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

2-way Crossover, Randomised, Single Dose and 2-stage Bioequivalence Phase I 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.

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02858193

Enrollment

Registered

2016-08-08

Start date

2016-07-04

Completion date

2016-10-10

Last updated

2024-11-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Bronchitis

Brief summary

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: * to describe the pharmacokinetic (PK) profile of carbocysteine after single oral administration of test and reference products; * to collect safety and tolerability data after single oral administration of test and reference products.

Detailed description

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).

Interventions

DRUGSCMC-lys powder 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.

DRUGFluifort® syrup

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.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 55 Years

Healthy volunteers

Yes

Inclusion criteria

To be enrolled in this study, subjects must fulfil all these criteria: 1. Informed consent: signed written informed consent before inclusion in the study 2. Sex and Age: males/females,18-55 years old inclusive 3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive 4. 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; 5. 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 6. 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: 1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit until 30 days after final visit 2. 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 3. A male sexual partner who agrees to use a male condom with spermicide 4. 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: 1. Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities 2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study 3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness 4. 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 5. 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 6. 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 7. 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) 8. Blood donation: blood donations for 3 months before this study 9. 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) caffeine (\>5 cups coffee/tea/day) or tobacco abuse (≥6 cigarettes/day) 10. Drug test: positive result at the drug test at screening 11. Alcohol test: positive alcohol breath test at day -1 12. Diet: abnormal diets (\<1600 or \>3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians 13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women

Design outcomes

Primary

Measure	Time frame	Description
Carbocysteine Plasma PK Parameters: Cmax	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	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
Carbocysteine Plasma PK Parameters: AUC0-t	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	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

Secondary

Measure	Time frame	Description
Carbocysteine Plasma PK Parameters: t1/2	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	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.
Carbocysteine Plasma PK Parameters: AUC0-∞	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	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
Number of TEAEs	From the screening visit up to the final visit/ETV (i.e.up to 4 weeks)	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.
Carbocysteine Plasma PK Parameters: Frel	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	Frel: Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)
Carbocysteine Plasma PK Parameters: Tmax	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	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.

Countries

Switzerland

Participant flow

Recruitment details

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.

Participants by arm

Arm	Count
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.	30
Total	30

Baseline characteristics

Characteristic	All Study Partecipants
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	30 Participants
Age, Continuous	38.9 years STANDARD_DEVIATION 10.6
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	1 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	29 Participants
Region of Enrollment Switzerland	30 participants
Sex: Female, Male Female	12 Participants
Sex: Female, Male Male	18 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 30	0 / 30
other Total, other adverse events	0 / 30	0 / 30
serious Total, serious adverse events	0 / 30	0 / 30

Outcome results

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