Ibuprofen 4% (w/v) Pivotal Bioequivalence Study

Study Overview
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Brief Summary
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Bioequivalence evaluation of Nurofen for Children® with reference formulation of Algifor® Junior by determining and comparing the rate and extent of absorption in both fed and fasted states

Official Title
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A Randomised, Single-dose, 4-way Crossover, Open-label, Pharmacokinetic Study Comparing a 4% (w/v) Suspension of Ibuprofen With a Reference 2% (w/v) Suspension of Ibuprofen in the Fed and Fasted States.

Conditions
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Bioequivalence of the Test Formulation

Intervention / Treatment
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* Drug: Nurofen for Children®
* Drug: Algifor® Junior


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who had given written informed consent. Age: ≥18 years ≤50 years. Sex: Male or female subjects who were eligible for entry. Female subject of childbearing potential with a negative pregnancy test at the screening visit and who were willing to use an effective method of contraception, if applicable (unless of non-childbearing potential or where abstaining from sexual intercourse was in line with the preferred and usual lifestyle of the subject) from first dose until 3 months after the final dose of Investigational Medicinal Product (IMP). Effective forms of contraception included: established use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, male sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). Female subject of non-child bearing potential with negative pregnancy test at the screening visit. For the purposes of this study, this was defined as the subject being amenorrheic for at least 12 consecutive months or at least 4 months post-surgical sterilisation (including bilateral fallopian tube ligation or bilateral oophorectomy with or without hysterectomy). Menopausal status was confirmed by demonstrating at screening that levels of follicle stimulating hormone (FSH) fell within the respective pathology reference range. In the event a subject's menopause status had been clearly established (for example, the subject indicated she had been amenorrheic for 10 years), but FSH levels were not consistent with a post-menopausal condition, determination of subject eligibility was at the discretion of the Principal Investigator following consultation with the Sponsor's Responsible Physician. Male subject willing to use an effective method of contraception, if applicable (unless anatomically sterile or where abstaining from sexual intercourse in line with the preferred and usual lifestyle of the subject) from first dose until 3 months after the final dose of IMP. Healthy subjects as determined by past medical history, physical examination, vital signs, electrocardiogram (ECG), and laboratory tests at screening. Healthy subjects with a body mass index (BMI) of ≥20 and ≤27 kg/m2. Exclusion Criteria: Pregnant or lactating females. A history and/or presence of significant disease of any body system, including psychiatric disorders as specified in Chapter 5 of the International Classification of Diseases (ICD) 10. Any condition that may have interfered with the absorption, distribution, metabolism or excretion of drugs. A history of allergy or intolerance (including angioedema, urticaria, bronchospasm and rhinitis) related to treatment with ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), or the excipients of the formulations. A history of or active peptic or duodenal ulcers or gastrointestinal bleed or upper gastro-intestinal bleed, or other significant gastro-intestinal disorders. A history of frequent dyspepsia, e.g. heartburn or indigestion. A history of migraine. Users of nicotine products i.e. current smokers and ex-smokers who had smoked within the 6 months prior to dosing with the study medication or users of cigarette replacements (e.g. e-cigarettes, nicotine patches or gums). A history of substance abuse (including alcohol). High consumption of stimulating drinks (coffee, tea, cola, energy drinks etc. total caffeine intake per day above 300 mg (1 cup of coffee equated to 50 mg)). Those with positive screen/test for drugs of abuse including alcohol on any occasion throughout the study. Ingestion of a prescribed drug at any time in the 14 days before dosing with study medication (excluding hormonal contraceptives and hormone replacement therapy), or consumption of enzyme inhibitors or inducers during the previous month (such as barbiturates, carbamazepine, erythromycin, phenytoin, etc.). Ingestion of an over-the-counter preparation within 7 days before dosing with study medication, including herbal