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A Clinical Trial to Compare the Efficacy and Safety of 1-week Treatment of Intravenous N-acetylcysteine (NAC) 600 mg Twice Daily, Ambroxol Hydrochloride 30 mg Twice Daily and Placebo as Expectorant Therapies in Adult Chinese Patients With Respiratory Tract Diseases and Abnormal Mucus Secretions

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ClinicalTrials.gov Identifier: NCT03843541
Recruitment Status : Completed
First Posted : February 18, 2019
Results First Posted : January 5, 2023
Last Update Posted : January 5, 2023
Sponsor:
Information provided by (Responsible Party):
Zambon SpA

Study Description
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Brief Summary:
This is a phase 3, multicenter, randomized, rater- and patient-blind, placebo- and active-controlled, 3-arm parallel group clinical trial. Patients will be randomized to N-acetylcysteine (NAC) or ambroxol or placebo in a 1:1:1 ratio. A total of approximately 333 patients in China will be randomized. The total study duration will be approximately 8 months including the enrolment period of approximately 7 months and the patient participation duration of 1 month or 4 weeks. Each patient will undergo a screening period of up to 1 week, a 1-week treatment period and a 2-week follow-up period. This study will be conducted in approximately 15-25 sites in China.

Condition or disease Intervention/treatment Phase
Respiratory Tract Diseases Abnormal Mucus Secretions Drug: N-acetylcysteine (NAC) 600 mg Drug: Ambroxol hydrochloride 30 mg Other: placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 333 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: There will be 3 treatment groups of NAC, ambroxol and placebo. A total of 333 patients will be randomized to NAC or ambroxol or placebo in a 1:1:1 ratio. Approximately 111 patients will be randomized in each treatment group.
Masking: Double (Participant, Outcomes Assessor)
Masking Description: Both rater and patient will be blinded.
Primary Purpose: Treatment
Official Title: A Phase III, Multi-centre, Randomized, Rater- and Patient-blind, Placebo- and Active-controlled, Parallel Group Clinical Trial to Compare the Efficacy and Safety of 1-week Treatment of Intravenous N-acetylcysteine (NAC) 600 mg Twice Daily (Active Test Treatment), Ambroxol Hydrochloride 30 mg Twice Daily (Active Control Treatment) and Placebo as Expectorant Therapies in Adult Chinese Patients With Respiratory Tract Diseases and Abnormal Mucus Secretions
Actual Study Start Date : June 25, 2019
Actual Primary Completion Date : January 23, 2021
Actual Study Completion Date : February 5, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Active test treatment-NAC
NAC 600mg will be administered by slow intravenous infusion twice daily for the 1-week treatment period.
 Drug: N-acetylcysteine (NAC) 600 mg
NAC will be administered twice a day, morning and evening, during treatment period.
Other Name: Fluimucil®
Active Comparator: Active control treatment-Ambroxol hydrochloride
Ambroxol hydrochloride 30 mg will be administered by slow intravenous infusion twice daily for the 1-week treatment period.
 Drug: Ambroxol hydrochloride 30 mg
Ambroxol hydrochloride will be administered twice a day, morning and evening, during treatment period.
Other Names:
  • Mucosolvan®
  • Fluibron®
Placebo Comparator: Placebo
Placebo will be administered by slow intravenous infusion twice daily for the 1-week treatment period.
 Other: placebo
Placebo will be administered twice a day, morning and evening, during treatment period.


Outcome Measures
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Primary Outcome Measures :
  1. Change From Baseline to Day 7 of Mean Sputum Viscosity Score of NAC and Placebo [ Time Frame: From baseline upto Day 7 ]
    The superiority of slow intravenous infusion of NAC to placebo in terms of change from baseline in sputum viscosity score was demonstrated. Sputum viscosity was assessed by ordinal categorical 4-point scales [0 = Liquid (normal viscosity), 1= Fluid (mildly increased viscosity), 2 = Viscous (moderately increased viscosity), 3 = Sticky (severely increased viscosity)] with 0 = best and 3= worst.

  2. Change From Baseline to Day 7 Treatment of Mean Expectoration Difficulty Score of NAC and Placebo [ Time Frame: From Baseline upto Day 7 ]
    The superiority of slow intravenous infusion of NAC 600 mg twice daily to placebo in terms of change from baseline in expectoration difficulty score was demonstrated. Expectoration difficulty was assessed by ordinal categorical 4-point scales [0 = No difficulty, 1 = Mild difficulty, 2 = Moderate difficulty, 3 = Marked difficulty] with 0 = best and 3 = worst.


