“Smartphone Medication Adherence Saves Kidneys” for Kidney Transplantation Recipients: Protocol for a Randomized Controlled Trial

Background Kidney transplant recipients’ poor medication adherence and poor control of comorbidities, particularly hypertension, are risk factors for graft rejection, graft loss, and death. Few randomized controlled trials (RCTs) have been successful in improving sustained medication adherence and blood pressure control among kidney transplantation recipients. We provide rationale for an RCT evaluating a mobile health medical self-management system for kidney transplantation recipients called Smartphone Medication Adherence Saves Kidneys (SMASK). Objective Our objective is to determine whether SMASK is efficacious in improving medication adherence and sustaining blood pressure control among kidney transplantation recipients with uncontrolled hypertension and poor medication adherence compared to an enhanced standard care. Methods This two-arm, 6-month, phase II single-site efficacy RCT will involve 80 kidney transplantation recipients. Participants will be randomly assigned to the SMASK intervention arm or control arm. SMASK includes multilevel components: automated reminders from an electronic medication tray; tailored text messages and motivational feedback, guided by the self-determination theory; and automated summary reports for providers. Evaluations will be conducted preintervention, at 3 and 6 months, and posttrial at 12 months. Specific aims are to test the hypotheses that compared to standard care, the SMASK cohort will demonstrate significantly improved changes at 3, 6, and 12 months in the primary outcome variables medication adherence (proportion with electronic monitor-derived score >0.90) and blood pressure control (proportion meeting and sustaining adherence to the Kidney Disease Improving Global Outcomes [KDIGO] guidelines for blood pressure control); the secondary outcome variables provider adherence to KDIGO guidelines, measured by timing of medication changes and changes in self-determination theory constructs; and the exploratory outcome variables estimated glomerular filtration rate, variability in calcineurin inhibitor trough levels, and proportion of patients meeting and sustaining the 24-hour ambulatory blood pressure below 130/80 mm Hg. After the 6-month evaluation, interviews with a random sample of SMASK subjects (n=20) and health care providers (n=3-5) will assess user reactions including acceptability, usability, and aids/barriers to sustainability. Data from the RCT and interviews will be triangulated to further refine and optimize SMASK and prepare for a multisite effectiveness RCT. Results The SMASK project received funding from National Institute of Diabetes and Digestive and Kidney Diseases in June 2016, obtained institutional review board approval in April 2016, and began data collection in July 2016. As of July 2018, we completed enrollment with a total of 80 participants. Conclusions This study will provide data regarding the efficacy of SMASK to improve medication adherence and blood pressure control in a cohort of hypertensive kidney transplant recipients. An efficacious SMASK intervention will pave the way for a larger, multicenter, effectiveness RCT powered sufficiently to evaluate clinical events in a real-world setting and with the potential to demonstrate improved outcomes at lower cost than standard care. International Registered Report Identifier (IRRID) DERR1-10.2196/13351

BMIO MCGILLICUDDY, J demonstrated effectiveness, the intervention will ameliorate the risk of premature graft loss among KTRs.

CRITIQUE 1:
Significance: 2 Investigator(s): 2 Innovation: 3 Approach: 5 Environment: 2 Overall Impact: This R01 Application from a new and early investigator is designed to test and refine the Smart phone Medication Adherence Saves Kidneys (SMASK) program. In US, 90,000 patients are currently listed for Transplantation while fewer than 20,000 transplants are performed annually, highlighting the need to optimize allograft longevity. It's a 6-month, 2-arm efficacy RCT that will be conducted in 116 Kidney Transplant Recipients (KTRs) with the aim of decreasing medication nonadherence to immunosuppressant's and uncontrolled HTN and overall goal to decrease the risk of premature graft rejection, graft loss and death. A pilot RCT of SMASK in 20 patients by the PI formed the foundation of the present application. The interdisciplinary investigative team has substantial experience in mhealth technologies and self-management programs and will be able to carry out the proposed project. MUSC have the necessary resources that include a top ranked Transplant Center to conduct the proposed project. Measure of impact of an adherence enhancement program on graft function markers (eGFR, and graft fibrosis), immunosuppressant medication trough level variability and 24hr ambulatory BP seems innovative. However, distracting from the enthusiasm for this application are weaknesses in some of the criteria. Randomization at subjects' level means that the 4 transplant nephrologists will have subjects in both arms of the study, a scenario that raises the possibility of contamination. The application did not demonstrate adequate direct engagement of the providers that take care of the patients in BP management and addressing the therapeutic inertia. There is no mention or engagement of caregivers in this application. Gathering exploratory information regarding the cost of the intervention would have strengthened the application. Participant burden is a minor concern and finally, the generazability of the intervention as described is a concern. The investigators will be recruiting 21-55yrs olds only thereby excluding large number of patients.

