Seamless Design Research Articles

Advanced Utilization of Intermediate Endpoints for Making Optimized Cost-Effective Decisions in Seamless Phase II/III Oncology Trials

Traditional oncology trials are usually expensive, take a long time, and suffer from high failure rates. With cancer being one of the leading causes of death worldwide, there is an increasingly urgent need to improve current oncology drug development so that more innovative therapies can become available to cancer patients much sooner. Adaptive seamless Phase II/III designs hold great promise as they can accelerate the decision-making by eliminating the white space between Phase II and Phase III. Most literature discusses trial adaptions by using the same endpoint for both trial stages. However, in oncology drug development, the Phase III endpoint is usually a clinical endpoint, that is, overall survival, which takes long time to observe. Use of the clinical endpoint for adaptive decision may delay the trial adaptation and make seamless Phase II/III designs less appealing. This is one of the main reasons why such designs are less used in practice in oncology drug development. In this article, we would like to address the following two issues: (1) how to incorporate intermediate endpoint (e.g., progression-free survival or objective response rate) data into the decision criteria; (2) how to derive objective adaption criteria from a benefit-cost ratio perspective to streamline the decision-making process. This work is based on two real design examples in the oncology therapeutic area: an operationally seamless design with dose-selection and a statistically seamless 2-in-1 design. However, the general approach is applicable to various other therapeutic areas.

P.149The MYODA operational seamless clinical trial design phase I to III: a new approach for rare diseases to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BIO101 (MAS activator) in paediatric patients with a genetically confirmed diagnosis of Duchenne muscular dystrophy

Clinical development of new medications is traditionally broken down into 3 phases. This prevents patients from participating in more than one of the development phases and comes with a burden on site staff (with repeated site initiation and training) leading to prolonged development timelines (up to 10 years) and difficulties in patient recruitment, especially in rare diseases such as DMD. There is a significant need, therefore, for utilization of novel designs, which will make clinical development more amenable for patients and more efficient for study site staff. Biophytis is developing BIO101 (20-hydroxyecdysone, MAS activator) for DMD. The pre-clinical proof-of-concept (PoC) for BIO101 demonstrates combined beneficial effects on skeletal muscle and respiratory functions in DMD animal models, suggesting a range of benefit in a broad DMD population. To ensure an optimal and patient-centered clinical development of BIO101, a seamless methodology is intended to be utilized. The trial design should take into consideration the needs and struggle of the patients who participate in the study. An operational seamless design is one that can cover the requirements, in terms of needed evidence, to support a new medicine (i.e. from phase I to phase III), while offering participants an access to the trial medication and reduce the need for repeated screening procedures. Biophytis proposes a 3-part study that combines Phase I to III of the clinical development in one operational seamless study with adaptive elements. Patients with DMD with various degrees of loss of ambulation will be recruited in one of the four-ascending multiple-dose cohorts of 1 week-duration (Part1), they will continue at the same dose for 24 weeks (Part2=phase II) in order to support dose(s) that will be tested for the pivotal Part 3. Continuing patients from Part 1 and 2 with additional patients will enter a 48 week-period (Part 3) to establish longer term safety and efficacy of BIO101.

Criteria for dose-finding in two-stage seamless adaptive design

ABSTRACTIn pharmaceutical/clinical development, two-stage seamless adaptive designs are commonly considered. Such designs include a two-stage phase I/II or phase II/III adaptive trial that combines one phase IIb study for dose-finding or treatment selection and one phase III study for efficacy confirmation into a single study. At the end of stage 1, promising dose(s) will be selected based on pre-specified selection criteria. In practice, since there is little power with limited subjects available at interim, commonly considered selection criteria for critical decision-making include (i) conditional power, (ii) precision analysis, (iii) predictive probability of success, and (iv) probability of being the best dose or treatment. The selected promising dose(s) will then proceed to the next stage for efficacy confirmation. In this article, we introduce, compare, and evaluate these criteria. Simulation studies and a numeric example are given to illustrate those criteria. Besides, we attempt to address some concerns for the two-stage seamless adaptive clinical trial.

