Icahn School of Medicine at Mount Sinai, New York, NY, USA.
UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Clin Trials. 2023 Oct;20(5):528-535. doi: 10.1177/17407745231176834. Epub 2023 Jun 2.
BACKGROUND/AIMS: Medication non-adherence is a leading cause of transplant rejection, organ loss, and death; yet no rigorous controlled study to date has shown compelling clinical benefits from an adherence-improving intervention. Non-adherent patients are less likely to participate in trials, and therefore, most studies enroll a majority of adherent patients who do not stand to benefit from the intervention, as they do not have the condition (non-adherence) under investigation. The improving Medication Adherence in adolescent Liver Transplant recipients trial specifically targets non-adherent patients to investigate whether a remote intervention to improve adherence results in reduced incidence of biopsy-confirmed rejection.
Improving Medication Adherence in adolescent Liver Transplant is a randomized single-blind controlled multisite, multinational National Institutes of Health-funded trial involving 13 pediatric transplant centers in the United States and Canada. An innovative, objective adherence biomarker-the Medication Level Variability Index, which is the standard deviation of a series of medication blood levels for each patient, is used to identify non-adherent patients at risk for rejection. The index is computed using electronic health record information for all potentially eligible patients based on repeated reviews of the entire clinic's roster. Identified patients, after consent, are randomized to intervention versus control (treatment as usual) arms. The remote intervention is delivered for 2 years by trained interventionists who reside in various locations in the United States. The primary outcome is the incidence of biopsy-confirmed acute cellular rejection, as confirmed by a majority vote of three pathologists who are masked to the study allocation and clinical information.
Improving Medication Adherence in adolescent Liver Transplant includes several innovative design elements. The use of a validated, objective adherence index to survey a large cohort of transplant recipients allows the teams to avoid bias inherent in both convenience sampling and referral-based recruitment and enroll only patients whose computed index indicates substantially increased risk of rejection. The remote intervention paradigm helps to engage patients who are by definition hard to engage. The use of an objective, masked medical (rather than behavioral) outcome measure reduces the likelihood of biases related to clinical information and ensures broad acceptance by the field. Finally, monitoring for potential adverse events related to increased medication exposure due to the adherence intervention acknowledges that a successful intervention (increasing adherence) could have detrimental side effects via increased exposure to and potential toxicity of the medication. Such monitoring is almost never attempted in clinical trials evaluating adherence interventions.
背景/目的：药物不依从是导致移植排斥、器官丧失和死亡的主要原因；但迄今为止，没有严格的对照研究表明，改善依从性的干预措施具有令人信服的临床益处。不依从的患者不太可能参与试验，因此，大多数研究都招募了大多数依从性患者，他们不会从干预中受益，因为他们没有正在研究的疾病（不依从）。改善青少年肝移植受者药物依从性试验专门针对不依从的患者，以调查远程干预是否能降低经活检证实的排斥反应发生率。
改善青少年肝移植药物依从性是一项由美国国立卫生研究院资助的随机、单盲、对照、多中心、多国试验，涉及美国和加拿大的 13 个儿科移植中心。一种创新的、客观的药物依从性生物标志物-药物水平变异性指数，它是每个患者一系列药物血药浓度的标准差，用于识别有排斥反应风险的不依从患者。该指数是使用电子健康记录信息为所有潜在合格患者计算的，该信息是基于对整个诊所名单的多次审查。在同意后，确定的患者被随机分配到干预组或对照组（常规治疗）。远程干预由居住在美国各地的经过培训的干预人员提供，为期 2 年。主要结局是活检证实的急性细胞排斥反应的发生率，该反应由三位病理学家的多数投票确定，他们对研究分配和临床信息进行了盲法。
改善青少年肝移植药物依从性包括几个创新的设计元素。使用经过验证的、客观的依从性指数来调查大量的移植受者，使研究人员能够避免便利抽样和基于推荐的招募所固有的偏见，并仅招募其计算指数表明排斥反应风险显著增加的患者。远程干预模式有助于接触那些因定义而难以接触的患者。使用客观、盲法的医疗（而不是行为）结局测量减少了与临床信息相关的偏见的可能性，并确保了该领域的广泛接受。最后，监测由于依从性干预而导致的药物暴露增加可能导致的潜在不良事件，这是因为增加依从性可能会增加药物暴露和潜在毒性，从而产生不利的副作用。在评估依从性干预的临床试验中，几乎从未尝试过这种监测。
