Outcome Measure In Clinical Trials Research Articles

Episodic Ataxia Type 1: Natural History and Effect on Quality of Life

Episodic ataxia type 1 (EA1) is a rare autosomal potassium channelopathy, due to mutations in KCNA1. Patients have childhood onset of intermittent attacks of ataxia, dizziness or imbalance. In order to quantify the natural history of EA1, its effect on quality of life and in preparation for future clinical trials, we set up an international multi-centre study of EA1. We recruited thirty-three participants with EA1: twenty-three completed 1-year follow-up and eighteen completed 2-year follow-up. There was very little accumulation of disability or impairment over the course of the 2 years of the study. The outcome measures of ataxia (SARA and functional rating of ataxia) and the activities of daily living scale were largely stable over time. Self-reported health-related quality of life (SF-36) scores were lower across all domains than controls, in keeping with a chronic condition. Physical subdomain scores appeared to deteriorate over time, which seems to be driven by the female participants in the study. This is an interesting finding and warrants further study. Attacks of EA1 reported by participants in real time via an interactive voice response system showed that symptoms were not stereotyped; however, attack duration and frequency was stable between individuals. This large prospective study is the first ever completed in subjects with EA1. We document the natural history of the disorder over 2 years. These data will enable the development of outcome measures for clinical trials of treatment.

Longitudinal Alterations in Gait Features in Growing Children With Duchenne Muscular Dystrophy.

Prolonging ambulation is an important treatment goal in children with Duchenne muscular dystrophy (DMD). Three-dimensional gait analysis (3DGA) could provide sensitive parameters to study the efficacy of clinical trials aiming to preserve ambulation. However, quantitative descriptions of the natural history of gait features in DMD are first required. The overall goal was to provide a full delineation of the progressive gait pathology in children with DMD, covering the entire period of ambulation, by performing a so-called mixed cross-sectional longitudinal study. Firstly, to make our results comparable with previous literature, we aimed to cross-sectionally compare 31 predefined gait features between children with DMD and a typically developing (TD) database (1). Secondly, we aimed to explore the longitudinal changes in the 31 predefined gait features in growing boys with DMD using follow-up 3DGA sessions (2). 3DGA-sessions (n = 124) at self-selected speed were collected in 27 boys with DMD (baseline age: 4.6–15 years). They were repeatedly measured over a varying follow-up period (range: 6 months–5 years). The TD group consisted of 27 children (age: 5.4–15.6 years). Per measurement session, the spatiotemporal parameters, and the kinematic and kinetic waveforms were averaged over the selected gait cycles. From the averaged waveforms, discrete gait features (e.g., maxima and minima) were extracted. Mann-Whitney U tests were performed to cross-sectionally analyze the differences between DMD at baseline and TD (1). Linear mixed effect models were performed to assess the changes in gait features in the same group of children with DMD from both a longitudinal (i.e., increasing time) as well as a cross-sectional perspective (i.e., increasing baseline age) (2). At baseline, the boys with DMD differed from the TD children in 17 gait features. Additionally, 21 gait features evolved longitudinally when following-up the same boys with DMD and 25 gait features presented a significant cross-sectional baseline age-effect. The current study quantitatively described the longitudinal alterations in gait features in boys with DMD, thereby providing detailed insight into how DMD gait deteriorates. Additionally, our results highlight that gait features extracted from 3DGA are promising outcome measures for future clinical trials to quantify the efficacy of novel therapeutic strategies.

Patient-reported outcomes and quality of life in PMM2-CDG.

Patient-reported outcomes (PROs) measure important aspects of disease burden, however they have received limited attention in the care of patients with Congenital Disorders of Glycosylation (CDG). We evaluated the PROs and correlation between clinical disease severity scoring and reported quality of life (QoL) in a PMM2-CDG patient cohort. Twenty-five patients with diagnosis of PMM2-CDG were enrolled as part of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study. Patient- Reported Outcomes Measurement Information System (PROMIS) was completed by caregivers to assess health-related QoL. Clinical disease severity was scored by medical providers using the Nijmegen Progression CDG Rating Scale (NPCRS). The domains such as physical activity, strength impact, upper extremity, physical mobility, and a satisfaction in social roles (peer relationships) were found to be the most affected in the PMM2-CDG population compared to US general population. We found a strong correlation between NPCRS 1 (current functional ability) and three out of ten PROMIS subscales. NPCRS 2 (laboratory and organ function) and NPCRS 3 (neurological involvement) did not correlate with PROMIS. Mental health domains, such as anxiety, were positively correlated with depressive symptoms (r = 0.76, p = 0.004), fatigue (r = 0.67, p = 0.04). Surprisingly, patients with severely affected physical mobility showed low anxiety scores according to PROMIS (inverse correlation, r = -0.74, p = 0.005). Additionally, there was a positive correlation between upper extremity and physical mobility (r = 0.75, p = 002). Here, we found that PROMIS is an informative additional tool to measure CDG disease burden, which could be used as clinical trial outcome measures. The addition of PROMIS to clinical follow-up could help improve the quality of care for PMM2-CDG by facilitating a holistic approach for clinical decision-making. SYNOPSIS: We recommend PROMIS as an informative tool to measure disease burden in PMM2-CDG in addition to traditional CDG disease severity scores.

