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.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Carbocysteine Plasma PK Parameters: Cmax
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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) 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
研究组 & 干预措施
Test - Reference (1.35 g of SCMC-lys monohydrate salt powder - Fluifort® syrup 90 mg SCMC-lys/mL)
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).
干预措施: SCMC-lys powder 1.35 g (Drug)
Test - Reference (1.35 g of SCMC-lys monohydrate salt powder - Fluifort® syrup 90 mg SCMC-lys/mL)
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).
干预措施: Fluifort® syrup (Drug)
Reference - Test (Fluifort® syrup 90 mg SCMC-lys/mL-1.35 g of SCMC-lys monohydrate salt powder)
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).
干预措施: SCMC-lys powder 1.35 g (Drug)
Reference - Test (Fluifort® syrup 90 mg SCMC-lys/mL-1.35 g of SCMC-lys monohydrate salt powder)
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).
干预措施: Fluifort® syrup (Drug)
结局指标
主要结局
Carbocysteine Plasma PK Parameters: Cmax
时间窗: 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
时间窗: 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
次要结局
- 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)
- 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)
- 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)
- 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)
- Number of TEAEs(From the screening visit up to the final visit/ETV (i.e.up to 4 weeks))