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

Triple Arm, Prospectively Randomized Multi Centre Study Phase IV to Evaluate Calcineurin Inhibitor Reduced, Steroid Free Immunosuppression After Renal Transplantation in Non-risk Patients

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.

Study Overview

• Status: Completed
• Conditions: Disorder Related to Renal Transplantation
• Intervention / Treatment: Drug: Basiliximab, Tacrolimus, MMF, Prednisolon; Drug: Basiliximab, Tacrolimus, MMF; Drug: Tacrolimus, MMF, rATG

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).

• Study Type: Interventional
• Enrollment (Anticipated): 600
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Universitaetsklinikum Berlin
  • Bonn, Germany, 53105
    • Universitaetsklinikum Bonn
  • Bremen, Germany, 28177
    • Klinikum Bremen-Mitte
  • Dresden, Germany, 01307
    • Carl Gustav Carus Universitätsklinikum
  • Erlangen, Germany, 91054
    • Universitaetsklinikum Erlangen
  • Essen, Germany, 45122
    • Universitaetsklinikum Essen
  • Frankfurt am Main, Germany, 60590
    • Universitatsklinikum Frankfurt
  • Freiburg, Germany, 79106
    • Universitaetsklinikum Freiburg
  • Hannoversch-Münden, Germany, 34346
    • Nephrologisches Zentrum Niedersachsen
  • Heidelberg, Germany, 69120
    • Universitätsklinikum Heidelberg
  • Jena, Germany, 07747
    • Universitätsklinikum Jena
  • Kaiserslautern, Germany, 67655
    • Transplantationszentrum Kaiserslautern
  • Koeln, Germany, 50924
    • Universitaetsklinikum Koeln
  • Koeln, Germany, 51109
    • Kliniken der Stadt Köln gGmbH - Krankenhaus Köln-Merheim
  • Leipzig, Germany, 04103
    • Universitätsklinikum Leipzig
  • Lübeck, Germany, 23538
    • Universitätsklinikum Schleswig-Holstein Campus Lübeck
  • Mainz, Germany, 55131
    • Universitätsklinikum Mainz
  • Mannheim, Germany, 68167
    • Universitaetsklinikum Mannheim
  • München, Germany, 81675
    • Klinikum Rechts der Isar der TU München
  • München, Germany, 81377
    • Universitätsklinikum München LMU
  • Münster, Germany, 48149
    • Universitaetsklinikum der WWU Münster
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
  • Rostock, Germany, 18057
    • Universitätsklinikum Rostock
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen
  • Würzburg, Germany, 97080
    • Universitaetsklinikum Würzburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: A; Standard: Advagraf, CellCept, Decortin H + 2x Simulect Day 0 + 4	Drug: Basiliximab, Tacrolimus, MMF, Prednisolon; Control group. Therapy with Prednisolon.; Other Names: Simulect; CellCept; Advagraf; Decortin
Experimental: B; Steroidfree: Advagraf, Cellcept, Decortin H until Day 8, 2x Simulect Day 0 + 4	Drug: Basiliximab, Tacrolimus, MMF; No Prednisolon after 7 days; Other Names: Simulect; CellCept; Advagraf
Experimental: C; Steroidfree: Advagraf, Cellcept, Decortin H until Day 8, 3 x Thymoglobulin	Drug: Tacrolimus, MMF, rATG; Induction therapy: rATG instead of Basiliximab. No Prednisolon.; Other Names: CellCept; Advagraf; Thymoglobulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Efficacy of immunosuppression measured in rejection rate confirmed by biopsy according to BANFF 97, modified 2005.	one year after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of patients with steroid-free immunosuppression	Rate of patients with steroid-free immunosuppression
patient and graft survival rate	patient and graft survival rate
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)
Number of steroid-resistant rejections	Number of steroid-resistant rejections
blood pressure level and also amount and types of blood pressure medications	blood pressure level and also amount and types of blood pressure medications
Lipid levels and also amount and types of lipid-lowering medications	Lipid levels and also amount and types of lipid-lowering medications
body weight, relative weight gain [kg], BMI	body weight, relative weight gain [kg], BMI
infection rate, infection type and infection severity	infection rate, infection type and infection severity
anemia requiring erythropoietin treatment	anemia requiring erythropoietin treatment
PTLD incidence	PTLD incidence
tumor incidence	tumor incidence
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
incidence of cataracts	incidence of cataracts
incidence of avascular necrosis	incidence of avascular necrosis
incidence of osteoporosis	incidence of osteoporosis (assessment of fracture rate, osteodensitometry)
Wound healing disorders	Wound healing disorders
incidence of chronic allograft nephropathy (CAN) (12-month histology)	incidence of chronic allograft nephropathy (CAN) (12-month histology)
incidence of CMV disease (qPCR >1000 copies/μL)	incidence of CMV disease (qPCR >1000 copies/μL)
incidence of BKV disease (qPCR >1000 copies/μL)	incidence of BKV disease (qPCR >1000 copies/μL)
incidence of EBV disease (qPCR >1000 copies/μL)	incidence of EBV disease (qPCR >1000 copies/μL)

Collaborators and Investigators

• Sponsor: University Hospital Freiburg
• Collaborators: Roche Pharma AG; Genzyme, a Sanofi Company; Astellas Pharma GmbH
• Investigators: Study Director: Ulrich Hopt, Prof.Dr.Dr., University Hospital Freiburg; Principal Investigator: Oliver Thomusch, Prof. Dr., University Hospital Freiburg; Principal Investigator: Christian Hugo, Prof. Dr., Universitaetsklinikum Erlangen

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: Lancet. 2017 Feb 25;389(10071):804.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: July 25, 2008
• First Submitted That Met QC Criteria: July 28, 2008
• First Posted (Estimate): July 29, 2008

Study Record Updates

• Last Update Posted (Estimate): October 1, 2014
• Last Update Submitted That Met QC Criteria: September 30, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Immunosuppression; Inhibitor; Calcineurin; Reduced; Kidney transplant status; Steroid free
• Additional Relevant MeSH Terms: 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; Basiliximab; Thymoglobulin
• Other Study ID Numbers: IT1850071; EudraCT No. 2007-006516-31; DRKS00000452 (Registry Identifier: German Clinical Trials Register)