Hoyles 2006.

Methods	Participants recruited from 5 centres in the United Kingdom Participants allocated to the active treatment group (prednisolone and CYC followed by AZA) or the placebo group via the minimisation method, with balancing for the following known prognostic factors: age, baseline HRCT pattern and extent of disease, and autoantibody profile
Participants	Ambulatory participants aged 18 to 75 years, who fulfil American College of Rheumatology (ACR; formerly, the American Rheumatism Association) preliminary criteria for a diagnosis of SSc, have SSc‐associated pulmonary fibrosis, as indicated by high‐resolution computed tomography (HRCT) or thoracoscopic lung biopsy, and comply with therapy and with regular specialty centre attendance Participants excluded from the study if they had previous AZA or CYC therapy for 3 months, had previous high‐dose oral corticosteroid therapy (30 mg of prednisolone or equivalent daily) for 3 months, had oral corticosteroid therapy (prednisolone dosage 10 mg daily) in the 3 months before study entry, had contraindications to oral corticosteroids such as poorly controlled diabetes or severe osteoporosis, were likely to require lung transplantation within 1 year, had a history of or laboratory data suggestive of other serious systemic or psychological disease unrelated to SSc, were pregnant or lactating, exhibited evidence of alcohol or drug abuse, or were unable to give written informed consent No significant differences in baseline characteristics between intervention and control groups Baseline FVC 80%
Interventions	Participants in the active treatment group received therapy with 20 mg oral prednisolone on alternate days and 6 IV infusions of CYC at a dose of 600 mg/m² (mean dose 1050 mg) at 4‐week intervals, followed by oral AZA at 2.5 mg/kg/d (maximum 200 mg/d) as maintenance therapy. Patients in the placebo group received placebo formulations that matched the active treatment.
Outcomes	Tests of lung function were performed at 3, 6, and 12 months. Pulmonary function testing was performed according to the guidelines of the British Thoracic Society. Tests of lung volume and airway resistance were conducted via a constant volume body plethysmograph. Single‐breath diffusing capacity for carbon monoxide (DLCO) was tested with a conventional carbon monoxide/helium gas mixture and corrected for haemoglobin (corrected DLCO) and alveolar volume (coefficient of gas transfer, Kco). Spirometry was performed using flow‐volume loops. All results were expressed as a percentage of normal predicted values based on age, sex, and height. A modified American Thoracic Society respiratory questionnaire was used to determine a baseline dyspnoea score; the minimum score of 0 represented breathlessness after 30 minutes of vigorous activity, and the maximum score of 20 represented breathlessness with minimal activity. Arterial blood gases were performed at 3, 6, and 12 months. HRCT (1.5‐mm cuts at 20‐mm intervals from lung apex to base in the supine position) was repeated at 1 year.
Notes	Other immunosuppressive agents, including colchicine, methotrexate, and D‐penicillamine, which might influence the course of lung fibrosis, were not permitted. Both groups continued to receive standard therapy for non‐pulmonary disease. Participants with early (not defined) pulmonary fibrosis including new referrals and existing patients were recruited. Early is not defined in the entry criteria. Many patients with severe or deteriorating disease were inevitably excluded. How patients were selected by investigators or referring physicians for entry is not clearly described. The bias is likely to affect both arms towards a lack of treatment effect. Supported by the Arthritis Research Campaign
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Used stratified sampling (minimisation method) for known prognostic factors: age, baseline HRCT pattern and extent of disease, and autoantibody profile
Allocation concealment (selection bias)	Low risk	Investigators were blinded to treatment allocation. Randomisation was undertaken at the Royal Brompton Hospital by members of the Clinical Trials and Evaluation Unit, who were not involved in the analysis of data. However, selection of participants for entry consideration was not clearly described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants in the placebo group received placebo formulations that matched the active treatment.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Radiologists were blinded to treatment category, but it was not explicitly stated whether other outcome assessors were blinded. It is not clear if study personnel managed adverse events and potentially would have been unblinded by the presence or lack of outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Eight of 45 participants (18%) were lost to follow‐up but had already been withdrawn from the study. Intention‐to‐treat analysis was used.
Selective reporting (reporting bias)	High risk	Prespecified outcomes were reported. Post hoc subgroup analysis for weight was included. Tests of lung function and arterial blood gases were performed at 3, 6, and 12 months. Only baseline and 12‐month data are compared.