Outcome Measure In Clinical Trials Research Articles

Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study

ObjectiveRecent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders.MethodsCaregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2.ResultsThe top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features.ConclusionThe top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.

Protocol for the development and validation of a patient reported measure (PRM) of treatment burden in stroke.

Treatment burden is the workload of healthcare for people with long-term conditions and the impact on wellbeing. A validated measure of treatment burden after stroke is needed. We aim to adapt a patient-reported measure (PRM) of treatment burden in multimorbidity, PETS (Patient Experience with Treatment and Self-Management version 2.0), to create a stroke-specific measure, PETS-stroke. We aim to examine content validity, construct validity, reliability and feasibility in a stroke survivor population. 1) Adaptation of 60-item PETS to PETS-stroke using a taxonomy of treatment burden. 2) Content validity testing through cognitive interviews that will explore the importance, relevance and clarity of each item. 3) Evaluation of scale psychometric properties through analysis of data from stroke survivors recruited via postal survey (n=340). Factor structure will be tested with confirmatory factor analysis and Cronbach's alpha will be used to index internal consistency. Construct validity will be tested against: The Stroke Southampton Self-Management Questionnaire; The Satisfaction with Stroke Care Measure; and The Shortened Stroke Impact Scale. We will explore known-groups validity by exploring the association between treatment burden, socioeconomic deprivation and multimorbidity. Test-retest reliability will be examined via re-administration after 2 weeks. Acceptability and feasibility of use will be explored via missing data rates and telephone interviews with 30 participants. We aim to create a validated PRM of treatment burden after stroke. PETS-stroke is designed for use as an outcome measure in clinical trials of stroke treatments and complex interventions to ascertain if treatments are workable for patients in the context of their everyday lives.

The T1-weighted/T2-weighted ratio as a biomarker of anti-NMDA receptor encephalitis

BackgroundAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To improve prognostic capabilities, we evaluate the T1-weighted/T2-weighted (T1w/T2w) ratio, a...

Correlation Between Fundus Autofluorescence Pattern and Retinal Function on Microperimetry in Choroideremia.

In patients with choroideremia, it is not known how smooth and mottled patterns on short-wavelength fundus autofluorescence (AF) imaging relate to retinal function. A retrospective case-note review was undertaken on 190 patients with choroideremia at two specialist centers for retinal genetics. Twenty patients with both smooth and mottled zones on short-wavelength AF imaging and concurrent mesopic microperimetry assessments were included. Mean retinal sensitivities within the smooth and mottled zones were compared between choroideremia patients, and identical points on mesopic microperimetry collected from 12 age-matched controls. Longitudinal analyses were undertaken at 2 and 5years in a subset of patients. In patients with choroideremia, mean retinal sensitivities at baseline were significantly greater in the smooth zone (26.1 ± 2.0 dB) versus the mottled zone (20.5 ± 4.2 dB) (P < 0.0001). Mean retinal sensitivities at baseline were similar in the smooth zone between choroideremia patients and controls (P = 0.054) but significantly impaired in the mottled zone in choroideremia compared to controls (P < 0.0001). The rate of decline in total sensitivity over 5 years was not significant in either the smooth or mottled zone in a small subset of choroideremia patients (n = 7; P = 0.344). In choroideremia, retinal sensitivity as determined by microperimetry correlates with patterns on AF imaging: retinal function in the smooth zone, where the retinal pigment epithelium is anatomically preserved, is similar to controls, but retinal sensitivity in the mottled zone is impaired. Patterns on AF imaging may represent a novel, objective outcome measure for clinical trials in choroideremia as a surrogate for retinal function.

Harmonized standard operating procedures for administering the ALS functional rating scale-revised

The ALS Functional Rating Scale-Revised is the most commonly used primary outcome measure in current ALS clinical trials. While rigorous training and certification is generally recognized as critical to reliable performance, differences have existed between training in the two groups responsible for most training in ALS outcome measures. We present a harmonized standard operating procedure which is intended to further reduce response variability by the use of identical training in North America and Europe.

