Mechanical ventilation (MV) therapy has been utilised in the intensive care unit (ICU) for 50 years to treat patients with respiratory illness by supporting the work of breathing, providing oxygen and removing carbon dioxide. MV therapy is utilised by 30-50% of ICU patients, and is a major driver of increased length of stay, increased cost and increased mortality. For patients suffering from acute respiratory distress syndrome (ARDS), the optimal MV settings are highly debated. ARDS patients suffer from a lack of recruited alveoli, and the application of positive end expiratory pressure (PEEP) is often used to maintain recruitment to maximise gas exchange and minimise lung damage. However, determining what level of PEEP is best for the patient is difficult. In particular, it involves a complex trade off between patient safety and ventilation efficacy. Currently, no clinical protocols exist to determine a patient-specific “best” PEEP. Model-based approaches provide an alternative patient-specific method to help clinical diagnosis and therapy selection. In particular, model-based methods can utilise a mix of both engineering and medical principles to create patient-specific models. The models are used for optimising ventilation settings and providing greater physiological insight into lung status than is currently available. Two model-based approaches are presented here. First, a quasi-static, minimal model of lung mechanics is presented based solely on fundamental lung physiology and mechanics. Secondly, a model of dynamic functional residual capacity (dFRC) is developed and presented based on model-based status of lung stress and strain. These models are validated with retrospective clinical data to evaluate the potential of such model-based approaches. Finally, the models are further validated with real time clinical data over a broader spectrum of pressure-volume ranges than prior studies to evaluate the clinical viability of model-based approaches to optimise MV therapy. When validated with real-time clinical trials data, the outputs of the recruitment model provide a range of optimal patient-specific values of PEEP based on different clinically and physiologically derived criteria. The recruitment model is also shown to have the ability to track the disease state of ARDS over time. The dFRC model introduces the PEEP stress parameter, β, which represents a unique population constant. The dFRC model suggests that clinically reasonable estimates of dFRC can be achieved by using this novel value of β, rather than the current, potentially hazardous, methods of deflating the lung to atmospheric pressure. Finally, a third model, combining the principles of recruitment and gas exchange is introduced. The combined model has the ability to estimate cardiac output (CO) changes with respect to PEEP changes during MV therapy. In addition, the model relates the coupled areas of circulation and pulmonary management, as well as linking these MV decision support models to oxygenation based clinical endpoints. A proof of concept is shown for this model by combining two different retrospective datasets and highlighting its ability to capture clinically expected drops in CO as PEEP increases. The model allows valuable cardiovascular circulation data to be predicted and also provides an alternative method and clinical end point by which PEEP could be optimised. The model requires further clinical validation before clinical use, but shows significant promise. The models developed and tested in this research enable rapid parameter identification from minimal, readily available clinical data, and thus provide a novel way of guiding therapy. The models can potentially provide clinicians with information to select an optimal patient-specific level of PEEP using only standard ventilation data, such as pressure-volume curves. In addition, the development of a dFRC stress model provides a unique population constant, β. Overall, the modelling approaches developed and validated in this research provide several novel methods of guiding therapy setting mechanical ventilation parameters and tracking and assess a patient’s lung condition. This research thus creates and provides novel validated methods for improving MV therapy with minimal cost or added invasiveness.

Medicines for human use worldwide are generated in part through the conduct of clinical trials. This is done to ensure safety and efficacy. The involvement of human subjects in drug trials has raised concerns for the protection of human rights. As a consequence of the medical misadventures, the Declaration of Helsinki was formulated in 1964 and revised up to 2002. Today, the International Conference of Harmonization of Good Clinical Practice of 1996 guidelines are used worldwide (including South Africa) in the conduct of clinical trials. This study took place in South Africa. The objectives of the study were to first develop an instrument to be used in identifying the current good clinical practice knowledge and training needs of clinical researchers / secondly identify the knowledge level and training needs using the designed instrument and thirdly, based on the findings, develop a Good Clinical Practice training model so as to facilitate the achievement of quality standards for the conduct of clinical trials in South Africa.

