Longitudinal comparison of the self-administered ALSFRS-RSE and ALSFRS-R as functional outcome measures in ALS.

Objective: Test the feasibility, adherence rates and optimal frequency of digital, remote assessments using the ALSFRS-RSE via a customized smartphone-based app. Methods: This fully remote, longitudinal study was conducted over a 24-week period, with virtual visits every 3 months and weekly digital assessments. 19 ALS participants completed digital assessments via smartphone, including a digital version of the ALSFRS-RSE and mood survey. Interclass correlation coefficients (ICC) and Bland-Altman plots were used to assess agreement between staff-administered and self-reported ALSFRS-R pairs. Longitudinal change was evaluated using ANCOVA models and linear mixed models, including impact of mood and time of day. Impact of frequency of administration of the ALSFRS-RSE on precision of the estimate slope was tested using a mixed effects model. Results: In our ALS cohort, digital assessments were well-accepted and adherence was robust, with completion rates of 86%. There was excellent agreement between the digital self-entry and staff-administered scores computing multiple ICCs (ICC range = 0.925-0.961), with scores on the ALSFRS-RSE slightly higher (1.304 points). Digital assessments were associated with increased precision of the slope, resulting in higher standardized response mean estimates for higher frequencies, though benefit appeared to diminish at biweekly and weekly frequency. Effects of participant mood and time of day on total ALSFRS-RSE score were evaluated but were minimal and not statistically significant. Conclusion: Remote collection of digital patient-reported outcomes of functional status such as the ALSFRS-RSE yield more accurate estimates of change over time and provide a broader understanding of the lived experience of people with ALS.

Upper limb movements as digital biomarkers in people with ALS.

BACKGROUND: Objective evaluation of people with amyotrophic lateral sclerosis (PALS) in free-living settings is challenging. The introduction of portable digital devices, such as wearables and smartphones, may improve quantifying disease progression and hasten therapeutic development. However, there is a need for tools to characterize upper limb movements in neurologic disease and disability. METHODS: Twenty PALS wore a wearable accelerometer, ActiGraph Insight Watch, on their wrist for six months. They also used Beiwe, a smartphone application that collected self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey responses every 1-4 weeks. We developed several measures that quantify count and duration of upper limb movements: flexion, extension, supination, and pronation. New measures were compared against ALSFRS-RSE total score (Q1-12), and individual responses to specific questions related to handwriting (Q4), cutting food (Q5), dressing and performing hygiene (Q6), and turning in bed and adjusting bed clothes (Q7). Additional analysis considered adjusting for total activity counts (TAC). FINDINGS: At baseline, PALS with higher Q1-12 performed more upper limb movements, and these movements were faster compared to individuals with more advanced disease. Most upper limb movement metrics had statistically significant change over time, indicating declining function either by decreasing count metrics or by increasing duration metric. All count and duration metrics were significantly associated with Q1-12, flexion and extension counts were significantly associated with Q6 and Q7, supination and pronation counts were also associated with Q4. All duration metrics were associated with Q6 and Q7. All duration metrics retained their statistical significance after adjusting for TAC. INTERPRETATION: Wearable accelerometer data can be used to generate digital biomarkers on upper limb movements and facilitate patient monitoring in free-living environments. The presented method offers interpretable monitoring of patients' functioning and versatile tracking of disease progression in the limb of interest. FUNDING: Mitsubishi-Tanabe Pharma Holdings America, Inc.

Expanded access protocol (EAP) program for access to investigational products for amyotrophic lateral sclerosis (ALS).

