Overall Design. This is a phase 2, open-label, multicenter study that will evaluate the efficacy and safety of selinexor and pembrolizumab in patients with advanced or metastatic CRC. The study schema is depicted in Figure 3. SOC = Standard of care, PD = progressive disease; MSI-H = microsatellite instability high; dMMR = deficient mismatch repair; QW = once weekly; BID=twice daily; CRC=colorectal cancer Approximately 78 patients with advanced or metastatic CRC will be enrolled, and randomized to Arm A, B or C based on the following stratification factor: • ECOG performance status 0 or 1 versus 2 All eligible patients in Arm A will be treated with selinexor 80 mg QW orally as a monotherapy on Day 1 of each week of a 42-day cycle. Arm B patients will be treated with selinexor at the same dose as Arm A in combination with pembrolizumab 400 mg IV once every 6 weeks. Arm C patients will be administered the standard of care treatment trifluridine and tipiracil 35 mg/m2/dose orally BID (max 80 mg / dose) on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. Trifluridine and tipiracil should be taken with food. Primary efficacy will be assessed by PFS, as assessed by the investigator per RECIST1.1 for selinexor plus pembrolizumab and for SOC assessed from randomization until disease progression or death from any cause, whichever occurs first. Objective response rate (XXX) defined as the proportion of patients who achieve complete response (CR) or partial response
Overall Design. This is a single-arm, open-label, repeat-dose (30 mg/day) study designed to assess the effects of ALXN1840 administration on Cu balance in healthy participants. This study will be conducted in a minimum of 2 groups. The first group will consist of approximately 6 participants and no more than 8 participants. The second group may only be initiated after the Safety Review Committee (SRC; defined in Section 9.7) reviews safety information (all AEs, safety laboratory data, and vital signs) through Day 18 and agrees that it is safe to continue enrollment to complete the study. If ceruloplasmin concentrations or AE findings are suggestive of over-depletion of Cu, the SRC may propose a dose reduction to 15 mg/day for remainder of the study population. This is a single arm study. Following screening and enrollment, participants will have a Run-in Period to support diet equilibration (Day -7 through Day -5) and measure of pretreatment Cu and Mo balance (Day -4 through Day -1). Following the Run-in Period, participants will be administered ALXN1840 at 30 mg/day for 15 days (Day 1 through Day 15). ALXN1840 will be administered orally after an overnight fast, and participants will remain fasted for a minimum of 2 hours following each dose administration. Following completion of the 15 days dosing period, participants will remain the clinical research unit (CRU) for an additional 16 days until discharge on Day 31. Total intake and output will be measured continuously from Day -4 through Day 30 with Day 1 through Day 15 representing the ALXN1840 treatment period and Day 16 through Day 30 representing the post-treatment period. The collection period will support assessment of Cu balance and Mo mass balance including assessment at steady state and terminal elimination. Participants will return to the CRU for a final study visit on Day 43 ± 2 days, approximately 28 days after the final dose of ALXN1840, to conclude the safety follow-up period. Participants meeting all study entry criteria prior to Cu/Mo controlled diet initiation are eligible for enrollment. At the time of enrollment, participants will be assigned a subject number for the study. Throughout the period in the CRU, participants will remain on a Cu- and Mo-controlled diet with a limited selection of meals utilized for breakfast, lunch and dinner throughout the study to ensure Cu/Mo control (Table 4). During the intake and output collection periods, daily urine will be pooled (24-hour collection) with volumes r...
Overall Design. This is an open-label, single arm, international multicentre Phase 2/3 study. The study, initially designed as a pilot Phase 2 study, with the target of enrolling 10 evaluable patients with primary HLH, based on the positive benefit risk profile observed in the patients enrolled in the study so far and in consideration of:
i) the rare nature of the disease;
ii) the lack of valuable therapeutic options especially for patients having failed previous HLH therapies or being unable to continue due to toxicity;
iii) the significant number of requests for compassionate use of NI-0501 for HLH patients;
Overall Design. The overall design of the electrical distribution system is provided on the one-line diagram, Drawing 0880 E001 Revision No. B. This presents the level of reliability, flexibility and selectivity desired for the Plant output and auxiliaries. The following discussion presents the overview of the electrical system design considering a complete build-out of the Plant including all future generators and equipment. It is understood that this initial construction will not include all these units, but will make some provision for future expansion in space or capacity where appropriate. No aspect of the initial system design or installation shall be such that it prevents the addition of the later units.
