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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Respiratory Tract Diseases, Abnormal Mucus Secretions

Intervention / Treatment
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* Drug: N-acetylcysteine (NAC) 600 mg
* Drug: Ambroxol hydrochloride 30 mg
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Chinese ethnicity and/or Chinese Signed the informed consent form before any study-related procedure Sputum viscosity score ≥ 2 at randomization visit Expectoration difficulty score ≥ 2 at randomization visit Willingness and ability to comply with study procedures Exclusion Criteria: Intolerance or contra-indication to treatment with NAC or ambroxol or allergy to any component of the study treatments (For female patients) ongoing pregnancy or lactation, or childbearing potential but unwillingness to adopt abstinence or contraception measures during the study Intake of an investigational drug within 1 month before the screening visit Use of expectorants or drugs with expectorant effect within 2 days before randomization visit 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 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 Serum alanine aminotransferase and/or aspartate transaminase more than 3 times above the upper limit of normal at screening visit Serum creatinine more than 3 times above the upper limit of normal at screening visit Addiction to alcohol or drugs Mental illness, or other reasons for non-cooperation in the investigator's opinion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active test treatment-NAC<br>NAC 600mg will be administered by slow intravenous infusion twice daily for the 1-week treatment period. | Drug: N-acetylcysteine (NAC) 600 mg<br>* NAC will be administered twice a day, morning and evening, during treatment period.<br>* Other names: Fluimucil®;|
| Active Comparator: Active control treatment-Ambroxol hydrochloride<br>Ambroxol hydrochloride 30 mg will be administered by slow intravenous infusion twice daily for the 1-week treatment period. | Drug: Ambroxol hydrochloride 30 mg<br>* Ambroxol hydrochloride will be administered twice a day, morning and evening, during treatment period.<br>* Other names: Fluibron®;|
| Placebo Comparator: Placebo<br>Placebo will be administered by slow intravenous infusion twice daily for the 1-week treatment period. | Other: placebo<br>* Placebo will be administered twice a day, morning and evening, during treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 7 of Mean Sputum Viscosity Score of NAC and Placebo | 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. | From baseline upto Day 7 | 
| Change From Baseline to Day 7 Treatment of Mean Expectoration Difficulty Score of NAC and Placebo | 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. | From Baseline upto Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 3 in Mean Sputum Viscosity Score of NAC and Placebo | 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. | From Baseline to Day 3 | 
| Change From Baseline to Day 3 in Mean Expectoration Difficulty Score of NAC and Placebo | 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. | From Baseline to Day 3 | 
| Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of NAC and Placebo | 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. | From Baseline upto Day 3 and Day 7 | 
| Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of NAC and Placebo | 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. | From Baseline upto Day 3 and Day 7 | 
| Change From Baseline to Day 3 and to Day 7 of Mean Sputum Volume of NAC and Placebo | 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. | From Baseline upto Day 3 and Day 7 | 
| Change From Baseline to Day 7 in Mean Sputum Viscosity Score of NAC and Ambroxol Hydrochloride | 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. | From baseline upto Day 7 | 
| Change From Baseline to Day 7 in Mean Expectoration Difficulty Score of NAC and Ambroxol Hydrochloride | 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 | From Baseline upto Day 7 | 
| Change From Baseline to Day 3 and to Day 7 in Mean Sputum Viscosity Score of Ambroxol Hydrochloride and Placebo | 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. | From Baseline upto Day 3 and Day 7 | 
| Change From Baseline to Day 3 and to Day 7 in Mean Expectoration Difficulty Score of Ambroxol Hydrochloride and Placebo | 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. | From Baseline upto Day 3 and Day 7 | 
| Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of Ambroxol Hydrochloride and Placebo | 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. | From Baseline upto Day 3 and Day 7 | 
| Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of Ambroxol Hydrochloride and Placebo | 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. | From Baseline upto Day 3 and Day 7 | 
| Change From Baseline to Day 3 and to Day 7 in Mean Sputum Volume of Ambroxol Hydrochloride and Placebo | 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. | From Baseline upto Day 3 and Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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N-acetylcysteine (NAC), ambroxol hydrochloride, bronchitis, cystic fibrosis, fibrosis bronchiectasis, increased sputum viscosity, cough, Chronic Obstructive Pulmonary Disease (COPD)