INTRODUCTION/AIMS: Expanded access protocols (EAPs) are a Food and Drug Administration (FDA)-regulated pathway for granting access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. There is limited information about the use of EAPs in amyotrophic lateral sclerosis (ALS); the aim of this report is to share the design, operational features, and costs of an EAP program for ALS. METHODS: The program was launched in 2018 at a single center. In alignment with FDA guidance, protocols were designed as individual (single participant) or intermediate size. Inclusion criteria were broad (e.g., no restrictions due to long disease duration or low vital capacity). Safety information was collected in all EAPs. Selected biomarkers were collected in nine of the EAPs. RESULTS: From July 2018 through February 2022, 17 EAPs were submitted for FDA and institutional review board (IRB) approval. The mean time from submission to approval from the FDA and IRB were 24 days and 37 days, respectively. A total of 164 participants were enrolled and, of these, 77 participants were still receiving IP as of February 2022. The mean duration of participation in an EAP was 12.6 mo. No drug-related serious adverse events were reported from any of the EAPs. Average site cost was $613.47 per participant per month, not including IP costs. CONCLUSION: EAPs provide a framework through which access to IP can be safely provided to people with ALS who do not qualify for clinical trials. Site resources are needed to launch and maintain these programs.

Wearable device and smartphone data quantify ALS progression and may provide novel outcome measures.

Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer the self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2-4 weeks. Each participant used a wrist-worn activity monitor (ActiGraph Insight Watch) or an ankle-worn activity monitor (Modus StepWatch) continuously. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcome measure development.

Primary lateral sclerosis natural history study - planning, designing, and early enrollment.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Longitudinal comparison of the self-entry Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-RSE) and Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) as outcome measures in people with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Improved functional outcome measures in amyotrophic lateral sclerosis (ALS) would aid ALS trial design and help hasten drug discovery. We evaluate the longitudinal performance of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) compared to the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised for Self-Entry (ALSFRS-RSE) as patient reported outcomes of functional status in people with ALS. METHODS: Participants completed the ROADS and the ALSFRS-RSE questionnaires at baseline, 3-, 6-, and 12- mo using Research Electronic Data Capture as part of a prospective, longitudinal, remote, online survey study of fatigue in ALS from 9/2020 to 12/2021. The scales were compared cross-sectionally (at baseline) and longitudinally. Correlation coefficients, coefficients of variation, and descriptive statistics were assessed. RESULTS: A total of 182 adults with ALS consented to the study. This volunteer sample was comprised of predominantly White, non-Hispanic, non-smoking participants. Consented participant survey completion was approximately 90% at baseline and greater than 40% at 12 mo. The ALSFRS-RSE and the ROADS had high, significant agreement at 3 and 6 mo by Cohen's kappa ≥71% (p < 0.001); the number of functional increases or plateaus on the two scales were not significantly different; and the coefficient of variation of functional decline was similar at the 6-month mark, though higher for the ROADS at 3 mo and lower at 12 mo. DISCUSSION: Although the ROADS performed similarly to the ALSFRS-RSE in an observational cohort, it has psychometric advantages, such as Rasch-modeling and unidimensionality. It merits further investigation as a patient reported outcome of overall disability and efficacy outcome measure in ALS trials.

An expanded access protocol of RT001 in amyotrophic lateral sclerosis-Initial experience with a lipid peroxidation inhibitor.

INTRODUCTION/AIMS: Lipid peroxidation is thought to play a biologically important role in motor neuron death in amyotrophic lateral sclerosis (ALS). 11,11 Di-deuterated linoleic ethyl ester (RT001) prevents lipid peroxidation in cellular and mitochondrial membranes. Herein we report on the use of RT001 under expanded access (EA). METHODS: We provided RT001 to patients with ALS via EA at a single site. The starting dose was 2.88 g/day, which was increased to to 8.64 g/day as tolerated. Participants were not eligible for alternative clinical trials. Participants were followed for adverse events and pharmacokinetic (PK) parameters were measured approximately 3 months after RT001 initiation. RESULTS: Sixteen participants received RT001 (5.6 ± 1.6 g/day; dose range, 1.92 to 8.64 g/day) for a mean period of 10.8 ± 7.1 months. After 3 months of treatment, PK studies showed that RT001 was absorbed, metabolized, and incorporated into red blood cell membranes at concentrations expected to be therapeutic based on in vitro models. The most common adverse events were gastrointestinal, including diarrhea, which occurred in 25% of the participants, and were considered possibly related to RT001. One participant (6%) discontinued due to an adverse event. Ten serious adverse events occurred: these events were recognized complications of ALS and none were attributed to treatment with RT001. DISCUSSION: RT001 was administered safely to a small group of people living with ALS in the context of an EA protocol. Currently, there is an ongoing randomized, double-blind, controlled study of RT001 in ALS.

