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| Name | Class |
|---|---|
| Cross Research S.A. | INDUSTRY |
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Objectives:
The objectives of the study was 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.
Primary end-point: to evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of carbocysteine after single oral administration of test and reference.
Secondary end-points:
This was a single centre, single dose, open, randomised, two-way, cross-over, two stage bioequivalence study. According to the two-stage design of the study, an initial group of subjects was treated in study stage 1 and data were analysed. If bioequivalence had been demonstrated, according to the protocol, the study would have been terminated after stage 1. Since this occurred, stage 2 was not performed.
The study was conducted as planned and consisted of a screening visit, a treatment phase of two study periods separated by a wash out interval of at least 4 days and a final visit / early termination visit (ETV).
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 Test/Reference (T/R) ratio of the geometric means.
The sequence of treatments in the two study periods was assigned to each randomised subject according to a computer generated randomisation list.
A wash-out period of at least 4 days between the two administrations is justified by the elimination half-life of the carbocysteine (1-2 h).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Test - Reference (1.35 g of SCMC-lys monohydrate salt powder - Fluifort® syrup 90 mg SCMC-lys/mL) | Experimental | In this arm, a single oral dose of test product (1 sachet; 1.35 g of SCMC-lys corresponding to 750 mg of carbocysteine-free base) was orally administered, under fasting conditions, in the first period (day 1, Visit 3, 8:00 ± 1h ), and, after a wash-out period of at least 4 days, a single dose of the reference product Fluifort® syrup 90 mg SCMC-lys/mL (15 mL of syrup, 1.35 g of SCMC-lys) was orally administered, under fasting conditions, in the second study period (day 1, visit 5, 8:00 ± 1h). |
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| Reference - Test (Fluifort® syrup 90 mg SCMC-lys/mL-1.35 g of SCMC-lys monohydrate salt powder) | Experimental | In this arm, a single oral dose of reference product Fluifort® syrup 90 mg SCMC-lys/mL (15 mL of syrup, 1.35 g of SCMC-lys) was orally administrated, under fasting conditions, in the first period (day 1, Visit 3, 8:00 ± 1h ), and, after a wash-out period of at least 4 days, a single dose of the test product 1 sachet; 1.35 g of SCMC-lys corresponding to 750 mg of carbocysteine-free base was orally administered, under fasting conditions, in the second study period (day 1, visit 5, 8:00 ± 1h). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| SCMC-lys powder 1.35 g | Drug | Powder for oral solution in sachets each containing 1.35 g of S-carboxymethyl-L-cysteine L-lysine monohydrate salt (SCMC-lys). One sachet of the powder of the test formulation: (1.35 g of SCMC-lys corresponding to 750 mg of carbocysteine-free base) was dissolved in 100 mL of hot (not boiling) still mineral water. Additional 100 mL of still mineral water at room temperature were added and mixed. The solution was swallowed and the glass was rinsed with 40 mL of still mineral water that was also drunk by the subjects. The final administered volume was 240 mL. All subjects were in fasting conditions from the evening before (at least 10 h, overnight).The final administered volume was 240 mL for both the test and reference treatments. |
| Measure | Description | Time Frame |
|---|---|---|
| Carbocysteine Plasma PK Parameters: Cmax | Cmax = maximum plasma concentration. Cmax of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of carbocysteine were measured in each study period at the timepoints hereunder reported. Arithmetic means+standard deviation are reported hereunder | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
| Carbocysteine Plasma PK Parameters: AUC0-t | AUC0-t= area under the concentration-time curve from administration to the last observed concentration time t, calculated with the linear trapezoidal method. AUC0-t of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentration of carbocysteine were measured in each study period at the timepoints hereunder specified.Arithmetic means±standard deviation are reported hereunder Please note that AUC0-t was considered a reliable estimate of the extent of absorption if the ratio AUC0-t/AUC0-∞ equalled or exceeded a factor of 0.8, i.e. if %AUCextra was <20%. Arithmetic means±standard deviation are reported hereunder | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| Carbocysteine Plasma PK Parameters: AUC0-∞ | AUC0-∞= Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration. AUC0-∞of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentration of carbocysteine were measured in each study period at the timepoints hereunder specified. Arithmetic means±standard deviation are reported hereunder |
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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:
Exclusion Criteria:
Subjects meeting any of these criteria will not be enrolled in the study:
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| Name | Affiliation | Role |
|---|---|---|
| Milko Radicioni, MD | CROSS Research S.A., Phase I Unit | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CROSS Research S.A., Phase I Unit | Arzo | Swiss | CH-6864 | Switzerland |
