma defined as previous steroid treatment or hospital admission within the last 5 years.
• Have a history of severe hypertension, ventricular tachycardia or other cardiac disease.
• Have a history of long-standing insulin dependent diabetes mellitus.

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:
AUC0-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.
AUC0-inf: The area under the plasma concentration versus time curve, from zero to infinity. AUC0-inf is calculated as the sum of the AUC0-t plus the ratio of the last measurable concentration to the elimination rate constant (Ct/Kel).
Cmax: Maximum measured plasma concentration directly obtained from the experimental data of plasma concentration versus time curves, without interpolation.
Kel: Apparent first-order elimination or terminal rate constant calculated from a semi-log plot of the plasma concentration versus time curve. The parameter will be calculated by linear least-squares regression analysis using the last three (or more) non-zero plasma concentrations and excluding Cmax.
Tmax: Time of maximum measured plasma concentration. If the maximum value occurs at more than one point, Tmax is defined as the time of the first occurrence.
T1/2el: Time required for the plasma drug concentration to decrease by one half. This value is estimated from the elimination rate constant (Kel) calculated from the slope of the linear relationship between the loge concentration and time during the terminal elimination phase.
Missing drug concentration data (value below LLOQ, missing value) will be treated as follows:
• Any missing concentration values are not included in the pharmacokinetic calculations.
• Values below LLOQ are treated as zero for all pharmacokinetic and statistical analyses.
Descriptive statistics, including the means, standard deviations, standard error of the mean and coefficient of variation, shall be reported for the plasma concentrations. For pharmacokinetic parameters, arithmetic means, standard deviations, standard error of the mean, minimum, median, maximum, coefficient of variation, inter-quartile ranges and geometric means shall be reported.

Safety Analysis:
AEs will be collected for all randomized participants and will be listed with type of AE, severity and relationship for each treatment group, using the safety population. Adverse events 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 study 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 treatment may be compared between treatments using repeated measures by ANOVA using Systat program.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
28/02/2019
Actual
10/06/2019
Date of last participant enrolment
Anticipated
28/03/2019
Actual
24/06/2019
Date of last data collection
Anticipated
30/04/2019
Actual
9/07/2019
Sample size
Target
30
Accrual to date
Final
30
Recruitment outside Australia
Country [1] 21065 0
Jordan
State/province [1] 21065 0
Amman, Jordan

Funding & Sponsors
Funding source category [1] 301277 0
Commercial sector/Industry
Name [1] 301277 0
AFT Pharmaceuticals Ltd
Country [1] 301277 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] 300924 0
None
Name [1] 300924 0
Address [1] 300924 0
Country [1] 300924 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302021 0
IRB of IPRC (International Pharmaceutical Research Centre)
Ethics committee address [1] 302021 0
Ethics committee country [1] 302021 0
Jordan
Date submitted for ethics approval [1] 302021 0
13/12/2018
Approval date [1] 302021 0
14/04/2019
Ethics approval number [1] 302021 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61274 0
Dr Majdi Abu Awida, M.D.
Address 61274 0
IPRC (International Pharmaceutical Research Centre)
1 Queen Rania Street-Sport City Circle, Amman 11196 Jordan
Country 61274 0
Jordan
Phone 61274 0
+ 962-6-5627648
Fax 61274 0
Email 61274 0
iprc@iprc.com.jo
Contact person for public queries
Name 61275 0
Jennifer Zhang
Address 61275 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road, Takapuna, Auckland, New Zealand 0622
Country 61275 0
New Zealand
Phone 61275 0
+64 9 488 0232 ext 710
Fax 61275 0
Email 61275 0
jenniferz@aftpharm.com
Contact person for scientific queries
Name 61276 0
Jennifer Zhang
Address 61276 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road, Takapuna, Auckland, New Zealand 0622
Country 61276 0
New Zealand
Phone 61276 0
+64 9 488 0232 ext 710
Fax 61276 0
Email 61276 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
The study results will be obtained from the overall 30 subjects in order to reach the statistical significance rather than using individual participant data. Therefore, sharing individual participant data is not deemed as necessary.


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.