Outcome Measure In Clinical Trials Research Articles

Measuring visual information gathering in individuals with ultra low vision using virtual reality

People with ULV (visual acuity ≤ 20/1600 or 1.9 logMAR) lack form vision but have rudimentary levels of vision that can be used for a range of activities in daily life. However, current clinical tests are designed to assess form vision and do not provide information about the range of visually guided activities that can be performed in daily life using ULV. This is important to know given the growing number of clinical trials that recruit individuals with ULV (e.g., gene therapy, stem cell therapy) or restore vision to the ULV range in the blind (visual prosthesis). In this study, we develop a set of 19 activities (items) in virtual reality involving spatial localization/detection, motion detection, and direction of motion that can be used to assess visual performance in people with ULV. We estimated measures of item difficulty and person ability on a relative d prime (d′) axis using a signal detection theory based analysis for latent variables. The items represented a range of difficulty levels (− 1.09 to 0.39 in relative d′) in a heterogeneous group of individuals with ULV (− 0.74 to 2.2 in relative d′) showing the instrument’s utility as an outcome measure in clinical trials.

An Explainable Spatial-Temporal Graphical Convolutional Network to Score Freezing of Gait in Parkinsonian Patients.

Freezing of gait (FOG) is a poorly understood heterogeneous gait disorder seen in patients with parkinsonism which contributes to significant morbidity and social isolation. FOG is currently measured with scales that are typically performed by movement disorders specialists (i.e., MDS-UPDRS), or through patient completed questionnaires (N-FOG-Q) both of which are inadequate in addressing the heterogeneous nature of the disorder and are unsuitable for use in clinical trials The purpose of this study was to devise a method to measure FOG objectively, hence improving our ability to identify it and accurately evaluate new therapies. A major innovation of our study is that it is the first study of its kind that uses the largest sample size (>30 h, N = 57) in order to apply explainable, multi-task deep learning models for quantifying FOG over the course of the medication cycle and at varying levels of parkinsonism severity. We trained interpretable deep learning models with multi-task learning to simultaneously score FOG (cross-validated F1 score 97.6%), identify medication state (OFF vs. ON levodopa; cross-validated F1 score 96.8%), and measure total PD severity (MDS-UPDRS-III score prediction error ≤ 2.7 points) using kinematic data of a well-characterized sample of N = 57 patients during levodopa challenge tests. The proposed model was able to explain how kinematic movements are associated with each FOG severity level that were highly consistent with the features, in which movement disorders specialists are trained to identify as characteristics of freezing. Overall, we demonstrate that deep learning models' capability to capture complex movement patterns in kinematic data can automatically and objectively score FOG with high accuracy. These models have the potential to discover novel kinematic biomarkers for FOG that can be used for hypothesis generation and potentially as clinical trial outcome measures.

External Validation of the IHS4-55 in a European Antibiotic-Treated Hidradenitis Suppurativa Cohort

Background: Previously, a new dichotomous outcome was developed, calculated as 55% reduction in the International Hidradenitis Suppurativa 4 (IHS4-55) score. It was validated in datasets of adalimumab and placebo-treated HS patients. External validation is an important aspect of clinical outcomes. Objectives: We aimed to externally validate the novel dichotomous IHS4-55 in a non-biologic treated dataset of HS patients. Methods: Data from a previously published European-wide prospective clinical study of antibiotic treatment of HS patients were used to assess the association of IHS4-55 achievement with individual reduction in inflammatory nodules, abscesses, and draining tunnels. Moreover, the associations between IHS4-55 positivity and achievement of the minimal clinically important differences (MCIDs) for Dermatology Life Quality Index (DLQI), Numerical Rating Scale (NRS) Pain, and NRS Pruritus were analyzed. Results: Data were obtained from 283 individual patients, of which 36.4% (103/283) were treated with clindamycin and rifampicin and 63.6% (180/283) with tetracyclines for 12 weeks. Achievers of the IHS4-55 demonstrated a significant reduction the counts of inflammatory nodules, abscesses, and draining tunnels (all p < 0.001). Additionally, IHS4-55 achievers had an odds ratio for achieving the MCID of DLQI, NRS Pain, and NRS Pruritus of 2.16 (95% CI 1.28–3.65, p < 0.01), 1.79 (95% CI 1.10–2.91, p < 0.05), and 1.95 (95% CI 1.18–3.22, p < 0.01), respectively. Conclusions: This study shows the external validity of the novel IHS4-55 by demonstrating a significant association between IHS4-55 achievement and a reduction in inflammatory lesion counts as well as achievement of MCIDs for DLQI, NRS Pain, and NRS Pruritus in an antibiotic-treated cohort. These findings support the use of the IHS4-55 as a novel primary outcome measure in clinical trials.

