Back to resultsA Study to Evaluate Pharmacokinetics, Safety and Tolerability of Single and Multiple Intravenous Doses of N-acetylcysteine (NAC) in Chinese Healthy Volunteers
Primary Purpose
Respiratory Tract Disorders
Status
Completed
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
N-acetylcysteine (NAC)
Sponsored by
About this trial
This is an interventional other trial for Respiratory Tract Disorders
Eligibility Criteria
Inclusion Criteria:
- Informed consent: signed written informed consent before inclusion in the study
- Ethnicity, Sex and Age: Chinese males and females, 18-45 year old inclusive
- Weight: body weight ≥50 kg
- Body Mass Index: 19-26 kg/m2 inclusive
- Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest in the sitting/supine 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
- Nicotine addiction (smoker subjects only): ability to abstain from smoking for the duration of the clinical study
Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception:
- Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 60 calendar days before the screening visit
- A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 60 calendar days before the screening visit
- A male sexual partner who agrees to use a male condom with spermicide
- A sterile sexual partner
Women of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. Women of childbearing potential should be willing to adopt abstinence or contraception measures during the study and two weeks post-dose. For all women, pregnancy test result must be negative at screening and day -1.
Exclusion Criteria:
- Electrocardiogram (12-lead ECG in 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, in particular significant laboratory abnormality indicative of hepatic condition (more than 3 times the upper limit)
- Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs 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, skin, haematological, endocrine, urologic, metabolic, neurological or psychiatric diseases, as determined by the investigator, that may interfere with the aim of the study; history of carcinoma in situ and malignant disease; active bacterial or viral infection and fever >38°C within 48 h prior to study treatment administration
- Virology: positive result of HIV, hepatitis B (HBV), hepatitis C (HCV) or Treponema pallidum (TP) assays
- Surgery: any surgery within 60 calendar days of screening (excluding diagnostic surgery)
- Medications: medications, including over the counter (OTC) medications, herbal remedies and traditional Chinese remedies for 2 weeks before the start of the study. Hormonal contraceptives for women will be allowed
- Investigative drug studies: participation in the evaluation of any investigational product for 1 month before this study
- Blood donation: blood donations for 90 calendar days 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 2015-2020] caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes/day)
- Abuse drug test: positive urine abuse drug test at screening or day -1
- 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; consumption of alcohol, grapefruit, products containing grapefruit, or beverages containing xanthines (coffee, tea, soda, coffee with milk, energy drinks) within 48 hours prior to the enrolment
- Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women
- Vaccination within 4 weeks of study treatment
- Other unspecified reasons that, in the opinion of the investigator, make the subject unsuitable for enrolment.
Sites / Locations
- Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Single dose regime of N-acetylcysteine (NAC)
Multiple dose regime of N-acetylcysteine (NAC)
Arm Description
On day 1 at 08:00 ±1 hours, one dose of 600 mg of NAC (300 + 300 mg ampoule) will be administered under fasting conditions.
On days 4 and 5 at 08:00 ±1 hours and 20:00 ±1 hours and at 08:00 ±1 on day 6, 5 doses of 600 mg of NAC (300 + 300 mg ampoule) will be administered.
Outcomes
Primary Outcome Measures
Peak Drug Concentration (Cmax) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single administration of the investigational product.
Time to Achieve Cmax (Tmax) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Terminal Elimination Rate Constant (Kel) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Half-life (t1/2) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Area Under the Concentration-time Curve (AUC) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Volume of Distribution (Vd) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Total Body Clearance (CLt) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Renal Clearance (CLr) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Percentage of the AUC(0-inf) Obtained by Extrapolation (%AUCextra)
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Plasma Concentration at Steady-state After Multiple Doses of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Css_max = maximum NAC plasma concentration at steady-state, Css_min=minimum plasma concentration at steady-state, Css_avg=average NAC plasma concentration at steady-state.
