Efficacy and Safety of a Reduced Immunosuppression vs. Standard Triple Therapy in Senior Renal Transplant Recipients

Phase 4

• Conditions: Immunosuppression After Renal Transplantation
• Interventions: Drug: Tacrolimus; Other: Reduced immunosuppression; Drug: Steroids; Drug: mycophenolate

• Registration Number: NCT02453867
• Lead Sponsor: Klemens Budde

Brief Summary

Study purpose To establish efficacy and safety of a reduced immunosuppressive therapy with tacrolimus once daily for senior (\>65 years of age) renal transplant recipients

Detailed Description

Study outline Stable senior transplant recipients (\>65 years of age) participating in the European SENIOR transplant registry may enter the trial at month 3 post-transplant, if they fulfil all of the in- and none of the exclusion criteria. At this time patients will be randomized 1:1 either to continue

Reference therapy:

Tacrolimus once daily (Advagraf®) Mycophenolate (either MMF ≥1g/d or EC-MPS ≥720g/d) Steroids (≥5mg prednisolone or equivalent) or to Investigational therapy: Tacrolimus once daily (Advagraf®) Steroid stop at month 3 (tapering within 2 weeks) Mycophenolate stop at month 6

Study Timeline

• Study First Submitted: 2015-04-03
• Study First Submitted QC: 2015-05-21
• Study First Posted: 2015-05-27
• Status Verified: 2017-08
• Last Update Submitted: 2017-08-08
• Last Update Posted: 2017-08-09
• Study Start: 2017-12
• Primary Completion: 2018-07
• Study Completion: 2019-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 400

Inclusion Criteria

1. Males or females, aged ≥65 years and participating in the European SENIOR transplant registry
2. Patients who received a renal allograft 3 - 3.5 months prior to randomization.
3. Patient must have received primary or secondary renal allograft from a blood group compatible donor
4. Standard criteria donors (SCD), expanded criteria donors (ECD), donors after cardiac death (DCD) and living donors (LD) are eligible
5. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained
6. Patients on continuous standard triple therapy with tacrolimus once daily (Advagraf, trough level ≥5ng/ml) in combination with mycophenolate (either ≥1.0g/day MMF or ≥720mg/d EC-MPS) and steroids (≥5mg prednisolone or equivalent) since transplantation
7. Stable graft function with serum creatinine ≤2.5 mg/dl.
8. Patients with low to standard immunological risk, who had a PRA over 20% and no known donor specific antibodies (DSA) at transplantation

Exclusion Criteria

1. Patient with mental dysfunction or inability to comply with the study protocol
2. Patients, who - according to the investigator - require for medical reasons (e.g. previous rejections) continuous triple therapy or a different tacrolimus exposure
3. Multi-organ recipients (other solid organ (e.g. pancreas) or bone marrow)
4. Blood group ABO-incompatible allografts
5. Patients who suffered from severe T-cell mediated rejection (over Banff II acute rejection), recurrent acute rejection (>1 episode), or steroid resistant rejection post-transplant
6. History of antibody-mediated rejection (acute or chronic)
7. History of rejection 2 months prior to inclusion
8. Documented presence of donor specific antibodies (DSA) according to local lab results at baseline
9. Panel reactive antibody (PRA) >20% prior to transplantation, measured according to local standard
10. Patients receiving or having received Sirolimus, Everolimus, Azathioprine, Belatacept or Cyclophosphamide within 3 months prior to enrolment
11. Patients having received any other induction therapy than Basiliximab (e.g. depleting polyclonal antithymocyte antibodies (ATG), OKT3, Alemtuzumab)
12. Patients with proteinuria >1.0 g/day (or >1.0 g/g creatinine) at screening or having experienced nephrotic syndrome due to recurrence of focal segmental glomerulosclerosis (FSGS)
13. History of alcohol or drug abuse with less than 6 months of sobriety
14. Patient with a known hereditary immunodeficiency
15. Patient with active malignancy posttransplant with the exception of local, non-invasive, fully excised, cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, or cervical carcinoma in situ
16. Patients with clinically symptomatic congestive heart failure or symptomatic coronary artery disease
17. Patients with documented (either by serology and/or nuclear acid testing (NAT) clinically active infections (e.g. with a known Hepatitis B, Hepatitis C, HIV, CMV or BK virus infection)
18. Participation in any other investigational clinical trial 3 months before participation in this study, except the SENIOR transplant registry
19. Patients with leukopenia (<2500 cells/nl) or neutropenia (<1500 cells/nl)
20. Patients with thrombocytopenia (<100 cells/nl)
21. Patients with liver transaminases or bilirubin values > 3x normal values
22. Any significant diseases or clinically significant findings, including psychiatric and behavioural problems, medical history and/or physical examination findings that would in the opinion of the investigator preclude the patient from participating in the study.
23. Patients who have been institutionalized by official or court order

