Abnormal Mucus Secretions, Respiratory Tract Diseases
Conditions
Keywords
N-acetylcysteine (NAC), ambroxol hydrochloride, bronchitis, cystic fibrosis, fibrosis bronchiectasis, increased sputum viscosity, cough, Chronic Obstructive Pulmonary Disease (COPD)
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.
Interventions
DRUGN-acetylcysteine (NAC) 600 mg
NAC will be administered twice a day, morning and evening, during treatment period.
DRUGAmbroxol hydrochloride 30 mg
Ambroxol hydrochloride will be administered twice a day, morning and evening, during treatment period.
OTHERplacebo
Placebo will be administered twice a day, morning and evening, during treatment period.
Sponsors
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Both rater and patient will be blinded.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Day 7 Treatment of Mean Expectoration Difficulty Score of NAC and Placebo | 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. |
| Change From Baseline to Day 7 of Mean Sputum Viscosity Score of NAC and Placebo | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Day 3 in Mean Expectoration Difficulty Score of NAC and Placebo | 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. |
| Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of NAC and Placebo | 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. |
| Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of NAC and Placebo | 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. |
| Change From Baseline to Day 3 and to Day 7 of Mean Sputum Volume of NAC and Placebo | 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. |
| Change From Baseline to Day 7 in Mean Sputum Viscosity Score of NAC and Ambroxol Hydrochloride | 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. |
| Change From Baseline to Day 3 and to Day 7 in Mean Sputum Viscosity Score of Ambroxol Hydrochloride and Placebo | 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. |
| Change From Baseline to Day 3 and to Day 7 in Mean Expectoration Difficulty Score of Ambroxol Hydrochloride and Placebo | 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. |
| Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of Ambroxol Hydrochloride and Placebo | 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. |
| Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of Ambroxol Hydrochloride and Placebo | 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. |
| Change From Baseline to Day 3 and to Day 7 in Mean Sputum Volume of Ambroxol Hydrochloride and Placebo | 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. |
| Change From Baseline to Day 7 in Mean Expectoration Difficulty Score of NAC and Ambroxol Hydrochloride | 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 |
| Change From Baseline to Day 3 in Mean Sputum Viscosity Score of NAC and Placebo | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | 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. |
Countries
China
Participant flow
Recruitment details
The study was conducted between 21-June-2019 and 5-February-2021 in 28 sites in China.
Pre-assignment details
Participants who met the inclusion and none of the exclusion criteria were enrolled to the study. All procedures were performed as per the trial flow chart.
Participants by arm
| Arm | Count |
|---|---|
| N-Acetylcysteine Participants received N-Acetylcysteine (NAC) 600 mg intravenous (IV) infusion twice daily (BD - morning and evening) for the 1-week treatment period. | 108 |
| Ambroxol Hydrochloride Participants received Ambroxol hydrochloride 30 mg intravenous infusion twice daily (morning and evening) for the 1-week treatment period. | 110 |
| Placebo Participants received placebo intravenous infusion twice daily (morning and evening) for the 1-week treatment period. | 110 |
| Total | 328 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administration of rescue mucolytic | 0 | 0 | 1 |
| Overall Study | Adverse Event | 4 | 2 | 3 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Lack of adherence to study medication | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 2 | 2 |
| Overall Study | Reporting drug over temperature, patients plan to transfer to hospital, and discharge from hospital. | 2 | 3 | 0 |
| Overall Study | Study subject withdrawal by parent or guardian | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 9 | 7 |
Baseline characteristics
| Characteristic | N-Acetylcysteine | Ambroxol Hydrochloride | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 64.7 years STANDARD_DEVIATION 11.65 | 64.7 years STANDARD_DEVIATION 12.76 | 64.5 years STANDARD_DEVIATION 12.79 | 64.6 years STANDARD_DEVIATION 12.38 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 110 Participants | 110 Participants | 328 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 36 Participants | 31 Participants | 32 Participants | 99 Participants |
| Sex: Female, Male Male | 72 Participants | 79 Participants | 78 Participants | 229 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 108 | 0 / 110 | 0 / 110 |
| other Total, other adverse events | 67 / 108 | 66 / 110 | 58 / 110 |
| serious Total, serious adverse events | 2 / 108 | 5 / 110 | 7 / 110 |
Outcome results
Primary
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.
Time frame: From baseline upto Day 7
Population: mITT population - The Modified ITT (mITT) Population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 7 of Mean Sputum Viscosity Score of NAC and Placebo | -1.2 Score | Standard Deviation 0.74 |
| Placebo | Change From Baseline to Day 7 of Mean Sputum Viscosity Score of NAC and Placebo | -1.0 Score | Standard Deviation 0.78 |
Comparison: For the superiority comparisons of NAC vs. placebo, the Bonferroni correction was used.p-value: <0.001Wilcoxon (Mann-Whitney)
Primary
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.
