Primary Outcome In Clinical Trials Research Articles

Sex and gender reporting in UK emergency medicine trials from 2010 to 2023: a systematic review

BackgroundFemale participants are underrepresented in randomised control trials conducted in urgent care settings. Although sex and gender are frequently reported within demographic data, it is less common for primary outcomes...

Composite end points and competing risks analysis.

Composite end points are common primary outcomes in clinical trials. Their main benefit of utilizing a composite outcome is increasing the number of primary outcome events, meaning fewer participants are required to deliver an adequately powered trial. By combining multiple important end points in the primary outcome rather than having to select only 1, composite end points potentially make clinically meaningful benefits easier to detect and avoid ranking outcomes hierarchically. However, there are a number of important considerations when designing and interpreting clinical trials that utilize composite end points. In this Statistical Primer, issues with composite end points such as competing events, halo effect, risk of bias, time-to-event limitations and the win ratio are discussed in the context of real world clinical trials.

Novel Method to Assess Treatment Effcacy in Preclinical Peripheral Arterial Disease Studies

Background: Peripheral arterial disease (PAD), a condition caused by atherosclerotic narrowing or occlusion of blood vessels in the lower extremities, affects ~200 million adults globally and lacks effective treatment options to improve limb function. Cilostazol is the only approved pharmacological treatment option for PAD patients, but its effect on walking performance is modest and the drug is not widely used clinically. Over the past several decades, numerous therapies (drug, gene, and cell-based) have shown promise in the preclinical setting but failed to achieve primary outcomes in clinical trials. While the failure of therapeutic translation is complex, most preclinical studies have employed perfusion recovery as a primary outcome variable whereas most clinical trials in PAD patients employ the six-minute walk test. Although perfusion is an important contributor to limb function and walking performance, assessing preclinical therapeutics solely via perfusion recovery may be a flawed approach. Objective: To address the need for a more comprehensive method to assess the effcacy of preclinical PAD therapeutics, we aimed to develop a protocol to assess hindlimb function that incorporates assessment of muscle power and perfusion across a six-minute testing period. Methods: To assess muscle contractile performance, the tibialis anterior or plantarflexor muscles were carefully exposed and the distal tendon mounted to the force-length controller (Aurora Scientific) and the muscles were stimulated via the sciatic nerve in anesthetized C57BL6 mice. After obtaining isometric forces, a six-minute functional test was performed using repeated isotonic (shortening) contractions against a submaximal load (30% or 45% of the reference force). Muscle fatigue was measured as a change in power across the testing period. Throughout the test, laser Doppler flowmetry was used to measure muscle blood flow. Hindlimb ischemia was used as an experimental model of PAD. Results: In healthy mice without PAD, the test produced the expected dose-dependent relationship between fatigue and workload with contractions performed at 30% of the reference force having less fatigue compared to 45% of the reference force ( P=0.0051), without a significant difference in muscle blood flow between the conditions. Compared the mice that received a sham surgery, those subjected to hindlimb ischemia displayed significantly lower maximal isometric forces (1514 ± 118 mN vs. 880 ± 85 mN, P=0.0001) and power at 35% maximal force (280 ± 12 vs. 105 ± 46 watts/kg, P=0.0002). Whereas sham mice lost ~25% power across the six-minute test, HLI mice displayed a ~70% loss of power. Regarding muscle blood flow, sham mice increased blood flow ~250% whereas HLI mice were only able to increase blood flow to ~105% ( P<0.001). Conclusions: This newly developed protocol successfully combines isotonic muscle function and limb perfusion assessments in the hindlimb of mice and can detect differences between healthy and PAD mice. Future work is needed to fully evaluate the accuracy and sensitivity of this method to select therapeutics in preclinical PAD models. This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (T.E.R.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Minimal Clinically Important Change of Movement Pain in Musculoskeletal Pain Conditions

