The equivalence assessment usually consists of three tests and is often conducted through a three-arm clinical trial. The first two tests are to demonstrate the superiority of the test treatment and the reference treatment to placebo, and they are followed by the equivalence test between the test treatment and the reference treatment. The equivalence is commonly defined in terms of mean difference, mean ratio or ratio of mean differences, i.e. the ratio of the mean difference of the test and placebo to the mean difference of the reference and placebo. In this dissertation, the equivalence assessment for both continuous data and discrete data are discussed. For the continuous case, the test of the ratio of mean differences is applied. The advantage of this test is that it combines a superiority test of the test treatment over the placebo and an equivalence test through one hypothesis. For the discrete case, the two-step equivalence assessment approach is studied for both Poisson and negative binomial data. While a Poisson distribution implies that population mean and variance are the same, the advantage of applying a negative binomial model is that it accounts for overdispersion, which is a common phenomenon of count medical endpoints. The test statistics, power function, and required sample size examples for a three-arm equivalence trial are given for both continuous and discrete cases. In addition, discussions on power comparisons are complemented with numerical results. / Statistics

Background and Objectives: Sharing of interim results by the Data Safety Monitoring Board (DSMB) with non-DSMB members is an important issue that can affect trial integrity. The objective of this dissertation was to determine the views of the stakeholders on what kind of interim results can or should be shared by the DSMB, why, and with whom among those responsible for the conduct of a trial. Methods: We first conducted a systematic search of the literature to assess views and current evidence on sharing interim results. Secondly, we conducted two cross-sectional surveys aimed at those involved in trials to solicit their views on what type of interim results should be shared by the DSMB with non-DSMB members, with whom and under what circumstances. Thirdly, we assessed for any potential association of demographic factors with the sharing of certain interim results and their perceived usefulness, using regression analysis. Results: Mixed views exist in the literature on interim result sharing practices. Evidence from the surveys conducted resulted in the following findings. What to share: Based upon the survey results from our cross-sectional survey (Chapter 4), the interim control event rate (IControlER), the adaptive conditional power (ACP) and the unconditional conditional power (UCP) should not be shared. Most respondents from this survey thought the interim combined event rate (ICombinedER) could be shared provided proper conditions and provisions are in place. However, based on our cross-sectional scenario-based survey (Chapter 3), it was demonstrated that the ICombinedER, when shared at interim, is compatible with three possible interim results (Drug X doing better than placebo, worse than placebo or performing the same as placebo). Why share or not share: Respondents indicate that the ICombinedER can be shared because it does not unmask relative effects between groups, and keeps the steering committee (SC) informed about the trial’s progress; however, with the condition that sharing this type of result should be specified a priori including for what purpose and be at the DSMB’s discretion, especially if the control group rate is known from the literature. However, it is important to note that the ICombinedER, demonstrated with evidence from our cross-sectional scenario-based survey (Chapter 3), is compatible with three possible interim results and should not be shared because it has low usefulness and is flawed due to multiple interpretations. The IControlER and the ACP should not be shared because they are unmasking of interim results. It was mentioned that ICombinedER is usually known by the SC and sponsor making it easy to determine group rates if the IControlER is known. The UCP should not be shared because it is a technical measure that is potentially misleading of interim results. With whom to share: Survey results from Chapter 4 indicated that the ICombinedER can be shared with the SC and that the IControlER, the ACP, and the UCP should not be shared with any non-DSMB members by the DSMB. However, evidence from Chapter 3 also indicates that the ICombinedER should not be shared with any non-DSMB member. Factors associated with sharing: Having experience with greater than 15 trials with private industry sponsorship was found to be associated with not sharing the IControlER and an increase in perceived usefulness in sharing the ACP. Though some other demographic factors were found to be associated with sharing the ICombinedER and the UCP, they were sensitive to missing data upon our sensitivity analysis and will require more validation. Conclusions: Though mixed views exist within an extensive literature review on interim result sharing practices, survey evidence from this dissertation suggests that the ICombinedER, IControlER, the ACP and the UCP should not be shared with any non-DSMB member. The IControlER and ACP can be unmasking of interim results and the UCP is a technical measure that is potentially misleading. We agree with this reasoning. The majority of respondents from the survey in Chapter 4 indicated that the ICombinedER can be shared with the SC because it does not unmask relative effects between groups, however it was also stipulated that sharing this measure should be specified a priori and for what purpose and be at the DSMB’s discretion, especially if the control group rate is known from the literature. Even though the majority from our second survey in Chapter 4 indicate sharing the ICombinedER with the SC, we do not recommend sharing the ICombinedER at interim with any non-DSMB member because, as demonstrated with evidence from our cross-sectional scenario-based survey in Chapter 3, this measure is compatible with three possible interim results potentially leading to the introduction of trial bias at interim by those privy this interim measure and their interpretation. Based on the findings from the survey from Chapter 4, there appears to be a lack of awareness in how sharing the ICombinedER is flawed, of low usefulness, and potentially dangerous. The perceived desire to have this measure shared seems misguided. Experience with greater than 15 trials with private industry sponsorship was found to be associated with not endorsing the sharing the IControlER and an increase in perceived usefulness in sharing the ACP by the DSMB at interim. In regards to implications for future research, this characteristic should be further evaluated to see if this subgroup has insight into interim trial management practices that protect from trial bias. Results from this research have implications for practice and guidelines concerning trial design and protocols, and DSMB charters. These results can also help assess the need for proper safeguards around sharing an interim result when deemed appropriate by the DSMB and under their discretion, that prevent the introduction of bias that could alter the final trial results generated. / Thesis / Doctor of Philosophy (PhD)

