Energy efficiency and consumption are now the most important and challenging issues in current Petascale and in designing future Exascale computing systems. The European Union Horizon 2020 READEX project uses an online approach to exploit application dynamism and tune large-scale HPC applications to improve energy efficiency and performance. The paper presents the READEX methodology, consisting of the Design-Time Analysis and Runtime Application Tuning, and describes the pre-analysis steps involving application dynamism and significant region detection. During design-time, the READEX tuning plugin evaluates configurations of hardware and software tuning parameters to determine the best settings for instances of application regions. The runtime tuning dynamically switches to the best configuration for an application region during production runs. Finally, the energy savings obtained for LULESH on the Taurus supercomputer highlight the effectiveness of this methodology.