Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001055897
Ethics application status
Approved
Date submitted
2/07/2021
Date registered
10/08/2021
Date last updated
4/04/2022
Date data sharing statement initially provided
10/08/2021
Date results information initially provided
25/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A pharmacokinetic study of acetaminophen, ibuprofen, and xylometazoline hydrochloride in healthy volunteers under fasting conditions.
Scientific title
Randomized, single dose, three-way crossover open label study to evaluate the pharmacokinetic parameters of 1000 mg Acetaminophen, 300 mg Ibuprofen and 1 mg/mL Xylometazoline hydrochloride (1 spray into each nostril; 0.138mL per spray), after an administration to 30 healthy adults under fasting conditions.
Secondary ID [1] 304685 0
ACIBXY-TNS0621/59
Universal Trial Number (UTN)
U1111-1267-5554
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain Relief 322668 0
Condition category
Condition code
Anaesthesiology 320279 320279 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 intervention treatments, and the comparator treatment under fasting conditions in a three-way crossover sequence:

Intervention Treatments:
Treatment A: Paracetamol 500 mg & Ibuprofen 150mg Film-Coated Tablets (500 mg acetaminophen + 150 mg ibuprofen per film coated tablet)
Administration: Two tablets (given at the same time) as a single dose (total dose 1000 mg acetaminophen + 300mg ibuprofen) will be administered orally with 240 mL of water.

Treatment B: Xylometazoline hydrochloride (1 mg/mL; 0.138 mL per spray; 0.138 mL of 1mg/mL xylometazoline hydrochloride will give a calculated dose of 0.138 mg of xylometazoline hydrochloride per spray).

Administration: One spray per nostril, a total of two sprays will be administered as a single dose (total of 0.276 mL of xylometazoline hydrochloride delivered, total calculated dose of 0.276 mg of xylometazoline hydrochloride).

Participants will be fasted for at least 10 hours overnight before dosing and for 4 hours after dosing. Water will be restricted for 1 hour pre-dose and 1 hour post-dose (with the exception of water administered as part of dosing).
The test product will be administered under the site staff's supervision and the exact dosing time will be documented.

There will be three study periods each separated by a washout period of at least 7 days between two consecutive periods and a subsequent 7 days of final follow-up period.
Intervention code [1] 321061 0
Treatment: Drugs
Comparator / control treatment
The comparator treatment is described below:
Treatment C: Paracetamol 500 mg & Ibuprofen 150mg Film-Coated Tablets and Xylometazoline hydrochloride

Administration: Two tablets of Paracetamol 500 mg & Ibuprofen 150mg Film-Coated Tablets (given at the same time) as a single dose (total dose 1000 mg acetaminophen + 300mg ibuprofen) will be administered orally with 240 mL of water, and one spray per nostril, a total of two sprays of Xylometazoline hydrochloride (1 mg/mL; 0.138 mL per spray; 0.138 mL of 1mg/mL xylometazoline hydrochloride will give a calculated dose of 0.138 mg of xylometazoline hydrochloride per spray) will be administered as a single dose (total of 0.276 mg of xylometazoline hydrochloride), taken together in combination.

Participants will be fasted for at least 10 hours overnight before dosing and for 4 hours after dosing. Water will be restricted for 1 hour pre-dose and 1 hour post-dose (with the exception of water administered as part of dosing).
The test product will be administered under the site staff's supervision and the exact dosing time will be documented.


Pharmacokinetic parameters of Treatment C (Paracetamol & Ibuprofen + Xylometazoline hydrochloride), will be compared against the pharmacokinetic parameters of the individual components alone (Treatment A - Paracetamol & Ibuprofen, and Treatment B - Xylometazoline hydrochloride).
Control group
Active

Outcomes
Primary outcome [1] 328136 0
To evaluate and compare the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, Tmax, Kel and t1/2el) of acetaminophen, ibuprofen and xylometazoline hydrochloride when taken separately and when taken together under fasting conditions.
Timepoint [1] 328136 0
Blood samples will be drawn pre-dose (0.00 hours) and at 5 minutes (0.083 hours), 10 minutes (0.167 hours), 20 minutes (0.333 hours), 30 minutes (0.50 hours), 45 minutes (0.75 hours) and 1.00, 1.25, 1.50, 2.00, 3.00, 4.00, 6.00, 8.00, 10.00 and 12.00 hours after study drug administration.
Secondary outcome [1] 397785 0
To compare the safety and tolerability of all treatment groups.