Estimation of the Resource Utilization and Costs of Cytokine Release Syndrome Observed in the Transcend-NHL Clinical Trial: A Micro-Costing Study

▪ INTRODUCTIONInformation on the differential resources and costs associated with managing treatment-related adverse events (TRAEs) from chimeric antigen receptor T-cell (CAR T) therapies, including cytokine release syndrome (CRS), have not been estimated and may differ by therapy. Lisocabtagene maraleucel (liso-cel; JCAR017) is a CD19-directed 4-1BB CAR T cell product administered in a defined composition at a precise 1:1 dose of CD8 and CD4 CAR T cells. TRANSCEND-NHL 001 is a multicenter seamless design pivotal phase 1 trial of liso-cel in R/R B-NHL (NCT02631044). The objectives of this analysis were to estimate the cost of CRS management observed in the TRANSCEND-NHL trial and to compare the CRS treatment with the trial's management guidelines. METHODSCase report forms detailed health resource utilization (HRU) related to CRS management among patients treated in the TRANSCEND-NHL trial who experienced CRS. CRS was graded per Lee et al. 2014. A two-step micro-costing method was used to identify resource use and estimate costs associated with CRS. Step 1 included analyzing HRU for managing each event, including number of inpatient days, number of intensive care unit (ICU) days, procedures (e.g. lab work, imaging, biopsy), and medications. HRU that occurred within the TRAE onset date and resolution date was included. Step 2 involved applying costs to each HRU. The base-case analysis included only HRU collected among patients from the TRANSCEND-NHL trial that was in accordance with trial's CRS management guidelines for each specified grade.Scenario analysis included HRU not specified in the guidelines. Unit costs were from the health system perspective and were adjusted to 2018 USD. Cost per inpatient day ($2,668) was estimated from HCUP Databases, and cost per ICU day ($6,546) was sourced from Dasta et al. 2005. Medication cost data are from REDBOOKTM using wholesale acquisition cost. Diagnostic and procedure costs are from the Centers for Medicare & Medicaid Services lab fee schedule and physician fee schedule, respectively. Analyses are stratified by grade and by site of care (inpatient or outpatient) at which the CAR T cell therapy was administered. RESULTSCRS occurred in 38 of 102 patients treated in the dose-finding/dose-expansion portions of the TRANSCEND-NHL clinical trial. Among the 38 patients, 19 patients experienced grade 1, 18 grade 2, and 1 grade 4 CRS. Total HRU and cost differed between CRS grades. Length of stay (LOS) associated with CRS management by grade are shown in Table 1. Median and average LOS increased with higher CRS grades. Mean LOS for grades 1 and 2 were 4 and 7 days, respectively. One patient with grade 4 had a 34-day LOS. No patients with CRS grade 1 were transferred to the ICU, and the mean ICU LOS for CRS grade 2 patients was 1 day. Mean LOS was longer among patients who were administered CAR T therapy in the inpatient setting (6.3 days) compared with the outpatient setting (5.3 days). Patients in TRANSCEND-NHL were successfully managed with conservative health resource utilization compared with the guidelines. For instance, while the trial management guidelines suggest tocilizumab for patients with Grade 2 CRS, this was administered to only half of Grade 2 CRS patients (9/18, 50%).Total cost is driven by LOS and for grades 1 and 2 CRS ranged from $11,226 to $25,617. LOS represented 94.4% and 83.5% of total cost in grades 1 and 2, respectively. The one CRS grade 4 patient incurred a 34-day LOS, contributing 94.9% of an estimated total cost of $201,836. Resource use not referenced in the guidelines was largely comprised of medication use and resulted in minimal increases in total cost. Costs due to resource use outside of the guidelines ranged from $1,698 to $21,055. The total cost of CRS management is reported in Figure 1. CONCLUSIONSThe results of this analysis show that hospital and ICU LOS are key drivers of CRS management cost and are mainly associated with managing grade 3/4 CRS. These results are based on national average costs; actual costs may vary between hospitals. The incidence of CRS and management guidelines vary across CAR T therapies and will affect both HRU and associated cost differences. CRS management is also contingent on patient characteristics. The biology of CAR Ts and resultant safety profile of the various products will likely drive dissimilarities in CRS management and cost. [Display omitted] DisclosuresSiddiqi:Juno Therapeutics: Other: Steering committee. Garcia:Juno Therapeutics, a fully owned subsidiary of Celgene: Employment, Equity Ownership. Dehner:Juno Therapeutics, a fully owned subsidiary of Celgene: Employment, Equity Ownership. Nguyen:Juno Therapeutics: Consultancy. Gitlin:Juno Therapeutics: Consultancy. Chung:Juno Therapeutics: Employment. Abramson:Verastem: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Merck: Consultancy; Humanigen: Consultancy; Seattle Genetics: Consultancy.

