An adaptive group sequential design for phase II/III clinical trials that select a single treatment from several

There is increasing interest in combining Phases II and III of clinical development into a single trial in which one of a small number of competing experimental treatments is ultimately selected and where a valid comparison is made between this treatment and the control treatment. Such a trial usually proceeds in stages, with the least promising experimental treatments dropped as soon as possible. In this paper we present a highly flexible design that uses adaptive group sequential methodology to monitor an order statistic. By using this approach, it is possible to design a trial which can have any number of stages, begins with any number of experimental treatments, and permits any number of these to continue at any stage. The test statistic used is based upon efficient scores, so the method can be easily applied to binary, ordinal, failure time, or normally distributed outcomes. The method is illustrated with an example, and simulations are conducted to investigate its type I error rate and power under a range of scenarios.

Steiner triple systems with two disjoint subsystems

It is shown that there exists a triangle decomposition of the graph obtained from the complete graph of order v by removing the edges of two vertex disjoint complete subgraphs of orders u and w if and only if u, w, and v are odd, ((v)(2)) - ((u)(2)) - ((w)(2)) equivalent to 0 (mod 3), and v >= w + u + max {u, w}. Such decompositions are equivalent to group divisible designs with block size 3, one group of size u, one group of size w, and v - u - w groups of size 1. This result settles the existence problem for Steiner triple systems having two disjoint specified subsystems, thereby generalizing the well-known theorem of Doyen and Wilson on the existence of Steiner triple systems with a single specified subsystem. (c) 2005 Wiley Periodicals, Inc.

Fixed block configuration GDDs with block size 6 and (3, r)-regular graphs

Chapter 1 is used to introduce the basic tools and mechanics used within this thesis. Most of the definitions used in the thesis will be defined, and we provide a basic survey of topics in graph theory and design theory pertinent to the topics studied in this thesis. In Chapter 2, we are concerned with the study of fixed block configuration group divisible designs, GDD(n; m; k; λ1; λ2). We study those GDDs in which each block has configuration (s; t), that is, GDDs in which each block has exactly s points from one of the two groups and t points from the other. Chapter 2 begins with an overview of previous results and constructions for small group size and block sizes 3, 4 and 5. Chapter 2 is largely devoted to presenting constructions and results about GDDs with two groups and block size 6. We show the necessary conditions are sufficient for the existence of GDD(n, 2, 6; λ1, λ2) with fixed block configuration (3; 3). For configuration (1; 5), we give minimal or nearminimal index constructions for all group sizes n ≥ 5 except n = 10, 15, 160, or 190. For configuration (2, 4), we provide constructions for several families ofGDD(n, 2, 6; λ1, λ2)s. Chapter 3 addresses characterizing (3, r)-regular graphs. We begin with providing previous results on the well studied class of (2, r)-regular graphs and some results on the structure of large (t; r)-regular graphs. In Chapter 3, we completely characterize all (3, 1)-regular and (3, 2)-regular graphs, as well has sharpen existing bounds on the order of large (3, r)- regular graphs of a certain form for r ≥ 3. Finally, the appendix gives computational data resulting from Sage and C programs used to generate (3, 3)-regular graphs on less than 10 vertices.

The effect of osteoporosis education on calcium intake and physical activity in a group of community-dwelling Black older adults

The unprecedented increase in the number of older adults is expected to increase the burden of osteoporosis on the individual and society. Blacks have been understudied in osteoporosis prevention education research. Although the risk of osteoporosis is low in this population, its consequences are significant. This study employs a two-group experimental design (experimental and wait-list control groups) to evaluate the effect of an osteoporosis education on two osteoporosis prevention behaviors (OPBs)—calcium intake (CI) and physical activity (PA), in a group of community-dwelling Black older adults, 50 years and older resident in South Florida. A final sample of 110 (mean age 70.15 years), 90% female and 10% male completed a battery of questionnaires at two assessment periods. The experimental group participated in six weekly education program sessions immediately following baseline assessment, and the wait-list control group received the education following end of program assessment by all participants. The weekly educational sessions were conducted in social settings (church or senior center) employing constructs of the Revised Health Belief Model. The sessions focused on improving CI; osteoporosis knowledge (OKT), self-efficacy (SE), health beliefs (HB) and PA. Findings revealed significantly greater increase in reported CI ( M = 556 mg, Wilks’ λ = .47, F (1,108)=122.97, p< .001, η2=.53), OKT (p< .001), and SE (p< .001) among participants in the experimental compared to the wait-list control group. There was no significant difference between the two groups for PA and most of the HB subscales. OKT and SE were the best predictors of CI, while perceived barrier was a predominant factor predicting PA. Over the study period, a change in SE was the only variable related to changes in both OPBs. Attrition rate was lower than expected, which can be attributed to the settings utilized for the study. These findings support the importance of utilizing a familiar social setting. These results suggested the effectiveness of a program offered in multiple short sessions among this underserved minority population to improve OKT and SE resulting in a change in OPBs (increase in CI). However, there is need to explore alternative strategies to improve PA in this population group.