An acute safety evaluation will be performed during each study period by recording spontaneously reported adverse events and by clinical assessments. All adverse events, including any serious adverse events, will be assessed and documented following the participant’s randomization until 7 days after the last dose of the study medication.

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. Vital signs include heart rate and blood pressure and are taken as per study centre standard protocols.

Haematological and biochemical assessment will be conducted on blood samples taken at the end of each study period.
Timepoint [1] 397785 0
Participants will check-in to the Study Centre the evening prior to study drug administration and will stay for the duration of the Study Period (at least 12 hours after dosing). Each Study Period will consist of a Baseline Period (pre-dosing) and a Treatment Period. Safety will be evaluated during each study period, and for 7 days following study drug administration.

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 4.00 and 12.00 hours after study drug administration.

Vital signs may be taken at other times if deemed necessary.

An additional blood sample will be taken at the end of each study period for haematology, biochemistry.

Eligibility
Key inclusion criteria
A participant will be eligible for inclusion in this study only if all of the following criteria are met:
• Male or female subjects 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 18.5 and 30.0 kg/m2.
• Have no significant disease (asthma, peptic or gastric ulcer, sinusitis, pharyngitis, gastrointestinal disease, pulmonary disease, renal disorder (impaired renal function), hepatic disorder (impaired hepatic function), cardiovascular disorder, neurological disease such as epilepsy, haematological disorders or diabetes, psychiatric, infective, dermatologic or immunological disorders) as determined by medical history, physical examination and laboratory tests.
• Have negative HIV and hepatitis B & C test results.
• Be able and willing to abstain from caffeine-containing beverages (e.g. coffee, soda, energy drinks or tea), caffeine-containing food (e.g. chocolate), and alcohol for at least 24 hours prior to study drug administration until the last study sample is collected in each period.
• Be able and willing to abstain from any food or beverages containing grapefruit for at least 7 days prior to study drug administration until the last study sample is collected in each period.
• Be able and willing to abstain from prescription drugs (not including oral contraceptives and the study medication) within at least 14 days or have used over-the-counter drugs within at least 7 days before the start of each study phase and during the study.
• Be able and willing to abstain from vitamins taken for nutritional purposes for at least 2 days prior to study drug administration until the last study sample is collected in each period.
• Be able and willing to abstain from smoking throughout the whole duration of the study.
• Have a medically acceptable normal 12-lead ECG (No QTc Prolongation).
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Study contra-indications
• 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.
• Have a history of allergic reactions to acetaminophen, ibuprofen and xylometazoline hydrochloride
• 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 at least 14 days or have used over-the-counter drugs or within at least 7 days before the start of each study phase and during the study.
• Unable and refuse to abstain the use of vitamins for nutritional purposes within at least
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 at least 7 days or caffeine containing foods or beverages within at least 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 any clinically significant results from laboratory tests, however, ALP, urea and creatinine will be accepted if below reference range, total protein and albumin will be accepted if above reference range after being evaluated by the physician as clinically not significant. Haematology tests with deviation of more than 5% of the reference limits. Laboratory tests are performed not longer than two weeks before the initiation of the clinical study.
• Be on a special diet (for example is vegetarian).
• Unable and refuse to abstain to engage in strenuous exercise within at least 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 C) 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).
• Any acute intranasal problems (e.g. common cold, acute hayfever) within 2 weeks of the first study drug administration or a history of nasal pathology, surgery or disorders (particularly hayfever, rhinitis or nasal polyps) which may possibly affect intranasal drug absorption.

NSAID and/or Acetaminophen Contra-Indications
• Have known hypersensitivity reaction to acetaminophen, ibuprofen, other NSAIDs or any other ingredients in the product.
• Have severe heart and renal failure (glomerular filtration below 30ml/min)
• Women during third trimester of pregnancy.
Acetaminophen:
• Have active alcoholism as chronic excessive alcohol ingestion may predispose patients to acetaminophen hepatoxicity.
Ibuprofen
• Have experienced asthma, urticaria, or allergic- type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs.
• Have active gastrointestinal bleeding or peptic ulceration. Use of ibuprofen is contraindicated during the third trimester of pregnancy.
• Have taken other products containing ibuprofen, aspirin, salicylates or with any other anti-inflammatory medicines.