Movement pain, which is distinct from resting pain, is frequently reported by individuals with musculoskeletal pain. There is growing interest in measuring movement pain as a primary outcome in clinical trials, but no minimally clinically important change (MCIC) has been established, limiting interpretations. We analyzed data from 315 participants who participated in previous clinical trials (65 with chronic Achilles tendinopathy; 250 with fibromyalgia) to establish an MCIC for movement pain. A composite movement pain score was defined as the average pain (Numeric Rating Scale: 0–10) during 2 clinically relevant activities. The change in movement pain was calculated as the change in movement pain from pre-intervention to post-intervention. A Global Scale (GS: 1–7) was completed after the intervention on perceived change in health status. Participants were dichotomized into non-responders (GS ≥4) and responders (GS <3). Receiver operating characteristic curves were calculated to determine threshold values and corresponding sensitivity and specificity. We used the Euclidean method to determine the optimal threshold point of the Receiver operating characteristic curve to determine the MCIC. The MCIC for raw change in movement pain was 1.1 (95% confidence interval [CI]: .9–1.6) with a sensitivity of .83 (95% CI: .75–.92) and specificity of .79 (95% CI: .72–.86). For percent change in movement pain the MCIC was 27% (95% CI: 10–44%) with a sensitivity of .79 (95% CI: .70–.88) and a specificity of .82 (95% CI: .72–.90). Establishing an MCIC for movement pain will improve interpretations in clinical practice and research. PerspectiveA minimal clinically important change (MCIC) of 1.1- points (95% CI: .9–1.6) for movement pain discriminates between responders and non-responders to rehabilitation. This MCIC provides context for interpreting the meaningfulness of improvement in pain specific to movement tasks.

Red Blood Cell Deformability and Morphological Dynamic Sickling As a Metric to Monitor Pharmacodynamic Response to Voxelotor

The recent introduction of new therapies, such as hemoglobin (Hb) oxygen affinity modifiers, fetal Hb (HbF) inducers, and gene therapy (replacement of HbS with non-sickling Hb), that affect the Hb polymerization rate for sickle cell disease (SCD), highlight the need for new metrics to assess changes in sickling characteristics as therapeutic response. Primary outcomes in clinical trials often focus on indirect clinical improvement i.e. decrease in vaso-occlusive events (VOC), Hb increase, fatigue and pain score. There is currently a lack of direct biomarkers to assess the pharmacodynamic impact of these therapies. Two methods have been developed to assess downstream Hb polymerization, LoRRca (oxygenscan), a commercial oxygen gradient ektacytometry that measures deformability as a function of oxygen tension (pO 2), and dynamic sickling assay (DSA), an enzymatic oxygen scavenging system that directly assesses morphological sickling. In the present study, we investigate the relationship between red blood cell (RBC) deformability and kinetics of sickling morphology after a treatment with different doses of voxelotor (GBT440, Global Blood Therapeutics), the only FDA approved Hb oxygen modifier. Blood samples from eight SCD patients were collected following the IRB #041718MP2E &amp; IRB #Pro00066220 protocols. RBCs were incubated with voxelotor at five different doses based on sample hematocrit (Hct): 25% (0.32 ± 0.06 mM), 50% (0.65 ± 0.11 mM), 75% (0.97 ± 0.17 mM), 100% (1.29 ± 0.23 mM) and 125% (1.62 ± 0.28 mM), or with an equal volume of DMSO-containing buffer (vehicle). Oxygenscan is performed (LoRRca, RR Mechatronics, The Netherlands) as per manufacturer's instructions. The following parameters are calculated: i) elongation index (EImin), measured at minimum RBC deformability, ii) point of sickling (PoS), the pO 2 at which RBC deformability decreases below 5% of EImax during deoxygenation and iii) ΔEI, the difference between EImin and EImax. DSA uses an enzymatic reaction that allows for tight control of the rate and depth of hypoxia, resulting in RBC morphological changes observed through time-lapse photography. Sickling profiles were constructed to represent: i) morphological points of sickling at 50% of induced fraction (mPoS i@50%), ii) rate of sickling at 50% of induced fraction (rate i@50%) and iii) area under the curve at 15 minutes (AUC 15). Paired t-test analysis of the LoRRca elongation curves show a significant dose response in Elmin (Vehicle: 0.16 ± 0.16; 25%: 0.20 ± 0.16, p=0.0033; 50%: 0.23 ± 0.15, p=0.0001; 75%: 0.27 ± 0.15, p=0.0004; 100%: 0.30 ± 0.14, p=0.0009; 125%: 0.35 ± 0.13, p=0.0015), ΔEl (Vehicle: 0.26 ± 0.11; 25%: 0.22 ± 0.11, p=0.0016; 50%: 0.18 ± 0.11, p=0.0003; 75%: 0.15 ± 0.08, p=0.0002; 100%: 0.11 ± 0.06, p=0.0004; 125%: 0.09 ± 0.07, p=0.0011) and PoS (Figure 1; Vehicle: 35 ± 11 mmHg; 25%: 32 ± 6, p=0.0092; 50%: 28 ± 7, p=0.0038; 75%: 25 ± 6, p&amp;lt;0.0001; 100%: 17 ± 5, p=0.0007; 125%: 14 ± 4, p=0.0015). These findings indicate improvements in RBC deformability under hypoxic conditions when the drug is present. Furthermore, paired t-test of DSA data showed a significant dose response with AUC 15 (Vehicle: 958 ± 104; 25%: 909 ± 105, p=0.0061; 50%: 845 ± 146, p=0.0004; 75%: 768 ± 194, p=0.0014; 100%: 672 ± 179, p&amp;lt;0.0001; 125%: 623 ± 192, p=0.0002), rate i@50% (Vehicle: 0.87 ± 0.26; 25%: 0.77 ± 0.30, p=0.1236; 50%: 0.61 ± 0.29, p=0.0003; 75%: 0.33 ± 0.13, p&amp;lt;0.0001; 100%: 0.28 ± 0.10, p&amp;lt;0.0001; 125%: 0.25 ± 0.09, p=0.0004) and mPoS i@50% (Figure 2; Vehicle: 4.4 ± 0.7 minutes; 25%: 4.7 ± 0.9, p=0.0260; 50%: 5.0 ± 1.2, p=0.0407; 75%: 5.9 ± 1.7, p=0.0082; 100%: 7.0 ± 1.6, p=0.0002; 125%: 7.8 ± 1.8, p=0.0004). These results indicate a delay in morphological sickling due to drug treatment. Based on the results of our study there is a dose-dependent decrease in RBC deformability and in the kinetics of morphologic sickling based of DSA following voxelotor treatment. These two methods have demonstrated a comparable ability to assess downstream therapeutic effects on delaying/inhibiting HbS polymerization. The combination of these two unique properties, RBC deformability and morphology change, can possibly provide a comprehensive approach to describe the cellular level of phenotypes, which may predict SCD severity. With further development these complementary assays have the potential to become important tools for drug development and monitoring response to SCD therapies.

Gene Therapy in Hereditary Retinal Dystrophies: The Usefulness of Diagnostic Tools in Candidate Patient Selections.

