Methods

Single‐centre double blind parallel placebo controlled RCT. Method of recruitment was not specified.
Concomitant antitussives, mucolytics and beta‐2 agonist disallowed. Clinical evaluation performed on baseline, days 3, 7 and final. Subjects assessed for signs and symptoms relevant to diagnosis of acute or chronic lung disease including sputum volume and characteristics, dyspnoea, cough, pulmonary auscultation, difficulty in expectorating.

Compliance not mentioned. Inclusion and exclusion criteria described in next column.

Description of withdrawals or dropouts not mentioned.

Assessment of quality
1. Allocation concealment: Grade B
2. Blinding: Grade A
3. Reporting of participants by allocation group: Grade B
4. Follow up: Grade C

Participants

14 subjects allocated to neltenexine, 14 to placebo. Three within group had pneumonia but data specific to pneumonia was unavailable. Mean age of total group was 57.5 years (SD 3.04).
Inclusion criteria: Adults (aged > 18 years) with acute and chronic lung disease.
Exclusion criteria: Pulmonary tuberculosis, lung cancer, allergy to neltenexine, severe bronchospasm (requiring beta‐2 agonist, corticosteroids or aminophylline), or pregnant or lactating women.

Interventions

Neltenexine (a mucolytic), 37.4 mg tds or placebo (one tablet tds) for 10 to 12 days.

Outcomes

Overall physicians' assessment of efficacy scored; excellent, good, moderate, not satisfactory. Exact quantification unspecified.
Sputum volume, sputum characteristics (1 = serous to 5 = very purulent), and 5‐point scores for dyspnoea, cough, pulmonary auscultation, difficulty in expectorating, from 0 (absent) to 4 very severe.

Notes

Wrote to authors with no response.
Data for pneumonia alone not available.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Unclear risk

B ‐ Unclear

Methods

Single‐centre double blind placebo controlled RCT. Subjects recruited from inpatients in the geriatric unit of Barnet General Hospital, England. The method of randomisation and allocation was not described. When the medication (active or placebo) was considered ineffective, the pharmacist was asked to change to alternate treatment. Data card and observation record prepared for each subject, other medications recorded and authors indicated that these factors were taken into account when assessing response to trial drugs (but did not specify how). Inclusion and exclusion criteria not described. Description of withdrawals or dropouts not mentioned.

Assessment of quality
1. Allocation concealment: Grade B
2. Blinding: Grade A
3. Reporting of participants by allocation group: Grade B
4. Follow up: Grade C

Participants

Total randomised unknown. Total described in group unclear as some subjects could have been counted twice given potential crossover methodology. If assumed crossover was undertaken for all, total randomised would be 34. Age of subjects not given. Subjects had variety of aetiological factors for cough (pneumonia, acute and chronic bronchitis, bronchiectasis, carcinoma, cardiac failure, cor pulmonale, nervous cough, coryza, influenza).

Inclusion and exclusion criteria not described.

Interventions

Dimyril (active ingredient = isoaminile citrate, a codeine derivative) or placebo in identical bottles. Dose used varied. Initially 3 to 4 times/day followed by 'as necessary' dosing of up to 5 times a day (1 to 2 g).

Outcomes

Outcomes not clearly specified.

Paper stated:
"The evidence of the patient, the several observers (day and night nurses, physician, and medico‐social worker), the number of doses per 24 hours, and (when recorded) the actual cough frequencies were considered in deciding whether or not the nuisance and frequency of cough had been reduced".

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Unclear risk

B ‐ Unclear

Methods

Multi‐centre double blind parallel placebo controlled RCT. Children recruited from 3 hospitals in Italy.

Potential subjects admitted into hospital for symptoms of pneumonia screened for inclusion criteria (next column). Double blinded study and all subjects were treated as inpatients and re‐evaluated daily for heart rate, respiratory rate, maximal rectal body temperature. Cough, dyspnoea and chest pathological scores also recorded daily. CXR on admission and end of treatment. Compliance not mentioned but presumed excellent given inpatient study.

All children given antibiotics (see column on intervention). Other co‐treatment (e.g. anti‐pyretic agents) not mentioned. Inclusion and exclusion criteria described in next column.

Description of withdrawals or dropouts not mentioned. As children were inpatients, assumed most followed up. CXR follow‐up rate 115/120 = 95.8%.

Assessment of quality
1. Allocation concealment: Grade B
2. Blinding: Grade A
3. Reporting of participants by allocation group: Grade B
4. Follow up: Grade A

Participants

Total of 120 children randomised ‐ 60 in each arm. Outcome measure available for 115 children (57 active arm, 58 controls), 95.8%.

Antibiotic with ambroxol group: mean age not given, 11 aged < 1 year, 9 aged 1 to 2 years, 19 aged 2 to 5 years, 21 aged 5 to 12 years. Gender ‐ M: 28; F: 32. Mean body weight 17.1 kg (SD 1.08).
Antibiotic with placebo: Mean age not given, 12 children aged < 1 year, 11 aged 1 to 2 years, 20 aged 2 to 5 years, 17 aged 5 to 12 years. Gender ‐ M: 38; F:22. Mean body weight 16.2 kg (SD 1.06).

