Primary Endpoint In Clinical Trials Research Articles

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

Nonparametric estimation in an illness-death model with component-wise censoring.

In disease settings where study participants are at risk for death and a serious nonfatal event, composite endpoints defined as the time until the earliest of death or the nonfatal event are often used as the primary endpoint in clinical trials. In practice, if the nonfatal event can only be detected at clinic visits and the death time is known exactly, the resulting composite endpoint exhibits "component-wise censoring." The standard method used to estimate event-free survival in this setting fails to account for component-wise censoring. We apply a kernel smoothing method previously proposed for a marker process in a novel way to produce a nonparametric estimator for event-free survival that accounts for component-wise censoring. The key insight that allows us to apply this kernel method is thinking of nonfatal event status as an intermittently observed binary time-dependent variable rather than thinking of time to the nonfatal event as interval-censored. We also propose estimators for the probability in state and restricted mean time in state for reversible or irreversible illness-death models, under component-wise censoring, and derive their large-sample properties. We perform a simulation study to compare our method to existing multistate survival methods and apply the methods on data from a large randomized trial studying a multifactor intervention for reducing morbidity and mortality among men at above average risk of coronary heartdisease.

Bipolar affective disorder

Abstract BodyAbstract: Biomarkers for diagnosis and treatment of Bipolar Disorder: hope or hype? Professor Allan Young, Centre for Affective Disorders, IoPPN, KCL London, SE5 8AF. allan.young@kcl.ac.uk The use of “biomarkers” (biological markers) in basic and clinical research as well as in clinical practice has become so commonplace in many areas of medicine that their presence as primary endpoints in clinical trials is now widely accepted. In clinical disciplines where specific biomarkers have been well characterized and repeatedly shown to correctly predict relevant clinical outcomes across a variety of treatments and populations, this use is entirely justified and appropriate. However, the validity of biomarkers in most psychiatric disorders continues to be evaluated. This lecture will review the current conceptual status of biomarkers as clinical and diagnostic tools for bipolar disorder and as surrogate endpoints in clinical research in bipolar disorder. The conceptual background in terms of current diagnostic categories and research domain criteria will be discussed and the various approaches with putative value (e.g., brain imaging, genetics, and neuroendocrinology) reviewed (1, 2). The lecture will end with a discussion of approaches to evaluating biomarkers of lithium response (3).ReferencesWise et al, Mol Psychiatry. 2016 May 24. doi: 10.1038/mp.2016.72. [Epub ahead of print]; Young AH. Harv Rev Psychiatry. 2014 Nov-Dec;22(6):331–3 Bellivier F, Young AH, et al, Bipolar Disord. 2020 Oct 23. doi: 10.1111/bdi.13023. Online ahead of print.DisclosurePaid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Principal Inve

Pharmacological Insights Into Safety and Efficacy Determinants for the Development of Adenosine Receptor Biased Agonists in the Treatment of Heart Failure.

Adenosine A1 receptors (A1R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been hampered by on-target side effects such as bradycardia and altered renal hemodynamics. Biased agonism has emerged as an attractive mechanism for A1R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A1R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterized, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A1R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca2+ influx relative to NECA and the cAMP pathway at the A1R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A1R. In contrast to VCP746, which displays more ‘adenosine-like’ signaling at the A2BR, neladenoson was a highly selective A1R agonist, with biased, weak agonism at the A2BR. Together these results show that unwanted hemodynamic effects of A1R agonists can be avoided by compounds biased away from Ca2+ influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A1R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients.

What is the most anticipated change induced by treatment using gender-affirming hormones in individuals with gender incongruence?

To identify the most eagerly anticipated change resulting from hormone therapy using gender-affirming hormones for patients with gender incongruence undergoing a clinical trial. Patients diagnosed with gender identity disorders based on the International Classification of Diseases 10th revision classification at three institutions in Japan for whom hormone therapy using gender-affirming hormones was initiated were analyzed. They were asked what the most anticipated change was due to gender-affirming hormone that they had thought of between giving informed consent and the first administration of the drug. The responders were 336 transgender men who were administered androgens and 48 transgender women who received estrogens. The median age at commencement of hormone therapy was 24years for transgender men and 28years for transgender women. For transgender men, the most frequent answer was cessation of menses (52.7%) followed by a deepened voice (32.4%). For transgender women, breast development (35.4%) was the most anticipated change, followed by gynoid fat deposition (29.2%). Cessation of menses in transgender men and breast development/gynoid fat deposition in transgender women might represent primary end-points in clinical trials evaluating the efficacy of hormonal treatment in these patients.

