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Trial registered on ANZCTR


Registration number
ACTRN12621001542886
Ethics application status
Approved
Date submitted
13/10/2021
Date registered
11/11/2021
Date last updated
23/09/2022
Date data sharing statement initially provided
11/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A pharmacokinetic study of acetaminophen, ibuprofen, and diphenhydramine 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 50 mg Diphenhydramine Hydrochloride, After An Administration To 30 Healthy Adults Under Fasting Conditions
Secondary ID [1] 305539 0
ACIBDI-T0821/74
Universal Trial Number (UTN)
U1111-1270-3746
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain 323929 0
Condition category
Condition code
Anaesthesiology 321442 321442 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each participant will receive each of the interventions (Treatment A and B), and the comparator (Treatment C) treatment under fasting conditions in a three-way cross over sequence. The sequence in which the participants receives each treatment will be randomly allocated.

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).

Intervention Treatments:

Treatment A:

Paracetamol 500mg plus Ibuprofen 150mg fixed-dose combination film-coated tablet (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 + 300 mg ibuprofen) will be administered orally with 240 mL of water.

Treatment B:

Diphenhydramine hydrochloride (50 mg diphenhydramine hydrochloride per tablet).
Administration: One tablet will be administered orally with 240 mL of water.

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 so that each participant will receive each of the interventions (Treatment A and B) and the comparator (Treatment C). Each study period will be separated by a washout period of at least 7 days between two consecutive periods. Once the participant completes the final period (Period 3), there is a follow-up period lasting for 7 days.
Intervention code [1] 321939 0
Treatment: Drugs
Comparator / control treatment
The comparator treatment is described below:

Treatment C: Paracetamol 500mg plus Ibuprofen 150mg fixed-dose combination Film-Coated tablet and Diphenhydramine 50mg tablet

Administration: Two tablets of the Paracetamol 500mg plus Ibuprofen 150mg Film-Coated tablet (total dose 1000mg paracetamol and 300mg Ibuprofen) and one tablet of diphenhydramine hydrochloride (total dose 50mg diphenhydramine hydrochloride) will be administered together in combination (at the same time) with 240 mL of water.

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 comparator product will be administered under the site staff's supervision and the exact dosing time will be documented.

There will be three study periods so that each participant will receive each of the interventions (Treatment A and B) and the comparator (Treatment C). Each study period will be separated by a washout period of at least 7 days between two consecutive periods. Once the participant completes the final period (Period 3), there is a follow-up period lasting for 7 days.
Control group
Active

Outcomes
Primary outcome [1] 329228 0
To evaluate and compare the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, Tmax, Kel and t1/2el) of acetaminophen and ibuprofen when taken together in combination under fasting conditions.
Timepoint [1] 329228 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.
Primary outcome [2] 329412 0
To evaluate and compare the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, Tmax, Kel and t1/2el) of diphenhydramine hydrochloride when taken alone under fasting conditions.
Timepoint [2] 329412 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.
Primary outcome [3] 329413 0
To evaluate and compare the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, Tmax, Kel and t1/2el) of acetaminophen, ibuprofen and diphenhydramine hydrochloride when taken together in combination under fasting conditions.
Timepoint [3] 329413 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] 401824 0
To compare the safety and tolerability of all treatment groups (composite secondary outcome).

Known adverse events of the study treatments (Paracetamol, Ibuprofen and Diphenhydramine) include: Gastrointestinal bleeding/ulceration, Indigestion/stomach pain, bronchospasm, water retention, renal failure, skin reactions, thromboembolic events, hepatotoxicity, drowsiness, dizziness, dry mouth/nose/throat, headache, muscle weakness and thicker nasal discharge. These adverse events will be monitored throughout the study via regular adverse event checks.

An acute safety evaluation will be performed during each study period by recording spontaneously reported adverse events and by clinical safety assessments (Vital signs, 12-lead ECG, blood biochemistry and haematology). All adverse events, including any serious adverse events, will be assessed by the Investigators and documented following the participant's randomization until 7 days after the last dose of the study medication.



Timepoint [1] 401824 0
Safety will be evaluated during each study period, and for 7 days following study drug administration.

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.

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 (Blood pressure via digital sphygmomanometer, heart rate via holter monitor, manual respiratory rate and body temperature via tympanic thermometer) 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 may be taken at other times if deemed necessary. Body temperature will be measured before dosing and approximately at the following times after dosing: 4th and 12th hour.

