Single Dose, Two-stage Bioequivalence Study of SCMC-Lys Salt 1.35 g Powder vs SCMC-Lys Salt 90 mg/mL Syrup

Study Overview
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Brief Summary
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To investigate the bioequivalence between two formulations containing S-carboxymethyl-L-cysteine L-lysine monohydrate salt (SCMC-lys) when administered as single oral dose in two consecutive study periods to healthy male and female volunteers under fasting conditions.

Detailed Description
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As a part of the Dompé farmaceutici S.p.A. extension line program, Dompé developed a new 1.35 g powder for oral solution formulation of carbocysteine L-lysine salt-monohydrate. The present bioequivalence phase I study is needed to compare the bioavailability and the concentration-time profile of the new 1.35 g powder for oral solution formulation with the reference compound Fluifort® 90 mg/mL syrup (15 mL corresponding to 1.35 g of SCMC- lys). The new 1.35 g powder for oral solution formulation of carbocysteine L-lysine salt- monohydrate is expected to be bioequivalent to Fluifort® 90 mg/mL syrup with the same indications: mucolytic, expectorant in acute and chronic respiratory tract disorders. Primary end-point is to evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of carbocysteine after single oral administration of test and reference. Secondary end-point are: To describe the pharmacokinetic (PK) profile of carbocysteine after single oral administration of test and reference; to collect safety and tolerability data after single oral administration of test and reference. Study Design: The trial has been designed in agreement with the Guideline on the investigation of bioequivalence. Due to the lack of information about the PK profile of the new formulation it was decided to use a two stage bioequivalence study design, that allows a re-calculation of the sample size in case the number of subjects initially enrolled in the study is not large enough to provide a reliable answer to the questions addressed due to underestimation of the variability or misleading estimation of the point estimate for the T/R ratio of the geometric means. The sample size of stage 1 was calculated assuming a point estimate for the T/R ratio of the geometric means of 1.053 (i.e. μR=0.95·μT) and a multiplicative coefficient of variation (CVm) of 20% for both AUC0-t and Cmax. A power of 90% was considered and, according to the Pocock spending function and to the current European bioequivalence guideline, the α level was set to 0.0294. Fifteen (15) subjects per sequence (i.e. 30 subjects overall) will be enrolled in the first stage of the study. After the end of study stage 1, PK parameters will be calculated and an ad interim bioequivalence test will be performed on the calculated PK parameters Cmax, AUC0-t and AUC0-∞. To safeguard the overall type I error, the α level of the bioequivalence test will be set to 0.0294 according to the Pocock spending function. Should bioequivalence be proven with the results of the subjects of the first stage, the primary objective of the study would then be satisfied and the second study stage will not take place. Should bioequivalence not be proven with the results of the subjects of the first stage and with an a posteriori calculated power > 90% for both AUC0-t and Cmax, the study will be stopped and the bioequivalence will not be proven. Should bioequivalence not be proven with the results of the subjects of the first stage and with an a posteriori calculated power ≤ 90% for AUC0-t or Cmax, the overall sample size for the study (stage 1 plus 2) will be calculated on the basis of the ad interim bioequivalence results. The additional subjects will be enrolled into the second study stage. After completion of stage 2, the PK analysis and the bioequivalence test will be performed on the pooled subjects of the two study stages. The α level of the bioequivalence test of stage 1 plus 2 will be set to 0.0294 according to the Pocock spending function. The second stage will be performed after notification of the sample size to the local Ethics Committee and to the central Swiss authority (Swissmedic).

Official Title
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Two-way Crossover, Randomised, Single Dose and Two-stage Bioequivalence Study of Carbocysteine-L-lysine Salt 1.35 g Powder for Oral Solution Formulation vs 90 mg/mL Syrup Formulation After Oral Administration to Healthy Volunteers.

Conditions
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Bronchitis

Intervention / Treatment
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* Drug: 1.35 g SCMC- lys powder
* Drug: Fluifort® syrup


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be enrolled in this study, subjects must fulfil all these criteria: Informed consent: signed written informed consent before inclusion in the study Sex and Age: males/females,18-55 years old inclusive Body Mass Index (BMI): 18.5-30 kg/m2 inclusive Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-89 mmHg, pulse rate (PR) 50-90 bpm and body temperature (BT) 35.5 - 37.5°C, measured after 5 min of rest in the sitting position; Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study Contraception and fertility (females only): females of child-bearing potential and with an active sexual life must not wish to get pregnant within 30 days after the end of the study and must be using at least one of the following reliable methods of contraception: Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit until 30 days after final visit A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit until 30 days after final visit A male sexual partner who agrees to use a male condom with spermicide A sterile sexual partner Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all female subjects, pregnancy test result must be negative at screening. Exclusion Criteria: Subjects meeting any of these criteria will not be enrolled in the study: Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness Allergy: ascertained or presumptive hypersensitivity to the active principles (carbocysteine-L-lysine salt) and/or formulations' ingredients; history of hypersensitivity to drugs (in particular to mucolytics) or allergic reactions in general, which the Investigator considers may affect the outcome of the study Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory (including asthma), skin, haematological, endocrine or neurological and autoimmune diseases that may interfere with the aim of the study Medications: medications, including over the counter (OTC) drugs [in particular carbocysteine-L-lysine salt, carbocysteine and N-acetylcysteine, mucolytics and /or mucoregulators in general], herbal remedies and food supplements taken 2 weeks before the start of the study. Hormonal contraceptives for females will be allowed Investigative drug studies: participation in the evaluation of any investigational product for 6 months before this study. The 6-month interval is calculated as the time between the last visit of the previous study and the first day of the present study (date of the informed consent signature) Blood donation: blood donations for 3 months before this study Drug, alcohol, caffeine, tobacco: history of drug, alcohol (>1 drink/day for females and >2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010 [29]) caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥6 cigarettes/day) Drug test: positive result at the drug test at screening Alcohol test: positive alcohol breath test at day -1 Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.35 g SCMC- lys powder<br>1.35 g of SMC L-lysine monohydrate salt powder for solution | Drug: 1.35 g SCMC- lys powder<br>* 1.35 g SCMC- lys powder for oral solution<br>* Other names: Carbocisteine lysine salt 1.35 g powder for oral solution;|
| Experimental: Fluifort® syrup<br>Fluifort® syrup 90 mg SCMC-lys/mL | Drug: Fluifort® syrup<br>* SCMC-lys Syrup 90 mg/ml<br>* Other names: Carbocisteine lysine salt 90 mg/ml syrup;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Cmax of carbocysteine calculated from plasma concentrations after single oral dose | 10 hrs | 
| AUC0-t | AUC0-t of carbocysteine calculated from plasma concentrations after single oral dose | 10 Hrs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-∞ | AUC0-∞ of carbocysteine calculated from plasma concentrations after single oral dose | 10 Hrs | 
| tmax | tmax of carbocysteine calculated from plasma concentrations after single oral dose | 10 Hrs | 
| t1/2 | t1/2 of carbocysteine calculated from plasma concentrations after single oral dose | 10 Hrs | 
| TEAEs | Treatment-emergent AEs | Screening | 
| TEAEs | Treatment-emergent AEs | 10 Hrs |