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Completed

NCT Number: NCT02540395

Prospective Donor Specific T Response Measurment for IS Minimization in de Novo Renal Transplantation

The main objective of the study is to demonstrate the utility and safety of the IFN-γ (Interferon Gamma) ELISPOT (Enzyme-linked immunosorbent spot) marker for the stratification of kidney transplant recipients into low and high IS (Immunosuppression) regimens. The enrichment study will test non-inferiority of low IS regimen compared to high IS regimen, assuming 10% of BPAR at 6-months in the control group, and allowing a non-inferiority limit of maximum 10%.

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Key information

Conditions

Disorder Related to Renal Transplantation Effects of Immunosuppressant Therapy

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Institut klinické a experimentální mediciny, Prague, Prague 4, Czechia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Men and women, age ≥18 years.
  • Subject must be a recipient of a first renal transplant from a deceased or living donor.
  • Subject must have a current documented PRA (Panel of reactive antibodies) <20% and no detectable anti-class I and II HLA (human leukocyte Antigens) antibodies by solid phase assay (Luminex®).
  • Subject is willing to provide signed written informed consent.
  • Women of Childbearing Potential (WOCBP) must be using a highly effective method of contraception (Pearl-Index < 1) to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL]. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG (Human chorionic gonadotropin)) within 72 hours prior to the start of clinical trial.

Exclusion criteria

  • Subjects undergoing renal transplant with a current documented PRA >20% and/or detectable anti-class I and II HLA antibodies by solid phase assay (Luminex®).
  • CDC (complement dependent cytotoxicity) positive cross match.
  • Subjects receiving an allograft from a donor older than 65 years with elevated creatinine levels and/or treated diabetes.
  • Cold ischemia time (CIT) higher than 24h.
  • Subjects with a prior solid organ transplant (SOT), including renal re-transplantation, or receiving a concurrent SOT.
  • Patients previously treated with daclizumab or basiliximab.
  • Subjects with underlying renal disease of:
  • Primary focal segmental glomerulosclerosis.
  • Type I or II membranoproliferative glomerulonephritis
  • Atypical Haemolytic uremic syndrome (HUS) / thrombotic thrombocytopenic purpura syndrome.
  • Subject with Hepatitis B chronic infection and/or active infection by Hepatitis C virus (positive PCR (polymerase chain reaction result) at the moment of transplant.
  • Subjects with known human immunodeficiency virus (HIV) infection.
  • Patients with active systemic infection that requires the continued use of antibiotics.
  • Patients with neoplasia except localized skin cancer receiving appropriate treatment.
  • Patients with severe anemia (hemoglobin < 6g/dl), leucopenia (WBC (White blood cells) <2500/mm3), thrombocytopenia (platelets <80.000/mm3).
  • Hemodynamically instable patients even if their hemoglobin level counts > 6 g/dl.
  • Patients with intestinal pathology or severe diarrhoea that can hinder absorption according to medical criteria.
  • Subjects with a known hypersensibility to any of the drugs used in this protocol.
  • Subjects who have used any investigational drug within 30 days prior to enrolment in this clinical trial.
  • WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period, women who are pregnant or breastfeeding or women with a positive pregnancy test on enrolment.
  • Subjects who are legally detained in an official institution

Treatment and study plan

Tacrolimus (for Group B)

Drug

Tacrolimus (for Group B) will be administered orally twice a day (bid). Tacrolimus (for Group B) will be initially given at the 0,1mg/kg bid to achieve a stable 12-hour trough level of 8-10 ng/mL during the first month after transplantation to progressively tapper to 6-8ng/ml thereafter.

Other names: Prograf

MMF (mycophenolate mofetil) (for Group B)

Drug

MMF (mycophenolate mofetil) will be administered orally to patients in group B at conventional doses (1gr/12h) before transplant procedure and during the first 7 days after transplant. For subjects who develop nausea, diarrhea, or other MMF(mycophenolate mofetil) -related gastrointestinal adverse effects (eg, symptoms fully assessed and deemed not to have an etiology other than intolerability to MMF), the MMF(mycophenolate mofetil) dose may be decreased to the maximally tolerated dose.

Subjects unable to tolerate the reduced dose may be converted to mycophenolate sodium (Myfortic™) or to Myfenax.

From day 8 on, patients will not receive MMF.

Other names: Cellcept, Myfortic, Myfenax

6-methyl prednisolone (Steroids) (for Group B)

Drug

At the time of surgery, all patients will receive 500mg of 6-methyl prednisolone (Steroids, Urbason, Methypred).

Patients in group B will receive 250mg of 6-methyl prednisolone (or equivalent) on day 2, 125 mg on day 3, 60 mg on day 4 and 30 mg on day 5. From day 6 on, patients will receive 0.25 mg/kg/d of 6-methyl-prednisolone (Steroids, Urbason, Methypred) until month 1, then tapering until discontinuation on month 2 will be performed.

Other names: Urbason, Methypred

Tacrolimus (for Group A)

Drug

The study group A will receive Tacrolimus (for Group A) (Prograf) to achieve 4-8 ng/ml trough levels during all the duration of the study.

Tacrolimus (for Group A) (Tacrolimus) capsules should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption.

Other names: Prograf

Mycofenolate mofetil (MMF) (for Group A)

Drug

Mycophenolate mofetil (MMF) (Cellcept, Myfortic, Myfenax) (for Group A) will be administered orally to patients in group A at conventional doses (1gr/12h). For subjects who develop nausea, diarrhea, or other Mycophenolate mofetil (MMF) (for Group A) -related gastrointestinal adverse effects (eg, symptoms fully assessed and deemed not to have an etiology other than intolerability to Mycophenolate mofetil (MMF) (for Group A), the Mycophenolate mofetil (MMF) (for Group A) dose may be decreased to the maximally tolerated dose.

Subjects unable to tolerate the reduced dose may be converted to mycophenolate sodium (Myfortic™).

The first dose of Mycophenolate mofetil (MMF) (for Group A) should be administered before transplantation.

Other names: Cellcept, Myfortic, Myfenax

6-methyl prednisolone (Steroids) (for Group A)

Drug

At the time of surgery, all patients will receive 500 mg of 6-methyl prednisolone (steroids for Group A).

Patients in arm A will receive 20 mg/day of 6-methyl prednisolone (steroids for Group A) (or the equivalent) during the first 2 weeks after transplantation, then tapering to 15 mg from week 3 to week 4 to finally be maintained at 5mg/day.

Other names: Urbason, Methypred

Primary outcomes

  1. assessment of anti-donor T-cell alloresponses using the IFN-γ ELISPOT test

    Time frame: 6 months

    Patients with a positive anti-donor IFN-γ ELISPOT assay result (>25 spots/300.000 PBMC (peripheral blood mononuclear cells )) will be ruled out of the study and patients with negative anti-donor IFN-γ ELISPOT test (<25 spots/300.000 PBMC) will be randomized in 2 different groups (1:1).

    The main objective of the study is to demonstrate the utility and safety of the IFN-γ ELISPOT marker for the stratification of kidney transplant recipients into low and high IS regimens.

Secondary outcomes

  1. Differences across Treatment arms in eGFR (estimated glomerular Filtration rate) (ml/min)

    Time frame: after 3, 6 and 12 months

  2. Differences across Treatment arms in Biopsy proven acute rejection rate (BPAR rate)

    Time frame: after 6 and 12 months

  3. Differences across Treatment arms in subclinical rejection rate using renal allograft biopsy

    Time frame: after 3 and 12 months

  4. Differences across Treatment arms in Prevalence of death, and graft loss

    Time frame: after 6 and 12 months

  5. Differences across Treatment arms in Prevalence of metabolic and cardiovascular co-morbidity (new onset diabetes mellitus (NODAT, dyslipidaemias, hypertension)

    Time frame: 12 months

  6. Differences across Treatment arms in Prevalence of subjects that remain MMF and steroid-free

    Time frame: after 6 and 12 months

  7. Differences across Treatment arms in Prevalence of Acute and chronic histologic lesions assessed by the Bannf'11 score in protocol biopsies

    Time frame: after 3 and 12 months

  8. Differences across Treatment arms in Prevalence of patients that remain on Therapy

    Time frame: after 12 months

  9. Differences across Treatment arms in Distribution of patients in distinct chronic kidney diseases (CKD) stages

    Time frame: after 12 months

  10. Differences across Treatment arms in treatment cost (cost/benefit)

    Time frame: after 1,3,6,12 and 24 months

  11. Differences across Treatment arms in development of a Panel reactive T (PRT)-cell response platform to evaluate general anti-HLA T-cell Responses using ELISPOT

    Time frame: at pre-transplantation, 3, 6 and 12 months after transplantation as well as at time of BPAR

  12. Differences across Treatment arms in assessment of anti-donor and anti-HLA antibodies by Solid phase assays (Luminex®) and B-cell ELISPOT

    Time frame: at pre-transplantation, 3, 6 and 12 months after transplantation as well as at time of BPAR

  13. Differences across Treatment arms in different viral load (CMV, EBV, BKV)

    Time frame: at months 1, 2, 3, 6 and 12 after transplantation

  14. Differences across Treatment arms in study of virus-specific T-cell responses (ELISPOT)

    Time frame: at at pre-transplantation, 3, 6 and 12 after transplantation

  15. Differences across Treatment arms in prevalence of transcriptional genes by RT-PCR in PBMC (peripheral blood mononuclear cells )

    Time frame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of BPAR

  16. Differences across Treatment arms in flow cytometry assessment of peripheral blood mononuclear cells (PBMC)

    Time frame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of BPAR

  17. Differences across Treatment arms in Quantitative analyses of urinary IP-10 (Interferon Gamma induced Protein)

    Time frame: at 4 weeks and at 3, 6 and 12 month after transplantation as well as at time of BPAR

  18. Differences across Treatment arms in Assessment of protocol biopsies

    Time frame: at month 3 and 12 after transplantation

  19. Differences across Treatment arms in MicroRNA assessment in sera and urine

    Time frame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation

  20. Differences across Treatment arms in evaluation of FOXP3 (Forkhead box P3) methylation degree at the TSDR (Treg-specific demethylated Region)

    Time frame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of rejection

Sponsors and collaborators

Lead sponsor

Prof. Dr. Petra Reinke

Other

Registry information

Official study title

Prospective Donor-specific Cellular Alloresponse Assessment for Immunosuppression Minimization in de Novo Renal Transplantation

Important dates

Study start
2015
Primary completion
2020
Study completion
2020
First posted
Sep 4, 2015
Registry last updated
Feb 1, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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