Minimal Residual Disease in Multiple Myeloma: Targeted Mass Spectrometry in Blood Vs Next Generation Sequencing in Bone Marrow

Background Multiple myeloma (MM) is a plasma cell malignancy arising in the bone marrow that is characterized by secretion of a monoclonal immunoglobulin (M-protein). M-protein detection is an integral part of MM diagnostics, performed using electrophoretic methods. This approach is reliable, fast and inexpensive, but not sensitive enough for detecting deeper responses, characterized by low M-protein concentration. Novel therapies have led to an increasing number of patients obtaining complete remission, however no curative therapy is available for MM. Even in remission, minimal residual disease (MRD) is present and can develop towards a relapse. MRD analysis plays an important role as primary endpoint in clinical trials, powerful prognostic marker, and MRD-status is increasingly used to guide therapy-decisions. Methods currently used for MRD detection are based on bone marrow aspirates (e.g. flow cytometry or next generation sequencing (NGS)). Not only are repetitive bone marrow aspirations uncomfortable for the patient, they also introduce a risk of non-representative sampling due to the possible patchy occurrence of the cancer cells in MM. Aim The aim is to measure MRD in a cohort of 41 multiple myeloma patients during follow-up using a targeted mass spectrometry assay. Unique peptides from the M-protein are selected based on RNA sequence information. Patient-specific peptides from M-proteins will be measured using mass spectrometry and MRD status will be compared to available NGS data. Methods Multiple myeloma patients were selected from the IFM 2009 Study (ClinicalTrials.gov number: NCT01191060) with available RNA sequence information and MRD data by NGS. We have selected 41 patients with three serum samples per patient; a baseline serum sample and two follow-up time points for MRD assessment. For each patient we have selected at least two peptides unique for the M-protein that could be observed in the baseline sample using mass spectrometry; one peptide from the light chain, and one from the heavy chain.(Zajec et al, J Proteome Res, 2018) In the case of light chain MM (3 patients in this study), only light chain peptides were selected. Serum samples were diluted 500 times, digested with trypsin and directly measured using targeted Orbitrap mass spectrometry technology. Results For all 41 patients we were successful in selecting and targeting unique peptides for M-protein quantification using mass spectrometry. MRD was assessed in follow-up serum samples (n=82, two time points for each patient) using NGS and mass spectrometry. In these follow-up patients, seven patients were negative by both NGS and mass spectrometry. Additionally, eight patients were negative by NGS but positive by mass spectrometry; and ten patients were negative by mass spectrometry and positive by NGS. The remainder of the follow-up samples (n=57) were positive by both mass spectrometry and NGS. Conclusion Unique peptides of the M-protein were found in all 41 multiple myeloma patients. Using these peptides, it was feasible to measure the M-protein in blood samples from multiple myeloma patients during follow-up. NGS and mass spectrometry MRD assessment have a concordance of 78% (64/82) in the follow-up samples. These are preliminary results without any immunoglobulin enrichment. We expect that further optimization can improve the sensitivity of mass spectrometry measurements. Future perspective Described experiments were performed on non-enriched serum without optimization of mass spectrometry parameters. Future experiments should be adapted accordingly and will increase the sensitivity of the mass spectrometry measurements. Internal standards for the peptides will be synthesized for absolute quantification (g/L value) of the M-protein during MRD. Disclosures No relevant conflicts of interest to declare.

