Clinical trial NCT03266393: Envarsus XR® in Adolescent Renal Transplant Recipients
Official title: A Prospective, Randomized, Single-center, Pilot Study of Envarsus XR® to Examine Safety, Medication Adherence, and Patient Reported Outcomes in Adolescent Renal Transplant Recipients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Kidney Transplantation
Renal Transplantation
Grafting, Kidney
Keywords: Envarsus XR
Kidney transplantation
Grafting, Kidney
Tacrolimus
Rejection
Adherence
Quality of Life
post-transplant immunosuppression
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: Veloxis Pharmaceuticals
First posted: 2017-08-30
Enrollment: 28
Sex: ALL
Minimum age (years): 13
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Once enrolled, patients will be randomized 1:1 to immediate release tacrolimus that the patient had been maintained on prior to the study (twice daily formulation) or Envarsus XR® using a permuted block randomization sequence to improve the likelihood of balance between groups. Following randomization, and independent of the formulation of tacrolimus, each patient will have a "run-in" period of 14 days to optimize the dose to reach a tacrolimus trough level within their therapeutic target. Randomization will be stratified based on each patient's follow-up period post-transplant in 2 stratification groups.
Primary purpose: TREATMENT

Brief summary: Adolescents commonly experience barriers to adherence that entail forgetfulness, distraction, poor planning, and scheduling problems. A once daily oral regimen may be superior to the current regimens that require twice daily dosing. It is currently unclear if Envarsus XR® would improve outcomes in adolescent organ transplant recipients. Each patient will receive tacrolimus (twice daily immediate release oral formulation) which they are using as part of their standard of care immunosuppressive regimen for a portion of the study and Envarsus XR® (a once daily extended-release oral tacrolimus formulation) for a portion of the study in a cross-over design. Besides the advantage to adherence behaviors, a sustained-release tacrolimus preparation may decrease burdensome side effects and increase quality of life. Following enrollment, each patient will be maintained in the study for 9 months.

Detailed description: This is a randomized, prospective, single-center, pilot study assessing once daily Envarsus XR® medication efficacy, adverse events, medication non-adherence, patient-reported outcomes, and abbreviated pharmacokinetics/ dose finding to evaluate a population of adolescent renal transplant recipients while on stable tacrolimus (twice daily) and then after conversion to Envarsus XR® to provide critical efficacy, safety, dose-finding, adherence, and patient reported outcome data that could lead to adoption of Envarsus XR® as a mainstay of pediatric/adolescent post-transplant immunosuppression.

Following randomization, and independent of the formulation of tacrolimus, each patient will have a "run-in" period of 14 days to optimize the dose to reach a tacrolimus trough level of 4 to 10 ng/ml.

* Drug Administration: After randomization (to either twice daily tacrolimus or once daily Envarsus ®) and the "run-in" period, patients will be continued on their assigned tacrolimus formulation for 4 months. He/she will then be then switched to the opposite tacrolimus formulation. Following the switch, there will be a 14 day run-in period to establish the optimal trough level (4-10 ng/ml) (analogous to the first run-in period) and then continued on that tacrolimus formulation for 4 months.
* Pharmacokinetics: Irrespective of whether a patient starts on Envarsus XR® after randomization or is switched to Envarsus XR® after 4 months of immediate release tacrolimus, the dose of Envarsus XR® will be determined by using a dose conversion ratio targeting 0.7 (but may range from 0.66-0.8 because of dosage strengths of Envarsus XR® dosing formulations) relative to the immediate release formulation that he/she was receiving as maintenance.

Eligibility criteria: Inclusion Criteria:

* Recipients of first kidney transplants (deceased or living donor) with stable allograft function
* 6 or more months after transplantation
* Currently on a stable dose of twice-daily tacrolimus and mycophenolate mofetil (MMF) or enteric coated mycophenolic acid (EC-MPA)± corticosteroids for a minimum of 6 months prior (patient has remained on a dosing that has changed no greater than ± 0.5mg/dose for a minimum of 4 months)
* Ability to comply with study procedures for the entire length of the study
* Patient and/or parent/legal guardian has been informed about the study survey and has signed an informed consent form.

Exclusion Criteria:

* Detectable donor specific anti-HLA antibody prior to enrollment (pre- or post-transplant)
* Actively being treated for an episode of biopsy proven acute cellular rejection (ACR) (Banff 1A or greater)
* Post-transplant history of biopsy proven ACR (Banff 1B or greater) or antibody mediated rejection (AMR)
* Currently receiving, planning to receive, or received within 7 days prior to study enrollment any drug interacting or interfering with tacrolimus metabolism (azole antifungals, erythromycin, clarithromycin, diltiazem, protease inhibitors, statins, grapefruit juice, rifampin or anti-seizure medications shown to interact with tacrolimus)
* Currently receiving an mTOR inhibitor (sirolimus, everolimus)
* Gastrointestinal illness that might affect the absorption of tacrolimus
* Unable or unwilling to complete study survey questionnaire
* Professional care taker is responsible for dispensing subject's medication
* Recipient of HLA identical or zero HLA mismatched organ transplant
* Documented history of medication non-adherence following transplantation prior to enrollment

Primary outcomes:
measure: Incidence of clinical or subclinical allograft injury at any timepoint as assessed by the appearance of de novo donor specific anti-HLA antibody (dnDSA) OR biopsy proven allograft rejection.
timeFrame: 9 months
measure: Change in Patient Reported Transplant Symptoms
timeFrame: Baseline, 2.5 months, 4.5 months, 7 months, 9 months
measure: Change in Patient Reported Medication Adherence and Barriers
timeFrame: Baseline, 2.5 months, 4.5 months, 7 months, 9 months
measure: Incidence of Adverse Events (AE) and Serious Adverse Events (SAE) as a measure of safety
timeFrame: 2 weeks, 2.5 months, 4.5 months, 5 months, 7 months, 9 months
measure: Change in Patient Reported Distress
timeFrame: Baseline, 2.5 months, 4.5 months, 7 months, 9 months
Secondary outcomes:
measure: Tacrolimus Dose Exposure
timeFrame: Day 14 after starting Envarsus XR ®
measure: Tacrolimus Trough Coefficient of Variation
timeFrame: Baseline; Days 7, 14, 44, 74, 104, 134, 142, 148, 178, 208, 238, 268
measure: Incidence of IgG3 and C1q positive Donor Specific Antibodies
timeFrame: Baseline, 2.5 months, 4.5 months, 7 months, 9 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Transplantation Services
state: California
Study officials:
affiliation: University of California, Los Angeles
name: Rachana Srivastava, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Filler G, Grygas R, Mai I, Stolpe HJ, Greiner C, Bauer S, Ehrich JH. Pharmacokinetics of tacrolimus (FK 506) in children and adolescents with renal transplants. Nephrol Dial Transplant. 1997 Aug;12(8):1668-71. doi: 10.1093/ndt/12.8.1668.
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: Rostaing L, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT Jr, Budde K; Envarsus Study Group. Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial. Am J Kidney Dis. 2016 Apr;67(4):648-59. doi: 10.1053/j.ajkd.2015.10.024. Epub 2015 Dec 22.
citation: Mellon L, Doyle F, Hickey A, Ward KD, de Freitas DG, McCormick PA, O'Connell O, Conlon P. Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients. Cochrane Database Syst Rev. 2022 Sep 12;9(9):CD012854. doi: 10.1002/14651858.CD012854.pub2.