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Conversion From Brand to Generic Tacrolimus in High Risk Transplant Recipients

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ClinicalTrials.gov Identifier: NCT02014103
Recruitment Status : Completed
First Posted : December 18, 2013
Last Update Posted : March 14, 2016
Sponsor:
Collaborators:
University of Colorado, Denver
Children's Hospital Medical Center, Cincinnati
Information provided by (Responsible Party):
Rita Alloway, University of Cincinnati

Brief Summary:

Conduct a retrospective study to evaluate the impact of generic conversion in adult transplant recipients on post transplant outcomes one year prior to conversion to one year post conversion. Variables for analysis will include but not limited to incidence of rejection, hospital admission, changes in renal function, changes in transplanted organ function. All tacrolimus levels and dose changes during this period will be collected and compared. Additional pharmacokinetic modeling of this data will be performed for comparison.

The prospective study will compare othe 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.


Condition or disease Intervention/treatment Phase
Complication of Transplant Drug: Tacrolimus Phase 4

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Detailed Description:

Primary hypothesis:

- Generic immunosuppressants for which bioequivalence were established in single-dose healthy volunteer studies are also bioequivalent to the brand in stable transplant patients that are considered high-risk such as CYP3A expressors, AA, and diabetics patients under steady-state conditions and there will be no difference in intra-subject variability.

Secondary hypotheses:

  • Generic immunosuppressants will be bioequivalent among each other in transplant patients independent of the type of risk (CYP3A5 expression, race, diabetes, age or a combination hereof).
  • All generic immunosuppressants and the brand will be bioequivalent to each other as confirmed in in vitro dissolution studies.
  • Tacrolimus metabolism and clearance will not be affected by the formulation.
  • Alternative bioequivalence metrics such as using narrower acceptance intervals and a population pharmacokinetic approach will confirm bioequivalence among the brand and the six generics in the aforementioned high-risk transplant patient populations.

To test these hypotheses, we propose the following four Aims:

AIM 1: Using a retrospective cohort design, we will evaluate the clinical and safety outcomes among adult transplant recipients whose tacrolimus dosage was converted from Prograf® to a generic formulation.

In a retrospective review, evaluate the impact of generic conversion in adult transplant recipients on post transplant outcomes one year prior to conversion to one year post conversion. Variables for analysis will include but not limited to incidence of rejection, hospital admission, changes in renal function, changes in transplanted organ function. All tacrolimus levels and dose changes during this period will be collected and compared. Additional pharmacokinetic modeling of this data will be performed for comparison.

Aim 2: Identification of a single lot with the longest expiration date from each unique manufactured product approved in the United States and conduct systematic dissolution, content uniformity and purity testing on all tacrolimus product.

We will conduct systematic dissolution testing of the brand and all currently approved tacrolimus drug formulations using the FDA-recommended dissolution method. We propose to test and compare the 1 mg capsule strength. In addition, we will compare the different formulations in terms of potency, purity and other quality attributes. This work will be carried out in the GMP-compliant facilities of The University of Iowa Pharmaceuticals (uip.pharmacy.uiowa.edu) and at the University of Colorado (iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado, Laboratory Director: U. Christians). Based on these studies, if all lots pass current USP standards, we will proceed to the clinical trial described in Aim 3.

Aim 3: 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. The daily monitoring of levels will allow us to specifically address whether the need of additional monitoring upon formulation conversion is necessary. 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, CABioequivalence will be tested using scaled average bioequivalence metrics and analysis of variance as appropriate and intra-individual variability of the formulations will be compared. This will also include the analysis of potential period and sequence effects. 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. In addition, the same study will be conducted in 36 pediatric patients.

Aim 4. Subgroup analysis, population pharmacokinetics, and average bioequivalence Aim 4 is an exploratory aim in which we will (A) address the concern that bioequivalence in the "general" patient population will not translate to special subgroups such as high risk transplant recipients as characterized by genotype, race, age, gender, sensitization (repeat transplant or cytotoxic PRA >35% or calculated PRA >50%), presence of concomitant steroids, presence of diabetes. and (B) test alternative bioequivalence metrics that have been proposed for the analysis for immunosuppressant generics such as narrower acceptance intervals, average bioequivalence was well as population pharmacokinetics.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of Clinical and Safety Outcomes Associated With Conversion From Brand-Name to Generic Tacrolimus Products in High Risk Transplant Recipients
Study Start Date : March 2015
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

Arm Intervention/treatment
Sequence 1
Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation 3, 5, 6, 4, 2, 1.
Drug: Tacrolimus
Administration of each formulation will be determined by sequence.
Other Name: Prograf

Sequence 2
Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation 3, 4, 6, 5, 1, 2.
Drug: Tacrolimus
Administration of each formulation will be determined by sequence.
Other Name: Prograf

Sequence 3
Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation 4, 3, 5, 1, 6, 2.
Drug: Tacrolimus
Administration of each formulation will be determined by sequence.
Other Name: Prograf




Primary Outcome Measures :
  1. Compare pharmacokinetic parameters of each tacrolimus formulation in transplant recipients [ Time Frame: December 2014 (up to one year) ]
    To estimate the ratio of C0, C12, AUC0-12h and Cmax and apply CI testing at steady state between all tacrolimus formulation combinations in transplant subjects.


Secondary Outcome Measures :
  1. To compare the safety and efficacy of each tacrolimus formulation in stable transplant subjects [ Time Frame: December 2014 (up to one year) ]
    Conduct safety lab testing specific to transplanted organ function and clinical assessments for adverse events.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT02014103


Locations
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United States, Ohio
University of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45267
Sponsors and Collaborators
University of Cincinnati
University of Colorado, Denver
Children's Hospital Medical Center, Cincinnati
Investigators
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Principal Investigator: Rita R Alloway, PharmD University of Cincinnati

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Responsible Party: Rita Alloway, Research Professor, University of Cincinnati
ClinicalTrials.gov Identifier: NCT02014103     History of Changes
Other Study ID Numbers: 13-223-SOL-00102
FDA ( Other Grant/Funding Number: HHSF223201310224C )
First Posted: December 18, 2013    Key Record Dates
Last Update Posted: March 14, 2016
Last Verified: March 2016
Keywords provided by Rita Alloway, University of Cincinnati:
bioequivalence
tacrolimus
transplant
CYP3A5 expressors/non expressors
Additional relevant MeSH terms:
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Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action