P814 Clinical trial design in Crohn’s disease: interpreting future endpoints based on post hoc analyses of the vedolizumab phase 3 trials GEMINI 2 and VISIBLE 2

Abstract Background Crohn’s disease (CD) is a chronic, relapsing–remitting disease characterized by inflammation of the gastrointestinal tract. Historically, the Crohn’s Disease Activity Index (CDAI) has been used to assess outcomes in clinical trials involving patients with CD. However, in contrast to the alignment of regulatory standards for trials in ulcerative colitis, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) differ regarding the most appropriate endpoint definitions for trials in CD. We examined how clinical remission endpoints in CD trials have evolved and conducted post hoc analyses of two vedolizumab trials, GEMINI 2 and VISIBLE 2, to understand how endpoint definitions influence clinical trial outcome measures of treatment efficacy. Methods Endpoint definitions of clinical remission in completed and ongoing phase 3 trials of advanced therapies in CD were extracted from published literature and ClinicalTrials.gov. Post hoc analyses of data from GEMINI 2 and VISIBLE 2 were conducted by measuring the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 as assessed by six endpoint definitions (A: stool frequency score [SFS] ≤ 2.8 and not worse than baseline score; B: SFS ≤ 3 and not worse than baseline score; C: abdominal pain score (APS) ≤ 1 and not worse than baseline score; D: SFS ≤ 2.8 and APS ≤ 1; E: SFS ≤ 3 and APS ≤ 1; F: CDAI ≤ 150) (Figure 1). Results Most phase 3 trials of advanced therapies in CD included a clinical remission endpoint that was defined by CDAI score: typically, CDAI &amp;lt; 150 or ≤ 150. However, several recent trials have also included a primary or secondary clinical remission endpoint defined using components of the CDAI score such as SFS and APS (Table 1). Post hoc analyses of GEMINI 2 and VISIBLE 2 revealed minimal change in %Δ for each of the new endpoint definitions tested compared with the primary analysis for each trial (Figure 1). Conclusion Objective measures, including patient-reported outcomes and components of the CDAI score such as SFS and APS, have been used to define clinical remission in recent CD trials. Despite differences in regulatory guidance for defining clinical remission, our post hoc analyses of GEMINI 2 and VISIBLE 2 reveal that the efficacy of vedolizumab, measured using a variety of endpoint definitions from recent CD trials, was similar to that previously reported using CDAI ≤ 150.

