An analysis of two randomized clinical trials indicates that the Simon 2-Stage futility trial design is a feasible approach when studying treatments for early Parkinson's disease (PD). The findings, published in Neurology, suggest this design could expedite the identification of disease-modifying treatments (DMTs) by allowing for earlier termination of trials for ineffective therapies. This is particularly relevant given the challenges and costs associated with traditional randomized controlled trials (RCTs) for PD.
Addressing the Translational Gap in Parkinson's Disease
Researchers have identified several generic medications that could potentially slow the progression of PD or affect neurodegeneration. However, evaluating these in rigorous RCTs is often time-consuming and expensive, especially with the need for follow-up periods of around two years. According to Marcus Werner Koch, MD, PhD, of the University of Calgary, and colleagues, regulatory and funding barriers further complicate trials aimed at repurposing generic medications, leading to a "translational gap" where promising treatments are not translated into clinical practice.
Futility trials, particularly those employing the Simon 2-Stage design, offer a potential solution. These trials typically involve a single arm and compare treatment results with historical controls. The Simon 2-Stage design incorporates an interim analysis, allowing for earlier termination of the trial if the treatment shows a lack of efficacy. This approach can save time and money, and it facilitates single-site studies with achievable sample sizes.
Analysis of DATATOP and PRECEPT Trials
The researchers conducted a post-hoc analysis of patient-level data from two phase 3 clinical trials: DATATOP (conducted in 1987-1988) and PRECEPT (conducted in 2002-2004). DATATOP involved 800 participants and compared placebo with tocopherol, selegiline, or a combination of both. PRECEPT enrolled 806 participants and compared placebo with different dosages of the mixed lineage kinase inhibitor CEP-1347. The average age of participants was approximately 60 years, and about 64% were male in both studies.
The analysis focused on a 12-month follow-up period to assess whether the Simon 2-Stage methodology could deliver results in half the time compared to the typical 24-month follow-up in most RCTs. The results suggested that futility trials using the Simon approach are indeed feasible in patients with PD. The researchers proposed using a five-point worsening on the Unified Parkinson Disease Rating Scale (UPDRS) motor score as the primary outcome measure.
Implications and Considerations
The researchers demonstrated that clinical trials using the Simon 2-Stage methodology could potentially require a quarter of the patients typically needed for an RCT. This approach may accelerate the discovery of new treatments by avoiding the inclusion of ineffective treatments in larger and more costly RCTs.
However, an accompanying editorial by Andreas Ziegler, Dr. rer. nat., and Matthias Schmid, Dr. rer. nat., highlighted some limitations of the Simon two-stage design. One concern is that the recruitment period must last longer than the time needed to assess the primary endpoint. Additionally, there's a risk of prematurely stopping the trial due to futility, even if the alternative hypothesis is true.
Despite these limitations, the editorialists praised the researchers for exploring alternative approaches to studying DMTs for PD. They noted that single-group trials with two or more stages can effectively reduce sample size, address ethical concerns, and improve practicability in the early stages of DMT development. They also suggested exploring approaches that offer greater flexibility and improved properties compared to the Simon's two-stage design, with special attention to handling missing data and complete reporting of such trials.
