Efficacy of Envarsus XR and Digital Health Technology in Reducing Tacrolimus Fluctuation and Frequency of Dose Changes

Study Overview
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Brief Summary
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Tacrolimus is an immunosuppressive agent prescribed to prevent organ rejection in post transplant patients, in combination with other immunosuppressants. In post-kidney transplant patients, tacrolimus blood trough(peak) level must be monitored frequently, and dose adjustments must be made as necessary to keep trough level within a very narrow target range. High tacrolimus intra-patient variability(IPV) can be a marker of medication non-adherence. The presence of medication non-adherence could be due to multiple factors e.g. Forgetfulness, misunderstanding or miscommunication due to language barrier etc. Our hypothesis is using QR code technology along with extended release Tacrolimus medication will reduce tacrolimus IPV fluctuation.

Detailed Description
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Tacrolimus is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants, in combination with other immunosuppressants. Envarsus XR (extended release tacrolimus) is a long acting form of tacrolimus that is prescribed as a single dose per day (every 24 hours) rather than immediate release tacrolimus (IR-Tac) which is prescribed as a two doses per day (every 12 hours). In post-kidney transplant patients, tacrolimus blood trough level must be monitored frequently, and dose adjustments must be made as necessary to keep trough level within a very narrow therapeutic range. High intra-patient variability (IPV) has also been reported to promote donor-specific antibody development, increased graft rejection rates and poor long-term outcome after kidney transplantation. In addition to increased potential for poor graft outcomes, these fluctuations and frequent dose adjustments are confusing and burdensome for patients, add to costs via medication expenses and need for lab checks, and consume the limited resources of transplant centers. Similarly, non-adherence with immunosuppression medications is common and also linked to poor graft outcomes in kidney transplant patients. High tacrolimus IPV can be a marker of medication non-adherence. The presence of medication non-adherence could be due to multiple factors such as forgetfulness to take the medication or remembering the correct dose, misunderstanding or miscommunication due to language barrier or logistical issues. High tacrolimus IPV could also be due to difficulty in taking medication every 12 hours, variation in bioavailability of different generic tacrolimus formulations or drug interactions. Considering the IPV of Tacrolimus level, patients and their families often have difficulty managing medications, especially during frequent changes in medication doses. This problem is more prevalent for older patients, who are often on multiple medications and for whom side effects and drug-drug interactions may lead to more harm. Once daily tacrolimus has had mixed results in reducing tacrolimus IPV. Very few studies have been done till now to measure the IPV among patients who received twice daily IR-Tac and converted to once daily Envarsus-XR. These studies were able to show significant reduction in IPV among patients who had high IPV prior to conversion. It is also noteworthy as compared to Astragraf, Envarsus XR has a more favorable pharmacokinetic profile. Envarsus XR uses Melt Dose technology to increase bioavailability and allow a more controlled release of the drug. This results in less fluctuation between maximum (peak) exposure and trough. From a clinical perspective, Envarsus is noninferior in terms of efficacy (composite endpoint, including kidney transplant graft loss, death, biopsy-proven acute rejection and loss to follow-up) when compared to IR-Tac with a similar safety profile. Digital health technologies have not been studied in regards to tacrolimus IPV but have shown promising results in improving medication adherence, including in kidney transplant population. TransMedAxTM application; a proposed digital health platform that will be developed to be used in this study. It will utilize dynamic QR code based technology customized to each individual patient, to improve medication adherence. It is especially geared towards patient populations who have frequent changes in medication dosages and have limited English language proficiency. A brief description of TransMedAxTM workflow is as follows: Patients will be asked to bring their medication bottle/pill box to the clinic. A QR code unique to the patient will be printed from TransMedAxTM website and attached to medication bottle. TransMedAxTM app will be downloaded on patient's phone. Research staff will input tacrolimus medication and dose into the patient's TransMedAxTM application account. The TransMedAxTM verbal instructions will be automatically translated into the patient's preferred language (English, Spanish, Haitian/Creole, or Mandarin). When this QR code is scanned by the patient using their smartphone camera, it will provide verbal instructions on Tacrolimus dosage and also display the time of the dose on patient's phone. The TransMedAxTM application installed on patient's phone home screen will allow patient to access this information at one-tap and send reminders when the tacrolimus is due. This application will also be used to monitor patient adherence using brief questionnaire. Many patients and clinicians hope technology will help improve safety, but technology may increase errors if not properly implemented. Our project will specifically focus on transplant patients in their home/outpatient setting, and addresses language barrier for communication, coordination, and information for these patients. Our focus is on improving patient self-management of tacrolimus medication and informed partnership with clinicians to improve safety. If successful, our work will have the following impact: Provide patients/families, and providers with a readily available tool to manage Tacrolimus doses. Improve adherence to the immunosuppressive therapy at appropriate doses prescribed by physician on timely manner. This measures will reduce the rate of acute rejection, graft loss and drug side effects and hence the hospitalization.