Time frame: From Baseline upto Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 7 Treatment of Mean Expectoration Difficulty Score of NAC and Placebo | -1.4 Score | Standard Deviation 0.78 |
| Placebo | Change From Baseline to Day 7 Treatment of Mean Expectoration Difficulty Score of NAC and Placebo | -1.1 Score | Standard Deviation 0.78 |
Comparison: For the superiority comparisons of NAC vs. placebo, the Bonferroni correction was used.p-value: 0.002Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: From Baseline upto Day 3 and Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -0.4 Score | Standard Deviation 0.52 |
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -0.7 Score | Standard Deviation 0.68 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -0.5 Score | Standard Deviation 0.6 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -0.6 Score | Standard Deviation 0.72 |
p-value: 0.052Modified Mann-Whitney U Statistic
p-value: 0.058Modified Mann-Whitney U Statistic
Secondary
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.
Time frame: From Baseline upto Day 3 and Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of NAC and Placebo | Change from baseline to Day 3 | -0.4 Score | Standard Deviation 0.55 |
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of NAC and Placebo | Change from baseline to Day 7 | -0.8 Score | Standard Deviation 0.77 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of NAC and Placebo | Change from baseline to Day 3 | -0.5 Score | Standard Deviation 0.6 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of NAC and Placebo | Change from baseline to Day 7 | -0.6 Score | Standard Deviation 0.72 |
p-value: 0.022Stratified Mann Whitney U Statistic
p-value: 0.11Stratified Mann Whitney U Statistic
Secondary
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.
Time frame: From Baseline upto Day 3 and Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Expectoration Difficulty Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -0.7 Score | Standard Deviation 0.57 |
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Expectoration Difficulty Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -1.3 Score | Standard Deviation 0.75 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Expectoration Difficulty Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -0.7 Score | Standard Deviation 0.64 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Expectoration Difficulty Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -1.1 Score | Standard Deviation 0.78 |
p-value: 0.38Modified Mann-Whitney U Statistic
p-value: 0.018Modified Mann-Whitney U Statistic
Secondary
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.
Time frame: From Baseline upto Day 3 and Day 7
Population: mITT population - The Modified ITT (mITT) Population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -0.5 Score | Standard Deviation 0.77 |
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -0.9 Score | Standard Deviation 0.99 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -0.5 Score | Standard Deviation 0.82 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -0.8 Score | Standard Deviation 0.97 |
p-value: 0.366Modified Mann-Whitney U Statistic
p-value: 0.027Modified Mann-Whitney U Statistic
Secondary
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.
Time frame: From Baseline upto Day 3 and Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of NAC and Placebo | Change from baseline to Day 3 | -0.5 Score | Standard Deviation 0.72 |
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of NAC and Placebo | Change from baseline to Day 7 | -0.8 Score | Standard Deviation 0.89 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of NAC and Placebo | Change from baseline to Day 3 | -0.5 Score | Standard Deviation 0.82 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of NAC and Placebo | Change from baseline to Day 7 | -0.8 Score | Standard Deviation 0.97 |
p-value: 0.093Stratified Mann Whitney U Statistic
p-value: 0.118Stratified Mann Whitney U Statistic
Secondary
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.
Time frame: From Baseline upto Day 3 and Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Viscosity Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -0.6 Score | Standard Deviation 0.55 |
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Viscosity Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -1.2 Score | Standard Deviation 0.78 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Viscosity Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -0.6 Score | Standard Deviation 0.64 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Viscosity Score of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -1.0 Score | Standard Deviation 0.78 |
p-value: 0.356Modified Mann-Whitney U Statistic
p-value: 0.007Modified Mann-Whitney U Statistic
Secondary
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.
Time frame: From Baseline upto Day 3 and Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Volume of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -4.53 mL/24h | Standard Deviation 12.018 |
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Volume of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -9.73 mL/24h | Standard Deviation 15.149 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Volume of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 3 | -4.14 mL/24h | Standard Deviation 12.235 |
| Placebo | Change From Baseline to Day 3 and to Day 7 in Mean Sputum Volume of Ambroxol Hydrochloride and Placebo | Change from baseline to Day 7 | -7.39 mL/24h | Standard Deviation 15.999 |
p-value: 0.309Modified Mann-Whitney U Statistic
p-value: 0.006Modified Mann-Whitney U Statistic
Secondary
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.
