Improving Medication Adherence and Outcomes in Adult Kidney Transplant Patients Using a Personal Systems Approach

SystemCHANGE Results of the MAGIC Randomized Clinical Trial

Cynthia L. Russell; Donna Hathaway; Laura M. Remy; Dana Aholt; Debra Clark; Courtney Miller; Catherine Ashbaugh; Mark Wakefield; Sangbeak Ye; Vincent S. Staggs; Rebecca J. Ellis; Kathy Goggin

Disclosures

American Journal of Transplantation. 2020;20(1):125-136. 

In This Article

Materials and Methods

Study Design

The design was a single-blinded (participants), 2-arm randomized controlled trial (RCT) using repeated measures. Table 1 delineates the study design. The research assistant (RA) collected demographic information, performed cognitive screening, and provided an EM cap and bottle. During the 3-month screening phase, all participants used EM to document MA. Those who were adherent (MA rate of ≥85%) exited the study. Those with a documented MA rate of less than 85% were given the opportunity to enter into the intervention phase of the study where they were randomized to either the SystemCHANGE™ intervention (treatment) or the attention control intervention (control). All participants received standard care. Table 1 and Table 2 delineate the elements of both interventions. After the 6-month intervention phase, there was a 6-month maintenance phase during which there was no intervention.

Setting

Initially, participants were recruited from two transplant centers in the midwestern and southern United States, namely University of Missouri Healthcare in Columbia, Missouri, and the University of Tennessee Health Science Center in Memphis, Tennessee. To accrue the target sample size more quickly, three additional midwestern transplant centers were added as recruitment sites: the University of Kansas Medical Center in Kansas City, Kansas; Barnes Jewish Hospital in St. Louis, Missouri; and St. Luke's Hospital in Kansas City, Missouri. Institutional review board (IRB) approval was obtained from the University of Missouri, University of Tennessee, and St. Luke's Hospital. The other two centers determined that no approval was required.

Changes to Trial Design

The details of the trial design were published previously.[27] Two changes to the trial design occurred. In year 2, three additional recruitment sites were added to achieve the target sample size as discussed previously. In response to the Data Safety Monitoring Board (DSMB) the study protocol was amended to include 6-month MA data for attention control intervention participants in order to identify anyone with very low MA (<0.30) and develop a plan to mitigate any associated risks if needed. Fortunately, no attention control participants experienced a medication nonadherence level below 30%. Based on recommendations from the DSMB, participant recruitment was stopped in year 3 and target sample size was changed to 75–80 due to large effects of the SystemCHANGE™ intervention on MA. This increases the chance of a type I error.

Participants

A random sample of participants was obtained from the list of all eligible kidney transplant centers from the two initial participating centers. When three additional centers were added, a convenience sampling approach was used. Individuals 18 years of age or older who had received a kidney-only transplant, self-administered at least one prescribed immunosuppressive medication taken twice daily with a functioning kidney transplant, were not in the hospital, and had no diagnosis that would immediately shorten the lifespan were eligible for participation. In addition, individuals needed to have access to a telephone; the ability to speak, hear, and understand English; the ability to open an EM cap; and have agreement from the transplant physician and nephrologist to participate in the study. Individuals were also assessed for cognitive impairment and required to score 4 or greater on the 6-item Telephone Mental Status Screen Derived from the Mini-Mental Status Exam.[28] IRB approval was obtained, and all participants provided informed consent prior to beginning the study. As directed by the individual institution's IRB, participants provided either written or oral consent.

Randomization and Masking

Block randomization was used with the project biostatistician preparing a computer-generated list of random arm assignment numbers blocked in balanced groups of four. For each arm assignment number on the list, an RA trained specifically for that arm (SystemCHANGE™ or attention control) called the first person on a list of eligible intervention participants to determine whether he/she was interested in enrolling in the next phase of the study (the intervention phase). If the participant agreed to enroll in the intervention phase, he/she was assigned to the arm for which the RA was recruiting, filling that slot on the randomization list. If the participant did not agree to enroll, the same RA called the next eligible participant to extend the invitation to enroll. This process continued until the enrollment slot was filled. Thus each eligible participant had the same chance of receiving a call from an RA enrolling for the SystemCHANGE™ arm as of receiving a call from an RA enrolling for the attention control arm. To minimize bias, patients were not given information about the nature of the two study arms, and all study personnel used the terms "SystemCHANGE™ intervention" and "Patient Education intervention" (the attention control intervention) when describing any pertinent study activities.

Training of RAs

Baccalaureate-prepared registered nurse RAs were trained by a SystemCHANGE™ expert using a detailed procedure manual, simulation, and role for both interventions. The expert provided the RAs with feedback on performance and retrained them as needed until they achieved 100% intervention protocol integrity.

Treatment Fidelity

To ensure RA fidelity to both arms, a fidelity protocol checklist was used during all participant encounters to document key elements of the protocol, including number of intervention sessions, session duration, length of time between sessions, and intervention steps. Each element was rated as completed, partially completed, not completed, or N/A. Field notes were kept for every encounter (participant's body language, environmental issues, presence of others in the home) and phone call (background noise, telephone line distortion, any difficulty hearing by RA or participant).

Procedures

To start the 6-month intervention phase, all participants received an in-person visit at baseline, either at their home or in the transplant clinic, followed by six telephone calls at months 1 through 6. Those randomized into the SystemCHANGE™ intervention were coached by the SystemCHANGE™ trained RA in implementing SystemCHANGE™. Study participants randomized to the attention control group received transplant patient education guided by the patient education trained RA using healthy living transplant brochures; these education sessions were provided at the same time points when the SystemCHANGE™ group received SystemCHANGE™ intervention delivery.

