Clinical research in central nervous system (CNS) diseases has long been fraught with challenges. High failure rates, complex pathophysiology, variability in disease progression, strong placebo effects, and difficulties in recruitment and outcome measurement have made CNS disorders one of the riskiest areas for drug development. However, recent innovations in trial design — coupled with advances in digital health and statistical modelling — are transforming how we conduct clinical research in diseases like Huntington’s disease (HD), Alzheimer’s disease (AD), and multiple sclerosis (MS). This blog explores three recent trials that exemplify these innovations and proposes statistical advancements to strengthen their impact.

Adaptive designs in Huntington’s disease: The PIVOT-HD trial

Traditional fixed designs often struggle to efficiently explore dose-response relationships or adapt to emerging data. Adaptive trial designs offer a dynamic solution, particularly valuable in neurodegenerative diseases like Huntington’s disease, where treatment response and disease progression can vary widely.

Case study: PIVOT-HD trial (NCT05358717)

The PIVOT-HD trial, led by PTC Therapeutics, is a Phase II adaptive study evaluating the safety, pharmacodynamics, and early signs of efficacy of PTC518, a novel small-molecule HTT-lowering therapy. PTC518 modulates mRNA splicing to reduce levels of the mutant huntingtin protein, a key driver of HD pathology.

What sets this trial apart is its seamless adaptive design. The trial is structured to adjust dosing and the randomization ratios based on interim pharmacodynamic and safety readouts. By incorporating planned decision-making, PIVOT-HD minimizes exposure to ineffective doses and accelerates identification of promising therapeutic windows.

Digital biomarkers and remote monitoring in Alzheimer’s disease: The DETECT-AD trial

Cognitive decline in AD is insidious and can be difficult to quantify with infrequent clinic visits and subjective tests. Digital health technologies are revolutionizing outcome assessment through continuous, objective, and sensitive data collection.

Case study: DETECT-AD (Digital Evaluations and Technologies Enabling Clinical Translation in Alzheimer’s Disease)

The DETECT-AD initiative, part of a broader effort supported by the NIH and multiple research institutions, is employing wearables, mobile apps, and speech analysis to detect early signs of Alzheimer’s disease in at-risk populations.

In the DETECT-AD observational study, participants use smartphone apps and passive sensors to monitor activities like walking, typing speed, and even voice characteristics. These digital biomarkers are being correlated with traditional cognitive assessments and brain imaging data to predict cognitive decline before clinical symptoms emerge.

Platform trials in multiple sclerosis: The OCTOPUS trial

In diseases like MS, where multiple mechanisms may underlie relapses and progression, traditional “one drug, one trial” designs are increasingly inefficient. Platform trials offer a more flexible and scalable solution.

Case study: The OCTOPUS trial (UK MS Society)

The OCTOPUS (Optimal Clinical Trials Platform for Progressive MS) trial is the world’s first multi-arm, multi-stage platform trial in progressive MS. Spearheaded by the UK MS Society, this innovative study aims to test multiple repurposed therapies simultaneously, using a shared control group and adaptive design principles.

OCTOPUS promises faster answers with fewer patients and more efficient use of resources, particularly crucial in progressive MS where effective treatments are lacking.

Statistical challenges and opportunities

Despite these advances, several statistical hurdles remain. Novel designs require equally innovative statistical approaches to preserve validity and ensure robust interpretation.

Broader adoption of Bayesian statistical frameworks

Bayesian approaches allow the integration of prior knowledge (e.g., historical control data or early biomarkers) and offer probabilistic interpretations of trial results. In adaptive and platform trials, Bayesian methods facilitate:

• Interim analyses with posterior probabilities guiding adaptations.
• Dynamic borrowing from concurrent or historical control arms.
• Greater flexibility in endpoint modelling across heterogeneous subgroups.

For example, the GBM AGILE platform trial in glioblastoma (a CNS tumor) successfully uses Bayesian methods to adapt enrollment and determine early stopping rules. A similar framework could benefit complex CNS conditions like MS or AD, where responses are highly individualized.

Incorporating real-world evidence (RWE) in trial planning and analysis

As clinical trials increasingly occur alongside large electronic health record (EHR) systems, real-world data (RWD) can inform trial design and enhance external validity. Specifically:

• RWD can help refine eligibility criteria to better represent actual patient populations.
• Real-world comparators can augment underpowered control groups or offer external validation.
• Longitudinal RWE provides insight into long-term treatment effects beyond trial duration.

In Alzheimer’s disease, initiatives like the AHEAD 3-45 study are already incorporating observational cohorts and RWE in trial simulation and endpoint modelling.

The next generation of neuroscience trials

The future of CNS clinical trials is increasingly adaptive, digital, and data driven. Innovative designs like PIVOT-HD, DETECT-AD, and OCTOPUS illustrate the power of new methodologies to make trials more efficient, sensitive, and patient-centric. However, to fully realize their potential, we must integrate robust statistical techniques such as Bayesian modelling and real-world data frameworks. These tools will help overcome inherent complexities in CNS research and bring transformative treatments closer to patients in need.

As we look ahead, collaboration between statisticians, clinicians, regulators, and technology developers will be essential in shaping the next generation of neuroscience trials — where precision, agility, and real-world relevance are no longer luxuries, but necessities.

Interested in learning more?

Register now to watch James Matcham’s on-demand webinar, “Clinical Trial Design Innovation in CNS Disorders.” This webinar features a review of regulatory guidelines and showcase recent successful trials in Alzheimer’s disease and other neurological disorders.

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