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| Name | Class |
|---|---|
| Sandoz | INDUSTRY |
The study is designed to compare the pharmacokinetics of generic tacrolimus (Sandoz) to branded tacrolimus (Prograf) in stable renal transplant patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
|
| 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Generic Tacrolimus | Drug | Generic Sandoz tacrolimus supplied as capsules of 0.5 mg, 1 mg and 5 mg dose strengths. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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
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
Patients who are taking a generic tacrolimus product other than tacrolimus (generic, Sandoz).
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Cincinnati Medical Center | Cincinnati | Ohio | 45267 | United States | ||
| University of Pennsylvania Health System |
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| ID | Title | Description |
|---|---|---|
| FG000 | Sequence 1 - Branded Tacrolimus / Generic Tacrolimus | 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). |
| FG001 | Sequence 2 - Generic Tacrolimus / Branded Tacrolimus | 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 dose they had been taking prior to enrollment (on a milligram for milligram basis). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Period 1 (Days 1 through 14): Participants randomized to Sequence 1 took branded tacrolimus (Prograf) and participants randomized to Sequence 2 took generic tacrolimus (Sandoz). Period 2 (Days 15 through 28): Participants randomized to Sequence 1 crossed over to treatment with generic tacrolimus and participants randomized to Sequence 2 crossed over to treatment with branded tacrolimus. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| 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 | 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. | 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. | Posted | Geometric Mean | 95% Confidence Interval | ng*hr/mL/mg | Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing. |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Generic Tacrolimus | Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA Version 13.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | MedDRA Version 13.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 |
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| ID | Term |
|---|---|
| D016559 | Tacrolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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|
| Branded Tacrolimus | Drug | Capsules supplied at dose strengths of 0.5 mg, 1 mg, and 5 mg. |
|
|
| 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). | 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. | 28 Days |
| Number of Participants With Reported Biopsy Proven Acute Rejection Episodes | 28 Days |
| Philadelphia |
| Pennsylvania |
| 19104 |
| United States |
| Protocol deviation |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | Branded Tacrolimus | Participants received branded tacrolimus (Prograf) orally twice a day for 14 days. |
|
|
|
| Secondary | 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. | PK Analysis set. | Posted | Mean | Standard Error | percent coefficient of variation | Days 7 and 14, and Days 21 and 28. |
|
|
|
| Secondary | 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). | PK analysis set, where data were available. | Posted | Mean | Standard Deviation | ng/mL | Days 14 and 28: predose |
|
|
|
| Secondary | 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. | Safety set | Posted | Number | participants | 28 Days |
|
|
|
| Secondary | Number of Participants With Reported Biopsy Proven Acute Rejection Episodes | Full analysis set. | Posted | Number | participants | 28 Days |
|
|
|
| Primary | 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. | 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. | Posted | Geometric Mean | 95% Confidence Interval | ng/mL/mg | Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing. |
|
|
|
|
| 0 |
| 71 |
| 0 |
| 71 |
| EG001 | Branded Tacrolimus | Participants received branded tacrolimus (Prograf) orally twice a day for 14 days. | 1 | 71 | 4 | 71 |
| Headache | Nervous system disorders | MedDRA Version 13.1 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA Version 13.1 | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
| C0 |
|
| ANOVA |
| 0.057 |
ANOVA model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and subjects nested within sequences as a random factor. |
| Ratio of geometric means |
| 1.09 |
| 2-Sided |
| 90 |
| 1.01 |
| 1.18 |
| No |
| Superiority or Other |