Clinical trial NCT02540395: Prospective Donor Specific T Response Measurment for IS Minimization in de Novo Renal Transplantation
Official title: Prospective Donor-specific Cellular Alloresponse Assessment for Immunosuppression Minimization in de Novo Renal Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Disorder Related to Renal Transplantation
Effects of Immunosuppressant Therapy
Keywords: Kidney transplantation
Immunosuppression
IFN-γ
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
First posted: 2015-09-04
Enrollment: 184
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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%.


Eligibility criteria: Inclusion Criteria:

1. Men and women, age ≥18 years.
2. Subject must be a recipient of a first renal transplant from a deceased or living donor.
3. 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®).
4. Subject is willing to provide signed written informed consent.
5. 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:

1. 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®).
2. CDC (complement dependent cytotoxicity) positive cross match.
3. Subjects receiving an allograft from a donor older than 65 years with elevated creatinine levels and/or treated diabetes.
4. Cold ischemia time (CIT) higher than 24h.
5. Subjects with a prior solid organ transplant (SOT), including renal re-transplantation, or receiving a concurrent SOT.
6. Patients previously treated with daclizumab or basiliximab.
7. 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.
8. 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.
9. Subjects with known human immunodeficiency virus (HIV) infection.
10. Patients with active systemic infection that requires the continued use of antibiotics.
11. Patients with neoplasia except localized skin cancer receiving appropriate treatment.
12. Patients with severe anemia (hemoglobin \< 6g/dl), leucopenia (WBC (White blood cells) \<2500/mm3), thrombocytopenia (platelets \<80.000/mm3).
13. Hemodynamically instable patients even if their hemoglobin level counts \> 6 g/dl.
14. Patients with intestinal pathology or severe diarrhoea that can hinder absorption according to medical criteria.
15. Subjects with a known hypersensibility to any of the drugs used in this protocol.
16. Subjects who have used any investigational drug within 30 days prior to enrolment in this clinical trial.
17. 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.
18. Subjects who are legally detained in an official institution

Primary outcomes:
measure: assessment of anti-donor T-cell alloresponses using the IFN-γ ELISPOT test
timeFrame: 6 months
Secondary outcomes:
measure: Differences across Treatment arms in eGFR (estimated glomerular Filtration rate) (ml/min)
timeFrame: after 3, 6 and 12 months
measure: Differences across Treatment arms in Biopsy proven acute rejection rate (BPAR rate)
timeFrame: after 6 and 12 months
measure: Differences across Treatment arms in subclinical rejection rate using renal allograft biopsy
timeFrame: after 3 and 12 months
measure: Differences across Treatment arms in Prevalence of death, and graft loss
timeFrame: after 6 and 12 months
measure: Differences across Treatment arms in Prevalence of metabolic and cardiovascular co-morbidity (new onset diabetes mellitus (NODAT, dyslipidaemias, hypertension)
timeFrame: 12 months
measure: Differences across Treatment arms in Prevalence of subjects that remain MMF and steroid-free
timeFrame: after 6 and 12 months
measure: Differences across Treatment arms in Prevalence of Acute and chronic histologic lesions assessed by the Bannf'11 score in protocol biopsies
timeFrame: after 3 and 12 months
measure: Differences across Treatment arms in Prevalence of patients that remain on Therapy
timeFrame: after 12 months
measure: Differences across Treatment arms in Distribution of patients in distinct chronic kidney diseases (CKD) stages
timeFrame: after 12 months
measure: Differences across Treatment arms in treatment cost (cost/benefit)
timeFrame: after 1,3,6,12 and 24 months
measure: 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
timeFrame: at pre-transplantation, 3, 6 and 12 months after transplantation as well as at time of BPAR
measure: Differences across Treatment arms in assessment of anti-donor and anti-HLA antibodies by Solid phase assays (Luminex®) and B-cell ELISPOT
timeFrame: at pre-transplantation, 3, 6 and 12 months after transplantation as well as at time of BPAR
measure: Differences across Treatment arms in different viral load (CMV, EBV, BKV)
timeFrame: at months 1, 2, 3, 6 and 12 after transplantation
measure: Differences across Treatment arms in study of virus-specific T-cell responses (ELISPOT)
timeFrame: at at pre-transplantation, 3, 6 and 12 after transplantation
measure: Differences across Treatment arms in prevalence of transcriptional genes by RT-PCR in PBMC (peripheral blood mononuclear cells )
timeFrame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of BPAR
measure: Differences across Treatment arms in flow cytometry assessment of peripheral blood mononuclear cells (PBMC)
timeFrame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of BPAR
measure: Differences across Treatment arms in Quantitative analyses of urinary IP-10 (Interferon Gamma induced Protein)
timeFrame: at 4 weeks and at 3, 6 and 12 month after transplantation as well as at time of BPAR
measure: Differences across Treatment arms in Assessment of protocol biopsies
timeFrame: at month 3 and 12 after transplantation
measure: Differences across Treatment arms in MicroRNA assessment in sera and urine
timeFrame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation
measure: Differences across Treatment arms in evaluation of FOXP3 (Forkhead box P3) methylation degree at the TSDR (Treg-specific demethylated Region)
timeFrame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of rejection
Other outcomes:
Locations:
city: Prague
country: Czechia
facility: Institut klinické a experimentální mediciny
state: Prague 4
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Berlin
country: Germany
facility: Department Nephrology and BCRT, Charité Universitätsmedizin Berlin
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum bij de Universiteit van Amsterdam
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
state: Barcelona
city: London
country: United Kingdom
facility: Guy's Hospital, Great Maze Pond
Study officials:
affiliation: Renal Transplant Unit, Department Nephrology Bellvitge Universitari Hospital
name: Josep M. Grinyó, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: