Energy efficient passive designs and constructions have been extensively studied in the last decades as a way to improve the ability of a building to store thermal energy, increase its thermal mass, increase passive insulation and reduce heat losses. However, many studies show that passive thermal designs alone are not enough to fully exploit the potential for energy efficiency in buildings: in fact, harmonizing the active elements for indoor thermal comfort with the passive design of the building can lead to further improvements in both energy efficiency and comfort. These improvements can be achieved via the design of appropriate Building Optimization and Control (BOC) systems, a task which is more complex in high-inertia buildings than in conventional ones. This is because high thermal mass implies a high memory, so that wrong control decisions will have negative repercussions over long time horizons. The design of proactive control strategies with the capability of acting in advance of a future situation, rather than just reacting to current conditions, is of crucial importance for a full exploitation of the capabilities of a high-inertia building. This paper applies a simulation-assisted control methodology to a high-inertia building in Kassel, Germany. A simulation model of the building is used to proactively optimize, using both current and future information about the external weather condition and the building state, a combined criterion composed of the energy consumption and the thermal comfort index. Both extensive simulation as well as real-life experiments performed during the unstable German wintertime, demonstrate that the proposed approach can effectively deal with the complex dynamics arising from the high-inertia structure, providing proactive and intelligent decisions that no currently employed rule-based strategy can replicate.