Gene therapy actually seems to have promising results in the treatment of Leber Congenital Amaurosis and some different inherited retinal diseases (IRDs); the primary goal of this strategy is to change gene defects with a wild-type gene without defects in a DNA sequence to achieve partial recovery of the photoreceptor function and, consequently, partially restore lost retinal functions. This approach led to the introduction of a new drug (voretigene neparvovec-rzyl) for replacement of the RPE65 gene in patients affected by Leber Congenital Amaurosis (LCA); however, the treatment results are inconstant and with variable long-lasting effects due to a lack of correctly evaluating the anatomical and functional conditions of residual photoreceptors. These variabilities may also be related to host immunoreactive reactions towards the Adenovirus-associated vector. A broad spectrum of retinal dystrophies frequently generates doubt as to whether the disease or the patient is a good candidate for a successful gene treatment, because, very often, different diseases share similar genetic characteristics, causing an inconstant genotype/phenotype correlation between clinical characteristics also within the same family. For example, mutations on the RPE65 gene cause Leber Congenital Amaurosis (LCA) but also some forms of Retinitis Pigmentosa (RP), Bardet Biedl Syndrome (BBS), Congenital Stationary Night Blindness (CSNB) and Usher syndrome (USH), with a very wide spectrum of clinical manifestations. These confusing elements are due to the different pathways in which the product protein (retinoid isomer-hydrolase) is involved and, consequently, the overlapping metabolism in retinal function. Considering this point and the cost of the drug (over USD one hundred thousand), it would be mandatory to follow guidelines or algorithms to assess the best-fitting disease and candidate patients to maximize the output. Unfortunately, at the moment, there are no suggestions regarding who to treat with gene therapy. Moreover, gene therapy might be helpful in other forms of inherited retinal dystrophies, with more frequent incidence of the disease and better functional conditions (actually, gene therapy is proposed only for patients with poor vision, considering possible side effects due to the treatment procedures), in which this approach leads to better function and, hopefully, visual restoration. But, in this view, who might be a disease candidate or patient to undergo gene therapy, in relationship to the onset of clinical trials for several different forms of IRD? Further, what is the gold standard for tests able to correctly select the patient? Our work aims to evaluate clinical considerations on instrumental morphofunctional tests to assess candidate subjects for treatment and correlate them with clinical and genetic defect analysis that, often, is not correspondent. We try to define which parameters are an essential and indispensable part of the clinical rationale to select patients with IRDs for gene therapy. This review will describe a series of models used to characterize retinal morphology and function from tests, such as optical coherence tomography (OCT) and electrophysiological evaluation (ERG), and its evaluation as a primary outcome in clinical trials. A secondary aim is to propose an ancillary clinical classification of IRDs and their accessibility based on gene therapy's current state of the art. OCT, ERG, and visual field examinations were performed in different forms of IRDs, classified based on clinical and retinal conditions; compared to the gene defect classification, we utilized a diagnostic algorithm for the clinical classification based on morphofunctional information of the retina of patients, which could significantly improve diagnostic accuracy and, consequently, help the ophthalmologist to make a correct diagnosis to achieve optimal clinical results. These considerations are very helpful in selecting IRD patients who might respond to gene therapy with possible therapeutic success and filter out those in which treatment has a lower chance or no chance of positive results due to bad retinal conditions, avoiding time-consuming patient management with unsatisfactory results.

(123) Novel Low Intensity Shockwave Therapy Sham Delivery Method (Zero Energy) Assessed Objectively by Grayscale and Doppler Ultrasound Results

