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BackgroundEarly phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE).MethodsThe initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants’ feedback.ResultsThe Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar.ConclusionsBy detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility.Trial registrationSPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network (https://www.equator-network.org/).

BACKGROUND Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). METHODS The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and Public Involvement and Engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants’ feedback.RESULTS The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted, and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. CONCLUSIONSBy detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness and reproducibility. RegistrationSPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network (https://www.equator-network.org/).

Additional file 5. Further details on the statistical analysis plan.

Additional file 9. Perception of proposed items and sensitivity analysis: Tables A9-1 – A9-3, Figures A9-1 – A9-13. Table A9-1. Summary of categorical and numerical ratings at Round One and 2. Figure A9-1. Percentage of participants changing their numerical scores at Round Two. Figure A9-2. Percentage of participants changing their categorical scores at Round Two. Table A9-2. Number of participants changing their ratings between Round One and Round Two. Table A9-3. Frequency and percentage of perfect agreement. Figure A9-3. Stacked bar plots of candidate item [17 SPIRIT-DEFINE] “Planned dosing regimens presented as a diagram or table, where applicable” by stakeholders. Figure A9-4. Stacked bar plots of candidate item [18 CONSORT-DEFINE] “Planned and delivered dosing regimens presented as a diagram or table, where applicable” by stakeholders. Figure A9-5. Stacked bar plots of candidate item [48 SPIRIT-DEFINE] “Statistical methods for additional analyses” by stakeholders. Figure A9-6. Stacked bar plots of candidate item [69 CONSORT-DEFINE] “Specify if and when results were reported whilst the trial was still ongoing” by stakeholders. Figure A9-7. Stacked bar plots of candidate item [70 SPIRIT-DEFINE] “Where the full trial protocol or the redacted version, with amendments, can be accessed” by stakeholders. Figure A9-8. Stacked bar plots of candidate item [17 SPIRIT-DEFINE] “Planned dosing regimens presented as a diagram or table, where applicable” by Continent. Figure A9-9. Stacked bar plots of candidate item [18 CONSORT-DEFINE] “Planned and delivered dosing regimens presented as a diagram or table, where applicable” by Continent. Figure A9-10. Stacked bar plots of candidate item [48 SPIRIT-DEFINE] “Statistical methods for additional analyses” by Continent. Figure A9-11. Stacked bar plots of candidate item [69 CONSORT-DEFINE] “Specify if and when results were reported whilst the trial was still ongoing” by Continent. Figure A9-12. Stacked bar plots of candidate item [70 SPIRIT-DEFINE] “Where the full trial protocol or the redacted version, with amendments, can be accessed” by Continent. Figure A9-13. Stacked bar plots of candidate item [5 SPIRIT-DEFINE] “Summary of findings from existing correlative biomarker, correlative and associated studies to support planned biomarker sub-study” by Continent.

Additional file 3. Organisations contacted for protocol templates or guidelines and responses.

Additional file 6. SPIRIT-DEFINE and CONSORT-DEFINE items generation for Delphi survey: Table A6-1. Table A6-1. References supporting the proposed candidate items in the DEFINE Delphi survey.

Additional file 11. Qualitative analysis. Table A11-1; Figure A11-1. Table A11-1. Themes and codes identified in the general comments received in Delphi survey. Figure A11-1. Tree diagram of the comments received per theme.

Additional file 8. Delphi survey participants demographics and harmonisation of roles: Tables A8-1 – A8-2. Table A8-1. Demographics of Delphi survey participants. Table A8-2. Harmonisation of participants’ defined roles.

Additional file 7. Toolkit for Lay Summary of EPDF Trial Results.

Additional file 4. Delphi Survey key stakeholder groups and methods of access.

Совершенствованию методов газодинамического проектирования осевых компрессоров уделяется большое внимание. Расчетному анализу подвергнуты варианты сверхзвуковой ступени осевого компрессора с разным втулочным отношением и предварительной закруткой потока. У всех исследованных вариантов задавался одинаковый массовый расход, условный коэффициент расхода и выходной угол лопаток на расчетном втулочном диаметре. Анализ выполнен по программе первичного проектирования, разработанной в Политехническом университете в квазитрехмерной постановке. В графическом виде представлены количественные результаты влияния втулочного отношения и закрутки потока на КПД, коэффициент напора и отношение давлений ступени. Анализ структуры потока и треугольников скоростей объясняет причины, по которым меняется КПД и коэффициент напора. Зависимости КПД и коэффициента напора от втулочного отношения и закрутки потока аппроксимированы системой алгебраических уравнений., Much attention is paid to improving the methods of gas-dynamic design of axial compressors. Variants of the supersonic stage of an axial compressor with different hub ratios and pre-swirling of the flow were subjected to computational analysis. All variants have the same mass flow rate, flow coefficient and outlet angles of the blades at the hub diameter. The analysis was carried out according to the program of primary design in a quasi-three-dimensional setting. The graphical representation shows the quantitative results of the influence of the hub ratio and of the flow swirl on the efficiency, the loading factor and the pressure ratio of the stage. An analysis of the flow structure and velocity triangles explains the reasons for the change in efficiency and loading factor. The dependences of the efficiency and the loading factor on the hub ratio and flow swirl are approximated by a system of algebraic equations.

