Phase IV Study to Evaluate Calcineurin Inhibitor Reduced, Steroid Free Immunosuppression After Renal Transplantation

Disorder Related to Renal Transplantation Clinical Trial

— Harmony  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00724022
• Other study ID #: IT1850071
• Secondary ID: EudraCT No. 2007
• Status: Completed
• Phase: Phase 4
• First received: July 25, 2008
• Last updated: September 30, 2014
• Start date: June 2008
• Est. completion date: July 2014

Study information

• Verified date: September 2014
• Source: University Hospital Freiburg
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 600
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Disorder Related to Renal Transplantation

Intervention

Drug:
• Basiliximab, Tacrolimus, MMF, Prednisolon
Control group. Therapy with Prednisolon.
• Basiliximab, Tacrolimus, MMF
No Prednisolon after 7 days
• Tacrolimus, MMF, rATG
Induction therapy: rATG instead of Basiliximab. No Prednisolon.

Locations

Country	Name	City	State
Germany	Universitaetsklinikum Berlin	Berlin
Germany	Universitaetsklinikum Bonn	Bonn
Germany	Klinikum Bremen-Mitte	Bremen
Germany	Carl Gustav Carus Universitätsklinikum	Dresden
Germany	Universitaetsklinikum Erlangen	Erlangen
Germany	Universitaetsklinikum Essen	Essen
Germany	Universitätsklinikum Frankfurt	Frankfurt am Main
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Nephrologisches Zentrum Niedersachsen	Hannoversch-Münden
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Jena	Jena
Germany	Transplantationszentrum Kaiserslautern	Kaiserslautern
Germany	Kliniken der Stadt Köln gGmbH - Krankenhaus Köln-Merheim	Koeln
Germany	Universitaetsklinikum Koeln	Koeln
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Universitätsklinikum Schleswig-Holstein Campus Lübeck	Lübeck
Germany	Universitätsklinikum Mainz	Mainz
Germany	Universitaetsklinikum Mannheim	Mannheim
Germany	Klinikum rechts der Isar der TU München	München
Germany	Universitätsklinikum München LMU	München
Germany	Universitaetsklinikum der WWU Münster	Münster
Germany	Universitätsklinikum Regensburg	Regensburg
Germany	Universitätsklinikum Rostock	Rostock
Germany	Universitätsklinikum Tübingen	Tübingen
Germany	Universitaetsklinikum Würzburg	Würzburg

Sponsors (4)

Lead Sponsor	Collaborator
University Hospital Freiburg	Astellas Pharma GmbH, Genzyme, a Sanofi Company, Roche Pharma AG

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy of immunosuppression measured in rejection rate confirmed by biopsy according to BANFF 97, modified 2005.		one year after transplantation	No
Secondary	Rate of patients with steroid-free immunosuppression	Rate of patients with steroid-free immunosuppression		No
Secondary	patient and graft survival rate	patient and graft survival rate		No
Secondary	graft function (calculated by the Cock- croft-Gault and MDRD-IV formula respectively calculated creatinine clearance by the Nankivell formula respectively cystatin C measurement)	graft function (calculated by the Cock- croft-Gault and MDRD-IV formula respectively calculated creatinine clearance by the Nankivell formula respectively cystatin C measurement)
Secondary	Number of steroid-resistant rejections	Number of steroid-resistant rejections
Secondary	blood pressure level and also amount and types of blood pressure medications	blood pressure level and also amount and types of blood pressure medications
Secondary	Lipid levels and also amount and types of lipid-lowering medications	Lipid levels and also amount and types of lipid-lowering medications
Secondary	body weight, relative weight gain [kg], BMI	body weight, relative weight gain [kg], BMI
Secondary	infection rate, infection type and infection severity	infection rate, infection type and infection severity
Secondary	anemia requiring erythropoietin treatment	anemia requiring erythropoietin treatment
Secondary	PTLD incidence	PTLD incidence
Secondary	tumor incidence	tumor incidence
Secondary	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	incidence of diabetes mellitus (ADA criteria, venous blood glucose concentration on an empty stomach =7.0 mmol/l, pathologic OGTT) and 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	30 days
Secondary	incidence of cataracts	incidence of cataracts
Secondary	incidence of avascular necrosis	incidence of avascular necrosis
Secondary	incidence of osteoporosis	incidence of osteoporosis (assessment of fracture rate, osteodensitometry)
Secondary	Wound healing disorders	Wound healing disorders
Secondary	incidence of chronic allograft nephropathy (CAN) (12-month histology)	incidence of chronic allograft nephropathy (CAN) (12-month histology)
Secondary	incidence of CMV disease (qPCR >1000 copies/µL)	incidence of CMV disease (qPCR >1000 copies/µL)
Secondary	incidence of BKV disease (qPCR >1000 copies/µL)	incidence of BKV disease (qPCR >1000 copies/µL)
Secondary	incidence of EBV disease (qPCR >1000 copies/µL)	incidence of EBV disease (qPCR >1000 copies/µL)