The Effect of Osteoporosis Education on Calcium Intake and Physical Activity in a Group of Community-Dwelling Black Older Adults

The unprecedented increase in the number of older adults is expected to increase the burden of osteoporosis on the individual and society. Blacks have been understudied in osteoporosis prevention education research. Although the risk of osteoporosis is low in this population, its consequences are significant. This study employs a two-group experimental design (experimental and wait-list control groups) to evaluate the effect of an osteoporosis education on two osteoporosis prevention behaviors (OPBs) – calcium intake (CI) and physical activity (PA), in a group of community-dwelling Black older adults, 50 years and older resident in South Florida. A final sample of 110 (mean age 70.15 years), 90% female and 10% male completed a battery of questionnaires at two assessment periods. The experimental group participated in six weekly education program sessions immediately following baseline assessment, and the wait-list control group received the education following end of program assessment by all participants. The weekly educational sessions were conducted in social settings (church or senior center) employing constructs of the Revised Health Belief Model. The sessions focused on improving CI; osteoporosis knowledge (OKT), self-efficacy (SE), health beliefs (HB) and PA. Findings revealed significantly greater increase in reported CI (M = 556 mg, Wilks’ λ = .47, F(1,108)=122.97, p< .001, η2=.53), OKT (p< .001), and SE (p< .001) among participants in the experimental compared to the wait-list control group. There was no significant difference between the two groups for PA and most of the HB subscales. OKT and SE were the best predictors of CI, while perceived barrier was a predominant factor predicting PA. Over the study period, a change in SE was the only variable related to changes in both OPBs. Attrition rate was lower than expected, which can be attributed to the settings utilized for the study. These findings support the importance of utilizing a familiar social setting. These results suggested the effectiveness of a program offered in multiple short sessions among this underserved minority population to improve OKT and SE resulting in a change in OPBs (increase in CI). However, there is need to explore alternative strategies to improve PA in this population group.

On the Hamilton-Waterloo problem

The Hamilton-Waterloo problem asks for a 2-factorisation of K-v in which r of the 2-factors consist of cycles of lengths a(1), a(2),..., a(1) and the remaining s 2-factors consist of cycles of lengths b(1), b(2),..., b(u) (where necessarily Sigma(i)(=1)(t) a(i) = Sigma(j)(=1)(u) b(j) = v). In thus paper we consider the Hamilton-Waterloo problem in the case a(i) = m, 1 less than or equal to i less than or equal to t and b(j) = n, 1 less than or equal to j less than or equal to u. We obtain some general constructions, and apply these to obtain results for (m, n) is an element of {(4, 6)1(4, 8), (4, 16), (8, 16), (3, 5), (3, 15), (5, 15)}.

Two-dimensional balanced sampling plans excluding contiguous units

A balanced sampling plan excluding contiguous units (or BSEC for short) was first introduced by Hedayat, Rao and Stufken in 1988. These designs can be used for survey sampling when the units are arranged in one-dimensional ordering and the contiguous units in this ordering provide similar information. In this paper, we generalize the concept of a BSEC to the two-dimensional situation and give constructions of two-dimensional BSECs with block size 3. The existence problem is completely solved in the case where lambda = 1.

Corrosão das armaduras do betão armado: causas, consequências, prevenção e projeto de durabilidade

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Civil

Bortezomib(Velcade (R))-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation.

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35.

Effect of different warm-up strategies on simulated laparoscopy performance: a randomized controlled trial.

OBJECTIVE: The objective of this trial was to assess which type of warm-up has the highest effect on virtual reality (VR) laparoscopy performance. The following warm-up strategies were applied: a hands-on exercise (group 1), a cognitive exercise (group 2), and no warm-up (control, group 3). DESIGN: This is a 3-arm randomized controlled trial. SETTING: The trial was conducted at the department of surgery of the University Hospital Basel in Switzerland. PARTICIPANTS: A total of 94 participants, all laypersons without any surgical or VR experience, completed the study. RESULTS: A total of 96 participants were randomized, 31 to group 1, 31 to group 2, and 32 to group 3. There were 2 postrandomization exclusions. In the multivariate analysis, we found no evidence that the intervention had an effect on VR performance as represented by 6 calculated subscores of accuracy, time, and path length for (1) camera manipulation and (2) hand-eye coordination combined with 2-handed maneuvers (p = 0.795). Neither the comparison of the average of the intervention groups (groups 1 and 2) vs control (group 3) nor the pairwise comparisons revealed any significant differences in VR performance, neither multivariate nor univariate. VR performance improved with increasing performance score in the cognitive exercise warm-up (iPad 3D puzzle) for accuracy, time, and path length in the camera navigation task. CONCLUSIONS: We were unable to show an effect of the 2 tested warm-up strategies on VR performance in laypersons. We are currently designing a follow-up study including surgeons rather than laypersons with a longer warm-up exercise, which is more closely related to the final task.

