Prospective Study Comparing Brand and Generic Immunosuppression on Transplant Outcomes, Adherence, & Immune Response in Kidney Transplant Recipients

• ClinicalTrials.gov Identifier: NCT02866682
• Recruitment Status: Completed
• First Posted: August 15, 2016
• Results First Posted: April 28, 2023
• Last Update Posted: April 28, 2023
• Sponsor: University of California, Los Angeles
• Collaborator: Food and Drug Administration (FDA)
• Information provided by (Responsible Party): Suphamai Bunnapradist, University of California, Los Angeles

Tracking Information

• First Submitted Date: July 26, 2016
• First Posted Date: August 15, 2016
• Results First Submitted Date: December 9, 2022
• Results First Posted Date: April 28, 2023
• Last Update Posted Date: April 28, 2023
• Actual Study Start Date: March 1, 2018
• Actual Primary Completion Date: June 11, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 5, 2023)

Time to First Occurrence of Acute Rejection, Failure, Death [ Time Frame: 1 year post-transplant ]

The definition of graft failure includes re-transplant and/or death and, in case of kidney transplant, also includes return to dialysis. Acute rejection was defined as biopsy-proven rejection according to Banff 2007 criteria. Please see the following article for details of the Banff '07 classification: https://www.sciencedirect.com/science/article/pii/S1600613522056428?via%3Dihub.

Original Primary Outcome Measures (submitted: August 10, 2016)

Time to first occurrence of acute rejection, failure, death [ Time Frame: 3 years post-transplant ]

The definition of graft failure includes re-transplant and/or death and in case of kidney transplant also includes return to dialysis. The definition of acute rejection in kidney transplant will be based on Banff 2007 classification, in heart transplant will be based on revised 2004 ISHLT grading and in liver transplant will be based on Banff schema for grading liver allograft rejection.

Current Secondary Outcome Measures (submitted: April 5, 2023)

• Number of Participants With Graft Rejection at 1 Year [ Time Frame: 1 year post-transplant ]
  Rejection was defined as biopsy-proven rejection according to Banff 2007 criteria. Please see the following article for details of the Banff '07 classification: https://www.sciencedirect.com/science/article/pii/S1600613522056428?via%3Dihub.
• Number of Participants With Graft Failure at 1 Year [ Time Frame: 1 year post-transplant ]
  Graft failure as determined by return to dialysis, death, or re-transplant
• Number of Participants With Infectious Episodes at 1 Year [ Time Frame: 1 year post-transplant ]
  Infectious episodes are defined as a positive test result for an infection.
• Number of Participants With Malignancy at 1 Year [ Time Frame: 1 year post-transplant ]
  Malignancy is defined as physician reported malignancy according to review of participants' medical history.
• Death or Loss-to-follow-up at 1 Year [ Time Frame: 1 year post-transplant ]
• Changes in Lymphocyte Subpopulations and Production of Donor Specific HLA Antibodies [ Time Frame: post-transplant ]
• Number of Participants Who Adhered to Medication Regimen [ Time Frame: post-transplant ]
  Patient adherence was assessed by their physician with participants marked as "adherent," "non-adherent," or "unknown."
• Quality of Life With Medication Regimen [ Time Frame: post-transplant ]
• Satisfaction With Medication Regimen [ Time Frame: post-transplant ]

Original Secondary Outcome Measures (submitted: August 10, 2016)

