Primary Endpoint In Clinical Trials Research Articles

Different meanings of a three-point decline in MMSE score in Alzheimer's disease and depressive disorder.

The Mini-Mental State Examination (MMSE) is a composite scale that is included in diagnostic algorithms and in procedures to assess severity of cognitive impairment and efficacy of therapeutic interventions. It is unclear, however, whether the MMSE provides information about the same deficits in different diseases. To assess patterns of MMSE scores in patients with confirmed diagnosis of Alzheimer's disease or depressive disorder. We used data from a previously published cross-sectional retrospective observational clinical cohort study. The final analysis included only patients in whom biomarker analysis showed results characteristic of Alzheimer's disease (n = 167) and patients with depressive disorder in whom Alzheimer's disease had been ruled out by analysis of biomarkers (n = 69). A three-point decline in MMSE score from 30 to 27 reflected impairment of memory recall in patients with Alzheimer's disease, whereas it reflected impairments in calculation and memory recall in patients with depressive disorder. A further three-point decline in MMSE score from 27 to 24 predominantly reflected additional calculation impairment in patients with Alzheimer's disease. Our results indicate that memory performance is the most important measure of disease severity and the main contributor to the decline in MMSE score at onset of clinical manifestation of Alzheimer's disease. In general, this suggests that memory should be the primary measure used in routine clinical care and the primary endpoint in clinical trials involving patients with Alzheimer's disease at onset of clinical manifestation. Changes in other measures of cognition should prompt consideration of possible comorbidities as a cause, rather than the impact of Alzheimer's disease itself.

Statistical approaches for component-wise censored composite endpoints.

Composite endpoints defined as the time to the earliest of two or more events are often used as primary endpoints in clinical trials. Component-wise censoring arises when different components of the composite endpoint are censored differently. We focus on a composite of death and a non-fatal event where death time is right censored and the non-fatal event time is interval censored because the event can only be detected during study visits. Such data are most often analysed using methods for right censored data, treating the time the non-fatal event was first detected as the time it occurred. This can lead to bias, particularly when the time between assessments is long. We describe several approaches for estimating the event-free survival curve and the effect of treatment on event-free survival via the hazard ratio that are specifically designed to handle component-wise censoring. We apply the methods to a randomized study of breastfeeding versus formula feeding for infants of mothers infected with human immunodeficiency virus.

Using multiple primary endpoints in clinical trials with a focus on heart failure

Using multiple primary endpoints in clinical trials with a focus on heart failure

Silencing the Mitochondrial Gatekeeper VDAC1 as a Potential Treatment for Bladder Cancer.

The strategy for treating bladder cancer (BC) depends on whether there is muscle invasion or not, with the latter mostly treated with intravesical therapy, such as with bacillus Calmette-Guérin (BCG). However, BCG treatment is unsuccessful in 70% of patients, who are then subjected to radical cystectomy. Although immune-checkpoint inhibitors have been approved as a second-line therapy for a subset of BC patients, these have failed to meet primary endpoints in clinical trials. Thus, it is crucial to find a new treatment. The mitochondrial gatekeeper protein, the voltage-dependent anion channel 1 (VDAC1), mediates metabolic crosstalk between the mitochondria and cytosol and is involved in apoptosis. It is overexpressed in many cancer types, as shown here for BC, pointing to its significance in high-energy-demanding cancer cells. The BC cell lines UM-UC3 and HTB-5 express high VDAC1 levels compared to other cancer cell lines. VDAC1 silencing in these cells using siRNA that recognizes both human and mouse VDAC1 (si-m/hVDAC1-B) reduces cell viability, mitochondria membrane potential, and cellular ATP levels. Here, we used two BC mouse models: subcutaneous UM-UC3 cells and chemically induced BC using the carcinogen N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Subcutaneous UM-UC3-derived tumors treated with si-m/hVDAC1 showed inhibited tumor growth and reprogrammed metabolism, as reflected in the reduced expression of metabolism-related proteins, including Glut1, hexokinase, citrate synthase, complex-IV, and ATP synthase, suggesting reduced metabolic activity. Furthermore, si-m/hVDAC1-B reduced the expression levels of cancer-stem-cell-related proteins (cytokeratin-14, ALDH1a), modifying the tumor microenvironment, including decreased angiogenesis, extracellular matrix, tumor-associated macrophages, and inhibited epithelial-mesenchymal transition. The BBN-induced BC mouse model showed a clear carcinoma, with damaged bladder morphology and muscle-invasive tumors. Treatment with si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles that were administered intravesically directly to the bladder showed a decreased tumor area and less bladder morphology destruction and muscle invasion. Overall, the obtained results point to the potential of si-m/hVDAC1-B as a possible therapeutic tool for treating bladder cancer.

