Outcome Measure In Clinical Trials Research Articles

Neurophysiologic Innovations in ALS: Enhancing Diagnosis, Monitoring, and Treatment Evaluation.

Amyotrophic lateral sclerosis (ALS) is a progressive disease of both upper motor neurons (UMNs) and lower motor neurons (LMNs) leading invariably to decline in motor function. The clinical exam is foundational to the diagnosis of the disease, and ordinal severity scales are used to track its progression. However, the lack of objective biomarkers of disease classification and progression delay clinical trial enrollment, muddle inclusion criteria, and limit accurate assessment of drug efficacy. Ultimately, biomarker evidence of therapeutic target engagement will support, and perhaps supplant, more traditional clinical trial outcome measures. Electrophysiology tools including nerve conduction study and electromyography (EMG) have already been established as diagnostic biomarkers of LMN degeneration in ALS. Additional understanding of the motor manifestations of disease is provided by motor unit number estimation, electrical impedance myography, and single-fiber EMG techniques. Dysfunction of UMN and non-motor brain areas is being increasingly assessed with transcranial magnetic stimulation, high-density electroencephalography, and magnetoencephalography; less common autonomic and sensory nervous system dysfunction in ALS can also be characterized. Although most of these techniques are used to explore the underlying disease mechanisms of ALS in research settings, they have the potential on a broader scale to noninvasively identify disease subtypes, predict progression rates, and assess physiologic engagement of experimental therapies.

Physical Activity Monitoring in Children in the 1-Year After 3 or More Days of Invasive Ventilation: Feasibility of Using Accelerometers.

To measure physical activity in a cohort of children who survived greater than or equal to 3 days of invasive ventilation. Prospective cohort study (2018-2021). Quaternary children's hospital PICU. Children (2-17 yr old) without a preexisting tracheostomy who were ambulatory pre-illness and received greater than or equal to 3 days of invasive ventilation. None. We measured duration and intensity of physical activity using hip- (< 6 yr old) or wrist- (≥ 6 yr old) worn ActiGraph GT3XP-BTLE accelerometers (ActiGraph, Pensacola, FL) for 7 days at three timepoints: hospital discharge, 3 months, and 12 months post-discharge. We measured duration of moderate or vigorous physical activity (MVPA) and nonsedentary activity, both characterized as percent of total awake wear time and total minutes per day. We categorized participants based on when they first attained a "high activity" day defined as greater than or equal to 60 minutes of MVPA or a day with percent of MVPA in the top quartile of all days measured. We evaluated 55 children of whom 43 (78%) had data from greater than or equal to 1 timepoint including 19 (35%) with data from all timepoints. Maximum daily MVPA increased across the three post-discharge timepoints (median, 16.0 min [interquartile range (IQR), 8.0-42.8 min], 48.3 min [27.8-94.3 min], and 68.4 min [34.7-111.0 min], respectively) as did maximum daily percent of awake wear time in MVPA (median, 4.3% [IQR, 2.8-9.0%], 10.1% [5.7-14.4%], and 11.1% [7.1-17.5%], respectively). Of the 43 participants, 27 achieved a high activity day: nine of 43 during the hospital discharge period, 14 of 43 during the 3 months post-discharge period, and four of 43 during the 12 months post-discharge period; 16 of 43 did not demonstrate high activity during the post-discharge year. In the 1-year after PICU discharge measuring physical activity with accelerometers in children 2-17 years old is feasible. Furthermore, demonstration of variable recovery trajectories in our pilot cohort suggests it has potential to be an outcome measure in clinical trials.

Mastering the Sequential Organ Failure Assessment Score: Critical Choices of Score Statistic, Timing, Imputations, and Competing Risk Handling in Major Trials-A Systematic Review.

