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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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ClinicalTrials.gov Identifier: NCT03881163
Recruitment Status : Not yet recruiting
First Posted : March 19, 2019
Last Update Posted : March 19, 2019
Sponsor:
Information provided by (Responsible Party):
Zambon SpA

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.

Condition or disease Intervention/treatment Phase
Respiratory Tract Disorders Drug: N-acetylcysteine (NAC) Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Intervention 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)
Primary Purpose: Other
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
Estimated Study Start Date : May 1, 2019
Estimated Primary Completion Date : June 5, 2019
Estimated Study Completion Date : June 5, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Single dose regime of N-acetylcysteine (NAC)
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.
Drug: N-acetylcysteine (NAC)
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.

Experimental: Multiple dose regime of N-acetylcysteine (NAC)
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.
Drug: N-acetylcysteine (NAC)
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 Measures :
  1. Peak drug concentration (Cmax) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  2. Time to achieve Cmax (tmax) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  3. Terminal elimination rate constant, calculated, if feasible, by log-linear regression using at least 3 points (kel) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  4. Half-life, calculated, if feasible, as ln2/kel (t1/2) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  5. Area under the concentration-time curve from single dose to the last observed concentration time t, calculated with the linear up/log down trapezoidal method (AUC(0-t) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  6. Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC(0-t) + Ct/kel, where Ct is the last measurable drug concentration (AUC 0-infinity) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  7. Area under the concentration-time curve at steady-state in the tau interval, calculated with the linear up/log down trapezoidal method [AUC(0-12)] after single dose of NAC [ 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, and 12 hours post-dose. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  8. Volume of distribution associated with the terminal slope, calculated, if feasible, as Dose/(AUC(0-infinity)*kel) (Vd) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  9. Total body clearance, calculated, if feasible, as Dose/ AUC(0-infinity) (CLt) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  10. Total amount of NAC excreted in urine [Ae(0-t)] after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  11. Total fraction of NAC dose excreted in urine [Fe(0-t)] after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  12. Renal clearance, calculated, if feasible, as Ae(0-t)/ AUC(0-infinity) (CLr) after single dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.

  13. Maximum NAC plasma concentration at steady-state (Css_max) after multiple doses of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.

  14. Time to achieve Css_max (tss_max) after multiple doses of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.

  15. Trough NAC plasma concentration at steady-state, measured as concentration at t=12 hour (Css_min) after multiple doses of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.

  16. Area under the concentration-time curve at steady-state from the last multiple dose to the last observed concentration time t, calculated with the linear up/log down trapezoidal method [AUCss(0-t)] after multiple doses of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.

  17. Area under the concentration-time curve at steady-state in the tau interval, calculated with the linear up/log down trapezoidal method [AUCss(0-12)] after multiple doses of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.

  18. Average NAC plasma concentration at steady-state, calculated as AUCss(0-12) /tau (Css_av) after multiple doses of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.

  19. Accumulation ratio, calculated as AUCss(0-12)/ AUC(0-12) (R) after multiple doses of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.

  20. Total amount of NAC excreted in urine [Aess(0-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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.

  21. Degree of fluctuation over one dosing interval at steady-state, calculated as (Css_max - Css_min)/ Css_av*100 (DF%) after multiple dose of NAC [ 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. ]
    To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.


Secondary Outcome Measures :
  1. Number of subjects with treatment emergent adverse events (TEAEs) [ Time Frame: At screening to Final Visit/ETV (Day 8) ]
    To collect safety and tolerability data after single and multiple dose administration of the investigational product.

  2. Number of subjects with abnormal blood pressure [ Time Frame: At screening, Day 1, Day 3, Day 6, and Final Visit/ETV (Day 8) ]
    To collect safety and tolerability data after single and multiple dose administration of the investigational product.

  3. Number of subjects with abnormal heart rate [ Time Frame: At screening, Day 1, Day 3, Day 6, and Final Visit/ETV (Day 8) ]
    To collect safety and tolerability data after single and multiple dose administration of the investigational product.

  4. Number of subjects with abnormal body weight [ Time Frame: At screening, Day 2, day 3 and Final Visit/ ETV (Day 8) ]
    To collect safety and tolerability data after single and multiple dose administration of the investigational product.

  5. Number of subjects with abnormal physical examination [ Time Frame: At screening, Day 2 and Day 3, Final Visit/ETV (Day 8) ]
    To collect safety and tolerability data after single and multiple dose administration of the investigational product.

  6. Number of subjects with abnormal hematology findings [ Time Frame: At screening and Final visit/ETV (Day 8) ]
    To collect safety and tolerability data after single and multiple dose administration of the investigational product.

  7. Number of subjects with abnormal blood chemistry [ Time Frame: At screening, Day 3, and Final Visit/ETV (Day 8) ]
    To collect safety and tolerability data after single and multiple dose administration of the investigational product.

  8. Number of subjects with abnormal urinalysis [ Time Frame: At screening, Day 3, and Final Visit/ETV (Day 8) ]
    To collect safety and tolerability data after single and multiple dose administration of the investigational product.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Informed consent: signed written informed consent before inclusion in the study
  2. Ethnicity, Sex and Age: Chinese males and females, 18-45 year old inclusive
  3. Weight: body weight ≥50 kg
  4. Body Mass Index: 19-26 kg/m2 inclusive
  5. 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
  6. 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
  7. Nicotine addiction (smoker subjects only): ability to abstain from smoking for the duration of the clinical study
  8. Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception:

    1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 60 calendar days before the screening visit
    2. 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
    3. A male sexual partner who agrees to use a male condom with spermicide
    4. 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:

  1. Electrocardiogram (12-lead ECG in 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, in particular significant laboratory abnormality indicative of hepatic condition (more than 3 times the upper limit)
  4. 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
  5. 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
  6. Virology: positive result of HIV, hepatitis B (HBV), hepatitis C (HCV) or Treponema pallidum (TP) assays
  7. Surgery: any surgery within 60 calendar days of screening (excluding diagnostic surgery)
  8. 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
  9. Investigative drug studies: participation in the evaluation of any investigational product for 1 month before this study
  10. Blood donation: blood donations for 90 calendar days before this study
  11. 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)
  12. Abuse drug test: positive urine abuse drug test at screening or day -1
  13. Alcohol test: positive alcohol breath test at day -1
  14. 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
  15. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women
  16. Vaccination within 4 weeks of study treatment
  17. Other unspecified reasons that, in the opinion of the investigator, make the subject unsuitable for enrolment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03881163


Contacts
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Contact: Valentina Vaja +390266524497 Valentina.Vaja@ZambonGroup.com

Sponsors and Collaborators
Zambon SpA

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Responsible Party: Zambon SpA
ClinicalTrials.gov Identifier: NCT03881163     History of Changes
Other Study ID Numbers: Z7244J01
First Posted: March 19, 2019    Key Record Dates
Last Update Posted: March 19, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Respiratory Tract Diseases
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes