Clinical trial NCT02318030: CNTRP POSITIVE Study
Official title: CNTRP Paediatric Outcomes in Transplant: Personalising Immunosuppression to Improve Efficacy (POSITIVE Study)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Transplant
Adaptive Immunity
EBV
Medication Adherence
PTLD
Keywords: Transplant
Adaptive Immunity
EBV
Medication Adherence
Tacrolimus
PTLD
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Alberta Children's Hospital
name: Stollery Children's Hospital
name: St. Justine's Hospital
name: The Children's Hospital of Winnipeg
name: Montreal Children's Hospital of the MUHC
name: Provincial Health Services Authority
name: Toronto General Hospital
name: Vancouver General Hospital
name: Royal Victoria Hospital, Canada
name: The Ottawa Hospital
name: Foothills Medical Centre
name: Centre hospitalier de l'Université de Montréal (CHUM)
name: University of British Columbia
First posted: 2014-12-17
Enrollment: 600
Sex: ALL
Minimum age (years): 0
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: End stage organ failure, Solid organ transplant

Brief summary: Adequate control of immunosuppression is critical in preventing graft failure after solid organ transplantation (SOT) and in avoiding life-threatening viral and malignant complications. Prolonging patient and graft survival and delaying re-transplantation as children reach adulthood is critical to optimal use of a scarce resource. This requires tailoring post-transplant management to the unique needs of the child. Immunosuppression management is challenging in infants, children and youth. The interval from birth to young adulthood sees profound changes in physiological processes, body size and immune maturation; infancy and adolescence are the periods of most rapid and dramatic change. Three pivotal factors affect immunosuppression control in the child: 1) age-dependent variation in drug metabolism; 2) developmental changes in immune function with increased childhood susceptibility to infections, including those caused by viruses; and 3) behavioural changes in adolescence and young adulthood linked with poor treatment adherence.

This project will identify the most important factors influencing immunosuppression control across the pediatric age range, from infancy to young adulthood, including age-related changes in drug metabolism, immune function, and susceptibility to viral infections, as well as health care system factors affecting treatment adherence. This is the first comprehensive, multi-organ transplant study to identify age-related biologic and health care systems determinants of variability in immunosuppression control in children and youth. Results will inform personalized age-appropriate strategies to improve immunosuppression control and reduce the unacceptably high graft failure and viral complication rates in this vulnerable population.

The POSITIVE Study brings together researchers across Canada and is one of 6 projects and 3 cores that constitute the Canadian Institute of Health Research (CIHR) funded interdisciplinary research program called the Canadian National Transplant Research Program (CNTRP). The CNTRP is a national program designed to increase organ and tissue donation in Canada and enhance the survival and quality of life of Canadians who receive transplants. As a national program, CNTRP provides robust power for pediatric studies that would not otherwise be possible. While primarily focused on issues unique to a pediatric and young adult population, this study will interact closely with all other CNTRP projects. These reciprocal interactions will accelerate new discovery that can be cross-applied in different populations outside of pre-specified age groups. Interactions will ensure rapid knowledge transfer, uptake and dissemination into practice. This is the largest national cohort study of pediatric transplant patients to date in Canada, and it will create a longitudinal dataset with clinical and biological specimens linkable to transplant registries and provincial administrative datasets.

Detailed description: The overall objective of this project is to analyze physiological factors that impact immune response and effect of immunosuppression across different pediatric age groups, to develop age-appropriate medical and health care strategies that can improve graft survival and reduce complications in a pediatric and young adult population. There are 3 primary aims of this study:

Aim 1: Develop age-appropriate calcineurin inhibitor (CNI) dosing for pediatric SOT patients: We hypothesize that physiologically-based (PB) modeling will enable personalized CNI dosing for infants, children and youth based on age, pharmacogenotype and immune maturity. Aim 1 deliverables include 1) a personalized physiologically-based CNI dosing algorithm in SOT; 2) validation of pediatric sensitive immunosuppression monitoring tools and their therapeutic targets; and 3) validation of immunologic assays for assessing age-specific immune responses. We anticipate that personalized CNI dosing will result in early attainment and maintenance of therapeutic drug concentrations, reduce the frequency of out-of-range concentrations post-transplant, improve safety and efficacy of immunosuppression, and reduce dependence on therapeutic drug monitoring to guide drug dosing. Standardized assessment of immune function may also monitor immunosuppression more reliably and eventually reduce the need for invasive monitoring like biopsies.

Aim 2: Develop risk prediction tools based on viral-host interactions that predispose young SOT and hematopoietic stem cell transplant patients to Epstein-Barr virus disorders/post-transplant lymphoproliferative disorder (EBV disorders/PTLD): We hypothesize that susceptibility to EBV disorders/PTLD is influenced by the interaction of high-risk EBV subtypes with host factors like age, immune maturation and intensity of immunosuppression. In the above context, "EBV disorders" refers to non-malignant EBV disease as well as sustained elevation of viral loads in the absence of PTLD. We will identify high-risk viral subtypes and age-related differences in host immunity that interact to increase susceptibility to EBV disorders/PTLD in young patients. Important clinical applications are: 1) knowledge of host susceptibility factors (age and immune maturation) at the time of transplant may assist choice of less intensive immunosuppression to reduce risk of developing EBV (e.g., avoidance of T cell depletion therapies, primary prevention) and promote use of EBV prophylaxis in at risk patients (secondary prevention); 2) an EBV genotype panel will be developed as a clinical tool for detecting high risk subtypes in patients with EBV. This will help identify patients exposed to EBV who should receive aggressive therapy for EBV and/or PTLD (personalized therapy). This innovative risk stratification will enable personalized immunosuppression strategies and strategies to prevent and treat EBV/PTLD.

