Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001208594
Ethics application status
Approved
Date submitted
3/11/2015
Date registered
6/11/2015
Date last updated
20/12/2018
Date data sharing statement initially provided
20/12/2018
Date results provided
20/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Pharmacokinetic study of acetaminophen and ibuprofen, solution for infusion and the oral tablet of acetaminophen and ibuprofen in healthy volunteers
Scientific title
Single-centre, single-dose, open-label, randomised, four-way cross-over study to evaluate and compare the pharmacokinetic parameters of a fixed dose combination of intravenous acetaminophen + intravenous ibuprofen, intravenous acetaminophen, intravenous ibuprofen and a fixed dose combination tablet of acetaminophen 325mg + ibuprofen 97.5mg, in healthy volunteers.
Secondary ID [1] 287771 0
AFT-MXIV-06
Universal Trial Number (UTN)
U1111-1176-1047
Trial acronym
Maxi-IV PK Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Analgesia 296658 0
Condition category
Condition code
Anaesthesiology 296880 296880 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each participant will be randomly allocated to receive a single dose of each of the following four treatments in a balanced four-way crossover sequence

Treatment A: intravenous acetaminophen 1000 mg + ibuprofen 300 mg in 100mL infusion
Treatment B: intravenous acetaminophen 1000 mg in 100mL infusion
Treatment C: intravenous ibuprofen 400 mg in 4 ml infusion
Treatment D: Oral acetaminophen 325 mg + ibuprofen 97.5 mg tablet, 3 tablets
Washout period between treatments - 7 days
Dose frequency - single dose
All participants complete all four periods (treatments A-D) in a cross-over fashion.
Intervention code [1] 293165 0
Treatment: Drugs
Comparator / control treatment
Treatment B: intravenous acetaminophen 1000 mg in 100mL infusion
Treatment C: intravenous ibuprofen 400 mg in 4 ml infusion
Treatment D: Oral acetaminophen 325 mg + ibuprofen 97.5 mg tablet, 3 tablets
Washout period between treatments - 7 days
Dose frequency - single dose
Control group
Active

Outcomes
Primary outcome [1] 296483 0
To describe the pharmacokinetic profile of acetaminophen 1000 mg + ibuprofen 300 mg/100 ml solution for infusion, with that of acetaminophen 1000 mg/100 mL solution for infusion and ibuprofen 400 mg/4mL solution for infusion
Timepoint [1] 296483 0
To define the pharmacokinetic parameters of acetaminophen 1000 mg + ibuprofen 300 mg/100 ml solution for infusion and compare them with that of , including:
Cmax
Tmax
t1/2
AUC(0-t)
AUC(0-8)
Intravenous Formulations Sampling Time Points:
Blood samples will be drawn at pre-dose, on completion of the 15 minutes intravenous infusion, and at 5, 10, 15, 20, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post completion of infusion.
Tablet Formulation:
Blood samples will be drawn pre-dose and at 5, 10, 20, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4 6, 8, 10 and 12 hours after study drug administration.
Primary outcome [2] 296484 0
To determine the relative bioavailability of the orally administered acetaminophen 325mg + ibuprofen 97.5mg tablets versus that of intravenous acetaminophen 1000mg+ ibuprofen 300mg /100 mL infusion by the plasma drug concentration assay
Timepoint [2] 296484 0
To define the relative bioavailability of intravenous acetaminophen 1000mg + ibuprofen 300mg/100mL infusion and acetaminophen 325mg + ibuprofen 97.5mg tablets, including:
Cmax
Tmax
t1/2
AUC(0-t)
AUC(0-8)
Blood samples will be drawn at pre-dose, on completion of the 15 minutes intravenous infusion, and at 5, 10, 15, 20, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post completion of infusion.
Tablet Formulation:
Blood samples will be drawn pre-dose and at 5, 10, 20, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4 6, 8, 10 and 12 hours after study drug administration.
Secondary outcome [1] 318576 0
Clinical safety will be evaluated during each study period and for the 7 days following each study drug administration
Timepoint [1] 318576 0
Safety will be evaluated during each study period, and for up to 7 days following last dose of study drug administration.
An acute safety evaluation will be performed during each study period by recording spontaneously reported AEs and by clinical assessments.
On Day 1 of each study period, an additional post-dose 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), 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.
AEs 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.

Eligibility
Key inclusion criteria
Healthy volunteers, males and females aged 18 to 50 years of age. Females must be sterile or using adequate contraception. Participants must not have taken any medications for at least 14 days before the start of each study phase, with the exception of oral contraceptives.
All volunteers must be deemed healthy on the basis of a medical history, physical exam (including vital signs and ECG recording), urinalysis, and blood biochemical and haematological examinations.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1..Women who are pregnant or nursing.
2. 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. 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.
3. Women of childbearing potential who are unwilling to undergo a urine pregnancy test.
4. Have an alcohol intake in excess of 14 units per week for females and 21 units per week for males.
5. Have a history of drug abuse or positive test results for drug abuse.
6. Is a current smoker.
7. Have used prescription drugs (not including oral contraceptives) within 14 days prior to study drug administration or have used over-the-counter drugs herbal products or vitamins within 7 days prior to study drug administration, unless the Principal Investigator and Sponsor agree that the product taken will not impact on study conduct, results or participant safety.
8. Currently, or in last 30 days, participating in a clinical trial involving another study drug
9. Have donated blood or blood products within 30 days prior to study drug administration
10. Have a clinically significant abnormal laboratory test (as determined by the Principle Investigator)
11. 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
12. Have any history of allergy or hypersensitivity to ibuprofen, aspirin or other NSAID
13. Have any history of allergy or hypersensitivity to acetaminophen
14. Have severe known haemopoetic, renal or hepatic disease, immunosuppression
15. Have a history of gastric ulceration, indigestion, stomach pain or GI bleeding or bleeding disorders
16. Currently suffering from dehydration through diarrhoea and/or vomiting
17. Have a history of severe asthma defined as previous steroid treatment or hospital admission within the last 5 years

