HD InsightsSeeing the Signs

Challenges in Clinical Trial Definitions of Early Manifestations of HD: Perspectives From a Clinical Research Team

Huntington’s disease (HD) has traditionally been diagnosed based on motor symptoms. Prior to the availability of genetic testing, this approach made sense and decreased the likelihood of false positives. However, similar to the case with more common neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), by the time a clinical diagnosis is made, significant neurodegeneration has already occurred.

But unlike in PD and AD, due to the heritability of HD, individuals can be identified before the onset of significant motor symptoms. This presents a potential window of opportunity for disease-modifying research. But to open that window, the full complement of symptoms need to be recognized.

UHDRS^® 

The Unified Huntington’s Disease Rating Scale (UHDRS^®), published by the HSG in 1996, was developed for clinical use to assess HD features and functional capacity and is particularly useful for tracking changes over time. The UHDRS^® was designed for repeated administrations, and for that reason, it has been widely used in clinical trials to assess response to treatments. Various sections within the UHDRS^® and the clinical UHDRS^® have been used for clinical trial endpoints. The cUHDRS^® is a composite endpoint that combines the UHDRS Total Functional Capacity (TFC), the UHDRS^® Total Motor Score (TMS), the Symbol Digit Modalities Test (SDMT), and the Stroop Word Reading (SWR). 

The UHDRS^® has had a significant impact on categorizing individuals with HD into premanifest or manifest stages, primarily using the diagnostic confidence level (DCL) within the motor section or the TMS. Therefore, the UHDRS^® has also been extensively used to determine eligibility for clinical trials.

Clinically, the premanifest stage describes individuals with a pathogenic gene expansion, who do not exhibit typical HD symptoms. The prodromal stage serves as a bridge between the premanifest and manifest stages. During this stage, patients begin to show mild motor, cognitive, and behavioral symptoms that are not severe enough to be classified as a disease manifestation. 

However, defining the prodromal stage can be subjective, which adds complexity to the classification. To facilitate comparison across studies, many researchers have labeled the prodromal stage as premanifest, although this may not be entirely accurate, as the presymptomatic stage is different from the prodromal stage. Since the early symptoms may be subtle or non-motor (e.g., cognitive or behavioral), it can be hard to define the exact transition from premanifest to manifest. Furthermore, the onset of symptoms is often gradual and dependent on the clinician’s subjective judgment, which can lead to variability in diagnosing motor and non-motor manifestations. 

It is now widely recognized, based on previous observational clinical trials such as TRACK-HD and PREDICT-HD, that striatal atrophy and subtle cognitive and motor symptoms occur years before symptoms significant enough to warrant a clinical diagnosis. These findings have emphasized the need for revised diagnostic criteria for both clinical and research purposes. In clinical practice, the clinical diagnostic criteria for ‘manifest HD’ are evolving, with ongoing debate about defining early manifestations of HD. The early motor, cognitive, and behavioral/psychiatric symptoms may be subtle, making it challenging to determine the transition from premanifest to manifest HD. 

Despite efforts, the clinical diagnosis of HD still occurs late in the disease course, by which time significant neurodegeneration has already taken place. Debates around HD clinical diagnosis criteria directly impact trial designs, and delayed diagnoses can have devastating consequences for clinical trials aiming to prevent or delay neuronal death. Therefore, research criteria must be based on objective measures with biological markers, rather than relying solely on criteria used for clinical practice.

The HD-ISS 

Recognizing the need to objectively categorize HD from birth to death (instead of using the dichotomized premanifest/manifest classification), the scientific community has developed a staging system based on biomarkers of pathogenesis, clinical signs and symptoms, and functional changes — the Huntington’s Disease Integrated Staging System (HD-ISS). 

This new system was specifically designed for clinical research, and it is undoubtedly a significant advancement in the field, as it facilitates enrollment of HD gene expansion carriers into clinical trials at early stages — i.e., when clinical symptoms and signs are still not present (stages 0 & 1). The HD-ISS was published in 2022 to overcome the limitations of using classifications and staging systems intended for clinical practice. 

Unlike the UHDRS^® DCL, which focuses on a single dimension, HD-ISS classification takes an objective, multifaceted approach, which allows for earlier clinical trial enrollment. The HD-ISS is redefining clinical trial design and enrollment, but it is important to note that it differs from clinical diagnostic and staging criteria.

Additional Considerations

A clear classification of disease stages is crucial for clinical trials. First, it aids in designing effective treatments, as early interventions are more likely to achieve disease modification. Second, clinical trials for symptomatic therapies may prioritize different stages due to the highly variable presentation of the disease. Last, a well-defined classification of disease stages helps select for a more homogeneous group of patients for clinical trials, reducing differences in outcomes and ensuring consistency between studies for accurate measurement of treatment effectiveness
and comparison of results.

Although common in the early stages of HD, psychiatric and behavioral symptoms have not been historically considered for the diagnostic criteria. This is true particularly because they are common outside of HD and can fluctuate from one visit to another, making it difficult to use them as markers of early HD manifestation. For example, the clinical signs/symptoms used to define the symptomatic stage in the HD-ISS include motor and cognitive, but not behavioral, symptoms. 

Successfully managing the challenge of whether or not to consider psychiatric/behavioral symptoms for the definition of early HD involves carefully weighing the benefits with the potential risks of incorrectly assigning symptoms to HD as an underlying cause. 

What we do know, based on countless cases, is that regardless of their diagnostic relevance, psychiatric and behavioral symptoms are clinically meaningful and can negatively impact the patient’s functionality and quality of life. 

Trial Recruiting Challenges

Recruiting and retaining individuals in the early stages (i.e., HD-ISS stages 0 & 1) for clinical trials can be difficult for several reasons, a few of which are mentioned here. First, these individuals are fully functional, with full-time jobs, families, and busy lives. Participating in a research study and managing the time commitment can be overwhelming. Moreover, the stigma surrounding HD can act as a barrier to participating in research, especially prior to symptom onset. Finally, those participating in gene-modifying trials will likely be excluded from future studies evaluating disease-modifying therapy (DMT) which can make selecting a DMT trial feel risky.