Time frame: From Baseline upto Day 3 and Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 of Mean Sputum Volume of NAC and Placebo | Change from baseline to Day 3 | -1.601 mL/24h | Standard Deviation 16.2611 |
| N-Acetylcysteine | Change From Baseline to Day 3 and to Day 7 of Mean Sputum Volume of NAC and Placebo | Change from baseline to Day 7 | -9.405 mL/24h | Standard Deviation 35.2191 |
| Placebo | Change From Baseline to Day 3 and to Day 7 of Mean Sputum Volume of NAC and Placebo | Change from baseline to Day 3 | -4.144 mL/24h | Standard Deviation 12.2348 |
| Placebo | Change From Baseline to Day 3 and to Day 7 of Mean Sputum Volume of NAC and Placebo | Change from baseline to Day 7 | -7.391 mL/24h | Standard Deviation 15.9992 |
p-value: 0.022Stratified Mann Whitney U Statistic
p-value: 0.402Stratified Mann Whitney U Statistic
Secondary
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.
Time frame: From Baseline to Day 3
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 in Mean Expectoration Difficulty Score of NAC and Placebo | -0.8 Score | Standard Deviation 0.61 |
| Placebo | Change From Baseline to Day 3 in Mean Expectoration Difficulty Score of NAC and Placebo | -0.7 Score | Standard Deviation 0.64 |
Comparison: For the superiority comparisons of NAC vs. placebo, the Bonferroni correction was used.p-value: 0.037Stratified Mann-Whitney U Statistic
Secondary
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.
Time frame: From Baseline to Day 3
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 3 in Mean Sputum Viscosity Score of NAC and Placebo | -0.6 Score | Standard Deviation 0.59 |
| Placebo | Change From Baseline to Day 3 in Mean Sputum Viscosity Score of NAC and Placebo | -0.6 Score | Standard Deviation 0.64 |
p-value: 0.239Stratified Mann-Whitney U Statistic
Secondary
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
Time frame: From Baseline upto Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 7 in Mean Expectoration Difficulty Score of NAC and Ambroxol Hydrochloride | -1.4 Score | Standard Deviation 0.78 |
| Placebo | Change From Baseline to Day 7 in Mean Expectoration Difficulty Score of NAC and Ambroxol Hydrochloride | -1.3 Score | Standard Deviation 0.75 |
p-value: <0.00198.75% CI: [0.45, 1]Modified Mann-Whitney U Statistic
Secondary
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.
Time frame: From baseline upto Day 7
Population: mITT population - The mITT population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Change From Baseline to Day 7 in Mean Sputum Viscosity Score of NAC and Ambroxol Hydrochloride | -1.2 Score | Standard Deviation 0.74 |
| Placebo | Change From Baseline to Day 7 in Mean Sputum Viscosity Score of NAC and Ambroxol Hydrochloride | -1.2 Score | Standard Deviation 0.78 |
p-value: 0.00297.5% CI: [0.43, 1]Modified Mann-Whitney U Statistic
Other Pre-specified
Number of Participants With Adverse Events
The safety and tolerability of intravenous NAC 600 mg twice daily was demonstrated.
Time frame: From screening to follow-up after the last administration of the investigational medicinal product (IMP) [assessed up to 19 months]
Population: The safety population included all subjects who provided informed consent and received at least 1 dose or partial dose of the IMP. Subjects were analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TEAE leading to drug withdrawal | 5 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one AE | 82 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TEAE of COVID-19 | 0 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TEAE leading to drug interruption | 0 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TESAE | 2 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one severe TEAE | 5 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TEAE leading to fatal outcome | 1 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TESAE leading to fatal outcome | 1 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TEAE | 67 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TESAE of COVID-19 | 0 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TESAE leading to drug withdrawal | 1 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one IMP-related TEAE | 11 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one TESAE leading to drug interruption | 0 Participants |
| N-Acetylcysteine | Number of Participants With Adverse Events | At least one SAE | 2 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE leading to fatal outcome | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE | 5 Participants |
| Placebo | Number of Participants With Adverse Events | At least one AE | 76 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE | 66 Participants |
| Placebo | Number of Participants With Adverse Events | At least one IMP-related TEAE | 11 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE leading to drug withdrawal | 2 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE leading to drug interruption | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one severe TEAE | 4 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE of COVID-19 | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one SAE | 5 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE leading to drug withdrawal | 1 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE leading to drug interruption | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE leading to fatal outcome | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE of COVID-19 | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE of COVID-19 | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one IMP-related TEAE | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE of COVID-19 | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE | 58 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE leading to fatal outcome | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE leading to drug withdrawal | 1 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE | 7 Participants |
| Placebo | Number of Participants With Adverse Events | At least one SAE | 7 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE leading to fatal outcome | 0 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE leading to drug interruption | 1 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TESAE leading to drug interruption | 1 Participants |
| Placebo | Number of Participants With Adverse Events | At least one severe TEAE | 7 Participants |
| Placebo | Number of Participants With Adverse Events | At least one TEAE leading to drug withdrawal | 3 Participants |
| Placebo | Number of Participants With Adverse Events | At least one AE | 71 Participants |