Background: A pilot study can be an important step in the assessment of an intervention by providing information to design the future definitive trial. Pilot studies can be used to estimate the recruitment and retention rates and population variance and to provide preliminary evidence of efficacy potential. However, estimation is poor because pilot studies are small, so sensitivity analyses for the main trial's sample size calculations should be undertaken. Methods: We demonstrate how to carry out easy-to-perform sensitivity analysis for designing trials based on pilot data using an example. Furthermore, we introduce rules of thumb for the size of the pilot study so that the overall sample size, for both pilot and main trials, is minimized. Results: The example illustrates how sample size estimates for the main trial can alter dramatically by plausibly varying assumptions. Required sample size for 90% power varied from 392 to 692 depending on assumptions. Some scenarios were not feasible based on the pilot study recruitment and retention rates. Conclusion: Pilot studies can be used to help design the main trial, but caution should be exercised. We recommend the use of sensitivity analyses to assess the robustness of the design assumptions for a main trial.

Background: With usual supplementation practices, most children are Vitamin D Deficient (VDD) following Congenital Heart Disease (CHD) surgery and alternative regimens need consideration. Methods/Results: i) A systematic review identified 88 pediatric trials of high dose vitamin D. Studies evaluating the Institute of Medicine (IOM) Tolerable Upper Intake Level (UL) did not rapidly normalize levels, while loading therapy (≥ 40000 IU) did so within 3 days. Hypercalcemia occurred more often with doses above 400000 IU. ii) A double blind RCT was designed to determine whether pre-operative administration of the IOM UL can prevent post-operative VDD. Results after the first 30 participants completed study procedures demonstrated it was possible to recruit (1.8 patients per month) and complete study procedures (i.e. blood collection). Unfortunately few participants (45%) received more than 30 doses of study drug. Conclusion: Prevention of post-operative VDD in the majority of CHD patients will require alternatives to the IOM recommendations.

Class of 2008 Abstract / Objectives: 1) To determine if data on weight change in the placebo arm of RCT's for weight loss were available, and 2) to conduct a pilot meta-analysis to estimate the average weight change in the placebo arm. Methods: Four randomized placebo controlled trials of rimonabant for weight loss were retrieved. A draft data extraction form was developed to record weight loss and demographic data. Potential for bias was assessed on design issues related to withdrawals, blinding, allocation procedure, adherence, and manufacturer influence. Based on available data, a forest plot was constructed and heterogeneity was assessed. The a priori alpha level was 0.05. Results: The placebo groups from all studies were similar. The pooled data indicated that individuals in the placebo arm lost an average of 3.3 kg, p < 0.001. One study had a significantly greater completion rate than the other studies. Participants were prescribed a hypocaloric diet and were instructed to increase physical activity but no data were reported on calories consumed or amount of physical activity. Weight loss of 5% ranged from 15-20% of participants. There was potential for bias relating to reported adherence, allocation concealment process, and manufacturer funding. Conclusions: Participants in the placebo arm of rimonabant trials lost an average of 3.3 kg, which was statistically significant. Little can be learned about weight loss in the placebo arm because no data on calories consumed, amount of exercise, or hunger were reported. Information from other RCT's is needed to provide additional data and to confirm the findings.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21705号 / 人健博第71号 / 新制||人健||5(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 市橋 則明, 教授 黒木 裕士, 教授 妻木 範行 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Extramedicínské (zne)užívání buprenorfinu v Gruzii a efektivní léčebná intervence MUDr. David Otiashvili Abstrakt Background Since early 2000s, the nonmedical abuse of buprenorphine (Subutex®) tablets, presumably smuggled from EU countries, has represented major phenomena of the problem drug scene in the Republic of Georgia. In a country with relatively high level of injecting drug use (estimated 40,000 persons, i.e. 1.5 % of population aged 15-64, of whom over 50% inject buprenorphine), this represent a major public health problem that needs detailed description and comprehensive set of interventions. Aim (i) To describe the extent of nonmedical buprenorphine ab/use in the Republic of Georgia, the characteristics of the nonmedical ab/users and their motivations for seeking and using the black market buprenorphine. Subsequently, (ii) to plan and pilot-test a treatment intervention that would be more specific and effective than the simple detoxification and/or harm reduction modalities available in Georgian on a routine basis. Setting Four regional centres of Georgia were included into the descriptive part of the study: the cities of Tbilisi, Gori, Zugdidi, and Batumi. The intervention (sub)study was conducted in one Tbilisi addiction treatment clinic. Participants and methods For the descriptive part of the...

