Clinical trial NCT00724022: Phase IV Study to Evaluate Calcineurin Inhibitor Reduced, Steroid Free Immunosuppression After Renal Transplantation
Official title: Triple Arm, Prospectively Randomized Multi Centre Study Phase IV to Evaluate Calcineurin Inhibitor Reduced, Steroid Free Immunosuppression After Renal Transplantation in Non-risk Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Disorder Related to Renal Transplantation
Keywords: Kidney transplant status
Steroid free
Reduced
Calcineurin
Inhibitor
Immunosuppression
Lead sponsor: University Hospital Freiburg
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
name: Astellas Pharma GmbH
name: Genzyme, a Sanofi Company
First posted: 2008-07-29
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Current practice of immune suppressive standard therapy after renal transplantation in non-risk patients is a triple therapy consisting of steroids, a calcineurin inhibitor and MMF. The aim of this clinical trial is to combine a reduction of CNI using tacrolimus and a concept of not using steroids in order to establish an immunosuppressive regimen in immunologically non-risk patients that is efficient and causes as few side effects as possible.

Detailed description: In this triple arm, prospectively randomized multi centre phase IV study 200 patients per study arm will be investigated for 12 months.

Based on the results of the Symphony study the low dose tacrolimus study arm will be modified to further improve efficacy (prevention of BPAR, best possible renal function) and safety (adverse event profile regarding infections, cardiovascular risk factors, malignant tumours) of immunosuppression. For this, CNI will be reduced and in addition the rate of steroid free patients after 1 week will be maximized to achieve a long lasting improved post surgical cardiovascular risk profile (in particular concerning de novo induction of diabetes mellitus and other adverse events caused by steroids). Safety should be increased without loss of efficacy of immunosuppression (measured in rejection rate and allograft loss rate) as compared to an immune suppressive therapy comprising steroids. Therefore, following the successful study arm of the Symphony study, immunosuppression in the first of the three study arms comprises a steroid in combination with Advagraf and CellCept in addition to a two dose induction therapy with Simulect (group A). The regimen of the second study arm is similar but discontinues steroids on day seven after transplantation (group B). Therapy of group three is similar to group B but Simulect is replaced by T-cell depleting polyclonal antibodies (Thymoglobulin) (group C).

Eligibility criteria: Inclusion Criteria:

* Post mortal kidney donation or living donation
* Primary and secondary renal transplantation, unless the graft was lost due to severe rejection within the first year
* PRA level ≤ 20%.
* Recipient ≥ 18 to 75 years of age
* AB0-compatible
* Negative crosshatch
* Patients with a signed informed consent form
* Women of child-bearing age must agree to an efficient contraception

Exclusion Criteria:

* Third or multiple transplantation
* Transplantation per a "non-heart beating" donor
* HLA-identical living donation
* Incompatibility to study medication (allergy, intolerance, hypersensitivity)
* Patients with existing malignant underlying disease or tumour anamnesis \< 5 years. Exception: basaloma or squamous cell carcinoma of the skin after successful therapy
* Female patients who do not use a safe method of contraception
* Patients with clinically significant, uncontrolled infectious diseases (incl. HIV) and/or severe diarrhoea, emesis, active malabsorption of the upper gastrointestinal tract or active peptic ulcer
* Patients currently, resp. within the last 30 days, participating in other studies
* Primary focal-sclerosing glomerulonephritis and membranoproliferative glomerulonephritis as an underlying disease
* Autoimmune disease as underlying disease (collagen diseases, colitis, HUS, SLE) which might require chronic cortisone therapy
* Additional disease requiring temporary or chronic cortisone therapy (including inhalation medicine)
* Chronic hepatitis B and hepatitis C infection
* Thrombopenia \< 70.000/mm3 or leukopenia \< 2.500/mm3 or neutropenia \< 1500/ mm3.
* Patients with hepatocirrhosis Child B or C or another severe disease of the liver
* Patients with symptoms of a significant somatic or psychiatric / mental illness. Patients who are not able to realize nature, relevance and consequences of the clinical trial and who are not able to comply, to cooperate and communicate adequately and to follow the instructions of the study or even to give their informed consent (according to § 40 article 4 and § 41 article 2 and 3 AMG).
* Patients who possibly depend on the sponsor or the trial physician
* Patients with signs of drug abuse or alcohol abuse
* Patients taking additional medicines with known interactions with the immune suppressive substances (MMF and tacrolimus) that preclude an adequate control of the immunosuppression
* Cold ischemia time of donor kidney \> 30 hours
* Pregnant or nursing patients