The general objective of this thesis was to improve understandings of design, conduct and analysis of randomized controlled trials (RCTs). The specific objective was to evaluate the methodological and statistical principles associated with conducting analyses of futility, a component of interim analysis, as part of the conduct of RCTs. This objective was addressed by first performing a systematic review, which included a detailed literature search, as well as data from a cohort of previously extracted studies. The systematic review was designed to identify futility analysis principles and methodologies in order to inform the design and conduct of retrospective futility analyses of two completed NCIC CTG trials. The results of these trials have been previously published; one trial met its stated endpoint and the other did not. Neither trial underwent an interim analysis of futility during its conduct. The retrospective futility analyses assessed the accuracy of frequently used methods, by comparing the results of each method to each other and to the original final analysis results. These assessments were performed at selected time points using both aggressive and conservative stopping rules. In order to increase the robustness of the comparisons, bootstrapping methods were applied. The results of this thesis demonstrate principles associated with the conduct of futility analyses and provide a basis for hypotheses-testing of optimum methodologies and their associated trade-offs. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-12-12 13:10:15.619

Background: Health-related quality of life (HRQL) outcomes have been increasingly used in phase III randomized controlled trials to characterize the benefits or risks of a cancer treatment. HRQL outcomes from clinical trials can also inform clinical practice in oncology settings. Previous qualitative research suggests that oncologists value HRQL outcomes but challenges to their clinical application exist. Little quantitative research has been conducted to examine these barriers. This study describes the opinions of oncologists toward HRQL outcomes, the ways in which HRQL outcomes can be presented, and the importance of suggested reporting standards for HRQL outcomes in clinical trials. It further examines the association between attitudinal and demographic factors associated with the self-reported current use and achievable use of HRQL outcomes in clinical practice. Methods: This study is a cross-sectional survey of oncologists. A web-based questionnaire was disseminated in Canada, United Kingdom, and Australia/New Zealand. The study included oncologist members of the NCIC Clinical Trials Group, the NCRI Clinical Studies Groups, and the Australasian Cancer Clinical Trials Groups. Respondents were asked to report their opinions toward HRQL outcomes and the factors associated with the use of these outcomes in clinical practice. Demographic characteristics were also collected. Chi-square tests were used to compare the proportion of responses between countries. Logistic regression was used to identify factors associated with the use of HRQL outcomes in clinical practice. Results: A total of 344 oncologists completed the survey. Most oncologists (65.9%) reported having a good knowledge of HRQL outcomes and 72% perceived HRQL outcomes to be useful. High current use of HRQL outcomes in clinical practice was associated with more medical practice experience; perceiving HRQL outcomes to be useful; perceiving HRQL measurements to be reliable; and reporting lack of understanding to rarely be a barrier to using HRQL outcomes. High achievable use of HRQL outcomes in clinical practice was associated with being a male oncologist, perceiving HRQL outcomes to be useful, and being an investigator in RCTs. Conclusions: Important factors associated with the use of HRQL outcomes in clinical practice were identified, highlighting the need for future research and education. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2013-09-30 12:56:09.362

Background: Despite substantial research and development investment in Alzheimer's disease (AD), effective therapeutics remain elusive. Significant emerging evidence has linked cholesterol, beta-amyloid and AD, and several studies have shown a reduced risk for AD and dementia in populations treated with statins. However, while some clinical trials evaluating statins in general AD populations have been conducted, these resulted in no significant therapeutic benefit. By focusing on subgroups of the AD population, it may be possible to detect endotypes responsive to statin therapy. Methods: Here we investigate the possible protective and therapeutic effect of statins in AD through the analysis of datasets of integrated clinical trials, and prospective observational studies. Results: Re-analysis of AD patient-level data from failed clinical trials suggested by trend that use of simvastatin may slow the progression of cognitive decline, and to a greater extent in ApoE4 homozygotes. Evaluation of continual long-term use of various statins, in participants from multiple studies at baseline, revealed better cognitive performance in statin users. These findings were supported in an additional, observational cohort where the incidence of AD was significantly lower in statin users, and ApoE4/ApoE4-genotyped AD patients treated with statins showed better cognitive function over the course of 10-year follow-up. Conclusions: These results indicate that the use of statins may benefit all AD patients with potentially greater therapeutic efficacy in those homozygous for ApoE4.

This study determined whether pre-operative exercise and education (PREHAB) improves the frailty status and physical activity behaviour of older adults undergoing elective cardiac surgery, more than standard care (StanC). Using a subset of patients from a multi-centre trial (NCT02219815), twenty-six patients over the age of sixty were randomized to receive StanC (n=12) or PREHAB (n=14). Blinded research assistants collected data at baseline prior to randomization and one week pre-operatively. Changes in frailty were assessed using a 30-item functional frailty index (FFI); whereas, changes in physical activity behaviour were assessed using accelerometers. Baseline data was not different between groups. Frailty status improved by 17%, 5% and 35% amongst StanC, PREHAB “non-completers” and PREHAB “completers”, respectively. No changes in moderate to vigorous physical activity were found pre-operatively. These data suggest that the PREHAB intervention is feasible to implement and may result in improved frailty status amongst frail older adults awaiting elective cardiac surgery. / October 2016

