Demonstrating the disease modifying effect through delayed start study design or delayed start analyses

Previously, I described a study designed called ‘randomized start design (RSD)’. One special case of the RSD, delayed start design, has been specifically gaining popularity in studies for identifying whether or not the efficacy improvement is due to the symptomatic change or due to the disease modifier. A disease modifier is desired.

Several studies with delayed start design or delayed start analysis have been published. The study design seems to be more popular in neurology disease area such as Parkison’s disease and Alzheimer’s disease.

• Liu-Seifert et al 2015 Delayed-start analysis: Mild Alzheimer’s disease patients in solanezumab trials, 3.5 years
• Olanow et al 2008 A Randomized, Double-Blind, Placebo-Controlled, Delayed Start Study to Assess Rasagiline as a Disease Modifying Therapy in Parkinson’s Disease (The ADAGIO Study): Rationale, Design, and Baseline Characteristics
• Olanow et al 2009 A Double-Blind, Delayed-Start Trialof Rasagiline in Parkinson’s Disease
• Schapira et al 2013 Pramipexole in patients with early Parkinson’s disease (PROUD): a randomised delayed-start trial
• Chapman et al 2015 Intravenous augmentation treatment and lung density in severe α1 antitrypsin defi ciency (RAPID): a randomised,double-blind, placebo-controlled trial

The concept of the delayed start study was proposed by Dr Ralph B. D'Agostino in his NEJM article "The Delayed-Start Study Design". In a web-based article, Dr Hauser described the details about the delayed start study design.

The delayed-start trial design is one approach to separating symptomatic improvement from a true effect on disease progression. In this design, one group receives active treatment and another group receives placebo during the first period of the trial, and both groups receive active treatment during the second period of the trial. The results in the second period may show whether an effect is long term and disease modifying or short term and symptomatic. Figure 1 presents a schematic of the delayed start trial.

The delayed-start trial has the potential to demonstrate disease modification based on the following logic: improvements in the active treatment group during the first trial period could be due to disease modification or symptomatic improvement. During the second trial period, however, when both groups are receiving the active treatment, a sustained benefit in the early-start group as compared with the delayed-start group would represent evidence for disease modification. If the effect of the experimental treatment was due solely to symptomatic improvement, then both groups would show similar improvement from baseline during the second stage of the trial when both are receiving the same treatment. 

 
Figure 1. Schematic of the Delayed-Start Clinical Trial Design 

In some studies, the stage 1 and stage 2 are separated as two different studies. The initial study design is not strictly the delayed start design. However, during the statistical analyses, the data from two stages are pooled and analyzed – this approach is called ‘delayed start analysis’ even though the stage 2 (extension study) may be originally designed for other purpose. This approach has been used in above papers by Liu-Seifert et al 2015 and Chapman et al 2015.

While the patients are randomized into the stage 1 of the study, patients are not blinded during the stage 2 of the study since all patients will receive the active treatment. This may cause the biases in the efficacy assessment during the stage 2 of the study.

In studies with delayed start design or delayed start analyses, the treatment effect is symptomatic improvement or disease modifier can be judged by the sustainable treatment effect in the stage 2. The diagram below illustrated the results indicating the symptomatic treatment improvement versus disease modifier.

The delayed start study starts to gain popularity in studying the disease modifying agents. However, it must be pointed out that the study design requires the reasonable lack of equipoise so that it is adequate to switch all patients from the double-blinded phase (stage 1) to the open label phase (stage 2) where all patients receive the active treatments.