Dirksen 2009.

Methods	Double‐blind, placebo‐controlled
Participants	82 ex‐ or never‐smokers from Copenhagen (Denmark), Malmö (Sweden) and Birmingham (UK) with severe alpha‐1 antitrypsin deficiency (serum concentration < 11 μM)
Interventions	Treated for 2 years (with an optional 6 months' extension) Treatment: weekly infusions of alpha‐1 antitrypsin 60 mg/kg Placebo: weekly infusions of 2% albumin
Outcomes	Primary: lung density measured by CT scan Secondary: FEV1, carbon monoxide diffusion, frequency of exacerbations, health status (SGRQ)
Notes	Trial sponsored by the manufacturer, Talecris Biotherapeutics, Inc. 1 of the authors had received a research grant from the Alpha‐1 Foundation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised in blocks of 4 for each city; block size was not disclosed to the study sites. Computer‐generated random code was used to produce randomisation envelopes
Allocation concealment (selection bias)	Unclear risk	Randomisation envelopes were issued to the unblinded pharmacist or designee at each study centre and were kept confidential. Randomisation envelopes were sent to the pharmacist with the study medication. Clinical site pharmacy personnel who prepared the study medication were not blinded. Unclear whether the envelopes were opaque and sealed
Blinding (performance bias and detection bias) All outcomes	Low risk	All participants received same total volume per kilogram bodyweight of study medication with no visible difference in external aspect between drugs, as variation in colour by lot was masked by using opaque sleeves. Throughout the course of the trial, individual treatment assignments were unknown to the clinicians; the monitors; the CT scan facility; and the sponsor's data management, clinical and biostatistical teams
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	82 participants enrolled, 77 randomised, 10 of whom later withdrew; change from baseline for the CT scans only available for 67 participants after 2 years
Selective reporting (reporting bias)	High risk	Mortality was recorded but not reported. Values for FEV1, DLCO and KCO were not available in the trial report, only on the journal's website
Other bias	High risk	Paper stated, "This study was sponsored by Talecris Biotherapeutics, Inc (Research Triangle Park, NC 27709, USA) and was conducted between November 2003 and January 2007. Two of the authors of the manuscript (MW and CD) are employees of Talecris and participated in the design of the study, in the collection, analysis and interpretation of data (CD was the statistician for the study), in the writing of the manuscript and in the decision to submit the manuscript for publication. The article‐processing charge would be sponsored by Talecris Biotherapeutics, Inc. Editorial assistance was provided by M. Kenig at PAREXEL and was supported by Talecris Biotherapeutics, Inc."

A1PI: alpha‐1 proteinase inhibitor; CT: computed tomography; DL_CO: carbon monoxide diffusing capacity; K_CO: carbon monoxide transfer coefficient; FEV₁: forced expiratory volume at one second; FVC: forced vital capacity; SGRQ: St. George's Respiratory Questionnaire; VC: vital capacity.