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

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ClinicalTrials.gov Identifier: NCT00724022
Recruitment Status : Completed
First Posted : July 29, 2008
Last Update Posted : October 1, 2014
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

Study Description
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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.

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

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : June 2008
Actual Primary Completion Date : July 2014
Actual Study Completion Date : July 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Basiliximab

Arms and Interventions
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Arm Intervention/treatment
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


Outcome Measures
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Primary Outcome Measures :
  1. Efficacy of immunosuppression measured in rejection rate confirmed by biopsy according to BANFF 97, modified 2005. [ Time Frame: one year after transplantation ]

Secondary Outcome Measures :
  1. Rate of patients with steroid-free immunosuppression
    Rate of patients with steroid-free immunosuppression

  2. patient and graft survival rate
    patient and graft survival rate

  3. 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)

  4. Number of steroid-resistant rejections
    Number of steroid-resistant rejections

  5. blood pressure level and also amount and types of blood pressure medications
    blood pressure level and also amount and types of blood pressure medications

  6. Lipid levels and also amount and types of lipid-lowering medications
    Lipid levels and also amount and types of lipid-lowering medications

  7. body weight, relative weight gain [kg], BMI
    body weight, relative weight gain [kg], BMI

  8. infection rate, infection type and infection severity
    infection rate, infection type and infection severity

  9. anemia requiring erythropoietin treatment
    anemia requiring erythropoietin treatment

  10. PTLD incidence
    PTLD incidence

  11. tumor incidence
    tumor incidence

  12. 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

  13. incidence of cataracts
    incidence of cataracts

  14. incidence of avascular necrosis
    incidence of avascular necrosis

  15. incidence of osteoporosis
    incidence of osteoporosis (assessment of fracture rate, osteodensitometry)

  16. Wound healing disorders
    Wound healing disorders

  17. incidence of chronic allograft nephropathy (CAN) (12-month histology)
    incidence of chronic allograft nephropathy (CAN) (12-month histology)

  18. incidence of CMV disease (qPCR >1000 copies/μL)
    incidence of CMV disease (qPCR >1000 copies/μL)

  19. incidence of BKV disease (qPCR >1000 copies/μL)
    incidence of BKV disease (qPCR >1000 copies/μL)

  20. incidence of EBV disease (qPCR >1000 copies/μL)
    incidence of EBV disease (qPCR >1000 copies/μL)


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00724022


Locations
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Sponsors and Collaborators
University Hospital Freiburg
Roche Pharma AG
Astellas Pharma GmbH
Genzyme, a Sanofi Company
Investigators
Layout table for investigator information
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
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: Prof. Dr.med. Oliver Thomusch, Professor, University Hospital Freiburg
ClinicalTrials.gov Identifier: NCT00724022    
Other Study ID Numbers: IT1850071
EudraCT No. 2007-006516-31
DRKS00000452 ( Registry Identifier: German Clinical Trials Register )
First Posted: July 29, 2008    Key Record Dates
Last Update Posted: October 1, 2014
Last Verified: September 2014
Keywords provided by Prof. Dr.med. Oliver Thomusch, University Hospital Freiburg:
Kidney transplant status
Steroid free
Reduced
 Calcineurin
Inhibitor
Immunosuppression
Additional relevant MeSH terms:
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Mycophenolic Acid
Prednisolone
Tacrolimus
Thymoglobulin
Basiliximab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
 Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents