Conversion From Brand to Generic Tacrolimus in High Risk Transplant Recipients

NCT ID: NCT02014103

Last Updated: 2024-10-15

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

71 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-03-31

Study Completion Date

2015-08-31

Brief Summary

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The prospective study will compare the relative bioavailability at steady-state pharmacokinetics of 6 tacrolimus formulations in a prospective, 6-way cross-over study including CYP3A5 expressors (n=30) and non-expressor (n=30) transplant patients.

Detailed Description

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Comparison of the relative bioavailability and steady-state pharmacokinetics of 6 tacrolimus formulations in a prospective, 6-way cross-over study including CYP3A5 expressors (n=30) and non-expressor (n=30) transplant patients. Six tacrolimus formulations will be tested and each patient will receive each formulation once. As we proposed to test bioequivalence in the steady-state, patients will receive the test formulations for one week prior to pharmacokinetic evaluation. The pharmacokinetic evaluation will incorporate limited sampling strategies with a focus on fully characterizing the Cmax out to hour 4 post dose. Subsequent PK sampling and trough blood concentrations will be monitored on a daily basis using dried blood spots that the study subjects will collect by themselves at home. It will be critical that the patients are adherent to their test medication to ensure that they have reached steady state. This will be monitored using test diaries, pill counts and MEMS caps (Medication Event Monitoring System (MEMS), AARDEX Corp, Palo Alto, CA. Bioequivalence will be tested using average bioequivalence metrics. A combination of limited sampling strategy and dry spot analysis in combination with population pharmacokinetic modeling will be utilized to fully characterize the PK profile of these formulations.

Conditions

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Complication of Transplant

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Sequence 1

Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation Sandoz, Panacea, Accord, Mylan, Dr. Reddy's, Astellas

Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.

Group Type ACTIVE_COMPARATOR

Prograf

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Sandoz

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Reddy Laboratory

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Mylan

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Accord

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Pancea Biotech Limited

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Sequence 2

Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation Accord, Sandoz, Dr. Reddy's, Panacea, Astellas, Mylan

Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.

Group Type ACTIVE_COMPARATOR

Prograf

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Sandoz

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Reddy Laboratory

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Mylan

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Accord

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Pancea Biotech Limited

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Sequence 3

Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation Dr. Reddys, Accord, Astellas, Sandoz, Mylan, Panacea

Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.

Group Type ACTIVE_COMPARATOR

Prograf

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Sandoz

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Reddy Laboratory

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Mylan

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Accord

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Pancea Biotech Limited

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Sequence 4

Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 4: Formulation Astellas, Dr. Reddy's, Mylan, Accord, Panacea, Sandoz

Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.

Group Type ACTIVE_COMPARATOR

Prograf

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Sandoz

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Reddy Laboratory

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Mylan

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Accord

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Pancea Biotech Limited

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Sequence 5

Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 5: Formulation Mylan, Astellas, Panacea, Dr. Reddy's, Sandoz, Accord

Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.

Group Type ACTIVE_COMPARATOR

Prograf

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Sandoz

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Reddy Laboratory

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Mylan

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Accord

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Pancea Biotech Limited

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Sequence 6

Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 6: Formulation Panacea, Mylan, Sandoz, Astellas, Accord, Dr. Reddy's

Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.

Group Type ACTIVE_COMPARATOR

Prograf

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Sandoz

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Reddy Laboratory

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Mylan

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Accord

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Tacrolimus, Pancea Biotech Limited

Intervention Type DRUG

Administration of each formulation will be determined by sequence.

Interventions

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Prograf

Administration of each formulation will be determined by sequence.

Intervention Type DRUG

Tacrolimus, Sandoz

Administration of each formulation will be determined by sequence.

Intervention Type DRUG

Tacrolimus, Reddy Laboratory

Administration of each formulation will be determined by sequence.

Intervention Type DRUG

Tacrolimus, Mylan

Administration of each formulation will be determined by sequence.

Intervention Type DRUG

Tacrolimus, Accord

Administration of each formulation will be determined by sequence.

Intervention Type DRUG

Tacrolimus, Pancea Biotech Limited

Administration of each formulation will be determined by sequence.

Intervention Type DRUG

Other Intervention Names

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Sandoz tacrolimus Reddy's Laboratory tacrolimus Mylan tacrolimus Accord Healthcare tacrolimus Panacea Biotech Limited tacrolimus

Eligibility Criteria

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Inclusion Criteria

1. 18 years or older
2. Able to participate and willing to give written informed consent/ assent/ consent by parent or legal guardian and to comply with the study visits and restrictions.
3. Subject who has received a primary or secondary transplant.
4. Subject who is at least 6 months post-transplant and on a stable dose of tacrolimus as defined by physician, one tacrolimus trough level within the physician defined target range within past 6 months and one additional trough level during the screening period within 30% of the physician defined target range.
5. BMI less than or equal to 40.

Exclusion Criteria

1. Evidence of any acute rejection
2. Subjects who require dialysis within 6 months prior to study entry
3. Recipients of multiple organ transplants
4. Subjects who have tested positive for HBsAG or HIV, or who are recipients of organ from donors who are known to be HBsAG or HIV positive. Virology screening at the time of transplant.
5. HepC positive subjects with liver biopsy proven recurrent disease considered relevant by physician oversight.
6. Subjects with any severe medical condition requiring acute or chronic treatment that in the investigator's opinion would interfere with study participation
7. History of malignancy, treated or untreated, with the past 2 years with the exception of carcinoma in situ or excised basal cell carcinoma, or hepatocellular carcinoma prior to transplant.
8. GFR ≤ 35 ml/min measured as estimated using the MDRD4 formula
9. Subjects with AST, ALT, total bilirubin ≥ 3 X ULN or other evidence of severe liver disease
10. Subjects with white blood cell (WBC) count ≤2,000/ mm3 or with thrombocytopenia (platelet count ≤ 75,000/ mm3), with an absolute neutrophil count of ≤ 1,500/ mm3 or hemoglobin \<8g/dL)
11. Subjects with clinically significant infections, requiring therapy, which, in the investigator's opinion, would interfere with the objectives of the study
12. Other mental or physical conditions which in the investigator's opinion, are considered clinically significant
13. Presence of intractable immunosuppressant complications or side effects resulting in dose adjustment of tacrolimus
14. Subjects who have been exposed to an investigational therapy within 30 days prior to enrollment or 5 half-lives of the investigational product, whichever is greater.
15. An anticipated change in the immunosuppressive regimen during subject participation other than that required by the protocol
16. Subject with severe GI disturbance or diarrhea which could interfere with tacrolimus absorption
17. Severe diabetic gastroparesis
18. Initiation of any medications that could interfere with tacrolimus blood levels, including OTC medications, herbal supplements, grapefruit or grapefruit juice.
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive BhCG laboratory test (\> 5 mIU/mL)
20. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are: 1) women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner; 2)women whose partners have been sterilized by vasectomy or 3)using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices (IUDs); periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Colorado, Denver

OTHER

Sponsor Role collaborator

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role collaborator

University of Cincinnati

OTHER

Sponsor Role lead

Responsible Party

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Rita Alloway

Research Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Rita R Alloway, PharmD

Role: PRINCIPAL_INVESTIGATOR

University of Cincinnati

Locations

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University of Cincinnati Medical Center

Cincinnati, Ohio, United States

Site Status

Countries

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United States

Other Identifiers

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FDA

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

13-223-SOL-00102

Identifier Type: -

Identifier Source: org_study_id

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