• Graft Rejection at 1 year [ Time Frame: 1 year post-transplant ]
• Graft Rejection at 2 years [ Time Frame: 2 years post-transplant ]
• Graft Rejection at 3 years [ Time Frame: 3 years post-transplant ]
• Graft Failure at 1 year [ Time Frame: 1 year post-transplant ]
• Graft Failure at 2 years [ Time Frame: 2 years post-transplant ]
• Graft Failure at 3 years [ Time Frame: 3 years post-transplant ]
• Incidence of Infectious Episodes at 1 year [ Time Frame: 1 year post-transplant ]
• Incidence of Infectious Episodes at 2 years [ Time Frame: 2 years post-transplant ]
• Incidence of Infectious Episodes at 3 years [ Time Frame: 3 years post-transplant ]
• Incidence of Malignancy at 1 year [ Time Frame: 1 year post-transplant ]
• Incidence of Malignancy at 2 years [ Time Frame: 2 years post-transplant ]
• Incidence of Malignancy at 3 years [ Time Frame: 3 years post-transplant ]
• Death or loss-to-follow-up at 1 year [ Time Frame: 1 year post-transplant ]
• Death or loss-to-follow-up at 2 years [ Time Frame: 2 years post-transplant ]
• Death or loss-to-follow-up at 3 years [ Time Frame: 3 years post-transplant ]
• Activity of Nuclear Factor of Activated T Cells (NFAT) - dependent cytokine expression levels [ Time Frame: post-transplant ]
• Changes in lymphocyte subpopulations and production of donor specific HLA antibodies [ Time Frame: post-transplant ]
• Adherence with medication regimen [ Time Frame: post-transplant ]
• Quality of Life with Medication Regimen [ Time Frame: post-transplant ]
• Satisfaction with Medication Regimen [ Time Frame: post-transplant ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Prospective Study Comparing Brand and Generic Immunosuppression on Transplant Outcomes, Adherence, & Immune Response in Kidney Transplant Recipients
• Official Title: Prospective Study Comparing Brand and Generic Immunosuppression on Transplant Outcomes, Adherence, & Immune Response

Brief Summary

As the patents for brand-name immunosuppressive medications expire, there is increasing interest in using generic immunosuppressive drugs. However, despite pharmacokinetic studies showing bioequivalence, questions remain regarding the clinical impact of use of generic immunosuppression.

The most important immunosuppressive agent in the modern transplant era is arguably tacrolimus, a calcineurin-inhibitor with a narrow therapeutic index. This study seeks to answer the question regarding the clinical impact of generic tacrolimus use as measured primarily by acute rejection, loss of graft function, and patient death through a randomized trial of 2 phases: Brand tacrolimus only, and Generic A tacrolimus only. Given that kidney transplantations are the most commonly performed transplants with well-defined measures of rejection and graft failure, this organs will be studied in a six-center study designed to accrue the target number of transplant recipients within the one-year study period.

The study has now been branched off into 2 phases. Phase 1: consists of randomization of patients onto brand and generic tacrolimus. This was completed once 40 brand patients were enrolled. Phase 2: consists of patients being enrolled only on generic tacrolimus (standard of care from subject's insurance). This will be completed once there is a total of 160 generic participants. 200 participants total in the study.

Detailed Description

A prospective, randomized, open-label, multicenter, parallel, observational study to assess safety and efficacy of 200 kidney transplant recipients comparing brand tacrolimus to generic tacrolimus over a one year follow up period. All subjects will receive other immunosuppressive medications including induction therapy (thymoglobulin, basiliximab, or no induction) and maintenance including mycophenolate mofetil and corticosteroid therapy as directed by standard-of-care at each center. Their medication information will be recorded in their study files.

The study population includes recipients of kidney allografts in the first 14 days after transplantation.

The totals of 7 visits over 12 months period are planned as follows. The blood samples specified below are for the translational research study labs. Subjects will continue to receive routine labs as part of their standard of care from their treating physician. These safety labs are done as part of their stand of care from their treating physician.

If the subject needs more study drug medication before his or her next study visit the subject will come in to the clinic to get a new supply.

First (Baseline) Visit (up to 14 days after transplant but before you are discharged from the hospital):

• Review and sign this consent form
• Review of your medical history
• Review of your current medications
• Review of your physical exam including vital signs (blood pressure, temperature, pulse and respiration rate), height and weight
• Review of clinical labs
• You will receive your study drug if you are in Part 1 of the study.

If you are a woman of child bearing potential, a pregnancy test will be completed prior to the start of the study. If you are pregnant, you cannot participate in this research study. You also cannot participate in this study if you are currently breastfeeding. You must use a medically acceptable method of birth control during the 1-year study period and for 6 weeks after the last dose of study medication.

It is possible that after the study doctor reviews your medical history and test results, he or she may tell you that you do not qualify to be in the study. If you do not qualify for the study, the doctor will tell you the reason(s) why. If you cannot be in this research study, you will not lose any medical benefits, you can still participate in other studies, and you can still receive the standard treatment prescribed by your physician.

After the Baseline Visit, you will have 6 additional study visits. These will be scheduled for 1, 2, 3, 6, 9, and 12 months after your transplant surgery. The following will occur at each visit:

Month 1, 2, 3, 6, and 9 Visits:

• Review of your current medications
• Review of your physical exam including vital signs (blood pressure, temperature, pulse and respiration rate), height and weight
• Review of any changes in your health and any reactions to the study medication will be recorded
• Review of your routine standard of care lab results
• Return completed dosing diary and receive new dosing diary
• You will receive your study drug if you are in Part 1 of the study

Month 12 Visit (End of Study Visit):

• Review of your current medications
• Review of any changes in your health and any reactions to the study medication will be recorded
• Review of your routine standard of care lab result
• Return your final completed dosing diary
• Return any study drug remaining in your possession to the study team if you are in Part 1 of the study

If you are Part 1 and require more study medication before your next study visit, you will come in to the clinic to get a new supply. If you are participating in Part 2, you will obtain more study drug from your local pharmacy.

You will continue having your routine blood and urine collections to monitor your kidney function as part of your standard of care treatment at UCLA, UCSD, UCI, and UCD. The schedule for these routine blood and urine collections will depend on your condition and will be at your treating physician's discretion.

Adherence will be measured with daily medication diaries and with the coefficient of variation of tacrolimus in subjects' blood.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Renal Transplant Rejection

Intervention

• Drug: Prograf
  Brand Drug for the duration of the study.
• Drug: Tacrolimus
  Generic

Study Arms

• Brand Tacrolimus Only : Prograf
  Arm 1 will receive brand tacrolimus for the entire study
  Intervention: Drug: Prograf
• Generic A Only
  Arm 2 will receive specific generic tacrolimus for the entire study
  Intervention: Drug: Tacrolimus

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 9, 2022): 176
• Original Estimated Enrollment (submitted: August 10, 2016): 300
• Actual Study Completion Date: June 11, 2021
• Actual Primary Completion Date: June 11, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Signed informed consent and or/assent
2. Between the ages of 18 and 70 years, inclusive
3. Current or future kidney transplant recipients, no more than 14 days after transplant and prior to hospital discharge. Inclusion of future kidney transplant recipients cannot exceed 30-days pre-transplant.
4. Able to swallow tablets and capsules at the time of randomization
5. Subjects must be receiving a primary or secondary kidney allograft from a deceased donor or from a non- HLA identical living donor
6. Negative cross match test, and compatible (A, B, AB or O) blood type
7. Subjects must have no known contraindications to tacrolimus
8. Women of childbearing potential (WOCBP) must have a negative pregnancy test and be willing to use 2 methods of contraception during the study and for 6 weeks after stopping the study drug.

WOCBP includes any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy with documented serum follicle stimulating hormone level > 35 mIU/cc). Women who are using oral, implanted, or injectable contraceptive hormones (intrauterine device), mechanical products or barrier methods (diaphragm, condoms, spermicides), are practicing abstinence, or have a sterile partner (e.g., vasectomy), will be considered of child bearing potential.

In addition, WOCBP who are taking MMF must use methods of birth control as stipulated in the package insert, namely:

Either intrauterine device, or partner with vasectomy, or one hormone (oral contraceptive pill, transdermal patch, vaginal ring, or progesterone injection or implant) and one barrier method (diaphragm or cervical cap with spermicide, contraceptive sponge, or male or female condom), or two barrier methods as described above.

WOCBP must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at the time of transplant.

Exclusion Criteria

1. Those who receive simultaneous combined organ transplants
2. Subjects with clinically significant active infections (for example, those requiring hospitalization, or as judged by the Investigator) or malignancies
3. Recipients who are concurrently receiving belatacept or anticipate to receive belatacept as part of their immunosuppressive regimen
4. Subjects currently enrolled in another investigational device or drug study
5. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for 6 weeks after stopping the study drug
6. Women who are breast-feeding or pregnant with a positive pregnancy test on enrollment or prior to study drug administration
7. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
8. Any psychiatric or medical condition that, in the investigator's opinion, may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02866682
• Other Study ID Numbers: 14-001423
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: Suphamai Bunnapradist, University of California, Los Angeles
• Original Responsible Party: Same as current
• Current Study Sponsor: University of California, Los Angeles
• Original Study Sponsor: Same as current
• Collaborators: Food and Drug Administration (FDA)

Investigators

• Principal Investigator: Suphamai Bunnapradist, M.D.,M.S.; University of California, Los Angeles

• PRS Account: University of California, Los Angeles
• Verification Date: April 2023