Hidradenitis suppurativa: new insights into disease mechanisms and an evolving treatment landscape.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic disabling and debilitating inflammatory disease with a high unmet medical need. The prevalence of HS reported in most studies is 1-2%, although it is likely to be under-reported and estimates vary globally owing to variance in data collection methods, ethnicity, geographical location and under-diagnosis. HS is characterized by persistent, painful cutaneous nodules, abscesses and draining tunnels commonly affecting the axillary, anogenital, inguinal and perianal/gluteal areas. Over time, chronic uncontrolled inflammation results in irreversible tissue destruction and scarring. Although the pathophysiology of HS has not been fully elucidated, the tumour necrosis factor (TNF)-α and interleukin (IL)-17 pathways have an important role, involving multiple cytokines. Currently, treatment options include topical medications; systemic therapies, including repeated and/or rotational courses of systemic antibiotics, retinoids and hormonal therapies; and various surgical procedures. The anti-TNF-α antibody adalimumab is currently the only biologic approved by both the US Food and Drug Administration and the European Medicines Agency for HS; however, its efficacy varies, with a clinical response reported in approximately 50% of patients in phase III trials. HS is a rapidly evolving field of discovery, with a diverse range of agents with distinct mechanisms of action currently being explored in clinical trials. Several other promising therapeutic targets have recently emerged, and agents targeting the IL-17 and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways are the most advanced in ongoing or completed phase III clinical trials. Alongside limited therapeutic options, significant challenges remain in terms of diagnosis and disease management, with a need for better treatment outcomes. Other unmet needs include significant diagnostic delays, thus missing the therapeutic 'window of opportunity'; the lack of standardized outcome measures in clinical trials; and the lack of established, well-defined disease phenotypes and biomarkers.

Abstract PO-066: Complete pathological response following neoadjuvant chemotherapy and recurrence free survival in patients with p16-positive oropharyngeal cancer

Abstract Introduction: Locoregionally advanced p16+ squamous cell carcinoma of the oropharynx (OPSCC) is most often treated either with primary chemoradiation (CRT) or surgery followed by adjuvant treatment. Surgery alone is often insufficient treatment as adverse features such as extranodal extension, close or positive margins, lymphovascular invasion, or multiple positive lymph nodes are often identified, resulting in the need for adjuvant radiation or CRT. Primary surgery is often not pursued in more advanced cases since surgical pathology may show adverse features requiring adjuvant CRT, resulting in "triple therapy", the effects of which may worsen risk of long-term treatment toxicity. Our institution has demonstrated excellent oncologic and quality of life outcomes using a neoadjuvant chemotherapy (NAC) regimen of cisplatin and docetaxel prior to surgical treatment with TORS and neck dissection. Due to high rates of clinical-to-pathologic downstaging, adjuvant treatment is often avoided entirely. Here, we explore whether the development of a complete pathologic (pCR) response following NAC associates with 2-year recurrence free survival. Methods: A retrospective cohort study of patients receiving neoadjuvant doublet cisplatin and docetaxel followed by surgery (NAC+S) at a single institution between October 2015 and March 2023 was performed and pathologic responses and 2-year recurrence free survival was recorded following IRB exemption. Results: Fifty-four patients with p16+ OPSCC treated with NAC+S were identified. 49 patients (91%) received three cycles of NAC; 5 patients (9%) received two cycles. Comparing clinical staging to pathologic analysis of surgical specimens, 40 of 54 patients (68%) experienced clinical-to-pathologic downstaging after NAC. A pCR was identified in 23 of 54 patients (43%). Of patients that did not develop a pCR, 9 of 31 patients (29%) received adjuvant treatment due to the identification of high-risk pathologic features. Of patients that developed a pCR, 1 of 23 (4%) developed disease relapse within 2 years. Of patients that did not develop a pCR but did not require adjuvant treatment, 2 of 22 (9%) developed disease relapse within 2 years. Of patients that did not develop a pCR but did require adjuvant treatment, 2 of 9 (22%) developed disease relapse within 2 years. A trend toward reduced risk of disease relapse was observed in patients that develop a pCR following NAC compared to those that do not but did not reach statistical significance (1 of 23 relapses with pCR, 4 of 31 relapses without pCR; P&amp;gt;0.05, two-sided Chi-square test). Conclusion: High rates of pCR following NAC were observed in this small retrospective cohort of patients with newly diagnosed p16+ OPSCC despite 84% of patients avoiding any adjuvant treatment. Patients that develop a pCR after NAC trend toward reduced risk of recurrence compared to those that do not. The development of pCR after NAC may be a suitable short-term clinical outcome measure in prospective clinical trials of NAC for patients with newly diagnosed p16+ OPSCC. Citation Format: Alisha R. Pershad, Maxwell Madani, Timothy B. Shaver, Arjun Joshi, Clint T. Allen, Joseph F. Goodman. Complete pathological response following neoadjuvant chemotherapy and recurrence free survival in patients with p16-positive oropharyngeal cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-066.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study

