Steroid Free Immunosuppression or Calcineurin Inhibitor Minimization After Basiliximab Induction Therapy in Kidney Transplantation: Comparison With a Standard Quadruple Immunosuppressive Regimen (Allegro)

A prospective, open, randomized trial, in which the investigators aim to achieve optimal immunosuppression after renal renal transplantation with maximal reduction of side effects, especially of vascular injury, chronic allograft nephropathy, osteoporosis and malignancies. Immunosuppression without steroids and CNI minimization is compared to standard immunosuppression, consisting of tacrolimus OD, mycophenolic acid and corticosteroids.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency; Kidney Transplantation
• Intervention / Treatment: Drug: tacrolimus OD, mycophenolic acid, prednisolone

Detailed Description

Before transplantation 300 patients will be randomized 1:1:1 in three groups. Group 1 will be treated with basiliximab induction and a three day course of steroids followed by a steroid free maintenance regimen consisting of standard-dose tacrolimus OD and mycophenolic acid. Group 2 will be treated with Basiliximab induction followed by standard-dose tacrolimus OD, mycophenolic acid and steroids. Group 3 will be treated with basiliximab induction followed by standard-dose tacrolimus OD for six months, whereafter the dose will be reduced plus mycophenolic acid and steroids. The total study period will be 2 years. Primary endpoint will be renal function, proteinuria and microalbuminuria measured 24 months after transplantation. Renal function will be measured by serum Creatinine, Creatinine clearances and CKD-EPI. Secondary endpoints will be the degree of tubular atrophy and interstitial fibrosis and the degree of arteriolar hyalinosis in renal biopsies taken at 12 and 24 months after transplantation. Biopsies will be evaluated according to the Banff Criteria for Renal Allograft Biopsy Interpretation. Quantitative morphometric analysis of interstitial fibrous tissue will be performed using the digital image analysis technique. Other secondary endpoints are patient and graft survival, the incidence of allograft rejection, cardiovascular accidents, pulse wave velocity, blood pressure, the number of antihypertensives, lipid profile, the incidence of malignancies, the incidence of infectious complications, the incidence of post transplant diabetes mellitus and the development of osteoporosis.

• Study Type: Interventional
• Enrollment (Actual): 305
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Academisch Medisch Centrum
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Leiden, Netherlands
    • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• recipient of a kidney graft (first of second) from a deceased or living (non-HLA identical) donor

Exclusion Criteria:

• patients with multi-organ transplants
• patients who are receiving a third or fourth transplant
• patients who have > 75% (current of historic) panel reactive antibodies
• patients receiving a kidney from a HLA identical living donr
• female patients who are pregnant or unwilling to used adequate contraception during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: standard immunosuupression; triple maintenance immunosuppression with tacrolimus OD (maintenance 6-10 ng/ml), mycophenolic acid 2 dd 540mg and prednisolone 7.5 mg	Drug: tacrolimus OD, mycophenolic acid, prednisolone; tacrolimus maintenance 6-10 ng/ml, in the low dose tacrolimus group after 6 months fixed dose reduction of 50% tacrolimus through levels will be 3-5 ng/ml mycophenolic acid 2 dd 720mg, after 2 weeks reduced to 2 dd 540 mg in all groups methylprednisolone 500, 250, 125 mg on day 0, 1, and 2 in all groups prednisolone 1 dd 10 mg, and from week 6 prednisolone 7.5 mg in the standard immunosuppression and low dose tacrolimus group No prednisolone will be given the steroid free group; Other Names: advagraf, mycophenolic acid
EXPERIMENTAL: steroidfree; maintenance immunosuppression with tacrolimus OD (target range 6-10 ng/ml), mycophenolic acid (2 dd 540 mg)	Drug: tacrolimus OD, mycophenolic acid, prednisolone; tacrolimus maintenance 6-10 ng/ml, in the low dose tacrolimus group after 6 months fixed dose reduction of 50% tacrolimus through levels will be 3-5 ng/ml mycophenolic acid 2 dd 720mg, after 2 weeks reduced to 2 dd 540 mg in all groups methylprednisolone 500, 250, 125 mg on day 0, 1, and 2 in all groups prednisolone 1 dd 10 mg, and from week 6 prednisolone 7.5 mg in the standard immunosuppression and low dose tacrolimus group No prednisolone will be given the steroid free group; Other Names: advagraf, mycophenolic acid
EXPERIMENTAL: low dose tacrolimus; triple maintenance immunosuppression with tacrolimus OD (maintenance 6-10 ng/ml), mycophenolic acid 2 dd 540mg and prednisolone 7.5 mg. After 6 months lowering of tacrolimus OD maintenance 3-5 ng/ml	Drug: tacrolimus OD, mycophenolic acid, prednisolone; tacrolimus maintenance 6-10 ng/ml, in the low dose tacrolimus group after 6 months fixed dose reduction of 50% tacrolimus through levels will be 3-5 ng/ml mycophenolic acid 2 dd 720mg, after 2 weeks reduced to 2 dd 540 mg in all groups methylprednisolone 500, 250, 125 mg on day 0, 1, and 2 in all groups prednisolone 1 dd 10 mg, and from week 6 prednisolone 7.5 mg in the standard immunosuppression and low dose tacrolimus group No prednisolone will be given the steroid free group; Other Names: advagraf, mycophenolic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
renal function parameters	renal function as measured by serum Creatinine and Creatinine Clearance, CKD-EPI, proteinuria	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
tubular atrophy and interstitial fibrosis	tubular atrophy and interstitial fibrosis in renal biopsies	24 months
rejection episodes	number of treated biopsy proven acute rejection episodes (as scored by pathologist via Banff classification)	two years
graft and patient survival	graft and patient survival	two years
myocardial infarctions	number of myocardial infarctions	two years
cerebrovascular accidents	number of cerebrovascular accidents	two years
number of participants with infectious complications	bacterial and viral infections as measured by culture (bacterial infections) or PCR (viral infections)	two years
number of participants with osteoporosis	as established by dexa bone densitometry	2 years

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Leiden University Medical Center
• Investigators: Principal Investigator: Jan-Stephan Sanders, MD, PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (ACTUAL): April 1, 2015
• Study Completion (ACTUAL): April 1, 2016

Study Registration Dates

• First Submitted: December 21, 2011
• First Submitted That Met QC Criteria: March 20, 2012
• First Posted (ESTIMATE): March 22, 2012

Study Record Updates

• Last Update Posted (ACTUAL): January 11, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: immunosuppression; kidney transplantation; steroids; tacrolimus OD
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Prednisolone; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: Allegro (Alias Study Number)