OSAKA: A multicenter, four arm, randomized, open label clinical studyinvestigating optimized dosing in a Prograf®/Advagraf®-basedimmunosuppressive regimen in kidney transplant subjects.Short Title: OSAKA Study(Optimizing ImmunoSuppression After Kidney Transplantation WithAdvagraf)ISN: PMR-EC-1210Transplantation with ADVAGRAF)
- Conditions
- Kidney transplantZ94.0Kidney transplant status
- Registration Number
- DRKS00000003
- Lead Sponsor
- ASTELLAS Pharma GmbH
- Brief Summary
Abstract Background: The once-daily (QD), prolonged-release formulation of tacrolimus has been shown to improve adherence versus twice-daily (BD) tacrolimus. Treatment nonadherence in transplant recipients has been associated with poor graft outcomes. Methods: This open-label, parallel-group study randomized adults with end-stage renal disease undergoing primary kidney transplantation or retransplantation to an initial dose of tacrolimus BD 0.2 mg/kg per day (Arm 1; n=309), QD 0.2 mg/kg per day (Arm 2; n=302), QD 0.3 mg/kg per day (Arm 3; n=304) all with mycophenolate mofetil and corticosteroids (tapered) over 24 weeks, or tacrolimus QD 0.2 mg/kg per day with mycophenolate mofetil, basiliximab, and corticosteroids given only perioperatively (Arm 4; n=283). The primary composite endpoint (efficacy failure; per protocol set) was defined as graft loss, biopsy-confirmed acute rejection, or graft dysfunction at week 24. Graft dysfunction was defined as estimated glomerular filtration rate Modification of Diet in Renal Disease-4 formula of less than 40 mL/min/1.73 m(2). The prespecified noninferiority margin was 12.5%. Results: The per protocol set included 976 patients: 237, 263, 246, and 230 patients in Arms 1 to 4, respectively. Noninferiority of the composite endpoint was demonstrated for Arm 2 versus Arm 1; Kaplan-Meier estimates of efficacy failure were 42.2% and 40.6%, respectively (difference, -1.6%; 95% confidence interval [CI], -12.2% to 9.0%). Noninferiority to Arm 1 was not confirmed for Arm 3 (difference, -3.5%; 95% CI, -13.6% to 6.6%) or Arm 4 (difference, -7.1%; 95% CI, -16.1% to 1.9%). Graft dysfunction (estimated glomerular filtration rate <40 mL/min/1.73 m(2)) was the main determinant of composite-endpoint efficacy failure across all arms. Conclusions: In patients representative of the European kidney transplant population, tacrolimus QD-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day tacrolimus BD. Trial registration: ClinicalTrials.gov NCT00717470.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Complete
- Sex
- All
- Target Recruitment
- 1200
Subject is eligible for the study if all of the following apply:
1. Age >= 18 years.
2. End stage kidney disease and a suitable candidate for primary renal transplantation or
re-transplantation (unless the graft was lost from rejection within 12 month).
3. Receiving a kidney transplant from a cadaveric or living (non HLA identical) donor
with compatible ABO blood type.
4. Female subject of childbearing potential must have a negative serum pregnancy test at
enrollment and must agree to maintain effective birth control during the study.
5. Capable of understanding the purpose and risks of the study, fully informed and given
written informed consent (signed Informed Consent has been obtained).
Subject will be excluded from participation if any of the following apply:
1. Receiving or having previously received an organ transplant other than a kidney.
2. Cold ischemia time of the donor kidney > 30 hours.
3. Receiving a graft from a non-heart-beating donor other than of Maastricht category 3
(withdrawn of support awaiting cardiac arrest).
4. Significant liver disease, defined as having continuously elevated SGPT/ALT and/or
SGOT/AST and/or total bilirubin levels >= 2 times the upper value of the normal range
of the investigational site or is receiving a graft from a hepatitis C or B positive donor.
5. Requiring initial sequential or parallel therapy with immunosuppressive antibody
preparation(s).
6. Requiring ongoing dosing with a systemic immunosuppressive drug prior to
transplantation.
7. Significant, uncontrolled concomitant infections and/or severe diarrhea, vomiting,
active upper gastro-intestinal tract malabsorption or active peptic ulcer.
8. Pregnant woman or breast-feeding mother.
9. Subject or donor known to be HIV positive.
10. Known allergy or intolerance to tacrolimus, macrolide antibiotics, corticosteroids,
basiliximab or mycophenolate mofetil or any of the product excipients.
11. Diagnosis of new-onset malignancy prior to transplantation, with the exception of
basocellular or squamous cell carcinoma of the skin which had been treated
successfully.
12. Currently participating in another clinical trial, and/or has taken an investigational drug
within 28 days prior to enrollment.
13. Any form of substance abuse, psychiatric disorder or condition which, in the opinion of
the investigator, may complicate communication with the investigator.
14. Unlikely to comply with the visits scheduled in the protocol.
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method The primary objective of this study is to compare the four therapy regimens with regard to efficacy failure rate. The secondary objective is to compare the efficacy and safety profiles of the four therapy regimens with each other. Efficacy failure rate will be assessed using a composite endpoint consisting of graft loss, biopsy confirmed acute rejection (BCAR) and graft dysfunction.
- Secondary Outcome Measures
Name Time Method Efficacy Variables:<br>- Renal function assessed by calculated GFR (Glomerular Filtration Rate) with MDRD formula at week 24 after transplantation<br>- Renal function assessed by calculated creatinine clearance with Cockcroft and Gault formula at week 24 after transplantation<br>- Acute rejection<br>* Incidence of and time to first acute rejection<br>* Incidence of and time to first corticosteroid-resistant acute rejection<br>* Overall frequency of acute rejection episodes<br>- Biopsy confirmed acute rejection<br>* Incidence of and time to first biopsy confirmed acute rejection<br>* Incidence of and time to first biopsy confirmed corticosteroid-resistant acute<br>rejection<br>* Overall frequency of biopsy confirmed acute rejection episodes<br>* Severity of biopsy confirmed acute rejections (Banff `97 criteria)