Sas version 9.3 or higher

Approximately 180 patients were planned to be enrolled, with a minimum of 60 each for CNePSCI and CPSP, and 10 for CNePPD, with the goal of achieving a completion rate of at least 100 patients receiving treatment for 1 year, in accordance with the ICH E1 guidelines [22 ]. The safety and efficacy analysis sets were identical and included all patients who provided informed consent and received at least one dose of study medication.
Continuous variables were summarized by the number of observations, mean, standard deviation (SD), median, and range. Categorical variables were summarized using frequency counts and percentages. No imputation was performed for missing safety data. Missing data for efficacy endpoints were handled according to the standard scoring instructions of the SF-MPQ questionnaire, using a last-observation carried forward (LOCF) approach. All statistical analyses were performed with SAS Version 9.3 or higher (SAS Institute Inc., Cary, NC, USA).

SAS® version 9.3 or higher (SAS, Cary, NC) was used to perform the statistical analyses. Sample size calculations were based on the probability of observing at least one case of a TEAE in all of the treatment groups. Randomization was stratified by sex, age group (<65, ≥65 years), and geographic region. Further details about the sample size calculations and the randomization process have been published previously.22For the efficacy analyses, the least‐squares mean estimates and two‐sided 95% confidence intervals (CIs) for changes from baseline within each treatment group and subgroup were estimated using an analysis of covariance (ANCOVA) model with treatment group, age group (<65, ≥65 years or <75, ≥75 years), sex, previous study history, geographic region, and interaction between age group and treatment group as fixed factors and baseline value as a covariate. A similar ANCOVA model was also used to analyze the vital sign results. No P values for differences between treatment groups were calculated for this subgroup analysis.

As this phase 1b/2a study did not involve the statistical testing of a hypothesis, a formal sample size was not determined. The planned number of subjects was considered adequate to evaluate PK, ADA and safety and tolerability of MEDI8897 before initiating a phase 2b trial. Baseline values were defined as those observed on day 1 (before dosing). In cases of missing data points, only observed data were analyzed. Data were analyzed using SAS version 9.3 or higher (SAS Institute, Inc., Cary, NC) on a UNIX platform.
PK parameters were estimated by noncompartmental analysis using Phoenix 64 WinNonlin 6.3 (Pharsight, Mountain View, CA). RSV antibody neutralization levels were summarized by mean (standard deviation) log₂ half-maximal inhibitory concentration (IC₅₀) values and geometric mean fold rise for each treatment group. The relationship between MEDI8897 PK and RSV-neutralizing antibody present in serum was evaluated using a parametric correlation analysis.
The number and percentage of infants positive for ADA at baseline and positive at any postbaseline time point were summarized. The effect of MEDI8897 ADA on PK was evaluated by visual examination of PK profiles because of the limitations of the currently available data. A model-based approach will be utilized to determine the impact of ADA on PK with additional data from a subsequent study.

Statistical data analysis was performed using SAS Version 9.3 or higher (SAS Institute, Inc; Cary, NC; 2000). Summary statistics and statistical analyses were performed for subjects included in the relevant analysis population. All statistical tests were two-sided and evaluated at a 5% level of significance. Missing ACR20 data were imputed using either a single mutation technique or a combination of nonresponder imputation and multiple imputation methods. Missing safety data were not imputed. However, because this was an international study that included patients with RA from Japan, Europe, and India, the outcome analysis for the primary and the most important secondary endpoint, ACR20 and DAS28, respectively, has been performed based on different statistical methodology, including imputation techniques requested by the Pharmaceuticals and Medical Devices Agency (PMDA) and European Medicines Agency (EMA). The results therefore include, in addition to the EMA-requested analysis of ACR20 and DAS28, the last observation carried forward, which is the PMDA-accepted analysis of missing data. An equivalence margin of 15% was estimated by carrying out meta-analysis of relevant studies and this approach was accepted by the EMA. The DAS28 reductions were analyzed using the least square means.