Regulatory Issues of Platform Trials: Learnings from EU-PEARL.

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

Simple blood tests to diagnose compensated advanced chronic liver disease and stratify the risk of clinically significant portal hypertension.

BACKGROUND AND AIMS: Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO). APPROACH AND RESULTS: Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 [95% CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95% CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95% CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95% CI:0.801-0.910], p = 0.351) and the ANTICIPATE model (AUROC:0.910 [95% CI:0.869-0.952], p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated. CONCLUSIONS: Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Predicting survival in patients with 'non-high-risk' acute variceal bleeding receiving ß-blockers+ligation to prevent re-bleeding.

BACKGROUND & AIMS: Pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice for high-risk acute variceal bleeding (AVB; i.e., Child-Turcotte-Pugh [CTP] B8-9+active bleeding/C10-13). Nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation for secondary prophylaxis. We investigated prognostic factors for re-bleeding and mortality in 'non-high-risk' AVB to identify subgroups who may benefit from more potent treatments (i.e., TIPS) to prevent further decompensation and mortality. METHODS: A total of 2,225 adults with cirrhosis and variceal bleeding were prospectively recruited at 34 centres between 2011-2015; for the purpose of this study, case definitions and information on prognostic indicators at index AVB and on day 5 were further refined in low-risk patients, of whom 581 (without failure to control bleeding or contraindications to TIPS) who were managed by non-selective beta-blockers/endoscopic variceal ligation, were finally included. Patients were followed for 1 year. RESULTS: Overall, 90 patients (15%) re-bled and 70 (12%) patients died during follow-up. Using clinical routine data, no meaningful predictors of re-bleeding were identified. However, re-bleeding (included as a time-dependent co-variable) increased mortality, even after accounting for differences in patient characteristics (adjusted cause-specific hazard ratio: 2.57; 95% CI 1.43-4.62; p = 0.002). A nomogram including CTP, creatinine, and sodium measured at baseline accurately (concordance: 0.752) stratified the risk of death. CONCLUSION: The majority of 'non-high-risk' patients with AVB have an excellent prognosis, if treated according to current recommendations. However, about one-fifth of patients, i.e. those with CTP ≥8 and/or high creatinine levels or hyponatremia, have a considerable risk of death within 1 year of the index bleed. Future clinical trials should investigate whether elective TIPS placement reduces mortality in these patients. IMPACT AND IMPLICATIONS: Pre-emptive transjugular intrahepatic portosystemic shunt placement improves outcomes in high-risk acute variceal bleeding; nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation. This is the first large-scale study investigating prognostic factors for re-bleeding and mortality in 'non-high-risk' acute variceal bleeding. While no clinically meaningful predictors were identified for re-bleeding, we developed a nomogram integrating baseline Child-Turcotte-Pugh score, creatinine, and sodium to stratify mortality risk. Our study paves the way for future clinical trials evaluating whether elective transjugular intrahepatic portosystemic shunt placement improves outcomes in presumably 'non-high-risk' patients who are identified as being at increased risk of death.

Influence of a Capsular Tension Ring on Capsular Bag Behavior of a Plate Haptic Intraocular Lens: An Intraindividual Randomized Trial.

PURPOSE: To evaluate the influence of a capsular tension ring (CTR) on rotational stability, decentration, tilt, and axial stability of an 11.0-mm plate haptic intraocular lens (IOL). DESIGN: Intraindividual, randomized, double-masked, controlled clinical trial. PARTICIPANTS: Patients scheduled for sequential same-day bilateral cataract surgery. METHODS: All patients were randomized to receive a CTR and a plate haptic IOL in one eye and a plate haptic IOL in the fellow eye only. Intraocular lens axis assessment was performed at the end of surgery, 1 hour, 1 week, 1 month, and 6 months using a high-precision evaluation method. Decentration and tilt of the crystalline and pseudophakic lenses were assessed before surgery and at 1 week and 6 months using an anterior segment OCT. MAIN OUTCOME MEASURES: Rotational stability from the end of surgery to 6 months and at all follow-up visits, decentration and tilt at 6 months, and differences in axial shift between 1 week and 6 months. RESULTS: One hundred thirty eyes of 65 patients were included in the study. Absolute rotation from the end of surgery to 6 months was 2.8 ± 3.9° and 3.2 ± 5.3° for the CTR and control groups, respectively (P = 0.613). Intraocular lens decentration and IOL tilt at 6 months were 0.29 ± 0.1 mm and 0.24 ± 0.1 mm and 6.7 ± 2.8° and 5.6 ± 1.6° for the CTR and control groups, respectively (P = 0.058; P < 0.01). A posterior IOL shift of 0.31 ± 0.31 mm and 0.19 ± 0.14 mm was observed in the CTR and control groups, respectively. CONCLUSIONS: Concomitant implantation of a CTR and a plate haptic IOL did not improve the overall rotational stability of the IOL compared with the control group. Against expectations, higher values of decentration, tilt, and axial shift were observed in the CTR group. The simultaneous use of a CTR and a plate haptic IOL in the absence of zonular weakness at the time of cataract surgery should be considered with caution. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Disturbances in sodium and chloride homeostasis predict outcome in stable and critically ill patients with cirrhosis.

