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. 2019 May 24;2019(5):CD013024. doi: 10.1002/14651858.CD013024.pub2

Shafuddin 2015.

Methods Design: double‐blind, randomised, placebo‐controlled multi‐centred study carried out across Australia and New Zealand
Duration: 12 weeks active treatment period followed by 48 weeks post‐treatment period
Setting: 16 centres (15 hospitals and one research centre) across Australia and New Zealand
Participants Population: 292 adults with symptomatic COPD and positive Chlamydia pneumoniae (C pneumoniae) serology
Baseline characteristics: age (mean, SD): 67.3 (8.58), current smoker (n): 71/292, tobacco consumption (pack year, mean, SD): 56.58 (33.3), number of previous exacerbations within two years (mean, SD): 5.11 (2.4), FEV1 (% predicted, mean, SD): 34 (14.8), FVC (L, mean, SD): 2.23 (0.83), FEV1/FVC (mean, SD): 42 (10.2)
Inclusion criteria: age 45 years and over, FEV1 ≤ 70% of predicted, FEV1/FVC ≤ 60% and reversibility < 15% and/or 200 mL, smoking history of ≥ 20 pack
years, at least three confirmed COPD exacerbations in the last two years, positive serology for C. pneumoniae (IgG antibody titre ≥ 1:64), informed consent to participate in the trial
Exclusion criteria: pulmonary disease other than COPD, antibiotic treatment four weeks prior to randomisation, exacerbations four weeks prior to randomisation, pregnancy or breastfeeding, hypersensitivity to trial antibiotics (macrolides, tetracyclines, beta‐lactams or sulphamethoxazole, trimethoprim), clinically significant cardiovascular, hepatic, renal or other systemic disease, known long QT syndrome or QTc > 450 ms, sick sinus syndrome, bradycardia (< 50 bpm), or severe hypokalaemia, epilepsy, treatment with an investigative drug four weeks prior to randomisation, treatment with medicine known to have important interactions with macrolides or tetracyclines, unlikely to comply
Interventions

  1. Roxithromycin (continuous; 300 mg daily)

  2. Roxithromycin (continuous; 300 mg daily plus doxycycline 100 mg daily)

  3. Matching placebo (not included in this review)
Outcomes

  1. Frequency and severity of acute infective exacerbations of COPD

  2. Health status, quality of life score (CRQ)

  3. FEV1 and FVC

  4. Titres of IgG and IgA antibodies for C pneumoniae

  5. PCR determination of C pneumoniae from sputum and monocytes

  6. IgA secretion to C pneumoniae in sputum

  7. Adverse events

  8. Number of hospitalisations due to COPD

  9. Number of visits to medical practitioners and other health professionals due to COPD

  10. Alterations to drug usage
Notes Funding: Sanofi‐Aventis Australia Pty Ltd (formally Hoechst Marion Roussel Pty Ltd)
Aim of study: the original aim of the study was to assess whether treatment with roxithromycin with or without doxycycline can eradicate C pneumoniae infection and subsequently reduce exacerbation rates, but the authors considered this hypothesis unsubstantiated and clinically no longer relevant. The study allowed authors to address the role of prophylactic antibiotics in reducing COPD exacerbations.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Each eligible participant was assigned a sequential subject number followed by randomisation number provided by Hoechst Marion Roussel, Australia. Subjects were supplied with one of the three treatments according to their randomisation number.
Allocation concealment (selection bias) Low risk Each eligible participant was assigned a sequential subject number followed by randomisation number provided by Hoechst Marion Roussel, Australia. Subjects were supplied with one of the three treatments according to their randomisation number.
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Study medication was packed by Hoechst Marion Roussel in bottles labelled with the randomisation and batch numbers. The investigators, pharmacists and subjects were blinded to the study medication in these bottles.
Blinding of outcome assessment (detection bias) 
 All outcomes Low risk Trialists confirm that all participants, personnel and outcome assessors remained blinded until data had been analysed.
Incomplete outcome data (attrition bias) 
 All outcomes High risk More participants dropped out of combined antibiotics treatment arm (21 versus 13 in single antibiotic arm and 10 in placebo arm), although according to trialists reasons were not related to study medication. All patients included in ITT analysis
Selective reporting (reporting bias) Low risk Planned outcomes according to trial
Other bias Unclear risk Imbalance in baseline characteristics may affect the study results

Bpm: beats per minute
 COPD: chronic obstructive pulmonary disease
 CRQ: Chronic Respiratory Questionnaire
 FEV1:FVC: forced expiratory volume in one second/forced vital capacity

FVC: forced vital capacity (Iitres)
 ICS: inhaled corticosteroids
 IgA: immunoglobulin A
 IgG: immunoglobulin G
 ITT: intention‐to‐treat
 SGRQ: Saint George's Respiratory Questionnaire