Clinical trial NCT04711291: Efficacy of Envarsus XR and Digital Health Technology in Reducing Tacrolimus Fluctuation and Frequency of Dose Changes
Official title: Efficacy of Envarsus XR and Digital Health Technology in Reducing Tacrolimus Fluctuation and Frequency of Dose Changes
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Medication Adherence
Renal Transplant
Keywords: QR code technology
Envarsus-XR
Tacrolimus trough level
Digital health technology
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Veloxis Pharmaceuticals
First posted: 2021-01-15
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. BIDMC adult kidney transplant recipient more than 2 years post transplant
2. On tacrolimus IR regimen
3. Estimated glomerular filtration rate (eGFR) \>45
4. Tacrolimus dose adjustments 2 or more times in past 12 months
5. Own and able to use a smart phone.
6. Able to consent

Exclusion Criteria:

1. Prisoners
2. Patients with primary language other than English, Spanish, Haitian/Creole, Mandarin
3. Patients who can't swallow whole tablets or capsules.

Primary outcomes:
measure: Number of tacrolimus dose changes in 12 month period.
timeFrame: 1 year follow up
Secondary outcomes:
measure: 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
timeFrame: 12 months
measure: Self-reported adherence via monthly questionnaire.
timeFrame: 12 months
measure: • Variability in tacrolimus trough levels, as checked on routine labs as part of standard care
timeFrame: 12 months
Other outcomes:
Locations:
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Nikhil Agrawal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Beth Israel Deaconess Medical Center
name: Martha Pavlakis, MD
role: STUDY_DIRECTOR
affiliation: Beth Israel Deaconess Medical Center
name: Amtul Aala, MD
role: STUDY_CHAIR
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