Evaluation of Cone- and Rod-Mediated Parameters in Dark Adaptation Testing as Outcome Measures in Age-Related Macular Degeneration

To investigate the suitability of 6 rod- or cone-mediated dark adaptation (DA) parameters as outcome measures for clinical trials in age-related macular degeneration (AMD), including their retest reliability, association with age and disease severity, and measurable longitudinal change over time. Prospective, longitudinal study (Clinicaltrials.gov: NCT01352975). A total of 191 patients with AMD and older participants followed longitudinally over 5 years. Dark adaptation testing was performed using the AdaptDx dark adaptometer with a maximum test time of 40 minutes. A 2-part exponential-linear curve was fitted to obtain values for cone decay, cone plateau, time to rod-cone break, rod intercept time (RIT), rod adaptation rate (S2), and area under the curve. Intersession retest reliability was assessed in tests performed within 2 weeks using the Bland-Altman analysis. The relationship of DA parameters with age, AMD severity, and reticular pseudodrusen (RPD) presence was evaluated using linear mixed models. Retest reliability, association with disease severity, and longitudinal change of 6 DA parameters. A total of 1329 DA curves were analyzed. Rod intercept time was the parameter that showed the greatest reliability (intraclass correlation coefficient of 0.88) and greatest association with age, AMD severity, and RPD (marginal R2 of 0.38), followed by the rod-mediated parameters area under the curve and rod-cone break. Cone plateau appeared constant at lower RIT values but increased with progressive rod dysfunction (RIT > 22.8 minutes) with a slope of 0.07 log units per 10 minutes RIT prolongation. Therefore, it might provide additional information in the advanced stages of AMD. Age-related macular degeneration severity and RPD presence are each associated with large differences in multiple DA curve parameters. In addition, substantial differences in some parameters occur with age, even accounting for AMD severity and RPD status. This supports the 2-hit hypothesis of age and disease status on DA (and perhaps AMD pathophysiology itself). Of the DA parameters, RIT has the highest retest reliability, closest correlation with AMD severity and RPD, and largest longitudinal changes. This underscores the suitability of RIT as an outcome measure in clinical trials. The cone plateau increases only in advanced stages of kinetic rod dysfunction, indicating rod dysfunction preceding cone dysfunction and degeneration in the temporal sequence of pathology in AMD.

POS0119 SLE-DAS REMISSION AND LOW DISEASE ACTIVITY STATES ARE ASSOCIATED WITH IMPROVED HEALTH-RELATED QUALITY OF LIFE AND FATIGUE: POST-HOC ANALYSIS OF THE BLISS-52 AND BLISS-76 PHASE III TRIALS.