TRANSCEND: Lisocabtagene Maraleucel (liso-cel; JCAR017) Healthcare Resource Utilization in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Relapsed/refractory (R/R) DLBCL is associated with high healthcare resource utilization (HRU) and cost (Danese 2017). Patients with R/R DLBCL have poor outcome with median OS <10 months (Van den Neste 2015). As transformative therapies are being developed for these patients, resource utilization may become an issue. Liso-cel is an investigational defined composition, CD19-directed 4-1BB CAR T cell product administered at a precise dose of CD8 and CD4 CAR T cells in a multicenter, seamless design Phase 1 pivotal trial of (R/R) DLBCL (TRANSCEND NHL 001; NCT02631044). In a recent analysis with 6 months follow-up, liso-cel treatment demonstrated a best overall response rate of 75% (55% CR) with low rates of severe cytokine release syndrome (1%) and neurologic events (13%) (Abramson 2018). The objective of this analysis is to characterize HRU, including site of care, associated with liso-cel in an interim analysis of the TRANSCEND pivotal trial.Methods: Eligible patients with R/R DLBCL, PMBCL, FL grade 3B, or MCL (≥18 years who received ≥2 lines of therapy) and adequate organ function (no minimum ALC requirement for apheresis) received lymphodepletion (LD) with fludarabine and cyclophosphamide, followed by a single flat-dose infusion of liso-cel at one of two dose levels (DL1, 5 × 107 cells; DL2, 1 × 108 cells). Clinical site of care for liso-cel infusion was not protocol-defined. HRU was collected at all sites.Results: 94 patients (91 patients in the efficacy database and 3 patients from the safety database that were not in the electronic clinical as of data cut) were included in the preliminary site of care analysis. 86 patients received liso-cel in the inpatient setting and 8 patients in the outpatient setting. Mean (SD) number of hospital days was 15.6 (9.6) and 9.3 (11.9) among patients receiving inpatient and outpatient liso-cel infusion, respectively, reflecting a 40% lower duration in mean hospital days. The median time to hospitalization following outpatient infusion was 5 days (range: 4-22). No patients infused in the outpatient setting required subsequent ICU care or received corticosteroids, and only one received tocilizumab for cytokine release syndrome (CRS). Of all treated patients in the efficacy database (n=91), 12% (11/91) of patients required ICU care for management of toxicity, including 10% (9/91) for CRS or neurotoxicity and 3% (3/91) for management of acute respiratory events. Rates of hemofiltration and ventilation for patients in this cohort were 2% (2/91) and 7% (6/91), respectively. Outcomes based on site of administration will be presented (based on longer follow-up).Conclusions: CAR T cell therapy represents an additional treatment option for patients with R/R DLBCL. Liso-cel has been infused in both the inpatient and outpatient setting. Outpatient infusion was associated with 40% lower mean hospital days compared with infusions administered in the inpatient setting. As enrollment is ongoing, updated data will be reported. DisclosuresPalomba:Celgene: Consultancy; Pharmacyclics: Consultancy. Garcia:Juno Therapeutics, a fully owned subsidiary of Celgene: Employment, Equity Ownership. Wang:Juno Therapeutics, a fully owned subsidiary of Celgene: Employment, Equity Ownership. Dehner:Juno Therapeutics, a fully owned subsidiary of Celgene: Employment, Equity Ownership. Chung:Juno Therapeutics, a fully owned subsidiary of Celgene: Employment. Maloney:Janssen Scientific Affairs: Honoraria; GlaxoSmithKline: Research Funding; Seattle Genetics: Honoraria; Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria.

