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

NCT02540395 | Completed DMC

• 2 other identifiers: CELLIMIN2014-001325-33
• Study Type: interventional
• Target: 184
• Locations: 6 countries
• Sites: 8

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%.

Conditions

Disorder Related to Renal Transplantation; Effects of Immunosuppressant Therapy

Keywords

Kidney transplantation; Immunosuppression; IFN-γ

Outcome Measures

Primary Outcomes (1)

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

  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.

  6 months

Secondary Outcomes (20)

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

  after 3, 6 and 12 months

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

  after 6 and 12 months

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

  after 3 and 12 months

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

  after 6 and 12 months

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

  12 months

Study Arms (2)

Group A: Standard of care

ACTIVE COMPARATOR

Standard of care immunosuppressive regimen based on TAC (Prograf) (achieving 4-8ng/ml trough levels), MMF (Cellcept, Myfortic, Myfenax)(1gr bid) and steroids (6-methyl prednisolone, Urbason, Methypred) (according to KDIGO guidelines). All patients in group A recieve the tripple-drug IS as suggested by guidelines. In case of rejection the patients are treated with high dosage of Methypred and/or Thymoglobuline

Drug: Tacrolimus (for Group A); Drug: Mycofenolate mofetil (MMF) (for Group A); Drug: 6-methyl prednisolone (Steroids) (for Group A)

Group B: "Low" Immunosuppression regimen

EXPERIMENTAL

(based on TAC monotherapy (Prograf) to achieve 8-10 ng/ml trough levels during the first 4 weeks after transplantation and 6-8 ng/ml thereafter, MMF (Cellcept, Myfortic, Myfenax) (1g bid) during the first 7 days post-transplant and stopped thereafter) and steroids (6-methyl prednisolone; Urbason, Methypred) (tapering until discontinuation on month 2 post-transplant). In contrast to Group A the patients are treated with a two drug IS combination consisting of Prograf and Methypred. In case of rejection the patients are treated with hifg dosage of Methypred and/or Thymoglobuline.

Drug: Tacrolimus (for Group B); Drug: MMF (mycophenolate mofetil) (for Group B); Drug: 6-methyl prednisolone (Steroids) (for Group B)

Interventions

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.

Also known as: Prograf

Group B: "Low" Immunosuppression regimen

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.

Also known as: Cellcept, Myfortic, Myfenax

Group B: "Low" Immunosuppression regimen

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.

Also known as: Urbason, Methypred

Group B: "Low" Immunosuppression regimen

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.

Also known as: Prograf

Group A: Standard of care

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.

Also known as: Cellcept, Myfortic, Myfenax

Group A: Standard of care

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.

Also known as: Urbason, Methypred

Group A: Standard of care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Prof. Dr. Petra Reinke: lead

Study Sites (8)

Institut klinické a experimentální mediciny

Prague, Prague 4, 14021, Czechia

Location

Centre Hospitalier Universitaire de Nantes

Nantes, 44093, France

Location

Department Nephrology and BCRT, Charité Universitätsmedizin Berlin

Berlin, 13353, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universitätsklinikum Regensburg

Regensburg, Germany

Location

Academisch Medisch Centrum bij de Universiteit van Amsterdam

Amsterdam, Netherlands

Location

Hospital Universitari de Bellvitge

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Guy's Hospital, Great Maze Pond

London, SE1 9RT, United Kingdom

Location

MeSH Terms

Interventions

Tacrolimus; Mycophenolic Acid; Steroids; Methylprednisolone

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Fused-Ring Compounds; Polycyclic Compounds; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes

Study Officials

• Josep M. Grinyó, Prof. Dr.

  Renal Transplant Unit, Department Nephrology Bellvitge Universitari Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: representative of the sponsor

Study Record Dates

• First Submitted: August 19, 2015
• First Posted: September 4, 2015
• Study Start: March 1, 2015
• Primary Completion: October 1, 2020
• Study Completion: October 31, 2020
• Last Updated: February 1, 2021

Record last verified: 2021-01

Locations

GB (1); DE (3); ES (1); NL (1); FR (1); CZ (1)