Abstract Introduction Most ED LiSWT studies use the IIEF as a primary outcome. While clinically relevant, the IIEF does not directly assess erectile tissue structure. To establish a more objective parameter, we investigated the estimation of hypoechoic area in grayscale ultrasound images of erectile tissue as an objective primary outcome for clinical trials assessing the efficacy of LiSWT. During erection, grayscale imaging of the penis demonstrates corpora cavernosa (CC) that is homogenous in healthy men and heterogeneous to varying degrees in men with ED. A critical aspect of using grayscale ultrasound is to determine that sham treatment reliably results in no significant improvement in erectile tissue structure. Other studies have used sham probes with cotton wadding or non-penetrable gel pads to dampen delivery of shockwave energy flux density, however a small amount of energy may still be delivered. We report a novel sham-controlled methodology in LiSWT RCT for ED. Objective To evaluate erectile tissue heterogeneity as an endpoint in LiSWT sham-controlled trials using grayscale analysis of percent hypoechoic regions in CC after sham delivery of zero energy flux density. Methods A single-blind, sham-controlled, randomized prospective study was performed in men with ED naïve to any kind of acoustic wave therapy. Those meeting inclusion/exclusion completed baseline assessments and were randomized to active or sham within each treatment arm. This interim sub-analysis only examined the sham group (n = 7). For each treatment, the shockwave device was already on in the exam room. When the subject was ready a curtain was suspended above his mid-section blocking the device, and noise cancelling headphones provided. When the probe was placed on the penis, a high-quality recording of shockwave sounds was activated for sham treatment. Twenty weeks after zero energy sham treatment, grayscale and DUS imaging using a 15.4 MHz probe under pharmacologic erection 3-4/4 hardness was performed before unblinding. Grayscale percent hypoechoic regions within the CC were assessed by computer-assisted histometry using Image J. (Fig 1) The IIEF was also administered to all patients at baseline and week 20. Grayscale data were analyzed by two-way repeated measures ANOVA. IIEF-EF scores and bloodflow values (PSV and EDV) were compared using the Wilcoxon matched-pairs signed rank test. Results Compared to baseline, there were no significant changes (p&amp;gt;0.7; see figure) at week 20 in hypoechoic area in the proximal, middle, and distal erect penile shaft. (Fig 2) Furthermore, there were no significant changes in PSV (p&amp;gt;0.15), EDV (p&amp;gt;0.2), or IIEF-EF (p&amp;gt;0.6) from baseline to week 20. Conclusions Using computer-assisted histometry to determine hypoechoic area in grayscale ultrasound images to assess penile erectile tissue heterogeneity, we demonstrated that a novel sham treatment protocol that ensures zero energy delivery does not change erectile tissue integrity. The lack of improvement in PSV, EDV, and IIEF-EF further support our findings with grayscale ultrasound. Future studies will assess the appropriateness of grayscale ultrasound image analysis as a primary endpoint in LiSWT clinical trials. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: TRT, Cynosure.

The effect of dichotomization of skewed adjustment covariates in the analysis of clinical trials

Baseline imbalance in covariates associated with the primary outcome in clinical trials leads to bias in the reporting of results. Standard practice is to mitigate that bias by stratifying by those covariates in the randomization. Additionally, for continuously valued outcome variables, precision of estimates can be (and should be) improved by controlling for those covariates in analysis. Continuously valued covariates are commonly thresholded for the purpose of performing stratified randomization, with participants being allocated to arms such that balance between arms is achieved within each stratum. Often the thresholding consists of a simple dichotomization. For simplicity, it is also common practice to dichotomize the covariate when controlling for it at the analysis stage. This latter dichotomization is unnecessary, and has been shown in the literature to result in a loss of precision when compared with controlling for the covariate in its raw, continuous form. Analytic approaches to quantifying the magnitude of the loss of precision are generally confined to the most convenient case of a normally distributed covariate. This work generalises earlier findings, examining the effect on treatment effect estimation of dichotomizing skew-normal covariates, which are characteristic of a far wider range of real-world scenarios than their normal equivalents.

A More Efficient Outcome for Alzheimer Disease Research: the Item Response Theory Based Score for the Clinical Dementia Rating (CDR®)