Serum Urate as a Surrogate Outcome for Gout Flares: Where Do We Stand Today?

In gout research, serum urate has been widely accepted as the primary endpoint in clinical trials of urate-lowering therapies by both the FDA and EMA for many years. However, for serum urate to be a meaningful outcome measure, it should reflect at least one important patient-centered clinical outcome, such as gout flares. The relationship between achieving a pre-specified “target” serum urate and a corresponding improvement in patient-centered outcomes has been difficult to show due to variation in reporting of both serum urate and gout flares in clinical trials; a paradoxical rise in gout flares after starting urate-lowering therapy and a delay after achieving the pre-specified target serum urate before gout flares settle coupled with the relatively short duration of the trials. However, recent evidence from individual-level patient data from two, two-year randomized controlled trials clearly shows that achieving target urate is associated with a subsequent reduction and cessation of gout flares. In this review, we examine the evidence supporting serum urate as a surrogate outcome for gout flares, the methods, and the challenges of showing the validity of surrogacy.

A Day 14 Endpoint for Acute GVHD Clinical Trials

The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment.

Correlation between Progression-Free Survival and Overall Survival in Patients with Relapsed Hodgkin Lymphoma: An Analysis of Individual Patient Data from Randomized GHSG Trials

Background: Progression-free survival (PFS) and overall survival (OS) are predominant measures of treatment efficacy in Hodgkin lymphoma (HL). Despite preference for OS from many regulatory authorities, PFS is most relevant to patients and frequently serves as primary endpoint in clinical trials. Recently we found a strong correlation between treatment effects on PFS and OS in the first-line setting (Bröckelmann PJ et al. EHA23/ICML23). However, their relationship in the relapsed setting remains unclear. We aimed to evaluate the correlation of PFS with OS after treatment of relapsed HL. Methods: We evaluated individual patient data of 375 patients with relapsed HL treated within the prospective randomized GHSG trials HDR1 (N= 141) and HDR2 (N= 234) between 02/1993 - 06/2007. Briefly, both trials included patients of 18 to 60 years of age with histologically confirmed relapsed HL after ≥1 prior line of treatment, who had not previously received high-dose chemotherapy and autologous stem-cell transplantation (ASCT). In HDR1 patients received two cycles of Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and ASCT. In HDR2, patients were assigned to two cycles of dexamethasone, cytarabine, and cisplatin (DHAP), and thereafter randomly assigned to either BEAM followed by ASCT or sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM followed by ASCT. All patients who received at least one dose of salvage chemotherapy within the respective trial were included in the analysis. We correlated treatment effects and risk factor effects on PFS and OS with the Wei-Lin-Weissfeld (WLW) method and adjusted the analysis for age and sex. Additionally, we applied copula models to correlate the time-to-event variables PFS and OS themselves using their marginal distributions. Results: With a median follow-up of 4.5 years, at least one PFS event, defined as relapse or progression of relapsed HL or death for any reason, was recorded in 146 of 375 patients (38.9%). At least one OS event, defined as death for any reason, was documented in 111 of 375 patients (29.6%). The hazard ratios for treatment effects on PFS and OS were 0.61 (95% confidence interval, CI= 0.38-0.98) and 1.01 (95% CI= 0.63-1.63) for HDR1 and 1.1 (95% CI= 0.69-1.75) and 0.8 (95% CI= 0.44-1.47) for HDR2, respectively. The WLW analysis revealed high correlations of treatment effects on PFS and OS at patient level within the trials. Pearson correlation r of the treatment effects on PFS and OS were r= 0.72 (95% confidence interval CI= 0.66-0.76, P< 0.001) in all 375 patients analyzed, r= 0.72 (95% CI= 0.63-0.79, P<0.001) in the HDR1 trial and r= 0.74 (95% CI= 0.67-0.79, P< 0.001) in the HDR2 trial. The analysis with different risk factors and copula models revealed similarly high correlations, confirming a strong relation between PFS and OS in relapsed HL patients. Conclusions: PFS and OS as well as treatment effects and prognostic effects on PFS and OS are highly correlated in patients treated for relapsed HL. Confirming results in first-line treatment, PFS thereby constitutes a highly relevant endpoint also in the setting of relapsed HL.

