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

This study has been completed.
Sponsor:
Collaborators:
Roche Pharma AG
Astellas Pharma GmbH
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Prof. Dr.med. Oliver Thomusch, University Hospital Freiburg
ClinicalTrials.gov Identifier:
NCT00724022
First received: July 25, 2008
Last updated: September 30, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Disorder Related to Renal Transplantation
Drug: Basiliximab, Tacrolimus, MMF, Prednisolon
Drug: Basiliximab, Tacrolimus, MMF
Drug: Tacrolimus, MMF, rATG
Phase 4

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

Resource links provided by NLM:


Further study details as provided by University Hospital Freiburg:

Primary Outcome Measures:
  • Efficacy of immunosuppression measured in rejection rate confirmed by biopsy according to BANFF 97, modified 2005. [ Time Frame: one year after transplantation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Rate of patients with steroid-free immunosuppression [ Designated as safety issue: No ]
    Rate of patients with steroid-free immunosuppression

  • patient and graft survival rate [ Designated as safety issue: No ]
    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 [ Time Frame: 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

  • 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)


Estimated Enrollment: 600
Study Start Date: June 2008
Study Completion Date: July 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
A
Standard: Advagraf, CellCept, Decortin H + 2x Simulect Day 0 + 4
Drug: Basiliximab, Tacrolimus, MMF, Prednisolon
Control group. Therapy with Prednisolon.
Other Names:
  • Simulect
  • Advagraf
  • CellCept
  • 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
  • Advagraf
  • CellCept
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:
  • Advagraf
  • CellCept
  • Thymoglobulin

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

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00724022

Locations
Germany
Universitaetsklinikum Berlin
Berlin, Germany, 13353
Universitaetsklinikum Bonn
Bonn, Germany, 53105
Klinikum Bremen-Mitte
Bremen, Germany, 28177
Carl Gustav Carus Universitätsklinikum
Dresden, Germany, 01307
Universitaetsklinikum Erlangen
Erlangen, Germany, 91054
Universitaetsklinikum Essen
Essen, Germany, 45122
Universitätsklinikum Frankfurt
Frankfurt am Main, Germany, 60590
Universitaetsklinikum Freiburg
Freiburg, Germany, 79106
Nephrologisches Zentrum Niedersachsen
Hannoversch-Münden, Germany, 34346
Universitätsklinikum Heidelberg
Heidelberg, Germany, 69120
Universitätsklinikum Jena
Jena, Germany, 07747
Transplantationszentrum Kaiserslautern
Kaiserslautern, Germany, 67655
Kliniken der Stadt Köln gGmbH - Krankenhaus Köln-Merheim
Koeln, Germany, 51109
Universitaetsklinikum Koeln
Koeln, Germany, 50924
Universitätsklinikum Leipzig
Leipzig, Germany, 04103
Universitätsklinikum Schleswig-Holstein Campus Lübeck
Lübeck, Germany, 23538
Universitätsklinikum Mainz
Mainz, Germany, 55131
Universitaetsklinikum Mannheim
Mannheim, Germany, 68167
Klinikum rechts der Isar der TU München
München, Germany, 81675
Universitätsklinikum München LMU
München, Germany, 81377
Universitaetsklinikum der WWU Münster
Münster, Germany, 48149
Universitätsklinikum Regensburg
Regensburg, Germany, 93053
Universitätsklinikum Rostock
Rostock, Germany, 18057
Universitätsklinikum Tübingen
Tübingen, Germany, 72076
Universitaetsklinikum Würzburg
Würzburg, Germany, 97080
Sponsors and Collaborators
University Hospital Freiburg
Roche Pharma AG
Astellas Pharma GmbH
Genzyme, a Sanofi Company
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
  More Information

No publications provided

Responsible Party: Prof. Dr.med. Oliver Thomusch, Professor, University Hospital Freiburg
ClinicalTrials.gov Identifier: NCT00724022     History of Changes
Other Study ID Numbers: IT1850071, EudraCT No. 2007-006516-31, DRKS00000452
Study First Received: July 25, 2008
Last Updated: September 30, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University Hospital Freiburg:
Kidney transplant status
Steroid free
Reduced
Calcineurin
Inhibitor
Immunosuppression

Additional relevant MeSH terms:
Antibodies, Monoclonal
Basiliximab
Methylprednisolone
Methylprednisolone Hemisuccinate
Methylprednisolone acetate
Mycophenolate mofetil
Mycophenolic Acid
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Tacrolimus
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Neuroprotective Agents
Peripheral Nervous System Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on November 25, 2014