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 because this is an open-label study
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
PK Analysis:
On the basis of the concentration-time data, the following pharmacokinetic parameters will be estimated for acetaminophen and ibuprofen from the plasma concentration against time data, using a non-compartmental model:
AUC(0-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.
AUC(0-8): The area under the plasma concentration versus time curve, from zero to infinity. AUC(0-8) is calculated as the sum of the AUC(0-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.
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.
T1/2: 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.
Plasma concentrations for each formulation 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.
PK Interaction Criteria:
The ratios used to test bioequivalence will be calculated from loge transformed data for Cmax, AUC(0-t). and AUC(0-8). This data will be analysed using ANOVA, the model to include terms for participant, period and formulation. The differences between the loge means and the 90% confidence interval of the difference derived from the residual variance from the ANOVA model, will be back-transformed to estimate the ratio of the two formulations with the 90% confidence interval of this ratio.
Additional statistical comparisons between formulations/administration will be undertaken for t1/2 and Tmax, t1/2 will be compared using ANOVA with terms for participant, period and formulation. Tmax will be compared using Wilcoxon signed-rank tests. These comparisons will be summarised as mean ratios and differences with appropriate confidence intervals. A two-tailed p-value <0.05 will be taken to indicate statistical significance.
Safety Endpoints:
AEs will be collected for all randomised participants and will be listed with type of AE, severity and relationship for each treatment group, using the safety population. Safety data will be summarised for each formulation using frequencies and percentages (% of participants with each specific AE). Known NSAID specific AEs maybe compared between formulations using Fisher’s exact tests and chi-square tests as appropriate when frequencies are sufficient.
The haematology and biochemistry data collected pre-study and after each period will be summarised 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 using repeated measures ANOVA and McNemar’s chi-square tests.
Sample size calculation:
A similar previous study exploring the bioequivalence of acetaminophen solutions provided estimates of the within-subject CV% of 12% and 4% for Cmax and AUC(0-8), respectively. Assuming the CV% is no more than 15% in this study, then a sample size of 30 participants will provide 90% power to detect bioequivalence between intravenous acetaminophen and intravenous ibuprofen and the respective two component of the fixed dose combination of acetaminophen 1000mg + ibuprofen 300mg/ 100mL infusion

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
14/03/2016
Actual
10/04/2016
Date of last participant enrolment
Anticipated
30/05/2016
Actual
13/04/2016
Date of last data collection
Anticipated
Actual
23/05/2016
Sample size
Target
30
Accrual to date
Final
30
Recruitment outside Australia
Country [1] 7286 0
New Zealand
State/province [1] 7286 0
Christchurch

Funding & Sponsors
Funding source category [1] 292309 0
Commercial sector/Industry
Name [1] 292309 0
AFT Pharmaceuticals Ltd.
Country [1] 292309 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
AFT Pharmaceuticals Ltd.
Address
Level 1, 129 Hurstmere Road, Takapuna, Auckland, 0622
Country
New Zealand
Secondary sponsor category [1] 290989 0
None
Name [1] 290989 0
N/A
Address [1] 290989 0
N/A
Country [1] 290989 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293782 0
Health and Disability Ethics Committee
Ethics committee address [1] 293782 0
Ethics committee country [1] 293782 0
New Zealand
Date submitted for ethics approval [1] 293782 0
26/11/2015
Approval date [1] 293782 0
27/01/2016
Ethics approval number [1] 293782 0
15/STH/229

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

Contacts
Principal investigator
Name 61278 0
Dr Richard Robson
Address 61278 0
Christchurch Clinical Study Trust. 31 Tuam Street, PO Box 2856, Christchurch 8011
Country 61278 0
New Zealand
Phone 61278 0
+ 64 3 3729 477
Fax 61278 0
+ 64 3 3729 478
Email 61278 0
[email protected]
Contact person for public queries
Name 61279 0
Hartley Atkinson
Address 61279 0
AFT Pharmaceuticals Ltd. Level 1, 129 Hurstmere Road, Takapuna, Auckland 0622
Country 61279 0
New Zealand
Phone 61279 0
+ 64 9 488 02 32
Fax 61279 0
+ 64 9 488 0234
Email 61279 0
[email protected]
Contact person for scientific queries
Name 61280 0
Ioana Stanescu
Address 61280 0
AFT Pharmaceuticals Ltd. Level 1, 129 Hurstmere Road, Takapuna, Auckland 0622
Country 61280 0
New Zealand
Phone 61280 0
+ 64 9 488 0232
Fax 61280 0
+ 64 9 488 0234
Email 61280 0
[email protected]

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 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.