There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Rasch Analysis of the Korean Version of the Tinnitus Handicap Inventory.

Tinnitus is the perception of abnormal sounds in the ears or head without external auditory stimulation. While classical test theory is often used in tinnitus questionnaire development, it has limitations in assessing item characteristics. Item response theory (IRT) offers more precise individual ability estimations and identifies key and less important items, making it superior for reliable measurement tools. This study investigated the suitability of the Korean version of the Tinnitus Handicap Inventory (K-THI) as a patient-reported outcome measure (PROM) for clinical trials. Using Rasch analysis based on IRT, we evaluated K-THI's measurement of tinnitus-related disability in 545 patients (40.4% men, 59.6% women). Five items (2, 7, 8, 19, and 24) did not fit the Rasch model, yet a unidimensional scale and good fit for person and item data emerged (person: 0.89; item: 0.98). The three-point rating scale in K-THI proved suitable. IRT allowed precise evaluation of K-THI's properties, vital for reliable PROMs in patient-centered care. Our findings highlight IRT's role in questionnaire development, contributing to the advancement of PROMs.

40608 Improving Clinical Trial Outcome Measures and Recruitment in Bullous Pemphigoid Utilizing Hybrid Teledermatology Strategy

40608 Improving Clinical Trial Outcome Measures and Recruitment in Bullous Pemphigoid Utilizing Hybrid Teledermatology Strategy

Multivariate modeling of magnetic resonance biomarkers and clinical outcome measures for Duchenne muscular dystrophy clinical trials.

Although regulatory agencies encourage inclusion of imaging biomarkers in clinical trials for Duchenne muscular dystrophy (DMD), industry receives minimal guidance on how to use these biomarkers most beneficially in trials. This study aims to identify the optimal use of muscle fat fraction biomarkers in DMD clinical trials through a quantitative disease-drug-trial modeling and simulation approach. We simultaneously developed two multivariate models quantifying the longitudinal associations between 6-minute walk distance (6MWD) and fat fraction measures from vastus lateralis and soleus muscles. We leveraged the longitudinal individual-level data collected for 10 years through the ImagingDMD study. Age of the individuals at assessment was chosen as the time metric. After the longitudinal dynamic of each measure was modeled separately, the selected univariate models were combined using correlation parameters. Covariates, including baseline scores of the measures and steroid use, were assessed using the full model approach. The nonlinear mixed-effects modeling was performed in Monolix. The final models showed reasonable precision of the parameter estimates. Simulation-based diagnostics and fivefold cross-validation further showed the model's adequacy. The multivariate models will guide drug developers on using fat fraction assessment most efficiently using available data, including the widely used 6MWD. The models will provide valuable information about how individual characteristics alter disease trajectories. We will extend the multivariate models to incorporate trial design parameters and hypothetical drug effects to inform better clinical trial designs through simulation, which will facilitate the design of clinical trials that are both more inclusive and more conclusive using fat fraction biomarkers.