Background: There is an established need to manage teasing and bullying of children who stutter (CWS) through changing the attitudes of their peers. The intervention, the Classroom Communication Resource (CCR), was implemented by teachers in classrooms. The primary objective of the main study was to determine the effectiveness of the CCR through a cluster Randomised Controlled Trial (RCT). The secondary objective of this study was to determine the treatment effect of the Stuttering Resource Outcomes Measure (SROM) within the subscales of Positive Social Distance (PSD), Social Pressure (SP) and Verbal Interaction (VI). The subgroup objective was to determine the primary objective between and across lower and higher school quintile clusters. Method: A cluster RCT was conducted. Participants in grade 7, aged 11 years and older, were randomly assigned to control and intervention groups using school and subgroup (quintile) clusters classifications. Following randomisation, stratification took place using a 1:1 allocation ratio. Participants viewed a video of a child who stuttered at baseline. Teachers administered the CCR (social story, role-play, discussion) in intervention groups only over a 60-90 minute session after they received an hour of training. Peer attitudes were measured at baseline and at 6 months post-intervention using the SROM in intervention and control groups. Results: A total of 10 schools were included whereby they were randomly allocated to control (k=5) and intervention groups (k=5). Within the schools, 454 participants were included with n =223 participants in the intervention and n= 231 in the control group. The study showed no statistically significant difference on the global SROM score (mean difference: -0.11 [95% confidence interval: -1.56, 1.34]; p = 0.88). Similarly, no significant differences were noted on SROM subscales: PSD (1.04 [-1.02,311]; p =0.32), SP (-0.45 [-1.22, 0.26]; p=0.21) and VI (0.05 [-1.01, 1.11]; 0.93), the secondary objective of this study. No significant subgroup effect on the global SROM score (lower vs higher quintile subgroups) [interaction p-value = 0.52] was observed during subgroup analysis. Results were however consistent with the hypothesis and quintile subgroups behaved similarly. Results were found clinically important when considering confidence intervals as well as the magnitude and direction of treatment effect. Conclusion: While the treatment effect showed no statistically significant differences on the global SROM and within the constructs of PSD, SP and VI, a clinically important result was noted when evaluating the meaningfulness of this study as well as its implications. Subgroup analysis showed that the quintiles behaved similarly, showing that the CCR was appropriate for schools within the lower and higher quintiles.

Extramedicínské (zne)užívání buprenorfinu v Gruzii a efektivní léčebná intervence MUDr. David Otiashvili Abstrakt Background Since early 2000s, the nonmedical abuse of buprenorphine (Subutex®) tablets, presumably smuggled from EU countries, has represented major phenomena of the problem drug scene in the Republic of Georgia. In a country with relatively high level of injecting drug use (estimated 40,000 persons, i.e. 1.5 % of population aged 15-64, of whom over 50% inject buprenorphine), this represent a major public health problem that needs detailed description and comprehensive set of interventions. Aim (i) To describe the extent of nonmedical buprenorphine ab/use in the Republic of Georgia, the characteristics of the nonmedical ab/users and their motivations for seeking and using the black market buprenorphine. Subsequently, (ii) to plan and pilot-test a treatment intervention that would be more specific and effective than the simple detoxification and/or harm reduction modalities available in Georgian on a routine basis. Setting Four regional centres of Georgia were included into the descriptive part of the study: the cities of Tbilisi, Gori, Zugdidi, and Batumi. The intervention (sub)study was conducted in one Tbilisi addiction treatment clinic. Participants and methods For the descriptive part of the...