The Sequential Organ Failure Assessment (SOFA) score originated as a tool for assessing organ dysfunction in critical illness but has expanded to become an outcome measure in clinical trials. We aimed to assess how the SOFA score was used as the primary or secondary endpoint of major randomized controlled trials (RCTs). Independent reviewers searched MEDLINE/PubMed, Scopus, and Embase databases. Articles were selected when they fulfilled: 1) RCT; 2) SOFA score was primary or secondary endpoint; and 3) published in the Lancet, New England Journal of Medicine, or Journal of the American Medical Association. Data collection included study details, outcomes, statistical differences in SOFA score, choice of score statistics, timepoints of SOFA reporting, and how missing data and competing risks analysis were managed. Twenty-three RCTs had SOFA score as outcome measure, eight used it as primary endpoint. Daily maximum SOFA was the key statistic in 11 RCTs, delta SOFA was used in eight, and mean SOFA in four. Mean SOFA was most frequently chosen as primary endpoint (4/8, 50%). There were 18 different outcome assessment timepoints, ranging from 1 to 28 days. Three RCTs reported statistically significant difference in SOFA between groups. Handling of missing SOFA scores was not described in ten of 23 RCTs. When described, it varied from study to study with variable imputation methods and variable accounting for the competing risk of mortality and ICU discharge. There is major variability in the choice of summary statistic for SOFA score analysis and assessment timepoints, when using it as outcome measure in RCTs. There was either no information or great variability in the handling of missing values, use of imputation, and accounting for competing risk. The current use of SOFA scores in RCTs lacks sufficient reproducibility and statistical and methodological robustness.

Montreal cognitive assessment as a cognitive outcome measure in progressive supranuclear palsy.

The Montreal Cognitive assessment (MoCA) is a well-validated global cognitive screening instrument. Its validity in progressive supranuclear palsy (PSP) has not been assessed. To evaluate the MoCA as an outcome measure in PSP clinical trials. Cognitive data from 162 participants in the placebo arm of the Biogen PASSPORT study (NCT03068468) were analyzed using linear mixed-effects modeling (LMM) and repeated measures correlation. There was a significant decline in the MoCA score over time of -1.4 (95% CI -0.84 to -1.97) points over a 48-week period (p < 0.0001). Small but significant changes (p < 0.01) were observed in all MoCA domains except abstraction. The MoCA correlated weakly with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) over time (r rm = 0.1, p = 0.02) but exhibited a stronger correlation with the PSP Rating Scale (PSPRS) (r rm = -0.25, p < 0.0001). The MoCA appears to have limited sensitivity in capturing cognitive decline in PSP.

Longitudinal Quantitative MRI Provides Responsive Outcome Measures for Early and Late Muscle Changes in ALS.

Studies have demonstrated the potential of muscle MRIs to measure disease progression in ALS. However, the responsiveness and utility of quantitative muscle MRIs in an ALS clinical trial remain unknown. This study aimed to determine the responsiveness of quantitative muscle MRIs to measure disease progression in ALS. Longitudinal quantitative muscle MRIs were obtained in an ALS study that delivered human neural progenitor cells to the spinal cord (NCT02943850). Participants underwent MRIs at baseline, 1, 3, 6, 9, and 12 months. MRI measures included fat fraction (ff), water T2 (T2m), cross-sectional area (CSA), and remaining muscle area (RMA). Non-MRI measures included strength via Accurate Test of Limb Isometric Strength (ATLIS) and the ALSFRS-R. Standardized response means (SRM) were calculated at 1, 3, 6, and 12 months. Significant increases in muscle FF and decreases in CSA and RMA were seen as early as 1 month from baseline. At 6 months, the most responsive measures were muscle FF (SRMthigh = 1.85, SRMcalf = 1.39), T2m (SRMthigh = 1.2, SRMcalf = 1.71), CSA (SRMthigh = -1.58, SRMcalf = -1.14), RMA (SRMthigh = -1.77, SRMcalf = -1.28), and strength tested via ATLIS (SRMknee extension = -1.79, SRMknee flexion = -1.3). The ALSFRS-R was the least responsive at 6 months (SRM = -0.85). Muscle FF and T2m correlated with ALSFRS-R leg subscores and MRI measures demonstrated varying degrees of correlation with strength. High responsiveness and low variability make quantitative muscle MRI a novel and complementary outcome measure for ALS clinical trials.

Ranked Importance of Visual Function Outcome Measures in Choroideremia Clinical Trials.