Inclusion criteria: Children admitted into hospital for pneumonia. Have had blood culture performed before commencement of antibiotics and positive for well defined bacterium or a CXR showing lobar and sub lobar involvement, with ESR ≥ 30 mm/h and C‐reactive protein ≥ 25 μg/mL.

Exclusion criteria: Taken antibiotics, mucolytics or mucoregulatory drugs in the preceding week.

Interventions

Trial medications consisted of ambroxol (1.5 to 2 mg/kg/day in two divided doses) or placebo for 10 days. All children also given antibiotics, chosen on basis of microbiological data or in accordance with literature on most probable aetiology for each age, for 7 to 10 days. Children aged < 5 years given oral amoxil or intramuscular ampicillin (50 mg/kg in 3 to 4 divided doses). Older children had oral erythromycin ethylsuccinate (50 mg/kg/day in 4 doses).

Outcomes

Cough, dyspnoea and chest pathological signs scored, ranging from 0 (absent) to 3 (very severe). CXR findings at the end of treatment was compared to pre‐treatment CXR and expressed as normalised, improved or unchanged.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Unclear risk

B ‐ Unclear

Methods

Multi‐centre double blind parallel RCT comparing amoxicillin plus bromhexine versus amoxycillin alone. Subjects recruited from 22 centres involving internalists or pulmonologists in the Philippines.

Potential subjects evaluated for inclusion criteria by history, examination, CXR, laboratory tests (blood counts, sputum). The method of randomisation and allocation was not described. Double blinded study and all subjects were treated as outpatients and re‐evaluated on days 3, 5, 7 and 10. Compliance monitored by pill counting.

Subjects allowed to receive medications for fever and constitutional symptoms but not any other cough expectorants or antimicrobials. Inclusion and exclusion criteria described in next column.

Description of withdrawals or dropouts mentioned for entire group. Maximum follow‐up rate 375/407 = 92% but less for other aspects.

Assessment of quality
1. Allocation concealment: Grade B
2. Blinding: Grade A
3. Reporting of participants by allocation group: Grade A
4. Follow up: Grade B

Participants

Total of 407 subjects randomised ‐ 201 in active Rx and 206 in control group. 392 completed study (192 active, 200 controls). Compliance of 80% in active group and 85% in control group.

Amoxil with bromhexine group: Mean age 32 (SD 13) years, gender ‐ 117 M: 75 F; 51 with pneumonia, 141 with bronchitis.
Amoxil alone: Mean age 32 (SD 12), gender ‐ 130 M: 70 F; 50 with pneumonia, 150 with bronchitis.

Inclusion criteria: Adolescents and adults aged 15 to 60 years with uncomplicated community acquired lower respiratory tract infection (pneumonia or bronchitis), clinically assessed to be bacterial in aetiology. Pneumonia defined as presence of cough < 2 weeks, purulent phlegm, fever and/or leucocytosis (> 10,000 mm³), and pulmonary infiltrates on CXR. Acute bronchitis defined as presence of cough < 2 weeks, purulent phlegm, fever and/or leucocytosis (> 10,000 mm³). Sputum culture had to be sensitive to amoxil or if organism resistant, subject included if clinical response at Day 3 occurred on amoxil.

Exclusion criteria: Frank respiratory failure, coexistent chronic disease (diabetes, renal failure, liver or renal impairment, terminal illness such as cancer, active tuberculosis, healed tuberculosis with bronchiectasis, chronic bronchitis or emphysema, heavy smokers (undefined)), pregnant or lactating, hypersensitivity to study drugs, or recent (< 2 weeks) treatment with antibiotics.

Interventions

Active Rx = amoxil 240 mg and bromhexine 8 mg, both 4 times/day for 7 days.

Control group: amoxil alone, 250 mg 4 times/day for 7 days.

Outcomes

Days 3, 5, 7 and 10. Subjects evaluated for clinical response, bacteriological response, subjective symptom scores, adverse events, compliance, complete blood count.

Clinical response:
Cured = complete disappearance of pre‐treatment symptoms and signs
Improvement = pre‐treatment symptoms and signs improved but not cured
Failure = pre‐treatment symptoms and signs did not improve or worsened
Indeterminate = clinical response could not be determined.

Clinical symptoms:
10 mm visual analog scale of symptoms of cough frequency, cough discomfort, difficulty breathing not related to cough, chest pain not related to cough, ease of expectoration.

Bacteriologic response:
Eradication = absence of pre‐treatment pathogen or no more culturable material could be expectorated
Persistence = presence of pre‐treatment pathogen
Super‐infection = appearance of resistant pathogen after starting treatment
Indeterminate = bacteriologic response could not be reliably assessed.

Notes

Wrote to authors with no response.
Data for pneumonia alone available only for global clinical response outcome.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Unclear risk

B ‐ Unclear