METHODS TO DERIVE A MODIFIED MAYO SCORE FROM ELECTRONIC HEALTH RECORDS DATA

Abstract BACKGROUND The modified Mayo Score (MMS), which consists of stool frequency, rectal bleeding, and endoscopic subscores, is the most commonly used method for measuring disease activity in Ulcerative Colitis (UC) patients. It is a standard outcome measure in clinical trials, and is recommended as a clinical trial endpoint by the US Food and Drug Administration. Each component has a score from 0-3; the total MMS ranges from 0 to 9. MMS is infrequently recorded in routine care, in part because it requires an endoscopic assessment. Real world data, including electronic health record (EHR) databases, are useful for studying longitudinal disease and treatment outcomes, but most EHR databases do not include Mayo scores. Building off the methods described by Rudrapatna et al., 2021, we calculated a derived MMS using data elements available in EHRs. METHODS Data were derived from the OM1 PremiOM UC Dataset (OM1, Boston, MA), a multisource real-world database with linked healthcare claims and EHR data on US patients with UC (2013-present). Each of the three subscores was extracted from clinical notes and endoscopy reports, either by automated natural language processing methods or by abstraction by a trained medical abstractor. Rectal bleeding and stool frequency scores occurring within 4 months before or up to 1 month after the endoscopic score were combined to calculate a MMS. Multiple MMSs could be calculated for each patient, but each component score could contribute to only one MMS. RESULTS Among 12,849 UC patients, only 38 had a full Mayo score recorded in their notes, and 1 had a modified Mayo recorded. After applying the above algorithm, we were able to calculate a derived MMS for 739 patients. 220 patients had &amp;gt; 1 score available. Figure 1 shows the distribution of derived MMSs. Patients with a MMS were younger and more likely to be Asian, more likely to be treated with biologic therapies and less likely to be treated with mesalamine compared with those who could not have a MMS calculated (Table 1). CONCLUSIONS A derived MMS can be calculated from data that may be recorded in the medical record. Further work to validate these measures against a gold standard should be considered, but was not feasible in the OM1 dataset due to the paucity of observed Mayo scores in EHR data. Increased emphasis on standardized collection of relevant information in EHR systems would further improve the availability of derived MMSs. The population for which a MMS can be derived may have more severe disease and more frequent interactions with the healthcare system as evidenced by higher proportion of patients prescribed biologic therapies. MMSs can be derived and used to describe UC patients and could potentially be used to study longitudinal changes in patient disease status and treatment effectiveness in settings where observed scores are not available.

METHODS TO DERIVE A CROHN'S DISEASE ACTIVITY INDEX FROM ELECTRONIC HEALTH RECORDS DATA

Abstract BACKGROUND The Crohn’s Disease Activity Index (CDAI) is currently the gold-standard for measuring disease activity in Crohn’s disease (CD) patients. It is the most commonly used outcome measure in clinical trials, however, due to the burden of completion, it is infrequently used in routine care. Real world data, including electronic health records (EHR), are useful for studying longitudinal disease and treatment outcomes in the real world, but most EHR databases do not include CDAI. Building off the methods presented by Rudrapatna et al. 2021, we calculated a derived CDAI using data elements available in EHRs. METHODS Data were derived from the OM1 PremiOM UC Dataset (OM1, Boston, MA), a multisource real-world database with linked healthcare claims and EHR data on US patients with CD (2013-present). Weight, body temperature and hematocrit were sourced from structured vital signs and laboratory data. Ideal body weight was calculated from height and gender using the Devine formula. Extraintestinal manifestations/complications were evaluated based on the presence or absence of ICD diagnosis codes for each condition. Abdominal mass was abstracted from clinical notes. Number of stools in the past 7 days, average daily abdominal pain, and general well being were extrapolated from single-day measures extracted from clinical notes rather than based on 7-day diaries. Each component value was multiplied by the weights outlined in Best et al. 1976. Components recorded within 4 months were added to calculate a derived CDAI. Multiple CDAIs could be calculated for each patient over time, but each component was allowed to contribute to only one CDAI score. RESULTS Among 13,159 CD patients, only 12 had a CDAI recorded in their notes. After applying the algorithm, we were able to calculate a derived CDAI for 1,378 patients. 489 patients had &amp;gt; 1 score derived. Figure 1 shows the distribution of derived CDAIs. Patients with a derived CDAI were younger and a higher proportion were treated with biologics and corticosteroids than those who could not have a CDAI calculated (Table 1). CONCLUSIONS A derived CDAI can be calculated from data that may be routinely recorded in EHRs. Efforts to standardize the collection of CDAI components in EHRs would further increase the availability of derived CDAIs. Further work to validate these derived scores against a gold standard and to replicate the findings in other real-world datasets should be considered. Validation was not feasible in this dataset due to the lack of recorded CDAIs. Derived CDAIs could potentially be used to study longitudinal changes in disease status and treatment effectiveness in settings where observed CDAIs are unavailable.

"suMus," a novel digital system for arm movement metrics and muscle energy expenditure.