Clinical trials of novel therapies for choroideremia require robust and clinically meaningful visual function outcome measures. Best-corrected visual acuity (BCVA) is mostly insensitive to changes in disease state, until late stages, and hence also to potential therapeutic gains after gene therapies. While the insensitivity of BCVA as an effective outcome measure is common wisdom, its low importance has not been rigorously demonstrated in the literature. This work uses statistical techniques to rank the relative importance of potential functional outcome measures in choroideremia. Retrospective dominance analysis was performed on data from a longitudinal interventional clinical trial performed at the Oxford Eye Hospital. Functional data from the untreated eye were analyzed and correlated with an anatomic measure of disease progression in the form of blue fundus autofluorescence area of the surviving outer retinal island. Each functional measure was then ranked in terms of variable importance. Microperimetry was the functional measure ranking first in terms of variable importance, followed by time since baseline visit, Pelli-Robson contrast sensitivity, high spatial frequency contrast sensitivity function, and low luminance visual acuity. Early Treatment Diabetic Screening chart BCVA under standard lighting conditions was ranked lowest among the panel of test modalities. Clinical trials in choroideremia for early and mid-stage disease would be justified in moving away from using standard BCVA as a clinical trial outcome measure as we have shown its sensitivity to be relatively low compared to microperimetry. We have also demonstrated how functional measures rank in terms of importance.

Caregiver perspectives enable accurate diagnosis of neurodegenerative disease.

The history from a relative or caregiver is an important tool for differentiating neurodegenerative disease. We characterized patterns of caregiver questionnaire responses, at diagnosis and follow-up, on the Cambridge Behavioural Inventory (CBI). Data-driven multivariate analysis (n=4952 questionnaires) was undertaken for participants (n=2481) with Alzheimer's disease (typical/amnestic n=543, language n=50, and posterior cortical n=50 presentations), Parkinson's disease (n =740), dementia with Lewy bodies (n=55), multiple system atrophy (n=55), progressive supranuclear palsy (n=422), corticobasal syndrome (n =176), behavioral variant frontotemporal dementia (n=218), semantic (n=125) and non-fluent variant progressive aphasia (n=88), and motor neuron disease (n=12). Item-level support vector machine learning gave high diagnostic accuracy between diseases (area under the curve mean 0.83), despite transdiagnostic changes in memory, behavior, and everyday function. There was progression in CBI subscores over time, which varied by diagnosis. Our results highlight the differential diagnostic information for a wide range of neurodegenerative diseases contained in a simple, structured collateral history. We analyzed 4952 questionnaires from caregivers of 2481 participants with neurodegenerative disease. Behavioral and neuropsychiatric manifestations of neurodegenerative disease had overlapping diagnostic boundaries. Simple questionnaire response patterns were sufficient for accurate diagnosis of each disease. We reinforce the value of a collateral history to support a diagnosis of dementia. The Cambridge Behavioural Inventory is sensitive to change over time and suitable as an outcome measure in clinical trials.

Determinants of long‐term paramagnetic rim lesion evolution in people with multiple sclerosis

AbstractObjectiveBaseline paramagnetic rim lesion (PRL) load predicts disease progression in people with multiple sclerosis (pwMS). Understanding how PRLs relate to other known MS‐related factors, and the practical utility of PRLs in clinical trials, is crucial for informing clinical decision‐making and guiding development of novel disease‐modifying treatments (DMTs).MethodsThis study included 152 pwMS enrolled in a larger prospective, longitudinal cohort study who had 3T MRI scans and clinical assessments at baseline and 5‐ or 10‐year follow‐ups. PRLs were identified on baseline 3T quantitative susceptibility maps and classified as persisting, disappearing, or newly appearing at follow‐up. The relationships between PRL evolution and clinical, radiological, environmental, and genetic characteristics were assessed, and clinical trial sample sizes were estimated using PRL appearance or disappearance as outcome measures.ResultsDMT use was associated with lower odds of new PRL appearance (for high‐efficacy DMTs: odds ratio = 0.088, p = 0.024), but not disappearance. Current smoking status was associated with greater baseline PRL number (B = 0.527 additional PRLs, p = 0.013). A 24‐month clinical trial in people with progressive MS for a DMT that doubles the rate of PRL rim disappearance would require an estimated 118 people with progressive MS per group at 80% statistical power.InterpretationEarly MS diagnosis and subsequent DMT initiation may reduce new chronic active inflammation. However, the utility of PRL disappearance or new PRL appearance as outcome measures in clinical trials is limited by potentially large sample sizes that are needed for moderate efficacy drugs.

Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease.

Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals. Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 22[95%CI 13,46], cortical PIB 32[20,57], CSF p-tau181 58[40,112]) for a four-year trial to have 80% power (5% statistical significance) to detect a 25% reduction in absolute levels of pathology, allowing 40% dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50% reduction in rate of change. Sample sizes ranged from 75-250 (examples precuneus volume: 137[80,284], cortical FDG: 256[100,1208], CDR-SB: 161[102,291]). Despite the rarity of ADAD, clinical trials with feasible sample sizes given the number of cases appear possible.

Evaluation of a six-minute walk test in the DE50-MD canine model of Duchenne muscular dystrophy and its effect on blood-borne biomarkers

Background Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by mutations in the dystrophin gene resulting in cycles of muscle degeneration, inflammation and regeneration. The 6-minute walk test (6MWT) is a key functional outcome measure for DMD patient clinical trials and has been adapted for use in animal models of the disease. The DE50-MD dog model of DMD closely reflects the DMD patient phenotype prior to loss of ambulation. For pre-clinical trials using this model, functional outcome measures must be established. Methods This longitudinal study compared distance walked in a 6MWT by DE50-MD and WT control dogs and assessed the utility of the 6MWT as a functional biomarker. Dogs underwent two 6MWTs conducted approximately 48-hours apart, at 3, 6, 9, 12, 15 and 18 months of age. In addition, we evaluated the stability of selected blood-borne biomarkers in 12-month old DE50-MD and WT dogs 0, 3, 6, 24 and 48 hours following a 6MWT. Results DE50-MD dogs exhibited significantly shorter 6-minute walk distance (6MWD) than WT dogs at all timepoints (P&lt;0.05), with no difference in 6MWD between the first and second 6MWT. C-C motif chemokine ligand 2 (CCL2), myomesin-3 (MYOM3) and myostatin (MSTN) were biomarkers of the DE50-MD phenotype that remained unchanged in DE50-MD dogs following the 6MWT, while creatine kinase (CK) activity significantly increased 3-hours following the test in DE50-MD dogs but remained unchanged in WT dogs. Conclusions The 6MWT effectively discriminates DE50-MD from WT dogs aged 3-18 months and a single 6MWT is sufficient for future studies. Serum MYOM3, CCL2 and MSTN are good biomarkers of the DE50-MD phenotype that are unaffected by this relatively low level exertion.

Patient-Reported Outcomes in RLBP1 Retinal Dystrophy: Longitudinal Assessment in a Prospective Natural History Study.

To evaluate the performance of two non-disease-specific patient-reported outcome (PRO) instruments, the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) and the Low Luminance Questionnaire (LLQ), in patients with retinaldehyde-binding protein 1 retinal dystrophy (RLBP1 RD). PROs were assessed using the VFQ-25 and LLQ. Rasch analysis was conducted to estimate person and item measures of the VFQ-25 and LLQ questionnaires to determine the association between the two PROs. In addition, the association between these two instruments and their correlations to weighted measures of visual function and disease progression were analyzed in this three-year PRO-focused sub-study of a five-year prospective natural history study. Forty-two patients participated, with most of them having completed at least two PRO follow-up visits at least one year apart. The mean VFQ-25 scores were lowest for distance activities (39.2-49.0) and peripheral vision (37.5-52.4), with mean LLQ subscale scores generally low (<41), except for the emotional distress subscale. Using Rasch analysis, calibrated item and person measures along with their standard errors were estimated for both ePROs. This indicated that the distribution of the VFQ-25 and LLQ item measures well covered the distribution of person function in this group. This suggests that the item difficulties well cover the person-level performance in this population. As well, the two PROs showed a strong and significant correlation at all assessed time points as assessed with Pearson correlation coefficient (0.81, 0.91, 0.81 and 0.87 at baseline, 1/1.5, 2/2.5 (P < 0.001) and 3/3.5 years (P = 0.002)). The composite scores of both PRO questionnaires strongly correlated with clinical measures of visual function. At 2 to 2.5 years of follow-up, meaningful statistically significant declines in peripheral vision (both VFQ-25 and LLQ), distance vision (VFQ-25), and extreme lighting in dark and bright light (LLQ) subscales were noted. This study demonstrated a strong association between VFQ-25 and LLQ scores and their association with clinical measures of visual function. PRO instruments can provide insights into the specific disabilities of this unique patient population and help to guide appropriate outcome measures for future clinical trials.

