Pharmacokinetics Study in de Novo Kidney Transplantation
Conditions
Keywords
Pharmacokinetics Study, Tacroliums, GFR, kidney, transplant rejection, allograft rejection, xenograft rejection, host vs graft disease, renal transplant
Brief summary
The purpose of this study was to investigate if Tacrolimus Hexal® has similar pharmacokinetic properties compared to Prograf® in de novo renal transplant patients and whether the comparable exposure resulted in similar renal function.
Detailed description
In Phase II of this study there was a high patient drop-out rate and an associated long recruitment timespan. Eighty-one patients were recruited to Phase I and only 45 of the required 54 patients were available for PK analysis. To complete Phase II, 245 (in addition to 81) patients were to be required to achieve calculated sample size. Therefore the protocol was amended to stop recruitment and analyze Phase I patient data of CERL080ADE27 (PK-Phase I). Patients that were still ongoing were scheduled for an end of study (EOS) visit. During this visit patients were informed by the investigator about the end of study and advised about further treatment course.
Interventions
DRUGPrograf
Prograf® capsules were supplied as capsules of 0.5 mg, 1 mg and 1.5 mg dose strengths.
DRUGTacrolimus Hexal
Tacrolimus Hexal® capsules were supplied to the investigators at dose strengths of 0.5 mg, 1 mg and 1.5 mg.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: primary or sec. kidney transplanted patiens, written consent, cold ischemia \< 24 h Exclusion: multi organ, immunological risc pts., PRA \>20%, Antibodys against HLA-type of donor organ, hypersensitivity against Tacro or MMF, Other protocol-defined inclusion/
Exclusion criteria
may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ANCOVA Model for Change in Nankivell GFR (mL/Min) at Month 6, Without Replacement of Missing Values (Full Analysis Set) | baseline to month 6 | Change in Nankivell glomerular filtration rate (GFR) from baseline to 6 months Glomerular Filtration Rate (GFR): The GFR is the best clinical estimate of renal function in health and disease, and correlates well with the clinical severity of renal function disturbances. Several studies have shown that in patients with progressive renal disease, GFR declines or reciprocal serum creatinine levels elevate linearly over time in a predictable manner. With the help of the serum creatinine values, the GFR was calculated via Nankivell formula. |
| ANOVA for Dose-normalized Tacrolimus 12-h-AUC (h/103*L) at Month 1 | end of month 1 | Compares the PK of Tacrolimus Hexal® assessed by the ratio of the AUC0-12h over one month period post transplantation vs. Prograf® in renal transplant patients |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | baseline to month 12 | The key secondary objective was to assess the incidence of individual endpoints BPAR, graft loss and death until month 6 post-transplantation. |
| ANCOVA Model for Change in CKD-EPI GFR (Chronic Kidney Disease Epidemiology Collaboration Glomerular Filtration Rate) at Month 6 Post-transplantation | baseline to Month 6 | ANCOVA model for change in CKD-EPI Glomerular Filtration Rate (GFR)\[ml/min\] without replacement of missing values |
| ANCOVA Model for Change in MDRD GFR (ml/Min) at Month 6, Without Replacement of Missing Values | least square (LS) mean change from baseline to Month 6 | MDRD GFR |
| ANCOVA Model for Change in Cockcroft-Gault GFR (ml/Min) at Month 6, Without Replacement of Missing Values | least square (LS) mean change from baseline to Month 6 | change in Cockcroft-Gault GFR |
Countries
Germany
Participant flow
Recruitment details
81 patients were randomized, but only 73 were assigned drug. 1 patient who was excluded from efficacy analyses, was randomized to Prograf but did not receive treatment but kept for safety reporting. 74 patients were used for safety analysis while only 73 were available for efficacy analysis
Pre-assignment details
This is a 2-phase study: PHASE I: In 1st phase of study, PK parameters were evaluated in total of 60 evaluable patients (30 patients per treatment group) Phase II was not conducted
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus Hexal® Investigational therapy: one capsule containing 0.5mg, 1mg or 5mg Tacrolimus Hexal®, one tablet containing 180mg or 360mg Myfortic®, corticosteroids and one vial containing 20mg lyophilisate Simulect® | 35 |
| Prograf® Control therapy: one capsule containing 0.5 mg, 1mg or 5mg Prograf®, one tablet containing 180mg or 360mg Myfortic®, corticosteroids and one vial containing 20mg lyophilisate Simulect® | 38 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Graft loss | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Surgical problems during nephrectomy | 2 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | Tacrolimus Hexal® | Prograf® | Total |
|---|---|---|---|
| Age, Continuous | 47.9 years STANDARD_DEVIATION 9.9 | 47.2 years STANDARD_DEVIATION 11.8 | 47.5 years STANDARD_DEVIATION 10.8 |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 29 Participants | 29 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 34 / 35 | 38 / 39 |
| serious Total, serious adverse events | 19 / 35 | 17 / 39 |
Outcome results
Primary
ANCOVA Model for Change in Nankivell GFR (mL/Min) at Month 6, Without Replacement of Missing Values (Full Analysis Set)
Change in Nankivell glomerular filtration rate (GFR) from baseline to 6 months Glomerular Filtration Rate (GFR): The GFR is the best clinical estimate of renal function in health and disease, and correlates well with the clinical severity of renal function disturbances. Several studies have shown that in patients with progressive renal disease, GFR declines or reciprocal serum creatinine levels elevate linearly over time in a predictable manner. With the help of the serum creatinine values, the GFR was calculated via Nankivell formula.