Objective: In the field of non-treatable muscular dystrophies, promising new gene and cell therapies are being developed and are entering clinical trials. Objective assessment of therapeutic effects on motor function is mandatory for economical and ethical reasons. Main shortcomings of existing measurements are discontinuous data collection in artificial settings as well as a major focus on walking, neglecting the importance of hand and arm movements for patients' independence. We aimed to create a digital tool to measure muscle function with an emphasis on upper limb motility. Methods: suMus provides a custom-made App running on smartwatches. Movement data are sent to the backend of a suMus web-based platform, from which they can be extracted as CSV data. Fifty patients with neuromuscular diseases assessed the pool of suMus activities in a first orientation phase. suMus performance was hence validated in four upper extremity exercises based on the feedback of the orientation phase. We monitored the arm metrics in a cohort of healthy volunteers using the suMus application, while completing each exercise at low frequency in a metabolic chamber. Collected movement data encompassed average acceleration, rotation rate as well as activity counts. Spearman rank tests correlated movement data with energy expenditure from the metabolic chamber. Results: Our novel application "suMus," sum of muscle activity, collects muscle movement data plus Patient-Related-Outcome-Measures, sends real-time feedback to patients and caregivers and provides, while ensuring data protection, a long-term follow-up of disease course. The application was well received from the patients during the orientation phase. In our pilot study, energy expenditure did not differ between overnight fasted and non-fasted participants. Acceleration ranged from 1.7 ± 0.7 to 3.2 ± 0.5m/sec2 with rotation rates between 0.9 ± 0.5 and 2.0 ± 3.4rad/sec. Acceleration and rotation rate as well as derived activity counts correlated with energy expenditure values measured in the metabolic chamber for one exercise (r = 0.58, p < 0.03). Conclusion: In the analysis of slow frequency movements of upper extremities, the integration of the suMus application with smartwatch sensors characterized motion parameters, thus supporting a use in clinical trial outcome measures. Alternative methodologies need to complement indirect calorimetry in validating accelerometer-derived energy expenditure data.

Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.

Blue cone monochromacy (BCM) is an X-linked retinopathy due to mutations in the OPN1LW/OPN1MW gene cluster. Symptoms include reduced visual acuity and disturbed color vision. We studied BCM color vision to determine outcome measures for future clinical trials. Patients with BCM and normal-vision participants were examined with Farnsworth-Munsell (FM) arrangement tests and the Color Assessment and Diagnosis (CAD) test. A retrospective case series in 36 patients with BCM (ages 6-70) was performed with the FM D-15 test. A subset of six patients also had Roth-28 Hue and CAD tests. All patients with BCM had abnormal results for D-15, Roth-28, and CAD tests. With D-15, there was protan-deutan confusion and no bimodal tendency. Roth-28 results reinforced that finding. There was symmetry in color vision metrics between the two eyes and coherence between sessions with the arrangement tests and CAD. Severe abnormalities in red-green sensitivity with CAD were expected. Unexpected were different levels of yellow-blue results with two patterns of abnormal thresholds: moderate elevation in two younger patients and severe elevation in four patients ≥35 years. Coefficients of repeatability and intersession means were tabulated for all test modalities. Given understanding of advantages, disadvantages, and complexities of interpretation of results, both an arrangement test and CAD should be useful monitors of color vision through a clinical trial in BCM. Our pilot studies in BCM of arrangement and CAD tests indicated both were clinically feasible and interpretable in the context of this cone gene disease.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

Bringing the patient’s perspectives forward in drug development and health-care evaluation

ABSTRACT Introduction For many years, psychologists and other social scientists have been pushing for the individual patient’s perspective – priorities, needs, feelings, and functioning – to be incorporated into drug development. This is usually achieved through the use of patient-reported outcome measures (PROMs) in clinical trials. Areas covered This paper discusses some key issues in the use of PROM data as the sole method of generating information about the patient’s perspective and outlines the relevance of narrative evidence to enhance understanding and interpretation of PROM data. Expert opinion The development and use of PROMs situates them at the vertex of two very different trends in medicine: patient-centered care and standardization. Indeed, the application of PROMs – which pull in the direction of standardization – results in a narrow conception of evidence by overriding the subjectivity of individual experiences, beliefs, and judgments. Without additional context, PROM data cannot easily support individual patient-level care. When collected systematically and with an interpretive phenomenological approach, narrative data can contain valuable information about the patient experience that numerical ratings from PRO measures do not capture.

