Trial Outcomes & Findings for Pharmacokinetics of Generic to Brand Tacrolimus in Stable Renal Transplant Patients (NCT NCT01256294)

NCT ID: NCT01256294

Last Updated: 2012-06-21

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 71 participants
• Primary outcome timeframe: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.
• Results posted on: 2012-06-21

Participant Flow

Participant milestones

Measure	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).	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).
Overall Study STARTED	36	35
Overall Study COMPLETED	32	33
Overall Study NOT COMPLETED	4	2

Reasons for withdrawal

Measure	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).	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).
Overall Study Adverse Event	1	0
Overall Study Withdrawal by Subject	1	1
Overall Study Protocol deviation	2	1

Baseline Characteristics

Pharmacokinetics of Generic to Brand Tacrolimus in Stable Renal Transplant Patients

Baseline characteristics by cohort

Measure	All Participants n=71 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.
Age Continuous	52.1 years STANDARD_DEVIATION 12.5 • n=5 Participants
Sex: Female, Male Female	28 Participants n=5 Participants
Sex: Female, Male Male	43 Participants n=5 Participants

PRIMARY outcome

Timeframe: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.

Population: 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.

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.

Outcome measures

Measure	Generic Tacrolimus n=65 Participants Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days.	Branded Tacrolimus n=66 Participants Participants received branded tacrolimus (Prograf) orally twice a day for 14 days.
Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State	51.73 ng*hr/mL/mg Interval 44.67 to 59.9	50.58 ng*hr/mL/mg Interval 43.68 to 58.57

PRIMARY outcome

Timeframe: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.

Population: 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.

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.

Outcome measures

Measure	Generic Tacrolimus n=65 Participants Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days.	Branded Tacrolimus n=66 Participants Participants received branded tacrolimus (Prograf) orally twice a day for 14 days.
Dose-normalized Maximum Plasma Drug Concentration (Cmax) at Steady State	8.34 ng/mL/mg Interval 7.24 to 9.61	7.62 ng/mL/mg Interval 6.61 to 8.78

SECONDARY outcome

Timeframe: Days 7 and 14, and Days 21 and 28.

Population: PK Analysis set.

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.

Outcome measures

Measure	Generic Tacrolimus n=65 Participants Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days.	Branded Tacrolimus n=66 Participants Participants received branded tacrolimus (Prograf) orally twice a day for 14 days.
Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters AUC0-12h	13.41 percent coefficient of variation Standard Error 10.438	11.02 percent coefficient of variation Standard Error 9.756
Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters Cmax	16.92 percent coefficient of variation Standard Error 15.485	17.86 percent coefficient of variation Standard Error 14.874
Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters C0	13.24 percent coefficient of variation Standard Error 9.766	11.07 percent coefficient of variation Standard Error 10.285

SECONDARY outcome

Timeframe: Days 14 and 28: predose

Population: PK analysis set, where data were available.

Trough plasma drug concentration measured prior to drug administration at steady state (after 14 days of treatment with each study drug).

Outcome measures

Measure	Generic Tacrolimus n=65 Participants Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days.	Branded Tacrolimus n=66 Participants Participants received branded tacrolimus (Prograf) orally twice a day for 14 days.
Trough Plasma Drug Concentration (C0) at Steady State Day 14 [N= 34, 33]	7.25 ng/mL Standard Deviation 1.580	7.01 ng/mL Standard Deviation 1.694
Trough Plasma Drug Concentration (C0) at Steady State Day 28 [N=31, 33]	7.26 ng/mL Standard Deviation 2.091	7.04 ng/mL Standard Deviation 2.379

SECONDARY outcome

Timeframe: 28 Days

Population: Safety set

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.

Outcome measures

Measure	Generic Tacrolimus n=71 Participants Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days.	Branded Tacrolimus n=71 Participants Participants received branded tacrolimus (Prograf) orally twice a day for 14 days.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) Any adverse event	8 participants	12 participants
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) Serious adverse event	0 participants	1 participants

SECONDARY outcome

Timeframe: 28 Days

Population: Full analysis set.

Outcome measures

Measure	Generic Tacrolimus n=71 Participants Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days.	Branded Tacrolimus n=71 Participants Participants received branded tacrolimus (Prograf) orally twice a day for 14 days.
Number of Participants With Reported Biopsy Proven Acute Rejection Episodes	0 participants	0 participants

Adverse Events

Generic Tacrolimus

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Branded Tacrolimus

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Measure	Generic Tacrolimus n=71 participants at risk Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days.	Branded Tacrolimus n=71 participants at risk Participants received branded tacrolimus (Prograf) orally twice a day for 14 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.00% 0/71	1.4% 1/71
Nervous system disorders Headache	0.00% 0/71	1.4% 1/71
Skin and subcutaneous tissue disorders Rash	0.00% 0/71	1.4% 1/71

Other adverse events

Measure	Generic Tacrolimus n=71 participants at risk Participants received generic tacrolimus (Sandoz) orally twice a day for 14 days.	Branded Tacrolimus n=71 participants at risk Participants received branded tacrolimus (Prograf) orally twice a day for 14 days.
Gastrointestinal disorders Vomiting	0.00% 0/71	5.6% 4/71

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER