A Bioequivalence Study of Two Ibuprofen Arginine Granules 400 mg Formulations Under Fasting and Fed Conditions in Chinese Healthy Adult Subjects

Study Overview
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Brief Summary
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The primary purpose of this study is to demonstrate the bioequivalence of two ibuprofen arginine granules 400 milligram (mg) formulations under fasting and fed conditions in Chinese healthy adult participants. The secondary purpose of this study is to assess the pharmacokinetic and safety profile of the test and reference preparations.

Detailed Description
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The bioequivalence study adopts a single-center, randomized, open-label, single-dose, two-treatment, two-sequence, two-period, two-cohort, two-way crossover design with at least 2-day washout period, under both fasting and fed conditions in Chinese healthy adult participants. It will be planned to enroll approximately 84 participants out of which the first 34 participants for the fasted cohort and the subsequent 50 participants for the fed cohort receiving ibuprofen arginine granules 400 mg. Participants will be randomly assigned to either one of the 2 treatment (Test or Reference product) sequences in a 1:1 ratio within fasted cohort and fed cohort.

Official Title
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A Randomized, Open-label, Single-center, Single-dose, Two Treatment, Two-sequence, Two-period, Two-cohort, Two-way Crossover Bioequivalence Study of Two Ibuprofen Arginine Granules 400 mg Formulations Under Fasting and Fed Conditions in Chinese Healthy Adult Subjects

Conditions
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Pain

Intervention / Treatment
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* Drug: Ibuprofen arginine granules 400 mg
* Drug: Ibuprofen arginine granules 400 mg (Spedifen)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants provision of a signed and dated informed consent and/or assent document indicating that the participant has been informed of all pertinent aspects of the study before any assessment is performed. Participants who is willing and able to comply with scheduled visits, treatment plan, laboratory tests, study restrictions, lifestyle considerations and other study procedures. Healthy Participants, which is defined as in general good physical health, as judged by the investigator and no clinically significant relevant abnormalities identified by a detailed medical history, full physical examination, including vital signs, 12-lead electrocardiogram (ECG) and laboratory tests. A Participants with a Body Mass Index (BMI) of 19-26 kilogram per meter square (kg/m^2) (including 19, excluding 26) [BMI equal to (=) weight (Kilogram [kg])/height^2 (m^2)]; and a total body weight more than or equal to >= 50 kilogram (kg) for males, and >= 45 kg for females, at screening. Participants with one negative polymerase chain reaction (PCR) or antigen test (on Day-1) for active Coronavirus disease 2019 (COVID-19). Participants of childbearing potential and are sexually active and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 30 days after the last dose of assigned treatment. Female participant who are not of childbearing potential must meet requirements in the Contraception section of protocol. Exclusion Criteria: Known or suspected intolerance or hypersensitivity or photosensitivity to the investigational products (or closely related compounds) or any of their stated ingredients. Allergy to skin disinfecting agents, tape, or latex rubber, whenever appropriate substitutions cannot be applied or in the investigator's opinion may pose a risk to the candidate. Diagnosis of long QT syndrome or QTcF > 450 millisecond (msec) at screening. Clinically significant vital sign abnormalities (systolic blood pressure lower than 90 or over 140 millimeters of mercury (mmHg), diastolic blood pressure lower than 60 or over 90 mmHg, or pulse rate less than 50 or over 100 beats per minute [bpm]). Use of any medication (including over-the-counter medications and Chinese herbal and traditional remedies) within 2 weeks before first scheduled study drug administration or within less than 10 times the elimination half-life of the concomitant medication (whichever is longer) or is anticipated to require any concomitant medication during that period or at any time throughout the study. Allowed treatments are: systemic contraceptives and hormone replacement therapy, as long as female participant is on stable treatment for at least 3 months before first scheduled study drug administration and continues treatment throughout the study. occasional use of acetaminophen (up to 2 grams [g] in 24 hours). Participants has a history of drug abuse or has positive urine drug abuse screening at screening or on Day-1. Participants reported regular consumption of > 5 cups (1 cup approximately 250 milliliters [mL]) of coffee or tea per day (or equivalent consumption of >= 500 mg caffeine per day using other products). Or consuming any beverages or food containing caffeine, such as coffee, tea, coke, chocolate, etc., within 48 hours prior to screening. Smoking or history of regular use of tobacco- or nicotine-containing products (for example nicotine patch, electronic cigarette) within 6 months prior to screening. Or a participant who is unwilling to abstain from tobacco or nicotine containing product use during the study. Evidence, as reported by an alcohol breath testing, for current alcohol abuse or reports a regular average alcohol consumption exceeding 18 g (women) or 35 g (men) of pure alcohol per day, that is (i.e.) 1 drink/day for women or 2 drinks/day for men [1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor] within 6 months prior to screening. Participation in other clinical trials involving investigational drug(s) within 90 days prior to screening. Those who have blood donation (including component donation) or blood loss >= 400 mL within 3 months before the study or have blood transfusion; those who have blood donation (including component donation) or blood loss >= 200 mL within 1 month before the study (except female physiological blood loss). Acute or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. Or any condition not identified in the protocol that in the opinion of the investigator would confound the evaluation and interpretation of the study data or may put the participant at risk. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease within the last 5 years that may increase the risk associated with study participation. Clinically relevant chronic or acute infectious illnesses or febrile infections within two weeks prior to start of the study. Participation with known COVID-19 positive contacts in the past 14 days. Participation with signs or symptoms highly suggestive of COVID-19 (including not limited to fever, cough, chills, new loss of taste or smell, etc.) that also align with the clinical judgement of the investigator, within 14 days of inpatient admission as defined by World Health Organization (WHO) or local guidance. Any vaccination, including COVID-19 vaccine, within 14 days prior to the first dose of investigational products. Any surgical or medical condition which may significantly alter the absorption, distribution, metabolism or excretion of any drug substance but not limited to any of the following: History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling or gastric banding (note: this is not applicable for minor abdominal surgery without significant tissue resection, e.g., appendectomy and herniorrhaphy). History of inflammatory bowel disease. History or current evidence of renal disease or impaired renal function at screening as indicated by abnormal levels of estimated glomerular filtration rate (eGFR) less than (<) 90 mL/min/1.73m^2 or the presence of clinically significant abnormal urinary constituents (e.g., albuminuria). History or current evidence of ongoing hepatic disease or impaired hepatic function at screening. A candidate will be excluded if more than one of the following lab value deviations are found: Aspartate aminotransferase (AST) (>= 1.2 upper limit of normal [ULN]), alanine transaminase (ALT) (>= 1.2 ULN), Gamma-glutamyl transferase (GGT) (>= 1.2 ULN), alkaline phosphatase (ALP) (>= 1.2 ULN), Bilirubin (>= 1.5 ULN) or creatine kinase (CK) (>= 3 ULN). A single deviation from the above values is acceptable and will not exclude the candidate, unless specifically advised by the investigator. Evidence of urinary obstruction or difficulty in voiding at screening. History or clinical evidence at screening of pancreatic injury or pancreatitis. Pregnant or lactating women, or participant intending to become pregnant over the duration of the study. Positive results (or out of normal range) any of the virology tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody or syphilis. Participants reports consumption of any drug metabolizing enzyme (for example (e.g.), CYP3A4 or other cytochrome P450 enzymes) inducing or inhibiting aliments, beverages or food supplements (e.g., broccoli, Brussels sprouts, grapefruit, grapefruit juice, star fruit, St. John's Wort etc.) within 2 weeks prior to screening until admission to the unit. Performance of strenuous physical exercise (body building, high performance sports) from 2 weeks prior to admission. Those who are not suitable for participation in this study as determined by the investigator.