Bortezomib(Velcade®)-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting.

Modification of personality variables through application of a psycho-educational program of full consciousness (mindfulness) in university students

This study examines the effects in university students of a psycho-educational program in full awareness (mindfulness) on certain personality variables. A quasi-experimental (group comparison) design with pretest and postest measurements was employed in an experimental (n = 26) and a control group (n = 27). Barratt impulsiveness Scale (BiS- 11), Acceptance and Action Questionnaire (AAQ), Social Avoidance and Distress Scale (SAD), and the Profile of Mood States (POMS) were applied to experimental and control groups. The results show statistically significant changes in impulsivity variables, experiential avoidance, social avoidance, social anxiety, tension and fatigue when comparing the posttest mean scores of the groups.

¿Impactó el programa de Tutores Pares a sus tutores?

Introducción: El programa de Tutores Pares-TP es una iniciativa creada en la EMCS de la Universidad del Rosario que brinda acompañamiento académico a través de estudiantes-tutores a pares menos avanzados. Éste entrega a sus Tutores sistemáticamente, herramientas para desempeñarse armónicamente en el ejercicio de guía y provee habilidades para el manejo del saber. Este estudio busca explorar posibles ´impactos´ generados tras la participación de estudiantes de medicina como TPs dentro de un programa estructurado. Materiales y métodos: Estudio cualitativo que involucró la construcción y aplicación de encuestas a grupos focales –TPs, Docentes y Familiares- creadas a partir de seis ejes/categorías que enmarcan al médico ideal. Las respuestas obtenidas de preguntas cerradas –en escala valorativa- y de naturaleza abierta fueron sometidas a análisis descriptivo –modas- y triangulación. Resultados: 41 tutores, agrupados en 4 grupos de análisis, evidenciaron un impacto general positivo con predominio en habilidades interpersonales (60%,65%,66%,45%, respectivamente), funciones/actividades basadas en la práctica y mejoramiento (57%,67%,60%,45%) y la forma como se emplean los conocimientos (47%,70%,67%,48%). Ocho docentes encuestados consideraron relevante el impacto del programa en habilidades interpersonales-(49%), conocimientos-(42%) y la interacción con colegas-(38%). En los padres de familia hay consenso en el cambio en habilidades interpersonales, funciones basadas en la práctica y mejoramiento y en actitudes-valores ético/morales. Dichos resultados están en paralelo con las observaciones plasmadas en las preguntas abiertas. Conclusiones: Se evidenció un impacto general positivo en la formación y desempeño profesional tras la participación como TPs dentro del programa; hallazgo que soporta aquellos publicados de experiencias académicas similares.

A randomised controlled trial of positive memory training for the treatment of depression within schizophrenia

Abstract Background: Depression is highly prevalent within individuals diagnosed with schizophrenia, and is associated with an increased risk of suicide. There are no current evidence based treatments for low mood within this group. The specific targeting of co-morbid conditions within complex mental health problems lends itself to the development of short-term structured interventions which are relatively easy to disseminate within health services. A brief cognitive intervention based on a competitive memory theory of depression, is being evaluated in terms of its effectiveness in reducing depression within this group. Methods/Design: This is a single blind, intention-to-treat, multi-site, randomized controlled trial comparing Positive Memory Training plus Treatment as Usual with Treatment as Usual alone. Participants will be recruited from two NHS Trusts in Southern England. In order to be eligible, participants must have a DSM-V diagnosis of schizophrenia or schizo-affective disorder and exhibit at least a mild level of depression. Following baseline assessment eligible participants will be randomly allocated to either the Positive Memory Training plus Treatment as Usual group or the Treatment as Usual group. Outcome will be assessed at the end of treatment (3-months) and at 6-month and 9-month post randomization by assessors blind to group allocation. The primary outcome will be levels of depression and secondary outcomes will be severity of psychotic symptoms and cost-effectiveness. Semi-structured interviews will be conducted with all participants who are allocated to the treatment group so as to explore the acceptability of the intervention. Discussion: Cognitive behaviour therapy is recommended for individuals diagnosed with schizophrenia. However, the number of sessions and length of training required to deliver this intervention has caused a limit in availability. The current trial will evaluate a short-term structured protocol which targets a co-morbid condition often considered of primary importance by service users. If successful the intervention will be an important addition to current initiatives aimed at increasing access to psychological therapies for people diagnosed with severe mental health problems. Trial registration: Current Controlled Trials. ISRCTN99485756. Registered 13 March 2014.