A 12-lead ECG will be conducted just prior to discharge at the final study period.

Haematological and biochemical assessments will be conducted on blood samples taken at the end of each study period. Haematological assessments include haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and mean corpuscular volume. Biochemical assessments include urea, creatinine, calculated glomerular filtration rate, glucose, albumin, total protein and liver function tests.

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 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
Participants will not be eligible for inclusion in this study if any of the following criteria are met:
Study contra-indications:

• Female who is pregnant or nursing (not applicable for male subjects).
• Female of childbearing potential who is 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 is 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 drugs of abuse during screening.
• Have a history of allergic reactions to acetaminophen, ibuprofen and diphenhydramine hydrochloride
• Unwilling to abstain from smoking throughout the whole duration of the study
• Unable and refuse to abstain the use of prescription drugs (not including oral contraceptives and the study medication) within at least 14 days or over-the-counter drugs 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 from engaging 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 from consuming 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).
• Subject has a difficulty fasting or consuming standard meals.


NSAID and/or Acetaminophen, Ibuprofen Contra-Indications or Exclusion Criteria:

• 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 30 ml/min)


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.

Diphenhydramine hydrochloride Contra-Indications or Exclusion Criteria
• Have hypersensitivity to diphenhydramine or any other component.
• Have severe hepatic, renal or respiratory insufficiency.
• Angle-closure glaucoma
• Bladder neck obstruction
• Urinary retention
• Chronic Bronchitis
• Stenosing peptic ulcer
• Pyloroduodenal obstruction
• Symptomatic prostatic hypertrophy
• Porphyria
• Asthma
• Epilepsy

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 diphenhydramine 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, AUC0-8, AUC0-t /AUC0-8 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 and diphenhydramine AEs may be 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.

Sample Size:

Sample size calculation is based on the power of Schuirmann’s two one-sided procedure for interval hypotheses using the ± 20 rule for the assessment of average bioequivalence.

Sample size has been selected based on the requirements for acetaminophen and ibuprofen since limited published data is currently available on the pharmacokinetic parameters of diphenhydramine.



Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
10/12/2021
Actual
26/04/2022
Date of last participant enrolment
Anticipated
22/12/2021
Actual
27/04/2022
Date of last data collection
Anticipated
21/01/2022
Actual
30/05/2022
Sample size
Target
30
Accrual to date
Final
30
Recruitment outside Australia
Country [1] 24203 0
Jordan
State/province [1] 24203 0
Amman

Funding & Sponsors
Funding source category [1] 309906 0
Commercial sector/Industry
Name [1] 309906 0
AFT Pharmaceuticals Ltd
Country [1] 309906 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] 310939 0
None
Name [1] 310939 0
Address [1] 310939 0
Country [1] 310939 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309628 0
IRB of IPRC (International Pharmaceutical Research Centre)
Ethics committee address [1] 309628 0
1 Queen Rania Street
Sport City Circle
Amman 11196
Jordan
Ethics committee country [1] 309628 0
Jordan
Date submitted for ethics approval [1] 309628 0
01/12/2021
Approval date [1] 309628 0
05/12/2021
Ethics approval number [1] 309628 0

Summary
Brief summary
This study is a Phase I study designed to determine and compare the pharmacokinetic profile of the combined use of diphenhydramine hydrochloride with fixed-dose combination tablet of Paracetamol (Acetaminophen) & Ibuprofen, with that of the individual components of diphenhydramine 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 114826 0
Dr Majdi Abu Awida
Address 114826 0
International Pharmaceutical Research Centre (IPRC)
1 Queen Rania Street
Sport City Circle
Amman 11196
Jordan
Country 114826 0
Jordan
Phone 114826 0
+96 2 656 2764
Fax 114826 0
Email 114826 0
[email protected]
Contact person for public queries
Name 114827 0
Laura Boddington
Address 114827 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road,
Takapuna,
Auckland,
New Zealand 0622
Country 114827 0
New Zealand
Phone 114827 0
+64 9 4880232
Fax 114827 0
Email 114827 0
[email protected]
Contact person for scientific queries
Name 114828 0
Laura Boddington
Address 114828 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road,
Takapuna,
Auckland,
New Zealand 0622
Country 114828 0
New Zealand
Phone 114828 0
+64 9 4880232
Fax 114828 0
Email 114828 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.