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Envarsus XR® in Adolescent Renal Transplant Recipients (EnvarsusXR)

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ClinicalTrials.gov Identifier: NCT03266393
Recruitment Status : Not yet recruiting
First Posted : August 30, 2017
Last Update Posted : September 7, 2018
Sponsor:
Collaborator:
Veloxis Pharmaceuticals
Information provided by (Responsible Party):
Meghan Pearl, MD, University of California, Los Angeles

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.

Condition or disease Intervention/treatment Phase
Kidney Transplantation Renal Transplantation Grafting, Kidney Drug: Envarsus XR Drug: Tacrolimus Phase 4

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 5 to 8 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 (5-8 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
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 of 5 to 8 ng/ml. Randomization will be stratified based on each patient's follow-up period post-transplant in 2 stratification groups.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : November 1, 2018
Estimated Primary Completion Date : June 1, 2020
Estimated Study Completion Date : June 1, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

Arm Intervention/treatment
Experimental: 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.
Drug: Envarsus XR
Once daily sustained-release tacrolimus
Other Name: extended release tacrolimus

Drug: Tacrolimus
Twice daily immediate-release tacrolimus
Other Name: immediate release tacrolimus

Experimental: 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.
Drug: Envarsus XR
Once daily sustained-release tacrolimus
Other Name: extended release tacrolimus

Drug: Tacrolimus
Twice daily immediate-release tacrolimus
Other Name: immediate release tacrolimus




Primary Outcome Measures :
  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. [ Time Frame: 9 months ]
    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.

  2. Change in Patient Reported Transplant Symptoms [ Time Frame: Baseline, 2.5 months, 4.5 months, 7 months, 9 months ]
    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®.

  3. Change in Patient Reported Medication Adherence and Barriers [ Time Frame: Baseline, 2.5 months, 4.5 months, 7 months, 9 months ]
    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.

  4. Incidence of Adverse Events (AE) and Serious Adverse Events (SAE) as a measure of safety [ Time Frame: 2 weeks, 2.5 months, 4.5 months, 5 months, 7 months, 9 months ]
    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.

  5. Change in Patient Reported Distress [ Time Frame: Baseline, 2.5 months, 4.5 months, 7 months, 9 months ]
    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®.


Secondary Outcome Measures :
  1. Tacrolimus Dose Exposure [ Time Frame: Day 14 after starting Envarsus XR ® ]
    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.

  2. Tacrolimus Trough Coefficient of Variation [ Time Frame: Baseline; Days 7, 14, 44, 74, 104, 134, 142, 148, 178, 208, 238, 268 ]
    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.

  3. Incidence of IgG3 and C1q positive Donor Specific Antibodies [ Time Frame: Baseline, 2.5 months, 4.5 months, 7 months, 9 months ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   13 Years to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Recipients of first kidney transplants (deceased or living donor)
  • 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
  • Diagnosed with recurrent glomerular disease
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03266393


Contacts
Contact: Margaret S. Holloway 310-206-8415 MHolloway@mednet.ucla.edu

Locations
United States, California
UCLA Transplantation Services Not yet recruiting
Los Angeles, California, United States, 90095
Sponsors and Collaborators
Meghan Pearl, MD
Veloxis Pharmaceuticals
Investigators
Principal Investigator: Meghan Pearl, MD University of California, Los Angeles

Publications:
Responsible Party: Meghan Pearl, MD, Principal Investigator, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT03266393     History of Changes
Other Study ID Numbers: 17-006138
First Posted: August 30, 2017    Key Record Dates
Last Update Posted: September 7, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Meghan Pearl, MD, University of California, Los Angeles:
Envarsus XR
Kidney transplantation
Grafting, Kidney
Tacrolimus
Rejection
Adherence
Quality of Life
post-transplant immunosuppression

Additional relevant MeSH terms:
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action