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard immunosuppression	Tacrolimus	starting immunosuppression: tacrolimus (Advagraf) (target trough levels \>5 ng/ml), mycophenolate mofetil \>1g/d in MMF or \>720 mg/d in mycophenolic acid, steroids from month 1-3 dosing according to local practice; 200 pts are planned to carry on with standard immunosuppression (tacrolimus (Advagraf), Mycophenolate, steroids) as stated above according to international guidelines for kidney transplant recipients from month 3 posttransplant to month 12 posttransplant
Standard immunosuppression	Steroids	starting immunosuppression: tacrolimus (Advagraf) (target trough levels \>5 ng/ml), mycophenolate mofetil \>1g/d in MMF or \>720 mg/d in mycophenolic acid, steroids from month 1-3 dosing according to local practice; 200 pts are planned to carry on with standard immunosuppression (tacrolimus (Advagraf), Mycophenolate, steroids) as stated above according to international guidelines for kidney transplant recipients from month 3 posttransplant to month 12 posttransplant
Reduced immunosuppression	Reduced immunosuppression	The Intervention is stopping medication: 200 pts are planned to receive a reduced immunosuppression after month 3: carry on with tacrolimus (Advagraf; trough levels \>5 ng/ml) steroids stop at month 3 mycophenolate stop at month 6
Reduced immunosuppression	Tacrolimus	The Intervention is stopping medication: 200 pts are planned to receive a reduced immunosuppression after month 3: carry on with tacrolimus (Advagraf; trough levels \>5 ng/ml) steroids stop at month 3 mycophenolate stop at month 6
Reduced immunosuppression	mycophenolate	The Intervention is stopping medication: 200 pts are planned to receive a reduced immunosuppression after month 3: carry on with tacrolimus (Advagraf; trough levels \>5 ng/ml) steroids stop at month 3 mycophenolate stop at month 6
Standard immunosuppression	mycophenolate	starting immunosuppression: tacrolimus (Advagraf) (target trough levels \>5 ng/ml), mycophenolate mofetil \>1g/d in MMF or \>720 mg/d in mycophenolic acid, steroids from month 1-3 dosing according to local practice; 200 pts are planned to carry on with standard immunosuppression (tacrolimus (Advagraf), Mycophenolate, steroids) as stated above according to international guidelines for kidney transplant recipients from month 3 posttransplant to month 12 posttransplant

Primary Outcome Measures

Name	Time	Method
Combined efficacy endpoint (BPAR, graft loss and death)	between randomization and month 12 posttransplant (month 9 of the study)	BPAR (biopsy proven acute rejection)

Secondary Outcome Measures

Name	Time	Method
Number of severe infections	between randomization and month 12 posttransplant	Numbers, type of infections will be registered
Number of opportunistic infections	between randomization and month 12 posttransplant	CMV infections, BKV infections; numbers, type of infection will be registered
Number of hospitalisations and days of hospitalisation	between randomization and month 12 posttransplant	number of episodes, days in hospital
Graft function by calculated glomarular filtration rate calculated by CKD-EPI	between randomization and month 12 posttransplant	Comparison of estimated glomerular filtration rate calculated by CKD-EPI formula
Number of occurrences and types of donor specific antibodies (DSA)	between randomization and month 12 posttransplant	surveillance of detection of new donor specific antibodies by Luminex assay