Quantifying neurobehavioral profiles across neurodevelopmental genetic syndromes and idiopathic neurodevelopmental disorders.

To examine neurobehavioral findings in three genetic syndromes (PTEN hamartoma tumor syndrome, Malan syndrome [mutations in the NFIX gene], and SYNGAP1-related disorder), a mixed group of other neurodevelopmental genetic syndromes (NDGS), idiopathic neurodevelopmental disorder, and neurotypical control participants. Using a longitudinal case-control design, caregivers reported neurobehavioral information for 498 participants (PTEN hamartoma tumor syndrome n = 112, Malan syndrome n = 24, SYNGAP1-related disorder n = 47, other NDGS n = 72, idiopathic neurodevelopmental disorder n = 54, neurotypical siblings n = 74, and unrelated neurotypical control participants n = 115) at three timepoints (baseline, and 1-month and 4-month follow-ups) using the online-administered Neurobehavioral Evaluation Tool (NET). NET scales had good scale and test-retest reliability. Unique patterns of neurobehavioral findings emerged, with SYNGAP1-related disorder and Malan syndrome showing generally more severe symptom and skill patterns than for other groups of patients. Patterns could be partly accounted for by estimated cognitive level, speech level, and the presence of autism spectrum disorder. However, even when accounting for these factors, group differences remained. Reliable change indices are reported. Genetic syndromes associated with neurodevelopmental disorders present with unique neurobehavioral profiles that can inform selection of outcome measures in future clinical trials. The NET may be a useful screening and monitoring instrument in clinical practice, where frequent in-person clinic attendance is difficult for many patients.

A scoping review of outcome measures in ovarian cancer clinical trials. J Clin Exp Reprod Med.2024;1(1):26-39.

A scoping review of outcome measures in ovarian cancer clinical trials. J Clin Exp Reprod Med.2024;1(1):26-39.

Longitudinal Assessment of Structural and Functional Changes in Rod-cone Dystrophy: A 10-year Follow-up Study

Emerging clinical trials for inherited retinal disease (IRD) require an understanding of long-term progression. This longitudinal study investigated the genetic diagnosis and change in retinal structure and function over 10 years in rod-cone dystrophies (RCDs). Longitudinal observational follow-up study. Individuals initially diagnosed with retinitis pigmentosa who underwent baseline assessment between 2010 and2013. Baseline and follow-up assessments included best-corrected visual acuity (VA), Goldmann visual field (GVF) perimetry, spectral-domain OCT imaging, electroretinogram, and panel-based genetic testing. Linear mixed models were used to investigate disease progression and interaction between progression rate and baseline measurement. Interocular symmetry in disease progression was assessed using intraclass correlation coefficients (ICCs). Change in VA, GVF area, and ellipsoid zone (EZ) width over 10 years in RCD. A total of 23 participants attended follow-up (mean age 63±15 years at follow-up; 48% female), with 20 classified as having RCD and 3 reclassified as having cone-rod dystrophy based on genetic diagnosis. At 10-year follow-up, only 60% of RCD participants showed progression of ≥15 letters in either or both eyes, and 40% did not meet the criteria in either eye. Between the eye with poorer versus better VA at baseline, high symmetry in disease progression was observed for GVF area (ICC=0.87; 95% confidence interval [CI]: 0.68-0.95), and moderate interocular symmetry in disease progression was observed for VA (ICC=0.50 [95%CI: 0.07-0.77]) and EZ width (ICC=0.64 [95% CI: 0.25-0.85]). Baseline values influenced progression for VA and percentage change in GVF area, whereas total percentage change in EZ width did not differ across baseline values. Many individuals with RCD did not have a significant 15-letter decline in VA over a 10-year follow-up, highlighting the challenges of relying on VA as a measure of disease progression. Symmetry between eyes varies, emphasizing a key consideration for selection of outcome measures in IRD clinical trials. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Improving care for amyotrophic lateral sclerosis with artificial intelligence and affective computing