5.2.1.1 The EPC scope shall include the following allowances for capacity expansion to 4x4x1 in the engineering and construction of SPP assuming equivalent components used for the Plant expansion:
1. Design/install all electrical embedment within the confines of the 3x3x1 arrangement (building extents)
2. Design/install U/G conductor pathways beneath the confines of 3x3x1 structures (building extents)
3. Reserve space for equivalent expansion equipment (indoor and outdoor) Design space/capacity for cable tray, conduit, termination blocks, etc. for equivalent expansion
4. Route U/G cable/wire between structures around areas reserved for Plant expansion
5. Allow space for the future installation of the 13,800:480V service transformer and the bus (with breakers) for CTG-4
5.2.1.1 All generator outputs are at 13.8kV, three-phase, three-wire, 60Hz, high resistance grounded.
5.2.1.2 Each combustion turbine generator and steam turbine generator shall be equipped with a 13.8kV main generator circuit breaker and a two-winding generator step-up (GSU) transformer. The GSU transformer for the STG shall be 42/56/70 MVA, 138-13.8kV, three phase, solidly grounded wye-delta, 60Hz and the three (3) CTG GSU transformers shall be 36/48/60 MVA, 138-13.8kV, three phase, soidly grounded wye-delta, 60Hz units.
Overall Design. The study is designed as a prospective, randomized, placebo-controlled, double-blinded clinical trial to compare DaxibotulinumtoxinA for Injection and placebo injections for the management of plantar fasciitis signs and symptoms.
Overall Design. The Simulink gateway builds on results from the ATESST2 project, a Simulink gateway was developed, and provides input/output facilities of models with Simulink to enable simulation. The plugin is divided in two parts (Figure 19): • A GUI plugin to the MATLAB/Simulink environment, which aids the user in creating models that conform to the format that is needed to being able to convert it into an EAST-ADL model. • An Eclipse plugin, which can convert between the intermediate format of Simulink models and EAST-ADL models The MATLAB plugin exports the MATLAB/Simulink models into a custom Ecore-based format. A subset of Simulink functions is used; only library blocks of subsystems are considered. However, any Simulink model could be converted into a structure of system reference blocks, without affecting the model’s simulation behaviour. The GUI plugin for Simulink mentioned above converts standard Simulink subsystems to system reference blocks, and tags them for conversion to EAST- ADL by putting them in a “FunctionTypes”-library, and assigning a unique ID, to allow bi-directional exchange and updates. To include the internal structure of a subsystem, the same pattern is repeated. Import works the other way around, FAA FunctionTypes and FunctionPrototypes are imported to empty library blocks in the “FunctionTypes”-library, and instances of them respectively. In addition to the above tool MetaCase has developed a Simulink-exchange mechanism for MetaEdit+, creating .mdl-files. A similar mapping is used as the above mentioned plugin. With MetaEdit+, KTH has developed another exchange from MetaEdit+ to Simulink and StateFlow, as a validator for the behavioural annex. Instead of .mdl-files, this plug-in relies on Matlab API for the creation of Simulink/Stateflow models.
