Primary endpoints covariates

It is also necessary to decide how the primary endpoint variables will be analysed, what factors will be taken into account and how the result will be expressed. This most frequently involves analysis of variance or covariance. Predetermined comparisons of two or more treatments or doses can be made at specific time points, (e.g. each visit or selected visits) or may be assessed over time, giving an area imder the time curve analysis which will avoid multiple time-point analyses. 

When the analysis is based on a continuous outcome there is commonly the choice of whether to use the raw outcome variable or the change from baseline as the primary endpoint. Whichever of these endpoints is chosen, the baseline value should be included as a covariate in the primary analysis. The use of change from baseline without adjusting for baseline does not generally constitute an appropriate covariate adjustment. Note that when the baseline is included as a covariate in the model, the estimated treatment effects are identical for both change from baseline and the raw outcome analysis. ... 

Detail regarding the methods of analysis for the primary endpoint(s) including specification of covariates to be the basis of any adjusted analyses... 

As the trial is ongoing there is also an opportunity to change some of the planned methods of analysis for example, information that a particular covariate could be important or that a different kind of effect could be seen in a certain subgroup may have become available based on external data from a similar trial that has now completed and reported. Such changes can be incorporated by modifying the SAP and if they represent major changes to the analysis, for example if they were associated with the analysis of the primary endpoint, then a protocol amendment would need to be issued. The reason for this, as mentioned earlier, is that only methods specified in the protocol can be viewed as confirmatory. 

A change in the statistical methods at the data analysis stage, for example including unplanned covariates or using a transformation of the primary endpoint... 

The analysis plan should also specify the hypothesis and objectives of the study, define the primary and secondary endpoints, and describe how the endpoints will be constructed (e.g., multiplying resource counts measured in the trial times a set of unit costs measured outside the trial). In addition, the analysis plan should identify the potential covariables that will be used in the analysis and specify the time periods of interest (e.g., costs and clinical outcomes at... 

At both the trial level and the development plan level, statisticians should take time to review the case report forms (CRFs) to make sure, in particular, that the data being collected will be appropriate for the precise, unambiguous and unbiased measurement of primary and secondary endpoints. Other aspects of the data being collected should also be reviewed in light of the way they will be used in the analysis. For example, baseline data will form the basis of covariates to be used in any adjusted analyses, intermediate visit data may be needed for the use of... 

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