CAPRISA 018: a phase I/II clinical trial study protocol to assess the safety, acceptability, tolerability and pharmacokinetics of a sustained-release tenofovir alafenamide subdermal implant for HIV prevention in women

IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV technologies that empower women to protect themselves are needed. Safe, potent antiretroviral agents such as tenofovir alafenamide (TAF), formulated as long-acting subdermal implants, offer an innovative solution.Methods and analysisCAPRISA 018 is a phase I/II trial to evaluate the safety, acceptability, tolerability and pharmacokinetics (PKs) of a TAF free base subdermal silicone implant containing 110 mg of TAF with an anticipated 0.25 mg/day release rate.The phase I trial (n=60) will assess the safety of one implant inserted in six participants (Group 1), followed by dose escalation components (Groups 2 and 3) assessing the safety, tolerability and PK of one to four TAF 110 mg implants releasing between 0.25 mg and 1 mg daily in 54 healthy women at low risk for HIV infection. Data from this phase I trial will be used to determine the dosing, implant location and implant replacement interval for the phase II trial.The phase II component (Group 4) will assess extended safety, PK, tolerability and acceptability of the implant in 490 at risk women, randomised in a 1:1 ratio to the TAF implant and placebo tablet or to the placebo implant and an oral pre-exposure prophylaxis tablet. Safety will be assessed by calculating the percentage change in creatinine clearance from baseline at weeks 4, 12, 24, 36, 72, 96 and 120, compared with the percentage change in the control group.Ethics and disseminationThe South African Health Products Regulatory Authority and the University of KwaZulu-Natal’s Biomedical Research Ethics Committee have approved the trial. Results will be disseminated through open access peer reviewed publications, conference presentations, public stakeholder engagement and upload of data into the clinical trials registry.Trial registration numberPACTR201809520959443.

Construction and Evaluation of a Virtual Reality Laparoscopic Surgery Collaborative Training Platform: Taking Laparoscopic Cholecystectomy as an Example

Backgroud: Virtual reality (VR) technology represents the future of medical education due to its unique advantages, especially with the Covid-19 pandemic lasting. We developed a laparoscopic VR surgery collaborative training platform hoping to shed light on future medical education in China.Methods: We constructed a VR surgery training platform and designed surgery curriculum on laparoscopic cholecystectomy (LC). 36 first-year postgraduate students in China standardized training program for resident doctor (C-STRD) from the Third Xiangya Hospital of Central South University were enrolled for validation trials. In the Phase I trial, 12 students performed LC in the exploration mode. After training in the surgery learning mode, they performed LC again. The LC scores before and after training were compared. In the Phase II trial, another 12 students were randomly assigned to either the collaborative group or the control group. The former trained with a senior surgeon collaboratively in the surgery learning mode and then performed LC alone in the exploration mode. The latter trained in the surgery learning mode by themselves and performed LC in the exploration mode. The LC scores between groups were compared. The user experience (intention to use, skills improvement, usability, degree of enjoyment) were analyzed through questionnaires from the above 24 students. Interest in surgery learning of Phase I students was compared with 12 students who didn’t experience the VR platform.Results: In Phase I trial, the mean LC scores of the students were elevated from 56.83 to 61.17 (p=0.042) after learning in surgery learning mode. In Phase II trial, collaborative group students had higher scores than their rivals (67.17 vs 61.33, p=0.014). Most students have a positive users’ experience regarding the intention to use and skills improvement. Collaborative group students had higher evaluation regarding usability. Students who experienced the VR platform were significantly more interested in future surgery learning (3.60 vs 2.58, p <0.05).Conclusion: Our study constructed a VR platform for collaborative surgery training, which showed an excellent training effect. Medical students rated the platform highly, and their interest in learning increased.

An adaptive gBOIN design with shrinkage boundaries for phase I dose-finding trials

Background With the emergence of molecularly targeted agents and immunotherapies, the landscape of phase I trials in oncology has been changed. Though these new therapeutic agents are very likely induce multiple low- or moderate-grade toxicities instead of DLT, most of the existing phase I trial designs account for the binary toxicity outcomes. Motivated by a pediatric phase I trial of solid tumor with a continuous outcome, we propose an adaptive generalized Bayesian optimal interval design with shrinkage boundaries, gBOINS, which can account for continuous, toxicity grades endpoints and regard the conventional binary endpoint as a special case. Result The proposed gBOINS design enjoys convergence properties, e.g., the induced interval shrinks to the toxicity target and the recommended dose converges to the true maximum tolerated dose with increased sample size. Conclusion The proposed gBOINS design is transparent and simple to implement. We show that the gBOINS design has the desirable finite property of coherence and large-sample property of consistency. Numerical studies show that the proposed gBOINS design yields good performance and is comparable with or superior to the competing design.