Retrospective chart review of urinary glycosaminoglycan excretion and long-term clinical outcomes of enzyme replacement therapy in patients with mucopolysaccharidoses

BackgroundMucopolysaccharidoses (MPS) are a group of rare, inherited metabolic diseases that result from a deficiency in one of several lysosomal enzymes essential for stepwise glycosaminoglycan (GAG) degradation, leading to GAG accumulation and widespread cellular pathology and clinical disease. Although disease presentation is heterogeneous, the clinical hallmarks are largely comparable across several MPS subtypes. Extensive data have shown that the level of urinary GAG (uGAG) excretion above normal is strongly correlated with disease severity and clinical outcomes in MPS diseases. Thus, change in uGAG excretion may have significant value as a potential primary endpoint in clinical trials of MPS diseases that are too rare to study using traditional clinical endpoints. MethodsA retrospective medical chart review was undertaken of patients with MPS I, II, and VI who had been treated long term with enzyme replacement therapy (ERT). The relationship between uGAG reduction and clinical outcomes relevant to the major clinical manifestations of these MPS diseases was evaluated. A multi-domain responder index (MDRI) score was calculated, measuring the following 4 domains: 6-min walk test, pulmonary function, growth rate, and Clinician Global Impression of Change. For each domain, a minimal important difference (MID) was defined based on published information of these outcome measures in MPS and other diseases. ResultsOf the 50 patients evaluated, 18 (36%) had MPS I, 23 (46%) had MPS II, and 9 (18%) had MPS VI. Forty-two were clinical practice patients and 8 had participated in clinical trials. Across all MPS subtypes, the mean (± SD) uGAG level at baseline was 66.0 ± 51.5 mg/mmol creatinine (n = 48) and there was a mean reduction of 54.6% following ERT. Analysis of the MDRI score based on the MID defined for each domain showed a greater magnitude of improvement in patients with increased uGAG reduction when compared with those patients with lower uGAG reduction for all assessed uGAG thresholds, and a trend toward a higher likelihood of positive mean MDRI score in patients with a uGAG reduction ≥40%. ConclusionsIn this retrospective study, uGAG reduction was associated with long-term clinical outcomes as assessed by a number of approaches, supporting the use of uGAG reduction as a biomarker primary endpoint.

Preservation of Organ Function after Transplantation for Sickle Cell Disease

Background Recipients of successful allogeneic hematopoietic stem cell transplant (HSCT) for sickle cell disease (SCD) have hemoglobin S levels that reflect those of the donor. SCD related organ damage targets vital organs and is variable based on age and disease severity, and can be further compromised by transplant related complications. Organ function parameters are generally not primary end-points for clinical trials but need longitudinal follow up. This study aims to describe organ function in transplant recipients followed for one or more years after HSCT for SCD. Methods Following Institutional Review Board approval, a retrospective chart review was undertaken of SCD patients >1-year from HSCT with donor engraftment. Demographic data and organ functions (lung, brain and eyes) pre, at one-year, and at most recent assessment were compared for each patient. Organ functions reviewed included, creatinine, brain imaging, intelligence quotient (IQ), pulmonary function, retinal examination, and ferritin levels. Results Twenty-two patients were included in this review. There were 10 matched sibling donor, 8 matched or mismatched unrelated donor, 1 haploidentical, and 3 cord blood transplant recipients. Four patients received repeat donor cell infusion for waning donor chimerism followed by stabilization. Median age at first HSCT was 10 years (range 4-21 years). Eleven patients had MRI changes pre-HSCT. At 1-year, 4 of 17 transplant recipients had new MRI changes (2 patients with PRES and 2 with worsening infarction). At last follow up 3 of 18 patients demonstrated new MRI changes: bilateral temporal mesial sclerosis (1) and silent infarcts (2). IQ testing was available both at baseline and anytime beyond 1 year in 7 patients. IQ improved or remained stable in 5 patients and was lower in 2 patients, but remained in the average range. Pulmonary function tests were available for 21 patients of which 4 patients had restrictive lung disease. Ferritin levels decreased in 13 of 18 patients beyond the first year post-HSCT. Ophthalmologic exams at baseline and after transplant were performed in 12 patients. While SCD retinopathy was detected at baseline in two patients, no retinopathy was noted after HSCT. Follow up is in progress for additional organs such as the heart and kidneys. Discussion Long-term follow up of SCD related parameters post-HSCT demonstrates the effect of the intervention on disease manifestations. Our data demonstrates stability or improvement in organ function in the majority of patients after HSCT. This retrospective analysis is limited by the lack of uniform assessment of SCD related parameters and by obstacles such as provider changes and insurance denials. Though our data indicates improvement in SCD parameters post-HSCT, it also underscores the importance of systematic follow up prospectively through clinical trials and registries following curative therapy for SCD.