Exploring New Therapeutic Avenues for Ophthalmic Disorders: Glaucoma-Related Molecular Docking Evaluation and Bibliometric Analysis for Improved Management of Ocular Diseases.

Ophthalmic disorders consist of a broad spectrum of ailments that impact the structures and functions of the eye. Due to the crucial function of the retina in the vision process, the management of eye ailments is of the utmost importance, but several unmet needs have been identified in terms of the outcome measures in clinical trials, more proven minimally invasive glaucoma surgery, and a lack of comprehensive bibliometric assessments, among others. The current evaluation seeks to fulfill several of these unmet needs via a dual approach consisting of a molecular docking analysis based on the potential of ripasudil and fasudil to inhibit Rho-associated protein kinases (ROCKs), virtual screening of ligands, and pharmacokinetic predictions, emphasizing the identification of new compounds potentially active in the management of glaucoma, and a comprehensive bibliometric analysis of the most recent publications indexed in the Web of Science evaluating the management of several of the most common eye conditions. This method resulted in the finding of ligands (i.e., ZINC000000022706 with the most elevated binding potential for ROCK1 and ZINC000034800307 in the case of ROCK2) that are not presently utilized in any therapeutic regimen but may represent a future option to be successfully applied in the therapeutic scheme of glaucoma following further comprehensive testing validations. In addition, this research also analyzed multiple papers listed in the Web of Science collection of databases via the VOSviewer application to deliver, through descriptive analysis of the results, an in-depth overview of publications contributing to the present level of comprehension in therapeutic approaches to ocular diseases in terms of scientific impact, citation analyses, most productive authors, journals, and countries, as well as collaborative networks. Based on the molecular docking study's preliminary findings, the most promising candidates must be thoroughly studied to determine their efficacy and risk profiles. Bibliometric analysis may also help researchers set targets to improve ocular disease outcomes.

The NuroSleeve, a user-centered 3D printed hybrid orthosis for individuals with upper extremity impairment

BackgroundActive upper extremity (UE) assistive devices have the potential to restore independent functional movement in individuals with UE impairment due to neuromuscular diseases or injury-induced chronic weakness. Academically fabricated UE assistive devices are not usually optimized for activities of daily living (ADLs), whereas commercially available alternatives tend to lack flexibility in control and activation methods. Both options are typically difficult to don and doff and may be uncomfortable for extensive daily use due to their lack of personalization. To overcome these limitations, we have designed, developed, and clinically evaluated the NuroSleeve, an innovative user-centered UE hybrid orthosis.MethodsThis study introduces the design, implementation, and clinical evaluation of the NuroSleeve, a user-centered hybrid device that incorporates a lightweight, easy to don and doff 3D-printed motorized UE orthosis and a functional electrical stimulation (FES) component. Our primary goals are to develop a customized hybrid device that individuals with UE neuromuscular impairment can use to perform ADLs and to evaluate the benefits of incorporating the device into occupational therapy sessions. The trial is designed as a prospective, open-label, single-cohort feasibility study of eight-week sessions combined with at-home use of the device and implements an iterative device design process where feedback from participants and therapists informs design improvement cycles.ResultsAll participants learned how to independently don, doff, and use the NuroSleeve in ADLs, both in clinical therapy and in their home environments. All participants showed improvements in their Canadian Occupational Performance Measure (COPM), which was the primary clinical trial outcome measure. Furthermore, participants and therapists provided valuable feedback to guide further development.ConclusionsOur results from non-clinical testing and clinical evaluation demonstrate that the NuroSleeve has met feasibility and safety goals and effectively improved independent voluntary function during ADLs. The study’s encouraging preliminary findings indicate that the NuroSleeve has met its technical and clinical objectives while improving upon the limitations of the existing UE orthoses owing to its personalized and flexible approach to hardware and firmware design.Trial Registration: ClinicalTrials.gov identifier: NCT04798378, https://clinicaltrials.gov/ct2/show/NCT04798378, date of registration: March 15, 2021.