Knowledge Translation in Glomerulonephritis: Successes in Translational Research From the Bench to Bedside.

Glomerulonephritis refers to a rare group of diseases characterized by glomerular inflammation, which collectively are a common cause of kidney failure. Until recently, there was a lack of high-quality clinical trials to inform the care of patients with glomerulonephritides. We identified examples of successful translational research spanning from basic science to clinical applications, and highlight gaps in implementation science. The focus of our review was derived from discussions between health care professionals, researchers, and patient partners. We also performed literature searches pertaining to the treatment of glomerulonephritis in PubMed and Google Scholar. Examples of successful knowledge translation were generated through review of new evidence in the past 5 years and by iterative discussions by the authors. We then conducted a narrative review of several themes related to knowledge translation in glomerulonephritis. This was complemented by an interview with a patient partner to provide an example of a patient's perspective living with glomerulonephritis. We summarized selected recent advances in glomerulonephritis and its knowledge translation in the following domains: (1) identification of auto-antibodies in membranous nephropathy and minimal change disease; (2) clinical trials of novel targeted therapies for IgA nephropathy and lupus nephritis, which have led to approval of new treatments; (3) developments in research networks and clinical trials in glomerulonephritis; (4) recognition of the importance in developing standardized patient reported outcome measures in clinical trials; and (5) barriers in knowledge translation including access to medication. A systematic search of the literature and formal assessment of quality of evidence were beyond the scope of this review.

From Patient Reported Outcome Measure (PROM) to Environment Related Outcome Measure (EROM): Towards "Green Breast Surgery".

Climate change is a global issue that has had significant impacts on public health and healthcare policy worldwide. The direct impact of climate change on healthcare has been associated with extreme weather events, resulting in a higher demand for disaster management resources and reduced healthcare access. Moreover, the increase of zoonotic spillover effects has increased the risk of transmission of different diseases, including COVID-19. The healthcare industry alone is responsible for 4.4% of greenhouse gas global emissions. The surgical theatre is a resource-intense healthcare activity and a major carbon emitter, thus surgical processes require rethinking. This article proposes the introduction of environmental-related outcome measures in clinical trials, which will associate highest clinical standards to a reduced impact of care on climate change. Breast cancer care may represent a model disease for the implementation of evidence-based protocols, such as Green Breast Surgery, aiming to optimize the carbon footprint of care without affecting oncological and non-oncological outcomes. Physicians and healthcare workers worldwide should be aware of the importance of addressing environmental issues in healthcare policy, implementing programs to reduce their carbon footprint, and contributing to a more sustainable future.

P205: Deep phenotyping of Kabuki syndrome to create meaningful and specific biomarkers and outcome measures for clinical trials

P205: Deep phenotyping of Kabuki syndrome to create meaningful and specific biomarkers and outcome measures for clinical trials

Minimal Clinically Important Difference (MCID) in Patient-Reported Outcome Measures for Neurological Conditions: Review of Concept and Methods

Abstract The concept of the minimal clinically important difference (MCID) emerged from the recognition that statistical significance alone is not enough to determine the clinical relevance of treatment effects in clinical research. In many cases, statistically significant changes in outcomes may not be meaningful to patients or may not result in any tangible improvements in their health. This has led to a growing emphasis on the importance of measuring patient-reported outcome measures (PROMs) in clinical trials and other research studies, in order to capture the patient perspective on treatment effectiveness. MCID is defined as the smallest change in scores that is considered meaningful or important to patients. MCID is particularly important in fields such as neurology, where many of the outcomes of interest are subjective or based on patient-reported symptoms. This review discusses the challenges associated with interpreting outcomes of clinical trials based solely on statistical significance, highlighting the importance of considering clinical relevance and patient perception of change. There are two main approaches to estimating MCID: anchor-based and distribution-based. Anchor-based approaches compare change scores using an external anchor, while distribution-based approaches estimate MCID values based on statistical characteristics of scores within a sample. MCID is dynamic and context-specific, and there is no single ‘gold standard’ method for estimating it. A range of MCID thresholds should be defined using multiple methods for a disease under targeted intervention, rather than relying on a single absolute value. The use of MCID thresholds can be an important tool for researchers, neurophysicians and patients in evaluating the effectiveness of treatments and interventions, and in making informed decisions about care.