P267 Validation of the short inflammatory bowel disease questionnaire as an outcome measure in Crohn’s disease patients

Abstract Background Health-related quality-of-life by the self-report, disease-specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is increasingly used as an outcome measure in Crohn`s disease (CD) patients in clinical trials. Higher SIBDQ scores indicate better quality-of-life; the range is 10 to 70. However, the construct validity of SIBDQ and its responsiveness to change of disease status require validation. Methods Adult (≥18 years) CD patients (n = 108) with Harvey–Bradshaw Index (HBI) >4 and <16 prospectively filled in the SIBDQ at two time-points (T1, T2) 3 months apart. Medical data at T1 and T2 were collected, and recorded by their physicians in the HBI. Biomarkers of disease activity included Calprotectin and C-reaction protein (CRP), measured at T1 and T2. The construct validity of SIBDQ in relation to biomarkers and HBI was determined by Pearson correlations and group comparisons using Student`s t-test. Statistical significance was taken as p < 0.05. Patients’ medications were prescribed without regard to the study protocol. Results Demographic and medical characteristics (median, %) of the cohort were: age 30 years; females 65%, married/partner 48%; higher education 83%; BMI 22; non-smokers/past-smokers 92%; disease duration 5 years; past Crohn’s disease-related surgery 17%; Montreal classification A2 89%, L2+L3 89%, B1+B2 89%, perianal disease 18%; medications: corticosteroids 4%, 5-ASA 5%, immunomodulators 21%, biologicals 43%. HBI and SIBDQ median scores at T1 and T2 were: HBI: 9 and 4 (p < 0.001); SIBDQ: 43 and 49 (p < 0.001). SIBDQ scores correlated inversely with Calprotectin (r = −0.395, p = .002), CRP (r = −0.208, p = .046), and HBI (r = −0.345, p < 0.001). Baseline HBI scores were used to divide the cohort into two groups for comparison: mild disease (5–7) vs. moderate disease (8–16). Mild disease patients reported higher SIBDQ scores than those with moderate disease (42.7 vs. 39.7, t = 1.96, p = 0.05). Regarding sensitivity of SIBDQ to clinical changes between T1 and T2, we found that change in SIBDQ correlated significantly with change in CRP across these two administrations (r = −0.232, p = 0.042). Finally, defining clinical response in CD as a decrease from baseline HBI score by ≥3 points, SIBDQ change scores were significantly larger in treatment responders (n = 51, M = 6.25) than non-responders (n = 30, M = 1.13, t = −3.042, p = 0.003). Conclusion The SIBDQ measure is a valid assessment of quality-of-life in CD, correlating with biomarkers and sensitive to change of disease activity, with potential for use as a patient-reported outcome in both clinical practice and as a primary end-point in clinical trials.

Beyond Performance Metrics: Automatic Deep Learning Retinal OCT Analysis Reproduces Clinical Trial Outcome

To validate the efficacy of a fully automatic, deep learning-based segmentation algorithm beyond conventional performance metrics by measuring the primary outcome of a clinical trial for macular telangiectasia type 2 (MacTel2). Evaluation of diagnostic test or technology. A total of 92 eyes from 62 participants with MacTel2 from a phase 2 clinical trial (NCT01949324) randomized to 1 of 2 treatment groups METHODS: The ellipsoid zone (EZ) defect areas were measured on spectral domain OCT images of each eye at 2 time points (baseline and month 24) by a fully automatic, deep learning-based segmentation algorithm. The change in EZ defect area from baseline to month 24 was calculated and analyzed according to the clinical trial protocol. Difference in the change in EZ defect area from baseline to month 24 between the 2 treatment groups. The difference in the change in EZ defect area from baseline to month 24 between the 2 treatment groups measured by the fully automatic segmentation algorithm was 0.072±0.035 mm2 (P= 0.021). This was comparable to the outcome of the clinical trial using semiautomatic measurements by expert readers, 0.065±0.033 mm2 (P= 0.025). The fully automatic segmentation algorithm was as accurate as semiautomatic expert segmentation to assess EZ defect areas and was able to reliably reproduce the statistically significant primary outcome measure of the clinical trial. This approach, to validate the performance of an automatic segmentation algorithm on the primary clinical trial end point, provides a robust gauge of its clinical applicability.