A Day 14 Endpoint for Acute Gvhd Clinical Trials

The overall response rate (ORR) 28 days (D28) after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). ORR combines complete response (CR) and partial response (PR) because CR and PR have very similar non relapse mortality (NRM). D28 ORR has some disadvantages: first, physicians usually decide to modify immunosuppression much earlier than D28, and second, NRM does not always correlate well with ORR at D28, particularly for patients who present with intermediate risk or low risk disease. MAGIC serum biomarkers at day 14 (D14) of GVHD treatment have been shown to correlate better with NRM than clinical symptom response (Srinagesh et al, Blood Advances, 2019). We therefore hypothesized that a combination of clinical symptom severity and biomarkers at D14 of treatment would predict NRM at least as well and possibly better than clinical response at D28. We studied 1144 patients from 23 MAGIC sites who were systemically treated with at least 0.25 mg/kg/day of systemic steroids (prednisone equivalents) and had clinical data and serum samples available in the MAGIC database and biorepository. We divided the patients into a training set (n=764) and a validation set (n=380). We used 12-month NRM from the time of acute GVHD onset as the primary outcome of interest. We first trained a recursive partitioning algorithm in the training set to create a response model (MAGIC D14 clinical response) according to overall GVHD grade at both onset and D14 that predicted 12-month NRM and then applied it to the validation set. Patients that either progressed to grade III/IV GVHD, continued having grade III/IV GVHD, or only improved to grade II at D14 from grade III/IV at D0 had high NRM and were classified as non-responders. Patients with grade I/II GVHD at day 0 who had grade 0-II GVHD at day 14 and patients who improved to grade 0/I at day 14 from grade III/IV at day 0 had low NRM and were classified as responders. Although counterintuitive, responders included patients whose GVHD remained at grade II because the 12 month NRM of this group was only 20%. The new clinical model predicted NRM as well as the D28 standard response model in the validation set. When we integrated the D14 MAP biomarker score (low: ≤ 0.290 vs high: >0.290) with the new D14 clinical response (D14 MAGIC integrated response), we observed three response groups of integrated response with strikingly different 12 month NRM (8%, 35%, 76%, p<0.001), in contrast to the D28 standard response (Figure 1A, 1B). D14 complete response required MAGIC clinical response with low MAP; D14 partial response required either MAGIC clinical response with high MAP or MAGIC clinical non-response with low MAP; and D14 non-response required MAGIC clinical non-response with high MAP. The D14 response groups also displayed significant differences in 12 month OS (82%, 58%, 14% respectively, p<0.001) We then compared the D14 integrated response with the D28 standard response for 12 month NRM prediction. This D14 integrated response model was superior for time-dependent AUC (0.78 vs 0.71, P=0.03), sensitivity (0.71 vs 0.54), positive predictive value (0.52 vs 0.48) and negative predictive value (0.92 vs 0.89), with minimal loss in specificity (0.85 vs 0.87) in the prediction of 12-month NRM compared to the D28 standard response model. Using decision curve analysis, the D14 integrated response displayed higher net benefit (correct identification of patients that will experience NRM by 12 months) over the whole range of threshold probabilities/preferences for changing immunosuppression when 12-month NRM was used as the outcome. We conclude first, that the definition of response that uses onset and D14 grades is as accurate as D28 ORR model; and second, that a model using clinical grades and biomarkers on D14 more accurately predicts long term NRM than the standard D28 definition and may be useful as a clinical trial endpoint.

OA14 The role of anifrolumab in treating life threatening systemic lupus erythematosus with severe mucocutaneous involvement

OA14 The role of anifrolumab in treating life threatening systemic lupus erythematosus with severe mucocutaneous involvement

Small Intestinal Permeability and Metabolomic Profiles in Feces and Plasma Associate With Clinical Response in Patients With Active Psoriatic Arthritis Participating in a Fecal Microbiota Transplantation Trial: Exploratory Findings From the FLORA Trial.

We investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate-treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT). This exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate-treatment, were included in a 26-week, double-blind, 1:1 randomized, sham-controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n=15) or sham (n=16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose-to-mannitol ratio (LMR) test at baseline (n=31) and at week 26 (n=26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1 H Nuclear Magnetic Resonance. Trial failures (n=7) had significantly higher LMR compared with responders (n=19) at week 26 (0.027 [0.017-0.33]) vs. 0.012 [0-0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n=19) versus failures (n=12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N-acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient=0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient=27, P = 0.02). Intestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder.

