De Koning 2020.

Study characteristics
Methods	Trial design: phase 3 RCT  Duration of follow‐up: 10 years  Number of trial locations: 4
Participants	Baseline characteristics Number of participants: LDCT arm (7900); control arm (7892) Age: median age LDCT arm (58 years old); control arm (58 years old)  Sex: LDCT arm (6583 males, 1317 females); control arm (6612 males, 1277 females, 3 missing) Smoking status: LDCT arm (4415 current, 3465 former, 20 missing); control arm (4333 current, 3536 former, 23 missing) Performance status: Dutch control arm only N = 7393 (1124 had excellent/very good health, 4922 had good health, 1347 had moderate/poor health). Dutch control arm only N = 7398 (3292 had high physical activity levels, 3318 had moderate physical activity levels, 788 had low physical activity levels) Ethnicity/race: not published Environmental exposures: not published Inclusion criteria Born between 1928 and 1956 Smoked > 15 cigarettes/day during > 25 years or smoked > 10 cigarettes/day over > 30 years Current or former smokers who quit smoking ≤ 10 years ago Exclusion criteria Moderate or bad self‐reported health who were unable to climb two flights of stairs Body weight ≥ 140 kg Current or past renal cancer, melanoma or breast cancer Lung cancer diagnosed < 5 years ago or ≥ 5 years ago but still under treatment Had a chest CT examination < 1 year before they filled in the first NELSON questionnaire Preintervention investigations Nil
Interventions	Intervention characteristics Frequency of scanning: baseline, year 1, year 3 and year 5.5  LDCT setting: 30 mA and 120 kVP to 140 kVP Duration of screening: 5.5 years  Interpretation of scans Volumetric or size Criteria: volumetric Use of volumetry software: yes Criteria for significance: any non‐calcified nodule with no benign characteristics Prespecified protocol for nodule follow‐up: yes Comparison Description: no screening
Outcomes	Primary outcome Lung cancer mortality  Secondary outcomes Lung cancer incidence (stage‐specific; time interval; screen‐detected versus interval cancers) and survival Detection rates for first (prevalence) and subsequent (Incidence) screening, as well as stage distribution Sensitivity, specificity and positive predictive value  Quality of Life Quality‐adjusted life years Cost‐effectiveness
Identification	Sponsorship source: Stichting Centraal Fonds Reserves van Voormalig Vrijwillige Ziekenfondsverzekeringen (RvvZ), Siemens Germany, G. Ph. Verhagen Stichting, Rotterdam Oncologic Thoracic Steering committee (ROTS), Erasmus Trust fund, Stichting tegen Kanker, Vlaamse Liga tegen Kanker Country: The Netherlands and Belgium Setting: hospital  Trial start date: August 2003 Completion of follow‐up: December 2015 Trial registration number: ISRCTN63545820 Corresponding author's name: Harry J Koning Institution: Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands Email: h.dekoning@erasmusmc.nl
Notes	Conflicts of interest  Carlijn van der Aalst reported receiving supplies from Siemens. Pom A. de Jong reported receiving grant support, paid to his institution, from Philips. Mathias Prokop reported receiving fees for serving on a speakers bureau from Bayer HealthCare and Bracco Imaging and grant support and fees for serving on a speakers bureau from Canon Medical Systems and Siemens. Joachim G.J.V. Aerts reported receiving consulting fees from Amphera, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Eli Lilly, F. Hoffmann–La Roche, Merck, and Takeda Oncology, holding pending patent #PCT/NL20/19/050636 on specific inhibition of Janus kinase 3 for modulating antitumour immune responses, and holding patent #9962433 on a method for preparing an immunogenic lysate, the lysate obtained, dendritic cells loaded with such lysate, and a pharmaceutical composition comprising the lysate or the dendritic cells. Rozemarijn Vliegenthart reported receiving fees for serving on a review committee from BTG International and grant support, paid to her institution, from Siemens. Kevin ten Haaf reported receiving supplies from Siemens.  Matthijs Oudkerk reported receiving lecture fees from AstraZeneca and Siemens Medical Solutions USA.  No other potential conflict of interest were reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Documented 1:1 randomisation
Allocation concealment (selection bias)	Low risk	Central allocation concealment method used, information from author
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants were not blinded.
Blinding of outcome assessment (detection bias) All outcomes	High risk	There were some concerns about the method of determining lung cancer‐related mortality. The 2012 publication by Horeweg et al. in Lung Cancer reviewed the preliminary 50 completed medical files of Dutch participants who were deceased and had a diagnosis of lung cancer. This trial reported a reduced specificity for death certificates (62.5%) and sensitivity of 95.2% compared with a clinical expert committee. This was subsequently followed by a larger sample of 263 participant deaths and the specificity rose to 98.8% and sensitivity of 92.6%. The committee reclassified 12.2% of causes of death. However, the remaining 163 male deaths then had cause of death determined by death certificate only. The assessors were unblinded in subsequent publication. There were no significant concerns about assessment of other outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	18 persons could not be linked because a digital form could not be retrieved for national linkages, > 98% coverage
Selective reporting (reporting bias)	Low risk	Cost analysis will be published, information from author
Other bias	High risk	There was an inadequate balance of males and females included in this trial. Additionally, method of assessment of primary lung cancer‐related mortality outcome was changed during the trial. The initial trial protocol planned only 4 years of screening, however an additional scan was introduced and screening extended to 6.5 years. Information provided by author clarified that the fourth round of screening was sought in 2009, after the trial had commenced. This change to screening is unlikely to have increased risk of bias.