15th Post-ECTRIMS Meeting: a review of the latest developments presented at the 2022 ECTRIMS Congress (Part II)

On 4 and 5 November 2022, Madrid hosted the 15th edition of the Post-ECTRIMS Meeting, where neurologists specialised in multiple sclerosis outlined the latest developments presented at the 2022 ECTRIMS Congress, held in Amsterdam from 26 to 28 October. To synthesise the content presented at the 15th edition of the Post-ECTRIMS Meeting, in an article broken down into two parts. This second part describes the new developments in terms of therapeutic strategies for escalation and de-escalation of disease-modifying therapies (DMT), when and in whom to initiate or switch to highly effective DMT, the definition of therapeutic failure, the possibility of treating radiologically isolated syndrome and the future of personalised treatment and precision medicine. It also considers the efficacy and safety of autologous haematopoietic stem cell transplantation, different approaches in clinical trial design and outcome measures to assess DMT in progressive stages, challenges in the diagnosis and treatment of cognitive impairment, and treatment in special situations (pregnancy, comorbidity and the elderly). In addition, results from some of the latest studies with oral cladribine and evobrutinib presented at ECTRIMS 2022 are shown.

DEVELOPMENT AND IMPLEMENTATION OF THE COGDRISK DEMENTIA RISK ASSESSMENT TOOL AND INTERACTIVE WEBSITE

Abstract We developed a comprehensive risk assessment tool for dementia – Cognitive Health and Dementia Risk Assessment (CogDrisk) and a version specifically for Alzheimer’s disease called CogDrisk-AD that could be applicable in low and high-resource settings. This tool incorporates risk and protective factors identified through systematic synthesis of observational studies that report risk ratios. Risk and protective factors included in the tool were selected on the strength of evidence as well as the availability of measures that are practicable in a range of clinical and research contexts. Seventeen risk/protective factors were identified for inclusion in the dementia algorithm to estimate the risk of dementia while sixteen factors were identified for the AD model, with an overlap in the majority of the factors. CogDrisk and the CogDrisk-AD were predictive of dementia and AD when validated across four high-quality international cohort studies. To enable the CogDrisk tool to be implemented in practice our team has developed an interactive website where individuals 18 years and above can complete the CogDrisk questionnaire, obtain a personalised risk profile, and receive feedback on their risk profile. The website was developed with the capacity to collect and store data. We anticipate that the tool can be used by members of the public, in clinical settings and as a screening or outcome measure for clinical trials.

221. Assessment and Proposed Revision of Clinical Trial Clostridioides difficile Infection Clinical Response and Outcomes Definitions