BackgroundPatients with ALS often face difficulties expressing emotions due to impairments in facial expression, speech, body language, and cognitive function. This study aimed to develop non-invasive AI tools to detect and quantify emotional responsiveness in ALS patients, providing objective insights. Improved understanding of emotional responses could enhance patient-provider communication, telemedicine effectiveness, and clinical trial outcome measures. MethodsIn this preliminary exploratory study, fourteen patients with ALS had audio recordings performed during routine clinic visits while wearing a wireless pulse oximeter. Emotion-triggering questions related to symptom progression, breathing, mobility, feeding tube, and financial burden were randomly asked. The same questions were posed in separate psychiatric evaluations. Natural language processing (NLP) was used to analyze transcriptions, topic classifications, sentiment, and emotional states, combining pulse and speech data. AI-generated reports summarized the findings. ResultsPulse alterations consistent with emotional arousal were identified, with longer consultations and positive communication reducing pulse fluctuations. Financial concerns triggered the strongest emotional response, while discussions about breathing, mobility, and feeding tube increased anxiety. AI-generated reports prioritized patient concerns and streamlined documentation for providers. ConclusionsThis study introduces a novel approach to linking pulse and speech analysis to evaluate emotional responses in ALS patients. AI and affective computing provide valuable insights into emotional responses and disease progression, with potential applications for other neurological disorders. This approach could augment clinical trial outcomes by offering a more comprehensive view of patient well-being.

Two-stage group-sequential designs with delayed responses – what is the point of applying corresponding methods?

BackgroundIn group-sequential designs, it is typically assumed that there is no time gap between patient enrollment and outcome measurement in clinical trials. However, in practice, there is usually a lag between the two time points. This can affect the statistical analysis of the data, especially in trials with interim analyses. One approach to address delayed responses has been introduced by Hampson and Jennison (J R Stat Soc Ser B Stat Methodol 75:3-54, 2013), who proposed the use of error-spending stopping boundaries for patient enrollment, followed by critical values to reject the null hypothesis if the stopping boundaries are crossed beforehand. Regarding the choice of a trial design, it is important to consider the efficiency of trial designs, e.g. in terms of the probability of trial success (power) and required resources (sample size and time).MethodsThis article aims to shed more light on the performance comparison of group sequential clinical trial designs that account for delayed responses and designs that do not. Suitable performance measures are described and designs are evaluated using the R package rpact. By doing so, we provide insight into global performance measures, discuss the applicability of conditional performance characteristics, and finally whether performance gain justifies the use of complex trial designs that incorporate delayed responses.ResultsWe investigated how the delayed response group sequential test (DR-GSD) design proposed by Hampson and Jennison (J R Stat Soc Ser B Stat Methodol 75:3-54, 2013) can be extended to include nonbinding lower recruitment stopping boundaries, illustrating that their original design framework can accommodate both binding and nonbinding rules when additional constraints are imposed. Our findings indicate that the performance enhancements from methods incorporating delayed responses heavily rely on the sample size at interim and the volume of data in the pipeline, with overall performance gains being limited.ConclusionThis research extends existing literature on group-sequential designs by offering insights into differences in performance. We conclude that, given the overall marginal differences, discussions regarding appropriate trial designs can pivot towards practical considerations of operational feasibility.