AbstractBackgroundCDR sum of boxes (CDR‐SB) is widely used as a primary outcome in Alzheimer disease (AD) research due to its reliability and accuracy. However, it is an ordinal rank measure instead of a continuous measure and therefore may not be able to capture subtle changes in cognition. Additionally, it weights each domain equally, without accounting for the patterns of the responses scores across CDR items. To generate a more optimal score, we developed a bi‐factor model based on the item response theory (IRT) which can account for different response pattern, item difficulty and discrimination level to provide an improved estimate of the dementia severity. We demonstrated the superiority of the IRT score in two independent cohorts.MethodBaseline item level CDR data from 2949 participants enrolled in the WashU Knight ADRC study were used to develop the IRT model. The best fitting IRT model was then applied to the longitudinal item level CDR data in both the Knight ADRC and DIAN‐TU‐001 (142 participants) studies to generate the IRT scores (a continuous measure) for each participant at each visit.ResultCorrelations between the CDR IRT score and SB were consistent at different visits (0.89 ∼ 0.92 for DIAN‐TU cohort, 0.92 ∼ 0.94 for Knight ADRC cohort). The IRT score had a much larger effect size (&gt; 60% for the DIAN‐TU cohort and &gt; 40% for the Knight ADRC cohort) than that of CDR‐SB when comparing converter to stable cognitively normal participants. For CDR‐SB of 0 group, the IRT score was significantly associated with some of the clinical/cognitive outcomes and biomarkers. For CDR‐SB &gt; 0 group, the IRT score had slightly higher correlations with other outcomes than CDR‐SB. The IRT score correlated better with the estimated age from dementia onset in the DIAN cohort. Using IRT score as the primary outcome in clinical trials could save 10% ∼ 30% of the sample size compared to that of using CDR‐SB.ConclusionThe CDR IRT score could potentially be used as a more efficient outcome in AD research to gain precision in detecting cognitive decline and improve power (or reduce sample size).

Predicting Fall Counts Using Wearable Sensors: A Novel Digital Biomarker for Parkinson's Disease.

People with Parkinson’s disease (PD) experience significant impairments to gait and balance; as a result, the rate of falls in people with Parkinson’s disease is much greater than that of the general population. Falls can have a catastrophic impact on quality of life, often resulting in serious injury and even death. The number (or rate) of falls is often used as a primary outcome in clinical trials on PD. However, falls data can be unreliable, expensive and time-consuming to collect. We sought to validate and test a novel digital biomarker for PD that uses wearable sensor data obtained during the Timed Up and Go (TUG) test to predict the number of falls that will be experienced by a person with PD. Three datasets, containing a total of 1057 (671 female) participants, including 71 previously diagnosed with PD, were included in the analysis. Two statistical approaches were considered in predicting falls counts: the first based on a previously reported falls risk assessment algorithm, and the second based on elastic net and ensemble regression models. A predictive model for falls counts in PD showed a mean R2 value of 0.43, mean error of 0.42 and a mean correlation of 30% when the results were averaged across two independent sets of PD data. The results also suggest a strong association between falls counts and a previously reported inertial sensor-based falls risk estimate. In addition, significant associations were observed between falls counts and a number of individual gait and mobility parameters. Our preliminary research suggests that the falls counts predicted from the inertial sensor data obtained during a simple walking task have the potential to be developed as a novel digital biomarker for PD, and this deserves further validation in the targeted clinical population.

European Leukemianet (ELN) Response Predicts Disease Progression but Not Thrombosis or Death in Polycythemia Vera (PV): An Analysis of a Multicenter Database

European Leukemianet (ELN) Response Predicts Disease Progression but Not Thrombosis or Death in Polycythemia Vera (PV): An Analysis of a Multicenter Database

Considerations regarding choice of primary outcome in clinical trials in deprescribing.

Considerations regarding choice of primary outcome in clinical trials in deprescribing.

ICU-free days as a more sensitive primary outcome for clinical trials in critically ill pediatric patients.

