A Bioequivalence Study of Advil PM Liqui-Gels Minis (Ibuprofen/Diphenhydramine Hydrochloride 200 mg/25 mg) Compared to the Current Marketed Advil PM Liqui-Gels (Ibuprofen/Diphenhydramine Hydrochloride 200 mg/25 mg) in Healthy Adult Subjects Under Fasted Conditions

Pain Clinical Trial

Official title:

A Randomized, Open Label, Single Center, Single Dose, Two Treatment, Two Period, Two Sequence Crossover Bioequivalence Study of Advil PM Liqui-Gels Minis (Ibuprofen/Diphenhydramine Hydrochloride 200 mg/25 mg) To Advil PM Liqui-Gels (Ibuprofen/Diphenhydramine Hydrochloride 200 mg/25 mg) in Healthy Adult Subjects Under Fasted Conditions

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05674721
• Other study ID #: 218677
• Status: Completed
• Phase: Phase 1
• Start date: January 5, 2023
• Est. completion date: March 21, 2023

Study information

• Verified date: April 2023
• Source: HALEON
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to support the submission of Advil PM Liqui-Gels Minis (ibuprofen/diphenhydramine hydrochloride 200 milligrams [mg]/25 mg) which is a size reduction of the currently marketed Advil PM Liqui-Gels, by determining if this product is bioequivalent to the reference product Advil PM Liqui-Gels (ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) under fasting conditions.

Description:

This is a single center, single dose, open-label, randomized, two-treatment, two-sequence, two-period crossover, bioequivalence study in healthy adult participants with at least a 7-day washout period. A sufficient number of participants will be screened to randomize approximately 44 to ensure at least 37 evaluable participants complete the entire study. Participants will be randomly assigned to one of 2 treatment sequences and receive a single dose of one of the treatments in each period following a crossover design.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: March 21, 2023
• Est. primary completion date: March 21, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study before any assessment is performed.

• Participant who is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

• Healthy participant, which is defined as in general good physical health, as judged by the investigator and no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead Electrocardiogram (ECG) or clinical laboratory tests.

• Body Mass Index (BMI) of 18.5 to 30.0 Kilogram per meter square (kg/m^2); and a total body weight greater than or equal to (>=)50.0 Kilogram (kg) for males and >=45.0 kg for females.

• Female participant of childbearing potential 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 is not of childbearing potential must meet at least one of the following criteria: A. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle-stimulating hormone (FSH) level >= 40 mili international unit per milliliter (mIU/mL) B. Have undergone a documented (including self-reported) hysterectomy and/or bilateral oophorectomy.

• Participant with two negative tests (one at screening within 72 hours of admission and one at check in Day-1 in Period 1) for active coronavirus disease 2019 (COVID-19), separated by more than (>)24 hours.

Exclusion Criteria:

• Participant who is an investigational site staff member directly involved in the conduct of the study and his/her family members, site staff member otherwise supervised by the Investigator, or participant who is a GlaxoSmithKline (GSK) employee directly involved in the conduct of the study.

• Participation in other studies involving investigational drug(s) within 30 days prior to study entry and/or during study participation.

• Acute or chronic medical or psychiatric 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.

• Pregnant female participant as confirmed by a positive pregnancy test or intending to become pregnant over the duration of the study.

• Breastfeeding female participant.

• Known or suspected intolerance or hypersensitivity to the study materials (or closely related compounds) or any of their stated ingredients (gelatin, medium-chain triglycerides, pharmaceutical ink, polyethylene glycol, potassium hydroxide, purified water, sorbitol sorbitan solution).

• Any history of asthma, urticaria, or other significant allergic diathesis or allergic reaction to any other pain reliever/fever reducer. Participant with uncomplicated seasonal allergic rhinitis can be accepted if expected allergy season is clearly outside enrollment/treatment period.

• Diagnosis of long QT syndrome or QTcF > 450 millisecond (msec) for males and > 470 msec for females 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 50 or over 90 mmHg, or pulse rate less than 50 or over 100 beats per minute [bpm]).

• Unwilling or unable to comply with the Lifestyle Considerations described in this protocol.

• Use of any medication (including over the counter [OTC] medications and herbal remedies) within 2 weeks or within less than 10 times the elimination half-life of the respective drug (whichever is longer) before first scheduled study drug administration or is anticipated to require any concomitant medication during that period or at any time throughout the study. Allowed treatments are:

1. 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.

2. occasional use of acetaminophen (up to 2 grams [g] daily).

• Evidence or history of clinically significant laboratory abnormality, 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.

• 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:

1. 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, for example, appendectomy and herniorrhaphy).

2. History of inflammatory bowel disease or gastrointestinal bleeding including peptic ulcers.

3. History or current evidence of renal disease or impaired renal function at screening as indicated by abnormal levels of serum creatinine (> 1.43 milligram/deciliter [mg/dL]) or blood urea nitrogen (BUN) (>= 35 mg/dL) or the presence of clinically significant abnormal urinary constituents (e.g., albuminuria).

