Envarsus XR® in Adolescent Renal Transplant Recipients

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Prospective, Randomized, Single-center, Pilot Study of Envarsus XR® to Examine Safety, Medication Adherence, and Patient Reported Outcomes in Adolescent Renal Transplant Recipients

Conditions
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Kidney Transplantation, Renal Transplantation, Grafting, Kidney

Intervention / Treatment
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* Drug: Envarsus XR
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A-Tacrolimus then Envarsus<br>Immediate release tacrolimus (twice a day oral formulation) 14 day run-in followed by 4 months of follow-up and then crossing over to Envarsus XR® with a 14 day run-in followed by 4 months of follow-up. | Drug: Envarsus XR<br>* Once daily sustained-release tacrolimus<br>* Other names: extended release tacrolimus;Drug: Tacrolimus<br>* Twice daily immediate-release tacrolimus<br>* Other names: immediate release tacrolimus;|
| Experimental: Arm B-Envarsus then Tacrolimus<br>Envarsus XR® 14 day run-in followed by 4 months of follow-up and then crossing over to immediate release tacrolimus (twice a day oral formulation) with a 14 day run-in followed by 4 months of follow-up. | Drug: Envarsus XR<br>* Once daily sustained-release tacrolimus<br>* Other names: extended release tacrolimus;Drug: Tacrolimus<br>* Twice daily immediate-release tacrolimus<br>* Other names: immediate release tacrolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Appearance of dnDSA will be assessed by Luminex Single Antigen Bead assay. Patients will be monitored for rejection by measuring serum creatinine, a marker of renal function. If the creatinine level suggests allograft dysfunction, a biopsy will be performed and the tissue assessed by the 2013 Banff Criteria to determine presence of absence of rejection. Incidence rates will be compared across 4 month follow-up periods of each for twice-daily tacrolimus and Envarsus XR® descriptively and using Poisson or negative binomial models with random coefficients (intercepts or slopes) to account for nesting of assessment time points within individuals. | 9 months | 
| Change in Patient Reported Transplant Symptoms | Change in transplant symptoms will be assessed longitudinally by the Modified Transplant Symptom Occurrence and Distress Scale (MTSODS-59R). The MTSODS-59R assesses 59 side effects from immunosuppressive medications. Scores on each measure will be calculated and described with means, medians, standard deviations, and ranges. Change within individuals will be summarized descriptively, plotted over the study timepoints, and analyzed with repeated measures random coefficients models (unconditional model with no predictors). These models will determine if there is a significant difference in these outcomes when patients are on twice-daily tacrolimus and Envarsus XR®. | Baseline, 2.5 months, 4.5 months, 7 months, 9 months | 
| Change in Patient Reported Medication Adherence and Barriers | Outcome will be assessed longitudinally by the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BASIS), Adolescent and Parent Medication Barriers Scale (AMBS/PMBS), and Attitudes Toward Transplant Scale - Patient (ATTS-P). The BASIS assesses adherence in the last 4 weeks (did not take dose, forgetting dose, perception of not needing, reducing amount). The AMBS/PMBS are 17/16 item scales measuring medication barriers (Disease Frustration/Adolescent Issues, Ingestion Issues, Regimen Adaptation/Cognitive). The ATTS-P 4 item Attitudes toward Medication subscale (e.g., Medication is not a problem - problematic, Medication is a relief - burdensome) will also be used. Scores on each measure will be calculated and numerically described. Change within individuals will be summarized descriptively, plotted over the study timepoints, and analyzed with repeated measures random coefficients models (unconditional model with no predictors) comparing mediation regimens. | Baseline, 2.5 months, 4.5 months, 7 months, 9 months | 
| Incidence of Adverse Events (AE) and Serious Adverse Events (SAE) as a measure of safety | Patients will be monitored for for the appearance of AEs or SAEs. Rates will be compared across 4 month follow-up periods of each for twice-daily tacrolimus and Envarsus XR® descriptively and using Poisson or negative binomial models with random coefficients (intercepts or slopes) to account for nesting of assessment time points within individuals. | 2 weeks, 2.5 months, 4.5 months, 5 months, 7 months, 9 months | 
| Change in Patient Reported Distress | Change in distress will be assessed longitudinally by the Patient Reported Outcomes Measurement Information System (PROMIS®) Pediatric/Parent Proxy Profile 25. The PROMIS® includes 25 questions generating several subscales for fatigue, pain interference, pain intensity, physical function-mobility, anxiety, depressive symptoms, and peer relationships. Scores on each measure will be calculated and described with means, medians, standard deviations, and ranges. Change within individuals will be summarized descriptively, plotted over the study timepoints, and analyzed with repeated measures random coefficients models (unconditional model with no predictors). These models will determine if there is a significant difference in these outcomes when patients are on twice-daily tacrolimus and Envarsus XR®. | Baseline, 2.5 months, 4.5 months, 7 months, 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tacrolimus Dose Exposure | Measured as area-under the curve (AUC), based on a limited sampling strategy. On day 14 after starting Envarsus XR ® patients will have an abbreviated pharmacokinetic assessment using the following time points: 0 hours (trough pre-dose) and at 8 and 12 hours post-dose. The AUC will be described. | Day 14 after starting Envarsus XR ® | 
| Tacrolimus Trough Coefficient of Variation | To determine the association between tacrolimus trough level % coefficient of variation (CV%) and patient non-adherence self- reporting and compare these measures between twice daily tacrolimus and Envarsus XR®. CV% will be calculated as CV% = (standard deviation/mean) × 100 of tacrolimus trough levels collected while taking each tacrolimus formulation. | Baseline; Days 7, 14, 44, 74, 104, 134, 142, 148, 178, 208, 238, 268 | 
| Incidence of IgG3 and C1q positive Donor Specific Antibodies | To determine the association of non-adherence with the development of IgG3 and C1q positive dnDSA. Incidence rates will be compared across 4 month follow-up periods of each for twice-daily tacrolimus and Envarsus XR® descriptively and using Poisson or negative binomial models with random coefficients (intercepts or slopes) to account for nesting of assessment time points within individuals. | Baseline, 2.5 months, 4.5 months, 7 months, 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Envarsus XR, Kidney transplantation, Grafting, Kidney, Tacrolimus, Rejection, Adherence, Quality of Life, post-transplant immunosuppression