Conversion From Brand to Generic Tacrolimus in High Risk... | NCT02014103

NCT02014103

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
FDA	Other Grant/Funding Number	HHSF223201310224C

Status Module

Name	Class
University of Colorado, Denver	OTHER
Children's Hospital Medical Center, Cincinnati	OTHER

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Sequence 1	Active Comparator	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.	Drug: Prograf Drug: Tacrolimus, Sandoz Drug: Tacrolimus, Reddy Laboratory Drug: Tacrolimus, Mylan Drug: Tacrolimus, Accord Drug: Tacrolimus, Pancea Biotech Limited
Sequence 2	Active Comparator	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.	Drug: Prograf Drug: Tacrolimus, Sandoz Drug: Tacrolimus, Reddy Laboratory Drug: Tacrolimus, Mylan Drug: Tacrolimus, Accord Drug: Tacrolimus, Pancea Biotech Limited
Sequence 3	Active Comparator	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.	Drug: Prograf Drug: Tacrolimus, Sandoz Drug: Tacrolimus, Reddy Laboratory Drug: Tacrolimus, Mylan Drug: Tacrolimus, Accord Drug: Tacrolimus, Pancea Biotech Limited
Sequence 4

Name	Type	Description	Arm Group Labels	Other Names
Prograf	Drug	Administration of each formulation will be determined by sequence.	Sequence 1 Sequence 2 Sequence 3 Sequence 4

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Compare AUC 0-12hr of Each Tacrolimus Formulation in Expressor and Non Expressor Transplant Recipients	Report the geometric mean and 95% confidence interval for AUC 0-12hr (ng*hr/ml) for each formulation in expressor and non expressor transplant recipients	Whole blood samples were collected immediately prior to dosing, at 1, 1.5, 1.75, 2, 2.5, 3 and 4 hours following dosing. Subjects were then instructed to performed fingersticks using dried blood spot cards at 8 and 12 hours post dose.
Compare Cmax of Each Tacrolimus Formulation in Expressor and Non Expressor Transplant Recipients	Report the geometric mean and 95% confidence interval for Cmax (ng/ml) for each formulation in expressor and non expressor transplant recipients	Whole blood samples were collected immediately prior to dosing, at 1, 1.5, 1.75, 2, 2.5, 3 and 4 hours following dosing. Subjects were then instructed to performed fingersticks using dried blood spot cards at 8 and 12 hours post dose.

Secondary Outcomes

Measure	Description	Time Frame
To Compare the Safety and Efficacy of Each Tacrolimus Formulation in Stable Transplant Subjects	Conduct safety lab testing specific to transplanted organ function and clinical assessments for adverse events.	Assessed at baseline and weekly for 6 weeks at each pharmacokinetic profile

Eligibility Module

Eligibility Criteria

Inclusion criteria

18 years or older
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.
Subject who has received a primary or secondary 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 less than or equal to 40.

Exclusion criteria

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.
HepC 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
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 AST, ALT, total bilirubin ≥ 3 X 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 BhCG laboratory test (> 5 mIU/mL)
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.

Name	Affiliation	Role
Rita R Alloway, PharmD	University of Cincinnati	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of Cincinnati Medical Center		Cincinnati	Ohio	45267	United States

ID	Title	Description
FG000	Expressors	Subjects with at least one *1 allele of CYP3A5
FG001	Non-expressors	Subjects homozygous for the *3 CYP3A5 allele

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG00035 subjects FG00136 subjects
Did Receive Allocated Intervention	One patient did not receive intervention due to elevated SrCr at baseline	FG00034 subjectsOne patient did not receive intervention due to elevated SrCr at baseline FG00136 subjects
Discontinued Intervention		FG0006 subjects6 interventions were discontinued. 5 due to protocol defined medication non adherence and one due to lack of venous access FG0015 subjects5 discontinued intervention Patient unable to complete PK due to personal reasons (2), tacrolimus dose adjustment required during PK (2), and protocol defined nonadherence (1)
Number Subjects Receiving Accord	Subjects were randomized to a sequence of formulation administration for each period. Subjects were withdrawn or dropped out at various periods of the study. The subjects who received identified formulation during the study period of participation are counted.	FG00034 subjects FG00134 subjects
Number Subjects Receiving Astellas	Subjects were randomized to a sequence of formulation administration for each period. Subjects were withdrawn or dropped out at various periods of the study. The subjects who received identified formulation during the study period of participation are counted.	FG00032 subjects FG00133 subjects
Number Subjects Receiving Dr. Reddy	Subjects were randomized to a sequence of formulation administration for each period. Subjects were withdrawn or dropped out at various periods of the study. The subjects who received identified formulation during the study period of participation are counted.	FG00034 subjects FG00133 subjects
Number Subjects Receiving Mylan	Subjects were randomized to a sequence of formulation administration for each period. Subjects were withdrawn or dropped out at various periods of the study. The subjects who received identified formulation during the study period of participation are counted.	FG00032 subjects FG00134 subjects
Number Subjects Receiving Panacea	Subjects were randomized to a sequence of formulation administration for each period. Subjects were withdrawn or dropped out at various periods of the study. The subjects who received identified formulation during the study period of participation are counted.	FG00033 subjects FG00133 subjects
Number Subjects Receiving Sandoz	Subjects were randomized to a sequence of formulation administration for each period. Subjects were withdrawn or dropped out at various periods of the study. The subjects who received identified formulation during the study period of participation are counted.	FG00034 subjects FG00132 subjects
Excluded From Analysis		FG0002 subjectsTwo were excluded from analysis for nonadherence within 48hr of PK visit FG0014 subjects4 were excluded from analysis. One dure to nonadherence within 48hour of PK visit and 3 due to drug interactions during study period
COMPLETED		FG00026 subjects FG00127 subjects
NOT COMPLETED		FG0009 subjects FG0019 subjects

Type	Comment	Reasons
Protocol Violation		FG0007 subjects FG0017 subjects
Adverse Event		FG0001 subjects FG001

ID	Title	Description
BG000	Expressors	Subjects with at least one *1 allele of CYP3A5
BG001	Non-expressors	Subjects homozygous for the *3 CYP3A5 allele

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Compare AUC 0-12hr of Each Tacrolimus Formulation in Expressor and Non Expressor Transplant Recipients

Report the geometric mean and 95% confidence interval for AUC 0-12hr (ng*hr/ml) for each formulation in expressor and non expressor transplant recipients

Posted

Mean

95% Confidence Interval

ng*hr/ml

Whole blood samples were collected immediately prior to dosing, at 1, 1.5, 1.75, 2, 2.5, 3 and 4 hours following dosing. Subjects were then instructed to performed fingersticks using dried blood spot cards at 8 and 12 hours post dose.

ID	Title	Description
OG000	Expressors	Subjects with at least one *1 allele of CYP3A5
OG001	Non-expressors	Subjects homozygous for the *3 CYP3A5 allele

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Accord	Subjects receiving the Accord formulation	0

ID	Term
D018942	Macrolides
D007783	Lactones
D009930	Organic Chemicals