Time frame: baseline to month 6
Population: The Full Analysis Set (FAS) consisted of all patients in whom study treatment was assigned. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus Hexal® | ANCOVA Model for Change in Nankivell GFR (mL/Min) at Month 6, Without Replacement of Missing Values (Full Analysis Set) | 47.65 mL/min | 95% Confidence Interval 20.24 |
| Prograf® | ANCOVA Model for Change in Nankivell GFR (mL/Min) at Month 6, Without Replacement of Missing Values (Full Analysis Set) | 38.60 mL/min | 95% Confidence Interval 18.83 |
p-value: 0.0003ANCOVA
Primary
ANOVA for Dose-normalized Tacrolimus 12-h-AUC (h/103*L) at Month 1
Compares the PK of Tacrolimus Hexal® assessed by the ratio of the AUC0-12h over one month period post transplantation vs. Prograf® in renal transplant patients
Time frame: end of month 1
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tacrolimus Hexal® | ANOVA for Dose-normalized Tacrolimus 12-h-AUC (h/103*L) at Month 1 | Adjusted, log-transformed Estimates (ANOVA) | 2.944 h/10^3*L |
| Tacrolimus Hexal® | ANOVA for Dose-normalized Tacrolimus 12-h-AUC (h/103*L) at Month 1 | Adjusted, back-transformed Estimates (ANOVA) | 18.991 h/10^3*L |
| Prograf® | ANOVA for Dose-normalized Tacrolimus 12-h-AUC (h/103*L) at Month 1 | Adjusted, log-transformed Estimates (ANOVA) | 3.020 h/10^3*L |
| Prograf® | ANOVA for Dose-normalized Tacrolimus 12-h-AUC (h/103*L) at Month 1 | Adjusted, back-transformed Estimates (ANOVA) | 20.484 h/10^3*L |
Secondary
ANCOVA Model for Change in CKD-EPI GFR (Chronic Kidney Disease Epidemiology Collaboration Glomerular Filtration Rate) at Month 6 Post-transplantation
ANCOVA model for change in CKD-EPI Glomerular Filtration Rate (GFR)\[ml/min\] without replacement of missing values
Time frame: baseline to Month 6
Population: The Full Analysis Set (FAS) consisted of all patients in whom study treatment was assigned. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus Hexal® | ANCOVA Model for Change in CKD-EPI GFR (Chronic Kidney Disease Epidemiology Collaboration Glomerular Filtration Rate) at Month 6 Post-transplantation | 48.33 mL/min | Standard Error 3.84 |
| Prograf® | ANCOVA Model for Change in CKD-EPI GFR (Chronic Kidney Disease Epidemiology Collaboration Glomerular Filtration Rate) at Month 6 Post-transplantation | 39.77 mL/min | Standard Error 4.61 |
Secondary
ANCOVA Model for Change in Cockcroft-Gault GFR (ml/Min) at Month 6, Without Replacement of Missing Values
change in Cockcroft-Gault GFR
Time frame: least square (LS) mean change from baseline to Month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tacrolimus Hexal® | ANCOVA Model for Change in Cockcroft-Gault GFR (ml/Min) at Month 6, Without Replacement of Missing Values | 60.45 (ml/min) |
| Prograf® | ANCOVA Model for Change in Cockcroft-Gault GFR (ml/Min) at Month 6, Without Replacement of Missing Values | 46.45 (ml/min) |
Secondary
ANCOVA Model for Change in MDRD GFR (ml/Min) at Month 6, Without Replacement of Missing Values
MDRD GFR
Time frame: least square (LS) mean change from baseline to Month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tacrolimus Hexal® | ANCOVA Model for Change in MDRD GFR (ml/Min) at Month 6, Without Replacement of Missing Values | 46.20 (ml/min) |
| Prograf® | ANCOVA Model for Change in MDRD GFR (ml/Min) at Month 6, Without Replacement of Missing Values | 38.52 (ml/min) |
Secondary
The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set)
The key secondary objective was to assess the incidence of individual endpoints BPAR, graft loss and death until month 6 post-transplantation.
Time frame: baseline to month 12
Population: The Full Analysis Set (FAS) consisted of all patients in whom study treatment was assigned. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus Hexal® | The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | Biopsy proven acute rejection (BPAR) | 2 Incidences |
| Tacrolimus Hexal® | The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | Graft loss | 0 Incidences |
| Tacrolimus Hexal® | The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | Death | 0 Incidences |
| Tacrolimus Hexal® | The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | Composite: BPAR, graft loss or death | 2 Incidences |
| Prograf® | The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | Composite: BPAR, graft loss or death | 4 Incidences |
| Prograf® | The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | Biopsy proven acute rejection (BPAR) | 3 Incidences |
| Prograf® | The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | Death | 1 Incidences |
| Prograf® | The Incidence of Biopsy-proven Acute Rejection (BPAR), Graft Loss and Death Until Month 12 (Full Analysis Set) (Full Analysis Set) | Graft loss | 1 Incidences |