Envarsus XR® in Adolescent Renal Transplant Recipients

NCT ID: NCT03266393

Last Updated: 2023-02-09

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-15
• Study Completion Date: 2023-03-31

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.

Conditions

Kidney Transplantation; Renal Transplantation; Grafting, Kidney

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A-Tacrolimus then Envarsus

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.

Group Type: EXPERIMENTAL

Envarsus XR

Intervention Type: DRUG

Once daily sustained-release tacrolimus

Tacrolimus

Intervention Type: DRUG

Twice daily immediate-release tacrolimus

Arm B-Envarsus then Tacrolimus

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.

Group Type: EXPERIMENTAL

Envarsus XR

Intervention Type: DRUG

Once daily sustained-release tacrolimus

Tacrolimus

Intervention Type: DRUG

Twice daily immediate-release tacrolimus

Interventions

Envarsus XR

Once daily sustained-release tacrolimus

Intervention Type: DRUG

Tacrolimus

Twice daily immediate-release tacrolimus

Intervention Type: DRUG

Other Intervention Names

extended release tacrolimus; immediate release tacrolimus

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

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Veloxis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

University of California, Los Angeles

OTHER

Sponsor Role: lead

Responsible Party

Rachana Srivastava

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Rachana Srivastava, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Locations

UCLA Transplantation Services

Los Angeles, California, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 9269646 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23734831 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26717860 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36094829 (View on PubMed)

Other Identifiers

17-006138

Identifier Type: -

Identifier Source: org_study_id