What Would be the Ideal Design of a Clinical Trial for CMT1A

Designing an ideal clinical trial for Charcot-Marie-Tooth disease type 1A (CMT1A) presents significant challenges due to the limited understanding of the disease landscape. "How does the treatment work? How soon will the treatment work? Which biomarkers will be responsive? How will clinical outcome assessments and biomarkers perform longitudinally? We do not know!" said Dr. Vera Fridman, an Associate Professor in the Neuromuscular Section at the University of Colorado's Anschutz Medical Campus. At the 2024 Peripheral Nerve Society annual meeting in Montreal, Canada, Dr. Fridman discussed the complexities and opportunities in designing clinical trials for CMT1A.

"I want to focus on early phase studies, Phase I and II in adult participants of CMT1A and look at disease-modifying treatments, and we ultimately want to treat pediatric participants. The main goal for these early phase trials is to establish safety and motivate Phase III studies. Patient groups and companies want more proof of concept introduced in these early phase studies, and our goal is to build that in as much as we can, have readiness for Phase III, and move to pediatric patients sooner rather than later.," said Dr. Fridman. She stressed the importance of planning for unexpected outcomes and including mildly affected patients in trials to capture a comprehensive spectrum of the disease.

A significant risk is the potential for false negative results, particularly if treatment responses are delayed and do not manifest within the trial timeline. Other considerations noted by Dr. Fridman included the necessity of a data safety monitoring board, planning for patient exit interviews (assessing both their perceived progress and their feedback on the trial infrastructure), and committing to long-term follow-up of patients.

Biomarkers and clinical outcomes were a central focus of the talk. Promising tools for improving sensitivity in CMT1A clinical trials, especially in pediatric populations, include calf MRI and foot muscular fat fraction. Dr. Fridman highlighted the relevance of several biomarkers in trials: Peripheral myelin protein 22 (PMP22) transcript levels, Neurofilament light chain (NFL), calf and foot muscle MRI, and Transmembrane protease, serine 5. NFL is the most established plasma biomarker, reflecting axonal degeneration. However, using different assays across studies and a wide range of normal values for differentiating CMT1A patients from controls present challenges. NFL levels may drop over time, but whether this indicates a true treatment effect or natural fluctuations is unclear. Dr. Fridman suggested that NFL data needs to be batched from different time points using the same analysis to reduce analytical variability between studies. Similarly, PMP22 expression is heterogeneous, making normalization crucial for reliable signals. It is unknown how much reduction in PMP22 is clinically meaningful and needed for patient benefit. More data is needed to understand the relationship among treatment, biomarkers, and clinical outcomes.

In summary, the ideal design for a CMT1A clinical trial should be inclusive, adaptive, and comprehensive, emphasizing biomarker validation and long-term patient follow-up. The insights gained from such trials could pave the way for effective therapeutic interventions for CMT1A and potentially other neurodegenerative diseases. Dr. Fridman proposed a maximalist approach for early-phase clinical trials. She concluded, "The goal of an ideal trial design is to be regret-free. We must keep our eyes open, take in who comes, and learn from the data."