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A Phase 4, Open Label Multi-Center, Prospective, Randomized Study of Comparing the Efficacy and Safety of Generic vs. Brand Tacrolimus on Kidney Transplant Outcomes in De Novo in Kidney, Heart and Liver Transplant Recipients

2016-08-16 10:08:21 | BioPortfolio

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 4 parallel groups: Brand tacrolimus only, brand tacrolimus for 6 months than switch to Generic A, Generic A only, or Generic A for 6 months than switch to any other generic tacrolimus. Given that kidney, liver, and heart transplantation are the most commonly performed transplants with well-defined measures of rejection and graft failure, these organs will be studied in a two-center study designed to accrue the target number of transplant recipients within the three-year study period.

Description

A prospective, randomized, open-label, multicenter, parallel, observational study to assess safety and efficacy of 300 kidney, heart and liver transplant recipients comparing brand tacrolimus to generic and a combination of generic and brand tacrolimus over the three 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, liver, or heart allografts in the first 14 days after transplantation.

The totals of 15 visits over 36 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. For detailed information about the study labs schedule see Table 5 Study Schedule, and for the study safety labs by organ see Appendix 4. 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 the study subject is discharged from the hospital):

- Subject reviews and signs consent form

- Review of subject's medical history

- Review of subject's current medications

- Review of subject's physical exam including vital signs (blood pressure, temperature, pulse and respiration rate), height and weight

- Review of any changes in subject's health and any reactions to the study medication will be recorded

- About 16 cc blood sample (about 3.2 teaspoons of blood) will be collected from the subject for translational research study laboratory tests

- Randomization of subject

- Subject will receive study drug.

Month 1 Visit:

- Review of subject's current medications

- Review of subject's physical exam including vital signs (blood pressure, temperature, pulse and respiration rate), height and weight

- Review of any changes in subject's health and any reactions to the study medication will be recorded

- Subject returns completed dosing diary and receives new dosing diary

- Subject will receive study drug.

Month 2/3 Visit:

- Review of subject's current medications

- Review of subject's physical exam including vital signs (blood pressure, temperature, pulse and respiration rate), height and weight

- Review of any changes in subject's health and any reactions to the study medication will be recorded

- About 16 cc blood sample (about 3.2 teaspoons of blood) will be collected from the subject for translational research study laboratory tests (Month 3 Visit only)

- Subject returns completed dosing diary and receives unfilled dosing diary

- Subject will receive study drug.

Month 6/9/12/24 Visit:

- Review of subject's current medications

- Review of subject's physical exam including vital signs (blood pressure, temperature, pulse and respiration rate), height and weight

- Review of any changes in subject's health and any reactions to the study medication will be recorded

- About 32 cc blood sample (about 6.5 teaspoons of blood) (Month 6 Visit only) and about 16 cc (about 3.2 teaspoons) for Month 9, 12 and 24 will be collected from the subject for translational research study laboratory tests

- Subject returns completed dosing diary and receives unfilled dosing diary

- Subject will receive study drug if applicable.

- If in Group 4 the subject will be receiving immunosuppressant drug from his or her local pharmacy

Month 15/21/27/33 Visit:

- Subject will receive study drug if applicable

- If in Group 4 the subject will be receiving immunosuppressant drug from his or her local pharmacy

- If in Group 4 and the subject is not coming to the clinic for his or her study visit the subject will receive a CleverCap and dosing diary by mail. The subject will also receive instructions on how to mail back the old CleverCap and dosing diary.

Month 18/30 Visit:

- Review of subject's current medications

- Review of any changes in subject's health and any reactions to the study medication will be recorded

- Subject returns completed dosing diary and receives unfilled dosing diary

- Subject will receive study drug if applicable.

- If in Group 4 the subject will be receiving immunosuppressant drug from his or her local pharmacy

Month 36 Visit (End of Study Visit):

- Review of subject's current medications

- Review of any changes in subject's health and any reactions to the study medication will be recorded

- About 16 cc blood sample (about 3.2 teaspoons of blood) will be collected from subject for translational research studies laboratory tests

- Subject returns final completed dosing diary

- Subject returns any study drug remaining in his or her possession to the study team A safety follow-up phone call will be made at month 37 (+/- I week) to record patient's wellbeing and graft survival. This call will serve as the last AE follow-up if any was reported at month 36.

Total blood 32 cc of blood (approximately 6.5 teaspoons) will be drawn from the subject at Month 6 study visit. At Baseline, Month 3, Month 9, Month 12, Month 24 and Month 36 study visits the subject will have drawn about 16 cc (approximately 3.2 teaspoons) of blood. During the course of the study (after approximately 3 years of participation in the study), the total amount of blood that will be drawn is approximately 128 cc (approximately 8.7 tablespoons or 1/2 cup). This is about a third of the amount usually drawn when someone donates a pint of blood. Also, the subject will continue having his or her routine blood and urine collection to monitor heart, liver or kidney function as part of his or her standard of care treatment at UCLA or UCSD and UCI. These routine blood collections are not included in the total blood for the study discussed above. The schedule for these routine blood and urine collection will depend on the subject's condition and will be at their treating physician's discretion.

Adherence will be measured with daily medication diaries, the CleverCaps electronic pill bottle caps, and with the coefficient of variation of tacrolimus in subjects' blood.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Renal Transplant Rejection

Intervention

Prograf, Prograf followed by Tacrolimus, Tacrolimus, Multiple Tacrolimus

Status

Not yet recruiting

Source

University of California, Los Angeles

Results (where available)

View Results

Links

Published on BioPortfolio: 2016-08-16T10:08:21-0400

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Medical and Biotech [MESH] Definitions

A 12-KDa tacrolimus binding protein that is found associated with and may modulate the function of calcium release channels. It is a peptidyl-prolyl cis/trans isomerase which is inhibited by both tacrolimus (commonly called FK506) and SIROLIMUS.

A family of immunophilin proteins that bind to the immunosuppressive drugs TACROLIMUS (also known as FK506) and SIROLIMUS. EC 5.2.1.-

A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that TACROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.

A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro.

Members of a family of highly conserved proteins which are all cis-trans peptidyl-prolyl isomerases (PEPTIDYLPROLYL ISOMERASE). They bind the immunosuppressant drugs CYCLOSPORINE; TACROLIMUS and SIROLIMUS. They possess rotamase activity, which is inhibited by the immunosuppressant drugs that bind to them.

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