Primary outcomes:
measure: Efficacy of immunosuppression measured in rejection rate confirmed by biopsy according to BANFF 97, modified 2005.
timeFrame: one year after transplantation
Secondary outcomes:
measure: Rate of patients with steroid-free immunosuppression
measure: patient and graft survival rate
measure: graft function (calculated by the Cock- croft-Gault and MDRD-IV formula respectively calculated creatinine clearance by the Nankivell formula respectively cystatin C measurement)
measure: Number of steroid-resistant rejections
measure: blood pressure level and also amount and types of blood pressure medications
measure: Lipid levels and also amount and types of lipid-lowering medications
measure: body weight, relative weight gain [kg], BMI
measure: infection rate, infection type and infection severity
measure: anemia requiring erythropoietin treatment
measure: PTLD incidence
measure: tumor incidence
measure: incidence of diabetes mellitus nd incidence of abnormal fasting blood sugar levels respectively incidence of impaired glucose tolerance, incidence of de novo insulin-requiring or oral-antidiabetic-requiring treatment over ≥30 days
timeFrame: 30 days
measure: incidence of cataracts
measure: incidence of avascular necrosis
measure: incidence of osteoporosis
measure: Wound healing disorders
measure: incidence of chronic allograft nephropathy (CAN) (12-month histology)
measure: incidence of CMV disease (qPCR >1000 copies/μL)
measure: incidence of BKV disease (qPCR >1000 copies/μL)
measure: incidence of EBV disease (qPCR >1000 copies/μL)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Universitaetsklinikum Berlin
city: Bonn
country: Germany
facility: Universitaetsklinikum Bonn
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Dresden
country: Germany
facility: Carl Gustav Carus Universitätsklinikum
city: Erlangen
country: Germany
facility: Universitaetsklinikum Erlangen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Hannoversch-Münden
country: Germany
facility: Nephrologisches Zentrum Niedersachsen
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Kaiserslautern
country: Germany
facility: Transplantationszentrum Kaiserslautern
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln
city: Koeln
country: Germany
facility: Kliniken der Stadt Köln gGmbH - Krankenhaus Köln-Merheim
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Campus Lübeck
city: Mainz
country: Germany
facility: Universitätsklinikum Mainz
city: Mannheim
country: Germany
facility: Universitaetsklinikum Mannheim
city: München
country: Germany
facility: Universitätsklinikum München LMU
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Münster
country: Germany
facility: Universitaetsklinikum der WWU Münster
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Rostock
country: Germany
facility: Universitätsklinikum Rostock
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Würzburg
country: Germany
facility: Universitaetsklinikum Würzburg
Study officials:
affiliation: University Hospital Freiburg
name: Ulrich Hopt, Prof.Dr.Dr.
role: STUDY_DIRECTOR
affiliation: University Hospital Freiburg
name: Oliver Thomusch, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitaetsklinikum Erlangen
name: Christian Hugo, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wittenbrink N, Herrmann S, Blazquez-Navarro A, Bauer C, Lindberg E, Wolk K, Sabat R, Reinke P, Sawitzki B, Thomusch O, Hugo C, Babel N, Seitz H, Or-Guil M. A novel approach reveals that HLA class 1 single antigen bead-signatures provide a means of high-accuracy pre-transplant risk assessment of acute cellular rejection in renal transplantation. BMC Immunol. 2019 Apr 27;20(1):11. doi: 10.1186/s12865-019-0291-2.
citation: Thomusch O, Wiesener M, Opgenoorth M, Pascher A, Woitas RP, Witzke O, Jaenigen B, Rentsch M, Wolters H, Rath T, Cingoz T, Benck U, Banas B, Hugo C. Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial. Lancet. 2016 Dec 17;388(10063):3006-3016. doi: 10.1016/S0140-6736(16)32187-0. Epub 2016 Nov 19.