Xylometazoline Hydrochloride Contra-Indications
• Contraindicated for patients with hypersensitivity to the active substance(s) or to any of the excipients.
• Like other vasoconstrictors Xylometazoline HCl nasal spray 1 mg/ml should not be used after trans-sphenoidal hypophysectomy or surgery exposing the dura mater.
• Xylometazoline should be avoided in patients with narrow angle glaucoma
• Xylometazoline should be avoided in patients with chronic nasal inflammation with very dry nasal passages.

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 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
On the basis of the concentration-time data, the following pharmacokinetic parameters will be estimated for acetaminophen, ibuprofen and xylometazoline from the plasma concentration against time data, using a non-compartmental model:
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.
AUC0-8: The area under the plasma concentration versus time curve, from zero to infinity. AUC0-8 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.

No value of Kel, AUC0-inf, AUC0-t /AUC0-inf or t1/2el will be reported for cases that do not exhibit a terminal log-linear phase in the concentration versus time profile.

The actual times of blood sampling will be used for these calculations as per internal SOPs, DMU-001, except the first six sampling points after dosing will be adjusted if there is a deviation more than 1 min.

Missing drug concentration data (value below LLOQ, missing value) will be treated as follows:
• Any missing concentration values are treated as missing and 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
Adverse events data will be summarized for each treatment using frequencies and percentages (% of participants with each specific AE). Known NSAID specific AEs maybe compared between treatments as appropriate when frequencies are sufficient. Individual safety data will be listed by treatment.
The haematology and biochemistry data collected pre-study and after each period will be summarized descriptively using means, medians, standard deviations, ranges, 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 will be compared using repeated measures ANOVA using SPSS Software.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/08/2021
Actual
12/09/2021
Date of last participant enrolment
Anticipated
18/10/2021
Actual
13/09/2021
Date of last data collection
Anticipated
30/11/2021
Actual
8/10/2021
Sample size
Target
30
Accrual to date
Final
30
Recruitment outside Australia
Country [1] 23940 0
Jordan
State/province [1] 23940 0
Amman

Funding & Sponsors
Funding source category [1] 309055 0
Commercial sector/Industry
Name [1] 309055 0
AFT Pharmaceuticals Ltd
Country [1] 309055 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] 309997 0
None
Name [1] 309997 0
Address [1] 309997 0
Country [1] 309997 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308932 0
IRB of IPRC (International Pharmaceutical Research Centre)
Ethics committee address [1] 308932 0
1 Queen Rania Street
Sport City Circle
Amman 11196
Jordan
Ethics committee country [1] 308932 0
Jordan
Date submitted for ethics approval [1] 308932 0
15/07/2021
Approval date [1] 308932 0
07/09/2021
Ethics approval number [1] 308932 0

Summary
Brief summary
This study is designed as a Phase I study designed to determine and compare the pharmacokinetic profile of the combined use of a nasal spray of xylometazoline hydrochloride (1mg/mL) with fixed-dose combination tablet of Paracetamol (Acetaminophen) & Ibuprofen, with that of the individual components of xylometazoline hydrochloride and Paracetamol (Acetaminophen) & Ibuprofen.
This study will include 30 healthy volunteers and will be conducted under fasting conditions.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112378 0
Dr Majdi Abu Awida
Address 112378 0
International Pharmaceutical Research Centre (IPRC)
1 Queen Rania Street
Sport City Circle
Amman 11196
Jordan
Country 112378 0
Jordan
Phone 112378 0
+96 2 656 2764
Fax 112378 0
Email 112378 0
iprc@iprc.com.jo
Contact person for public queries
Name 112379 0
Dr Laura Boddington
Address 112379 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road,
Takapuna,
Auckland,
New Zealand 0622
Country 112379 0
New Zealand
Phone 112379 0
+64 9 4880232
Fax 112379 0
Email 112379 0
laura.boddington@aftpharm.com
Contact person for scientific queries
Name 112380 0
Dr Laura Boddington
Address 112380 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road,
Takapuna,
Auckland,
New Zealand 0622
Country 112380 0
New Zealand
Phone 112380 0
+64 9 4880232
Fax 112380 0
Email 112380 0
laura.boddington@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 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.