Tashkin 2006.

Methods	Ambulatory participants recruited from 13 centres Parallel placebo‐controlled double‐blind trial
Participants	Participants with limited or diffuse systemic scleroderma, if they had evidence of active alveolitis on examination of bronchoalveolar‐lavage (BAL) fluid (defined as neutrophilia ≥ 3%, eosinophilia ≥ 2%, or both), or on thoracic high‐resolution computed tomography (CT), any ground‐glass opacity, onset of the first symptom of scleroderma other than Raynaud's phenomenon within the previous 7 years, FVC between 45% and 85% of predicted value, and grade 2 exertional dyspnoea according to the baseline instrument of the Mahler Dyspnea Index (as measured via the magnitude‐of‐task component) Primary exclusion criteria included a single‐breath carbon monoxide diffusing capacity (DLCO) that was < 30% of predicted value, a history of smoking within preceding 6 months, other clinically significant pulmonary abnormalities, or clinically significant pulmonary hypertension requiring drug therapy. Patients taking prednisone at a dose > 10 mg/d, those who had previously been treated for longer than 4 weeks with oral cyclophosphamide or had received ≥ 2 intravenous doses, and those who had recently received other potentially disease‐modifying medications were also excluded. Data show no significant differences between groups except that scores for the HAQ disability index were significantly lower (indicating greater health) in the placebo group than in the cyclophosphamide group. Baseline FVC 68%
Interventions	Cyclophosphamide and placebo were formulated into matching gelcaps at a dose of 25 mg, and treatment was initiated with a dose of 1 mg per kilogram of body weight per day (to the nearest 25 mg). Doses were increased monthly by 1 capsule up to 2 mg per kilogram. Prednisolone up to 10 mg per day was permitted as a co‐intervention.
Outcomes	Measurements were made at baseline and at 3‐month intervals throughout the study, except the Mahler Dyspnoea Index. Primary outcome: FVC (expressed as a percentage of predicted value) at 12 months Lung volume measurements were repeated at 6‐month intervals. Prespecified secondary outcomes included values for total lung capacity (expressed as a percentage of predicted value), DlCO (diffusing capacity adjusted for alveolar volume (Dl:Va)), the disability index of the Health Assessment Questionnaire (HAQ), and the Medical Outcomes Study 36‐item Short‐Form General Health Survey (SF‐36). Mahler Transitional Dyspnoea Index (scale from −9 to +9, with the plus sign indicating improvement and the minus sign indicating worsening) Post hoc: skin thickness Cough is reported in a separate manuscript as part of this trial.
Notes	Professor Tashkin provided unpublished data for subgroup analyses. Funded by NIH and University grants. Medication supplied free of charge by Bristol‐Myers Squibb. Trial authors state that funders had no influence on the trial or the publication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned with the use of a permuted‐block design and 1:1 allocation (in blocks of 4 to 6 participants per centre).
Allocation concealment (selection bias)	Low risk	Cyclophosphamide and placebo were formulated into matching gelcaps. To preserve blinding of investigators, an independent medication control officer assessed adverse events and regulated all doses of study medication, in accordance with the study protocol.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Cyclophosphamide and placebo were formulated into matching gelcaps.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The primary outcome (FVC) was determined by trained, project‐certified hospital‐based pulmonary function technologists. As these technicians were unaware of changes in study medication or results of other outcomes, it is unlikely that they could have become unintentionally unblinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Of a total of 158 patients, 3 assigned to placebo and 1 assigned to cyclophosphamide withdrew before starting study treatment and were not included in the analysis. A total of 20 participants in the cyclophosphamide group and 13 in the placebo group withdrew within 12 months after randomisation, most because of adverse events or serious adverse events. Many participants who withdrew were available for endpoint measurement at 12 months; however some 12‐month data were extrapolated from 6‐ or 9‐month data. For remaining participants who withdrew prematurely, a generalised estimating‐ equation regression model was fitted, and data missing at 12 months were imputed. Intention‐to‐treat analysis was used.
Selective reporting (reporting bias)	Low risk	Post hoc skin thickness was added. Otherwise all prespecified outcomes were reported. Cough index is reported in a separate manuscript.