BACKGROUND: Hyponatremia has prognostic implications in patients with cirrhosis, and thus, has been incorporated in the 2016 MELD-UNOS update. Changes in serum chloride are commonly perceived as 'just' parallel to changes in serum sodium. However, these are less well studied in the context of cirrhosis. AIMS: To investigate whether serum chloride independently predicts outcomes in patients with advanced chronic liver disease (ACLD) and stable clinical course or with critical illness. METHODS: 891 patients with ACLD (defined by hepatic venous pressure gradient [HVPG] ≥6 mm Hg) were followed after HVPG measurement between 2003 and 2020 (ACLD cohort). 181 critically ill patients with cirrhosis admitted to the ICU between 2004 and 2007 were recruited for the ICU cohort. Hypo-/hypernatremia (normal: 136-145 mmol/L) and hypo-/hyperchloremia (normal: 98-107 mmol/L) at baseline were assessed. RESULTS: ACLD cohort: 68% of male patients with a median MELD (adjusted for Na) of 11 (9-17) were included (Child-Pugh-stages-A/B/C: 46%/38%/16%) and followed for a median of 60 months. Lower serum chloride (adjusted average HR per mmol/L: 0.965 [95% confidence interval (95% CI): 0.945-0.986], p = 0.001) showed a significant association with hepatic decompensation/liver-related mortality on multivariable Cox regression analysis adjusted for age, HVPG, albumin and MELD. In line, hypochloremia was significantly associated with hepatic decompensation/liver-related mortality (adjusted average HR: 1.656 [95% CI:1.267-2.163], p < 0.001). ICU cohort: 70% of patients were male, median MELD was 31(22-39) at ICU admission (92% with Child-Pugh-stage-C). After adjusting for hypo-/hypernatremia, MELD, and blood pH, hypochloremia remained independently associated with ICU-mortality (aOR Cl: 3.200 [95%CI: 1.209-8.829], p = 0.021). CONCLUSION: Hypochloremia is associated with increased mortality in clinically stable and critically ill patients with cirrhosis independently of MELD including serum sodium.

Designing an exploratory phase 2b platform trial in NASH with correlated, co-primary binary endpoints.

Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and a disease with high unmet medical need. Platform trials provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. In this article, we describe some of the activities of the EU-PEARL consortium (EU Patient-cEntric clinicAl tRial pLatforms) regarding the use of platform trials in NASH, in particular the proposed trial design, decision rules and simulation results. For a set of assumptions, we present the results of a simulation study recently discussed with two health authorities and the learnings from these meetings from a trial design perspective. Since the proposed design uses co-primary binary endpoints, we furthermore discuss the different options and practical considerations for simulating correlated binary endpoints.

Evaluation of a Bariatric Monitoring Pass for Primary Care Physicians.

INTRODUCTION: There are a growing number of patients undergoing bariatric surgery requiring lifelong follow-up. Therefore, follow-up care can no longer be covered by specialized outpatient clinics alone due to the sharp rise in the number of bariatric patients. Bariatric Patients in Primary Care: Postoperative Nutrition and Lifestyle Management (BagEL) is a survey to evaluate a newly developed structured disease management program including nutrition and lifestyle management in primary care. METHODS: The study is conceived as a randomized cohort study with a control group. An expert questionnaire for general practitioners (GPs) was developed to assess the usability of a structured postoperative care system regarding nutrition and lifestyle management for bariatric patients in primary care. A structured follow-up program in primary care with a so-called bariatric monitoring passport (BMP) was provided for patients in the intervention (INT) group and the existing information sheet "Metabolic surgery and perioperative care" for the control (CON) group. 124 patients, who met inclusion criteria and who underwent a bariatric procedure first time, served as ambassadors for delivery of the expert questionnaire and study documents to their individual GPs. RESULTS: A total of 39 (31.5%) different GPs from 124 ambassador patients responded. For the primary outcome "Does the aftercare-booklets support treatment of bariatric patients?" GPs of the INT group rated the new designed aftercare booklet (INT) significantly more helpful for treating bariatric patients than the one from the CON group (p = 0.041). DISCUSSION/CONCLUSION: These results suggest that GPs are welcoming supportive tools like our BMP to improve the care of long-term follow-up of bariatric patients and should actively participate in the development of lifelong disease management plans necessary to cope with the rapidly growing number of patients.

Decision rules for identifying combination therapies in open-entry, randomized controlled platform trials.

Platform trials have become increasingly popular for drug development programs, attracting interest from statisticians, clinicians and regulatory agencies. Many statistical questions related to designing platform trials-such as the impact of decision rules, sharing of information across cohorts, and allocation ratios on operating characteristics and error rates-remain unanswered. In many platform trials, the definition of error rates is not straightforward as classical error rate concepts are not applicable. For an open-entry, exploratory platform trial design comparing combination therapies to the respective monotherapies and standard-of-care, we define a set of error rates and operating characteristics and then use these to compare a set of design parameters under a range of simulation assumptions. When setting up the simulations, we aimed for realistic trial trajectories, such that for example, a priori we do not know the exact number of treatments that will be included over time in a specific simulation run as this follows a stochastic mechanism. Our results indicate that the method of data sharing, exact specification of decision rules and a priori assumptions regarding the treatment efficacy all strongly contribute to the operating characteristics of the platform trial. Furthermore, different operating characteristics might be of importance to different stakeholders. Together with the potential flexibility and complexity of a platform trial, which also impact the achieved operating characteristics via, for example, the degree of efficiency of data sharing this implies that utmost care needs to be given to evaluation of different assumptions and design parameters at the design stage.

HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) caused by chronic hepatitis C who have achieved sustained virologic response (SVR). We developed risk stratification algorithms for de novo HCC development after SVR and validated them in an independent cohort. METHODS: We evaluated the occurrence of de novo HCC in a derivation cohort of 527 patients with pre-treatment ACLD and SVR to interferon-free therapy, in whom alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. We validated our results in 1,500 patients with compensated ACLD (cACLD) from other European centers. RESULTS: During a median follow-up (FU) of 41 months, 22/475 patients with cACLD (4.6%, 1.45/100 patient-years) vs. 12/52 decompensated patients (23.1%, 7.00/100 patient-years, p <0.001) developed de novo HCC. Since decompensated patients were at substantial HCC risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de novo HCC development during FU than pre-treatment values or absolute/relative changes. Models based on post-treatment AFP, alcohol consumption (optional), age, LSM, and albumin, accurately predicted de novo HCC development (bootstrapped Harrel's C with/without considering alcohol: 0.893/0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low- (~2/3 of patients) and high-risk (~1/3 of patients) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk: 0% vs. 16.5%) and validation (3.3% vs. 17.5%) cohorts. An alternative approach based on alcohol consumption (optional), age, LSM, and albumin (i.e., without AFP) also showed a robust performance. CONCLUSIONS: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol consumption, accurately stratified patients with cACLD based on their risk of de novo HCC after SVR. Approximately two-thirds were identified as having an HCC risk <1%/year in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC surveillance. LAY SUMMARY: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately two-thirds) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound.

Adjunctive treatment with high-titre convalescent plasma in severely and critically ill COVID-19 patients - a safe but futile intervention. A comparative cohort study.

BACKGROUND: Convalescent plasma (CP) containing antibodies derived from coronavirus disease 2019 (COVID-19) survivors has been proposed as a promising therapeutic option for severe COVID-19. METHODS: In our intensive care unit (ICU), 55 patients (46 male, median age 61 years) with PCR-confirmed COVID-19 (35 = 63.6% on mechanical ventilation, 7 = 14.5% on high-flow nasal oxygen, 12 = 20% on non-invasive ventilation, 1 = 1.8% without respiratory support) were treated with high-titre CP (200 mL per dose, range 1-6 doses, median 3 doses per patient, minimum titre > 1:100, Wantai test). 139 COVID-19 patients treated in the same ICU who did not receive CP served as control group. In 27 patients, the effect of CP on the individual levels of SARS-CoV-2 IgG antibodies was assessed by ELISA in serum sample pairs collected before and after CP transfusion. RESULTS: The first CP dose was administered at a median of 8 days after symptom onset. 13 patients in the plasma cohort died (28-day mortality 24.1%), compared to 42 (30.2%) in the cohort who did not receive CP (p = 0.5, Pearson Chi-squared test). Out of the 27 individuals investigated for the presence of IgG antibodies, 8 did not have detectable IgG levels before the first CP transfusion. In this subpopulation, 3 patients (37.5%) died. Not a single confirmed adverse reaction to CP was noted. CONCLUSIONS: While adjunctive treatment with CP for severe and life-threatening COVID-19 was a very safe intervention, we did not observe any effect on mortality.

