Bioequivalence of a Fixed Dose Combination Tablet Containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl Compared to Two Film Coated Fixed Dose Combination Tablets RhinAdvil(R)(200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) Administered in Healthy Subjects

Bioequivalence of a Fixed Dose Combination Tablet Containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl Compared to Two Film Coated Fixed Dose Combination Tablets RhinAdvil® (200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) Administered in at Least 48 Healthy Male and Female Subjects (Open-label, Randomized, Laboratory Blind, Single Dose, Two-way Crossover, Phase I Trial).

Primary objective To demonstrate the bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets containing 200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) as a fixed dose combination tablet with respect to the analytes, ibuprofen and pseudoephedrine.

Secondary objective To assess the bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets containing 200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) as a fixed dose combination tablet with respect to R- and S-ibuprofen (enantiomers of ibuprofen).

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Ibuprofen; Drug: Pseudoephedrine-HCl

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Bloemfontein, South Africa, 9301
    • Bloemfontein Early Phase Clinical Unit, PAREXEL International (South Africa)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Healthy males and females according to the following criteria:
• Based upon a complete medical history, including physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), clinical laboratory tests
• Age ≥21 to ≤50 years
• Minimum weight 50kg - both males and females
• Body Mass Index ≥18.5 to ≤29.9 kg/m2
• Signed and dated written informed consent in accordance with Good Clinical Practice (GCP) and local legislation prior to admission to the trial
• Male or female patients. Women of childbearing potential1 must be ready and able to use highly effective methods of birth control per International Committee on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly e.g. implants, injectables, combined hormonal contraceptives, intrauterine device, or surgical sterilisation (including hysterectomy). In addition to this, also a barrier method (e.g. male condom) will be required, if the female is not surgically sterilised. A list of contraception methods meeting these criteria is provided in the patient information. Abstaining from sexual activity (if this is the usual lifestyle of the subject) is considered an acceptable method of birth control.

Exclusion criteria:

• Any finding of the medical examination (including Blood Pressure, Pulse Rate and Electrocardiogram) deviating from normal and of clinical relevance at the discretion of the investigator
• Any evidence of a clinically relevant concomitant disease
• Any relevant Gastrointestinal (e.g. ulcera, hernia, bleedings and spasm), hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Any relevant surgery of the gastrointestinal tract (except appendectomy)
• Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or relevant neurological disorders at the discretion of the investigator
• History of relevant orthostatic hypotension, fainting spells or blackouts
• Chronic or relevant acute infections
• History of relevant allergy or hypersensitivity (including allergy to drug or its excipients) as judged clinically relevant by the investigator
• Intake of drugs with a long half-life (>24 hours) within at least 1 month or less than 10 half-lives of the respective drug prior to first drug administration
• Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within 14 days prior to randomisation
• Participation in another trial with an investigational drug within 2 months prior to administration or during the trial
• Smoker (>10 cigarettes or >3 cigars or >3 pipes/day)
• Inability to refrain from smoking on trial days as judged by the investigator
• Alcohol abuse (average consumption of more than 2 units per day for females and more than 3 units per day for males)
• Drug abuse
• Blood donation (more than 100 mL within four weeks prior to administration of the trial drug in this study)
• Excessive physical activities within 1 week prior to randomisation or during the trial
• Any laboratory value outside the reference range that is of clinical relevance at the discretion of the investigator
• Inability to comply with dietary regimen of the study centre
• Unwilling to avoid excessive sunlight exposure
• Use of drugs which might reasonably influence the results of the trial or that prolong the QT/corrected QT interval (QTc) within 14 days prior to administration or during the trial, and CYP2C8m substrates such as amiodarone, amodiaquine, paclitaxel, rosiglitazone, pioglitazone and repaglinide or CYP2C9 such as warfarin, tolbutamide, phenytoin, losartan, acenocoumarol within 1 month or six half-lives (whichever is greater)
• A marked baseline prolongation of the QTc B interval (e.g., repeated demonstration of a QTc B interval >450 ms)
• A history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalaemia, family history of Long QT Syndrome)

Special exclusion criteria:

