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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Improved precision medicine by increasing self-management and medication control in adolescents

Alternative title: Forbedret presisjonsmedisin gjennom økt grad av selvkontrollert medisinering hos ungdom

Awarded: NOK 4.5 mill.

Long term medical treatment of adolescent patients with chronic disease is challenging and non-adherence is common. Currently non-adherence is the major cause of reduced graft survival in adolescent (age 16-25 years) solid organ transplants. Improving adherence in this group of patients will be important not only to the individual patient but also better utilized the limited resource of available organs for transplantation in the whole population. Monitoring of immunosuppressive medication is routinely performed by blood-samples taken early in the morning at the hospital. This gives a trough value (C0) which is used for dose corrections according to so called “therapeutic windows”. A change in dose leads to a new blood test to see if the dose is correct i.e. a time consuming proses. The main objective of this project is to investigate if utilizing a modern and patients centered technology will improve adherence in adolescent organ transplanted patients. Improved adherence will improve graft outcome. 1. During the project we developed and validated a method for home-based finger-prick sampling for drug monitoring in adolescents. We found no difference in tacrolimus concentration in an ordinary blood-sample when compared to the result in a patient-taken finger-prick sample. 2. Development of a computer based model for improved and individualized dosing of tacrolimus. Data gathered from the participants included have been incorporated into the doseapplication BestDose for tacrolimus. So fare we still do not have enough data from adolescent patients to finish the youth- model. When finished it must be tested and evaluated in an external cohort of adolescent kidney transplant recipients. 3. Use smartphone technology for direct communication adolescents for drug dose adjustments. During spring/summer 2021 the app TusenTac was up-graded, improved and changed (USIT, UiO) to fit a young user. There were, however, additional comments from the adolescents who tested the upgraded version and a new contact was taken with USIT spring 2022. There are still omgoing improvements. A major challenge in making the app user friendly has been a lack of “direct communication” i.e. possibility for treating physician to enter tacrolimus trough level and recommended tacrolimus dose directly into the app. This problem has so far not been solved due to complicated data privacy security rules in Norway. During fall 2023 we contacted the leader for "Hjemmesykehuset" to see if our app may be integrated in OUS app Dignio. 4. The combination of home-based finger-prick monitoring and the TusenTac app was tested in a pilot-project by adol. organ transpl. patients. The study gathered data on graft-function, tacrolimus-trough values etc from 1 year prior to and one year after the pilot project. Results from this project indicate that adolescents adherence behavior may be classified into 3 categories; one group with optimal medical adherence with no improvement during intervention with the use of the Tusen Tac app/home-based finger-prick, one group experiencing a clear improvement during the intervention and one whom will need additional intervention on top off the Tusen Tac app/finger-prick in order to improve adherence. Approximately 50% of the participants were non-adherent and in half of these, we registered improved adherence during and right after the pilot-project. The results from the pilot-project indicated that original power-calculations for a planed prospective study were incorrect. In order to detect a change/improvement in medical adherence by intervention (use of TusenTac app/home-based finger-prick) one would either need to include a larger number of patients or only include patients with poor or sub-optimal adherence. With current number of eligible organ transplant recipients in Norway (and Sweden) we calculated an anticipated inclusion period of 3-4 years. The ongoing Covid-19 pandemic was also thought to make inclusion complicated. The planned prospective evaluation project was there for abolished. 5.To improve our understanding of medical non-adherence in adolescents we performed a retrospective registry analysis. Data from all standard immun. risk kidney transplant recipients engrafted in Norway before age 50 during 2000-2020 were included. We compared number of rejection/ reasons for rejections/development of donor specific antibodies/number of graft loses/medical adherence in adolescent (below 26 years of age) vs young adults (26-50 years of age) following kidney transplantation. Data from a total of 1830 kidney transplant recipients were included with 371 classified as adolescents and find that non-adherence during the «transition phase» i.e age 14-26 is the most important reason graft loss. During the time period when the recipient was 18-22 years i.e. immediately after transfer form follow-up at the pediatric ward to the adult ward was most challenging with increased non-adherence leading to 78 graft losses.

Medical treatment of adolescent patients with chronic disease is challenging and non-adherence is common. Non-adherence is the major cause of reduced graft survival in adolescent solid organ transplants. The main objective of the project is to improve adherence in adolescent patients by utilizing modern, patients centered technology. By combining a medication managing smartphone app (TusenTac) with home-based finger prick sampling for drug monitoring, the hypothesis is that the increased patient involvement obtained will transfer into better adherence. A positive "add-on" effect is that this also provide a unique opportunity for patients to, via the app, share accurate dosing and side-effect information with the health care provider in real time. This is central information needed for optimal output from modern computerized dosing tools, the new gold standard of therapeutic drug monitoring. In order to optimize the use of the TusenTac app it is essential that it is adapted to the users. It should not only deliver data but the user also needs relevant feedback in return. WP1 focus on how to individually optimize feedback to assure continued use of the app over time. Finger prick sampling for drugs like tacrolimus is applicable in adults (previously published from our center). In this project we initially validated the method in youth. It works i.e. dry blood spot tacrolimus monitoring is applicable also in this population! The results have been published (WP2). We are now working on the possibility of analyzing hemoglobin and creatinine in the same dry blood spot. Results in adults are promising. We have performed a nationwide registry analysis in kidney transplanted adolescents engrafted from 2000 to 2020 with focus on non-adherence and graft loss. The data verify that non-adherence is the main reason for graft loss in this age group. The study has been accepted for publication (WP3). The challenge is how to implement dry blood spot, in combination with the TusenTac app, to improve adherence (WP1). In order to provide scientific evidence for this, a large prospective clinical trial in adolescents was planned. There have been some large challenges due to the ongoing Covid-19 pandemic and data safety/security issues with the app that that so far remain unsolved. Communication has so far not been possible. The initial pilot trial utilizing dry blood spot and a test model of the Tusen Tac app was therefore prolonged with long term data from included participants (WP1). The data are reassuring and are under preparation for submission. When the project is finalized and we get an improved version of the app we strongly believe that the TusenTac app will be optimized for use in adolescents and that home-based micro sampling is ready for use in the clinic. We will implement both technologies when treating adolescent kidney transplanted adolescents.

Funding scheme:

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering