A Bioequivalence Study of an Acetylcysteine 2% Oral Solution Versus a Reference Fluimucil 2% Oral Solution

Study Overview
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Brief Summary
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This is an open-label, randomized, single-center, 2-period, 2-sequence, single-dose crossover design study in adult male and female healthy participants. Eligible participants will receive either treatment A (reference): Fluimucil® Acetylcysteine 2% oral solution, 200 mg N- acetylcysteine (NAC) in 10 mL dose, or treatment B (test): Acetylcysteine 2% oral solution, 200 mg NAC in 10 mL dose. Blood sampling will be collected pre-dose and up to 48 hours in each period. After completion of the second study period (i.e. last pharmacokinetic (PK) sample on Day 3 of Period 2) participants will be discharged from the clinic.

Official Title
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A Randomized, Open-Label, Two-Period, Crossover Bioequivalence Study in Healthy Adult Subjects After Single Oral Dosing of a NCH-GSK Acetylcysteine 2% Oral Solution Versus a Reference Fluimucil® Acetylcysteine 2% Oral Solution

Conditions
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Infections, Respiratory Tract

Intervention / Treatment
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* Drug: Fluimucil® 2% solution
* Drug: Acetylcysteine 2% solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must understand and provide written informed consent before any assessment is performed, understand the study procedures, and be willing to complete the required assessments. Male and female participants of any ethnic origin between 18 and 45 years of age. Body Mass Index (BMI) of 18.5 to 30 kg/m2, inclusive. Minimal body weight of 50 kg, inclusive. Normal vital signs as follows: Oral body temperature between 35.0 and 37.5 ºC inclusive; Sitting systolic blood pressure between 90 and 140 mmHg inclusive; Sitting diastolic blood pressure between 55 and 90 mmHg inclusive; Sitting pulse rate between 50 and 100 bpm inclusive. In general, good physical health, as judged by the Investigator and determined by medical/surgical history, physical examination, electrocardiogram (ECG, 12-lead) and clinical laboratory (clinical chemistry and hematology) findings. Exclusion Criteria: Use of other investigational drugs within 3 months or 10 half-lives of enrollment, whichever is longer. History of or known hypersensitivity to any of the study drugs, excipients or to drugs of similar chemical or pharmacological classes. Diagnosis of long QT syndrome or QTc (Fridericia preferred, but Bazett acceptable) ≥ 450 msec for males and ≥ 470 msec for females at screening. History of malignancy or neoplastic disease of any organ system (except for localized basal cell skin carcinoma), treated or untreated, within the past 5 years prior to screening, regardless of whether there is evidence of local recurrence or metastases. Pregnant, Women of child-bearing potential or breastfeeding women. Any surgical or medical condition which may significantly alter the absorption, distribution, metabolism or excretion of any drug substance History (within 5 years prior to study start) of clinically significant gastritis, pyloric channel stenosis, peptic ulcer or duodenal ulceration, gastro-esophageal reflux, gastrointestinal bleeding, rectal bleeding or other clinically significant GI abnormalities. History (within 5 years prior to study start) of orthostatic hypotension, cardiovascular disease, stroke, transient ischemic attack, fainting or blackouts. Clinically relevant chronic or acute infectious illnesses or febrile infections within 2 weeks prior to start of the study. Newly occurred (within 2 weeks of screening visit) cutaneous and mucosal alterations. Participants with histamine intolerance. Positive results in any of the virology tests for Human Immunodeficiency Virus-Ab, Hepatitis C Antibody (HCV-Ab), Surface Antigen of the Hepatitis B Virus (HBsAg), and Hepatitis B Core Antibody (HBc-Ab). Any evidence of clinically significant cardiovascular, pulmonary, renal, hepatic, gastrointestinal, hematological, endocrinological, metabolic, autoimmune, neurological, psychiatric or other diseases at screening. Participant has used any medication (including over-the-counter medications) within 2 weeks before first scheduled study drug administration or within < 10 times the elimination halflife of the respective drug (whichever is longer), or is anticipated to require any concomitant medication during that period or at any time throughout the study. Participant reports consumption of any drug metabolizing enzyme (e.g. CYP3A4 or other cytochrome P450 enzymes) inducing or inhibiting aliments, beverages or food supplements within two weeks prior to the first scheduled study drug administration, or is anticipated to consume such products during that two-week period or at any time throughout the study. Any history of drug hypersensitivity, asthma, urticaria, or other significant allergic diathesis, illicit drug abuse. Participant shows evidence for current alcohol abuse or smoking. Vulnerable individuals. Participation in a previous clinical study with or without another investigational product and with  470 ml blood drawn, or blood donation within the last 3 months prior to screening or previous enrollment into the current study. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Fluimucil® (reference) then Acetylcysteine (test) 2% solution<br>Participants will be orally administered with 10ml of 2% oral solution of Fluimucil® (reference) following a wash out period of at least a week then administration of by 10ml of 2% oral solution of Acetylcysteine (test). | Drug: Fluimucil® 2% solution<br>* Participants will be orally administered with 10ml of 2% oral solution of Fluimucil® (reference).<br>|
| Experimental: Acetylcysteine (test) 2% solution then Fluimucil® (reference)<br>Participants will be orally administered with 10ml of 2% oral solution of Acetylcysteine (test) following a wash out period of at least a week then administration of by 10ml of 2% oral solution of Fluimucil® (reference). | Drug: Acetylcysteine 2% solution<br>* Participants will be orally administered with 10ml of 2% oral solution of Acetylcysteine (test)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve from time zero to last sampling time [AUC(0-last)] | AUC(0-last) of acetylcysteine will be calculated using trapezoidal rule. Blood samples will be taken pre-dose and upto 48 hours post-dose of administration of the reference/test product in each period. | 3 days | 
| Maximum Plasma Concentration (Cmax) | Cmax of acetylcysteine will be obtained graphically from the plasma concentration over time profile. Blood samples will be taken pre-dose and upto 48 hours post-dose of administration of the reference/test product in each period. | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve from time zero to infinity [AUC(0-inf.)] | AUC(0-inf.) of acetylcysteine will be calculated using trapezoidal rule. Blood samples will be taken pre-dose and upto 48 hours post-dose of administration of the reference/test product in each period. | 3 days | 
| Time to reach maximum plasma concentration (Tmax) | Tmax of acetylcysteine will be obtained graphically from the plasma concentration over time profile. Blood samples will be taken pre-dose and upto 48 hours post-dose of administration of the reference/test product in each period. | 3 days | 
| Termination rate constant (Lambda_z) | Lambda_z will be computed as the slope of the regression line of ln (C(t)) on time. | 3 days | 
| Residual Area (RA) | RA will be calculated as percent extrapolated area (= (AUCinf - AUClast)/ AUCinf)*100%). | 3 days | 
| Elimination half life (t1/2) | T1/2 will be computed as T1/2 = 0.693/ λz | 3 days |