PSY52 PATIENT-REPORTED OUTCOME MEASURES IN ATOPIC DERMATITIS AND CHRONIC HAND ECZEMA IN ADULTS

Patient-reported outcome measures (PROMs) provide an important complement to physician-assessed clinical outcome measures in dermatologic diseases such as atopic dermatitis (AD) and chronic hand eczema (CHE). AD and CHE are chronic and relapsing inflammatory skin conditions that often co-occur. While both diseases result in various signs and symptoms that are burdensome and can negatively affect patients’ lives, there may be distinct differences in the signs, symptoms, burden, and health-related quality of life (HRQOL) impact of these diseases. The objective of this study was to identify and evaluate PROMs used in studies of AD and CHE. The aim was to explore the assessment of key symptoms and impacts, and identify any gaps in the measures in use. A structured review of the PubMed database was conducted to identify PROMs used or developed for use in AD or CHE. The Dermatology Life Quality Index (DLQI), the Pruritus/Itch Numeric Rating Scale (NRS), the Patient-Oriented Eczema Measure (POEM), and the Quality of Life in Hand Eczema Questionnaire (QOLHEQ) were identified and reviewed in detail. With these measures, the AD and CHE symptoms and impacts most commonly evaluated in the literature include dermatology-related HRQOL in the domains of symptoms and feelings, daily activities, leisure, work and school, personal relationships, and adverse effects; pruritus; sleep disturbance; AD-specific symptoms (dryness, itching, flaking, cracking, bleeding, and weeping/oozing); and CHE-specific symptoms (pain, itch, fissuring, redness, bleeding, and dryness). A review of regulatory labels of drugs approved for AD by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) found that, among the four measures reviewed, the Pruritus NRS was included in the FDA and EMA labels for dupilumab, the DLQI was included in the EMA labels for dupilumab and tacrolimus, and the POEM was included in the EMA label for dupilumab. Key symptoms of AD (e.g. itching, flaking, cracking) and CHE (e.g. pain, itching, fissuring) are increasingly being assessed with PROMs; however, primary endpoints in clinical trials are often based on clinician-reported outcome measures. As therapeutic strategies in dermatology are targeted at specific dermatologic symptoms and diseases affecting specific sites (e.g. CHE), future research should explore patients’ experiences with these symptoms and sites and the changes with treatment that are most meaningful to them.

PND118 PATIENTS WITH CHRONIC PAIN DISORDERS: PREFERENCE OF EPRO SCREEN DISPLAY AND FEATURES

Electronic patient reported outcomes (ePROs) are often primary endpoints in clinical trials for pain treatment. While ePRO has many advantages, patient preference and usability of the technology are important to help reduce patient burden and improve patient engagement. This study investigates patient’s preference of how ePRO content are displayed on a digital screen and features. Participants (N=551), who reported a chronic pain diagnosis (e.g., migraines, fibromyalgia, arthritis), completed an online survey with screenshots of ePRO screens and about their preference of font size, number of items to complete on a screen, and orientation of a pain visual analog scale (VAS). Participants familiar with screen magnification features indicated how they preferred to resolve issues of font size that were too small to read. Majority of participants (77.4%) preferred 16-point font text over 14-point font (16.8%) but 5.8% thought that neither font size were big enough. For the number of items displayed on a screen, 45.1% preferred more than one item if the items were related, 24.8% would answer many items on one screen if there were less screens to go through, and 30.1% wanted only one item per screen. With the VAS, most participants preferred the scale to be displayed in a horizontal (60.4%) versus vertical orientation (11.2%). 28.4% had no preference. 77.3% stated familiarity with accessibility features, including screen magnification, on electronic devices. Of those participants, 58.4% preferred larger font text and to scroll down the screen, if needed, rather than magnification. However, 41.6% preferred not to scroll but rather use the device's magnification feature to zoom in. Understanding patient with chronic pain disorders preference of ePRO features and how content are displayed on screen is important to designing ePRO instruments that are easier to use. This may reduce patient burden and lead to increased patient engagement in clinical trials.