Secondary Outcome Measures :
  1. Change From Baseline to Day 3 in Mean Sputum Viscosity Score of NAC and Placebo [ Time Frame: From Baseline to Day 3 ]
    The superiority of slow intravenous infusion of NAC to placebo in terms of change from baseline in sputum viscosity score was demonstrated. Sputum viscosity was assessed by ordinal categorical 4-point scales [0 = Liquid (normal viscosity), 1= Fluid (mildly increased viscosity), 2 = Viscous (moderately increased viscosity), 3 = Sticky (severely increased viscosity)] with 0 = best and 3= worst.

  2. Change From Baseline to Day 3 in Mean Expectoration Difficulty Score of NAC and Placebo [ Time Frame: From Baseline to Day 3 ]
    The superiority of slow intravenous infusion of NAC to placebo in terms of change from baseline in expectoration difficulty score was demonstrated. Expectoration difficulty was assessed by ordinal categorical 4-point scales [0 = No difficulty, 1 = Mild difficulty, 2 = Moderate difficulty, 3 = Marked difficulty] with 0 = best and 3 = worst.

  3. Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of NAC and Placebo [ Time Frame: From Baseline upto Day 3 and Day 7 ]
    The superiority of the slow intravenous infusion of NAC to placebo in terms of change from baseline in sputum color score was demonstrated. Sputum color was assessed by means of ordinal categorical 4-point scales [0 = Mostly white, 1= Mostly pale yellow, 2 = Mostly dark yellow, 3 = Very dark yellow /green] with 0 = best and 3= worst.

  4. Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of NAC and Placebo [ Time Frame: From Baseline upto Day 3 and Day 7 ]
    The superiority of the slow intravenous infusion of NAC to placebo in terms of change from baseline in cough score was demonstrated. Cough score was assessed by means of ordinal categorical 4-point scales [0 = No cough, 1= Sporadic and mild cough, 2 = Moderate cough, 3 = Severe Cough] with 0 = best and 3= worst.

  5. Change From Baseline to Day 3 and to Day 7 of Mean Sputum Volume of NAC and Placebo [ Time Frame: From Baseline upto Day 3 and Day 7 ]
    The superiority of the slow intravenous infusion of NAC to placebo in terms of change from baseline in sputum volume was demonstrated. Patients collected 24-hour sputum (morning to same time of the following morning) in a graduated cup and volume was expressed as mL/24h.

  6. Change From Baseline to Day 7 in Mean Sputum Viscosity Score of NAC and Ambroxol Hydrochloride [ Time Frame: From baseline upto Day 7 ]
    The non-inferiority of NAC versus ambroxol in terms of change from baseline to Day 7 of mean sputum viscosity score was demonstrated. Sputum viscosity was assessed by ordinal categorical 4-point scales [0 = Liquid (normal viscosity), 1= Fluid (mildly increased viscosity), 2 = Viscous (moderately increased viscosity), 3 = Sticky (severely increased viscosity)] with 0 = best and 3= worst.

  7. Change From Baseline to Day 7 in Mean Expectoration Difficulty Score of NAC and Ambroxol Hydrochloride [ Time Frame: From Baseline upto Day 7 ]
    The non-inferiority of NAC versus ambroxol in terms of change from baseline to Day 7 of mean expectoration difficulty score was demonstrated. Expectoration difficulty was assessed by ordinal categorical 4-point scales [0 = No difficulty, 1 = Mild difficulty, 2 = Moderate difficulty, 3 = Marked difficulty] with 0 = best and 3= worst

  8. Change From Baseline to Day 3 and to Day 7 in Mean Sputum Viscosity Score of Ambroxol Hydrochloride and Placebo [ Time Frame: From Baseline upto Day 3 and Day 7 ]
    The superiority of the slow intravenous infusion ambroxol hydrochloride to placebo in terms of change from baseline in sputum viscosity score was demonstrated. Sputum viscosity was assessed by ordinal categorical 4-point scales [0 = Liquid (normal viscosity), 1= Fluid (mildly increased viscosity), 2 = Viscous (moderately increased viscosity), 3 = Sticky (severely increased viscosity)] with 0 = best and 3= worst.

  9. Change From Baseline to Day 3 and to Day 7 in Mean Expectoration Difficulty Score of Ambroxol Hydrochloride and Placebo [ Time Frame: From Baseline upto Day 3 and Day 7 ]
    The superiority of the slow intravenous infusion of ambroxol hydrochloride to placebo in terms of change from baseline in expectoration difficulty score was demonstrated. Expectoration difficulty was assessed by ordinal categorical 4-point scales [0 = No difficulty, 1 = Mild difficulty, 2 = Moderate difficulty, 3 = Marked difficulty] with 0 = best and 3 = worst.

