Defended theses

Today, therapeutic evaluation primarily relies on the randomized controlled trial with a two-parallel group design. However, for rare diseases, this standard is challenging due to the required sample sizes. Thus, this thesis set three objectives, corresponding to three distinct studies. The first objective was to review the study designs used to evaluate therapies in a given group of rare diseases, specifically rare superficial vascular anomalies (SVA), which particularly affect the pediatric population. A systematic literature review analyzing trials conducted between January 2000 and January 2021 on the treatment of rare SVA was carried out. This review helped to compile an inventory of the study designs used as well as the justifications underlying the choice of these methodological designs. The second objective aimed to deepen the analysis of a methodological design identified for the therapeutic evaluation of rare SVA, namely the "individual stepped-wedge randomized trial," in order to facilitate its implementation by determining an appropriate sample size calculation. The validity of this sample size calculation formula has then been assessed using a Monte Carlo simulation approach. Finally, the third objective of the thesis was to identify the methodological design considered most relevant by a panel of experts, to conduct clinical trials on rare SVA. This work used the international Delphi consensus method, bringing together medical experts and patient association representatives, by presenting them with various clinical and therapeutic situations. This approach led to a consensus on several specific clinical situations, thus providing a basis to guide future therapeutic studies in rare SVA. 

In a cluster randomized trial, randomization units are groups of individuals, rather than individuals themselves. Nursing homes are facilities for older adults in need of care. Regarding the type of intervention assessed in such settings, cluster randomized trial is as a well-adapted design. With the global ageing of the population, trials in nursing homes are required but still underrepresented and the reasons are, among others, methodological issues such as the high risk of attrition, essentially due to death. The objective of this PhD thesis was to provide a validated approach to estimate an intervention effect when a cluster randomized trial is planned in nursing homes and faces the risk of a high rate of discontinuation due to death. In the first part of this work we investigated, through a methodological review, the strategies used to deal with that attrition. The review was based on reports of cluster randomized trials planned in nursing homes and published between 2005 and 2020 in selected general medicine and geriatric journals with high impact factors. In the second part of this work, we focused on the closed-cohort recruitment strategy, the most frequently used design but also the most exposed to the risk of attrition. The aim of the second part was to assess how an open-cohort design could have been considered as a relevant alternative to a closed-cohort design. The last part of this work was to assess through a Monte Carlo simulation study how bias can be reduced when estimating an intervention effect using an open-cohort design as compared to a closed cohort, in the context of cluster randomized trial in nursing home with not at random missing data.
Most of the interventions assessed in nursing homes are at cluster level, making the open-cohort a well-adapted design. Individual attrition is no longer an issue and it provides low biased estimates of the intervention effect. Open-cohort must be considered more often when cluster randomized trials are planned in nursing homes.

The aim of the first part of this study was to obtain a satisfactory psychometric tool for assessing the personal recovery (PR) of bipolar people in France. A systematic review and an exploratory qualitative study with bipolar sufferers enabled us to identify specific salient themes: the importance of self-management, and of the quality of connectedness with others and the necessity of changes in the metacognitive relationships maintained with the disorders. We then translated and adapted Jones et al.'s BRQ recovery scale in the light of these results, to obtain a 31-item, 7-dimension scale that we were able to validate psychometrically, the BRQ-Fr. The second part of the study focused on the effects of a therapeutic education program on PR, using a mixed qualitative and quantitative approach. The discourse of caregivers on the one hand, and participating patients on the other, were analyzed. They all described a relational security and new carer-client relationships, a promotion of empowerment and a destigmatization, as well as positive identity changes. A prospective pre-post study with a 3-month follow-up showed positive changes in the feeling of PR as measured by the QRB-Fr, and in the stage of PR as measured by the STORI scale, as well as in self-assessments of depression, self-esteem and self-efficacy.