Pediatric transplant recipients must maintain stable immunosuppression to prevent rejection and organ loss, yet medication nonadherence rates are unacceptably high. 1,2 Adolescent recipients are more likely to become nonadherent as they age 2-4 ; however, intervention efforts have shown limited success. 5 A promising (but understudied) approach is related to the association between nonadherence and posttraumatic stress symptoms (PTSS).In posttraumatic stress disorder (PTSD), psychiatric symptoms emerge following exposure to a potentially traumatic event (PTE). To meet the definition of a disorder, individuals must endorse symptoms from four clusters (i.e., intrusion, avoidance, negative alterations in cognitions and mood, and changes in arousal/reactivity) as well as substantial distress and/or dysfunction. 6 While these diagnostic criteria are important for identifying individuals most in need of psychiatric treatment, subthreshold symptomatology (i.e., PTSS) may still be associated with increased risk for clinically significant distress or impairment. 7,8

Remote interventions are increasingly used in transplant medicine but have rarely been rigorously evaluated. We investigated a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients. Patients were recruited from a larger multisite trial if they had a Medication Level Variability Index (MLVI) ≥2.0, indicating worrisome tacrolimus level fluctuation. The manualized intervention included three weekly phone calls and regular follow-up calls. A comparison group included patients who met enrollment criteria after the subprotocol ended.Outcomes were defined before the intent-to-treat analysis. Feasibility was defined as ≥50% of participants completing the weekly calls. MLVI was compared pre-and 180 days postenrollment and between intervention and comparison groups. Of 18 eligible patients, 15 enrolled. Seven additional patients served as the comparison.Seventy-five percent of participants completed ≥3 weekly calls; average time on protocol was 257.7 days. Average intervention group MLVI was significantly lower (indicating improved blood level stability) at 180 days postenrollment (2.9 ± 1.29) compared with pre-enrollment (4.6 ± 2.10), p = .02. At 180 days, MLVI decreased by 1.6 points in the intervention group but increased by 0.6 in the comparison group DUNCAN-PARK et Al. | 3113 AJT 1 | INTRODUC TI ON Remote communications (e.g., telephone, video, or text messaging) can improve access to medical services. 1 More recently, clinicians and institutions have turned to remote communication to minimize contagion during the COVID-19 pandemic. 2Remote contacts may have particular appeal in the long-term management of transplant recipients. First, reducing exposure to pathogens is especially important in immunosuppressed individuals, 3 and indeed, transplant programs have rapidly turned to telehealth in the context of COVID-19. [4][5][6] Second, many transplant recipients travel extensively for their care, 7,8 and remote technology may reduce this burden. Third, immunosuppressant nonadherence remains the leading cause of preventable graft failure, [9][10][11][12][13][14][15] and frequent remote encounters could facilitate adherence. But, there are challenges. Remote interventions may be less effective at communicating with patients than in-person encounters, confidentiality must be maintained, and some patients may not have the means or comfort with technology to participate. 16,17 Key components of a robust evaluation of telehealth interventions include assessing predefined outcomes in prospective multisite trials. 18 Yet, despite its promise, there is a dearth of such investigations into telehealth in pediatric populations. [19][20][21]

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. Methods 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. Discussion 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.