Objectives: 1) To evaluate the quality of randomized clinical trials (RCTs) in rare diseases using Juvenile Idiopathic Arthritis (JIA) as an example, 2) to evaluate the time to treatment response in patients with rheumatic diseases, 3) to evaluate the power of the Randomized Placebo-Phase Design (RPPD) under various response time distributions, and 4) to examine the use of Value of Information (VOI) methodology in the optimal design of clinical trials for rare disease using hemophilia prophylaxis with factor VIII as an example. Methods. The methods include a systematic review, a secondary analysis of data from an RCT and from a patient registry, a computer simulation study, and an evaluation of hypothetical RCT scenarios with VOI methodology. Results. The quality of RCTs in JIA based on selected quality indicators was poor with some positive changes over time. In the data sets used for the assessment of hazard distributions, the response times followed mostly generalized gamma or lognormal distributions. The impact of time-to-event distribution on the power of RCTs was assessed in computer simulations. Based on the simulation results, the highest sample sizes were observed for response times following the exponential distribution. In most scenarios, the parallel groups RCT design had higher power than the RPPD. The conclusion of the VOI analyses indicated that at threshold values lower than 400,000 the current evidence supported the use of on-demand therapy. Threshold values higher than 1,000,000 supported the use of tailored or alternate day prophylaxis. At threshold values between 400,000 - 1,000,000 the optimal decision varied from on-demand to prophylaxis therapies. Conclusions. New, more powerful and acceptable designs should be developed for rare diseases. When time-to-event outcomes are used, investigators should use various sources of information to evaluate response time distributions before the new trial is designed, and consider this information in sample size calculation and analysis. VOI methodology should be used in the planning stage of studies to determine the relevant costs and benefits of future research, and to determine the optimal trial parameters that maximize the cost-benefit trade-off.

Objectives: 1) To evaluate the quality of randomized clinical trials (RCTs) in rare diseases using Juvenile Idiopathic Arthritis (JIA) as an example, 2) to evaluate the time to treatment response in patients with rheumatic diseases, 3) to evaluate the power of the Randomized Placebo-Phase Design (RPPD) under various response time distributions, and 4) to examine the use of Value of Information (VOI) methodology in the optimal design of clinical trials for rare disease using hemophilia prophylaxis with factor VIII as an example. Methods. The methods include a systematic review, a secondary analysis of data from an RCT and from a patient registry, a computer simulation study, and an evaluation of hypothetical RCT scenarios with VOI methodology. Results. The quality of RCTs in JIA based on selected quality indicators was poor with some positive changes over time. In the data sets used for the assessment of hazard distributions, the response times followed mostly generalized gamma or lognormal distributions. The impact of time-to-event distribution on the power of RCTs was assessed in computer simulations. Based on the simulation results, the highest sample sizes were observed for response times following the exponential distribution. In most scenarios, the parallel groups RCT design had higher power than the RPPD. The conclusion of the VOI analyses indicated that at threshold values lower than 400,000 the current evidence supported the use of on-demand therapy. Threshold values higher than 1,000,000 supported the use of tailored or alternate day prophylaxis. At threshold values between 400,000 - 1,000,000 the optimal decision varied from on-demand to prophylaxis therapies. Conclusions. New, more powerful and acceptable designs should be developed for rare diseases. When time-to-event outcomes are used, investigators should use various sources of information to evaluate response time distributions before the new trial is designed, and consider this information in sample size calculation and analysis. VOI methodology should be used in the planning stage of studies to determine the relevant costs and benefits of future research, and to determine the optimal trial parameters that maximize the cost-benefit trade-off.

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

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.

