Envarsus XR® in Adolescent Renal Transplant Recipients

NCT03266393 | Active Not Recruiting Phase 4 FDA Drug

• 1 other identifier: 17-006138
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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.

Conditions

Kidney Transplantation; Renal Transplantation; Grafting, Kidney

Keywords

Envarsus XR; Kidney transplantation; Grafting, Kidney; Tacrolimus; Rejection; Adherence; Quality of Life; post-transplant immunosuppression

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (3)

• Tacrolimus Dose Exposure

  Day 14 after starting Envarsus XR ®

• Tacrolimus Trough Coefficient of Variation

  Baseline; Days 7, 14, 44, 74, 104, 134, 142, 148, 178, 208, 238, 268

• Incidence of IgG3 and C1q positive Donor Specific Antibodies

  Baseline, 2.5 months, 4.5 months, 7 months, 9 months

Study Arms (2)

Arm A-Tacrolimus then Envarsus

EXPERIMENTAL

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; Drug: Tacrolimus

Arm B-Envarsus then Tacrolimus

EXPERIMENTAL

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; Drug: Tacrolimus

Interventions

Envarsus XR DRUG

Once daily sustained-release tacrolimus

Also known as: extended release tacrolimus

Arm A-Tacrolimus then Envarsus; Arm B-Envarsus then Tacrolimus

Tacrolimus DRUG

Twice daily immediate-release tacrolimus

Also known as: immediate release tacrolimus

Arm A-Tacrolimus then Envarsus; Arm B-Envarsus then Tacrolimus

Eligibility Criteria

• Age: 13 Years - 20 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Recipients of first kidney transplants (deceased or living donor) with stable allograft function
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, Los Angeles: lead
• Veloxis Pharmaceuticals: collaborator

Study Sites (1)

UCLA Transplantation Services

Los Angeles, California, 90095, United States

Location

Related Publications (4)

• 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.

  PMID: 9269646 BACKGROUND

• 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.

  PMID: 23734831 BACKGROUND

• 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.

  PMID: 26717860 BACKGROUND

• 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.

  PMID: 36094829 DERIVED

MeSH Terms

Conditions

Rejection, Psychology

Interventions

Tacrolimus

Condition Hierarchy (Ancestors)

Social Behavior; Behavior

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Rachana Srivastava, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: August 10, 2017
• First Posted: August 30, 2017
• Study Start: January 15, 2019
• Primary Completion: March 31, 2023
• Study Completion: March 31, 2023
• Last Updated: February 9, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)