BackgroundAccurate and practical outcome measures for clinical trials in systemic lupus erythematosus (SLE) are lacking. The SLE Disease Activity Score (SLE-DAS) is a recently validated 17-item instrument, with high accuracy and sensitivity to changes in SLE disease activity. The SLE-DAS definitions of remission and low disease activity (LDA) were newly validated against disease activity physician-applied measures in the clinical setting [1, 2]. Criterion validity of SLE-DAS for Patient Reported Outcomes, namely health-related quality of life (HR-QoL) and fatigue needs to be assessed.ObjectivesTo evaluate if the attainment of SLE-DAS remission and LDA states is associated with improvements in HR-QoL and fatigue.MethodsPost-hoc analysis of the merged study population in the BLISS-52 and -76 trials (NCT00424476; NCT00410384) of intravenous belimumab versus placebo for moderate to severe SLE disease activity. We analysed the Functional Assessment of Chronic Illness Therapy (FACIT) and 36-Item Short Form Survey (SF-36) trial data. Fulfillment of SLE-DAS remission (defined as absence of all SLE-DAS clinical items and prednisone ≤5mg/day) and LDA (defined as SLE-DAS≤2.48 and prednisone ≤7.5mg/day) definitions were retrospectively assessed from the individual participants’ data. Mean changes from study baseline to week 52 in FACIT and SF-36 physical component summary (PCS) and mental component summary (MCS) and domain scores were compared between patients attaining at week 52 the SLE-DAS remission vs non-remission and the SLE-DAS LDA vs non-LDA using multivariate regression analysis adjusted for baseline scores.ResultsA total of 1684 SLE patients were included. Few patients were in SLE-DAS remission (0.5%) and LDA (0.8%) at study entry. At week 52, 12.5% patients attained SLE-DAS remission and 17.5% attained SLE-DAS LDA. Mean improvements in SF-36 PCS and MCS scores were greater in patients that attained SLE-DAS remission vs non-remission (5.4 vs 3.4, and 4.6 vs 2.7, respectively; multivariate p<0.005 for both) and SLE-DAS LDA vs non-LDA (5.0 vs 3.4 and 4.6 vs 2.6, respectively; multivariate p<0.005 for both), at week 52 (Figure 1). Similarly, improvements in all individual domain scores were greater in SLE-DAS remission vs non-remission patients (all multivariate p<0.005) and SLE-DAS LDA vs non-LDA patients (all multivariate p<0.005) (Figure 1). Importantly, improvements in the summary scores and in all the individual domain scores largely exceeded the minimum clinically important differences (MCIDs) of 2.5 and 5 points, respectively, in those patients attaining SLE-DAS remission or LDA.Figure 1.Mean changes in SF-36 domains and summary scores from baseline to week 52. #p<0.005; *p<0.001; MICD, Minimum Clinically Important Difference; MCS, Mental Component Summary; PCS, Physical Component Summary; SF-36, Medical Outcomes Survey Short Form; SLE-DAS, Systemic Lupus Erythematosus Disease Activity Score.Additionally, mean improvements in FACIT scores were higher in SLE-DAS remission than non-remission (6.3 vs 3.6, multivariate p<0.001) and in SLE-DAS LDA than non-LDA (5.9 vs 3.6, multivariate p<0.001), and exceeded the MCID of 4 points.ConclusionAttainment of SLE-DAS remission and LDA is associated with meaningful improvement in HR-QoL and fatigue.

OP0147 THE SLE-DAS REMISSION AND LOW DISEASE ACTIVITY STATES DISCRIMINATE DRUG FROM PLACEBO AND BETTER HEALTH-RELATED QUALITY OF LIFE: POST-HOC ANALYSIS OF THE BLISS-52 AND BLISS-76 PHASE III TRIALS.

BackgroundAccurate and practical outcome measures for clinical trials in systemic lupus erythematosus (SLE) are lacking. The SLE Disease Activity Score (SLE-DAS) is a recently validated 17-item instrument, with high accuracy and sensitivity to changes in SLE disease activity. The SLE-DAS definitions of remission and low disease activity (LDA) were newly validated in the clinical setting1,2. These definitions may constitute accurate and easy to apply endpoints for SLE trials.Objectives(1) To evaluate the ability of SLE-DAS remission and LDA definitions to discriminate drug from placebo in SLE phase 3 trials; (2) To determine if attainment of these SLE-DAS targets are associated with better health-related quality of life (HR-QoL).MethodsPost-hoc analysis of the merged study population in the BLISS-52 and -76 trials (NCT00424476; NCT00410384) of intravenous belimumab versus placebo for moderate to severe SLE disease activity. We analyzed the British Isles Lupus Assessment Group (BILAG), Physician Global Assessment (PGA), Functional Assessment of Chronic Illness Therapy (FACIT) and 36-Item Short Form Survey (SF-36) trial data. The fulfillment of SLE-DAS remission and LDA definitions were retrospectively assessed from the individual participants’ data. Proportion of patients attaining SLE-DAS Boolean remission (defined as absence of all SLE-DAS clinical items and prednisone ≤5mg/day) and LDA (defined as SLE-DAS≤2.48 and prednisone ≤7.5mg/day), at week 52, was compared between belimumab and placebo arms, using likelihood ratio chi-square test. We further compared the SF-36 physical component summary (PCS) and mental component summary (MCS) and domain scores and the FACIT score between patients attaining SLE-DAS remission vs non-remission and SLE-DAS LDA vs non-LDA, using t-test and Mann-Whitney test.ResultsA total of 1684 SLE patients were included: 562 on placebo, 559 on belimumab 1mg/Kg and 563 on belimumab 10mg/Kg. At week 52, significantly more patients attained SLE-DAS LDA on belimumab 1mg/Kg and 10mg/Kg as compared with placebo (13.0% vs 17.9%, OR=1.459, p=0.023, and 13.0% vs 21.7%, OR=1.853, p<0.001, respectively). Likewise, more patients attained SLE-DAS remission on belimumab 10mg/Kg as compared with placebo (10.1% vs 14.7%, OR= 1.532, p=0.019) (Table 1). Importantly, none of the patients achieving SLE-DAS remission or LDA presented a new BILAG A or more than 1 new B domain score, neither a worsening in PGA≥0.3.Table 1.Attainment of SLE-DAS Boolean remission and LDA at week 52 in BLISS-52 and BLISS-76 trials, according to the treatment groups (n =1684).PlaceboBelimumab 1mg/KgBelimumab 10mg/KgSLE-DAS remission (n=211)10.1%12.7%, OR=1.289 (0.89-1.866), p=0.17814.7%, OR 1.532 (1.069-2.195), p=0.019SLE-DAS LDA (n=295)13.0%17.9%, OR=1.459 (1.052-2.025), p=0.02321.7%, OR 1.853 (1.349-2.545), p<0.001LDA: Low disease activity; SLE-DAS Boolean remission: absence of all SLE-DAS clinical items and prednisone ≤5mg/day; SLE-DAS LDA: SLE-DAS≤2.48 and prednisone ≤7.5mg/day.At week 52, patients attaining SLE-DAS remission and SLE-DAS LDA presented higher SF-36 domain and summary scores (all p<0.001) (Figure 1). Additionally, FACIT scores were higher in patients attaining SLE-DAS remission than non-remission patients (mean±SD: 38.24±10.65 vs 33.45±12.13, p<0.001), and in patients attaining SLE-DAS LDA than non-LDA (mean±SD: 37.22±11.00 vs 33.37±12.17, p<0.001), at week 52.Figure 1.Mean SF-36 domain and summary scores at week 52; *p<0.001; MCS, Mental Component Summary; PCS, Physical Component Summary; SF-36, Medical Outcomes Survey Short Form.ConclusionThe SLE-DAS remission and LDA showed discriminant validity for identifying patients receiving active drug in clinical trials. These treatment targets are associated with better HR-QoL and lower fatigue.

Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials

ObjectivesIn the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder...

Prospective Natural History Study in 24 Adult Patients With LGMDR12 Over 2 Years of Follow-up: Quantitative MRI and Clinical Outcome Measures.

Limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12) is a rare hereditary muscular dystrophy for which outcome measures are currently lacking. We evaluated quantitative MRI and clinical outcome measures to track disease progression to determine which tests could be useful in future clinical trials to evaluate potential therapies. We prospectively measured the following outcome measures in all participants at baseline and after 1 and 2 years: 6-minute walk distance (6MWD), 10-meter walk test (10MWT), the Medical Research Council (MRC) sum scores, Biodex isometric dynamometry, serum creatine kinase, and 6-point Dixon MRI of the thighs. We included 24 genetically confirmed, adult patients with LGMDR12 and 24 age-matched and sex-matched healthy controls. Patients with intermediate-stage thigh muscle fat replacement at baseline (proton density fat fraction [PDFF] 20%-70%) already showed an increase in PDFF in 8 of the 14 evaluated thigh muscles after 1 year. The standardized response mean demonstrated a high responsiveness to change in PDFF for 6 individual muscles over 2 years in this group. However, in patients with early-stage (<20%) or end-stage (>70%) muscle fat replacement, PDFF did not increase significantly over 2 years of follow-up. Biodex isometric dynamometry showed a significant decrease in muscle strength in all patients in the right and left hamstrings (-6.2 Nm, p < 0.002 and -4.6 Nm, p < 0.009, respectively) and right quadriceps muscles (-9 Nm, p = 0.044) after 1 year of follow-up, whereas the 6MWD, 10MWT, and MRC sum scores were not able to detect a significant decrease in muscle function/strength even after 2 years. There was a moderately strong correlation between total thigh PDFF and clinical outcome measures at baseline. Thigh muscle PDFF imaging is a sensitive outcome measure to track progressive muscle fat replacement in selected patients with LGMDR12 even after 1 year of follow-up and correlates with clinical outcome measures. Biodex isometric dynamometry can reliably capture the loss of muscle strength over the course of 1 year in patients with LGMDR12 and should be included as an outcome measure in future clinical trials as well.

Application of Patient-Reported Outcome Measurements in Clinical Trials in China

Regulatory authorities, industry peers, and international health policies have emphasized the value of assessing patient-reported outcomes (PROs) in clinical studies. Despite the increase in the number of clinical studies in the last decade in China, little is known about the extent of the use of PROs. To evaluate the application and characteristics of PRO instruments as primary and secondary outcomes in randomized clinical trials in China. A cross-sectional study of interventional clinical trials conducted in China from January 1, 2010, to December 31, 2020, was performed. Data obtained from the Chinese Clinical Trial Registry and ClinicalTrials.gov databases were evaluated. Trials were categorized according to those that (1) precisely listed PRO tools as outcomes, (2) mentioned patient subjective feelings in outcomes but did not clarify which tools were used for assessment, and (3) did not mention any PRO measurements. Data on study phase, setting, participant age, and sex were extracted from trials that considered patient feelings, along with the target diseases and names of the PRO tools. Among a total of 34 033 trials, 6915 (20.3%) listed the explicit PRO instruments used and 3178 (9.3%) included PRO in their outcomes but did not include the names of the assessment tools. From more than 32 million people included in the registered trials, data on 1.5 million (4.7%) patients were scientifically collected by PRO instruments, and subjective feelings were assessed for 693 867 (2.1%) participants. Pain (16.8%), cancer (15.6%), and musculoskeletal symptoms (13.3%) were the most common conditions for which PROs were precisely collected by tools. The most common tools for PRO measurements were the visual analog scale, Short-Form 36, and Hamilton Depression Scale. In this cross-sectional study, the use of PROs increased during the study period in clinical trials conducted in China. However, patient opinion appears to still be rarely measured. The application of PRO is geographically unevenly distributed. Development of PRO instruments, especially those suitable for the Chinese population, may be useful. Further expansion of PROs with respect to the scope of diseases is needed to avoid missing important data.

