The Improving Medication Adherence in Adolescents Who Had a Liver Transplant (iMALT) study aimed to test a tailored telemetric intervention to reduce rejection incidence by improving medication adherence in a group of adolescent liver transplants. This was a prospective, multi-center, randomized controlled trial. The study was conducted in transplant centers in the United States and Canada. Pediatric adolescent and young adult (age at enrollment ≥ 12 and < 20 years) transplant recipients were eligible for participation in the study. Eligible participants were randomly assigned to an intervention or control group and followed for two years post enrollment.

The study was a prospective, randomized, controlled, single-blind trial that delivered a remote intervention to nonadherent (Medication Level Variability Index (MLVI) score > 2 units) adolescent and young adult liver transplant recipients. The MLVI score was used to identify at-risk participants and also for monitoring during the intervention. The predefined primary outcome was the 2-year incidence of rejection, evaluated using a masked reading of biopsy slides by 3 pathologists. Consent withdrawal, re-transplantation, or death were coded as rejection for the purpose of the primary outcome.

Sensitivity analyses were assessed at the site’s biopsy interpretation (local read). Sensitivity and some of the predefined secondary analyses assessed individual components of the primary objective (i.e., rejection) to ensure that any observed effect was not simply due to a large effect on only one of its components. Secondary outcomes included analyses of serum alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels and MLVI scores.

Primary outcome measures included the incidence of biopsy-proven acute cellular rejection (number of participants experiencing at least one episode of rejection) at any time during the 2 years of follow up; biopsy-confirmed late acute rejection as determined by the majority of 3 masked readings of liver biopsy images by 3 pathologists that were not from the clinical site at which the participant was treated; and participants with incomplete follow-up (for example due to death, re-transplant, listing for re-transplantation) were assumed to have experienced a rejection for the purpose of the primary analysis.

Secondary outcome measures included incidence and rate of locally determined biopsy proven rejection; rate of centrally determined biopsy proven rejection; time to rejection from enrollment; occurrence of death; mean number of achieving above threshold ALT > 150; mean/maximal ALT (defined as the mean of all levels recorded during the study period and the maximal level recorded during the study period); mean number of achieving above threshold GGT > 150; and mean/maximal GGT (defined as the mean of all levels recorded during the study period and the maximal level recorded during the study period).

Eligible participants were between 12 and 20 years of age at enrollment, and were at least 2.5 years post their most recent liver transplantation. Guardian consent and adolescent assent were obtained at the time of enrollment. Participants were required to be on a prescribed tacrolimus regimen, and their MLVI score (measured as the standard deviation of tacrolimus levels) was greater than 2 when calculated by the site over the two-year period prior to the review date.

Patients were excluded from the study if they had received a transplant of an organ other than the liver, were currently listed for any organ transplantation, or were expected to transition to another service such as an adult clinic or another hospital within the two-year study period. Pregnant patients were also ineligible. A temporary exclusion applied to patients who were not medically stable or were hospitalized for more than 48 consecutive hours in the past three months. In addition, the Site PI, Study PI, or Medical Monitor could exclude any patient determined to be an unsuitable candidate for the intervention.

In 148 participants (TI group n = 72, and the SOC group n = 76), with a mean age of 15.5 years, there were twice as many primary events in SOC (12; 15.8%) compared with TI (6; 8.3%) (relative risk = 0.57; 95% confidence interval [0.24, 1.35], p = 0.20). All secondary outcomes improved in the TI versus SOC groups. The study was underpowered since the iMALT study sites used the MLVI score in clinical care, significantly reducing overall rejections compared with the previous MALT study cohort, where the MLVI score was not used (rejection was observed in 12/76 participants in the iMALT study, SOC versus 13/25 participants in the MALT study; p < 0.0001). The effect on the primary outcome, therefore, was not statistically significant; thus, the intervention was not evidence-based. MLVI score, an electronic health record-derived behavioral marker, can be used to target interventions to patients with clinically significant nonadherence.