A patient survey indicates quality of life and progression-free survival as equally important outcome measures in multiple myeloma clinical trials

A patient survey indicates quality of life and progression-free survival as equally important outcome measures in multiple myeloma clinical trials

Evaluating the pragmatic characteristics of advance care planning outcome measures in dementia clinical trials: A scoping review.

Advance care planning (ACP) is a process that involves discussing a person's goals, values, and preferences; it is particularly important for persons living with dementia (PLWD) given that dementia is incurable and progressive. To ensure results that will impact real-world practices, ACP outcome measures must be psychometrically strong, meaningful to key partners, and pragmatic to collect. Therefore, we conducted a scoping review of outcome measures utilized in ACP randomized controlled clinical trials (RCTs) enrolling PLWD or their care partners and evaluated their pragmatic characteristics. We searched MEDLINE/PubMed, EMBASE, CINAHL, PsycINFO, and Web of Science for peer-reviewed ACP RCTs enrolling PLWD or their care partners from 2011 to 2021. We abstracted characteristics of primary and secondary outcome measures, including pragmatic characteristics using an adapted Psychometric and Pragmatic Evidence Rating Scale and ACP outcome domains using the standardized ACP Outcome Framework (i.e., process, action, healthcare, or quality of care). We included 21 ACP RCTs. Trials included 103 outcome measures (39 primary and 64 secondary), of which 11% measured process, 14% measured action, 49% measured healthcare, and 26% measured quality of care. Twenty-four (23%) outcome measures were highly pragmatic, the majority of which (67%) reflected healthcare outcome measures. Sixty-one (59%) outcomes were assessed as highly relevant to PLWD or their care partners. Only 20% (n = 21) of outcome measures were embedded into clinical practice. Most (62%) RCTs were conducted in nursing homes, and 33% were focused PLWD with advanced stage disease. In RCTs testing ACP interventions to support PLWD, only 23% of outcome measures were highly pragmatic, and most of these measured healthcare utilizations. Outcome assessments were rarely integrated into the EHR during routine clinical care. New outcome measures that address the lived experience of PLWD and their care partners plus have high pragmatic characteristics are needed for embedded pragmatic clinical trials.

Proposal to Add FDG-PET as an Outcome Measure for Clinical Trials in Patients With Prodromal Lewy Body Dementia.

Proposal to Add FDG-PET as an Outcome Measure for Clinical Trials in Patients With Prodromal Lewy Body Dementia.

Review: The use of functional magnetic resonance imaging (fMRI) in clinical trials and experimental research studies for depression.

Functional magnetic resonance imaging (fMRI) is a non-invasive technique that can be used to examine neural responses with and without the use of a functional task. Indeed, fMRI has been used in clinical trials and pharmacological research studies. In mental health, it has been used to identify brain areas linked to specific symptoms but also has the potential to help identify possible treatment targets. Despite fMRI's many advantages, such findings are rarely the primary outcome measure in clinical trials or research studies. This article reviews fMRI studies in depression that sought to assess the efficacy and mechanism of action of compounds with antidepressant effects. Our search results focused on selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed treatments for depression and ketamine, a fast-acting antidepressant treatment. Normalization of amygdala hyperactivity in response to negative emotional stimuli was found to underlie successful treatment response to SSRIs as well as ketamine, indicating a potential common pathway for both conventional and fast-acting antidepressants. Ketamine's rapid antidepressant effects make it a particularly useful compound for studying depression with fMRI; its effects on brain activity and connectivity trended toward normalizing the increases and decreases in brain activity and connectivity associated with depression. These findings highlight the considerable promise of fMRI as a tool for identifying treatment targets in depression. However, additional studies with improved methodology and study design are needed before fMRI findings can be translated into meaningful clinical trial outcomes.