Systematic review of available software for multi-arm multi-stage and platform clinical trial design.

BACKGROUND: In recent years, the popularity of multi-arm multi-stage, seamless adaptive, and platform trials has increased. However, many design-related questions and questions regarding which operating characteristics should be evaluated to determine the potential performance of a specific trial design remain and are often further complicated by the complexity of such trial designs. METHODS: A systematic search was conducted to review existing software for the design of platform trials, whereby multi-arm multi-stage trials were also included. The results of this search are reported both on the literature level and the software level, highlighting the software judged to be particularly useful. RESULTS: In recent years, many highly specialized software packages targeting single design elements on platform studies have been released. Only a few of the developed software packages provide extensive design flexibility, at the cost of limited access due to being commercial or not being usable as out-of-the-box solutions. CONCLUSIONS: We believe that both an open-source modular software similar to OCTOPUS and a collaborative effort will be necessary to create software that takes advantage of and investigates the impact of all the flexibility that platform trials potentially provide.

Reliability of coronary computed tomography angiography in acute coronary syndrome in an emergency setting.

BACKGROUND: Cardiovascular computed tomography (cardiovascular CT) is currently used as a fast non-invasive method for the visualization of coronary plaques and walls and the assessment of lumen stenosis severity. Previous studies demonstrated the high negative predictive value of CT for the exclusion of coronary lumen stenoses. In this study we hypothesize that coronary CT angiography (CTA) represents a reliable method as diagnostic procedure in acute coronary syndrome (ACS) even in emergency settings. METHODS: 36 patients (51 lesions) with ACS who underwent cardiovascular CT, intravascular ultrasound (IVUS) and invasive coronary angiography (ICA) within 48 h were included. The percentage of coronary stenoses were measured and compared by three methods. Influence of available predictors that can potentially affect the measurement results was assessed. RESULTS: Cardiac CTA provided comparable results to IVUS (mean difference -0.45%, PPV: 98%, NPV: 75%). ICA tends to estimate lower stenoses degrees than cardiac CTA and IVUS (mean difference 13.19% and 13.64%, respectively). The final diagnosis and positive remodeling did not lead to any significant influence on measurements. CONCLUSIONS: The cardiovascular CT results show that even in emergency settings it is possible to identify morphological changes as sequels of coronary artery sclerosis with comparable results to the reference method IVUS. Deviations of IVUS and cardiovascular CT from ICA are comparable and can to a large extent be explained by differences in the measurement technique.

The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review.

PURPOSE: Recent years have seen a change in the way that clinical trials are being conducted. There has been a rise of designs more flexible than traditional adaptive and group sequential trials which allow the investigation of multiple substudies with possibly different objectives, interventions, and subgroups conducted within an overall trial structure, summarized by the term master protocol. This review aims to identify existing master protocol studies and summarize their characteristics. The review also identifies articles relevant to the design of master protocol trials, such as proposed trial designs and related methods. METHODS: We conducted a comprehensive systematic search to review current literature on master protocol trials from a design and analysis perspective, focusing on platform trials and considering basket and umbrella trials. Articles were included regardless of statistical complexity and classified as reviews related to planned or conducted trials, trial designs, or statistical methods. The results of the literature search are reported, and some features of the identified articles are summarized. FINDINGS: Most of the trials using master protocols were designed as single-arm (n = 29/50), Phase II trials (n = 32/50) in oncology (n = 42/50) using a binary endpoint (n = 26/50) and frequentist decision rules (n = 37/50). We observed an exponential increase in publications in this domain during the last few years in both planned and conducted trials, as well as relevant methods, which we assume has not yet reached its peak. Although many operational and statistical challenges associated with such trials remain, the general consensus seems to be that master protocols provide potentially enormous advantages in efficiency and flexibility of clinical drug development. IMPLICATIONS: Master protocol trials and especially platform trials have the potential to revolutionize clinical drug development if the methodologic and operational challenges can be overcome.

Comparison of Long-Term Rotational Stability of Three Commonly Implanted Intraocular Lenses.

