Special trial designs have been developed to distinguish the symptomatic and disease modifying effects of treatment using clinical outcome measures. These designs, termed 'two-period' designs, include the so-called withdrawal and delayed-start (or 'staggered-start') designs and their variations. This chapter describes these study designs in terms of their rationale, assumptions, design features, implementation, statistical analysis, and sample size considerations. It also discusses the important limitations of the designs. Simulation studies using disease progression modeling suggest that the withdrawal design may provide more power than the delayed start design to detect disease-modifying effects of a treatment. A statistical model for data from a complete two-period design assumes that a normally-distributed outcome termed µ 2. There are alternative approaches to evaluating the disease-modifying effects of an intervention that require only a single treatment period.