The maintenance phase began for both groups following completion of the intervention phase and continued for an additional 6 months. This phase was designed to examine how participants maintained MA in the absence of an intervention while continuing to use EM. All participants were provided compensation during all phases of the study up to $335. All outcomes were collected by RAs from the participants' medical record at completion of the study.

SystemCHANGE™ Intervention

The SystemCHANGE™ intervention supports patient-designed, RA interventionist-guided, small experiments using Deming's Plan-Do-Check-Act cycle to redesign the personal environmental system and daily health behavior routines. The SystemCHANGE™ intervention began with an in-person visit by the RA where the participant was guided to assess his or her individual systems including important others who shape medication taking, how the personal systems and others influence medication taking routines, and the individual's plan for a small "experiment(s)" focused on using the environment for improving MA. The proposed individual systems' solutions to improve adherence was then implemented, adherence data were tracked using EM, and monthly adherence data were evaluated with the support of the RA. The participant was implementing the small "experiment".

Providing MA feedback is the "Check" step of the SystemCHANGE™ intervention. Feedback reports graphically displayed comparisons of actual medication taking time with desired time (goal time set by participants). Graphical feedback is used by participants to evaluate if and when the selected personal system solution is working as a strategy to improve adherence. If the solution is working, then graphs reflect consistency in the time medications are taken compared with the goal time. If the graphs do not reflect this consistency, then participants are encouraged to select another system solution from the list generated at the first session. Further details on the SystemCHANGE™ intervention have been previously published.[27,29]

At the completion of each month during the 6-month intervention phase, participants were mailed their EM report and contacted by the RA to evaluate their MA, in addition to the effectiveness of the implemented solutions. The participants reflected on what they were learning about their medication taking, how the implemented solution was changing their MA, and any other changes to medication taking routines that might be needed. If the MA score remained stagnant or decreased, the RA would encourage the participant to implement a new solution and evaluate its effectiveness the following month. If MA continued to improve, or was >85%, the participant was encouraged to continue the same solution.

Attention Control Intervention

To increase the retention of the attention control group in the study, both the SystemCHANGE™ and attention control interventions were designed to deliver exactly the same amount of time and attention to both groups. The 6-month attention control intervention involved an in-person visit where the first of six educational brochures, developed by the International Transplant Nurses Society addressing healthy living in transplant recipients, was reviewed.[30] Each subsequent month for 6 months, the RA contacted the participant to discuss one of the materials. The duration of these interactions was designed to be equivalent to the SystemCHANGE™ intervention. Attention control participants continued to use the EM system during this phase.

Maintenance Phase

Both groups entered a 6-month maintenance phase after the active interventions. During this phase, both groups continued using the EM cap and bottle but did not receive any interaction with the RA other than their monthly receipt of the study stipend.

Outcomes

The primary outcome was the average 6-month immunosuppressive MA rate defined as doses taken on time/total doses as measured by the Medication Event Monitoring System SmartCap® (MEMSCap™). Adherence at 12 months was a secondary outcome. The MA rate calculation method has been previously described but is briefly described here.[32] If the dose of the medication is taken within a 3-hour window (±1.5 hours of the prescribed time) a "0.50" is assigned; if the dose is not taken within the 3-hour window but is taken within a 12-hour window (±6 hours of the prescribed time) a "0.25" is assigned, and if the dose is not taken within a 12-hour window (±6 hours of the prescribed time, ie, if the dose was missed) a 0 is assigned (p. 526). Perfect adherence is 1.00 and complete nonadherence is 0.00. Exploratory outcomes were creatinine/BUN, infections, acute and chronic rejections, kidney failure, and death. Safety and adverse events were assessed in an ongoing fashion by the Primary Investigators and a DSMB, which met biannually. Perceived health status, which reflects people's overall perception of their health, including both physical and psychological dimensions, was measured by one question, "How is your health in general?" Respondents selected excellent, very good, good, fair, poor, or very poor. The question has good reliability and validity.[33]

Statistical Analysis

Sample size and power calculations were based on comparing expected immunosuppressive MA rates of participants in each group at the completion of the 6-month intervention.[27] We expected a mean MA difference of 0.10 based on our pilot study findings and the literature and assumed an effect size (standardized mean difference) of 0.70 based on a conservative estimate from our pilot work. Based on an alpha of 0.05, 86 participants (43 per arm) provided 90% power to detect this effect with a two-sample t-test.

Statistical analyses were carried out using CRAN R (RStudio 1.0.136) and SAS 9.4. The primary analysis was conducted using an intention-to-treat approach. Participants who dropped out for any reason (eg, death, stroke, started dialysis, could not follow protocol) prior to the 6-month time point were assigned an adherence score of 0. We compared the 6-month adherence rates for the two groups first using a two-sided Wilcoxon-Mann-Whitney test, then with a linear regression model that included participant race (white, nonwhite), marital status (married, not married), perceived health score, and perceived social support as covariates. Adherence rates at 12 months were compared in the same way.

In a secondary analysis, we assessed the MA patterns in both the SystemCHANGE™ and attention control groups to determine when the intervention became effective (eg, what "dose" is needed) and examine the pattern of decay in MA over time, throughout both the intervention and maintenance phases, for both groups. Using a mixed model with a random participant intercept to account for clustering, we modeled monthly MA as a function of group, a linear time slope, and a group-by-slope interaction.

Exploratory outcomes (eg, creatinine/BUN, infections, acute and chronic rejections, kidney failure, death) were analyzed using frequencies and means. Creatinine and BUN were categorized into low, high, or normal ranges.

Role of the Funding Source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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