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

Multicenter, Prospective, Randomized Study Investigating the Efficacy and Safety of a Reduced Immunosuppressive Therapy With Tacrolimus Once Daily in Comparison to Standard Triple Immunosuppression in Senior Renal Transplant Recipients

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

Study Overview

• Status: Unknown
• Conditions: Immunosuppression After Renal Transplantation
• Intervention / Treatment: Drug: Tacrolimus; Drug: mycophenolate; Drug: Steroids; Other: Reduced immunosuppression

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 Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lukas J Lehner, MD; Phone Number: 004930450613559; Email: lukas.lehner@charite.de
• Study Contact Backup: Name: Klemens Budde, MD; Phone Number: 004930450614086; Email: klemens.budde@charite.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Standard immunosuppression; 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	Drug: Tacrolimus; Tacrolimus is used in both the acitve comparator arm and the interventional arm; Other Names: Advagraf; Drug: mycophenolate; Mycophenolate is used in the acitve comparator arm for the whole study period; Mycophenolate is stopped at month 6 after Transplantation (month 3 of the study) in the experimental arm; Drug: Steroids; Steroids are used continually in the active comparator arm and are stopped at the beginning of the study (month 3 after Transplantation) as an Intervention in the experimental arm
EXPERIMENTAL: 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	Drug: Tacrolimus; Tacrolimus is used in both the acitve comparator arm and the interventional arm; Other Names: Advagraf; Drug: mycophenolate; Mycophenolate is used in the acitve comparator arm for the whole study period; Mycophenolate is stopped at month 6 after Transplantation (month 3 of the study) in the experimental arm; Other: Reduced immunosuppression; Stop steroids at month 3 Stop mycophenolate at month 6 continue tacrolimus once daily (Advagraf, trough levels > 5ng/ml) Stop mycophenolate at month 6

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Klemens Budde
• Collaborators: Charite University, Berlin, Germany; DESCARTES Working Group On Transplantation; European Kidney Transplant Association (EKITA); European Renal Association - European Dialysis and Transplant Association
• Investigators: Principal Investigator: Klemens Budde, MD, Charite Universitaetsmedizin Berlin

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): December 1, 2017
• Primary Completion (ANTICIPATED): July 1, 2018
• Study Completion (ANTICIPATED): July 1, 2019

Study Registration Dates

• First Submitted: April 3, 2015
• First Submitted That Met QC Criteria: May 21, 2015
• First Posted (ESTIMATE): May 27, 2015

Study Record Updates

• Last Update Posted (ACTUAL): August 9, 2017
• Last Update Submitted That Met QC Criteria: August 8, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: kidney transplantation; tacrolimus once daily; Senior; senior kidney transplant recipients; reduced immunosuppression; recipients >65 years
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: REDUCE; 2014-002643-18 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: aggregated data are available through the Steering committee of DESCARTES and EKITA

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No