Evaluate Efficacy Study of Combination Therapy of Everolimus and Low Dose Tacrolimus in Renal Allograft Recipients (PROTECT)

To Evaluate Prevention Effect Of Everolimus and Low-dose Tacrolimus in Comparison With Standard-dose Tacrolimus Therapy With Mycophenolic Acid on the New Onset Diabetes Mellitus After Transplantation in the Renal Allograft Recipients

To evaluate prevention effect of combination therapy of Everolimus and low-dose Tacrolimus in comparison with standard-dose Tacrolimus therapy with Mycophenolic acid on the New Onset Diabetes Mellitus after transplantation in the renal allograft recipients

Study Overview

• Status: Unknown
• Conditions: Kidney; Complications, Allograft
• Intervention / Treatment: Drug: Everolimus; Drug: Tacrolimus; Drug: Mycophenolic acid

Detailed Description

An open-label, randomized, multi-center, comparative parallel study to evaluate prevention effect of combination therapy of Everolimus and low-dose Tacrolimus in comparison with standard-dose Tacrolimus therapy with Mycophenolic acid on the New Onset Diabetes Mellitus after transplantation in the renal allograft recipients: PROTECT study

• Study Type: Interventional
• Enrollment (Anticipated): 234
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Recruiting
    • division of nephrology;Seoul St Mary's Hospital
    • Contact: Chul Woo Yang; Phone Number: 82-2-2258-6851; Email: yangch@catholic.ac.kr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 20 year old
2. At least 3 months after kidney transplantation
3. Subject who is using Tacrolimus ± purine synthesis inhibitor + steroid without change within the past 3 months (except the dosage)
4. MDRD eGFR ≥ 50 mL/min or serum creatinine < 2.0mg/dL within the past 3 months in the 6months after kidney transplantation
5. Rate of change of serum creatinine < +30% within the past 3 months in the 6months after kidney transplantation (if serum creatinine decreased, without rate of change is inclusion possible. if serum creatinine result was normal,regardless of the rate of change is able to register.)
6. Urine protein/creatinine ratio < 1g/g Cr (spot urine) Subject who is not applicable to the diagnostic criteria NODAT on
7. the baseline in the 6months after kidney transplantation
8. Subjects who agree with written informed consent

Exclusion Criteria:

1. Subjects who received combined non-renal transplantation
2. Subject who received re-transplantation
3. ABO blood group incompatible(when anti-ABO Antibody titer <1:128 is inclusion possible.)