BackgroundOur objective was to assess the association between intensive care unit (ICU)‐free days and patient outcomes in pediatric prehospital care and to evaluate whether ICU‐free days is a more sensitive outcome measure for emergency medical services research in this population.MethodsThis study used data from a previous pediatric prehospital trial. The original study enrolled patients ≤12 years of age and compared bag‐valve‐mask‐ventilation (BVM) versus endotracheal intubation (ETI) during prehospital resuscitation. For the current study, we defined ICU‐free days as 30 minus the number of days in the ICU (range, 0–30 days) and assigned 0 ICU‐free days for death within 30 days. We compared ICU‐free days between the original study treatment groups (BVM vs ETI) and with the original trial outcomes of survival to hospital discharge and Pediatric Cerebral Performance Category (PCPC).ResultsMedian ICU‐free days for the BVM group (n = 404) versus ETI group (n = 416) was not statistically different: 0 ICU‐free days (interquartile range, 0–10) versus 0 (0–0), P = 0.219. Median ICU‐free days were greater for BVM group in 3 subgroups: foreign body aspiration 30 (0–30) versus 0 (0–21), P = 0.028; child maltreatment 0 (0–14.2) versus 0 (0‐0), P = 0.004; and respiratory arrest 25 (1–29) versus 7.5 (0–27.7), P = 0.015. In the original trial, neither survival nor PCPC demonstrated differences in all 3 subgroups—survival was greater with BVM for child maltreatment and respiratory arrest and favorable PCPC was greater with BVM for foreign body aspiration. Overall, in the current study, patients with more ICU‐free days also had greater survival to hospital discharge and more favorable PCPC scores.ConclusionsThis initial study of the association between ICU‐free days and patient outcomes during prehospital pediatric resuscitation appears to support the use of ICU‐free days as a clinical endpoint in this population. ICU‐free days may be more sensitive than either mortality or PCPC alone while capturing aspects of both measures.

Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington's Disease.

The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a multidimensional measure of progression in Huntington's disease (HD) being used as a primary outcome in clinical trials investigating potentially disease-modifying huntingtin-lowering therapies. Evaluating volumetric and structural connectivity correlates of the cUHDRS. One hundred and nineteen premanifest and 119 early-HD participants were included. Gray and white matter (WM) volumes were correlated with cUHDRS cross-sectionally and longitudinally using voxel-based morphometry. Correlations between baseline fractional anisotropy (FA); mean, radial, and axial diffusivity; and baseline cUHDRS were examined using tract-based spatial statistics. Worse performance in the cUHDRS over time correlated with longitudinal volume decreases in the occipito-parietal cortex and centrum semiovale, whereas lower baseline scores correlated with decreased volume in the basal ganglia and surrounding WM. Lower cUHDRS scores were also associated with reduced FA and increased diffusivity at baseline. The cUHDRS correlates with imaging biomarkers and tracks atrophy progression in HD supporting its biological relevance. © 2021 International Parkinson and Movement Disorder Society.

Imaging Outcomes in Clinical Trials of Treatments for Glaucoma

Currently, all therapies for glaucoma have been licensed based on their ability to lower intraocular pressure (IOP). However, the main outcome of interest to people with glaucoma is vision-related (VR) quality of life (QoL). Instruments measuring VR QoL are unlikely to be sensitive enough to function as the primary outcome for clinical trials,1 but they remain important as secondary outcomes to capture side-effects of treatment. Although lowering IOP has been shown to slow visual field (VF) loss,2 IOP is a far-removed surrogate for VR QoL in glaucoma.

Evidence supporting wound care end points relevant to clinical practice and patients' lives. Part 3: The Patient Survey.

The 2006 U.S. Food and Drug Administration Guidance for Industry emphasizes wound closure as the primary outcome for clinical trials in wound healing. Wound care professionals understand that complete wound healing is not always achievable when evaluating new treatments. FDA, Association for the Advancement of Wound Care, and Wound Healing Society are working collaboratively to identify scientifically achievable, clinically relevant, and patient-centered endpoints with sufficient support to serve as primary outcomes for clinical trials. The Opinion Survey from People with Wounds presented here addresses an important but understudied issue: the gap between clinician, healthcare insurance companies, government agencies, and patient perspectives regarding clinically meaningful and scientifically achievable primary endpoints for wound care. The survey, adapted from the clinician survey with adjustment for health literacy, was pilot tested and revised based on a limited number of patients in a single clinic. After central IRB approval, the on-line survey was administered in English and Spanish and submitted anonymously to a server with the cooperation of multiple wound clinics and societies. Four hundred and thirty-eight patients and caregivers from across the United States responded over a 10-month period. Based on this survey, the most valuable clinical endpoints were reduced infection, recurrence, and amputation. The most valuable quality of life outcomes were increased independence, reduced social isolation, and pain. The top five endpoints in terms of usefulness for measuring clinical trial success were time to heal, wound size, infection, recurrence, and pain. Narrative responses from wound patients emphasized the inability to perform activities of daily living and pain as major factors that impacted their daily lives. Engagement of patients in clinical trials and evaluation of potential treatments is critical to improving wound care. This survey provides insight into the needs of patients with wounds and provides a roadmap for structuring future clinical trials to better meet those needs.