The reliability and validity of the TBI-CareQOL system in four diverse caregiver groups

PurposeEstablishing the psychometric reliability and validity of new measures is an ongoing process. More work is needed in to confirm the clinical utility of the TBI-CareQOL measurement development system in both an independent cohort of caregivers of traumatic brain injury (TBI), as well as in additional caregiver groups.MethodsAn independent cohort of caregivers of people with TBI (n = 139), as well as three new diverse caregiver cohorts (n = 19 caregivers of persons with spinal cord injury, n = 21 caregivers for persons with Huntington disease, and n = 30 caregivers for persons with cancer), completed 11 TBI-CareQOL measures (caregiver strain; caregiver-specific anxiety; anxiety; depression; anger; self-efficacy; positive affect and well-being; perceived stress; satisfaction with social roles and activities; fatigue; sleep-related impairment), as well as two additional measures to examine convergent and discriminant validity (PROMIS Global Health; the Caregiver Appraisal Scale).ResultsFindings support the internal consistency reliability (all alphas > 0.70 with the vast majority being > 0.80 across the different cohorts) of the TBI-CareQOL measures. All measures were free of ceiling effects, and the vast majority were also free of floor effects. Convergent validity was supported by moderate to high correlations between the TBI-CareQOL and related measures, while discriminant validity was supported by low correlations between the TBI-CareQOL measures and unrelated constructs.ConclusionFindings indicate that the TBI-CareQOL measures have clinical utility in caregivers of people with TBI, as well as in other caregiver groups. As such, these measures should be considered as important outcome measures for clinical trials aiming to improve caregiver outcomes.

Digital endpoints in clinical trials of Alzheimer's disease and other neurodegenerative diseases: challenges and opportunities.

Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD (Remote assessment of disease and relapse-Alzheimer's disease), IDEA-FAST (Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases) and Mobilise-D (Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing.

Microperimetry as an Outcome Measure in RPGR-associated Retinitis Pigmentosa Clinical Trials.

To explore which microperimetry sensitivity index (pointwise sensitivity, mean sensitivity, and volume sensitivity) is suitable as a microperimetry outcome measure in patients with X-linked RPGR-associated retinitis pigmentosa (RP). Microperimetry data from patients with RPGR-associated RP were collected and analyzed retrospectively. Fourteen participants completed triplicate microperimetry testing, across 2 consecutive days for the repeatability analyses. Longitudinal data was obtained from 13 participants who completed microperimetry testing at two separate visits. The test-retest coefficients of repeatability (CoR) for pointwise sensitivity were ±9.5 dB and ±9.3 dB, in the right and left eyes, respectively. The mean sensitivity CoR for the right and left eyes was ±0.7 dB and ±1.3 dB. Volume sensitivity CoR was ±144.5dB*deg2 and ±324.2 dB*deg2 for the right and left eyes, respectively. The mean sensitivities were positively skewed toward zero in those with a high number of nonseeing points (arbitrarily assigned to -1.0 dB) and just seen points (0.0 dB). Volume sensitivities were unaffected by the averaging effects of skewed data. Clinical trials should report population-specific test-retest variability to determine a clinically significant change. Pointwise sensitivity indices should be used with caution as outcome measures in clinical trials owing to high levels of test-retest variability. Global indices seem to be less prone to variability. Volume sensitivity indices seem to be superior for use in RPGR-associated RP clinical trials compared with mean sensitivity because they are unaffected by the averaging effects of highly skewed data. Careful selection of sensitivity indices (VA) is required when using microperimetry as a clinical trial outcome measure.