DF-CONSORT: protocol for the rapid methodological review

BackgroundIncomplete reporting of the design, conduct and analysis of early phase dose-finding trials can hinder interpretability and reproducibility, and lead to erroneous conclusions on tolerability and efficacy. This methodological review investigates the reporting quality of published trials using broadly the CONSORT 2010 checklist with added items unique to dose-finding trials.MethodsMEDLINE (PubMed) was searched for articles published in 2011-2020. Phase I or I/II trials, with planned interim dosing decisions (de/escalate, stay at the current level or an early stop), which aim to find a recommended dosing regimen(s) for further testing, were included. Data were extracted for 476 randomly selected trials, stratified by cancer/non-cancer settings.ResultsThe key items that are frequently not reported include: n (%) reported cancer(n=238) non-cancer (n=238)Methods Planned/maximum sample size 69 (29%) 105 (44%) with justification 35 (15%) 59 (25%) Recruitment method 19 (8%) 51 (21%) Oversight committees 39 (16%) 90 (38%) roles and structure 17 (7%) 40 (17%) Who makes dose decisions 10 (4%) 39 (16%) Definition of analysis population: dose-determination 108 (45%) 111 (47%) Safety 114 (48%) 129 (54%) key outcomes 100 (42%) 131 (56%) Rationale for starting dose 52 (22%) 42 (18%)Results Baseline demographic and clinical characteristics by each dose level 70 (29%) 148 (62%) Settings and locations where data were collected 86 (36%) 149 (63%) Participant flow diagram/table 85 (36%) 144 (61%) Losses/exclusions for each dose level 30 (13%) 85 (36%)Only 1 (0.4%) cancer trial was randomised compared to 180 (75.6%) non-cancer trials. Notably, very few trials (6.3%) provided accessible protocols. Improvement in the reporting over time is evident in some items, including participant flow and sample size justification.ConclusionImportant methodological features in design, conduct and analysis are frequently omitted. Overall, non-cancer trials appear to be better reported, as mainly randomised, they may have adopted CONSORT 2010 guidance. This review confirms the need for robust consensus-driven guidance for researchers and journals reporting dose-finding trials, to allow accurate assessment of their results to reduce research waste.

Для проектирования центробежных компрессоров применяются различные подходы и методики. Это инженерные одномерные и квазитрехмерные программы, а также CFD-программы. Окончательное суждение об эффективности проекта даёт испытание компрессора или его модели. Совместно НИЛ «Газовая динамика турбомашин» СПбПУ и НПО «Турботехника» был спроектирован центробежный компрессор турбонагнетателя ДВС. Для проверки безразмерных характеристик компрессор был испытан с двумя геометрически подобными рабочими колёсами с диаметром 175 (ТКР 175Э) и 140 мм (ТКР 140Э). Математическая модель Метода универсального моделирования рассчитывает КПД на расчетном режиме для всех испытаний обоих компрессоров с погрешностью 0,89%, а КПД по характеристике в целом с погрешностью 1,55%. Характеристики компрессора ТКР 140Э были рассчитаны при помощи коммерческой CFD-программы ANSYS. Для ТКР-140Э получено значительное расхождение по величине КПД, но хорошее совпадение по зоне работы, что не получалось в предыдущих расчетах. Коэффициент внутреннего напора по расчету завышен на 9%, что соответствует результатам предыдущих расчетов авторов., Various approaches and techniques are used to design centrifugal compressors. These are engineering one-dimensional and quasi-three-dimensional programs, as well as CFD programs. The final judgment about the effectiveness of the project is given by testing the compressor or its model. SPbPU Research Laboratory “Gas Dynamics of Turbomachines” and NPO “Turbotekhnika” jointly designed a centrifugal compressor for an internal combustion engine turbocharger. To check the dimensionless characteristics, the compressor was tested with two geometrically similar impellers with a diameter of 175 (TKR 175E) and 140 mm (TKR 140E). The mathematical model of the Universal Modeling Method calculates the efficiency in the design mode for all tests of both compressors with an error of 0.89%, and the efficiency for whole characteristic with an error of 1.55%. The characteristics of the TKR 140E compressor were calculated using the commercial CFD program ANSYS. For TKR-140E, we obtained a significant discrepancy in the value of the efficiency, but also a good agreement in the area of operation, which was not obtained in the previous calculations. According to the calculation, the work coefficient is overestimated by 9%, which corresponds to the results of the previous calculations by the authors.

Компьютерные программы первичного проектирования на основе математических моделей потерь напора и отклоняющей способности решеток А. Комарова используются на первом этапе создания проточной части осевых компрессоров. Для проведения газодинамического исследования с использованием CFD-методов необходимо создать расчётную модель проточной части, полученной в результате проектирования. В работе описаны этапы создания параметризованной расчётной модели четырехступенчатого осевого компрессора. Параметризация проведена таким образом, чтобы при проектировании проточной части в программе первичного проектирования полученная геометрия передавалась в программный комплекс ANSYS CFX. При копировании данных происходит автоматическое построение лопаток, меридионального контура и расчётных сеток. Полученная модель готова к проведению дальнейшего газодинамического расчёта. Использование параметризованной модели делает возможным проведение оптимизации с несколькими изменяемыми параметрами и разными критериями эффективности., Computer programs for primary design based on mathematical models of pressure losses and A. Komarov’s model of flow deviation angle are used at the first stage of constructing axial compressors flow path. To conduct a gas-dynamics research using CFD methods, it is necessary to create a computational model of the flow path obtained as a result of the design. The paper describes the main points of creating a parameterized design model of a four-stage axial compressor. The parameterization is carried out in a way to ensure that the geometry obtained by the primary flow path design program is transferred to the ANSYS CFX software package. When copying the data, the blades, meridional contour and computational grids are constructed automatically. The resulting model is ready for further gas-dynamics calculations. The use of the parameterized model enables optimization with several adjustable parameters and various criteria of efficiency.