Time to Achieve Css_max (tss_max) After Multiple Doses of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Area Under the Concentration-time Curve at Steady State After Multiple Doses of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
AUCss(0-12h)=AUC at steady-state from the last multiple dose to 12 hours post-dose, AUCss(0-t)=AUC at steady-state from the last multiple dose to the last observed concentration time t.
Accumulation Ratio After Multiple Doses of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Total Amount of NAC Excreted in Urine From the Last Multiple Dose to 32 h at Steady-state [Aess(0-32)]
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Degree of Fluctuation Over One Dosing Interval at Steady-state (DF%) After Multiple Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Degree of fluctuation over one dosing interval at steady-state is calculated as (Css_max - Css_min)/ Css_av*100
Secondary Outcome Measures
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
To collect safety and tolerability data after single and multiple dose administration of the investigational product.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03881163
Brief Title
A Study to Evaluate Pharmacokinetics, Safety and Tolerability of Single and Multiple Intravenous Doses of N-acetylcysteine (NAC) in Chinese Healthy Volunteers
Official Title
Phase I Study to Evaluate Pharmacokinetics, Safety and Tolerability of Single and Multiple i.v. Doses of N-acetylcysteine (NAC) in Chinese Healthy Volunteers
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Completed
Study Start Date
November 11, 2019 (Actual)
Primary Completion Date
January 18, 2020 (Actual)
Study Completion Date
January 18, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Zambon SpA
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a single and multiple dose, single centre, open-label, one-way, pharmacokinetics, safety and tolerability clinical trial of Phase I to be performed in Chinese healthy male and female volunteers. Twenty-four (24) healthy male and female Chinese volunteers will be included in the study. Drop-out subjects will not be replaced. The study has been designed in agreement with the Chinese Technical Guideline on Clinical Pharmacokinetic Research of Chemical Drugs, 18 March 2005 and the European Guideline on the Investigation of Bioequivalence. No randomisation will take place in this study. All the participant will receive the same treatment with the investigational medicinal product (IMP), i.e. NAC, 300 mg/ 3 mL solution for injection.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Respiratory Tract Disorders
7. Study Design
Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Factorial Assignment
Model Description
All the subjects enrolled in the study will receive the same treatment with the investigational medicinal product (IMP), i.e. NAC, 300 mg/ 3 mL solution injection as single dose and multiple dose regime. Single dose of IMP will be administered under fasting conditions on day 1 at 08:00 ±1 h. Multiple doses (5) of IMP will be administered twice a day (b.i.d.) on days 4 and 5 at 08:00 ±1 h and 20:00 ±1 h and one dose will be administered on day 6 at 08:00 ±1.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Single dose regime of N-acetylcysteine (NAC)
Arm Type
Experimental
Arm Description
On day 1 at 08:00 ±1 hours, one dose of 600 mg of NAC (300 + 300 mg ampoule) will be administered under fasting conditions.
Arm Title
Multiple dose regime of N-acetylcysteine (NAC)
Arm Type
Experimental
Arm Description
On days 4 and 5 at 08:00 ±1 hours and 20:00 ±1 hours and at 08:00 ±1 on day 6, 5 doses of 600 mg of NAC (300 + 300 mg ampoule) will be administered.
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine (NAC)
Intervention Description
Two ampoules of IMP (300 + 300 mg) corresponding to a total dose of 600 mg of NAC diluted in 10 mL of NaCl 0.9% sterile saline solution, will be administered by a 5-minute i.v. infusion.
Primary Outcome Measure Information:
Title
Peak Drug Concentration (Cmax) After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose
Title
Time to Achieve Cmax (Tmax) After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Terminal Elimination Rate Constant (Kel) After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Half-life (t1/2) After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Area Under the Concentration-time Curve (AUC) After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Volume of Distribution (Vd) After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Total Body Clearance (CLt) After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Renal Clearance (CLr) After Single Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Percentage of the AUC(0-inf) Obtained by Extrapolation (%AUCextra)
Description
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Time Frame
On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Plasma Concentration at Steady-state After Multiple Doses of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Css_max = maximum NAC plasma concentration at steady-state, Css_min=minimum plasma concentration at steady-state, Css_avg=average NAC plasma concentration at steady-state.