The main object of the research is to analyze the effect of the clinical intervention algorithms proposed for reducing antibiotic use for older adults in long-term care facilities (LTCFs) by managing urinary tract infections (UTIs). 20 paired nursing homes were enrolled in the 12-month study. Within each pair, one was randomized to use of the intervention algorithms and the other to use of regular management. Cluster-level paired t-tests (unweighted and weighted) and regression analyses (unweighted and weighted) were used in the analysis of the data. Paired t-tests show that the algorithms did not significantly reduce the antibiotic use, the number of urine cultures or the antibiotic use for urinary infections in most months. However, they did reduce the proportion of antibiotic use for urinary infections significantly in most months. Regression analysis indicates that the difference between the control group and intervention group has no significant increasing or decreasing trend with time (month). And the algorithms significantly reduced the antibiotic use for urinary infections, number of cultures and the proportions through the 12-month study. The analyses reached a similar conclusion using nonparametric methods and weighted analysis. / Thesis / Master of Science (MS)

VAT plays a crucial role in creating a single internal market in the EU. However, the applicability of VAT rules in regard to the conduct of clinical trials and investigational medicinal products (IMPs) remains uncertain due to different interpretations among the Member States and the lack of case laws regarding clinical trials. This thesis examines the EU VAT Directive and the case law provided by the ECJ using a teleological approach to interpret the concept of medical care and identify applicable provisions for the conduct of clinical trials and transactions involving IMPs. The analysis provides insights into the VAT treatment of clinical trials conducted within the EU.

Lanthionine synthetase C-like protein 2 (LANCL2) is a member of the LANCL protein family, which is broadly expressed throughout the body. LANCL2 is the molecular target of abscisic acid (ABA), a compound with insulin-sensitizing and immune modulatory actions. LANCL2 is required for membrane binding and signaling of ABA in immune cells. Direct binding of ABA to LANCL2 was predicted in silico using molecular modeling approaches and validated experimentally using ligand-binding assays and kinetic surface plasmon resonance studies. The therapeutic potential of the LANCL2 pathway ranges from increasing cellular sensitivity to anticancer drugs, insulin-sensitizing effects and modulating immune and inflammatory responses in the context of immune-mediated and infectious diseases. A case for LANCL2-based drug discovery and development is also illustrated by the anti-inflammatory activity of novel LANCL2 ligands such as NSC61610 against inflammatory bowel disease in mice. This dissertation discusses the value of LANCL2 as a novel therapeutic target for the discovery and development of new classes of orally active drugs against chronic metabolic, immune-mediated and infectious diseases and as a validated target that can be used in precision medicine. Specifically, in Chapter 2 of the dissertation, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of LANCL1 as a template. Our molecular docking studies predicted that ABA and other PPAR - agonists share a binding site on the surface of LANCL2. In Chapter 3 of the dissertation, structure-based virtual screening was performed. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. In Chapter 4 of the dissertation, we developed a novel integrated approach for creating a synthetic patient population and testing the efficacy of the novel pre-clinical stage LANCL2 therapeutic for Crohn's disease in large clinical cohorts in silico. Efficacy of treatments on Crohn's disease was evaluated by analyzing predicted changes of Crohn's disease activity index (CDAI) scores and correlations with immunological variables were evaluated. The results from our placebo-controlled, randomized, Phase III in silico clinical trial at 6 weeks following the treatment shows a positive correlation between the initial disease activity score and the drop in CDAI score. This observation highlights the need for precision medicine strategies for IBD. / Ph. D.