Home monitoring for patients with ILD and the COVID-19 pandemic

Home monitoring for patients with ILD and the COVID-19 pandemic

Evidence-Based and Clinically Relevant Outcomes for Hemorrhage Control Trauma Trials.

To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia. A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators. An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability. For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.

Progression of Alzheimer's Disease by Self-Reported Cancer History in the Alzheimer's Disease Neuroimaging Initiative.

Cross-sectional studies suggest self-reported cancer history is associated with decreased risk of Alzheimer's disease (AD). However, little is known about how self-reported cancer affects longitudinal AD progression, the primary outcome in clinical trials and observational studies. To determine self-reported cancer history's effect on longitudinal AD progression in an observational study. We utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to evaluate progression to AD by self-reported all-cancer, breast, prostate, colorectal, or non-melanoma skin cancer history. Linear mixed effects models were used to examine baseline differences and rates of progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) by self-reported cancer history. Age at AD onset was examined using consensus clinical diagnoses with Cox proportional hazards regression. Among 1,271 participants, models revealed no significant differences in progression over time but did reveal significantly lower baseline ADAS-Cog score, indicating better cognition at a given age in those with self-reported cancer history. Cox models indicated those with self-reported cancer history had significantly later age of AD onset (HR: 0.67, 95% CI: 0.53-0.85) after adjustment for covariates. Participants with self-reported cancer history entered ADNI with better cognition and later age of AD onset, but progressed similarly to participants without such history, indicating differences in AD between those with and without self-reported cancer history emerge early in the disease course. Such differences in longitudinal progression by self-reported cancer history could affect AD trials and observational studies, given the current focus on early disease course. Further investigation is warranted with detailed longitudinal assessment of cancer and AD.

Clinical Trials of Adult Stuttering Treatment: Comparison of Percentage Syllables Stuttered With Self-Reported Stuttering Severity as Primary Outcomes.

Purpose In a companion paper, we found no statistical reason to favor percentage syllables stuttered (%SS) over parent-reported stuttering severity as a primary outcome measure for clinical trials of early stuttering. Hence, considering the logistical advantages of the latter measure, we recommended parent-reported stuttering severity for use as an outcome measure. The present report extends the prior analysis to a comparison of %SS with self-reported stuttering severity (SRSS) for use as an outcome measure in clinical trials of stuttering treatments for adults. Method We analyzed data from four randomized clinical trials for adults that incorporated %SS and SRSS data at prerandomization and at 6 months post randomization. We analyzed the distributions associated with the two measures, their agreement, and their estimates of effect sizes. Results The positively skewed distribution of %SS warrants much reservation about its value as a clinical trial outcome measure. This skew causes inherent instability because of spurious data associated with low scores, which occur commonly at the low end of such a distribution. This inherent instability is compounded by inherent problems with absolute reliability of %SS measures. These problems are reduced with the much more normal distribution of SRSS. Conclusions The logistical arguments in favor of SRSS apply similarly to adults as they do when parents report the stuttering severity of their children. However, there are statistical reasons to favor SRSS over %SS measures as a primary outcome of clinical trials with adult participants: SRSS has acceptable discriminant validity and a normal distribution, and it is less error prone than %SS. We recommend SRSS as a primary outcome for clinical trials of adults with stuttering.