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibuprofen arginine granules 400 mg<br>Participants will be randomly assigned as per cross-over design to receive one sachet of Ibuprofen arginine granules 400 mg (test product) on day 1 of period 1 and will receive one sachet of Ibuprofen arginine granules 400 mg (Spedifen) (reference product) on day 1 of period 2 with at least 2 days washout period. Participants will be instructed to consume the product orally by dissolving it in 240 mL of warm water. | Drug: Ibuprofen arginine granules 400 mg<br>* Experimental- Ibuprofen arginine granules 400 mg, one sachet administration containing 400 mg ibuprofen granules.<br>Drug: Ibuprofen arginine granules 400 mg (Spedifen)<br>* Marketed drug- Ibuprofen arginine granules 400 mg (Spedifen), one sachet administration containing 400 mg ibuprofen granules.<br>|
| Active Comparator: Ibuprofen arginine granules 400 mg (Spedifen)<br>Participants will be randomly assigned as per cross-over design to receive one sachet of Ibuprofen arginine granules 400 mg (Spedifen) (reference product) on day 1 of period 1 and will receive one sachet of Ibuprofen arginine granules 400 mg (test product) on day 1 of period 2 with at least 2 days washout period. Participants will be instructed to consume the product orally by dissolving it in 240 mL of warm water. | Drug: Ibuprofen arginine granules 400 mg<br>* Experimental- Ibuprofen arginine granules 400 mg, one sachet administration containing 400 mg ibuprofen granules.<br>Drug: Ibuprofen arginine granules 400 mg (Spedifen)<br>* Marketed drug- Ibuprofen arginine granules 400 mg (Spedifen), one sachet administration containing 400 mg ibuprofen granules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Plasma Concentration-time Curve (AUC) From Zero Hours to Last Measurable Concentration (AUC[0-t]) of ibuprofen arginine granules in fed condition | Blood samples will be collected at indicated timepoints and pharmacokinetic (PK) analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and 10, 30, 45, 60, 75, 90, 120 minutes (min), 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 hours post-dose | 
| AUC From Zero Hours Extrapolated to Infinity AUC [0-inf] of ibuprofen arginine granules in fed condition | Blood samples will be collected at indicated timepoints and pharmacokinetic (PK) analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and 10, 30, 45, 60, 75, 90, 120 minutes (min), 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 hours post-dose | 
| Maximum Observed Drug Concentration (Cmax) of ibuprofen arginine granules in fed condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and 10, 30, 45, 60, 75, 90, 120 min, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 hours post-dose | 
| AUC[0-t] of ibuprofen arginine granules in fasted condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and at 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 hours post-dose | 
| AUC [0-inf] of ibuprofen arginine granules in fasted condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and at 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 hours post-dose | 
| Cmax of ibuprofen arginine granules in fasted state | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and at 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach Cmax (Tmax) and terminal phase half-life (t1/2) in fed condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and 10, 30, 45, 60, 75, 90, 120 min, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 hours post-dose | 
| Terminal Elimination Rate Constant (λz) of ibuprofen arginine granules in fed condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and 10, 30, 45, 60, 75, 90, 120 min, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 hours post-dose | 
| Percentage of extrapolated area of AUC(0- inf) (%AUCex) of ibuprofen arginine granules in fed condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and 10, 30, 45, 60, 75, 90, 120 min, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 hours post-dose | 
| Tmax and t1/2 in fasted condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and at 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 hours post-dose | 
| λz of ibuprofen arginine granules in fasted condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and at 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 hours post-dose | 
| %AUCex of ibuprofen arginine granules in fasted condition | Blood samples will be collected at indicated timepoints and PK analysis will be performed. PK parameters will be determined by non-compartmental methods. | Pre-dose (within 2 hours prior to dosing) and at 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 hours post-dose |