Trial document




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  DRKS00000452

Trial Description

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Title

HARMONY:
A triple arm, prospectively randomized, multi-center study phase IV to evaluate calcineurin inhibitor reduced and steroid-free immunosupression in low immunological risk patients.

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Trial Acronym

Harmony

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URL of the Trial

http:///

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Brief Summary in Lay Language

Current practice of immune suppressive standard therapy to prevent rejection after renal transplantation is a triple pack therapy consisting of steroids, a calcineurin inhibitor and MMF. Unfortunately, the desirable effect of preventing the rejection does not come without adverse drug effects and especially steroids show a profile with a wide range of adverse effects.The aim of this clinical trial is to combine a reduction of the calcineurin inhibitor using tacrolimus and a just very short-time use of steroids in order to minimize the adverse effect rate without increasing the rejection rate at the same time.

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Brief Summary in Scientific Language

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. With this therapy, rejection rates of/below 25% and graft and patient survival rates over 90% can be achieved 12 months post transplant. Due to higher potency, considering the adverse event profile of immunosuppression regarding cardiovascular risk factors, infections, malignant tumours, nephrotoxicity etc. becomes increasingly important. The adverse event profile of CNI respectively steroids is the reason for two current trends/concepts of the medical practice in kidney transplantation: CNI reduction/CNI-free regimen and steroid minimization/steroid-free regimen. 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. In this triple arm, prospectively randomized multi-center study phase IV 200 patients per treatment arm will be investigated for 12 months. Within this timeframe, 8 control investigations will take place. Provided that they fulfill predefined inclusion and exclusion criteria, all patients may only be allowed to participate in the clinical study after an information discussion, a written patient information and also their written consent afterwards.

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Organizational Data

  •   DRKS00000452
  •   2010/07/23
  •   2008/05/14
  •   yes
  •   Approved
  •   087/08, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   2007-006516-31 
  •   NCT00724022  (Clinicaltrials.gov)
  •   UKF001600  (Register klinische Studien des Universitätsklinikums Freiburg)
  •   4033996 
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Health Condition or Problem studied

  •   Z94.0 -  Kidney transplant status
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Interventions/Observational Groups

  •   Standard: Advagraf, CellCept, Decortin H + 2x Simulect Day 0 + 4
  •   Steroidfree: Advagraf, Cellcept, Decortin H until Day 8, 2x Simulect Day 0 + 4
  •   Steroidfree: Advagraf, Cellcept, Decortin H until Day 8, 3 x Thymoglobulin
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   IV
  •   [---]*
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Primary Outcome

Rate and degree of severity of acute rejections confirmed by biopsy and also assessment of the time to first rejection confirmed by biopsy.

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Secondary Outcome

• Rate of patients with steroid-free immunosuppression • 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)
• Number of steroid-resistant rejections • blood pressure level and also amount and types of blood pressure medications
• Lipid levels and also amount and types of lipid-lowering medications • body weight, relative weight gain [kg], BMI • infection rate, infection type and infection severity • anemia requiring erythropoietin treatment
• PTLD incidence • tumor incidence • inzidence 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 avascular necrosis
• incidence of osteoporosis (assessment of facture rate, osteodensitometry) • Wound healing disorders • incidence of chronic allograft nephropathy (CAN) (12-month histology) • incidence of CMV disease (qPCR >1000 copies/μL) • incidence of BKV disease (qPCR >1000 copies/μL) • incidence of EBV disease (qPCR >1000 copies/μL)
There are 8 control investigations: At at the time point zero, after 2 weeks, 4 weeks, 2 months, 3 months, 6 months, 9 months and 12 months.
At timepoint zero, inclusion and exclusion criteria are examined, the patient’s written consent is given, medical history, pregnancy test, data about the transplantation, vital signs, routine blood tests.
At timepoint 2-8, vital signs are measured and routine blood tests are examined. DXA-osteodensitometry is also an option at these timepoints. At each timepoint, data are recorded continuously. Normally, a biopsy is only performed on suspicion for a rejection. Within the design of this clinical trial, it is envisaged to perform a biopsy within 72 hours depending on the clinical risk/benefits analysis.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • [---]*
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Recruitment

  •   Actual
  •   2008/08/08
  •   600
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   75   Years
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Additional Inclusion Criteria

Inclusion Criteria:
To be eligible for the study, patients must fulfill all of the following 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 crossmatch.
• Patients with a signed informed consent form.
• Women of child-bearing age must agree to an efficient contraception.

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Exclusion Criteria

Exclusion Criteria:
Patients may not be allowed to participate in the clinical study, if they fulfill one of the following 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.

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Addresses

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    • Universitätsklinikum Freiburg
    • Mr.  Prof. Dr. Dr. h.c.  Ulrich Theodor  Hopt 
    • Hugstetter Str 55
    • 79106  Freiburg
    • Germany
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    • Uniklinik-Freiburg
    • Mr.  Prof. Dr.  Oliver  Thomusch 
    • Hugstetter Str. 55
    • 79106  Freiburg
    • Germany
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    • Uniklinik-Freiburg
    • Ms.  Karoline  Roether 
    • Hugstetterstr. 55
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Astellas Pharma GmbH
    • Georg-Brauchle-Ring 64-66
    • 80992  München
    • Germany
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    • Genzyme GmbH
    • Mr. 
    • Siemensstr. 5b
    • 63263  Neu Isenburg
    • Germany
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    •   Tel: +49 6012 3674-0
    •   Fax: +49 6102 3674 445
    •   [---]*
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Status

  •   Recruiting complete, follow-up complete
  •   2014/07/31
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.