FPGA-Centric Design Process for Avionic Simulation and Test

Real-time computing systems are increasingly used in aerospace and avionic industries. In the face of power challenge, performance requirements and demands for higher flexibility, hardware designers are directed toward reconfigurable computing using field programmable gate arrays (FPGAs) that offer high computation rates per watt and adaptability to the application constraints. However, considering reconfigurable computing in the avionic design process leads to several challenges for system developers. Indeed, such technology should be validated along the verification & validation cycle starting with simulation tools, passing through the test benches and finishing with the integration phase. For each step, the FPGA can play an essential role to achieve better performances, more adaptive systems, and cost-effective solutions. In this paper, we present a seamless FPGA-centric design process for avionic equipments. Along this process, we redefine the role of the FPGA circuits to cover the simulation, the test, and the integration steps. First, reconfigurable logics are used in the frame of heterogeneous CPU/FPGA computing in order to obtain high speed-up for real-time avionic simulation. The proposed environment supports dynamic execution model enabling reconfiguration during runtime to avoid the timing constraint violation. Second, the FPGA is used as a key solution to offer versatile test benches and to converge toward unified test and simulation tools. We have designed several commercial input output intellectual property systems with dynamic runtime reconfiguration capabilities, in order to mitigate component obsolescence and to provide increased flexibility and decreased design time. Third, at the integration phase, we use the conventional tools to make profit from reconfigurable technology in embedded avionic applications in order to deliver high computation rates and to adapt their functioning mode to provide reliability, fault tolerance, deterministic timing guarantees, and energy efficiency.

High durable CR rates and preliminary safety profile for JCAR017 in R/R aggressive b-NHL (TRANSCEND NHL 001 Study): A defined composition CD19-directed CAR T-cell product with potential for outpatient administration.

120 Background: JCAR017 is a defined composition, CD19-directed 4-1BB CAR T cell product administered at a precise dose of CD8 and CD4 CAR T cells in a seamless design Phase 1 pivotal trial of relapsed/refractory (R/R) B-cell NHL (TRANSCEND NHL 001; NCT02631044). Methods: Patients (pts) with R/R DLBCL NOS, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. The FULL dataset includes all pts in the DLBCL cohort (i.e. excludes MCL). The CORE dataset includes pts meeting inclusion for a planned pivotal DLBCL cohort (DLBCL NOS [ de novo or transformed from follicular lymphoma], ECOG 0-1, no prior allo-SCT). Results: As of July 7, 2017, 69 pts were treated in the DLBCL cohort and evaluable for safety. In the FULL dataset, 21 pts (30%) had cytokine release syndrome (CRS), with 1 serious CRS event (1%; Gr 4). Neurotoxicity (NT) at any grade developed in 14 (20%), including 10 (14%) with Gr 3-4 events. There were no Gr 5 CRS or NT events. Median time to onset of first CRS and NT was 5 days and 10 days, respectively, 13 (19%) received anti-cytokine therapy and only one required vasopressor support. In the CORE dataset (n = 49), similar rates of CRS and NT were shown. The majority of pts, 64% (44/69), had no CRS or NT, and median onset of CRS and NT were 5 and 11 days, respectively, suggesting outpatient delivery of JCAR017 may be feasible. In the DLBCL cohort, 68 pts were evaluable for efficacy; best overall response, 3-month, and 6-month response rates in the FULL dataset were 75% (51/68), 49% (27/55), and 40% (14/35), respectively; and, in the CORE dataset, were 84% (41/49), 65% (26/40), and 57% (13/23). The best overall, 3-month, and 6-month CR rates were 61% (30/49), 53% (21/40), and 52% (12/23), respectively, in the CORE dataset. Among 16 double/triple hit pts, best ORR was 81%, and 3-month CR rate was 60%. A trend toward improved response rate at 3 months was observed in pts treated at DL2 compared to DL1. Conclusions: At the symposium, we will report updated efficacy and the preliminary safety profile for JCAR017, which supports potential outpatient administration in R/R Aggressive B-NHL patients. Clinical trial information: NCT02631044.

Correlation of patient characteristics and biomarkers with clinical outcomes of JCAR017 in R/R aggressive B-NHL (TRANSCEND NHL 001 study).

122 Background: JCAR017 is a defined composition, CD19-directed 4-1BB CAR T cell product administered at a precise dose of CD8 and CD4 CAR T cells in a seamless design Ph1 pivotal trial of R/R B-cell NHL (TRANSCEND NHL 001; NCT02631044). Methods: Blood samples were collected for biomarker analyses at protocol-defined time points. PK (CAR T cell expansion and persistence) was measured using flow cytometry. Cytokines were measured on a Luminex platform. Additional analytes will be presented. All reported p-values are 2-sided without multiplicity adjustment. Results: Safety (n = 59) and efficacy (n = 54) outcomes were analyzed for correlations with patient (pt) characteristics and biomarkers. Dose level did not correlate with cytokine release syndrome (CRS) or neurotoxicity (NT) despite higher median Cmax and median AUC0-28 at DL2. In pts with NT or ≥Gr 2 CRS, CD4 and CD8 CAR T cell levels were 5-10 fold and 3-5 fold higher, respectively, than median DL2 levels. Pt factors that correlated with any grade CRS and NT were ECOG 2 (p = 0.03) and high disease burden (p &lt; 0.05). Higher levels of IL-8, IL-10, and CXCL10 before CART cell infusion were associated with Gr 3-4 NT (each p&lt; 0.05), suggesting that inherent pt factors may result in higher CAR T expansion and associated CRS and NT. Lower pre-CAR T cell ferritin, LDH, CXCL10, G-CSF, and IL-10 were associated with CR/PR, and lower pre-CAR T cell ferritin, CRP, LDH, CXCL10, IL-8, IL-10, IL-15, MCP-1, MIP-1β, TNF-α were associated with 3-month durable response (each p&lt; 0.05). Median Cmax and AUC0-28 of CD8 CAR T cells were higher in responding patients and with durable response at Month 3 (CD8 Cmax median = 20.8 vs 5.5; CD8 AUC median = 235 vs 55 in CR/PR vs PD at Month 3). Of pts evaluable for persistence at 3 months (n = 29), 90% and 93% had detectable CD8+ and CD4+ CAR+ T cells; of those with available PK results at time of relapse (n = 11), 82% had persistence at time of relapse. Conclusions: JCAR017 demonstrated increased CAR T cell expansion and persistence and higher durability of response at higher dose levels, with manageable toxicities. CAR T cells were also detected at time of relapse, suggesting potential opportunities for future combination clinical trials. Clinical trial information: NCT02631044.

Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer

Background: The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC). This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC.Methods: In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients. Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progression-free survival (PFS) and toxicity. In addition, we investigated the mutational status of PIK3CA (E542K, E545K, H1047R) in tumor tissues (n=14) and cell-free DNA (cfDNA) from blood samples (n=23) using droplet digital PCR.Results: In phase I (n=9), we found that the MTD of GPE was gemcitabine 800 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8 every 3 weeks along with everolimus 5 mg daily. Phase II was terminated early after 14 patients had been enrolled because of slow recruitment and concerns about efficacy. Results of the combined analysis of phases I and II showed the objective response rate (ORR) of GPE (n=16) was 31.3% and the median PFS was 5.5 months (95% CI, 3.5-7.5). Stomatitis and hematologic toxicities were observed most frequently in the GPE arm. PIK3CA mutations were identified in 8 (57.1%) tumor samples and 17 (73.9%) cfDNA samples; there was no significant association between PIK3CA mutation status and response to GPE treatment.Conclusions: Although the majority of patients with metastatic TNBC demonstrated PIK3CA mutations in cfDNA, the addition of everolimus to gemcitabine/cisplatin did not have a synergistic effect in these patients. Further studies are needed to determine the most effective way to target the PI3K/AKT/mTOR pathway in TNBC patients.

Adaptive Seamless Design for Establishing Pharmacokinetic and Efficacy Equivalence in Developing Biosimilars.

Recently, numerous pharmaceutical sponsors have expressed a great deal of interest in the development of biosimilars, which requires clinical trials to demonstrate that the pharmacokinetic (PK) and clinical efficacy are equivalent. Pharmacodynamics (PD) may be used in evaluating efficacy if there are relevant PD markers available. However, in their absence, it is necessary to design the associated clinical trials to include efficacy measures as the primary endpoint. In this study, we propose a novel adaptive seamless PK and efficacy design with an efficient framework to remedy the risk of misspecification of efficacy parameters and to discontinue the trial evaluating the efficacy for futility based on the PK evaluation. Here, we consider the clinical development of biosimilars including their evaluation in patients rather than healthy volunteers under a situation where both PK and efficacy parameters are required to demonstrate equivalence. The original idea of the proposed method was to organize a clinical trial that includes the statistical analysis of PK as an interim analysis, with sample size recalculation of the efficacy data. Our simulation study indicated that the proposed design would allow trials to be more efficient than with the classical design. This proposal provides appealing advantages, such as a shorter time period, additional cost savings, and a smaller number of patients required.

A modeling front-end for seamless design and generation of context-aware Dynamically Reconfigurable Systems-on-Chip

In this paper, we present a Model Driven Engineering (MDE) methodology for facilitating the modeling of the partial reconfiguration process, and for implementing Dynamic Reconfigurable System-on-Chip (DRSoC). The rationale for this approach is to provide a modeling front-end that enables to visually compose a hardware platform, containing heterogeneous components, using both static and context-management hardware wrappers. A model transformations engine (MTE) processes the high-level models to obtain the inputs for the Xilinx dynamic partial reconfiguration (DPR) design flow, with the benefit of better exploiting and reusing the designer intentions regarding the allocation of tasks into reconfigurable areas. Furthermore, the automatic synthesis of a reconfiguration controller (RecOS) with context-management and task relocation capabilities is supported in this version of our tool. The latter feature is possible due to the integration of relocation tool OORBIT into the design chain, but we point out at other avenues of research. We present a case study in which we assess the benefits of the methodology and present a thorough analysis of the reconfiguration costs associated with the context and relocation management, showing speedups of 1.5x over other solutions.

Practical characteristics of adaptive design in phase 2 and 3 clinical trials.

Adaptive design methods are expected to be ethical, reflect real medical practice, increase the likelihood of research and development success and reduce the allocation of patients into ineffective treatment groups by the early termination of clinical trials. However, the comprehensive details regarding which types of clinical trials will include adaptive designs remain unclear. We examined the practical characteristics of adaptive design used in clinical trials. We conducted a literature search of adaptive design clinical trials published from 2012 to 2015 using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, with common search terms related to adaptive design. We systematically assessed the types and characteristics of adaptive designs and disease areas employed in the adaptive design trials. Our survey identified 245 adaptive design clinical trials. The number of trials by the publication year increased from 2012 to 2013 and did not greatly change afterwards. The most frequently used adaptive design was group sequential design (n=222, 90.6%), especially for neoplasm or cardiovascular disease trials. Among the other types of adaptive design, adaptive dose/treatment group selection (n=21, 8.6%) and adaptive sample-size adjustment (n=19, 7.8%) were frequently used. The adaptive randomization (n=8, 3.3%) and adaptive seamless design (n=6, 2.4%) were less frequent. Adaptive dose/treatment group selection and adaptive sample-size adjustment were frequently used (up to 23%) in "certain infectious and parasitic diseases," "diseases of nervous system," and "mental and behavioural disorders" in comparison with "neoplasms" (<6.6%). For "mental and behavioural disorders," adaptive randomization was used in two trials of eight trials in total (25%). Group sequential design and adaptive sample-size adjustment were used frequently in phase 3 trials or in trials where study phase was not specified, whereas the other types of adaptive designs were used more in phase 2 trials. Approximately 82% (202 of 245 trials) resulted in early termination at the interim analysis. Among the 202 trials, 132 (54% of 245 trials) had fewer randomized patients than initially planned. This result supports the motive to use adaptive design to make study durations shorter and include a smaller number of subjects. We found that adaptive designs have been applied to clinical trials in various therapeutic areas and interventions. The applications were frequently reported in neoplasm or cardiovascular clinical trials. The adaptive dose/treatment group selection and sample-size adjustment are increasingly common, and these adaptations generally follow the Food and Drug Administration's (FDA's) recommendations.