4. Sensitized patients before transplantation

   • Pretransplant or peak PRA titer > 50%
   • Pretransplant T cell cytotoxicity crossmatch (+)
5. HLA-identical living related donor
6. Subject who has diabetes mellitus / NODAT before transplantation
7. Subject who has suffered acute rejection episode within the past 3 months in the 6months after kidney transplantation
8. Subject with hypersensitivity to everolimus
9. Subject who should continue nephrotoxic drug until enrollment (Aminoglycoside, amphotericin B, cisplatin)
10. Subject with GI disorder that might interfere with the ability to absorb oral medication. (eg, gastrectomy or insufficiently treated diabetic gastroenteropathy)
11. Subjects with active peptic ulcer
12. HIV, HBsAg, or HCV Ab tests (+)
13. Abnormal liver function test (AST or ALT or total bilirubin> upper normal limit x3)
14. ANC <1.5*109/L or WBC <2.5*109/L or platelet <75*109/L
15. Treatment with an investigational drug within 30 days preceding the first dose of trial medication
16. Women who are either pregnant, lactating, planning to become pregnant in the next 12 months.
17. Subjects with history of cancer(except successfully treated), localized nonmelanocytic skin cancer, PTLD(Post-transplant lymphoproliferative disorder)
18. Subjects with clinically significant infections within the past 4 weeks in the 6months after kidney transplantation
19. Subjects who took major surgery within the past 4 weeks in the 6months after kidney transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tacrolimus plus Everolimus; Low dose Tacrolimus + Everolimus	Drug: Everolimus; Decrease the level of Tacrolimus and add on Everolimus instead of Mycophenolic acid which is standard treatment.; Other Names: Certican; Drug: Tacrolimus; Decrease the level of Tacrolimus and add on Everolimus instead of Mycophenolic acid which is standard treatment.; Other Names: Tacroli
Active Comparator: Tacrolimus plus Mycophenolic acid; standard dose Tacrolimus + Mycophenolic acid	Drug: Tacrolimus; Decrease the level of Tacrolimus and add on Everolimus instead of Mycophenolic acid which is standard treatment.; Other Names: Tacroli; Drug: Mycophenolic acid; Decrease the level of Tacrolimus and add on Everolimus instead of Mycophenolic acid which is standard treatment.; Other Names: Cellcept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Development of NODAT (Fasting glucose ≥ 126 mg/dL, Random glucose ≥ 200 mg/dL) at 12 months	To evaluate prevention effect of combination therapy of Everolimus and low-dose Tacrolimus in comparison with standard-dose Tacrolimus therapy with Mycophenolic acid on the New Onset Diabetes Mellitus after transplantation at 12 months after date of randomization.	0 to 12 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin resistance by HOMA-IR	Change from Baseline(V2) in Insulin resistance by HOMA-IR at 12months(V6)	0 to 12 months
Insulin secretion by HOMA-beta	Change from Baseline(V2) in insulin secretion by HOMA-beta at 12 months(V6)	0 to 12 months
OGTT (Fasting and PP2hr)	Change from baseline in OGTT (Fasting and PP2hr) at 12 months(V6)	0 to 12 months
Needs for anti-diabetic medication or insulin	Needs for anti-diabetic medication or insulin at Baseline(V2)	at Baseline(V2)
Needs for anti-diabetic medication or insulin at 3 month(V3)	Needs for anti-diabetic medication or insulin at 3 month(V3)	at 3 month(V3)
Needs for anti-diabetic medication or insulin at 6 month(V4)	Needs for anti-diabetic medication or insulin at 6 month(V4)	at 6 month(V4)
Needs for anti-diabetic medication or insulin at 9 month(V5)	Needs for anti-diabetic medication or insulin at 9 month(V5)	at 9 month(V5)
Needs for anti-diabetic medication or insulin at 12 month(V6)	Needs for anti-diabetic medication or insulin at 12 month(V6)	at 12 month(V6)
Creatinine clearance (MDRD eGFR) at Baseline(V2)	Creatinine clearance (MDRD eGFR) at Baseline(V2)	at Baseline(V2)
Creatinine clearance (MDRD eGFR) at 3 month(V3)	Creatinine clearance (MDRD eGFR) at 3 month(V3)	at 3 month(V3)
Creatinine clearance (MDRD eGFR) at 6 month(V4)	Creatinine clearance (MDRD eGFR) at 6 month(V4)	at 6 month(V4)
Creatinine clearance (MDRD eGFR) at 9 month(V5)	Creatinine clearance (MDRD eGFR) at 9 month(V5)	at 9 month(V5)
Creatinine clearance (MDRD eGFR) at 12 month(V6)	Creatinine clearance (MDRD eGFR) at 12 month(V6)	at 12 month(V6)
12 month graft survival	After date of randomization, evaluate graft survival rate at 12 months(V6)	at 12 months(V6)
12 month patient survival rate	After date of randomization, evaluate patient survival rate at 12 months(V6)	at 12 months(V6)
Change from baseline in Microalbuminuria(MAU) at 12 months	Change from baseline in Microalbuminuria(MAU) at 12 months	at 12 months(V6)
Proportion of patients with significant proteinuria greater than 1g/gCr at Baseline(V2)	Proportion of patients with significant proteinuria greater than 1g/gCr at Baseline(V2)	at Baseline(V2)
Proportion of patients with significant proteinuria greater than 1g/gCr at 3 month(V3)	Proportion of patients with significant proteinuria greater than 1g/gCr at 3 month(V3)	at 3 month(V3)
Proportion of patients with significant proteinuria greater than 1g/gCr at 6 month(V4)	Proportion of patients with significant proteinuria greater than 1g/gCr at 6 month(V4)	at 6 month(V4)
Proportion of patients with significant proteinuria greater than 1g/gCr at 9 month(V5)	Proportion of patients with significant proteinuria greater than 1g/gCr at 9 month(V5)	at 9 month(V5)
Proportion of patients with significant proteinuria greater than 1g/gCr at 12 month(V6)	Proportion of patients with significant proteinuria greater than 1g/gCr at 12 month(V6)	at 12 month(V6)
Number of episode of biopsy proven acute rejection (BPAR)	Cumulative incidence rate of Biopsy Proven Acute Rejection(BPAR) at 12months(V6) after date of randomization.	at 12 month(V6)
Number of hospitalization of any cause (except admission for protocol biopsy) at Baseline(V2)	Number of hospitalization of any cause (except admission for protocol biopsy) at Baseline(V2)	at Baseline(V2)
Number of hospitalization of any cause (except admission for protocol biopsy) at 3 month(V3)	Number of hospitalization of any cause (except admission for protocol biopsy) at 3 month(V3)	at 3 month(V3)
Number of hospitalization of any cause (except admission for protocol biopsy) at 6 month(V4)	Number of hospitalization of any cause (except admission for protocol biopsy) at 6 month(V4)	at 6 month(V4)
Number of hospitalization of any cause (except admission for protocol biopsy) at 9 month(V5)	Number of hospitalization of any cause (except admission for protocol biopsy) at 9 month(V5)	at 9 month(V5)
Number of hospitalization of any cause (except admission for protocol biopsy) at 12 month(V6)	Number of hospitalization of any cause (except admission for protocol biopsy) at 12 month(V6)	at 12 month(V6)
Number of opportunistic infections (BKVN) at Baseline(V2)	Number of opportunistic infections (BKVN) at Baseline(V2)	at Baseline(V2)
Number of opportunistic infections (BKVN) at 12month(V6)	Number of opportunistic infections (BKVN) at 12month(V6)	at 12 month(V6)
Prevalence of NODAT at Baseline(V2)	Prevalence of NODAT at Baseline(V2)	at Baseline(V2)
Prevalence of NODAT at 3 month(V3)	Prevalence of NODAT at 3 month(V3)	at 3 month(V3)
Prevalence of NODAT at 6 month(V4)	Prevalence of NODAT at 6 month(V4)	at 6 month(V4)
Prevalence of NODAT at 9 month (V5)	Prevalence of NODAT at 9 month (V5)	at 9 month (V5)
Prevalence of NODAT at 12 month(V6)	Prevalence of NODAT at 12 month(V6)	at 12 month(V6)

Collaborators and Investigators

• Sponsor: Seoul St. Mary's Hospital
• Collaborators: Novartis
• Investigators: Principal Investigator: Chul-Woo Yang, MD, St Mary's Hospital, London

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Anticipated): December 1, 2015
• Study Completion (Anticipated): December 1, 2015

Study Registration Dates

• First Submitted: December 23, 2013
• First Submitted That Met QC Criteria: January 13, 2014
• First Posted (Estimate): January 15, 2014

Study Record Updates

• Last Update Posted (Estimate): September 25, 2014
• Last Update Submitted That Met QC Criteria: September 22, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus
• Other Study ID Numbers: CRAD001AKR11T