Overall Design. This section provides an overview of the design of the mobile app/library that performs authentication of the user by leveraging sensor data generated by the integrated sensors of the smartphone device. The mobile app/library collects sensor data, extracts behavioural cues that will allow the derivation of behavioural patterns of the user and further will enable the validation of the identity of the user. The sensor data are initially pre-processed in order to convert them in the appropriate format. Following, the normalised sensor data are forwarded to the behavioural cues extraction components. Each of the behavioural cues component processes the sensor data that are related to the particular module. The data stream is fed in the behaviour extraction module that learns and authenticates the user. The results from the learning and authentication process are forwarded to the authentication inference component that fuses the results from the different authentication components. Once the authentication inference component fuses the different authentication results, an overall authentication decision is generated and propagated to the interface that the BehavAuth library exposes to third party apps. The design of the library/app is event based in order to minimise the energy consumption of the smartphone. The library is coordinated by a background service that operates as a manager responsible for the interconnection of the different components of the authentication library. The data collection process that is taking place is event based, so when each sensor generates a sample, then the sample is forwarded to the behavioural cue and the behaviour extraction modules. The behavioural cues and behavioural pattern extraction modules are executed on separate threads, in order to off-load the background service that performs the coordination of the library and to enable constant availability of the service without interruption. Sensor data Preprocessing Behavioural cues extraction Speed Distance Location Social Interaction Authentication Inference Behavioural patterns Speed Distance Location Social Interaction
Overall Design. This study is a Phase 2 randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of vibegron in women with IBS-D or IBS-M. Subjects who meet all eligibility criteria will be randomized in a 1:1 ratio to receive either vibegron 75 mg or matched placebo. Randomization will be stratified by baseline abdominal pain intensity score (< 6 vs ≥ 6 on a 0 to 10 numeric rating scale [NRS]) and IBS subtype (IBS-D vs IBS-M). Enrollment for subjects with IBS-M will be capped at 50% of the total subject population (ie, up to 50% of the study population will be subjects with IBS-M). Stratification will be performed via central randomization across the study (not per site). A Data Safety Monitoring Board (DSMB) will be retained to assess, on an ongoing basis, all safety aspects of this study, including SAEs, major adverse cardiac events (XXXX), adverse events of special interest (AESIs), and all other AEs. The committee will meet to review the safety data at the following 3 times when the (1) first 25% of subjects enrolled complete the Week 4 visit (Visit 5); (2) first 50% of subjects enrolled complete the Week 4 visit (Visit 5); and
Overall Design. Define and develop overall site design including, but not limited to, navigation schemes, menu bars, general site flow and interactivity, original artwork and image processing and treatment.
Overall Design. This is an international, multicenter, long-term, follow-up study of HLH patients who have received at least one dose of NI-0501 in the context of a previous NI-0501 clinical study in which no long-term follow-up is already planned. Patients having received NI-0501 under a compassionate use (CU) treatment protocol may also be considered for enrolment, whenever appropriate. The NI-0501-05 study is performed both in the US and in Europe according to twin protocols called NI-0501-05-P-IND #111015 and NI-0501-05-EudraCT #0000-000000-00, respectively. In the event that an appropriate donor has not been identified by Week 8 or in case of the need to delay transplantation for reasons unrelated to the administration of NI-0501, patients from study NI- 0501-04- US-P-IND#111015 can continue receiving NI-0501 treatment beyond the foreseen 8 weeks upon request of the Investigator, providing a favorable benefit/risk has been established. A close monitoring of these patients will be performed in the context of this study (NI-0501-05), according to the schedule of assessment reported in Appendix A, where the end of treatment period visit of the NI- 0501-04 study will be the first visit for these patients entering NI-0501-05 study (refer to NI-0501-04- US Study Protocol, Table 2). Due to the probability that, by Week 8, patients may be receiving NI- 0501 infusions less frequently than every 3 days, the schedule of assessment, as described in Appendix A, may be adapted to suit the schedule of administration, maintaining the safety and efficacy assessments visits at least on a weekly basis. After NI-0501 discontinuation, patients will be monitored weekly for a period of 4 weeks (4-week follow-up) before entering the long-term follow-up study described above. Study NI-0501-05 enrolls 2 different groups of patients: patients who underwent or will undergo HSCT, and patients for whom HSCT is not envisioned. The follow-up of these 2 different patients` groups is generally similar. The study design and visits` schedule for each patients`group is specifically described in Sections 3.1.1 and 3.1.2, respectively.