• Subjects with history of bronchospasm, rhinitis or urticaria associated with Nonsteroidal anti-inflammatory drug (NSAID) - Asthma
• Risk of or manifested narrow-angle glaucoma
• Risk of urinary retention due to urethro-prostatic diseases / prostatic enlargement
• Subjects with the rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase isomaltase deficiency
• Regular treatment with any systemically available medication (except hormonal contraceptives and hormonal replacement therapy e.g. estrogens, L-thyroxine)
• Subjects, who report a frequent occurrence of migraine attacks
• For female subjects of childbearing potential only:

Positive pregnancy test, pregnancy or planning to become pregnant during the study or within 2 months after study completion

• No adequate contraception during the study including three months before first dosing until 2 month after study completion.
• Lactation

Administrative reasons:

• Subjects suspected or known not to follow instructions
• Subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the study

The exclusion criteria are chosen to assure that subjects with specific risks for administration of the investigational medicinal products and subjects with conditions, which may have an impact on pharmacokinetic parameters, cannot be included

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ibuprofen+Pseudoephedrine-HCl; Fixed dose combination	Drug: Ibuprofen; Fixed dose combination; Drug: Pseudoephedrine-HCl; Fixed dose combination
Active Comparator: Ibuprofen+Pseudoephedrine-HCl (RhinAdvil®); Fixed Dose Combination	Drug: Ibuprofen; Fixed dose combination; Drug: Pseudoephedrine-HCl; Fixed dose combination

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Ibuprofen. (AUC0-tz)	This endpoint calculates area under the concentration-time curve of Ibuprofen in plasma over the time interval from 0 to the time of last quantifiable time point.	Samples were collected Pre-dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
Maximum Concentration of Ibuprofen in Plasma (Cmax).	This outcome is maximum measured concentration of the Ibuprofen in plasma	Samples were collected pre dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Pseudoephedrine (AUC0-tz).	This endpoint calculates area under the concentration-time curve of Pseudoephedrine in plasma over the time interval from 0 to the time of last quantifiable time point.	Samples were collected pre dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
Maximum Concentration of Pseudoephedrine in Plasma (Cmax).	This outcome is maximum measured concentration of the Pseudoephedrine in plasma	Samples were collected pre dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-time Curve of Ibuprofen in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞).	This endpoint calculates area under the concentration-time curve of Ibuprofen in plasma over the time interval from 0 extrapolated to infinity	Samples were collected Pre-dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
Area Under the Concentration-time Curve of Pseudoephedrine in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞).	This endpoint calculates area under the concentration-time curve of Pseudoephedrine in plasma over the time interval from 0 extrapolated to infinity	Samples were collected pre dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
AUC0-tz of R-Ibuprofen	This endpoint calculates area under the concentration-time curve of R-Ibuprofen in plasma over the time interval from 0 to the time of last quantifiable time point.	Samples were collected Pre-dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
AUC0-∞ of R-Ibuprofen	This endpoint calculates area under the concentration-time curve of R-Ibuprofen in plasma over the time interval from 0 extrapolated to infinity	Samples were collected Pre-dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
Cmax of R-Ibuprofen	This outcome is maximum measured concentration of the R-Ibuprofen in plasma	Samples were collected pre dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
AUC0-tz of S-Ibuprofen	This endpoint calculates area under the concentration-time curve of S-Ibuprofen in plasma over the time interval from 0 to the time of last quantifiable time point.	Samples were collected Pre-dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
AUC0-∞ of S-Ibuprofen	This endpoint calculates area under the concentration-time curve of S-Ibuprofen in plasma over the time interval from 0 extrapolated to infinity	Samples were collected Pre-dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
Cmax of S-Ibuprofen	This outcome is maximum measured concentration of the S-Ibuprofen in plasma	Samples were collected pre dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.
S/R-ibuprofen Ratio for AUC0-tz	AUC0-tz S-ibuprofen / AUC0-tz R-ibuprofen	Samples were collected pre dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2016
• Primary Completion (Actual): January 31, 2017
• Study Completion (Actual): February 8, 2017

Study Registration Dates

• First Submitted: November 10, 2016
• First Submitted That Met QC Criteria: November 10, 2016
• First Posted (Estimate): November 15, 2016

Study Record Updates

• Last Update Posted (Actual): September 27, 2018
• Last Update Submitted That Met QC Criteria: January 23, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Central Nervous System Stimulants; Sympathomimetics; Vasoconstrictor Agents; Nasal Decongestants; Ibuprofen; Ephedrine; Pseudoephedrine
• Other Study ID Numbers: 1024.9