A meta-analysis of GFR slope as a surrogate endpoint for kidney failure.

Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min-1 per 1.73 m2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R2) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R2 = 0.55 (95% BCI 0.25-0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression.

A potential primary endpoint for clinical trials in glaucoma neuroprotection

The purpose of this retrospective, longitudinal study is to evaluate the relationship between MD slope from visual field tests collected over a short period of time (2 years) and the current United States’ Food and Drug Administration (FDA) recommended endpoints for visual field outcomes. If this correlation is strong and highly predictive, clinical trials employing MD slopes as primary endpoints could be employed in neuroprotection clinical trials with shorter duration and help expedite the development of novel IOP-independent therapies. Visual field tests of patients with or suspected glaucoma were selected from an academic institution and evaluated based on two functional progression endpoints: (A) five or more locations worsening by at least 7 dB, and (B) at least five test locations based upon the GCP algorithm. A total of 271 (57.6%) and 278 (59.1%) eyes reached Endpoints A and B, respectively during the follow up period. The median (IQR) MD slope of eyes reaching vs. not reaching Endpoint A and B were −1.19 (−2.00 to −0.41) vs. 0.36 (0.00 to 1.00) dB/year and −1.16 (−1.98 to −0.40) vs. 0.41 (0.02 to 1.03) dB/year, respectively (P < 0.001). It was found that eyes experiencing rapid 24-2 visual field MD slopes over a 2-year period were on average tenfold more likely to reach one of the FDA accepted endpoints during or soon after that period.

Healthcare utilization and quality of life for atrial fibrillation burden: the CIRCA-DOSE study.

Atrial tachyarrhythmia recurrence ≥30 s remains the primary endpoint of clinical trials; however, this definition has not been correlated with clinical outcomes or pathophysiological processes. This study sought to determine the atrial tachyarrhythmia duration and burden associated with meaningful clinical outcomes. The time and duration of every atrial tachyarrhythmia episode recorded on implantable cardiac monitor were evaluated. Healthcare utilization and quality of life in the year following ablation were prospectively collected. Three hundred and forty-six patients provided 126 110 monitoring days. One-year freedom from recurrence increased with arrhythmia duration thresholds, from 52.6 (182/346) to 93.3% (323/346; P < 0.0001). Patients with atrial fibrillation (AF) recurrence limited to durations ≤1 h had rates of healthcare utilization comparable with patients free of recurrence, while patients with AF recurrences lasting >1 h had a relative risk for emergency department consultation of 3.2 [95% confidence interval (CI) 2.0-5.3], hospitalization of 5.3 (95% CI 2.9-9.6), and repeat ablation of 27.1 (95% CI 10.5-71.0). Patients with AF burden of ≤0.1% had rates of healthcare utilization comparable with patients free of recurrence, while patients with AF burden of >0.1% had a relative risk for emergency department consultation of 2.4 (95% CI 1.9-3.9), hospitalization of 6.8 (95% CI 3.6-13.0), cardioversion of 9.1 (95% CI 3.3-25.6), and repeat ablation of 21.8 (95% CI 9.2-52.2). Compared with patients free of recurrence, the disease-specific quality of life was significantly impaired with AF episode durations >24 h, or AF burdens >0.1%. AF recurrence, as defined by 30 s of arrhythmia, lacks clinical relevance. AF episode durations >1 h or burdens >0.1% were associated with increased rates of healthcare utilization.

Evaluation considerations for using surrogate endpoints in anticancer clinical trials

The prolongation of patient's overall survival is the accepted as gold standard to prove clinical values of anti-cancer drugs. However, if overall survival is taken as the primary endpoint in clinical trials for cancer types with a relatively good prognosis in the process of new anti-cancer drug research and development, the time to market the drugs will be prolonged due to the long follow-up time. In addition, overall survival is often interfered by confounding factors such as follow-up treatment. Therefore, regulatory agencies have established an accelerated review model using surrogate endpoints for the approval of new anti-cancer drugs, but there are still some problems in the use of surrogate endpoints in cancer clinical trials. From the perspective of new drug review, the authors expounds the key points of confirming and rationally using surrogate endpoints in clinical trials of anti-cancer drugs, which will improve the level of clinical trials of new anti-cancer drugs and accelerate the development of anti-tumor drugs.

Adaptive Behavior in Young Autistic Children: Associations with Irritability and ADHD Symptoms.