Strengths
Project aimed at efficacy testing and refinement of an individually tailored smart phone-based medication adherence and BP monitoring program for medication non-adherent for kidney transplant recipients with uncontrolled hypertension (SMASK).
There is a need to develop more efficacious approaches to preventing the graft loss and medical co-morbidity that is attributable to medication non-adherence.
The need to improve the extremely high rates of uncontrolled BP associated with graft dysfunction, graft loss and death among transplant patients.

Investigator(s):
The PI is a Transplant surgeon and an early and new investigator. He is currently completing his NIH KL2 Clinician Scientist award, a 3yrs clinical research training program. He developed a mHealth self -management program and administered the feasibility RCT project. His pilot RCT of 20 patients using the SMASK program formed the foundation of the present application.
The PI has established effective collaborations with experienced investigators within the institution and his mentor is collaborating with him on this project.
The interdisciplinary team has substantial experience in mhealth technologies and selfmanagement programs. The team has significant experience in software/server interface development and practiced based behavioral RCTs.

Strengths
Use of mHealth to improve transplant rejection, BP control, comorbidity and death among transplant patients A practitioner component specifically designed to reduce therapeutic inertia by providing the treating practitioner with information regarding subject MNA and BP levels alongside the KDIGO BP goals and MUSC stepped care guidelines for BP control in KTRs.
Measure of impact of an adherence enhancement program on graft function markers (eGFR, and graft fibrosis), immunosuppressant medication trough level variability and 24hr ambulatory BP.
Weaknesses mHealth is currently been tried in different populations. Electronic monitoring and home BP measurements and feedback to provider are not entirely new.

Approach: Strengths
A 2-arm RCT design (n=116) with the subjects as the units of randomization. Use of Self-determination theory as the theoretical underpinning for development of SMASK.
Use of an iterative design process guided by behavioral change theories to gather direct guidance from KTRs and health care providers Use of mHealth Technologies to monitor, in real time, MNA and home measured BP to facilitate delivery of immediate feedback Provision of healthcare providers with personalized automated summary reports to facilitate timelier medication regimens changes and earlier sustained BP control Inclusion of Follow -up evaluation, focus groups with SMASK providers and SMACK subjects.

Attention control for the Standard care cohorts
The statistical section is well developed Randomization at subjects' level means that the 4 transplant nephrologists will have subjects in both arms of the study, a scenario that raises the possibility of contamination.
Lack of substantial engagement of the patient's physician managing the BP in the study protocol. Only one team MD will be receiving the summary BP reports every 2 weeks and making the necessary changes per protocol. The treating physician will not be engaged actively in the process. The measurement and the usefulness of the Therapeutic inertia may not be reflective of an individual patient's provider data, since only one MD is receiving all the summary BP reports and making changes to the medication.
There are so many messages and reminders, (multiple reminders to check BP, escalating reminders to take medications using the MedMinder (from light to chime to cell phone calls/SMS), this may lead to participant fatigue or overburden. The patient should be asked how often they will like to get a reminder as part of the design.
Messages are going to be customized to each individual patient based on their belief, values and goals this reviewer questions the generazability of this process beyond the intervention period.
There is no mention or engagement of caregivers in this application. One of the inclusion criteria is that the patient should be able to take their own BP. What if the patient can't but has a caregiver that can help to do that?
Lack of exploratory aim to information regarding the cost of the intervention

Strengths
The MUSC have the necessary resources that include a top ranked Transplant Center to conduct the proposed project.
The SC Clinical and Translational Research Institute, Office of Biomedical Informatics Systems and The Technology Applications Center for Healthful Lifestyles (TACHL) are available to support this project.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):

Inclusion of Women, Minorities and Children:
G1A -Both Genders, Acceptable M1A -Minority and Non-minority, Acceptable C3A -No Children Included, Acceptable 50% of the participants will be women and minority will be included, 60% of the participants will be African American Overall Impact: The application will evaluate an integrated intervention to improve medication adherence and blood pressure control in post kidney transplant patients. The area of research is very significant given the high prevalence of ESRD, the important role of transplantation, and major negative impact of non-adherence on patients' outcomes. The PI is a new investigator with adequate training, he is well prepared to lead the study, the team is multidisciplinary and resources are excellent. The study is innovative in testing an integrated monitoring system with reporting to providers to improve medication adherence and blood pressure control. Strengths of the proposal include the use of a randomized controlled design, adequate preliminary data, detailed patient population and study measures, and long-term assessment of outcomes. Weaknesses are related to the management of antihypertensive medications in the intervention arm and several limitations of the proposed analysis plan and power calculation. Overall, strengths outweigh study weaknesses.