Time Frame
On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Time to Achieve Css_max (tss_max) After Multiple Doses of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Time Frame
On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Area Under the Concentration-time Curve at Steady State After Multiple Doses of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
AUCss(0-12h)=AUC at steady-state from the last multiple dose to 12 hours post-dose, AUCss(0-t)=AUC at steady-state from the last multiple dose to the last observed concentration time t.
Time Frame
On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Accumulation Ratio After Multiple Doses of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Time Frame
On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Total Amount of NAC Excreted in Urine From the Last Multiple Dose to 32 h at Steady-state [Aess(0-32)]
Description
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Time Frame
On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Title
Degree of Fluctuation Over One Dosing Interval at Steady-state (DF%) After Multiple Dose of NAC
Description
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Degree of fluctuation over one dosing interval at steady-state is calculated as (Css_max - Css_min)/ Css_av*100
Time Frame
On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose.
Secondary Outcome Measure Information:
Title
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description
To collect safety and tolerability data after single and multiple dose administration of the investigational product.
Time Frame
From screening to Final Visit/early termination visit (ETV, Day 8)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Informed consent: signed written informed consent before inclusion in the study
Ethnicity, Sex and Age: Chinese males and females, 18-45 year old inclusive
Weight: body weight ≥50 kg
Body Mass Index: 19-26 kg/m2 inclusive
Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest in the sitting/supine 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
Nicotine addiction (smoker subjects only): ability to abstain from smoking for the duration of the clinical study
Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception:
Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 60 calendar days before the screening visit
A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 60 calendar days before the screening visit
A male sexual partner who agrees to use a male condom with spermicide
A sterile sexual partner
Women of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. Women of childbearing potential should be willing to adopt abstinence or contraception measures during the study and two weeks post-dose. For all women, pregnancy test result must be negative at screening and day -1.
Exclusion Criteria:
Electrocardiogram (12-lead ECG in 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, in particular significant laboratory abnormality indicative of hepatic condition (more than 3 times the upper limit)
Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs 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, skin, haematological, endocrine, urologic, metabolic, neurological or psychiatric diseases, as determined by the investigator, that may interfere with the aim of the study; history of carcinoma in situ and malignant disease; active bacterial or viral infection and fever >38°C within 48 h prior to study treatment administration
Virology: positive result of HIV, hepatitis B (HBV), hepatitis C (HCV) or Treponema pallidum (TP) assays
Surgery: any surgery within 60 calendar days of screening (excluding diagnostic surgery)
Medications: medications, including over the counter (OTC) medications, herbal remedies and traditional Chinese remedies for 2 weeks before the start of the study. Hormonal contraceptives for women will be allowed
Investigative drug studies: participation in the evaluation of any investigational product for 1 month before this study
Blood donation: blood donations for 90 calendar days 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 2015-2020] caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes/day)
Abuse drug test: positive urine abuse drug test at screening or day -1
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; consumption of alcohol, grapefruit, products containing grapefruit, or beverages containing xanthines (coffee, tea, soda, coffee with milk, energy drinks) within 48 hours prior to the enrolment
Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women
Vaccination within 4 weeks of study treatment
Other unspecified reasons that, in the opinion of the investigator, make the subject unsuitable for enrolment.
Facility Information:
Facility Name
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
City
Shanghai
State/Province
No.197 Ruijin Er Road
Country
China
12. IPD Sharing Statement
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A Study to Evaluate Pharmacokinetics, Safety and Tolerability of Single and Multiple Intravenous Doses of N-acetylcysteine (NAC) in Chinese Healthy Volunteers
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