Attention-deficit/hyperactivity disorder (ADHD) symptoms affect 40-60% of autistic children and have been linked to differences in adaptive behavior. It is unclear whether adaptive behavior in autistic youth is directly impacted by co-occurring ADHD symptoms or by another associated feature of both autism and ADHD, such as increased irritability. The current study examined relationships between irritability, ADHD symptoms, and adaptive behavior in 3- to 7-year-old autistic children. Results suggest that, after adjusting for co-occurring ADHD symptoms, higher levels of irritability are associated with differences in social adaptive behavior specifically. Understanding relationships between irritability, ADHD, and adaptive behavior in autistic children is critical because measures of adaptive behavior, such as the Vineland Scales of Adaptive Functioning, are often used as a proxy for global functioning, as well as for developing intervention plans and measuring outcomes as primary endpoints in clinical trials.

The efficacy and safety of macitentan in Fontan-palliated patients: results of the 52-week randomised, placebo-controlled RUBATO trial

Abstract Background The clinical utility and long-term effects of endothelin receptor antagonists (ERAs) in Fontan-palliated patients remain unclear and there are currently no approved therapies. A decline in peak VO2 between consecutive cardiopulmonary exercise tests (CPETs) is highly prognostic for death or transplant in adult Fontan patients, hence its use as a primary endpoint in clinical trials of ERAs in patients with Fontan circulation. Purpose The RUBATO trial aimed to assess the efficacy and safety of macitentan, an endothelin receptor antagonist, in Fontan-palliated patients over 52 weeks. Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 RUBATO trial, Fontan-palliated patients were randomised 1:1 to macitentan 10 mg once-daily or placebo for 52 weeks. Eligible patients were aged ≥12 years, in New York Heart Association functional class II or III, had no limitations for CPET (including no pacemakers), had undergone lateral tunnel or extracardiac conduit Fontan (total cavopulmonary connection) &amp;gt;1 year before screening and showed no signs of Fontan failure or clinical deterioration within 3 months before screening. Primary efficacy endpoint was change in peak VO2 from baseline to week 16. Secondary endpoints were change in peak VO2 from baseline over 52 weeks and change in mean count per minute of daily physical activity from baseline to week 16 as measured by an accelerometer. Adverse events were also assessed. Results 137 patients were randomised to macitentan (n=68) or placebo (n=69). 92.7% of patients completed 52 weeks of double-blind treatment: 7 and 3 patients prematurely discontinued study treatment in macitentan and placebo arms, respectively. Patient baseline characteristics are shown in Table 1. At week 16, the mean (SD) change from baseline in peak VO2 was –0.16 (2.86) with macitentan vs –0.67 (2.66) mL/kg/min with placebo (median unbiased estimate of the difference between macitentan and placebo: 0.62 mL/kg/min [99% repeated confidence interval –0.62; 1.85], p=0.1930). No treatment effect was observed in the two secondary endpoints (Table 2): mean (SD) count per minute of daily physical activity decreased from baseline to week 16 by 3.02 (92.44) with macitentan and by 14.34 (117.56) with placebo (p=0.4512). The most common AEs were headache (10.3% vs 8.7% on placebo), nasopharyngitis (5.9% vs 4.3%), and pyrexia (5.9% vs 4.3%). AEs leading to treatment discontinuation were reported in 3 (4.4%) and 1 (1.4%) of macitentan and placebo patients. Conclusion The 52-week RUBATO trial provides an important addition to data on the clinical utility of ERAs in Fontan-palliated patients. The primary efficacy endpoint was not met and no treatment effect was observed for the two secondary endpoints. Macitentan was well tolerated; safety findings were consistent with the known safety profile of macitentan 10 mg. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Actelion Pharmaceuticals Ltd., a Janssen pharmaceutical company of Johnson &amp; Johnson.

Correlation of the combined symptom and medication score with quality of life, symptom severity and symptom control in allergic rhinoconjunctivitis.

