Novartis Presents New Clinical Trial ALS Digital Health Biomarkers

At Panagora’s 7th Annual Digital Biomarkers in Clinical Trials Summit, Novartis presented a groundbreaking study on digital home-based assessments for patients with amyotrophic lateral sclerosis (ALS). Vanessa Vallejo, Senior Clinical Scientist, and Arne Müller, Associate Director and Senior Principal Data Scientist for Clinical Digital Endpoints, shared their comprehensive findings, highlighting the potential of digital endpoints to revolutionize ALS clinical trials.

Understanding ALS and the Study’s Objectives

Vanessa Vallejo began by providing an in-depth overview of ALS, a rare but devastating neurodegenerative disease also known as Lou Gehrig’s disease. She highlighted the grim statistics: an average life expectancy of three to five years post-symptom onset, with death often resulting from respiratory failure. Vallejo explained that the majority of ALS cases are sporadic, with only about 10% being familial or genetic. The disease typically progresses from initial symptoms like muscle twitching and fatigue to severe difficulties in swallowing, eating, and breathing, eventually leading to a complete loss of mobility and independence. Vallejo emphasized the importance of the ALS Functional Rating Scale-Revised (ALSFRS-R), the gold standard for assessing ALS progression. This questionnaire measures various functional domains through a series of questions, each scored from zero to four, with a maximum total score of 48. However, she pointed out the limitations of this method, such as its subjective nature and the potential for variability in patient responses. Vallejo stressed the potential advantages of digital endpoints, which can offer more objective measurements and allow for more comprehensive data collection at home, providing deeper insights into the different functional domains affected by ALS.

Study Design and Methodology

The study involved a nine-month observational period for each participant, with six in-clinic visits and additional home-based assessments. Vallejo detailed the digital setup, which included a master app capable of launching various assessments that mapped to the ALSFRS-R’s functional domains. These assessments measured slow vital capacity, speech, cognition, gait, fine motor function, and tongue strength. The app was designed to be user-friendly, allowing participants to complete the assessments at home with minimal assistance. Vallejo noted that 20 participants completed the study, while 13 discontinued, primarily due to disease progression. The inclusion criteria required participants to be non-ventilator dependent, able to grasp a pen and walk short distances.

Key Findings and Challenges

Arne Müller discussed the study’s findings, particularly speech and fine motor function. He presented data showing that the home-collected ALSFRS-R questionnaire closely matched the in-clinic version, suggesting the feasibility of using home-based assessments in future clinical studies. Müller acknowledged that patients tended to overrate themselves slightly when completing the questionnaire at home, possibly due to a more relaxed environment or less rigorous oversight than in a clinical setting. One of the significant challenges highlighted was adherence to digital endpoints over the study’s duration. While adherence was high initially, it declined over time, a common issue in long-term digital endpoint studies. Müller attributed this to various factors, including medical reasons such as hospitalization or disease progression and the complexity of specific tasks. For example, the “time up and go” test, which measures gait and mobility, received feedback from some patients who felt unsafe performing it at home. Additionally, the non-Bluetooth-enabled tongue strength measure posed logistical challenges, as participants had to bring the device to the clinic for data transfer.

Müller also discussed the feedback from patients regarding the digital endpoints. While overall scores were not too bad, questions about the meaningfulness of the assessments and their ability to control the disease were rated poorly. This indicated that patients were unsure about the purpose and significance of the digital assessments, highlighting the need for better training and education for both patients and clinical sites. One innovative aspect of the study involved assessing fine motor function using an iPad and Apple Pen to draw Archimedes spirals. The data collected from these exercises, such as pen pressure, angle, speed, and noise, showed good correspondence with the ALSFRS-R fine motor scale. Participants were asked to draw these spirals freehand and to trace pre-drawn spirals, providing a range of data points for analysis. However, Müller noted the potential for learning effects, as patients could become better at drawing spirals over time, which could skew the results. Müller also discussed the speech analysis, focusing on speaking rate as a key parameter. The data showed that speaking rate was a good discriminator between different ALSFRS-R speech scores, although not always in a linear way. He presented profiles of selected participants over time, showing varying trends in speech and fine motor function. Some participants showed a decline in self-reported scores that matched the digital endpoint data, while others did not, indicating the complexity and variability of ALS progression.

Conclusion and Recommendations

In conclusion, Müller acknowledged that adherence to digital endpoints tends to drop over time, which is expected in longer assessments. He suggested that the frequency of assessments might be reduced to avoid patient fatigue and improve compliance. Additionally, the study highlighted the importance of developing meaningful digital endpoints for patients and involving them in the design process. The presentation concluded with a call for more thorough communication between clinical sites and patients to explain the significance of digital assessments. Müller also mentioned ongoing efforts to combine all digital endpoints into a single model to create a comprehensive score for ALS progression. The Novartis team’s study underscores the potential of digital biomarkers in enhancing ALS clinical trials, offering a more nuanced and patient-friendly approach to monitoring disease progression. As the field continues to evolve, such innovative methodologies could pave the way for more effective and efficient clinical trials, benefiting patients and advancing our understanding of ALS.