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Kidney Transplant RecipientsPhase 4PKNCT01889758

Pharmacokinetic Studies of Tacrolimus in Transplant Patients

A Phase 4 study testing Prograf and Tacrolimus in people with Kidney Transplant Recipients and Liver Transplant Recipients, run by University of Cincinnati at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The study is designed to compare the steady-state pharmacokinetics of Prograf (Brand) and the two most disparate generic formulations (Generic Hi and Generic Lo) in a fully replicated, 3-way cross-over study in stable kidney (n=36) and liver transplant (n=36) subjects. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Prograf and Tacrolimus
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
78 participants
Where
2 sitesUnited States
Study dates
Jun 2013to Jan 2016
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥18 years old, male or female
  • Able to participate and willing to give written informed consent and to comply with the study visits and restrictions.
  • Subject who has received a primary or secondary kidney or liver transplant.
  • 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.
  • BMI greater than or equal to 19 but less than or equal to 40.
  • Ability to perform daily finger sticks to provide blood sample

Who cannot join

  • Evidence of any acute rejection
  • Subjects who require dialysis within 6 months prior to study entry
  • Recipients of multiple organ transplants
  • 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.
  • Hep C positive subjects with liver biopsy proven recurrent disease considered relevant by physician oversight.
  • Subjects with any severe medical condition requiring acute or chronic treatment that in the investigator's opinion would interfere with study participation
Show all 22Show fewer
  • 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.
  • GFR ≤ 35 ml/min measured as estimated using the MDRD4 formula
  • Subjects with aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin ≥ 3 X upper limit of normal (ULN) or other evidence of severe liver disease
  • 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)
  • Subjects with clinically significant infections, requiring therapy, which, in the investigator's opinion, would interfere with the objectives of the study
  • Other mental or physical conditions which in the investigator's opinion, are considered clinically significant
  • Presence of intractable immunosuppressant complications or side effects resulting in dose adjustment of tacrolimus
  • 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.
  • An anticipated change in the immunosuppressive regimen during subject participation other than that required by the protocol
  • Subject with severe GI disturbance or diarrhea which could interfere with tacrolimus absorption
  • Severe diabetic gastroparesis
  • Initiation of any medications that could interfere with tacrolimus blood levels, including OTC medications, herbal supplements, grapefruit or grapefruit juice.
  • 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 beta human chorionic gonadotrophin (BhCG) laboratory test (> 5 mIU/mL)
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are
  • women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner; women whose partners have been sterilized by vasectomy or
  • 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.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • The Christ Hospital

    Cincinnati, Ohio, 45267

  • University of Cincinnati

    Cincinnati, Ohio, 45267

Other trials in United States

About this study

The study is designed to compare the steady-state pharmacokinetics of Prograf (Brand) and the two most disparate generic formulations (Generic Hi and Generic Lo) in a fully replicated, 3-way cross-over study in stable kidney (n=36) and liver transplant (n=36) subjects.

Read the detailed description

To identify the most disparate tacrolimus generic drug formulations among those currently approved in the United States. 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 1mg capsule strength (3 production lots/ manufacturer). 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 and the University of Colorado. Based on these studies the two most disparate generic tacrolimus formulations (Generic Hi and Generic Lo) will be selected and compared with the Brand (PrografR, Astellas, Deerfield, IL) in the clinical trial.

This is an open label, prospective, multicenter, randomized, replicate, six-period, three-sequence cross-over study to compare the steady state pharmacokinetics of PrografR to Generic Hi to Generic Lo in stable kidney and liver transplant subjects. The PK assessor will be blinded to the assigned treatment sequence and formulation. The person analyzing the levels and analyzing the results will be blinded to formulation sequence. Each subject will be randomized to one of the three sequences where Generic Hi and Generic Lo represent the two generics and B the brand, Prograf. The blood samples will be collected at C0 (before morning dose) and then 20, 40, 60(1hr), 80, 100, 120(2hr), 140, 160, 180(3hr) minutes, 4, 5, 6, 8 and 12 hour after dosing with each formulation. Adherence will be monitored by patient diary, pill counts, and MEMS cap. Safety and efficacy parameters will be monitored weekly.

This study will be carried out in full compliance with the rules of Good Clinical Practice (GCP) including development of an electronic database and monitoring plan.

Resulting pharmacokinetic parameters will be analyzed by a variety of pharmacokinetic tests such as narrower acceptance intervals, individual and scaled average bioequivalence was well as population pharmacokinetics.

Being tested
Prograf, Tacrolimus
Keywords
bioequivalence, tacrolimus, kidney, liver, transplant

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PrografDrug

    Also called Brand

    Brand: Prograf Capsules, 1.0mg Tacrolimus capsules containing white to off white powder equivalent to 1.0 mg of anhydrous tacrolimus are hard gelatin capsules with white opaque body and ivory capsules.

  • TacrolimusDrug

    Also called Generic tacrolimus hi

    Generic Hi: Generic tacrolimus Capsules, 1.0mg. Manufacturer to be determined (Aim 1).

