Clinical trial NCT04156204: Immunosuppressant Medication Dosed Daily After Kidney Transplant
Official title: Kidney Immunosuppression Dosed Daily Only (KIDDO) - A Pilot Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Kidney Transplant Rejection
Medication Adherence
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
First posted: 2019-11-07
Enrollment: 1
Sex: ALL
Minimum age (years): 13
Maximum age (years): 22
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Longitudinal Pilot Study
Primary purpose: OTHER

Brief summary: Medication non-adherence is a major risk factor for graft dysfunction and graft loss among pediatric and adult transplant recipients. Rates of non-adherence in these populations are estimated between 30 and 70%, with the highest prevalence in adolescent and young adult (AYA) transplant recipients. Treatment-related factors known to impact rates of adherence include the number of medication doses per day and the number of tablets or capsules a patient takes per day, or "pill burden". One approach to minimizing dosing frequency and pill-burden includes transitioning patients to once-daily formulations. The current literature investigating utilization of once-daily immunosuppressive regimens in the AYA kidney transplant population is limited.

Detailed description: One approach to minimizing dosing frequency and pill-burden includes transitioning patients to once-daily formulations.3 The current literature investigating utilization of once-daily immunosuppressive regimens in the AYA kidney transplant population is limited. Two studies have demonstrated safe and effective conversion of twice-daily tacrolimus to the Astagraf® in stable pediatric solid organ transplant recipients.4,5 Patients maintained equivalent tacrolimus exposure and experienced similar rates of rejection and graft loss in the first year post-conversion.5 To date, experience with another once-daily extended release (XR) tacrolimus product, Envarsus XR®, has not been published in the AYA population. Additionally, adherence studies evaluating a once-daily immunosuppression regimen including extended-release tacrolimus and azathioprine (which is dosed once daily as opposed to the twice daily dosing required for azathioprine's alternative mycophenolate mofetil) have not been conducted.

Of note, and even though twice-daily mycophenolate has been shown to be superior to once-daily azathioprine early post-transplant, more long-term data suggest that this advantage may not persist.6 Furthermore, a recent Cochrane review addressed the question of mycophenolate versus azathioprine as primary anti-proliferative immunosuppression for kidney transplant recipients; it concluded that "balancing the benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent" is appropriate for the individual patient. 7 Moreover, once-daily immunosuppression with tacrolimus extended-release and once-daily azathioprine has been used with excellent results at a British center that focusses on AYA kidney transplant recipients.

Eligibility criteria: Inclusion Criteria:

1. Age 13-22 years
2. Tanner stage 4/5
3. "Stable" kidney transplant status, as determined by the primary transplant team
4. At minimum 1 year post-kidney transplant or patients meeting all of the above inclusion criteria except 4) who have instead been transitioned to azathioprine by the primary transplant team due to intolerability of mycophenolate mofetil secondary to adverse medication effects (i.e. neutropenia, gastrointestinal intolerance etc.)

Exclusion Criteria:

1. \< Tanner stage 4
2. Kidney transplant performed at an institution other than Children's Hospital Colorado, Lurie Children's Hospital of Chicago, or Cincinnati Children's Hospital
3. Recipients of dual solid organ transplants (i.e. heart kidney, liver kidney).

Primary outcomes:
measure: Health-Related Quality of Life: as assessed by change in PedsQL
timeFrame: Day 0, Day 60, Day 210
measure: Adherence to medical therapies and medications: as assessed by Medication Event Monitoring System (MEMS) at Day 30
timeFrame: Day 30
measure: Adherence to medical therapies and medications: as assessed by Medication Event Monitoring System (MEMS) at Day 60
timeFrame: Day 60
measure: Adherence to medical therapies and medications: as assessed by Medication Event Monitoring System (MEMS) at Day 210
timeFrame: Day 210
measure: Adherence to medical therapies and medications: as assessed by Change in Tacrolimus Trough Concentration Variance
timeFrame: Day 0, Day 30, Day 60, and Day 240
measure: Adherence to medical therapies and medications:as assessed by Change in Adolescent Medication Barriers Scale (AMBS)
timeFrame: Day 0, Day 60, Day 210
measure: Adherence to medical therapies and medications: as assessed by Change in The Medical Adherence Measure (MAM)
timeFrame: Day 0, Day 60, Day 210
Secondary outcomes:
measure: Long-term measures of graft and patient survival: as assessed by change in serum creatinine and urinary protein
timeFrame: Day 0, Day 30, Day 60, Day 210, and Day 240
measure: Long-term measures of graft and patient survival: as assessed by change in markers of proteinuria
timeFrame: Day 30 and Day 210
measure: Long-term measures of graft and patient survival: as assessed by number of episodes of rejection
timeFrame: Up to Day 240
measure: Long-term measures of graft and patient survival: as assessed by change in presence of donor-specific antibody monitoring
timeFrame: Day 0 and Day 240
measure: Long-term measures of graft and patient survival: as assessed by change in presence of BK virus screening results
timeFrame: Day 0 and Day 240
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
Study officials:
affiliation: Children's Hospital Colorado
name: Jens Goebel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Colorado
name: Mary Chandran, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Foster BJ, Dahhou M, Zhang X, Platt RW, Samuel SM, Hanley JA. Association between age and graft failure rates in young kidney transplant recipients. Transplantation. 2011 Dec 15;92(11):1237-43. doi: 10.1097/TP.0b013e31823411d7.
citation: Sabaté, E (2003) Adherence to long-term therapies: evidence for action. World Health Organization, Geneva
citation: Steinberg EA, Moss M, Buchanan CL, Goebel J. Adherence in pediatric kidney transplant recipients: solutions for the system. Pediatr Nephrol. 2018 Mar;33(3):361-372. doi: 10.1007/s00467-017-3637-0. Epub 2017 Mar 27.
citation: Min SI, Ha J, Kang HG, Ahn S, Park T, Park DD, Kim SM, Hong HJ, Min SK, Ha IS, Kim SJ. Conversion of twice-daily tacrolimus to once-daily tacrolimus formulation in stable pediatric kidney transplant recipients: pharmacokinetics and efficacy. Am J Transplant. 2013 Aug;13(8):2191-7. doi: 10.1111/ajt.12274. Epub 2013 Jun 4.
citation: Heffron TG, Pescovitz MD, Florman S, Kalayoglu M, Emre S, Smallwood G, Wisemandle K, Anania C, Dhadda S, Sawamoto T, Keirns J, Fitzsimmons W, First MR. Once-daily tacrolimus extended-release formulation: 1-year post-conversion in stable pediatric liver transplant recipients. Am J Transplant. 2007 Jun;7(6):1609-15. doi: 10.1111/j.1600-6143.2007.01803.x.
citation: Clayton PA, McDonald SP, Chapman JR, Chadban SJ. Mycophenolate versus azathioprine for kidney transplantation: a 15-year follow-up of a randomized trial. Transplantation. 2012 Jul 27;94(2):152-8. doi: 10.1097/TP.0b013e31825475a3.
citation: Wagner M, Earley AK, Webster AC, Schmid CH, Balk EM, Uhlig K. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev. 2015 Dec 3;2015(12):CD007746. doi: 10.1002/14651858.CD007746.pub2.