Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000087550
Ethics application status
Approved
Date submitted
14/12/2023
Date registered
31/01/2024
Date last updated
27/10/2024
Date data sharing statement initially provided
31/01/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Pharmacokinetic study evaluating the pharmacokinetic parameters of different doses of Maxigesic® IV (intravenous paracetamol + intravenous ibuprofen) in healthy Japanese volunteers and Caucasian volunteers
Scientific title
Maxigesic IV PK Study: Single-centre, randomised, open label, single dose study to evaluate the pharmacokinetic parameters of different doses of Maxigesic® IV (intravenous paracetamol + intravenous ibuprofen) in healthy Japanese volunteers and Caucasian volunteers
Secondary ID [1] 311181 0
AFT-MXIV-14
Universal Trial Number (UTN)
U1111-1300-6929
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Analgesia 332359 0
Condition category
Condition code
Anaesthesiology 329067 329067 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomly assigned to one of the two possible study drug treatment
sequences in a fashion that ensures each individual receives each treatment, that for each
study period at least 24 participants (12 Japanese and 12 Caucasian) are allocated to each
treatment and that the first-order carry-over effects are minimised.

Treatment A: 100 mL of Maxigesic® IV (paracetamol 1000 mg + intravenous ibuprofen 300 mg in 100mL infusion) = Maxigesic IV HIGH dose (1000 mg paracetamol + 300 mg ibuprofen)

Each intravenous study formulation will be administered as a single, intravenous dose,
infused over 15 minutes into an intravenous cannula. The administration of each dose will be documented in the Case Report Form (CRF) by a study nurse.

Washout period between treatments - at least 48 hours

All participants complete both periods (treatments A and B) in a cross-over fashion.
Intervention code [1] 327627 0
Treatment: Drugs
Comparator / control treatment
Treatment B: 50 mL of Maxigesic® IV (paracetamol 1000 mg + intravenous ibuprofen 300 mg in 100mL infusion) + 50 mL of sterile saline solution = Maxigesic IV MID dose (500 mg paracetamol + 150 mg ibuprofen)

Each intravenous study formulation will be administered as a single, intravenous dose,
infused over 15 minutes into an intravenous cannula. The administration of each dose will be documented in the Case Report Form (CRF) by a study nurse.

Washout period between treatments - at least 48 hours
All participants complete both periods (treatments A and B) in a cross-over fashion.
Control group
Active

Outcomes
Primary outcome [1] 336874 0
The outcome is the pharmacokinetic profile of Maxigesic® IV in healthy Japanese subjects and Caucasian subjects including Cmax, Tmax, t½, AUC(0-t) and AUC(0-8).
Timepoint [1] 336874 0
Blood samples will be drawn at pre-dose (within one hour prior to administration of study drug), 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.
Primary outcome [2] 336875 0
The outcome is the description of dose proportionality of two different doses of Maxigesic IV (Mid and High)
Timepoint [2] 336875 0
Blood samples will be drawn at pre-dose (within one hour prior to administration of study drug), 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.
Secondary outcome [1] 429996 0
To monitor the safety and tolerability of all treatment groups. The safety and tolerability will be assessed as a composite secondary outcome.
Timepoint [1] 429996 0
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.

At the end of each treatment period, vital signs measurements (blood pressure, heart rate, respiratory rate, temperature) and urinalysis samples will be evaluated.
.
All AEs including SAEs will be assessed continuously and documented following the participant’s randomisation until 7 days after the last dose of the study medication by spontaneous reporting and at a final follow-up phone call on Day 12.