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30 healthy volunteers were randomized, receiving a single dose of test and reference treatment. Based on the cross-over design, a single dose of product was given orally in one of the two possible sequences: in the "test-reference" arm, subjects received SCMC-lys 1.35 g oral powder firstly and then the product Fluifort®. In the "reference-test" arm, subjects received reference product Fluifort® first, than SCMC-lys 1.35 g oral powder. A wash-out interval separated the 2 treatments.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sequence "Test -Reference" | Participants first received a single oral dose of test product (1 sachet; 1.35 g of SCMC-lys) under fasting condition (day 1, Visit 3, 8:00 ± 1h ). After a wash-out period of at least 4 days the partecipants then received a single dose of the reference product Fluifort® syrup 90 mg SCMC-lys/mL (15 mL of syrup, 1.35 g of SCMC-lys) always under fasting conditions. There were no premature discontinuations during the study |
| FG001 | Sequence "Reference - Test" | Participants first received a single oral dose of reference product Fluifort® syrup 90 mg SCMC-lys/mL (15 mL of syrup, 1.35 g of SCMC-lys) under fasting condition (day 1, Visit 3, 8:00 ± 1h ). After a wash-out period of at least 4 days the partecipants then received a single dose of the test product (1 sachet; 1.35 g of SCMC-lys) always under fasting conditions. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Treatment Period |
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| Washout Period (at Least 4 Days) |
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| Second Treatment Period |
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The 30 randomised subjects completed the study per protocol and were included in the PK and Safety population analyses.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Partecipants | Enrolled population: all enrolled subjects. This analysis was used for the analysis of demographic, baseline and background characteristics. Safety population: all subjects who received at least one dose of investigational product. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Carbocysteine Plasma PK Parameters: Cmax | Cmax = maximum plasma concentration. Cmax of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of carbocysteine were measured in each study period at the timepoints hereunder reported. Arithmetic means+standard deviation are reported hereunder | PK population: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product(s) intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that may affect the PK results | Posted | Mean | Standard Deviation | µg/mL | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
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AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), according to the period of occurrence, as follows: - PTAEs: all AEs occurring before the first dose of IMP and not worsening after the first dose of IMP - TEAEs: all AEs occurring or worsening after the first dose of IMP. AE were assessed from screening through study termination, an average of 4 weeks
No TEAE occurred during the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | SCMC-lys 1.35 g Oral Solution (Test Product) | SCMC-lys 1.35 g powder for oral solution in sachets each containing 1.35 g of S-carboxymethyl-L-cysteine L-lysine monohydrate salt (SCMC-lys). One sachet of the powder of the test formulation: (1.35 g of SCMC-lys corresponding to 750 mg of carbocysteine-free base) was dissolved in 100 mL of hot (not boiling) still mineral water. Additional 100 mL of still mineral water at room temperature were added and mixed. The solution was swallowed and the glass was rinsed with 40 mL of still mineral water that was also drunk by the subjects. The final administered volume was 240 mL. All subjects were in fasting conditions from the evening before (at least 10 h, overnight). The final administered volume was 240 mL for both the test and reference treatments. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Development & Operations | Dompé farmaceutici SpA | +39 02 583831 | clinical.trials@dompe.com |
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| ID | Term |
|---|---|
| D001991 | Bronchitis |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D011208 | Powders |
| D012996 | Solutions |
| ID | Term |
|---|---|
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
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| Fluifort® syrup | Drug | Fluifort® 90 mg/mL syrup (15 mL corresponding to 1.35 g SCMC-lys) Fifteen (15) mL of syrup (1.35 g of SCMC-lys corresponding to 750 mg of carbocysteine-free base) poured in a glass were drunk by the subjects. Afterward, the glass was rinsed twice with a volume of 100 mL and 125 mL of still mineral water and the rinses were drunk immediately by the subjects. The final administered volume was 240 mL for both the test and reference treatments. |
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| pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
| Carbocysteine Plasma PK Parameters: Tmax | Tmax = Time to achieve Cmax. Tmax (0-10hours) of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentration of carbocysteine were measured in each study period at the timepoints hereunder specified. | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
| Carbocysteine Plasma PK Parameters: t1/2 | t1/2= Half-life, calculated, if feasible, as ln2/λz. t1/2 (0-10 hours) of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentration of carbocysteine were measured in each study period at the timepoints hereunder specified. | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
| Carbocysteine Plasma PK Parameters: Frel | Frel: Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference) | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
