Malerba 2004.

Methods	Randomised, double‐blind, placebo‐controlled, parallel, multi‐centre (26). ITT and OT. Duration 12 months
Participants	242 participants with COPD (ATS definition) and chronic bronchitis. Age 40 to 75; FEV₁ 60% to 80% (GOLD stage IIA); pathological chest auscultatory findings; at least 1 exacerbation in previous 12 months Exclusions: CF, bronchiectasis, asthma, centrilobular emphysema, peptic ulcer or liver, kidney or heart insufficiency Other mucoactive and anti‐cough agents, OCS, or ICS not permitted. ICS withdrawn at least 4 weeks before study Mean age 60 years; 75% had smoking history; FEV₁ 2.12 (SD 0.6) L; mean 2.7 (SD 1.3) exacerbations in past 12 months Dropouts: 34 (16%)
Interventions	Ambroxol 75 mg twice daily or placebo
Outcomes	Exacerbations over first 6 months (winter period) and at 12 months Secondary: cough intensity and frequency, difficult expectoration, dyspnoea, days on antibiotics, number of working days lost, number of days of hospitalisation
Notes	Italian. AMETHIST study Post hoc analysis on participants with more severe condition
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information not available
Allocation concealment (selection bias)	Unclear risk	Information not available
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	14% dropout rate (34/242), but only 3% excluded from intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Main outcomes reported; some post hoc analysis