Thesis advisor: Judith Shindul-Rothschild / Clinical Characteristics Of People In Randomized Clinical Trials Of First Episode Schizophrenia Spectrum Disorders: Attrition Versus Non-Attrition Groups Submitted by Joanne D. Wojcik PhD, RN Dissertation Advisor Judith Shindul-Rothschild, PhD, RN Abstract Background: Early identification of psychosis and intensive treatment has been the focus of the treatment of people with a first episode (FE) schizophrenia spectrum disorder (SSD). Attrition rates in studies of people in the first episode are high, which makes it difficult to understand the meaning of the study outcomes. High attrition rates affect the validity of a study by decreasing its power and the study's ability to detect differences between treatment groups. Additionally, the people who leave a study may be different from those who stay in demographic, illness and treatment characteristics. Method: This study is a secondary analysis of a group of FE SSD participants enrolled in one of three separate double-blind, randomized, drug trials. The variables were first analyzed across the three drug study data sets to determine if the patient populations are comparable across the three studies to allow for the merging of the data. Exploratory and descriptive statistics of study participants were conducted in a comparison of the three studies, for the merged group, and for the attrition and non-attrition groups. Effect sizes (Cohen's d) were calculated for each variable in the individual studies and in the merged dataset for the magnitude of difference between the attrition and non-attrition groups. Results: The three studies were merged after analysis found no consistent difference in demographic and illness characteristics between the three studies. There was no significant difference between the attrition and non-attrition groups in the merged data in demographic and illness characteristics. Treatment characteristics consistently found lack of efficacy and patient withdrawal of consent to be the two most frequent reasons for attrition from the studies. In addition, participants receiving a typical agent were less likely to complete the study. Effect size calculations found attrition group to more likely be Caucasian, with a lower median income. The attrition group had more years of education, but was not in school in the year previous to hospitalization. Conclusion: Historically, attrition is a major problem in clinical trials of people in a first episode of schizophrenia spectrum disorders. People receiving typical antipsychotic medication are more likely to leave a study. Most common reasons for attrition include lack of efficacy and withdrawal of consent / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.

Ensaios Clínicos controlados e randomizados representam um pilar para a medicina baseada em evidência e, para que estes sejam confiávéis, a condução deve se basear nos princípios e padrões estabelecidos pelas Boas Práticas em Pesquisa Clínica (BPC). Segundo as BPC, o investigador e sua equipe são responsáveis pela execução do estudo e, por isso, precisam ser qualificados por treinamentos. Deste modo, visto a diversidade de pesquisadores, ambiente heterogêneo para recrutamento e potencial técnico dos profissionais de saúde da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo foi desenvolvido e validado o conteúdo de um questionário para avaliação de conhecimento em BPC. Por meio de levantamento bibliográfico, tradução e consulta com especialistas em Pesquisa Clínica, as temáticas do questionário foram estruturadas em três dimensões principais: guia de BPC, legilação brasileira quanto à participação de seres humanos em pesquisa e Termo de Consentimento Livre e Esclarecido (TCLE). Dentro destas dimensões foram trabalhados os domínios: conceito BPC; princípios das BPC; responsabilidades; eventos adversos; controle de dados; Resoluções brasileiras 466/12, 441/11 e 251/97; princípios éticos; e, TCLE quanto a populações vulneráveis, pessoas com incapacidade, crianças, pacientes críticos, ressarcimento e indenização. A avaliação da validade de conteúdo, conforme relevância e representatividade, foi definida por meio do Indice de Validação de Conteúdo (CVI). As afirmações formuladas, verdadeiras ou falsas, foram validadas por seis juízes, com experiência em Pesquisa Clínica, conforme grau de relevância, clareza da informação (texto e estrutura), e se concordavam com a resposta. O instrumento foi estruturado por meio do site SurveyMonkey e foi desenhado questionário demográfico para que fosse possível a caracterização da amostra investigada. Na sequência foi realizado estudo piloto com uma amostra da população alvo e, executou-se o refinamento do instrumento por meio da análise das respostas e avaliação textual. Por fim, o questionário validado contém uma pergunta em que declara o consentimento para a pesquisa, doze perguntas para caracterizar o perfil da amostra e 34 questões de conhecimento em BPC e Bioética conforme dimensão e domínios préestabelecidos. Tal instrumento será utilizado para compor o plano de Gestão do Conhecimento da Unidade de Pesquisa Clínica, de modo a identificar falhas de conhecimento em BPC e bioética e, consequentemente, gerar dados para melhorar os treinamentos rotineiramente realizados pela Unidade / Controlled and randomized clinical trials represent a mainstay for evidencebased medicine and, for these to be reliable, their conduct should be based on the principles and standards established by Good Clinical Practice (GCP). The GCP recognizes that the investigator and the team of individuals at a trial site are responsible for the execution of the trial and, therefore, must be qualified by training. Thus, considering the diversity of researchers, heterogeneous environment for recruitment and technical potential of the health professionals of the Ribeirão Preto Medical School of the University of São Paulo, a questionnaire was developed and had its content validated to evaluate knowledge in GCP. Through literature review and consultation with clinical trials experts, the questionnaire themes were structured into three main dimensions: GCP guideline, Brazilian laws involving human research and Informed Consent Form (ICF). Within these dimensions were worked the domains: concept BPC; principles of GCP; responsibilities; adverse events; data management; Brazilian Resolutions; ethical principles; and, ICF regarding vulnerable subjects, people with disabilities, children, critical patients, compensation and reparation. The assessment of content validity, according to relevance and representativeness, was defined through the Content Validation Index (CVI). The statements formulated, as true or false, were validated by six judges, with experience in Clinical Trials, according to degree of relevance, textual and structural clarity of information, agreement with the question. The instrument was structured through the SurveyMonkey site and a demographic questionnaire was designed to allow the characterization of the sample to be investigated. A pilot study was carried out with a sample of the target population, and the refinement of the instrument was performed through the analysis of the responses and textual evaluation. Finally, the validated questionnaire contains a question in which it declares consent for the research, twelve questions to characterize the profile of the sample and 34 questions of knowledge in GCP and Bioethics according to the pre-established dimensions and domains. Such instrument will be used to compose the Knowledge Management plan of the Clinical Trial Unit, in order to identify knowledge gaps in GCP and bioethics and, consequently, providing data to improve the training regularly performed by the Unit

