Evaluation of evolution of renal function in maintenance liver transplant recipients receiving either RAD001 (everolimus) plus reduced TAC or RAD001 (everolimus) plus MMF

• Register: EUCTR
• Last refreshed on: 12 October 2015
• Main ID: EUCTR2015-000590-12-DE
• Date of registration: 01/07/2015
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma GmbH
• Public title: Evaluation of evolution of renal function in maintenance liver transplant recipients receiving either RAD001 (everolimus) plus reduced TAC or RAD001 (everolimus) plus MMF
• Scientific title: A 24-month multi-center, open-label, randomized, controlled study to evaluate the evolution of renal function in maintenance liver transplant recipients receiving either RAD001 (everolimus) plus reduced TAC or RAD001 (everolimus) plus MMF - not applicable
• Date of first enrolment: 03/09/2015
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-000590-12
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Germany

Contacts

• Name: Medical Competence Center
• Affiliation: Novartis Pharma GmbH

• Name: Medical Competence Center
• Affiliation: Novartis Pharma GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion criteria at Screening Visit (Visit 1):
1. Patients willing and capable of providing written informed consent for study participation and able to participate in the study.
2. Adults 18 to 70 years of age at the time of inclusion, who received a primary liver allo¬graft from a deceased or living donor and are treated with a CNI containing immuno¬sup¬pres¬sive regimen.
3. Patients who had a liver transplant 6 to 24 months prior to Screening.
4. Estimated kidney function (MDRD 4) between chronic kidney disease (CKD) IIIb/ 30 mL/min < eGFR < CKD II/60 mL/min with deteriorating renal function (at the in¬ves¬ti-ga¬tor’s discretion), indicated by earlier local laboratory assessments not older than 3 months previous to Screening.
5. Acceptable graft function (aspartate amino transferase (AST), alanine aminotransferase (ALT) and total bilirubin = 3 × upper limit of normal (ULN) and alkaline phosphatase (ALP) = 5 × ULN), indicated by earlier local laboratory assessments not older than 3 months previous to Screening.

Inclusion criteria at Baseline Visit (Visit 2):
1. Estimated kidney function (MDRD 4) between CKD IIIb/ 30 mL/min < eGFR < CKD II/60 mL/min with deteriorating renal function (at the investigator’s discretion).
2. Acceptable graft function (AST, ALT and total bilirubin = 3 × ULN and ALP = 5 × ULN).

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 600
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 144

Exclusion criteria:
Exclusion criteria at Screening Visit (Visit 1):
1. Recipient of multiple solid organ transplants.
2. Patients with active chronic inflammatory bowel disease and recurrent autoimmune hepatitis (at the investigator’s discretion).
3. Patients with an mTOR-inhibitor based immunosuppressive therapy.
4. Patient with an identifiable cause of renal dysfunction other than CNI toxicity.
5. Patients who have any sign of malignant diseases other than neoplasms of the skin.
6. Patient who has received an unlicensed drug / therapy within one month prior to study entry or presence of any hypersensitivity to drugs similar to everolimus (e.g. macrolides).
7. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive HCG la¬bo-ra¬tory test.
8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to Screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject.
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cer¬vi-cal/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository.
• Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception, women should have been stable on the same pill for a minimum of three months.
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).

Exclusion criteria at Baseline Visit (Visit 2):
1. Patients with clinically significant or uncontrolled systemic infection requiring active use of intravenous antibiotics/antivirals at baseline.
2. Patients who are in a critical care setting at the time of baseline requiring life support measures, such as mechanical ventilation and dialysis.
3. Patient with platelet count = 50 000/mm3, white blood cell (WBC) count = 3 000/mm3, ab-so¬lute neutrophil count = 1 000/mm3 and hemoglobin = 8 g/dL.
4. Patients with more than one acute rejection 6 months prior to baseline and any acute re-jection within 6 weeks prior to baseline.
5. Patients with uncontrolled hyperlipidemia or proteinuria = 1.0 g/ 24 h (Protein/Creatinine-Ratio).
6. Hepatitis C virus positive patient who needs an active antiviral treatment and/or human immuno¬deficiency virus (HIV) positive patient. Negative laboratory results for HIV ob-tained 6 months prior to baseline are acceptable.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

liver transplantation
MedDRA version: 18.0 Level: LLT Classification code 10050434 Term: Prophylaxis against liver transplant rejection System Organ Class: 100000004865

Therapeutic area: Body processes [G] - Immune system processes [G12]

Intervention(s)

Trade Name: Certican
Product Name: Certican 0,25 mg
Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
CAS Number: 159351-69-6
Current Sponsor code: RAD001
Other descriptive name: EVEROLIMUS
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.25-

Trade Name: Certican
Product Name: Certican 0,5 mg
Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
CAS Number: 159351-69-6
Current Sponsor code: RAD001
Other descriptive name: EVEROLIMUS
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Certican
Product Name: Certican 0,75 mg
Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
CAS Number: 159351-69-6
Current Sponsor code: RAD001
Other descriptive name: EVEROLIMUS
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.75-

Trade Name: Certican
Product Name: Certican 1 mg
Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
CAS Number: 159351-69-6
Current Sponsor code: RAD001
Other descriptive name: EVEROLIMUS
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-

Product Name: Tacrolimus Monohydrate
Pharmaceutical Form:
INN or Proposed INN: Tacrolimus Monohydrate
CAS Number: 109581-93-3
Other descriptive name: TACROLIMUS MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 0.5-5

Trade Name: Cellcept
Product Name: Cellcept 250 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Mycophenolate Mofetil
CAS Number: 128794-94-5
Other descriptive name: MYCOPHENOLATE MOFETIL
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-

Trade Name: Cellcept
Product Name: Cellcept 500 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Mycophenolat Mofetil
CAS Number: 128794-94-5
Other descriptive name: MYCOPHENOLATE MOFETIL
C

Primary Outcome(s)

Secondary Objective: Secondary objectives are to evaluate the following:
• Efficacy failure defined as graft loss, tBPAR, death and loss to follow-up.
• Reasons for premature discontinuation of study medication and dose interruptions.
• The incidence of de novo malignant tumors.

Main Objective: The primary objective is to demonstrate that an immunosuppressive regimen based on everolimus plus MMF is superior compared to everolimus plus reduced TAC in preserving kidney function as measured by eGFR (abbreviated Modification of Diet in Renal Disease formula with 4 variables (MDRD-4 formula)) at Month 6 in maintenance liver transplant recipients.

Primary end point(s): Demonstration that an immunosuppressive regimen based on everolimus plus MMF is superior compared to everolimus plus reduced TAC in preserving kidney function as measured by eGFR in maintenance liver transplant recipients.

Timepoint(s) of evaluation of this end point: Month 6

Secondary Outcome(s)

Secondary end point(s): • Efficacy failure defined as graft loss, tBPAR, death and loss to follow-up.
• Reasons for premature discontinuation of study medication and dose interruptions.
• The incidence of de novo malignant tumors.

Timepoint(s) of evaluation of this end point: Month 24

Secondary ID(s)

CRAD001HDE53

Source(s) of Monetary Support

Novartis Pharma GmbH