Strengths
ESRD is a significant public health problem and transplantation is an important form of treatment Medication non-adherence is a major cause of transplant rejection (30%-40% of all cases), graft loss, uncontrolled hypertension and death among renal transplant recipients Current approaches to non-adherence are only partially successful leaving many transplant recipients at risk for poor outcomes

Weaknesses
Some weaknesses in the design and statistical analysis may limit the validity and impact of study findings

Strengths
The PI is a new investigator with excellent clinical training. He recently completed a KL-2 award and lists 15 relevant publications (4 as first author; total number of publications is not provided) The team of investigators is multidisciplinary with experts in medicine, health communications, transplant surgery, nursing, pharmacology, biostatistics, and information technology There are prior collaborations among researchers Weaknesses None noted

Innovation: Strengths
Will use a multi-component, integrated program to monitor in real time medication adherence and BP control providing these data to the treating team Use of personalized messages is somewhat novel

Weaknesses
Some components have been previously used to improve medication adherence in other chronic conditions

Strengths
Good preliminary data regarding the effectiveness of the intervention from pilot study of 20 hypertensive kidney transplant recipients The intervention was developed using the theory of using self-determination. The theoretical framework is well integrated into the measurement model and data analysis plan Will use an RCT design with intention to treat analysis ensuring strong internal validity of study findings. Balanced attention control Adequate inclusion/exclusion criteria Will assess long-term outcomes (up to 18 months post randomization)

Well described outcome measures. Will use objective measures of medication adherence and laboratory/pathological measures of renal function and graft fibrosis
Weaknesses A single transplant physician will receive all adherence reports and prescribe antihypertensive medications. This investigator may be highly invested in the success of the trial and not blinded to study arm (as reports will be only generated for those randomized to intervention) potentially introducing bias. One of secondary outcomes is therapeutic inertia (operationalized as adherence to KDIGO guidelines), however; there will be a substantial unbalance in the way BP is managed in both arms (single investigator vs. usual care) Unclear if other drugs (besides hypertension medications and immunosuppressive drugs) will be managed with the MedMinder Rationale for 24 hour ambulatory blood pressure monitoring is not provided. Unclear if daily home blood pressure monitoring will be limited to the intervention arm

Limited information is provided on study measures and instruments
Sample size calculations do not consider dropouts, the study will be only powered to detect large differences in adherence (OR: 4) Data analysis proposes to include a random physician effect but patients in the intervention arm will be primarily managed by a single provider. Plans to include mediators as covariates in adjusted analysis of treatment effect are problematic. Aim 2: inclusion of outcomes (BP and adherence) as predictors in the model assessing SDT constructs would lead to endogeneity

Strengths
Resources at the University of South Carolina are excellent

Inclusion of Women, Minorities and Children:
G1A -Both Genders, Acceptable M1A -Minority and Non-minority, Acceptable

C3A -No Children Included, Acceptable
While a large percentage of the population will be Black, there will be no representation of Hispanics. No justification is provided Vertebrate Animals:

Not Applicable (No Vertebrate Animals)
Biohazards:

Budget and Period of Support:
Recommended as Requested Overall Impact: Failure to adhere to medication regimen and uncontrolled hypertension are significant risk factors for mortality and morbidity among kidney transplant recipients. Interventions to date have had limited success, and using self-determination theory (SDT) as a conceptual framework, the authors propose a system using smart phone reminders, summary reports, and alerts sent directly to providers to address the problem of long-term graft survival. This may be associated with cognitive impairment, including forgetfulness and poor planning. Given that the medical regimen is typically complex (12-15 medications up to four times a day, with adherence to timing an important variable). One estimate is that about half of transplant recipients have smart phones, and the investigators plan to use these devices for real-time interaction with non-adherent patients. Although the use of mHealth technology for the management of a chronic condition is not novel, its use with kidney transplant recipients (KTRs) has not previously been evaluated. Preliminary research by the study team found a high prevalence of medication errors by patients, and poorly controlled hypertension, and a feasibility trial of their program showed improvements in both systolic blood pressure and adherence in the intervention group. They propose a randomized controlled trial (RCT) with a total sample of 116 persons. The smart phone and an electronic medication tray (MedMinder) will be used to monitor medications and provide the patient with reminder about medication and blood pressure measurement. Outcomes will be measured at 3, 6, 12, and 18 months. Overall, the clinical trial is well-designed with meaningful long-term follow-up, but it has some limitations. The likelihood of missing data and attrition is relatively high, especially given the prevalence of cognitive impairment (especially of executive functioning) in the sample. Given that estimates of cognitive impairment among persons with ESRD range from about 16% to nearly 40%, and that executive function deficits may adversely affect subjects' ability to regulate their own behavior. Hence, a substantial portion of the sample may have difficulty following through with the intervention. In addition, the investigators may be missing an important mediating variable in their analyses. Overall impact of the study is likely to be good.

Acceptable Risks and/or Adequate Protections
Minimal risk with exception of renal biopsies, which are standard of clinical care. Consultants are required to absent themselves from the room during the review of any application if their presence would constitute or appear to constitute a conflict of interest.