A method of designing early clinical trials is developed for finding an optimum dose level of a new drug to be recommended for use in later phases. During the trial, the efficacious doses are allocated to the patients more often and those with a high probability of toxicity are less likely to be chosen. The method proposed is adaptive in the sense that the statistical models are updated after the data from each cohort of patients are collected and the dose level is adjusted at each stage based on the current data. Two classes of designs are presented. Although both are for efficacy and toxicity responses, one of them also considers pharmacokinetic information. The dose optimisation criteria are based on the probability of success and on the determinant of the Fisher information matrix for estimation of the dose-response parameters. They can be constrained by both acceptable levels of the probability of toxicity and desirable levels of the area under the concentration curve or the maximum concentration. The method presented is general and can be applied to various dose-response and pharmacokinetic models. To illustrate the methodology, it is applied to two different classes of models. In both cases, the pharmacokinetic model incorporates the population variability by making appropriate assumptions about the model parameters, while the dose responses are assumed to be either trinomial or bivariate binomial. Various design properties of the method are examined by simulation studies. Efficiency measures and the sensitivity of the designs to the assumed prior parameter values are presented. All of the computations are conducted in R, where the D- v optimal sampling time points are obtained by using the package PFIM. The results show that the proposed adaptive method works well and could be appropriate as a seamless phase IB/IIA trial design.

This thesis deals with sequential and adaptive methods for clinical trials, and how such methods can be used to achieve efficient clinical trial designs. The efficiency gains that can be achieved through non-adaptive group sequential methods are well established, while the newer adaptive methods seek to combine the best of the classical group sequential framework with an approach that gives increased flexibility. Our results show that the adaptive methods can provide some additional efficiency, as well as increased possibilities to respond to new internal and external information. Care is however needed when applying adaptive methods. While sub-optimal rules for adaptation can lead to inefficiencies, the logistical challenges can also be considerable. Efficient non-adaptive group sequential designs are often easier to implement in practice, and have for the cases we have considered been quite competitive in terms of efficiency. The four problems that are presented in this thesis are very relevant to how clinical trials are run in practice. The solutions that we present are either new approaches to problems that have not previously been solved, or methods that are more efficient than the ones currently available in the literature. Several challenging optimisation problems are solved through numerical computations. The optimal designs that are achieved can be used to benchmark new methods proposed in this thesis as well as methods available in the statistical literature. The problem that is solved in Chapter 5 can be viewed as a natural extension to the other problems. It brings together methods that we have used to the design of individual trials, to solve the more complex problem of designing a sequence of trials that are the core part of a clinical development program. The expected utility that is maximised is motivated by how the development of new medicines works in practice.