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Kidney TransplantationPhase 4EnvarsusXRNCT03266393

Envarsus XR® in Adolescent Renal Transplant Recipients

A Phase 4 study testing Envarsus XR and Tacrolimus in people with Kidney Transplantation and Renal Transplantation, run by University of California, Los Angeles at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 13 to 20 years
What is being tested?
Envarsus XR and Tacrolimus
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
28 participants
Where
1 siteUnited States
Study dates
15 Jan 2019to 31 Mar 2023
Phase
Phase 4
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 13 to 20 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 10Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • UCLA Transplantation Services

    Los Angeles, California, 90095

Other trials in United States

About this study

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

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.

Read the 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.
Being tested
Envarsus XR, Tacrolimus
Keywords
Envarsus XR, Kidney transplantation, Grafting, Kidney, Tacrolimus, Rejection, Adherence, Quality of Life, post-transplant immunosuppression
Medical subject headings
Rejection, Psychology

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Envarsus XRDrug

    Also called extended release tacrolimus

    Once daily sustained-release tacrolimus

  • TacrolimusDrug

    Also called immediate release tacrolimus

    Twice daily immediate-release tacrolimus

Study groups in NCT03266393
Study groupRoleWhat they receive
Arm A-Tacrolimus then EnvarsusExperimentalImmediate 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.
Receives: Drug: Envarsus XR; Drug: Tacrolimus
Arm B-Envarsus then TacrolimusExperimentalEnvarsus 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.
Receives: Drug: Envarsus XR; Drug: Tacrolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 9 months

  2. 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®.

    Measured: Baseline, 2.5 months, 4.5 months, 7 months, 9 months

  3. 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.

    Measured: Baseline, 2.5 months, 4.5 months, 7 months, 9 months

  4. 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.

    Measured: 2 weeks, 2.5 months, 4.5 months, 5 months, 7 months, 9 months

  5. 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®.

    Measured: Baseline, 2.5 months, 4.5 months, 7 months, 9 months

Secondary outcomes (3)

  1. 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.

    Measured: Day 14 after starting Envarsus XR ®

  2. 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.

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

  3. 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.

    Measured: Baseline, 2.5 months, 4.5 months, 7 months, 9 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Aug 2017
  2. Study start15 Jan 2019
  3. Primary completion31 Mar 2023 (estimated)
  4. Study completion31 Mar 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
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)
Enrolment
28 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03266393
Sponsor's protocol ID
17-006138
Acronym
EnvarsusXR
Status last verified
Feb 2023
First submitted
10 Aug 2017
Last updated
9 Feb 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 9269646

  • 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.

    PubMed 23734831

  • 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.

    PubMed 26717860

  • 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.

    PubMed 36094829

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Envarsus XR and Tacrolimus in people with Kidney Transplantation and Renal Transplantation, run by University of California, Los Angeles at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 9 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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. (time frame: 9 months). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03266393, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Feb 2023.

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