Study protocol for the iMarkHD study in individuals with Huntington's disease

Background: Huntington's disease (HD) is still often defined by the onset of motor symptoms, inversely associated with the size of the CAG repeat expansion in the huntingtin gene. Although the cause of HD is known, much remains unknown about mechanisms underlying clinical symptom development, disease progression, and specific clinical subtypes/endophenotypes. Objective: In the iMarkHD study, we aim to investigate four discrete molecular positron emission tomography (PET) tracers and magnetic resonance imaging (MRI) markers as biomarkers for disease and symptom progression. Methods: Following MRI optimization in five healthy volunteers (cohort 1), we aim to recruit 108 participants of whom 72 are people with HD (PwHD) and 36 healthy volunteers (cohort 2). Pending interim analysis, these numbers could increase to 96 PwHD and 48 healthy controls. Participants will complete a total of 10 study visits, consisting of a screening visit followed by a clinical and MRI visit and PET visits at baseline, year 1, and year 2. PET targets include the cannabinoid 1, histamine 3, and serotonin 2A receptors, and phosphodiesterase 10A, whereas MRI will be multimodal, including, but not limited to, the assessment of cerebral blood flow, functional connectivity, and brain iron. Results: Recruitment is currently active and started in September 2022. Conclusions: By combining PET and multi-modal MRI assessments we expect to provide a comprehensive examination of the molecular, functional, and structural framework of HD progression. As such, the iMarkHD study will provide a solid base for the identification of treatment targets and novel outcome measures for future clinical trials.

Disease-modifying therapies for Parkinson disease: lessons from multiple sclerosis.

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide onlysymptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs.

Patient-reported assessments of chronic cough in clinical trials: accessory or primary endpoints?

Chronic cough is a complex disorder that affects up to 5-10% of the general population. It can be challenging to manage as there are few effective treatments, although several novel antitussives are in clinical development. The endpoints used to assess their efficacy in clinical trials should be optimal; most large clinical trials currently use objective measures as the primary outcome, especially cough frequency. There are strengths in this approach, although taking the view that other measures of chronic cough are less important, including patient-rated cough severity, psychosocial impact and other associated symptoms. Patient-reported outcome measures (PROMs) explore patients' personal experiences of health and disease, and the effects of particular conditions on their lives. Numerous validated PROMs exist for chronic cough, from simple visual analogue scales, to those that focus on cough hypersensitivity and cough-specific quality of life. Medicine regulators in the European Union (EU) and United States of America (USA) encourage the use of PROMs in clinical trials but have voiced concerns over their content validity, clinically meaningful thresholds for change, and discordance with objective measures. There are recent and ongoing studies to address these limitations. This review discusses currently available PROMs used to assess chronic cough and discusses their potential role as primary outcome measures in clinical trials.

Exploring Scotopic Microperimetry as an Outcome Measure in Choroideremia.

Choroideremia is an X-linked outer retinal degeneration. Early symptoms include nyctalopia and progressive visual field loss, but visual acuity is preserved until late disease stages. Dark-adapted two-color fundus-controlled perimetry (also known as scotopic microperimetry) has been developed to enable spatial assessment of rod and cone photoreceptor function. This study explores the use of scotopic microperimetry in patients with choroideremia. Twenty patients with choroideremia and 21 age-matched healthy controls completed visual acuity and scotopic microperimetry testing, which used the Scotopic Macular Integrity Assessment (S-MAIA) microperimeter. A subset of participants completed repeat scotopic testing to enable Bland-Altman repeatability analyses. Test reliability was assessed using fixation stability, fixation losses, and assessment of the rod-free zones. Pointwise sensitivity, mean sensitivity, and volume sensitivity indices were analyzed. False positive responses were the main source of poor test reliability, indicated by stimuli responses in the physiological blind spot and lack of rod-free mapping. Scotopic cyan and red sensitivities were significantly reduced in choroideremia participants (n = 17) compared to healthy controls (n = 16) (P < 0.01, Mann-Whitney U test). Scotopic cyan sensitivity was statistically lower than scotopic red sensitivity in both healthy controls and choroideremia (P < 0.01, Wilcoxon signed rank test). Interpretation of scotopic cyan-red differences should be used with caution due to high test-retest variability. Scotopic microperimetry could be a useful outcome measure in patients with early choroideremia. Careful selection of test grid design and sensitivity indices is required. Scotopic microperimetry may be a useful outcome measure in clinical trials for patients with early stage choroideremia.