Using Smartphones to Reduce Research Burden in a Neurodegenerative Population and Assessing Participant Adherence: A Randomized Clinical Trial and Two Observational Studies.

BACKGROUND: Smartphone studies provide an opportunity to collect frequent data at a low burden on participants. Therefore, smartphones may enable data collection from people with progressive neurodegenerative diseases such as amyotrophic lateral sclerosis at high frequencies for a long duration. However, the progressive decline in patients' cognitive and functional abilities could also hamper the feasibility of collecting patient-reported outcomes, audio recordings, and location data in the long term. OBJECTIVE: The aim of this study is to investigate the completeness of survey data, audio recordings, and passively collected location data from 3 smartphone-based studies of people with amyotrophic lateral sclerosis. METHODS: We analyzed data completeness in three studies: 2 observational cohort studies (study 1: N=22; duration=12 weeks and study 2: N=49; duration=52 weeks) and 1 clinical trial (study 3: N=49; duration=20 weeks). In these studies, participants were asked to complete weekly surveys; weekly audio recordings; and in the background, the app collected sensor data, including location data. For each of the three studies and each of the three data streams, we estimated time-to-discontinuation using the Kaplan-Meier method. We identified predictors of app discontinuation using Cox proportional hazards regression analysis. We quantified data completeness for both early dropouts and participants who remained engaged for longer. RESULTS: Time-to-discontinuation was shortest in the year-long observational study and longest in the clinical trial. After 3 months in the study, most participants still completed surveys and audio recordings: 77% (17/22) in study 1, 59% (29/49) in study 2, and 96% (22/23) in study 3. After 3 months, passively collected location data were collected for 95% (21/22), 86% (42/49), and 100% (23/23) of the participants. The Cox regression did not provide evidence that demographic characteristics or disease severity at baseline were associated with attrition, although it was somewhat underpowered. The mean data completeness was the highest for passively collected location data. For most participants, data completeness declined over time; mean data completeness was typically lower in the month before participants dropped out. Moreover, data completeness was lower for people who dropped out in the first study month (very few data points) compared with participants who adhered long term (data completeness fluctuating around 75%). CONCLUSIONS: These three studies successfully collected smartphone data longitudinally from a neurodegenerative population. Despite patients' progressive physical and cognitive decline, time-to-discontinuation was higher than in typical smartphone studies. Our study provides an important benchmark for participant engagement in a neurodegenerative population. To increase data completeness, collecting passive data (such as location data) and identifying participants who are likely to adhere during the initial phase of a study can be useful. TRIAL REGISTRATION: ClinicalTrials.gov NCT03168711; https://clinicaltrials.gov/ct2/show/NCT03168711.

Ultrasound-guided glenohumeral joint injections for shoulder pain in ALS: A case series.

Introduction: Shoulder pain is a common secondary impairment for people living with ALS (PALS). Decreased range of motion (ROM) from weakness can lead to shoulder pathology, which can result in debilitating pain. Shoulder pain may limit PALS from participating in activities of daily living and may have a negative impact on their quality of life. This case series explores the efficacy of glenohumeral joint injections for the management of shoulder pain due to adhesive capsulitis in PALS. Methods: People living with ALS and shoulder pain were referred to sports medicine-certified physiatrists for diagnostic evaluation and management. They completed the Revised ALS Functional Rating Scale and a questionnaire asking about their pain levels and how it impacts sleep, function, and quality of life at baseline pre-injection, 1-week post-injection, 1 month post-injection, and 3 months post-injection. Results: We present five cases of PALS who were diagnosed with adhesive capsulitis and underwent glenohumeral joint injections. Though only one PALS reported complete symptom resolution, all had at least partial symptomatic improvement during the observation period. No complications were observed. Conclusions: People living with ALS require a comprehensive plan to manage shoulder pain. Glenohumeral joint injections are safe and effective for adhesive capsulitis in PALS, but alone may not completely resolve shoulder pain. Additional therapies to improve ROM and reduce pain should be considered.