Study protocol to develop a patient-reported outcome measuring disability associated with unilateral vocal fold paralysis: a mixed-methods approach with the CoPE collaborative

IntroductionPatient-reported outcome (PRO) measures are increasingly developed with multisite, representative patient populations so that they can serve as a primary endpoint in clinical trials and longitudinal studies. Creating multisite infrastructure...

Cerebrospinal fluid CXCL10 as a surrogate marker of therapy-response and therapy-predict for HTLV-1-Associated myelopathy/tropical spastic paraparesis

Since HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a debilitating, progressive disease with no effective treatments, there is a dire need to develop a novel therapy that truly improves the long-term functional prognosis. However, this true endpoint is virtually impossible to consider as a primary endpoint in clinical trials, as it takes decades. Therefore, development of surrogate markers that enable to assess the effectiveness of new interventions more rapidly with greater accuracy is essential. Currently, there are several candidate surrogate markers for HAM/TSP. Cerebrospinal fluid (CSF) CXCL10 in particular is involved in the pathogenesis and correlates with disease progression. Changes in surrogate marker levels should be observed in response to treatment and they should correlate with prognosis. Here, we investigated these aspects of several markers, including CSF CXCL10. Patient information, motor function evaluation results, and CSF examination data from 13 patients with HAM/TSP who received steroid pulse therapy were collected retrospectively. We compared the levels of CXCL10 and neopterin, total protein, cell counts, anti-HTLV-1 antibody titer (all CSF markers), and Osame motor disability scores (OMDS) before and after pulse therapy. In conclusion, CXCL10 and neopterin levels in CSF declined in response to steroid pulse therapy and correlated with changes in prognosis based on continuation of treatment. In addition, patients with HAM/TSP who benefited from steroid pulse therapy had high CSF CXCL10 levels. Therefore, the CSF CXCL10 level would be useful as a surrogate marker of therapy-response and therapy-predict in patients with HAM/TSP.

Association of Antihyperglycemic Therapy with Risk of Atrial Fibrillation and Stroke in Diabetic Patients

Type 2 diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD). Atrial fibrillation (AF) and stroke are both forms of CVD that have major consequences in terms of disabilities and death among patients with diabetes; however, they are less present in the preoccupations of scientific researchers as a primary endpoint of clinical trials. Several publications have found DM to be associated with a higher risk for both AF and stroke; some of the main drugs used for glycemic control have been found to carry either increased, or decreased risks for AF or for stroke in DM patients. Given the risk for thromboembolic cerebrovascular events seen in AF patients, the question arises as to whether stroke and AF occurring with modified incidences in diabetic individuals under therapy with various classes of antihyperglycemic medications are interrelated and should be considered as a whole. At present, the medical literature lacks studies specifically designed to investigate a cause–effect relationship between the incidences of AF and stroke driven by different antidiabetic agents. In default of such proof, we reviewed the existing evidence correlating the major classes of glucose-controlling drugs with their associated risks for AF and stroke; however, supplementary proof is needed to explore a hypothetically causal relationship between these two, both of which display peculiar features in the setting of specific drug therapies for glycemic control.