How Well Does Patient-reported Functional Disability Correspond to Measures of Physical Fitness in Adolescents with Fibromyalgia?

The Functional Disability Inventory (FDI) is one of the most commonly used patient-reported outcome measures in clinical trials of pediatric pain. In addition to self-reported impairment, studies using activity monitoring devices show that adolescents with widespread musculoskeletal pain often exhibit sedentary behavior. Little is known about how impairment in daily physical activities is reflected in objectively-assessed physical fitness among adolescents with widespread pain. During a baseline assessment for a clinical trial, adolescents with juvenile fibromyalgia (N=226, Mage=15.26, 85% female) completed questionnaires (FDI, PROMIS-Fatigue, pain intensity VAS) and two validated assessments of physical functioning (The Harvard Step Test [HST], a test of aerobic fitness; and the Six-Minute Walk Test [6MWT], the distance a participant is able to walk in 6 minutes). We hypothesized that measures of physical fitness would predict variance in self-reported physical functioning (FDI scores) after controlling for pain and fatigue. We computed bivariate correlations followed by a hierarchical linear regression analysis with pain intensity and fatigue entered in the first step, fitness assessments in the second step, and FDI scores as the dependent variable. FDI scores were strongly associated with fatigue and pain levels (r=.55, p<.001 and r=.47, p<.001, respectively), but only modestly associated with HST (r=-.29, p<.001) and 6MWT scores (r=-.16, p=.02). In the regression model, pain and fatigue together explained 59% of the variance in FDI scores, while fitness measures explained only 2% unique variance (∆r2=.02, p=.07). HST significantly predicted FDI scores (β=-.16, t=-2.21, p=.03), but 6MWT distance did not. After controlling for pain intensity and fatigue, only the HST showed a significant relationship to self-reported functional disability. Overall, fitness measures contributed negligibly to FDI scores. Results support the need to examine cognitive and emotional factors (e.g., fear of movement) which may contribute to physical impairment among youth with chronic pain. Grant support from NIAMS/NIH R01 AR070474 (PI: Kashikar-Zuck).

Risk assessment tools for survival prognosis: An era of new surrogacy endpoints for clinical outcome measurement in pulmonary arterial hypertension clinical trials?

Developing a new medication in a rare disease indication like pulmonary arterial hypertension (PAH) is very challenging. This is especially true now that clinical trials often employ time to clinical worsening (TTCW) as an endpoint (thus requiring a relatively large and lengthy trial) and since patients are more frequently prescribed combination therapy. During the last few decades, several tools have been developed to predict mortality in PAH and have demonstrated generally good discrimination. The objective of this review article is to assess the available data on the different tools and methods described in the literature and identify potential candidates that could be used as surrogate endpoints in pivotal randomized clinical trials in future. Some of these tools have been validated in various registries and in post-hoc analyses of clinical trial data, but none have been assessed in a prospective clinical trial and we still lack the evidence necessary for endorsement by health authorities. In this review, we identify several promising options that warrant further investigation as potential surrogate endpoints in clinical trials to replace TTCW or 6-minute walk distance. Prospective inclusion of such tools in new clinical trials may help build a stronger surrogacy for prognosis of disease progression and mortality.

Histologic lesion type correlates of magnetic resonance imaging biomarkers in four-repeat tauopathies

Primary four-repeat tauopathies are characterized by depositions of the four-repeat isoform of the microtubule binding protein, tau. The two most common sporadic four-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to four-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in four-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus post-mortem pathological diagnosis of a four-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy and mean diffusivity were modelled using linear regression with post-mortem tau lesion scores considered separately, based on cellular type (neuronal versus glial), or summed (total tau). Results showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P < 0.001), substantia nigra (P = 0.03) and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P < 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P < 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in four-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, whereas white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in four-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.