  • TacrolimusDrug

    Also called Generic tacrolimus lo

    Generic Lo: Generic tacrolimus Capsules, 1.0mg. Manufacturer to be determined (Aim 1).

Study groups in NCT01889758
Study groupRoleWhat they receive
Sequence 1Active comparatorTacrolimus Hi for 1 week with full PK on Day 7, then tacrolimus Lo for 1 week with full PK on Day 14, then Prograf for 1 week with full PK on Day 21, then tacrolimus Hi with full PK on Day 28, then Prograf for 1 week with full PK on Day 35, and then tacrolimus Lo for 1 week with full PK on Day 42
Receives: Drug: Prograf; Drug: Tacrolimus
Sequence 2Active comparatorTacrolimus Lo for 1 week with full PK on Day 7, then Prograf for 1 week with full PK on Day 14, then tacrolimus Hi for 1 week with full PK on Day 21, then tacrolimus Lo with full PK on Day 28, then tacrolimus Hi for 1 week with full PK on Day 35, and then Prograf for 1 week with full PK on Day 42
Receives: Drug: Prograf; Drug: Tacrolimus
Sequence 3Active comparatorPrograf for 1 week with full PK on Day 7, then tacrolimus Hi for 1 week with full PK on Day 14, then tacrolimus Lo for 1 week with full PK on Day 21, then Prograf with full PK on Day 28, then tacrolimus Lo for 1 week with full PK on Day 35, and then tacrolimus Hi for 1 week with full PK on Day 42
Receives: Drug: Prograf; Drug: Tacrolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Comparison of bioequivalence between brand name prograf to generic Hi tacrolimus in all participants

    Ratio of C0, C12, AUC0-12h and Cmax and apply confidence interval (CI) testing at steady state of Prograf to generic Hi in stable kidney and liver transplant subjects

    Measured: Day 7, 14, 21, 28, 35, 42

  2. Comparison of bioequivalence between brand name prograf to generic Lo tacrolimus in all participants

    Ratio of C0, C12, AUC0-12h and Cmax and apply confidence interval (CI) testing at steady state of Prograf to Generic Lo in stable kidney and liver transplant subjects.

    Measured: Day 7, 14, 21, 28, 35, 42

  3. Comparison of bioequivalence between generic Hi tacrolimus to generic Lo tacrolimus in all participants

    Ratio of C0, C12, AUC0-12h and Cmax and apply confidence interval (CI) testing at steady state of Generic Hi to Generic Lo in stable kidney and liver transplant subjects.

    Measured: Day 7, 14, 21, 28, 35, 42

Secondary outcomes (5)

  1. Comparing the bioavailability of each tacrolimus formulations in stable kidney and liver transplant subjects using the dose-normalized C0, C12, AUC0-12h and Cmax data

    Measured: Day 7, 14, 21, 28, 35, 42

  2. Evaluating intra-patient variability of tacrolimus pharmacokinetics of each formulation by comparing C0, C12, AUC0-12h, and Cmax

    Measured: Day 7, 14, 21, 28, 35, 42

  3. Evaluating and comparing the pharmacokinetics of tacrolimus metabolites in terms of C0, C12, AUC0-12h, Cmax and intra-individual variability

    Measured: Day 7, 14, 21, 28, 35, 42

  4. Comparing the safety of Prograf, Generic Hi and Generic Lo in stable kidney and liver transplant subjects

    This is a pharmacokinetic comparison study, but safety data will be collected via adverse and serious adverse event reporting as these are the standard efficacy parameters in transplant studies.

    Measured: Day 7, 14, 21, 28, 35, 42

  5. Comparing the efficacy of Prograf, Generic Hi and Generic Lo in stable kidney and liver transplant subjects

    This is a pharmacokinetic comparison study, but efficacy will be measured by kidney/liver function or biopsy-proven acute rejection or graft loss.

    Measured: Day 7, 14, 21, 28, 35, 42

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jun 2013 (estimated)
  2. Study startJun 2013
  3. Primary completionJan 2016
  4. Study completionJan 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
78 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01889758
Sponsor's protocol ID
U01 Grant
Other IDs
FDA UO1 Grant
Acronym
PK
Status last verified
Feb 2016
First submitted
21 Jun 2013
Last updated
22 Feb 2016
Results posted
No
Data monitoring committee
No

Publications

  • Alloway RR, Vinks AA, Fukuda T, Mizuno T, King EC, Zou Y, Jiang W, Woodle ES, Tremblay S, Klawitter J, Klawitter J, Christians U. Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial. PLoS Med. 2017 Nov 14;14(11):e1002428. doi: 10.1371/journal.pmed.1002428. eCollection 2017 Nov.

    PubMed 29135993

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Prograf and Tacrolimus in people with Kidney Transplant Recipients and Liver Transplant Recipients, run by University of Cincinnati at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Comparison of bioequivalence between brand name prograf to generic Hi tacrolimus in all participants (time frame: Day 7, 14, 21, 28, 35, 42). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01889758, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Feb 2016.

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