Official Title
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Efficacy of Envarsus XR and Digital Health Technology in Reducing Tacrolimus Fluctuation and Frequency of Dose Changes

Conditions
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Medication Adherence, Renal Transplant

Intervention / Treatment
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* Combination Product: Conversion to Envarsus-XR and use of smart phone app, TransMedAx
* Drug: Convert to Envarsus XR once daily


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BIDMC adult kidney transplant recipient more than 2 years post transplant On tacrolimus IR regimen Estimated glomerular filtration rate (eGFR) >45 Tacrolimus dose adjustments 2 or more times in past 12 months Own and able to use a smart phone. Able to consent Exclusion Criteria: Prisoners Patients with primary language other than English, Spanish, Haitian/Creole, Mandarin Patients who can't swallow whole tablets or capsules.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: BIDMC kidney transplant patients currently taking immediate release tacrolimus (IR-Tac) will be screened for enrollment into the trial. Eligible patients will be randomized to one of three treatment arms in a 1:1:1 fashion. We aim to randomize seventy-five (75) patients into one of three treatment arms (1:1:1) as described. Arm 1: Remain on tacrolimus immediate release (IR-Tac) prescribed doses every 12 hours; Arm 2: Convert to tacrolimus extended release (Envarsus XR) prescribed dose every 24 hours; OR Arm 3: Convert to tacrolimus extended release (Envarsus XR) prescribed dose every 24 hours used in combination with the smart phone application, TransMedAxTM.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Remain on IR-Tac prescribed doses every 12 hours<br>Patient will remain in Tacrolimus IR-Tac Arm and will complete medication adherence questionnaire monthly. They will not receive any notifications from TransMedAx application. Research staff and PI will collect their Tacrolimus Trough levels and change in tacrolimus dose levels during their routine follow up. | |
| Active Comparator: Convert to Envarsus XR once daily<br>Subjects randomized to this arm will switch from IR-Tac to Envarsus XR and will complete medication adherence questionnaire. However, patients in this group will not receive any notifications from TransMedAx application. Research staff and PI will collect their Tacrolimus trough levels and change in tacrolimus dose during their follow up. | Drug: Convert to Envarsus XR once daily<br>* Convert from tacrolimus immediate release to tacrolimus extended release (Envarsus XR) prescribed dose every 24 hours<br>|
| Experimental: Convert to Envarsus XR once daily combined with TransMedAx app use<br>Subjects randomized to this arm will switch from IR-Tac to Envarsus XR, will receive notification by scanning a QR code through TransMedAx application and will complete medication adherence questionnaire. Research staff and PI will collect their Tacrolimus trough levels and change in tacrolimus dose during their follow up. | Combination Product: Conversion to Envarsus-XR and use of smart phone app, TransMedAx<br>* Convert to tacrolimus extended release (Envarsus XR) prescribed dose every 24 hours used in combination with the smart phone application, TransMedAx. Patients in this arm will be trained to use the app along with conversion to Envarsus-XR. Once patient scan the code on medicine bottle and the app will remind them about the time and dose of the medication in their native language.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of tacrolimus dose changes in 12 month period. | How frequent was the dose changes in 12 month follow up post transplant, excluding changes made due to change in therapeutic target. | 1 year follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in number of tacrolimus dose adjustments in follow up period compared to 12 months prior to enrolment, excluding changes made due to change in therapeutic target | We will note the change in number of Tacrolimus dose adjustments in follow up period and compared the dose changes 12 months prior to enrollment. We will exclude the changes made due to change in therapeutic target. | 12 months | 
| Self-reported adherence via monthly questionnaire. | We will monitor the patient compliance with self medications among arms and note frequency of non adherence. | 12 months | 
| • Variability in tacrolimus trough levels, as checked on routine labs as part of standard care | We will monitor the fluctuations in Tacrolimus Trough levels among patients randomized to different arms and compared their variability with the one in Arm 3 | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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QR code technology, Envarsus-XR, Tacrolimus trough level, Digital health technology