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Submitted by Neusa Fagundes (neusa.fagundes@unioeste.br) on 2018-08-23T17:52:03Z No. of bitstreams: 2 Márcio_Camargo2018.pdf: 1289257 bytes, checksum: 6b195c00237854a0b325ec5a5c953cac (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-08-23T17:52:03Z (GMT). No. of bitstreams: 2 Márcio_Camargo2018.pdf: 1289257 bytes, checksum: 6b195c00237854a0b325ec5a5c953cac (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-05-14 / This double-blind randomized clinical trial evaluates the influence of increased application time in two adhesive system two-step etch-and-rinse (Peak® Universal Bond (P); Ultradent Products Ind and Single Link (SL); Angelus Dental Products Industry) applied in non-carious cervical lesions (NCCLs). Methods: A total of 219 restorations were randomly placed in 35 patients according to the following groups: P1 - applied according to the manufacturer’s; P2X – applied for the double time; SL1 and SL2X (the same application mode). The resin composite Amelogen (Ultradent) was placed incrementally. The restorations were evaluated immediately (baseline) and 6 months, using the FDI and USPHS criteria. Statistical analyses were performed using appropriate tests (=0.05). Results: Twenty-four restorations were lost at 6 months (4 for P1, 2 for P2X, 9 for SL1 and 9 for SL2X) (p < 0.05 between groups). Post-operative sensitivity wasn’t observed in any of the recall periods. Thrity-five restorations were considered to have minor discrepancies in marginal adaptation at the 6-month recall using the FDI criteria (8 for P1, 7 for P2X, 12 for SL1 and 8 for SL2X; p > 0.05 between groups). Ten restorations were considered to have minor discrepancies in marginal discoloration at the 6-month recall (2 for P1, 1 for P2X, 3 for SL1 and 2 for SL2X; p > 0.05 between groups). Conclusion: The increased application time of adhesive system two-step etch-and-rinse didn’t improve the clinical behavior of composite restorations placed in NCCLs. In the meantime, clinical behavior may be influenced by the composition of adhesive systems. / Este ensaio clínico controlado randomizado, duplo cego avaliou a influência do aumento do tempo de aplicação em dois sistemas adesivos convencionais de dois passos, Peak® Universal Bond (P) (Ultradent Products Ind) e Single Link (SL) (Angelus Dental Products Industry) aplicados para restaurar lesões cervicais não cariosas (LCNC). Material e Método: No desenho experimental um total de 219 restaurações foram distribuídas aleatoriamente em 35 pacientes de acordo com os seguintes grupos: P1 e SL1 - aplicados de acordo com o fabricante por 10s; P2X e SL2X - aplicados por 20 s. A resina composta Amelogen (Ultradent) foi colocada de forma incremental. As restaurações foram avaliadas imediatamente (baseline), e em 6 meses, utilizando os critérios FDI e USPHS. As análises estatísticas foram realizadas utilizando testes de Friedman e Mc Nemar (α = 0,05). Resultado: Vinte e quatro restaurações foram perdidas aos 6 meses (4 para P1, 2 para P2X, 9 para SL1 e 9 para SL2X) (p<0,05). A sensibilidade pós-operatória não foi relatada durante a avaliação. Trinta e cinco restaurações apresentaram pequenas discrepâncias na adaptação marginal usando os critérios FDI (8 para P1, 7 para P2X, 12 para SL1 e 8 para SL2X; p>0,05 entre os grupos). Oito restaurações apresentaram pequena discrepância no manchamento marginal na avaliação de 6 meses (2 para P1, 1 para P2X, 3 para SL1 e 2 para SL2X; p> 0,05 entre grupos). Conclusão: Aumentar o tempo de aplicação do sistema adesivo convencional de dois passos não melhora o desempenho clínico das restaurações em resina compostas realizadas em LCNCs. Entretanto, este desempenho/performance pode ser influenciado pela composição dos sistemas adesivos.

Indiana University-Purdue University Indianapolis (IUPUI) / Currently, the predominant view in research ethics maintains that physicians can morally justify offering randomized clinical trial enrollment to their patients only if some form of equipoise is present. Thus, the physician must experience (either individually or communally) a state of reasoned uncertainty concerning the relative merits of two or more competing treatments for a given disease before she may recommend that her patient participate in a clinical trial. Increasingly, however, this position has been subject to critical attention and considerable negative scrutiny. My argument engages this trend by turning to the history of philosophy; here I claim that the use of the term “equipoise” in the medical research context is extremely similar to terms and concepts from the philosophical tradition of skepticism, and as a result of this similarity it is possible to understand the principle of equipoise’s vulnerability to already published criticisms. A comparison of the criticisms of equipoise within the medical research literature to criticisms of philosophical skepticism reveals a potentially grim future for equipoise as a legitimate guiding principle for the ethical conduct of clinical research.

The number of annual implantable cardioverter defibrillator (ICD) implants has substantially increased over the last 5 years and is expected to grow rapidly. Implantable cardioverter defibrillators have a proven mortality benefit by terminating the life-threatening arrhythmias, even near end of life. In patients with moderate/severe symptomatic heart failure, enough clinical literature representing mortality benefits has been published, but limited numbers of studies have reviewed the dwindling risk-benefit profile near end of life, studying quality of life (QoL)/psychosocial impact. Criteria outlining either continued use or deactivation policy/procedures near end of life have not been clearly defined and/or largely implemented, which in turn requires more focused research using multifactorial approach to determine improved patient-centered outcomes.

Clinical trials are used to determine the efficacy and safety of a medication prior to approval for commercial use and to influence the prescribing habits of clinicians. The lack of uniformity in the diagnostic thresholds used in clinical trials on osteoporosis makes it difficult to compare the results of these trials. The use of placebo, different anatomical sites, T-score cutoff points, and risk factors precludes any meaningful comparison being made between the outcomes of clinical trials. Finally, the lack of uniform reporting format makes it difficult to retrieve important information to compare one medication to another. Because the diagnostic thresholds used affect the outcomes of these trials, health care providers need to be aware of these criteria to determine whether the results of a particular clinical trial can be applied to a particular patient.

Randomized controlled trials (RCTs) are the hallmark of evidence-based medicine and form the basis for translating research data into clinical practice. This review summarizes commonly applied designs and quality indicators of RCTs to provide guidance in interpreting and critically evaluating clinical research data. It further reflects on the principle of equipoise and its practical applicability to clinical science with an emphasis on critical care and neurological research. We performed a review of educational material, review articles, methodological studies, and published clinical trials using the databases MEDLINE, PubMed, and ClinicalTrials.gov. The most relevant recommendations regarding design, conduction, and reporting of RCTs may include the following: 1) clinically relevant end points should be defined a priori, and an unbiased analysis and report of the study results should be warranted, 2) both significant and nonsignificant results should be objectively reported and published, 3) structured study design and performance as indicated in the Consolidated Standards of Reporting Trials statement should be employed as well as registration in a public trial database, 4) potential conflicts of interest and funding sources should be disclaimed in study report or publication, and 5) in the comparison of experimental treatment with standard care, preplanned interim analyses during an ongoing RCT can aid in maintaining clinical equipoise by assessing benefit, harm, or futility, thus allowing decision on continuation or termination of the trial.