medications, vitamin/fish oil supplements, ibuprofen and other NSAID. Donation of blood in quantity >400 mL, e.g., to the blood transfusion service in the previous 12 weeks before enrolment into the study. Known human immune deficiency virus (HIV) positive status, or a positive viral serology screen. Topical use of ibuprofen within 7 days before dosing with IMP. Those previously randomized into this study. Employee at study site. Partner or first degree relative of the Investigator. Those who have participated in a clinical trial in the previous 12 weeks. Those unable, in the opinion of the Investigator, to comply fully with the study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Test (fed): Nurofen for Children<br>Nurofen for Children® 400 mg/10 ml by mouth under fed condition Subjects participated in Treatment Sequence: BACD, DCAB, ADBC and CBDA. | Drug: Nurofen for Children®<br>* Nurofen for Children® 400 mg/10 ml<br>* Other names: NfC®;|
| Active Comparator: Test (fasted): Nurofen for Children<br>Nurofen for Children® 400 mg/10 ml by mouth under fasted condition. Subjects participated in Treatment Sequence: BACD, DCAB, ADBC and CBDA. | Drug: Nurofen for Children®<br>* Nurofen for Children® 400 mg/10 ml<br>* Other names: NfC®;|
| Experimental: Reference (fed): Algifor Junior<br>Algifor® Junior 400 mg/20 ml by mouth under fed condition. Subjects participated in Treatment Sequence: BACD, DCAB, ADBC and CBDA. | Drug: Algifor® Junior<br>* Algifor® Junior 400 mg/20 ml<br>* Other names: Ibuprofen oral suspension;|
| Experimental: Reference (fasted): Algifor Junior<br>Algifor® Junior 400 mg/20 ml by mouth under fasted condition. Subjects participated in Treatment Sequence: BACD, DCAB, ADBC and CBDA. | Drug: Algifor® Junior<br>* Algifor® Junior 400 mg/20 ml<br>* Other names: Ibuprofen oral suspension;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Ibuprofen | One Subject in Period 3 Reference (fasted) was not included in PK Parameter Summary Set as per statistical analysis plan (SAP) Population definitions. | Pre-dose (Day -1), 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 180, 240, 360, 480 and 720 minutes (Day 0) post-dose | 
| Area Under Plasma Concentration-time Curve From Administration to the Last Quantifiable Concentration at Time t (AUC0-t) of Ibuprofen |  | Pre-dose (Day -1), 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 180, 240, 360, 480 and 720 minutes (Day 0) post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Elimination Rate Constant (Kel) of Ibuprofen | Kel was calculated as the absolute value of the log-linear regression slope of the elimination phase (logged) over time (linear) using the post Cmax concentrations [at least 3 non-below the limit of quantification (BLQ)] that maximized the adjusted R2. | Pre-dose (Day -1), 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 180, 240, 360, 480 and 720 minutes (Day 0) post-dose | 
| Area Under Plasma Concentration-time Curve From Administration to Infinity (AUC0-inf) of Ibuprofen | AUC0-inf was calculated as AUC0-t + (Ct/Kel) where Ct was the last quantifiable concentration at time t. | Pre-dose (Day -1), 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 180, 240, 360, 480 and 720 minutes (Day 0) post-dose | 
| Ratio of AUC0-t/AUC0-inf (AUCR) |  | Pre-dose (Day -1), 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 180, 240, 360, 480 and 720 minutes (Day 0) post-dose | 
| Time to Maximum Plasma Concentration (Tmax) of Ibuprofen |  | Pre-dose (Day -1), 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 180, 240, 360, 480 and 720 minutes (Day 0) post-dose | 
| Plasma Concentration Half-life (T1/2) of Ibuprofen |  | Pre-dose (Day -1), 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 180, 240, 360, 480 and 720 minutes (Day 0) post-dose | 
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Mild = Adverse event (AE) did not limit usual activities; subject may have experienced slight discomfort. Moderate = AE resulted in some limitation of usual activities; subject may have experienced significant discomfort. Severe = AE resulted in an inability to carry out usual activities; subject may have experienced intolerable discomfort/pain. Unassessable/Unclassified = Insufficient information to be able to make an assessment Conditional/ Unclassified = Insufficient information to make an assessment at present Unrelated = No possibility that the AE was caused by the IMP Unlikely = Slight, but remote, chance that the AE was caused by the IMP, but the balance of judgment was that it was most likely not due to the investigational medicinal product (IMP). Possible = Reasonable suspicion that the AE was caused by the IMP Probable = Most likely that the AE was caused by the IMP Certain = AE was definitely caused by the IMP | Up to Day 7 (follow-up) |