4. History or current evidence of ongoing hepatic disease or impaired hepatic function at screening. A participant will be excluded if more than one of the following lab value deviations are found: 1) Aspartate aminotransferase (AST) (>= 1.2 upper limit of normal [ULN]), Alanine transaminase (ALT) (>= 1.2 ULN), 2) Gamma-glutamyl transferase (GGT) (>= 1.2 ULN), Alkaline phosphatase (ALP) (>= 1.2 ULN), 3) total bilirubin (> 2.00 mg/dL) or creatine kinase (>= 3 ULN). A single deviation from the above values is acceptable and will not exclude the candidate, unless specifically advised by the investigator.

5. Evidence of urinary obstruction (for example, due to benign prostate hyperplasia) or difficulty in voiding at screening.

6. Diagnosis of angle-closure (narrow angle) glaucoma.

7. History or clinical evidence at screening of pancreatic injury or pancreatitis.

• Participant with signs and symptoms suggestive of COVID-19 (for example, fever, cough, and so on within 14 days of inpatient admission as defined by World Health Organization (WHO) or local guidance.

• Participant with known COVID-19 positive contacts in the past 14 days.

• Any vaccination, including COVID-19 vaccine, within 14 days prior to the first dose.

• History of drug abuse within 1 year prior to screening or recreational use of soft drugs (such as marijuana) within 1 month or hard drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine derivatives) within 3 months prior to screening.

• History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to screening that exceeds 10 units for women or 15 units for men of alcohol per week (1 unit = 340 mL of beer 5 percent [%], 140 mL of wine 12%, or 45 mL of distilled alcohol 40%).

• Positive urine drug screen or alcohol breath test at screening.

• Participant reported regular consumption of beverages or food containing xanthine derivatives or xanthine-related compounds (for example, coffee, tea, caffeine-containing sodas and chocolate), equivalent to >= 500 mg xanthine per day.

• Current smoker, defined as the use of tobacco or nicotine products during the 3 months prior to screening until admission to the unit or a positive urine cotinine test at screening.

• Participant reports consumption of any drug metabolizing enzyme (e.g., CYP3A4 or other cytochrome P450 enzymes) inducing or inhibiting aliments, beverages or food supplements (for example, broccoli, Brussels sprouts, grapefruit, grapefruit juice, star fruit, St. John's Wort and so on) within 2 weeks prior to admission to the unit.

• Performance of strenuous physical exercise (body building, high performance sports) from 2 weeks prior to admission and throughout the entire study.

• 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 Participant.

• 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.

• Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to dosing.

• Hemoglobin value less than (<)12.0 grams per deciliter (g/dL) for males and < 11.5 g/dL for females.

• Participant who has previously been enrolled in this study.

Related Conditions & MeSH terms

• Pain

Intervention

Drug:
• Advil PM Liqui-Gels Minis
Ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg, Oral capsule which is a size reduction of the currently marketed reference product.
• Advil PM Liqui-Gels
Ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg, Oral capsule.

Locations

Country	Name	City	State
United States	Syneos Health	Miami	Florida

Sponsors (1)

Lead Sponsor	Collaborator
HALEON

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Observed Plasma Concentration (Cmax) for Ibuprofen	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12 and 16 hours following dosing
Primary	Cmax for Diphenhydramine	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing
Primary	Area Under the Plasma Concentration Versus Time Curve Calculated from Time 0 to the Last Measurable Sampling TimePoint (t) (AUC [0-t]) for ibuprofen	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12 and 16 hours following dosing
Primary	AUC (0-t) for Diphenhydramine	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing
Primary	Area Under the Plasma Concentration Versus Time Curve Calculated from Time 0 to infinity (AUC [0-inf]) for ibuprofen	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12 and 16 hours following dosing
Primary	AUC [0-inf]) for Diphenhydramine	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing
Secondary	Terminal Elimination Rate Constant (?z) for Ibuprofen	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12 and 16 hours following dosing
Secondary	?z for Diphenhydramine	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing
Secondary	Time of the Maximum Plasma concentration (Tmax) for Ibuprofen	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12 and 16 hours following dosing
Secondary	Tmax for Diphenhydramine	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing
Secondary	The elimination half-life (t1/2) for Ibuprofen	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12 and 16 hours following dosing
Secondary	t1/2 for Diphenhydramine	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing
Secondary	Apparent Volume of Distribution (Vz/F) for Ibuprofen	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12 and 16 hours following dosing
Secondary	Vz/F for Diphenhydramine	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing
Secondary	Apparent Total Clearance (CI/F) for Ibuprofen	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12 and 16 hours following dosing
Secondary	CI/F for Diphenhydramine	Blood samples will be collected at indicated timepoints and PK analysis will be performed.	One hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing
Secondary	Ease of Swallowing on 5-Point Ordinal Scale	Immediately after dosing the assessment of 'ease of swallowing' will be done via one question with an ordinal response (ease of swallowing on 5-point ordinal scale) of each product. Rank the 'ease of swallowing' of the product included 5= very easy to swallow; 4 = above average to swallow; 3 = average to swallow; 2 = somewhat easy to swallow; 1 = not easy to swallow. Higher score indicates more ease in swallowing.	Day 1 in treatment period 1 and 2 (each period is of 3 days)