Renal TransplantPhase 4NCT01256294

Pharmacokinetics of Generic to Brand Tacrolimus in Stable Renal Transplant Patients

A Phase 4 study testing Generic Tacrolimus and Branded Tacrolimus in people with Renal Transplant, run by Novartis 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 pharmacokinetics of generic tacrolimus (Sandoz) to branded tacrolimus (Prograf) in stable renal transplant patients. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Renal Transplant
What is being tested?: Generic Tacrolimus and Branded Tacrolimus
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 71 participants
Where: 2 sitesUnited States
Study dates: Oct 2010to May 2011
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

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

Able to participate and willing to give written informed consent and to comply with the study visits and restrictions.
Patient who has received a primary or secondary kidney transplant
Patient 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.
Body mass index (BMI) greater than or equal to 19 but less than or equal to 35
Patients who are taking tacrolimus (generic, Sandoz) or Prograf

Who cannot join

Evidence of any acute rejection
Patients who require dialysis within 6 months prior to study entry
Recipients of antibodies blood group (ABO) incompatible allograft or positive crossmatch
Recipients of multiple organ transplants
Patients who have tested positive for hepatitis B surface antigen (HBsAG) or human immunodeficiency virus (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 was acceptable unless more recent tests were available.
History of malignancy, treated or untreated, within the past 2 years with the exception of carcinoma in situ or excised basal cell carcinoma

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Glomerular filtration rate ≤35 ml/min measured by modification of diet in renal disease (MDRD4)
No anticipated change in the immunosuppressive regimen during patient participation other than that required by the protocol
Initiation of any medications that could interfere with tacrolimus blood levels, including over the counter 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 human chorionic gonadotropin (hCG) 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 other means
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.
Patients who are taking a generic tacrolimus product other than tacrolimus (generic, Sandoz).

Trial locations and contacts

2 sites in 1 country.

United States2 sites

University of Cincinnati Medical Center
Cincinnati, Ohio, 45267
University of Pennsylvania Health System
Philadelphia, Pennsylvania, 19104

Other trials in United States

About this study

Official title: A Prospective, Multi-center, Open-label, Randomized, Two Period, Two Sequence, Crossover Study to Compare the Steady State Pharmacokinetics of Generic Tacrolimus (Sandoz) to Prograf in Stable Renal Transplant Patients

The study is designed to compare the pharmacokinetics of generic tacrolimus (Sandoz) to branded tacrolimus (Prograf) in stable renal transplant patients.

Conditions: Renal Transplant
Being tested: Generic Tacrolimus, Branded Tacrolimus
Keywords: Renal transplant, kidney transplant, immunosuppressive therapy, anti-rejection medication, pharmacokinetics, tacrolimus

What participants receive

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

Generic TacrolimusDrug
Also called Sandoz
Generic Sandoz tacrolimus supplied as capsules of 0.5 mg, 1 mg and 5 mg dose strengths.
Branded TacrolimusDrug
Also called Prograf
Capsules supplied at dose strengths of 0.5 mg, 1 mg, and 5 mg.

Study groups in NCT01256294
Study group	Role	What they receive
Sequence 1 - Branded Tacrolimus / Generic Tacrolimus	Experimental	In Period 1 (Days 1-14) participants received branded tacrolimus (Prograf) orally twice a day and in Period 2 (Days 15 - 28) participants received generic tacrolimus (Sandoz) orally twice a day. Participants received the same stable dosage of tacrolimus they had been taking prior to enrollment (on a milligram for milligram basis). Receives: Drug: Generic Tacrolimus; Drug: Branded Tacrolimus
Sequence 2 - Generic Tacrolimus / Branded Tacrolimus	Active comparator	In Period 1 (Days 1 - 14) participants received generic tacrolimus (Sandoz) orally twice a day and in Period 2 (Days 15 - 28) participants received branded tacrolimus (Prograf) orally twice a day. Participants received the same stable dosage of tacrolimus they had been taking prior to enrollment (on a milligram for milligram basis). Receives: Drug: Generic Tacrolimus; Drug: Branded Tacrolimus

What is being measured

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

Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State
Dose-normalized area under the concentration-time curve from time 0 to 12 hours (AUC0-12h) at steady state after 14 days of treatment with each study drug.
Geometric mean and 95% confidence intervals were determined from an analysis of variance (ANOVA) model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and patients nested within sequences as a random factor.
Measured: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.
Dose-normalized Maximum Plasma Drug Concentration (Cmax) at Steady State
Maximum (peak) plasma drug concentration after drug administration at steady state (after 14 days of treatment with each study drug). Geometric mean and 95% confidence intervals were determined from an analysis of variance (ANOVA) model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and patients nested within sequences as a random factor.
Measured: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.