Abstract Background Clostridioides difficile infection (CDI) research is limited by a lack of standardized definitions for clinical response and disease outcomes, which impacts clinical drug development and results comparison between studies. We aimed to assess outcome definitions in CDI therapeutic trials to propose new versions that are clinically relevant, discrete and objective. Methods A multidisciplinary group of CDI experts met monthly to review response endpoints from published clinical trials of antibiotic therapy for CDI. Previously published phase III or IV trials were assessed for outcome definitions. Discussions were held to reach a consensus on new clinical trial endpoints for adults and children to improve the accuracy and clinical relevance of measures of treatment success. Results Significant heterogeneity was noted amongst the primary endpoints in phase III and IV CDI antibiotic treatment trials. Initial clinical cure (ICC), strictly defined as &amp;lt; 3 unformed bowel movements/24 hour, and sustained clinical cure (SCC) were primary outcome measures for recent clinical trials. The strict ICC definition incompletely measures treatment success as assessed in clinical practice and, since ICC is necessary to achieve SCC, may lead to type II error for SCC. A set of proposed alternative outcome definitions was developed using the terms initial response (IR) and sustained response (SR) (Figure 1). IR allows for investigator assessment of overall improvement in CDI response more analogous to clinical practice and will lead to more patients eligible to meet SR. Achievement of SR requires both IR and no need for retreatment of CDI by day 30 after antibiotic completion and is the more relevant endpoint for CDI therapeutic development. The use of a less restrictive IR definition will more accurately capture early responses to treatment and importantly increase the validity of SR. The shortening of follow-up period by 30 days is also anticipated to reduce costs and efforts associated with conducting trials. Timeline of CDI outcome assessments for clinical trials Conclusion The set of definitions proposed here will more accurately capture clinical success and standardize the approach to outcome assessment in trials of CDI therapeutics. Disclosures Carolyn D. Alonso, MD, Cidara Therapeutics: Advisor/Consultant|Merck: Advisor/Consultant Oliver A. Cornely, Prof. Dr., Abbott: Honoraria|Abbvie: Advisor/Consultant|Actelion: Board Member|Al-Jazeera Pharmaceuticals: Honoraria|Allecra Therapeutics: Board Member|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Honoraria|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Biocon: Advisor/Consultant|Biosys: Advisor/Consultant|BMBF: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Board Member|Cidara: Expert Testimony|Cidara: Grant/Research Support|CoRe Consulting: Stocks/Bonds|Da Volterra: Advisor/Consultant|DLR: Grant/Research Support|DZIF: Grant/Research Support|Entasis: Board Member|EU Directorate-General for Resarch and Innovation: Grant/Research Support|F2G: Grant/Research Support|German Patent and Trade Mark Office: German patent (DE 10 2021 113 007.7)|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Grupo Biotoscana/United Medical/Knight: Honoraria|Hikma: Honoraria|IQVIA: Board Member|Janssen: Board Member|Matinas: Advisor/Consultant|Matinas: Grant/Research Support|MedPace: Advisor/Consultant|MedPace: Grant/Research Support|MedScape: Honoraria|MedUpdate: Honoraria|Menarini: Advisor/Consultant|Merck/MSD: Grant/Research Support|Merck/MSD: Honoraria|Molecular Partners: Advisor/Consultant|MSG-ERC: Advisor/Consultant|Mundipharma: Grant/Research Support|Mylan: Honoraria|Noxxon: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Grant/Research Support|Paratek: Board Member|Pardes: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Projektträger Jülich: Grant/Research Support|PSI: Advisor/Consultant|PSI: Board Member|Pulmocide: Board Member|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Seres: Advisor/Consultant|Shionogi: Board Member|Wiley (Blackwell): Editor-in-Chief, Mycoses Kevin W. Garey, PharmD, MS, Acurx Pharmaceuticals: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support|Summit Pharmaceuticals: Grant/Research Support Dale N. Gerding, MD, Destiny Pharma plc.: Advisor/Consultant Stuart Johnson, M.D., Ferring Pharmaceuticals: Membership on Ferring Publication Steering Committee|Ferring Pharmaceuticals: Employee|Summit Plc: Advisor/Consultant Stacy A. Kahn, MD, Lilly: Stocks/Bonds Ciaran P. Kelly, n/a, Artugen: Advisor/Consultant|Facile Therapeutics: Advisor/Consultant|Ferring Pharma: Advisor/Consultant|Finch: Advisor/Consultant|Finch: Advisor/Consultant|First Light Biosciences: Advisor/Consultant|First Light Biosciences: Ownership Interest|Milky Way Biosciences: Advisor/Consultant|Milky Way Biosciences: Grant/Research Support|Pfizer: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Summit Therapeutics: Advisor/Consultant Larry K. Kociolek, MD, MSCI, Merck: Grant/Research Support Thomas J. Louie, MD, Artugen: Advisor/Consultant|Artugen: Grant/Research Support|Crestone: Advisor/Consultant|Crestone: Grant/Research Support|Finch Therapeutics: Advisor/Consultant|Finch Therapeutics: Grant/Research Support|Rebiotix: Advisor/Consultant|Rebiotix: Grant/Research Support|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|summit plc: Advisor/Consultant|summit plc: Grant/Research Support|Vedanta Biosciences: Advisor/Consultant|Vedanta Biosciences: Grant/Research Support Maria Vehreschild, Prof. Dr., 3M: speaker fee|Astellas: Advisor/Consultant|Astellas: speaker fee|biologische heilmittel heel gmbh: Grant/Research Support|BioNtech: Grant/Research Support|EUMEDICA: Advisor/Consultant|Farmak International Holding: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Speaker fee|Gilead Sciences: Advisor/Consultant|Immunic AG: Advisor/Consultant|MaaT: Advisor/Consultant|Merck: Advisor/Consultant|Merck: speaker fee|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: speaker fees|Pfizer: speaker fee|Roche Molecular Systems: Grant/Research Support|Roche Molecular Systems: speaker fees|SocraRTec R&amp;D GmbH: Advisor/Consultant|Takeda California: Grant/Research Support Professor Mark H. Wilcox, MD, FRCPath, GSK: Advisor/Consultant|GSK: Board Member|GSK: Grant/Research Support|Pfizer: Advisor/Consultant|Phico Therapeutics: Board Member|Seres: Advisor/Consultant|Seres: Board Member|Seres: Grant/Research Support|Summit: Advisor/Consultant|Summit: Grant/Research Support Erik R. Dubberke, MD, MSPH, Abbott: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Grant/Research Support|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Seres: Advisor/Consultant|Summit: Advisor/Consultant|Synthetic Biologics: Grant/Research Support.

