Statistical analyses
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SECONDARY, COLD, BLIND
The primary endpoint was defined as the AUC of WURSS-21 QoL composite sub-scores assessed during first 8 days of symptoms. The WURSS-21 QoL composite sub-score was calculated by summing the scores of the 9 consecutive items of WURSS-21, from item 12 (“think clearly”) to item 20 (“live your personal life”), as documented in the subject diary. The AUC was assessed by applying the trapezoidal approximation. The two-sided confirmatory null-hypothesis for the primary endpoint, the major secondary endpoints and continuous other secondary endpoints were analyzed for between-group comparison using the non-parametric two-sided Wilcoxon (Mann-Whitney U) rank-sum test, unstratified as well as stratified by study center (Van-Elteren or generalized Mann-Whitney test) to assess the treatment effect adjusted by the influence of sites. The stratified Van-Elteren test will be presented below for this multi-center trial. Multiple testing was performed without exploratory adjustment. For categorical other secondary endpoints, χ2 tests, unstratified as well as stratified by study center (Cochran-Mantel-Haenszel test), were used for between-group comparison. For continuous data, standard statistical characteristics were presented (number of subjects with non-missing data, mean, standard deviation, median, minimum and maximum and quartiles). Categorical data (nominal or ordinal) were summarized using frequency tables.The statistical analyses were defined as confirmatory for the primary and, in a hierarchical order, the two major secondary endpoints, and exploratory for all other secondary endpoints. All inferential statistical testing was performed as two-sided. The confirmatory significance level was fixed to a type I error rate alpha of 5% (two-sided). In order to control the overall experiment type I error rate, the primary endpoint and the two major secondary endpoints were to be tested in a fixed sequence as The full analysis set (FAS) was defined in the statistical analysis plan (SAP), prior to unblinding and statistical analysis, as all subjects of the all subjects treated set (AST, n = 438) for which at least one of the confirmatory endpoints could be evaluated. Incorrectly randomized subjects with an unfulfilled entry criterion were excluded from the FAS (n = 436) if the specific criterion violation had been measured and documented prior to randomization and, before breaking the blind, was considered to be of major importance. Analyses with respect to safety were performed for the AST. Analyses with respect to efficacy were conducted both for the FAS and the per-protocol set (PPS). Summary results are presented here for the FAS.All available data were to be included in the analyses and summarized as far as possible. Unless otherwise specified, no substitution of missing data should take place, i.e., missing data were not to be replaced but handled as ‘missing’ in the statistical evaluation. This included time points after a subject had prematurely terminated the study. The WURSS-21 QoL composite subscore is based on 9 items assessed daily in the cold diary. A daily value was computed as sum of the 9 item score points of that day, if at least 7 of them were available; the missing item score points were imputed by the mean of the subject’s other available score items on the given day. If less than 7 score items were available on a day, the WURSS-21 QoL composite subscore was not computed. The total Jackson score is based on 8 items assessed twice daily in the cold diary. For each item, values for morning assessment and evening assessment were used to calculate one single value per day as the mean of both values. If only one assessment (morning or evening) was available on a day, the daily value was based only on the single assessment. If both assessments were missing, the daily value was not computed. The total Jackson score for a given day was computed as sum of the 8 item score points of that day, if at least 6 of them were available; the missing item score points were imputed by the mean of the subject’s other available score items on the given day. If less than 6 score items were available on a day, the total Jackson score was not computed. For the calculation of an AUC based on daily values (i.e. for days 1–8), a value for each day was expected. In case of missing values, the following imputation rules applied:If in a subject for less than half of the planned days a value was available, the AUC was not computed.If a value in the middle of the period was missing, it was imputed as mean of the subject’s previously and subsequently available values (linear interpolation).If the last value of the period was missing, it was imputed by the subject’s last available value before (LOCF approach); subsequent values after the period (e.g. on day 9) were not considered.The statistical analysis was performed using the SAS