Cerebrospinal Fluid CXCL10 as a Candidate Surrogate Marker for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a debilitating, progressive disease without effective treatment; therefore, development of disease modifying therapy that improves long-term functional outcomes is an unmet need for patients. However, it is virtually impossible to consider this as a primary endpoint in clinical trials owing to the prolonged disease course. Therefore, development of surrogate markers that help predict the effectiveness of new interventions is essential. Currently, several candidate surrogate markers have been identified for HAM/TSP. Cerebrospinal fluid (CSF) C-X-C motif chemokine 10 (CXCL10) is involved in the pathogenesis of HAM/TSP and was shown to correlate with disease progression. However, it remains unclear whether changes in CSF CXCL10 levels are observed in response to treatment and whether these correlate with prognosis. Here we investigated several markers, including CSF CXCL10, in this respect. Data pertaining to patient characteristics and results of motor function evaluation and CSF examination of 13 HAM/TSP patients who received steroid treatment were retrospectively analyzed. Osame motor disability scores (OMDS), 10 m walking time, and CSF levels of CXCL10, neopterin, total protein, cell counts, and anti-HTLV-1 antibody titer were compared before and after steroid therapy. Levels of all CSF markers, with the exception of cell count, were significantly decreased after treatment. Nine of the 13 patients (69.2%) showed improvement in OMDS and were considered responders. Pre-treatment CSF levels of CXCL10 and anti-HTLV-1 antibody titer in responders were higher than those in non-responders (p = 0.020 and p = 0.045, respectively). Patients who continued low-dose oral prednisolone maintenance therapy after methylprednisolone pulse therapy showed sustained improvement in OMDS and CSF CXCL10 and neopterin levels lasting for 2 years. In contrast, OMDS and the CSF marker levels in patients who discontinued treatment returned to pre-treatment levels. This rebound phenomenon was also observed in patients who discontinued oral prednisolone therapy independently of pulse therapy. Our findings suggest that CSF CXCL10 may serve as a therapy-response and therapy-predictive marker for HAM/TSP. In addition, since decrease in CSF CXCL10 level was associated with good functional prognosis, CSF CXCL10 is a potential surrogate marker for treatment of HAM/TSP.

Patient-Reported Outcome Measures in Atopic Dermatitis and Chronic Hand Eczema in Adults.

Patient-reported outcome measures (PROMs) provide an important complement to physician-assessed clinical outcome measures in dermatologic diseases such as atopic dermatitis (AD) and chronic hand eczema (CHE). AD and CHE are chronic and relapsing inflammatory skin conditions that often co-occur. While both diseases result in various signs and symptoms that are burdensome and can negatively affect patients’ lives, there may be distinct differences in the signs, symptoms, burden, and health-related quality of life (HRQOL) impact of these diseases. The objective of this study was to identify and evaluate PROMs used in studies of AD and CHE. The aim was to explore the assessment of key symptoms and impacts, and identify any gaps in the measures in use. A structured review of the PubMed database was conducted to identify PROMs used or developed for use in AD or CHE. The Dermatology Life Quality Index (DLQI), the Pruritus/Itch Numeric Rating Scale (NRS), the Patient-Oriented Eczema Measure (POEM), and the Quality of Life in Hand Eczema Questionnaire (QOLHEQ) were identified and reviewed in detail. With these measures, the AD and CHE symptoms and impacts most commonly evaluated in the literature include dermatology-related HRQOL in the domains of symptoms and feelings, daily activities, leisure, work and school, personal relationships, and adverse effects; pruritus; sleep disturbance; AD-specific symptoms (dryness, itching, flaking, cracking, bleeding, and weeping/oozing); and CHE-specific symptoms (pain, itch, fissuring, redness, bleeding, and dryness). A review of regulatory labels of drugs approved for AD by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) found that, among the four measures reviewed, the Pruritus NRS was included in the FDA and EMA labels for dupilumab, the DLQI was included in the EMA labels for dupilumab and tacrolimus, and the POEM was included in the EMA label for dupilumab. Key symptoms of AD (e.g. itching, flaking, cracking) and CHE (e.g. pain, itching, fissuring) are increasingly being assessed with PROMs; however, primary endpoints in clinical trials are often based on clinician-reported outcome measures. As therapeutic strategies in dermatology are targeted at specific dermatologic symptoms and diseases affecting specific sites (e.g. CHE), future research should explore patients’ experiences with these symptoms and sites and the changes with treatment that are most meaningful to them.Electronic supplementary materialThe online version of this article (10.1007/s40271-019-00373-y) contains supplementary material, which is available to authorized users.

