Statistical methods
Statistical methods for primary and secondary outcomes
{20a}
The experimental arm will be compared against the control arm for all
primary analyses.
Cumulative proportions of time to event endpoints will be reported using
Kaplan Meier method. the hazard ratio and the 95% confidence intervals
for the locoregional recurrence rate will be computed using the Cox
regression analysis. The upper bound of the 95% confidence intervals
would be used to demonstrate non-inferiority for locoregional recurrence
which would be concluded if the same exceeds the predefined threshold of
1.63. The Chi-square test with continuity correction will be used for
comparing the binary / categorical variables, while the Wilcoxon test
will be used for comparing continuous variables.
All tests will be two-sided and a significance level of 5% will be used
for declaring statistical significance. The proportion of patients
experiencing any Grade 3 - 4 AE will be reported in each arm and
compared between the two arms using the Chi-square test or Fisher’s
exact test. Similar comparisons will be done for each AE term between
the two groups. Comparison of AE between the two arms will be done on
full analysis set as well as the per-protocol set.
Multivariable analysis for the primary and secondary endpoints will be
conducted using Cox regression analysis. For every model, the underlying
assumptions for the model will be checked which would include checks for
proportional hazards assumptions, outlier and overly influential
detection as well as a check for the linearity assumptions. Additionally
bootstrapping will be used to estimate the calibration and
discrimination of the model. Further details can be found in the
statistical analysis plan.
Interim analyses {21b}
An interim analysis for safety will be planned at 3 years when 16 events
in total are expected to have occurred. As a result of this interim
analysis, the sample size has been increased to 2100 patients. The
critical Z value at the time of interim analysis is 3.47 for futility.
The following table illustrates the key features of the design