PURPOSE: To compare rotational stability and its influencing factors in 3 different widely used hydrophobic acrylic intraocular lenses (IOLs) from the end of surgery (EoS) to 4-7 months (6 months) in over 380 eyes. DESIGN: Prospective interventional comparative clinical study. METHODS: Setting: Department of Ophthalmology, Medical University of Vienna. PATIENT POPULATION: A total of 381 eyes of 199 patients with age-related cataract received an IOL Acrysof SN60WF, Tecnis ZCB00, or Envista MX60 in a consecutive order. INTERVENTION: Implantation of an Acrysof, Tecnis, or Envista IOL randomized to the 0 ± 10, 45 ± 10, 90 ± 10, or 135 ± 10° axis in 1 or both eyes. Baseline measurement was performed with patients supine still on the operating table. Postoperative follow-ups were conducted after 1 hour, 1 week, 1 month, and 6 months. MAIN OUTCOME MEASURES: Difference of absolute rotation from the EoS to 6 months. RESULTS: Absolute rotations from the EoS to 6 months were 1.65 ± 2.1, 2.65 ± 4.1, and 3.18 ± 5.8° for the Acrysof, Tecnis, and Envista group, respectively. Rotational stability was statistically significantly superior in the Acrysof compared with the Envista group (P = .014), but not compared with the Tecnis group (P = .10). No significant difference was found between the Tecnis and Envista groups (P = .761). Maximum values of 15.8, 38.6, and 44.9° were observed for the Acrysof, Tecnis, and Envista group, respectively. CONCLUSION: The Acrysof IOL showed the least amount of absolute rotation compared with the Tecnis and Envista IOLs. Outliers possibly requiring secondary intervention were observed in all groups. The amount of rotation was greatest during the first postoperative hour.

The fetal fibronectin test is superior to cervical length measurement in predicting preterm birth in twin pregnancies: a retrospective observational study.

OBJECTIVES: Twin pregnancies have a higher likelihood to experience spontaneous preterm birth (PTB). Those with imminent PTB need to be determined in order to undergo fetal lung maturation with glucocorticoids and therewith improve neonatal outcomes. The aim of this study was to assess the predictive value of the fetal fibronectin (fFN) test and the measurement of cervical length in twin pregnancies with symptoms of imminent PTB. STUDY DESIGN: We performed an observational study on all twin pregnancies at the Medical University Vienna. Women were admitted to the hospital either due to symptoms of imminent PTB or due to a shortening of the cervical length before completed 34 weeks of gestational age. Logistic regression analysis was performed to assess the predictive value of the fFN test and cervical length on imminent preterm birth. RESULTS: The data of 82 women with twin pregnancies were eligible, of which 10 (12 %) had a positive, 45 (55 %) a negative, 21 (26 %) an unclear fFN result, and 6 (7 %) showed missing data. Cervical length ≤20 mm did not show any statistical significant prediction of PTB in our study cohort. After 7 days, 4/10 (40 %) pregnant women with positive fFN test gave birth, while 4/45 (9 %) women with a negative fFN test gave birth. Within 14 days after hospitalization, 6/10 (60 %) women with a positive fFN test gave birth, compared to 4/45 (9 %) with a negative fFN test. The positive fFN test was a statistically significant predictor of PTB within 7 days (p = 0.02) and 14 days (p = 0.004), respectively. CONCLUSION: The fFN test has the potential to detect women with twin pregnancies, who are at risk of giving birth within the following days. Hence, the practice of hospitalizing women solely due to the shortening of the cervical length cannot be supported.

Psychotic-like experiences in esoterism: A twilight zone?

BACKGROUND: Over the past decades, research has suggested the existence of a psychosis continuum ranging from psychotic-like experiences (PLEs) in the general population to psychotic symptoms in patients with affective and schizophrenia spectrum disorders. Especially individuals interested in esoterism were more often reported having experienced PLEs. However, there is little information on the extent of PLEs in this subculture. The aim of this study was to assess the extent of PLEs in a non-clinical population with interest in esoterism by means of an anonymized clinically used screening questionnaire. PARTICIPANTS AND METHODS: The 16-item version of the Prodromal Questionnaire (PQ-16), a self-report screening questionnaire assessing the presence of PLEs was administered to individuals with interest in esoterism (IE) and a control group without interest in esoterism (NI). RESULTS: The sample included 402 individuals. 224 subjects (55.7%) reported interest in esoterism and 178 subjects (44.3%) showed no such interest. In an ANCOVA, interest in esoterism was shown to have a significant impact on the PQ-16 score (<0.001). Also, age (p=0.022) and the interaction between age and interest in esoterism had a significant impact on the PQ-16 score (p=0.004). Specifically, younger individuals interested in esoterism showed increased PQ-16 scores, whereas scores decreased with increasing age. In individuals without interest in esoterism, age had no relevant impact on the score. CONCLUSION: Younger individuals interested in esoterism seem to be more prone to reporting psychotic-like experiences compared to individuals without interest in esoterism and compared to their older counterparts.