Patient reported outcomes in ALS: characteristics of the self-entry ALS Functional Rating Scale-revised and the Activities-specific Balance Confidence Scale.

Objective: This study characterized two patient-reported outcome measures (PROMs): a patient-facing adaptation of the revised amyotrophic lateral sclerosis (ALS) Functional Rating Scale ("self-entry ALSFRS-R") and the Activities-specific Balance Confidence (ABC) Scale. Methods: ALS patients presenting to clinic completed PROMs that included (1) the self-entry ALSFRS-R, (2) the Activities-specific Balance Confidence Scale (ABC Scale), and (3) a question about falls. PROM data were compared to one another and to the traditional ALSFRS-R collected by trained evaluators in clinic ("standard ALSFRS-R"). Results: Over the data collection period, 449 ALS patients completed at least one of the three PROMs. Self-entry vs. standard ALSFRS-R total scores (n = 183) had high agreement (intraclass correlation (ICC)=0.81, 95% CI = 0.67, 0.88). Self-entry ALSFRS-R total scores were significantly higher than standard ALSFRS-R total scores (2.3 points, p < 0.001). In a subset of participants who contributed data at two timepoints, the average ALSFRS-R decline was not significantly different between methods (n = 49). ABC scores correlated highly with self-entry and standard ALSFRS-R Gross Motor subdomain scores (Pearson's r = 0.72, p < 0.001 and Pearson's r = 0.76, p < 0.001, respectively; n = 130). ABC score was negatively correlated with the number of reported falls within the last month (Spearman's r=-0.40; p < 0.001; n = 130). A 10-point decrease in ABC score increased odds of a reported fall by 16%. Conclusions: In a multidisciplinary clinic setting, self-entry and standard ALSFRS-R scores were similar, but not interchangeable. Self-entry scores were higher than standard ALSFRS-R scores but declined at a similar rate to the standard ALSFRS-R. ABC scores correlated with self-reported fall history and thus may provide useful data for clinical care.

Smartphone data during the COVID-19 pandemic can quantify behavioral changes in people with ALS.

INTRODUCTION: Passive data from smartphone sensors may be useful for health-care research. Our aim was to use the coronavirus disease-2019 (COVID-19) pandemic as a positive control to assess the ability to quantify behavioral changes in people with amyotrophic lateral sclerosis (ALS) from smartphone data. METHODS: Eight participants used the Beiwe smartphone application, which passively measured their location during the COVID-19 outbreak. We used an interrupted time series to quantify the effect of the US state of emergency declaration on daily home time and daily distance traveled. RESULTS: After the state of emergency declaration, median daily home time increased from 19.4 (interquartile range [IQR], 15.4-22.0) hours to 23.7 (IQR, 22.2-24.0) hours and median distance traveled decreased from 42 (IQR, 13-83) km to 3.7 (IQR, 1.5-10.3) km. The participant with the lowest functional ability changed behavior earlier. This participant stayed at home more and traveled less than the participant with highest functional ability, both before and after the state of emergency. DISCUSSION: We provide evidence that smartphone-based digital phenotyping can quantify the behavior of people with ALS. Although participants spent large amounts of time at home at baseline, the COVID-19 state of emergency declaration reduced their mobility further. Given participants' high level of daily home time, it is possible that their exposure to COVID-19 could be less than that of the general population.