Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol

Background: To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously. Methods/Design: We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT. Discussion: The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases

The influence of a digital clinical reasoning test on medical student learning behavior during clinical clerkships

Recently, a new digital clinical reasoning test (DCRT) was developed to evaluate students’ clinical-reasoning skills. Although an assessment tool may be soundly constructed, it may still prove inadequate in practice by failing to function as intended. Therefore, more insight is needed into the effects of the DCRT in practice. Individual semi-structured interviews and template analysis were used to collect and process qualitative data. The template, based on the interview guide, contained six themes: (1) DCRT itself, (2) test debriefing, (3) reflection, (4) practice/workplace, (5) DCRT versus practice and (6) ‘other’. Thirteen students were interviewed. The DCRT encourages students to engage more in formal education, self-study and workplace learning during their clerkships, particularly for those who received insufficient results. Although the faculty emphasizes the different purposes of the DCRT (assessment of/as/for learning), most students perceive the DCRT as an assessment of learning. This affects their motivation and the role they assign to it in their learning process. Although students appreciate the debriefing and reflection report for improvement, they struggle to fill the identified knowledge gaps due to the timing of receiving their results. Some students are supported by the DCRT in exhibiting lifelong learning behavior. This study has identified several ways in which the DCRT influences students’ learning practices in a way that can benefit their clinical-reasoning skills. Additionally, it stresses the importance of ensuring the alignment of theoretical principles with real-world practice, both in the development and utilization of assessment tools and their content. Further research is needed to investigate the long-term impact of the DCRT on young physicians’ working practice.</p

Effect of ginkgo biloba on the pharmacokinetics of raltegravir in healthy volunteers

Contains fulltext : 111049.pdf (publisher's version ) (Open Access)Medicinal herbs may cause clinically relevant drug interactions with antiretroviral agents. Ginkgo biloba extract is a popular herbal product among HIV-infected patients because of its positive effects on cognitive function. Raltegravir, an HIV integrase inhibitor, is increasingly being used as part of combined antiretroviral therapy. Clinical data on the potential inhibitory or inductive effect of ginkgo biloba on the pharmacokinetics of raltegravir were lacking, and concomitant use was not recommended. We studied the effect of ginkgo biloba extract on the pharmacokinetics of raltegravir in an open-label, randomized, two-period, crossover phase I trial in 18 healthy volunteers. Subjects were randomly assigned to a regimen of 120 mg of ginkgo biloba twice daily for 15 days plus a single dose of raltegravir (400 mg) on day 15, a washout period, and 400 mg of raltegravir on day 36 or the test and reference treatments in reverse order. Pharmacokinetic sampling of raltegravir was performed up to 12 h after intake on an empty stomach. All subjects (9 male) completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence intervals) of the area under the plasma concentration-time curve from dosing to infinity (AUC(0-infinity)) and the maximum plasma concentration (C(max)) of raltegravir with ginkgo biloba versus raltegravir alone were 1.21 (0.93 to 1.58) and 1.44 (1.03 to 2.02). Ginkgo biloba did not reduce raltegravir exposure. The potential increase in the C(max) of raltegravir is probably of minor importance, given the large intersubject variability of raltegravir pharmacokinetics and its reported safety profile