P230 Feasibility study of mobile phone photography as a possible outcome measure of systemic sclerosis-related digital ulcers

Abstract Background/Aims Digital ulcers cause pain and disability in patients with systemic sclerosis (SSc). They are often used as outcome measures in clinical trials; however, trials have been hampered by a lack of reliable outcome measures of healing. Photographic monitoring of digital ulcers using smartphones could overcome this difficulty. Our objective was to assess the feasibility of patients collecting mobile-phone images of their digital ‘lesions’ as a first step in a programme of research to develop a smartphone-based outcome measure. Methods An imaging protocol was developed with input from a patient representative group. Patients with SSc-related digital lesions were recruited and instructed to photograph one or more finger lesions each day over 30 days using their smartphone, at the same time each day. Instructions on how to take the photographs were given either face-to-face or remotely. An adhesive dot, placed adjacent to the lesion(s), provided a 1cm reference scale to help extract accurate measurements. Images were uploaded by each patient to a secure Dropbox folder. Image quality was assessed using six criteria: blurriness, shadow, uniform lighting, dot location, dot angle, and central positioning of the lesion. After image collection, patients were asked to complete a feedback questionnaire, with most questions on a scale of 1 (very easy) to 10 (very difficult). Results Twelve patients (10 female, age 37 to 72 years, disease duration 1 to 27 years) returned 331 photographs of 19 lesions (maximum three lesions per patient). Each patient sent a median of 30 photographs (IQR 14 to 33), with a median of 15 photographs per lesion (IQR 2 to 31). Of the 331 photographs, 24 were ‘duplicates’ taken on the same day, meaning that there were 263 ‘missing’ photographs (i.e., 570 photographs would have been taken if 19 lesions had been photographed every day). Image quality results included the following: 255 (77%) of photographs were sufficiently in focus; 268 (81%) had some shadow; lighting was even in 55 (17%); dot location was acceptable in 231 (70%); dot angle was ideal in 107 (32%); the lesion was centred in 254 (77%). Patient feedback showed 9/10 responses would be willing to record images at least 1-3 times per week, and the overall patient experience taking photographs was good, with a median rating of 3 (IQR 3 to 4). Conclusion Capturing photographs of digital lesions with a smartphone was feasible for most patients. They were able to take photographs in focus and with lesions central in the image. Support will be required to improve lighting, shadow, and dot positioning while minimising discomfort. These encouraging results will inform the next research phase to develop a smartphone app for monitoring finger lesions. Disclosure A.K. Davison: None. H. Patrick: None. P. New: None. G. Dinsdale: None. V.P. Taxiarchi: None. W.G. Dixon: None. A. Vail: None. A.K. Murray: None. M. Dickinson: None. C. Taylor: None. A.L. Herrick: None.

P228 Mobile phone thermal imaging as an ambulatory assessment tool in Raynaud’s phenomenon

Abstract Background/Aims Raynaud’s phenomenon (RP) is episodic colour change of the skin in response to cold or emotional stress. Thermography is currently used to investigate RP in the hospital setting to differentiate primary RP (PRP) from RP secondary to systemic sclerosis (SSc), and to determine the severity of RP. However, RP attacks typically occur out in the community, and are therefore difficult to replicate or quantify within the clinic. Low-cost, portable mobile phone-based thermal imaging may offer a solution, allowing patients to capture thermal images of their hands during RP attacks whenever they occur. The aim of this study was firstly to assess feasibility of patients using mobile phone thermography, and secondly to investigate the quantitative parameters that can be extracted from thermal images captured in this way. Methods Patients (n = 13) with RP secondary to SSc (all female, median age [range] 58 [32-71] years, median duration [range] of RP 12 [1-43] years) were recruited into a 7-day study. Patients were each given a FLIR One thermal camera and smartphone handset. They were asked to image their hands twice daily (mornings/evenings) and, if possible, capture sequences of three images during RP attacks (‘start’, ’middle’ and ’end’, as assessed by the patient). Collected images were assessed for suitability for further analysis (whole hands, dorsal aspect only) and then manually marked-up using custom software (MATLAB) to extract temperature data from regions of interest on the distal aspects of the index, middle, ring and little fingers, and on the hand. Results Twelve patients (92%) completed the study (one patient lost to follow-up). Patients returned 352 images in total (range: 4-54), of which 251 were suitable for further analysis. The median [interquartile range] patient rating of the overall difficulty of using the thermal camera to image their hands/RP was 3 [4] on a scale from 1:Very Easy to 10:Very difficult. Mean [SD] non-attack temperatures (mornings and evenings grouped) were: 25.4 [0.2] °C for the digits and 28.4 [0.5] °C for the dorsum. During RP attacks mean [SD] temperatures were: 22.3 [0.1] °C for the digits and 27.4 [0.9] °C for the dorsum. Including data from only those patients who imaged RP attacks (n = 9), the within-patient temperature difference, mean [SD], (non-attack images minus RP attacks) for the digits was -3.9 [3.5] °C. Conclusion Mobile phone thermography is a feasible method, including as rated by patients, for collecting rich, quantitative data about RP and importantly including RP episodes outside the clinic or hospital setting. The ability to detect differences in temperature due to RP attacks may enable new, sensitive outcome measures for clinical trials in RP. Further work on the sensitivity of this method to temperature changes induced by (e.g.) the introduction of vasodilator therapy is now required. Disclosure G. Dinsdale: None. S. Nazeer: None. J. Manning: None. A. Murray: None. A. Herrick: None.

