Treatment with tacrolimus versus cyclosporine has been shown to be safe and comparable regarding early outcome such as rejection rates and early mortality, as outlined in our literature review . However, there are few comprehensive studies and data on long-term outcome, particularly on CLAD, is scarce.
Safety assessments will consist of monitoring and recording all infections, any malignancies, AEs, SAEs, and suspected unexpected serious adverse reactions (SUSARs), the regular monitoring of hematology, blood chemistry, physiological testing, and regular measurement of vital signs. To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient is randomized and until 4 weeks after the patient has stopped study participation must be reported to the sponsor within 24 h or at first possible weekday of learning of its occurrence, whichever comes first.
Sample Size and Power Calculation
In order to detect a difference in CLAD between the two treatment groups in the ScanCLAD study, we calculated our sample size according to the following assumptions: 2-year inclusion, 3-year follow-up, 80% power, and two-sided significance level of 5%. On the basis of these assumptions, the numbers needed were calculated as follows: CLAD incidence in CyA and Tac arm of 30% (BOS alone approximately 30% at 3 years  with cyclosporine) and 15% (50% reduction was seen in the Treede study  with Tac, although from 22% to 11%), respectively, and 30% censuring (early dropouts) which would require 121 patients in each arm, altogether 242 patients in the study.
A statistical analysis plan (SAP) was written and approved by the ethics committees (EC). All analyses and tabulations will be performed using the latest release of Stata software statistical program (currently version 14.0). The analysis will be done when all patients have completed the trial at 36 months after LTx (or discontinued prematurely). Unless otherwise stated, all statistical tests will be two-sided and use the 5% level of statistical significance. Confidence intervals will be presented with 95% as the level of confidence. All summary statistics will be presented for the treatment groups. Frequency distributions will be provided for categorical variables and the two treatment groups will be compared with the chi-square or Fisher’s exact test. Descriptive statistics of mean, standard deviation, minimum, median and maximum will be presented for continuous variables; comparison of the two treatment groups will be performed with suitable chosen two-sample tests. Time to event data including rates of affected patients will be assessed by Kaplan–Meier statistics and compared between the two groups with the log rank test. Cumulative incidence will also be analyzed by competing risk methods when competing risks are present and will be compared between the two groups with the Fine and Gray’s test or similar test. Data from all centers that participate in this study will be combined.
Populations for Analysis
The enrolled patient (ENR) population will include all patients who signed an informed consent regardless of whether lung transplantation was performed or not.
The intention-to-treat (ITT) population will consist of all randomized patients. The ITT population will be analyzed following the ITT principle. However, this analysis is not the main analysis of the study, since some patients will inevitably be sent home without transplantation because of worsening of donor organ function or other reasons, explained by the fact that randomization occurs prior to transplantation. The ITT population will therefore include patients who never underwent transplantation or received study drug.
The most important populations of study to analyze are the following:
The per protocol transplanted (PPtrans) population will consist of all patients in whom transplantation was performed and who were randomized and treated with at least one dose of randomized treatment. The PPtrans population is also the safety population (SAF).
The per protocol CLAD (PPCLAD) population (or full-analysis set population, FAS) will consist of all randomized patients who received at least one dose of any immunosuppressive therapy, underwent transplantation, and had at least one post-baseline assessment of the primary efficacy variable (CLAD). Randomized patients without data on the primary outcome variable will be excluded from this population.
The per protocol drug (PPdrug) population will consist of all ITT patients who did not show major deviations from the protocol procedures that may have an impact on the study outcome, remained on randomized study drug, and who have completed the treatment phase at 36 months according to protocol.
There will be no planned interim analysis initiated by the steering committee; however, if the data and safety monitoring board (DSMB) wants one performed it can be done blinded.
The eCRF software creates the enrollment and randomization numbers at enrollment and randomization visits, respectively. Randomization is performed using a web-based system and patients are randomized in a 1:1 ratio to one of the two treatment groups. Two sets of randomization numbers will be prepared for stratified randomization: (1) patients with a diagnosis of cystic fibrosis and (2) patients without a diagnosis of cystic fibrosis.
During the study, a field monitor will visit the site regularly to check the completeness of patient records, the accuracy of entries in the eCRFs, the adherence to the protocol and Good Clinical Practice (GCP), and the progress of enrollment. Monitoring standards are followed and all checks of the consistency of the source data with the CRFs are performed according to the study-specific monitoring plan.
Gothia Forum, a non-profit organization associated with Gothenburg University and Sahlgrenska University Hospital, assists the sponsor (GD) and all PIs in organizing the study according to GCP rules. The study database is placed on a central internet server. Designated investigator staff will enter the data required by the protocol into the database. Automatic validation programs check for data discrepancies in the eCRFs and, by generating appropriate error messages, allow modification or verification of the entered data by the investigator staff before being saved in the database.
Database Management and Quality Control
Gothia Forum will review the eCRFs entered by investigational staff for completeness and accuracy and instruct the site personnel to make any required corrections or additions.