How to assess and predict success or failure of intra-detrusor injections with onabotulinumtoxinA

Intra-detrusor injection therapy with onabotulinumtoxinA is generally accepted as a highly effective, minimally invasive and well-tolerated day procedure for patients with refractory overactive bladder (OAB) and neurogenic detrusor overactivity (NDO). The aim of this study was to summarize currently available methods of assessing treatment efficacy and risk factors that may influence the therapeutic effect of this approach. We found that there are discrepancies in the assessment methods. The evaluation of intra-detrusor injections with onabotulinumtoxinA in clinical trials are not always transposable into day-to-day practice. Moreover, the primary endpoints in clinical trials do not explore the entirety of meaningful patient-centered outcomes. Therefore, in daily clinical practice with patients with overactive bladder syndrome, the therapy should be assessed with objective measures (bladder diaries) and patient-oriented outcomes analyzing the quality of life (questionnaires). In neurogenic individuals, therapeutic efficacy should be additionally evaluated with urodynamic studies. Potential risk factors that may influence the treatment outcomes include urodynamically proven detrusor overactivity, elevated maximum detrusor pressure, greater maximum cystometric capacity, impaired bladder compliance, older age, male gender, a higher baseline bother score, previous anticholinergic treatment, and repeated injections with a subsequent decline in efficacy. The risk of intermittent catheterization following injections seems to depend on the etiology of detrusor overactivity, the injected dose, the injection technique, and the definition of significant post-void residual urine requiring catheterization.

A new approach for sizing trials with composite binary endpoints using anticipated marginal values and accounting for the correlation between components.

Composite binary endpoints are increasingly used as primary endpoints in clinical trials. When designing a trial, it is crucial to determine the appropriate sample size for testing the statistical differences between treatment groups for the primary endpoint. As shown in this work, when using a composite binary endpoint to size a trial, one needs to specify the event rates and the effect sizes of the composite components as well as the correlation between them. In practice, the marginal parameters of the components can be obtained from previous studies or pilot trials; however, the correlation is often not previously reported and thus usually unknown. We first show that the sample size for composite binary endpoints is strongly dependent on the correlation and, second, that slight deviations in the prior information on the marginal parameters may result in underpowered trials for achieving the study objectives at a pre-specified significance level. We propose a general strategy for calculating the required sample size when the correlation is not specified and accounting for uncertainty in the marginal parameter values. We present the web platform CompARE to characterize composite endpoints and to calculate the sample size just as we propose in this paper. We evaluate the performance of the proposal with a simulation study and illustrate it by means of a real case study using CompARE.

Evidence supporting wound care end points relevant to clinical practice and patients' lives. Part 2. Literature survey.

Patients with wounds bear significant clinical, personal, and economic burdens yet complete wound healing is the only United States Food and Drug Administration (FDA) recognized primary clinical trial end point. The overall goal of this project is to work with FDA to expand the list of acceptable primary end points, recognizing that new and innovative treatments, devices, and drugs may not have complete healing as the focus. Part 1 of the project surveyed 628 wound care experts who identified and content-validated 15 end points most relevant to clinical practice and benefitting patients' lives as primary outcomes in clinical trials. Part 2 is focused on critical appraisal of the evidence in the wound care literature supporting FDA criteria to qualify these 15 end points as primary end points in clinical trials. Further research involved systematic review of the literature regarding the most promising end points. Forty volunteer, interdisciplinary, wound healing experts in fields related to the end points compiled evidence from systematic MEDLINE searches and society databases supporting the FDA criteria of reliability, clinical construct validity, capacity to detect concurrent or longitudinal change, and responder analysis. The search revealed 485 references involving over 462,000 subjects supporting FDA-required parameters for all 15 end points More than 50 references supported FDA-required parameters qualifying the following outcomes for use in clinical trials supporting interventions for FDA clearance: Pain reduction, Physical function and ambulation, Infection reduction, Time to heal, and Percent wound area reduction in 4-8 weeks. Among these, only Time to heal is currently recognized by the FDA as a primary wound outcome in clinical trials. These results suggest that wound science is already serving patients and professionals by improving these content-validated outcomes that merit regulatory consideration.