CNTRP POSITIVE Study

NCT02318030 | Completed

• 1 other identifier: 1000045186
• Study Type: observational
• Target: 600
• Locations: 1 country
• Sites: 1

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.

Conditions

Transplant; Adaptive Immunity; EBV; Medication Adherence; PTLD

Keywords

Transplant; Adaptive Immunity; EBV; Medication Adherence; Tacrolimus; PTLD

Outcome Measures

Primary Outcomes (10)

• Tacrolimus trough blood concentrations

  1 year from time of transplant

• Time to attain stable therapeutic tacrolimus trough blood concentration

  Stable therapeutic blood concentration defined as two levels in target therapeutic range without change in dose.

  1 year from time of transplant

• Frequency of out-of-range trough levels during follow-up

  Blood concentrations will be captured at 36-48 hours post tacrolimus initiation after transplant, 7, 14, and 30 days after and 3 months and 12 months post transplant.

  1 year from time of transplant

• Determination of trough target therapeutic range

  Blood concentrations will be captured at 36-48 hours post tacrolimus initiation after transplant, 7, 14, and 30 days after and 3 months and 12 months post transplant.

  1 year from time of transplant

• Viral genotype

  Relationship between major EBV subtypes and clinical and virologic outcomes (illness severity, viral loads, PTLD), evaluated in age groups of \<2 years, 2-10 years, 11-18 years and adults \>18 years

  1 year from time of transplant

• Taking Adherence to immunosuppressive medications measured using pharmacy refill data and structured self-report

  Participant pharmacies will be contacted at end of study to determine if medications are being refilled as would be expected if all doses were consumed as prescribed.

  6 months from a minimum of 3 months post time of transplant

• Immune maturation across pediatric age groups

  Baseline & 1 year from time of transplant

• Functional immunoassay

  Baseline \& 1 year from time of transplant

  1 year from time of transplant

• Change in immune function before and after transplant as it correlates with immune maturation and intensity of immunosuppression

  Baseline & 1 year from time of transplant

• Viral immunoassays

  Baseline & 1 year from time of transplant

Secondary Outcomes (6)

• Graft rejection

  1 year from time of transplant

• Complications (cancer, infections, CVS, CNS, other

  1 year from time of transplant

• Graft outcomes

  Baseline, 3 months, 6 months

• Adverse events

  Baseline, 3 months, 6 months

• Timing adherence to immunosuppressive medications

  6 months from a minimum of 3 months post time of transplant

Study Arms (2)

Solid organ transplant

Hematopoietic Stem Cell Transplant

Eligibility Criteria

• Age: 0 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

End stage organ failure, Solid organ transplant

You may qualify if:

• 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

Sponsors & Collaborators

• The Hospital for Sick Children: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• Alberta Children's Hospital: collaborator
• Stollery Children's Hospital: collaborator
• St. Justine's Hospital: collaborator
• The Children's Hospital of Winnipeg: collaborator
• Montreal Children's Hospital of the MUHC: collaborator
• Provincial Health Services Authority British Columbia: collaborator
• Toronto General Hospital: collaborator
• Vancouver General Hospital: collaborator
• Royal Victoria Hospital, Canada: collaborator
• The Ottawa Hospital: collaborator
• Foothills Medical Centre: collaborator
• Centre hospitalier de l'Université de Montréal (CHUM): collaborator
• University of British Columbia: collaborator

Study Sites (1)

SickKids Hospital

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (3)

• 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.

  PMID: 30584591 BACKGROUND

• 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.

  PMID: 33755393 RESULT

• 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.

  PMID: 34339090 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Immune function testing: blood Pharmacokinetic testing: blood EBV/PTLD viral sequencing: blood EBV/PTLD immunoassays: blood

MeSH Terms

Conditions

Medication Adherence

Condition Hierarchy (Ancestors)

Patient Compliance; Patient Acceptance of Health Care; Treatment Adherence and Compliance; Health Behavior; Behavior

Study Officials

• Seema Mital, MD

  SickKids Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Cardiologist

Study Record Dates

• First Submitted: November 25, 2014
• First Posted: December 17, 2014
• Study Start: April 1, 2014
• Primary Completion: November 1, 2019
• Study Completion: April 1, 2020
• Last Updated: October 8, 2021

Record last verified: 2021-09

Locations

CA (1)