An interactive R-Shiny app for quickly visualizing a tidy, long dataset with multiple dimensions with an application in clinical trial simulations for platform trials

Visualizing tidy, long data with multiple dimensions is a task often encountered when performing scientific computer simulations. In general, in such simulations the impact of many input variables on many outcome metrics is investigated. One area where such complex data structures containing the simulated data are encountered is clinical trial simulation. When visualizing the complex data, we are usually interested in the marginal effect of (one or several) input variables, which mostly renders existing visualization software useless or tedious to use. We have developed an R-Shiny app designed specifically for this task, which significantly speeds up the workflow. In this article, the app is described alongside two illustrative examples, one of which illustrates the use of the app for visualizing actual platform trial simulation data

SIMPLE—A modular tool for simulating complex platform trials

Platform trials are becoming increasingly popular within drug development, attracting interest by patients, clinicians, regulatory agencies and statisticians. More often than not, these platform trial designs are highly complex and involve many weakly predictable events (e.g. number of investigational treatments that will enter over time) to determine the impact of relevant design parameters (e.g. decision rules, sharing of information across cohorts and allocation ratios) on the operating characteristics with high confidence. Simulations may address these uncertainties at the design stage. However, the number and combination of design elements for potential implementation in real platform trials is immense. As a result, simulation software which is developed based on specific project needs is typically limited in the variety of available design options for comparison, as such software is developed for a particular need, not for researching all potential new approaches to clinical research and statistical science. On the other hand, software solutions which allow for a wide range of design options may easily overload the user with requirements for design specifications. We have developed an R software package (“SIMPLE”), which is modular in the sense that if users want to simulate the most common platform designs, minimal effort and understanding of the package is needed, but it allows the users to take control of different parts of the simulation (e.g. patient accrual, outcome simulation, etc.) step-by-step, thereby facilitating the simulation of arbitrarily complex platform trials. We will give an overview of this software package alongside some examples on how to simulate common platform trial designs and derive their operating characteristics

PONE-D-18-04265_data

PONE-D-18-04265_dat

Data from: Mechanism of anti-remodelling action of treprostinil in human pulmonary arterial smooth muscle cells

Treprostinil is applied for pulmonary arterial hypertension (PAH) therapy. However, the mechanism by which the drug achieves its beneficial effects in PAH vessels is not fully understood. This study investigated the effects of treprostinil on PDGF-BB induced remodelling parameters in isolated human pulmonary arterial smooth muscle cells (PASMC) of four PAH patients. The production of TGF-β1, CTGF, collagen type-I and -IV, and of fibronectin were determined by ELISA and PCR. The role of cAMP was determined by ELISA and di-deoxyadenosine treatment. Proliferation was determined by direct cell count. Treprostinil increased cAMP levels dose and time dependently, which was not affected by PDGF-BB. Treprostinil significantly reduced PDGF-BB induced secretion of TGF-β1 and CTGF, both was counteracted when cAMP generation was blocked. Similarly, the PDGF-BB induced proliferation of PASMC was dose dependently reduced by treprostinil through signalling via cAMP - C/EBP-α p42 - p21(WAf1/Cip1). In regard to extracellular matrix remodelling, treprostinil significantly reduced PDGF-BB - TGF-β1 - CTGF induced synthesis and deposition of collagen type I and fibronectin, in a cAMP sensitive manner. In contrast, the deposition of collagen IV was not affected. The data suggest that this action of treprostinil in vessel wall remodelling may benefit patients with PAH and may reduce arterial wall remodelling

Designing an exploratory phase 2b platform trial in NASH with correlated, co-primary binary endpoints [dades primàries]

Simulated data; ResultsDatos simulados; ResultadosDades simulades; ResultatsPlatform trials in NASH provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. It contains the results of a simulation study. Includes S1 Table Simulated data used for results.Els assaigs de plataforma en NASH ofereixen grans beneficis per als patrocinadors i els participants pel que fa a l'acceleració dels programes de desenvolupament de medicaments. Es presenten els resultats d'un estudi de simulació. Inclou Taula S1 Dades simulades utilitzades per als resultats.Los ensayos de plataforma en NASH ofrecen grandes beneficios para los patrocinadores y los participantes en términos de aceleración de los programas de desarrollo de fármacos. Se presentan los resultados de un estudio de simulación. Incluye Tabla S1 Datos simulados utilizados para los resultados.EU-PEARL has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and CHILDREN’S TUMOR FOUNDATION, GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT NON PROFIT ORGANISATION, SPRINGWORKS THERAPEUTICS INC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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

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

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

BACKGROUND&AIMS Pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice in high-risk acute variceal bleeding (AVB; i.e., Child-Turcotte-Pugh [CTP] B8-9+active bleeding/C10-13). Nevertheless, 'non-high-risk' patients with poor outcomes remain despite the combination of non-selective beta-blockers (NSBB) and endoscopic variceal ligation (EVL) 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 2225 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. 581 well-characterised low-risk patients without failure to control bleeding or TIPS contraindications who were managed by NSBB/EVL were finally included. Patients were followed for one 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 outcome, 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