| Number of TEAEs | TEAE=Treatment Emergent Adverse Events. TEAEs were assessed throughout the study, from the screening to the final visit/early termination visit (ETV) which take place after visit 5 on day 1 of period 2, more precisely after the 10h blood sampling and vital sign. | From the screening visit up to the final visit/ETV (i.e.up to 4 weeks) |
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| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| OG001 | Fluifort® 90 mg/mL Syrup (Reference Product) | Fluifort® 90 mg/mL syrup (15 mL corresponding to 1.35 g SCMC-lys) Fifteen (15) mL of syrup (1.35 g of SCMC-lys corresponding to 750 mg of carbocysteine-free base) poured in a glass were drunk by the subjects. Afterward, the glass was rinsed twice with a volume of 100 mL and 125 mL of still mineral water and the rinses were drunk immediately by the subjects. The final administered volume was 240 mL for both the test and reference treatments. |
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| Primary | Carbocysteine Plasma PK Parameters: AUC0-t | AUC0-t= area under the concentration-time curve from administration to the last observed concentration time t, calculated with the linear trapezoidal method. AUC0-t of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentration of carbocysteine were measured in each study period at the timepoints hereunder specified.Arithmetic means±standard deviation are reported hereunder Please note that AUC0-t was considered a reliable estimate of the extent of absorption if the ratio AUC0-t/AUC0-∞ equalled or exceeded a factor of 0.8, i.e. if %AUCextra was <20%. Arithmetic means±standard deviation are reported hereunder | PK population: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product(s) intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that may affect the PK results | Posted | Mean | Standard Deviation | µg/mL*h | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
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| Secondary | Carbocysteine Plasma PK Parameters: AUC0-∞ | AUC0-∞= Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration. AUC0-∞of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentration of carbocysteine were measured in each study period at the timepoints hereunder specified. Arithmetic means±standard deviation are reported hereunder | PK population: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product(s) intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that may affect the PK results | Posted | Mean | Standard Deviation | µg/mLxh | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
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| Secondary | Carbocysteine Plasma PK Parameters: Tmax | Tmax = Time to achieve Cmax. Tmax (0-10hours) of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentration of carbocysteine were measured in each study period at the timepoints hereunder specified. | PK population: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product(s) intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that may affect the PK results | Posted | Mean | Standard Deviation | h | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
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| Secondary | Carbocysteine Plasma PK Parameters: t1/2 | t1/2= Half-life, calculated, if feasible, as ln2/λz. t1/2 (0-10 hours) of carbocysteine was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentration of carbocysteine were measured in each study period at the timepoints hereunder specified. | PK population: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product(s) intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that may affect the PK results | Posted | Mean | Standard Deviation | h | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
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| Secondary | Carbocysteine Plasma PK Parameters: Frel | Frel: Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference) | PK population: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product(s) intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that may affect the PK results µg/mL | Posted | Mean | Standard Deviation | % of bioavailability | pre-dose (0), 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 h post-dose |
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| Secondary | Number of TEAEs | TEAE=Treatment Emergent Adverse Events. TEAEs were assessed throughout the study, from the screening to the final visit/early termination visit (ETV) which take place after visit 5 on day 1 of period 2, more precisely after the 10h blood sampling and vital sign. | Safety population: all subject who received at least one dose of investigational product. | Posted | Number | Number of events | From the screening visit up to the final visit/ETV (i.e.up to 4 weeks) |
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|
| 0 |
| 30 |
| 0 |
| 30 |
| 0 |
| 30 |
| EG001 | Fluifort® 90 mg/mL Syrup (Reference Product) | Fluifort® 90 mg/mL syrup (15 mL corresponding to 1.35 g SCMC-lys) Fifteen (15) mL of syrup (1.35 g of SCMC-lys corresponding to 750 mg of carbocysteine-free base) poured in a glass were drunk by the subjects. Afterward, the glass was rinsed twice with a volume of 100 mL and 125 mL of still mineral water and the rinses were drunk immediately by the subjects. The final administered volume was 240 mL for both the test and reference treatments. | 0 | 30 | 0 | 30 | 0 | 30 |
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| D008173 |
| Lung Diseases, Obstructive |
| D008171 | Lung Diseases |