Photoreceptor Function and Structure in Autosomal Dominant Vitelliform Macular Dystrophy Caused by BEST1 Mutations.

The purpose of this study was to evaluate rod and cone function and outer retinal structure within macular lesions, and surrounding extralesional areas of patients with autosomal dominant Best vitelliform macular dystrophy caused by BEST1 mutations. Seventeen patients from seven families were examined with dark- and light-adapted chromatic perimetry and optical coherence tomography. Subsets of patients had long-term follow-up (14-22 years, n = 6) and dark-adaptation kinetics measured (n = 5). Within central lesions with large serous retinal detachments, rod sensitivity was severely reduced but visual acuity and cone sensitivity were relatively retained. In surrounding extralesional areas, there was a mild but detectable widening of the subretinal space in some patients and some retinal areas. Available evidence was consistent with subretinal widening causing slower dark-adaptation kinetics. Over long-term follow-up, some eyes showed formation of de novo satellite lesions at retinal locations that years previously demonstrated subretinal widening. A subclinical abnormality consisting of a retina-wide mild thickening of the outer nuclear layer was evident in many patients and thickening increased in the subset of patients with long-term follow-up. Outcome measures for future clinical trials should include evaluations of rod sensitivity within central lesions and quantitative measures of outer retinal structure in normal-appearing regions surrounding the lesions.

Salivary gland ultrasound is associated with the presence of autoantibodies in patients with Sjögren's syndrome: A Danish single-centre study.

To investigate whether ultrasound findings of major salivary glands are correlated with serological markers, autoantibodies, patient- or doctor-reported disease activity in a Danish cohort of patients with primary Sjögren's Syndrome (pSS). In all, 49 patients at Odense University Hospital with pSS diagnosed according to the 2002 American-European Consensus Group (AECG) classification criteria were included. Patients were characterized using the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI, score of systemic complications) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), serologic markers, Schirmer's test and salivary test. Salivary gland ultrasound (SGUS) was performed of the submandibular and parotid glands and scored according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) semi-quantitative scoring system. More patients with abnormal SGUS had antinuclear antibodies (ANA) (p = 0.002), anti-Ro52 (p = 0.001), anti-Ro60 (p<0.001), anti-La (p<0.001) and IgM-RF (p<0.001). Titers for ANA (p = 0.02) and anti-Ro52 (p = 0.03) were higher in patients with abnormal SGUS. Twenty-three of the pSS patients had no pathological findings on SGUS. There was no correlation between SGUS severity and ESSDAI- or ESSPRI-scores. Abnormal SGUS findings are associated with autoantibodies of high specificity for pSS but not with ESSDAI, ESSPRI or inflammatory markers.

MiToS and King’s staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial

Objective To evaluate the Milano-Torino staging (MiToS) and King’s staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS. Methods This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King’s stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage. Results The full analysis set consisted of 456 patients randomized 3:1 (reldesemtiv n = 342, placebo n = 114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King’s stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King’s stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King’s. Conclusion This exploratory analysis showed the feasibility of MiToS and King’s staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.