FDA recently issued its guidance "Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease ". The guidance cited alternative trial designs and the Randomized Start Design (RSD) was recommended.
A randomized-start or randomized-withdrawal trial design (with clinical outcome measures) appears to be a more convincing means of demonstrating such an effect. For ethical reasons, a randomized-start design would be most appropriate for use in AD. In this study design, patients are randomized to drug and placebo, and at some point, placebo patients are crossed over to active treatment. If patients in the trial who were initially on placebo then assigned to active treatment fail to catch up (after a reasonable period of time) to patients who received active treatment for the entire duration of the trial, a disease modifying effect of treatment would have been shown. We are unaware of any instances to date where this design has been successfully used in a clinical trial to establish a disease modifying effect.
RSD has been discussed for its use in many CNS and neurological diseases such as Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, Post Polio syndrome. These diseases all have very slow progression. Treatment effect for these diseases can be separated as effect on symptomatic component and the disease modifying component. "Disease modifying" can be defined as treatments or interventions that affect the underlying pathophysiology of the disease and have a beneficial outcome on the course of the disease.
A similar design to RSD may be called "delayed start design". The delayed-start design is used in order to overcome a problem that occurs in similar studies of medicines that may slow the progression of the disease but also have an effect on symptoms. Typically in these studies used to determine the effects of a drug on slowing disease progression, the medicines or placebo are started and stopped in all patients at the same time. After stopping the drugs, the researchers then wait for several weeks to measure the patients’ symptoms. This waiting time is referred to as the “washout” period, in which the effects of the drug are “washed out” of the body. Patients whose symptoms remain better at the end of the washout period time are presumed to have had their disease slowed by the treatment. However, no one knows what length of time is needed for a true symptomatic washout period. When a study uses a delayed-start design, all patients are presumed to be experiencing the same degree of symptom relief at the end of the trial because they are all taking the medication. If the patients who have received the medicine for the longer period of time have fewer symptoms, it is presumed to be due to the medicine slowing the effects of the disease.
· The Randomized Start Design for Assessing Disease-Modifying Effects in ParkinsonDisease: Issues and Controversies by David Oakes
· Designing clinical trials to test disease-modifying agents—application to the treatment trials of Alzheimer's disease by Xiong