Eligibility
Key inclusion criteria
A participant will be eligible for inclusion in this study only if all of the following criteria
are met:
• Male and female volunteers aged between 18 and 50 years, inclusive, on the day of consent.
• Voluntarily provide written informed consent before the initiation of any study related
procedures.
• Have a Body Mass Index (BMI) between 18.0 and 32.0 kg/m2.
• Have a body weight of at least 50 kg
• Have no significant disease (cardiac, pulmonary, GI, hepatic, renal, haematological, neurological, infective, or psychiatric) as determined by medical history, physical examination and laboratory tests as determined by the Principal Investigator.
• Have negative HIV and hepatitis B & C test results.
• Be able and willing to abstain from caffeine-containing beverages (e.g. coffee, soda, or tea), caffeine-containing food (e.g. chocolate), and alcohol for 24 hours prior to study drug administration until after the last study sample is collected in each dosing period.
• Be able and willing to abstain from all prescription and over-the-counter medications (excluding the study drug and oral contraceptive) and herbal remedies for the duration of the study as determined by the Principal Investigator.
• Have a normal 12-lead ECG or one with an abnormality considered to be clinically insignificant as determined by the Principal Investigator.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants will not be eligible for inclusion in this study if any of the following criteria
are met:
• Women who are pregnant or nursing.
• 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.
• Women of childbearing potential who are unwilling to undergo a urine pregnancy test.
• 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.
• Is a current smoker.
• 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.
• Currently, or in last 30 days, participating in a clinical trial involving another study drug
• Have donated blood or blood products within 30 days prior to study drug administration
• Have a clinically significant abnormal laboratory test (as determined by the Principal Investigator)
• 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
• Have any history of allergy or hypersensitivity to ibuprofen, aspirin or other NSAID
• Have any history of allergy or hypersensitivity to paracetamol
• 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

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)
The randomisation sequence will be generated by computer, prior to the study, by an
independent statistician. The statistician will maintain a schedule of participant numbers
and drug sequence allocation.
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
On the basis of the concentration-time data, the following pharmacokinetic parameters will be estimated for paracetamol 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.

The primary 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. The secondary pharmacokinetic parameters will be Kel, Vz, CL. 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. These pharmacokinetic parameters will be compared by treatment and ethnicity.

Power model for dose proportionality: The relationship between the PK parameter (y) and dose is defined as follows:
y = alpha x dose beta.
This becomes a linear relationship following a logarithmic transformation, to which a linear regression approach can be applied:
log (y) = µ+ beta x log (dose)
Assuming that the underlying relationship between log (y) and log (dose) is linear, a value of 1 for beta indicates perfect dose proportionality. Therefore, the estimate of beta together with a suitable CI can be used to quantify dose proportionality.

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 ethnicities using Fisher’s exact tests and chi-square tests as appropriate when frequencies are sufficient.

The haematology and biochemistry data collected pre-study and during the study 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.

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 ethnicities using repeated measures ANOVA and McNemar’s chi-square tests.

Participant demographic and background characteristics will be descriptively summarised using means, standard deviations, ranges, frequencies and percentages as appropriate.



Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/03/2024
Actual
4/04/2024
Date of last participant enrolment
Anticipated
Actual
6/05/2024
Date of last data collection
Anticipated
Actual
4/06/2024
Sample size
Target
24
Accrual to date
Final
24
Recruitment outside Australia
Country [1] 26035 0
New Zealand
State/province [1] 26035 0
Auckland

Funding & Sponsors
Funding source category [1] 315439 0
Commercial sector/Industry
Name [1] 315439 0
AFT Pharmaceuticals Ltd.
Country [1] 315439 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] 317509 0
None
Name [1] 317509 0
Address [1] 317509 0
Country [1] 317509 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314351 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 314351 0
Ethics committee country [1] 314351 0
New Zealand
Date submitted for ethics approval [1] 314351 0
24/01/2024
Approval date [1] 314351 0
12/02/2024
Ethics approval number [1] 314351 0
2024 EXP 19433

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

Contacts
Principal investigator
Name 131278 0
Dr Paul Hamilton
Address 131278 0
Pacific Clinical Research Network, Level 2/2 Fred Thomas Drive, Takapuna, Auckland 0622
Country 131278 0
New Zealand
Phone 131278 0
+64 9 242 3321
Fax 131278 0
Email 131278 0
[email protected]
Contact person for public queries
Name 131279 0
Laura Boddington
Address 131279 0
AFT Pharmaceuticals Ltd. Level 1, 129 Hurstmere Road, Takapuna, Auckland, New Zealand 0622
Country 131279 0
New Zealand
Phone 131279 0
+64 9 4880232
Fax 131279 0
Email 131279 0
[email protected]
Contact person for scientific queries
Name 131280 0
Laura Boddington
Address 131280 0
AFT Pharmaceuticals Ltd. Level 1, 129 Hurstmere Road, Takapuna, Auckland, New Zealand 0622
Country 131280 0
New Zealand
Phone 131280 0
+64 9 4880232
Fax 131280 0
Email 131280 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.