BackgroundThe European Academy of Allergy and Clinical Immunology recommended the Combined Symptom and Medication Score (CSMS) as primary endpoint in clinical trials on allergen‐specific immunotherapy (AIT) in allergic rhinoconjunctivitis. Here, the correlation between the CSMS and the validated standardised Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)), Rhinitis Control Assessment Test (RCAT) and Visual Analogue Scale (VAS) was analysed.MethodsTwo prospective, multicentre, non‐interventional studies on tree pollen, grass pollen and house dust mite allergic patients were performed. The first study comprised 167 patients receiving AIT (AIT population), and the second included 56 patients treated with symptomatic medication only (control population). For up to two seasons (pollen)/exposure periods (house dust mites), participants documented their symptoms and medication intake in a CSMS diary, including VAS. In addition, the standardised RQLQ(S) and the RCAT were completed during study visits.ResultsComparison between CSMS and RQLQ(S) revealed a positive correlation in the AIT population (r = 0.426) and in the control population (r = 0.569). For CSMS and RCAT, a negative correlation with r = −0.409 (AIT) and r = −0.547 (control) was shown. Positive correlation between CSMS and VAS was also demonstrated with r = 0.585 (AIT) and r = 0.563 (control).ConclusionThese results support the assumption that the CSMS correlates with quality of life, symptom severity and symptom control on the one hand, while the moderate strength of correlations on the other hand mirrors distinctions of the CSMS compared to the assessments used here.

Operator assessment versus core laboratory adjudication of recanalization following endovascular treatment of acute ischemic stroke: a systematic review and meta-analysis

BackgroundSuccessful recanalization after endovascular thrombectomy serves as the primary endpoint in clinical trials and is a crucial predictor of long-term outcomes. Radiographic outcomes for various interventions have been shown to...

Impact of Lenalidomide Treatment on Overall Survival in Patients With Lower-Risk, Transfusion-Dependent Myelodysplastic Syndromes.

For patients with lower-risk (LR) myelodysplastic syndromes (MDS), overall survival (OS) is rarely a primary clinical trial endpoint. Treatments such as lenalidomide can reduce red blood cell (RBC) transfusion burden (TB) and serum ferritin, but the long-term impact on OS remains undetermined. Data from 3 trials evaluating lenalidomide in patients with LR-MDS (the phase 2 MDS-003 and phase 3 MDS-004 trials in del[5q]; the phase 3 trial MDS-005 in non-del[5q] patients) were pooled. Predictors of OS were assessed by multivariate analysis using time-dependent models for TB and RBC transfusion independence (RBC-TI), and a landmark analysis of RBC-TI at 17 weeks. Separate analyses using MDS-004 and MDS-005 data determined the relationship between OS and serum ferritin. Median follow-up for MDS-003, MDS-004, and MDS-005 was 3.2, 3.0, and 1.7 years, respectively. In multivariate analyses, transfusion of ≥6 RBC units over 8 weeks was a significant predictor of shorter OS vs. 0 units in the time-dependent TB model (hazard ratio [HR] 4.65; 95% confidence interval [CI] 3.32-6.52; P < .0001). RBC-TI achievement was associated with prolonged OS in the time-dependent (HR 0.48; 95% CI 0.37-0.62; P < .0001) and landmark model (HR 0.57; 95% CI 0.44-0.75; P < .0001). Increased serum ferritin was associated with shorter OS (P < .0001). This analysis of prospective trial data in patients with LR-MDS confirms lenalidomide may improve OS by reducing TB and serum ferritin. OS should be considered as an endpoint in future lower risk MDS clinical trials.

Best Practices in Liver Biopsy Histologic Assessment for Nonalcoholic Steatohepatitis Clinical Trials: Expert Opinion

Background. In most clinical trials focusing on precirrhotic nonalcoholic steatohepatitis (NASH), a liver biopsy is required for confirmation of diagnosis, staging fibrosis, and grading steatohepatitis activity. Reliance on the biopsy, both as a requisite for study entry, as well as for a primary endpoint in clinical trials, poses several challenges that need to be overcome: patient reluctance to undergo the procedure; potential sampling error; concern regarding the handling, processing and shipping of the biopsy of the biopsy material to the central reader(s); and the degree of pathologists’ intra- and interobserver variability in biopsy interpretation. Aims. To provide recommendations for improving the liver biopsy process in order to maximize the accuracy of its histological interpretation in NASH clinical trials. Methods and Results. These recommendations were created by an expert panel of participants from the United States and European Union who met multiple times and reached alignment through review of available data and their individual clinical experiences. The recommendations include the methodology for biopsy procedure, central lab and pathology processing of the specimen, and recommendations to minimize the intra- and intersubject variability. Finally, we are discussing digital pathology technology and machine learning applications as important additions to enhance liver biopsy interpretation.Conclusions. Liver biopsy poses multiple challenges in clinical trials in NASH, and there is a need to standardize the processes to maximize accuracy and minimize variability. Many questions remained unanswered due to limited available data. New evolving modalities may help in the future, but generation of robust data is warranted.