The Effect of Cataract on Color Vision Measurement with the Low-Vision Cambridge Colour Test: Providing an Adjustment Factor for Clinical Trials.

PurposeTo quantify the effect of cataract on color vision as measured by the low-vision Cambridge Colour Test (lvCCT; Cambridge Research Systems) and to understand whether different types and severities of cataract have different effects on color vision.DesignCohort study.ParticipantsPatients aged 18 to 95 undergoing routine cataract surgery at the Oxford Eye Hospital.MethodsThe lvCCT was performed to measure color sensitivity in both eyes both before and after surgery. The crystalline lens was examined and graded according to the Lens Opacities Classification System III to determine the type and severity of cataract. Measures of repeatability were performed for the data to explore test–retest bias using Bland–Altman analysis. The Wilcoxon signed-rank test was performed to assess the effect of cataract on color vision by comparing control and surgical test measurements. Three multiple linear regressions were performed to relate cataract grading or severity to color vision measurements.Main Outcome MeasuresColor discrimination along each of the protan, deutan, and tritan confusion lines.ResultsThe Wilcoxon signed-rank test showed a statistically significant difference in both the protan (P = 0.024) and tritan (P = 0.020) axes on comparison of control and surgical test measurements. As severity of cataract increased, color vision sensitivity was affected more greatly, and nuclear sclerotic cataract showed the most profound effect on color vision sensitivity in the lvCCT; however, the linear regression models showed that these observations did not reach statistical significance.ConclusionsCataract surgery has a statistically significant effect on color vision in both the protan and tritan axes. The effects of specific subtypes of cataract and different severities could not be elucidated because of the high prevalence of patients with mixed cataract. The lvCCT color sensitivity measurements are used regularly as outcome measures in clinical gene therapy trials involving vitreoretinal surgery, and vitrectomy accelerates cataract formation. Therefore, it is important to quantify the effect of cataract on color vision measurements so that it may be taken into account when used as an outcome measure in clinical trials. We were unable to derive a precise correction factor for cataract on color vision measurements.

377 Mapping Clinical Trial Outcome Measures for Atopic Dermatitis

OBJECTIVES/GOALS: Atopic Dermatitis (AD) affects 10% of people globally and is studied widely in clinical trials. However, clinical outcomes assessment (COA) for AD are not standardized, hindering easy comparisons across different studies. This study examines AD studies to identify the most used COAs. METHODS/STUDY POPULATION: Clinicaltrials.gov was searched to identify AD trials conducted between 2011 and 2021. Ongoing and completed trials were classified according to the therapeutic modality: Biologic, Immunosuppressive, or Other (botanicals and antibiotics). Further, AD trials were examined to determine which of the COAs listed in the FDA compendium issued in 2021 were included: the Investigators Global Assessment (IGA), the Eczema Area and Severity Index (EASI-75), and the Pruritus Numeric Rating Scale (NRS). The results were analyzed to determine which COA is most frequently used and if there were differences across therapeutic modalities or trial phases. RESULTS/ANTICIPATED RESULTS: Across a total of 50 AD trials registered in clinicaltrials.gov, EASI-75 was the most used COA; the item was included in 12 of 16 biologics, 5 of 14 immunosuppressives, and 7 of 20 other products. Moreover, AD trials of biologics included more of the FDA-suggested COAs than those studying other modalities. There were also differences across the clinical trial phases in that most phase III AD trials (83.33%, n=8) included two of the three COAs listed (IGA and EASI-75) compared to less than half of phase I/II trials (vs. 43.75%, n=32). DISCUSSION/SIGNIFICANCE: Findings from this study indicate a lack of COA harmonization across AD trials, impeding comparative analysis of the trial results. Establishing a common standard for COA would foster communication and transparency among key stakeholders including researchers, healthcare providers, and patients.

Association of Emerging β-Amyloid and Tau Pathology With Early Cognitive Changes in Clinically Normal Older Adults.

Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology. One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB- (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time. Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those <CL20 and expanded to include learning/memory retrieval (FCSRT-FR], Selective Reminding Test Total Recall [SRT-tr], Logical Memory Immediate Recall) in the <CL40 group. FTP had limited effects under CL20, with only rising right IT FTP slope related to declining FCSRT-FR and SRT-tr learning/memory retrieval. When we expanded to include those initially <CL40, rising FTP level or slope was related to declines across all tasks, and PiB slope effects on memory retrieval but not DSST score were reduced. A composite measure of processing speed and memory retrieval tasks provided the strongest prediction of decline under CL40, while PACC score remained optimal at high levels of Aβ (>CL40). Early, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function. This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.

Normative Value of Patellar Tendon Thickness in Indian Young Adult Population - A Cross Sectional Study

Purpose: Patellar Tendinopathy (PT) is a highly prevalent condition in lower extremity. Ultrasonography is used as diagnostic tool and outcome measure in clinical trials on PT. As the thickness of the tendon increases in tendinopathy conditions, it is important to establish a normal value of the tendon thickness. Therefore, normal and pathological tendon can be differentiated from each other. Though normal tendon thickness was established for western country population, it is important to have a normal reference value for Indian population as Indians belong to different race and ethnic background. So, the purpose of the study was to establish a normative data of patellar tendon thickness in young Indian adult population. Methodology: A total of 48 subjects, 28 males and 20 females were included based on inclusion and exclusion criteria. The inclusion criteria were subjects aged between 18 and 35 years of age, both male and female, currently not suffering from any of the musculoskeletal pain in the lower extremity. Included subjects were positioned supine with mild knee flexion and undergone ultrasound measurement of patellar tendon thickness at both 0.5 centimetres proximal to the tibial tuberocity and 0.5 centimetres distal to the apex of the patellar tendon of both the extremities by an experienced radiologist. The measurements were recorded in centimetres. Results: Patellar tendon thickness of the recruited subjects for right and left side with geometric mean and 95% confidence was calculated. The overall Proximal thickness geometrical mean and confidence interval were. 0.35 (CI0.34 to 0.37). Meanwhile, the mid and distal thickness were0.33 (CI 0.32 to 0.35) and 0.35 (CI 0.33 to 0.36) respectively. Original value: This is a primary study established a normative value of patellar tendon thickness for young Indian adult population. Paper type: A cross sectional study

Research-Based Intervention (RBI) for Autism Spectrum Disorder: Looking beyond Traditional Models and Outcome Measures for Clinical Trials.

The rising prevalence of Autism Spectrum Disorders (ASD) has led to a quickly increasing need for effective interventions. Several criteria and measures have been developed to critically assess these interventions with particular focus on the evaluation of the efficacy. Given the huge diversity of ASD symptoms and the different levels of severity across individuals, identifying a one size fits all intervention approach is challenging, and the question What works and for whom? Remains still unanswered. Why do we seem to be dragging our feet on this fundamental issue? The main aim of this paper is to answer this question through four non-alternative points. First, there are a scarce number of studies with a solid methodology. Secondly, most trials on intervention efficacy for ASD are designed exclusively in terms of behavioral outcomes. Thirdly, there is a reduced use of biologically oriented outcome measures. Fourthly, in most clinical trials, appropriate practices emerging from research evidence are not systematically applied. A strong effort to improve the methodology of clinical trials is mandatory for the future of autism research. The development of a research-based intervention (RBI) perspective aimed at better integrating: (a) evidence-based approaches; (b) more sensitive behavioral outcome measures; and (c) biomarkers, with the aim of increasing a more detailed clustering of phenotypes, may strongly improve our approach to a precision medicine.

Parent-provided photographs as an outcome measure for childhood chalazia

To determine whether smartphone photographs of children's eyelids are reliable for diagnosing the presence of chalazia. In this prospective cross-sectional study, 60 participants, 7 months to 16.5 years of age, at four sites were enrolled; all participants had a chalazion measuring at least 2 mm on at least one eyelid based on an in-person clinical examination by a pediatric eye care professional. Smartphone photographs taken by the parent during the office visit were uploaded to the study website. A masked reader assessed each photograph for the presence or absence of chalazia; results were compared with the gold standard clinical examination results. Sensitivity and specificity for the presence of chalazion by eyelid were calculated. Photographs were available for 240 eyelids; 85 had at least one chalazion and 155 were without a chalazion based on clinical examination. The masked reader correctly classified 68 of 85 eyelids with at least one chalazion and 151 of 155 eyelids without chalazia for a sensitivity of 80% (95% CI, 72%-86%) and a specificity of 97% (95% CI, 94%-99%). Sensitivity improved to 89% for chalazia 5 mm or larger and 94% when superficially located within the eyelid. Parental smartphone photographs appear to be useful in assessing chalazia in children as an alternative to in-office follow-up examinations. These photographs may be a valuable outcome measure in future clinical trials of chalazia treatment, especially when assessing larger lesions.