Secondary outcomes (4)

Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters
The intra-patient variability of tacrolimus pharmacokinetics of each formulation was evaluated by comparing AUC0-12h, maximum drug concentration (Cmax) and trough drug concentration (C0) at Days 7 and 14, and Days 21 and 28. Intra-patient variability was assessed by a calculation of the coefficient of variation, by patient, using the repeated measurements within each Period, where the coefficient of variation (%) = standard deviation/mean*100.
Measured: Days 7 and 14, and Days 21 and 28.
Trough Plasma Drug Concentration (C0) at Steady State
Trough plasma drug concentration measured prior to drug administration at steady state (after 14 days of treatment with each study drug).
Measured: Days 14 and 28: predose
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
An AE was defined as the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event was not considered to be related to study drug. An SAE was an event which: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; required or prolonged inpatient hospitalization; was medically significant, i.e., an event that jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above.
Measured: 28 Days
Number of Participants With Reported Biopsy Proven Acute Rejection Episodes
Measured: 28 Days

Timeline

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

Oct 2010May 2011

First posted8 Dec 2010 (estimated)
Study startOct 2010
Primary completionMay 2011
Study completionMay 2011

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Renal TransplantStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

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: 71 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01256294
Sponsor's protocol ID: CERL080AUS90
Status last verified: May 2012
First submitted: 1 Nov 2010
Last updated: 21 Jun 2012
Results posted: Yes, on ClinicalTrials.gov

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Non-Invasive Monitoring of Pediatric Kidney Transplant Recipients and Immunosuppression Personalization: an Open-labeled Multicenter Randomized Controlled Study
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All Renal Transplant trials

Study at a glance

From the registry record, last updated by the sponsor on 21 Jun 2012. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Prospective, Multi-center, Open-label, Randomized, Two Period, Two Sequence, Crossover Study to Compare the Steady State Pharmacokinetics of Generic Tacrolimus (Sandoz) to Prograf in Stable Renal Transplant Patients
ClinicalTrials.gov ID: NCT01256294
Acronym / sponsor ID: CERL080AUS90
Conditions: Renal Transplant
Keywords: Renal transplant, kidney transplant, immunosuppressive therapy, anti-rejection medication, pharmacokinetics, tacrolimus
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 71 participants (actual)
Lead sponsor: NovartisIndustry (pharma, biotech, devices)
Collaborators: Sandoz
Study start: Oct 2010
Primary completion: May 2011 (actual)
Study completion: May 2011 (actual)
First posted: 8 Dec 2010 (estimated)
Results: Posted 21 Jun 2012

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The study is designed to compare the pharmacokinetics of generic tacrolimus (Sandoz) to branded tacrolimus (Prograf) in stable renal transplant patients.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Sequence 1 - Branded Tacrolimus / Generic Tacrolimus	Experimental	Drug: Generic Tacrolimus, Drug: Branded TacrolimusIn Period 1 (Days 1-14) participants received branded tacrolimus (Prograf) orally twice a day and in Period 2 (Days 15 - 28) participants received generic tacrolimus (Sandoz) orally twice a day. Participants received the same stable dosage of tacrolimus they had been taking prior to enrollment (on a milligram for milligram basis).
Sequence 2 - Generic Tacrolimus / Branded Tacrolimus	Active comparator	Drug: Generic Tacrolimus, Drug: Branded TacrolimusIn Period 1 (Days 1 - 14) participants received generic tacrolimus (Sandoz) orally twice a day and in Period 2 (Days 15 - 28) participants received branded tacrolimus (Prograf) orally twice a day. Participants received the same stable dosage of tacrolimus they had been taking prior to enrollment (on a milligram for milligram basis).