Application specific instruction set processor for sensor conditioning in automotive applications

In the automotive electronic market, sensor conditioning is one of the driving applications. Sensor solutions are pervasive in the vehicle, while signal processing in such application is getting more and more complex. Currently the design strategy is often the standard ASIC flow, but the design effort can be reduced by automatic or platform-aided design strategies, or by using software-based solutions. In this paper SensASIP platform is presented. It is a design platform targeting a microprocessor architecture enhanced by dedicated instructions for computing intensive sensor signal processing tasks. SensASIP allows a seamless design flow from MATLAB-based algorithm definition and instruction set design and simulation, down to hardware macrocell HDL description and implementation in CMOS technology. SensASIP features are described through two automotive sensor conditioning examples. Special focus is put on its increased flexibility and reduced design-effort vs. standard ASIC design approach and on its low complexity overhead vs. other state-of-art software-based solutions.

Advanced control strategies for the multicolumn countercurrent solvent gradient purification process

The multicolumn countercurrent solvent gradient purification process (MCSGP) is a semicontinuous, chromatographic separation process used in the production of monoclonal antibodies) . The process is characterized by high model complexity and periodicity that challenge the development of control strategies, necessary for feasible and efficient operation and essential toward continuous production. A novel approach for the development of control policies for the MCSGP process, which enables efficient continuous process control is presented. Based on a high fidelity model, the recently presented PAROC framework and software platform that allows seamless design and in‐silico validation of advanced controllers for complex systems are followed. The controller presented in this work is successfully tested against disturbances and is shown to efficiently capture the process periodic nature. © 2016 American Institute of Chemical Engineers AIChE J, 62: 2341–2357, 2016

SoPHy+: Programming model and software platform for hybrid resource management of many-core accelerators

As demand of higher computing power is steadily increasing, it becomes popular to equip a many-core accelerator in a computer system to run concurrent applications. Efficient management of compute resources in such a system is challenging because various factors such as workload variation, QoS requirement change, and hardware failure may cause dynamic change in system status. Recently, a variety of resource management techniques for many-core accelerators have been proposed. They are usually tailored for a specific target architecture. In this paper, we present SoPHy+, which supports various types of many-core accelerators, based on a hybrid resource management technique. SoPHy+ provides a seamless design flow from programming front-end, which generates dataflow-style function codes automatically from the task specification, to run-time environment, which adaptively manages compute resources for concurrent applications in response to system status change. SoPHy+ has been implemented on two different many-core architectures: the Intel Xeon Phi coprocessor and an Epiphany-like NoC virtual prototype. Experimental results prove that SoPHy+ is capable of adapting to the run-time workload variation effectively with affordable overhead of run-time resource management.

Assessment of self-learning adaptive traffic signal control on congested urban areas: independent versus coordinated perspectives

In this paper, we introduce a simulation testbed framework to evaluate the performance of a self-learning adaptive traffic signal control system. The core contribution of this paper is the assessment of the system’s two modes of operations (independent versus coordinated) under different congestion levels and network configurations. The insights and conclusions of the paper are based on the synergetic effect of the following: (1) appropriate design of the adaptive system parameters, (2) seamless design of generic interfaces between the adaptive system and the simulation environment using application programming interfaces, (3) rigorously calibrated simulation model and a comprehensive set of performance and environmental measures, and (4) investigation of the system components required for building a complete functioning system in the field. The system was designed and lab-tested on two case studies in the City of Burlington, Ontario. The intersections were designed and operated using the adaptive system and compared to the actuated optimized and coordinated base case timings plans. The analysis of the simulation results shows that overall the adaptive system outperforms the base case scenario by up to 25% savings in delay at the network level, and 15% reduction in CO2emission. On the other hand, the results of the two testbed models indicate that the performance of the adaptive system varies according to the intersection conditions and flows, network configuration, traffic volume, variability in flow arrivals, and the proximity of intersections to each other.