Objectives: To determine the subacute effects of cervicothoracic spinal thrust/non-thrust in addition to shoulder non-thrust plus exercise in patients with subacromial pathology. Methods: This was a randomized, single blinded controlled trial pilot study. This trial was registered at ClinicalTrials.gov (NCT01753271) and reported according to Consolidated Standards of Reporting Trials requirements. Patients were randomly assigned to either shoulder treatment plus cervicothoracic spinal thrust/non-thrust or shoulder treatment-only group. Primary outcomes were average pain intensity (Numeric Pain Rating Scale) and physical function (Shoulder Pain and Disability Index) at 2 weeks, 4 weeks, and patient discharge. Results: 18 patients, mean age 43.1(15.8) years satisfied the eligibility criteria and were analyzed for follow-up data. Both groups showed statistically significant improvements in both pain and function at 2 weeks, 4 weeks, and discharge. The between-group differences for changes in pain or physical function were not significant at any time point. Discussion: The addition of cervicothoracic spinal thrust/non-thrust to the shoulder treatment-only group did not significantly alter improvement in pain or function in patients with subacromial pathology. Both approaches appeared to provide an equally notable benefit. Both groups improved on all outcomes and met the criteria for clinical relevance for both pain and function. Level of Evidence: 2b.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第18908号 / 人健博第22号 / 新制||人健||2(附属図書館) / 31859 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 菅沼 信彦, 教授 鈴木 眞知子, 教授 中原 俊隆 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Study design of a randomized-controlled trial investigating the effects of probiotic supplementation on induction of prediabetes remission to normoglycemia in adults with prediabetes. / BACKGROUND: Patients with prediabetes are at a high risk of developing type 2 diabetes (T2D) and the current strategies to prevent the progression of prediabetes to T2D are difficult to implement at the population level. Recently, the role of gut microbiota has emerged as a possible link to metabolic disease. The modulation of the gut microbiota in individuals with prediabetes through probiotic supplementation may improve metabolic dysfunction and induce remission of prediabetes to normoglycemia. OBJECTIVES: The primary objective of this trial is to determine the effect of 900 billion CFU/day of VSL#3®, a multi-strain probiotic supplement for 20 weeks, on induction of drug-free remission to normoglycemia (HbA1c<6.0%) in adults with prediabetes compared to placebo 20 weeks post-randomization. METHODS: In a randomized, triple-blind, controlled multi-centre trial, 568 adults with prediabetes will undergo a 2-week run-in after which they will be randomly allocated to 20 weeks of either 900 billion CFUs of VSL#3® per day or placebo. Prediabetes remission will be measured using HbA1C at week 20 and 32. Change in insulin resistance (HOMA-IR), beta-cell function (HOMA-B), weight, BMI, waist circumference and fecal relative abundance of bacteria will be measured from baseline at week 20 and 32. Exploratory regression analyses will involve a multiple logistic regression model to assess whether the change in relative abundance of the Rosburia genus from baseline at week 20 is an independent predictor of drug-free prediabetes remission at week 20. DISCUSSION: Individuals with prediabetes are at high risk of developing T2D and the induction of prediabetes remission would be important to patients and clinicians. The role of microbiota in metabolic processes presents the potential for therapeutic applications of probiotics. If successful, probiotics would offer a therapeutic option for reversing prediabetes to normoglycemia that is simple, cheap and easy to incorporate into standard clinical care. / Thesis / Master of Science (MSc) / BACKGROUND: Patients with prediabetes are at a high risk of developing type 2 diabetes (T2D) and the current strategies to prevent the progression of prediabetes to T2D are difficult to apply at the population level. Recently, the role of gut bacteria has emerged as a possible link to metabolic disease. Changing the gut microbiota in people with prediabetes through probiotic supplements may improve metabolic function and result in remission of prediabetes to normal glucose control. OBJECTIVES: The primary objective of this study is to determine the effect of VSL#3®, a probiotic supplement, for 20 weeks, on induction of drug-free remission to normal glucose control in adults with prediabetes compared to placebo, 20 weeks after randomization. METHODS: In a randomized, triple-blind, controlled multi-centre trial, 568 adults with prediabetes will be randomly assigned to 20 weeks of either VSL#3® per day or placebo. Prediabetes remission will be measured using HbA1C at week 20 and 32. Change in insulin resistance (HOMA-IR), beta-cell function (HOMA-B), weight, BMI, waist circumference and fecal bacteria will be measured from baseline at week 20 and 32. DISCUSSION: Individuals with prediabetes are at high risk of developing T2D and the induction of prediabetes remission would be important to patients and clinicians. The role of gut bacteria in metabolic health presents the potential for probiotics to be therapy options. If successful, probiotics would be simple, cheap and easy to incorporate into standard clinical care.