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

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

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.

Study Overview

• Status: Completed
• Conditions: Respiratory Tract Diseases; Abnormal Mucus Secretions
• Intervention / Treatment: Drug: N-acetylcysteine (NAC) 600 mg; Drug: Ambroxol hydrochloride 30 mg; Other: placebo

• Study Type: Interventional
• Enrollment (Actual): 333
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Baotou, China
    • Inner Mongolia Baogang Hospital
  • Beijing, China
    • Beijing Tongren Hospital
  • Beijing, China
    • Beijing Hospital
  • Beijing, China
    • China-Japan Friendship Hospital
  • Beijing, China
    • Peking University Shougang Hospital
  • Changchun, China
    • Jilin Province People's Hospital
  • Changchun, China
    • The First Bethune Hospital of Jilin University
  • Chengdu, China
    • West China Hospital, Sichuan University
  • Chengdu, China
    • Chengdu Fifth People's Hospital
  • Chongqing, China
    • The First Affiliated Hospital of Chongqing Medical University
  • Deyang, China
    • Deyang People's Hospital
  • Hohhot, China
    • Inner Mongolia People's Hospital
  • Jinhua, China
    • Jinhua city central hospital/Jinhua hospital ,School of Medicine,Zhejiang UNIVERSITY
  • Nanchang, China
    • Nanchang University-The Second Affiliated Hospital
  • Nanjing, China
    • Nanjing First Hospital
  • Nanjing, China
    • Zhongda Hospital, Southeast University - Pulmonology
  • Pingxiang, China
    • Jiangxi Pingxiang People's Hospital
  • Qingdao, China
    • Qingdao Municipal Hospital
  • Shanghai, China
    • Shanghai Pulmonary Hospital
  • Shanghai, China
    • Shanghai General Hospital
  • Shanghai, China
    • Minhang District Central Hospital
  • Shanghai, China
    • Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
  • SuiNing, China
    • Suining Central Hospital
  • Taiyuan, China
    • The First Hospital of Shanxi Medical University
  • Taiyuan, China
    • First Hospital Of ShanXi Medical University
  • Wuhan, China
    • Tongji Hospital, Tongji Medical College of Huazhong University Science and Technology
  • Wuxi, China
    • Wuxi Peoples' Hospital affiliated to Nanjing Medical University
  • Yangzhou, China
    • Yangzhou First People's Hospital
  • Yinchuan, China
    • General Hospital of Ningxia Medical University
  • Zhanjiang, China
    • Affiliated Hospital of Guangdong Medical University - Respiration
  • Zigong, China
    • The First People's Hospital of Zigong
  • No. 299, Qing Yang Rd., Wuxi City, Jiangsu
    • Wuxi, No. 299, Qing Yang Rd., Wuxi City, Jiangsu, China
      • Wuxi Peoples' Hospital affiliated to Nanjing Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 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.

What is the study measuring?

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Zambon SpA

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2019
• Primary Completion (Actual): January 23, 2021
• Study Completion (Actual): February 5, 2021

Study Registration Dates

• First Submitted: February 13, 2019
• First Submitted That Met QC Criteria: February 13, 2019
• First Posted (Actual): February 18, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2023
• Last Update Submitted That Met QC Criteria: April 8, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: cystic fibrosis; cough; Chronic Obstructive Pulmonary Disease (COPD); bronchitis; N-acetylcysteine (NAC); ambroxol hydrochloride; fibrosis bronchiectasis; increased sputum viscosity
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine; Ambroxol
• Other Study ID Numbers: Z7244L01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No