Durable Linings for the Tap Holes of Ore-Roasting Furnaces

The reasons for the short service life of the lining of the tap holes in ore-roasting furnaces at nickel and tin factories are analyzed. It is established that the main reasons are the large number of seams in the lining and the low resistance of the sintered periclase-chromite refractories to slag and abrasion.Work has been done to create a seamless design of tap hole made of a slag-resistant refractory. Blocks made of PShFB-grade refractories have been developed along with a fused periclase-chromite refractory (grade PKhPP) and a new high-temperature adhesive. Use of the seamless tap holes has increased the life of their lining by a factor of 2.0 – 2.5.

Overview of Custom Microcontroller using Xilinx Zynq XC7Z020 FPGA

This paper presents an overview of customizable microcontroller using a Xilinx Zynq XC7Z020 FPGA as an alternative to increase its performance as user need. This alternative arises due to many of the systems, which developed mostly by using microcontroller are not giving any room for customization to increase its performance or I/O ports. There is any possibility that the system designed to be used by using general processor such as PC to increase its performance but it will give another problem such as interface difficulty for high speed I/O, real time processing, increases complexity, and many more. Customization is introduced by combining hard IP processor and FPGA in one chip instead of practicing two separate devices, processor and FPGA, which is commonly use in high performance embedded design. This approach allows seamless design development and development time reduction for customization.

Analysis of Two-Stage Adaptive Seamless Trial Design

In the past decade, adaptive design methods in clinical research have attracted much attention because it offers the principal investigators (1) potential flexibility for identifying clinical benefit of a test treatment under investigation, but efficiency for speeding up the development process. One of the most commonly considered adaptive designs is probably a two-stage seamless (e.g., phase I/II or phase II/III) adaptive design. The two-stage seamless adaptive designs can be classified into four categories depending upon study objectives and study endpoints at different stages. These categories include (I) design with same study objectives and study endpoints at different stages, (II) designs with same study objectives but different study endpoints at different stages, (III) designs with different study objectives but same study endpoints at different stages, and (IV) designs with different study objectives and different study endpoints at different stages. In this article, an overview of statistical methods for analysis of these different types of two-stage designs is provided. In addition, a case study concerning the evaluation of a test treatment for treating hepatitis C infected patients utilizing type (IV) trial design is presented.

G.P.116: SCOPE-DMD, an EU FP7 funded consortium for skipping trail across Europe in Duchenne muscular dystrophy

The SCOPE-DMD project builds on results from the TREAT-NMD and BIO-NMD EU projects to investigate a personalised-medicinal product through to market for the treatment of Duchenne Muscular Dystrophy (DMD). The initial goal of the project is to develop a therapy that can restore the expression of a functional dystrophin protein in targeted DMD patients that would potentially benefit from skipping of exon 45 of the DMD gene. The project uses an innovative clinical study design and novel outcome measures to reduce development timelines. The SCOPE-DMD study is an exploratory, open-label, dose-escalation phase IIb clinical trial that will assess the efficacy, safety, pharmacodynamics and pharmacokinetics of weekly subcutaneous doses of PRO045 in subjects with DMD. The study is of seamless design that is driven by the need to maximise the data from an exceptionally small patient population and to provide continuity of care in this rapidly progressing disease – a result of direct feedback from parents. It is made up of two phases: a dose escalation phase with 15 patients and an extended pivotal phase with an additional 55 patients. The consortium consists of 2 SMEs and 3 academic institutes coordinated by Newcastle University. Based on extensive experience from clinical trials of two other AONs in DMD patients, the consortium has worked on a highly innovative development plan that if successful, could be applied to future clinical trials in DMD and other rare diseases. Also magnetic resonance imaging, novel biomarkers and functional outcome measures including accelerometry, myotools and the Performance of Upper Limb (PUL) module will be incorporated into the trial protocol in addition to more established ones. Both expertise and scientific knowledge come together in this consortium to launch an innovative drug product but also to provide a regulatory and pathway-to-market precedence to benefit future patients with rare disorders getting earlier access to treatment.