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

Able to participate and willing to give written informed consent and to comply with the study visits and restrictions.
Patient who has received a primary or secondary kidney transplant
Patient 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.
Body mass index (BMI) greater than or equal to 19 but less than or equal to 35
Patients who are taking tacrolimus (generic, Sandoz) or Prograf

Key exclusion criteria (15 listed)

Evidence of any acute rejection
Patients who require dialysis within 6 months prior to study entry
Recipients of antibodies blood group (ABO) incompatible allograft or positive crossmatch
Recipients of multiple organ transplants
Patients who have tested positive for hepatitis B surface antigen (HBsAG) or human immunodeficiency virus (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 was acceptable unless more recent tests were available.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Generic TacrolimusAlso: SandozGeneric Sandoz tacrolimus supplied as capsules of 0.5 mg, 1 mg and 5 mg dose strengths.	Drug	Sequence 1 - Branded Tacrolimus / Generic Tacrolimus, Sequence 2 - Generic Tacrolimus / Branded Tacrolimus
Branded TacrolimusAlso: PrografCapsules supplied at dose strengths of 0.5 mg, 1 mg, and 5 mg.	Drug	Sequence 1 - Branded Tacrolimus / Generic Tacrolimus, Sequence 2 - Generic Tacrolimus / Branded Tacrolimus

Primary outcome

Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State
Time frame: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.
Dose-normalized area under the concentration-time curve from time 0 to 12 hours (AUC0-12h) at steady state after 14 days of treatment with each study drug. Geometric mean and 95% confidence intervals were determined from an analysis of variance (ANOVA) model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and patients nested within sequences as a random factor.
Dose-normalized Maximum Plasma Drug Concentration (Cmax) at Steady State
Time frame: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.
Maximum (peak) plasma drug concentration after drug administration at steady state (after 14 days of treatment with each study drug). Geometric mean and 95% confidence intervals were determined from an analysis of variance (ANOVA) model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and patients nested within sequences as a random factor.

4 secondary outcomes

Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters
Time frame: Days 7 and 14, and Days 21 and 28.
Trough Plasma Drug Concentration (C0) at Steady State
Time frame: Days 14 and 28: predose
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Time frame: 28 Days
Number of Participants With Reported Biopsy Proven Acute Rejection Episodes
Time frame: 28 Days

Results and safety

Results posted to the registry on 21 Jun 2012, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Sequence 1 - Branded Tacrolimus / Generic Tacrolimus	36	32
Sequence 2 - Generic Tacrolimus / Branded Tacrolimus	35	33

Primary outcome: Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State

Time frame: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.. Geometric mean (95% Confidence Interval). Unit: ng*hr/mL/mg

Measure	Generic Tacrolimus n = 65	Branded Tacrolimus n = 66
Value	51.73 (44.67 to 59.90)	50.58 (43.68 to 58.57)

Generic Tacrolimus vs Branded Tacrolimus: Ratio of geometric means: 1.02 (95% CI 0.96 to 1.09)
Generic Tacrolimus vs Branded Tacrolimus: Ratio of geometric means: 1.02 (90% CI 0.97 to 1.08), p = 0.486, ANOVA

Population analysed: Pharmacokinetic (PK) analysis set included the subset of patients from the Full Analysis Set (all patients to whom study medication had been assigned) with evaluable PK data.

Primary outcome: Dose-normalized Maximum Plasma Drug Concentration (Cmax) at Steady State

Time frame: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.. Geometric mean (95% Confidence Interval). Unit: ng/mL/mg

Measure	Generic Tacrolimus n = 65	Branded Tacrolimus n = 66
Value	8.34 (7.24 to 9.61)	7.62 (6.61 to 8.78)

Generic Tacrolimus vs Branded Tacrolimus: Ratio of geometric means: 1.09 (95% CI 1.00 to 1.20)
Generic Tacrolimus vs Branded Tacrolimus: Ratio of geometric means: 1.09 (90% CI 1.01 to 1.18), p = 0.057, ANOVA

Population analysed: Pharmacokinetic (PK) analysis set included the subset of patients from the Full Analysis Set (all patients to whom study medication had been assigned) with evaluable PK data.

4 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Generic Tacrolimus	0 of 71 (0%)	0 of 71 (0%)	Not reported
Branded Tacrolimus	1 of 71 (1.4%)	4 of 71 (5.6%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 21 Jun 2012.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.

Related trials for Renal Transplant

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Novartis Pharmaceuticals study director

Novartis Pharmaceuticals

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Generic Tacrolimus and Branded Tacrolimus in people with Renal Transplant, run by Novartis 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 5 inclusion and 15 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 21 Jun 2012. 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?

Yes. Results are posted in the registry (first posted 21 Jun 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State (time frame: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.). The study lists 2 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 NCT01256294.

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 21 Jun 2012.