<p dir="ltr">We examined the effect of a modernized collaborative care intervention for depression on multiple psychological risk and protective factors for diabetes and characterized intervention process outcomes using data from the eIMPACT-DM trial.</p>

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24998号 / 医博第5032号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 佐藤 俊哉, 教授 山本 洋介, 教授 永井 洋士 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p dir="ltr">Accumulating evidence suggests a potential role for almond consumption in ameliorating post-prandial glycemia. Yet their effect on HbA1c, an indicator of long-term glycemic control, is mixed. The purpose of this study was to examine the potential of sustained almond consumption to reduce HbA1c concentrations among individuals with elevated HbA1c concentrations. A 16-week randomized, parallel-arm, controlled trial was conducted. Eighty-one adults with elevated HbA1c concentrations (>5.7%) were randomly assigned to incorporate two servings (2 oz) of raw almonds (A group; N=39) or energy-matched snacks (pretzels C group; N=42) into their daily diets. Half of these intervention foods were to be ingested at breakfast and the other half as a replacement for either a mid-morning or mid-afternoon snack. Throughout the intervention period, measurements were made of body weight, body composition, plasma lipids, HbA1c, alpha and gamma-tocopherol, glycemia (by meal tolerance test) and continuous glucose monitoring, dietary intake, and hedonic responses to test foods at stipulated time points. Participants consuming almonds ingested 253 kcal/d more than participants in the control group (p=0.02), but this did not result in a significant difference in body weight (A: 0.2kg SEM ±0.5, C: 0.4kg SEM ±0.5); p>0.05). No statistically significant differences were observed in HbA1c concentrations (A: 0.1% SEM ±0.1, C: 0% SEM ±0.1; p>0·05), blood chemistries, body composition, or glycemia over time or between groups. However, Healthy Eating Index scores improved within the almond group as compared to the control group (A: 8.3 points SEM ±1.9, C: -2.3 points SEM ±2.1; p<0.001). Additionally, the hedonic rating of almonds did not decline within the almond group in comparison to the control group's reduced liking of the pretzel snack. Alpha-tocopherol increased significantly, and gamma-tocopherol tended to decrease in the almond group, indicating compliance with the dietary intervention. Overall, daily ingestion of 2 oz of raw almonds in a regular diet for 16 weeks did not alter short-term or longer-term glycemia or HbA1c concentrations in adults with elevated HbA1c concentrations, but they were well-tolerated and improved diet quality without promoting weight gain.</p>

Background: Nutritional deficiencies are frequent in celiac disease (CeD), and one of the most common is zinc (Zn) deficiency. Supplements are often prescribed to treat Zn deficiency; however, they have been associated with adverse events and reduced absorption of other minerals. Data collected in our clinic showed that 38% of CeD patients would opt for a diet to improve Zn, however, such a diet may be challenging due to food interactions with phytic acid, which blocks Zn absorption. Therefore, the feasibility and efficacy of a Zn-optimized diet compared to supplementation is unknown. Aims: To assess the feasibility of the protocol and collect data on estimated effect sizes for secondary outcomes to plan a properly powered randomized controlled trial (RCT). Methods: We conducted an open-label, pilot RCT. CeD patients were randomized to Zn supplementation (Zn gluconate 25mg) or a Zn-optimized diet for 3 months and followed up with a 3-month pragmatic approach. We evaluated enrollment rates and adherence to both interventions. Plasma and urine Zn, stool samples, and questionnaires were collected pre- and post-intervention. Results: We enrolled 28 participants and 16 of them have completed the study. Interim analysis shows an enrollment fraction of 26% (i.e. 28/108 eligible participants), and a dropout rate of 17.9%. Eighty-two % of participants allocated to the Zn-supplement intervention and 50% in the dietary intervention were compliant at 3 months. Based on the effect size for normalization of plasma Zn at 3 months, 142 participants are required for an adequately powered RCT in the future. There were no significant differences in gastrointestinal or extra-intestinal symptoms, quality of life, anxiety and depression or adverse events between interventions. Conclusion: Based on this preliminary analysis, recruitment of participants will take 6 months longer than expected. Assessment of reasons for diet non-adherence will allow implementation of strategies to improve feasibility. / Thesis / Master of Science in Medical Sciences (MSMS)

京都大学 / 新制・論文博士 / 博士(社会健康医学) / 乙第13613号 / 論社医博第19号 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 森田 智視, 教授 椛島 健治, 教授 村井 俊哉 / 学位規則第4条第2項該当 / Doctor of Public Health / Kyoto University / DFAM