  10. Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of Ambroxol Hydrochloride and Placebo [ Time Frame: From Baseline upto Day 3 and Day 7 ]
    The superiority of slow intravenous infusion of ambroxol hydrochloride to placebo in terms of change from baseline in sputum color was demonstrated. Sputum color was assessed by means of ordinal categorical 4-point scales [0 = Mostly white, 1= Mostly pale yellow, 2 = Mostly dark yellow, 3 = Very dark yellow /green] with 0 = best and 3= worst.

  11. Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of Ambroxol Hydrochloride and Placebo [ Time Frame: From Baseline upto Day 3 and Day 7 ]
    The superiority of slow intravenous infusion of ambroxol hydrochloride to placebo in terms of change from baseline in cough score was demonstrated. Cough score was assessed by means of ordinal categorical 4-point scales [0 = No cough, 1= Sporadic and mild cough, 2 = Moderate cough, 3 = Severe Cough] with 0 = best and 3= worst.

  12. Change From Baseline to Day 3 and to Day 7 in Mean Sputum Volume of Ambroxol Hydrochloride and Placebo [ Time Frame: From Baseline upto Day 3 and Day 7 ]
    The superiority of slow intravenous infusion of ambroxol hydrochloride to placebo in terms of change from baseline in mean sputum volume was demonstrated. Patients collected 24-hour sputum (morning to same time of the following morning) in a graduated cup and volume was expressed as mL/24h.


Other Outcome Measures:
  1. Number of Participants With Adverse Events [ Time Frame: From screening to follow-up after the last administration of the investigational medicinal product (IMP) [assessed up to 19 months] ]
    The safety and tolerability of intravenous NAC 600 mg twice daily was demonstrated.


Eligibility Criteria
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Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female adult (≥18 years old) hospitalized patients with respiratory tract diseases and abnormal mucus secretions such as: acute bronchitis, chronic bronchitis and exacerbations, emphysema, mucoviscidosis and bronchiectasis.
  2. Chinese ethnicity and/or Chinese
  3. Signed the informed consent form before any study-related procedure
  4. Sputum viscosity score ≥ 2 at randomization visit
  5. Expectoration difficulty score ≥ 2 at randomization visit
  6. Willingness and ability to comply with study procedures

Exclusion Criteria:

  1. Intolerance or contra-indication to treatment with NAC or ambroxol or allergy to any component of the study treatments
  2. (For female patients) ongoing pregnancy or lactation, or childbearing potential but unwillingness to adopt abstinence or contraception measures during the study
  3. Intake of an investigational drug within 1 month before the screening visit
  4. Use of expectorants or drugs with expectorant effect within 2 days before randomization visit
  5. Diagnosis of active tuberculosis, lung cancer, pulmonary fibrosis, acute pulmonary thromboembolism or any other respiratory condition that might, in the opinion of the investigator, compromise the safety of the patient or affect the interpretation of the results
  6. Medical history of and/or illness (including laboratory abnormality) and/or treatment that in the investigator's opinion may interfere with the patient's safety, compliance, or study evaluations
  7. Serum alanine aminotransferase and/or aspartate transaminase more than 3 times above the upper limit of normal at screening visit
  8. Serum creatinine more than 3 times above the upper limit of normal at screening visit
  9. Addiction to alcohol or drugs
  10. Mental illness, or other reasons for non-cooperation in the investigator's opinion
Contacts and Locations
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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): NCT03843541


Locations
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Sponsors and Collaborators
Zambon SpA
  Study Documents (Full-Text)

Documents provided by Zambon SpA:
Study Protocol  [PDF] December 19, 2018
Statistical Analysis Plan  [PDF] April 14, 2021

More Information
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Responsible Party: Zambon SpA
ClinicalTrials.gov Identifier: NCT03843541    
Other Study ID Numbers: Z7244L01
First Posted: February 18, 2019    Key Record Dates
Results First Posted: January 5, 2023
Last Update Posted: January 5, 2023
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Zambon SpA:
N-acetylcysteine (NAC)
ambroxol hydrochloride
bronchitis
cystic fibrosis
 fibrosis bronchiectasis
increased sputum viscosity
cough
Chronic Obstructive Pulmonary Disease (COPD)
Additional relevant MeSH terms:
Layout table for MeSH terms
Respiratory Tract Diseases
Acetylcysteine
Ambroxol
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