Aim 3: Develop health care systems strategies to enhance medication adherence in adolescents and young adults: Medication adherence is determined by factors at a variety of different "levels": patient-level (patient-, condition-, and therapy-related factors), "micro"-level (social factors and interactions with the care team), "meso"-level (organization and expertise of the healthcare team and care processes), and "macro"-level (high-level healthcare systems factors, including care and medication cost coverage, and overall care environment). We hypothesize that there are significant differences in modifiable meso- and macro-level systems factors between pediatric programs, between adult programs, and between pediatric and adult programs. Furthermore, we hypothesize that modifiable meso- and macro-level systems factors are independently associated with medication adherence. This aim has two primary objectives:

Objective 1: To characterize differences between Canadian solid organ transplant programs in potentially modifiable meso- and macro-level systems factors.

Objective 2: To identify potentially modifiable meso- and macro-level factors that are determinants of adherence, adjusting for potential confounders.

Eligibility criteria: Inclusion Criteria:

Aim 1

* Listed for or recipient of solid organ transplant
* Planned immunosuppression with oral or enteral tacrolimus post-transplant

Aim 2

* Solid organ transplant or hematopoietic stem cell transplant recipients \<18 years old
* New onset primary EBV during the first year post transplant (either Donor EBV seropositive, recipient EBV seronegative (D+R-) or donor and recipient seronegative (D-R-) at time of transplant) or new onset EBV/PTLD in the first post-transplant year.
* HSCT patients who develop secondary EBV within the first post transplant year.

Aim 3

* Single organ, kidney, liver, and heart recipients that are at least 3 months post-transplant and 2 months post hospital discharge
* Intact graft function (not currently listed for re-transplant for any organ type or on dialysis
* Receiving maintenance immunosuppression

Primary outcomes:
measure: Tacrolimus trough blood concentrations
timeFrame: 1 year from time of transplant
measure: Time to attain stable therapeutic tacrolimus trough blood concentration
timeFrame: 1 year from time of transplant
measure: Frequency of out-of-range trough levels during follow-up
timeFrame: 1 year from time of transplant
measure: Determination of trough target therapeutic range
timeFrame: 1 year from time of transplant
measure: Viral genotype
timeFrame: 1 year from time of transplant
measure: Taking Adherence to immunosuppressive medications measured using pharmacy refill data and structured self-report
timeFrame: 6 months from a minimum of 3 months post time of transplant
measure: Immune maturation across pediatric age groups
timeFrame: Baseline & 1 year from time of transplant
measure: Functional immunoassay
timeFrame: 1 year from time of transplant
measure: Change in immune function before and after transplant as it correlates with immune maturation and intensity of immunosuppression
timeFrame: Baseline & 1 year from time of transplant
measure: Viral immunoassays
timeFrame: Baseline & 1 year from time of transplant
Secondary outcomes:
measure: Graft rejection
timeFrame: 1 year from time of transplant
measure: Complications (cancer, infections, CVS, CNS, other
timeFrame: 1 year from time of transplant
measure: Graft outcomes
timeFrame: Baseline, 3 months, 6 months
measure: Adverse events
timeFrame: Baseline, 3 months, 6 months
measure: Timing adherence to immunosuppressive medications
timeFrame: 6 months from a minimum of 3 months post time of transplant
measure: Drug Holidays for immunosuppressive medications
timeFrame: 6 months from a minimum of 3 months post time of transplant
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: SickKids Hospital
state: Ontario
Study officials:
affiliation: SickKids Hospital
name: Seema Mital, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Papaz T, Allen U, Blydt-Hansen T, Birk PE, Min S, Hamiwka L, Phan V, Schechter T, Wall DA, Urschel S, Foster BJ, Mital S. Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy (POSITIVE Study): The Collaboration and Design of a National Transplant Precision Medicine Program. Transplant Direct. 2018 Nov 27;4(12):e410. doi: 10.1097/TXD.0000000000000842. eCollection 2018 Dec.
citation: Min S, Papaz T, Lambert AN, Allen U, Birk P, Blydt-Hansen T, Foster BJ, Grasemann H, Hamiwka L, Litalien C, Ng V, Berka N, Campbell P, Daniel C, Saw CL, Tinckam K, Urschel S, Van Driest SL, Parekh R, Mital S. An Integrated Clinical and Genetic Prediction Model for Tacrolimus Levels in Pediatric Solid Organ Transplant Recipients. Transplantation. 2022 Mar 1;106(3):597-606. doi: 10.1097/TP.0000000000003700.
citation: Dabirzadeh A, Dahhou M, Zhang X, Sapir-Pichhadze R, Cardinal H, White M, Johnston O, Blydt-Hansen TD, Tibbles LA, Hamiwka L, Urschel S, Birk P, Bissonnette J, Matsuda-Abedini M, Harrison J, Schiff J, Phan V, De Geest S, Allen U, Mital S, Foster BJ. Care processes and structures associated with higher medication adherence in adolescent and young adult transplant recipients. Pediatr Transplant. 2021 Dec;25(8):e14106. doi: 10.1111/petr.14106. Epub 2021 Aug 2.