A 24 month, multicenter, randomized, open-label safety and efficacy study of concentration-controlled everolimus with reduced calcineurin inhibitor vs mycophenolate with standard calcineurin inhibitor in de novo renal transplantation

• Register: EUCTR
• Last refreshed on: 5 February 2018
• Main ID: EUCTR2013-000322-66-ES
• Date of registration: 08/10/2013
• Prospective Registration: Yes
• Primary sponsor: Novartis Farmacéutica, S.A.
• Public title: A 24 month, multicenter, randomized, open-label safety and efficacy study of concentration-controlled everolimus with reduced calcineurin inhibitor vs mycophenolate with standard calcineurin inhibitor in de novo renal transplantation
• Scientific title: A 24 month, multicenter, randomized, open-label safety and efficacy study of concentration-controlled everolimus with reduced calcineurin inhibitor vs mycophenolate with standard calcineurin inhibitor in de novo renal transplantation - Advancing renal TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen (TRANSFORM) - Advancing renal TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen (TRANSFORM)
• Date of first enrolment: 21/11/2013
• Target sample size: 2040
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-000322-66
• 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
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Colombia, Croatia, Czech Republic, Egypt, France, Germany, Greece, Guatemala, India, Indonesia, Italy, Japan, Jordan, Korea, Republic of, Kuwait, Lebanon, Malaysia, Mexico, Netherlands, Norway, Panama, Philippines, Poland, Portugal, Russian Federation, Saudi Arabia, Singapore, Slovakia, Slovenia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, United States, Venezuela, Bolivarian Republic of

Contacts

• Name: Departamento Médico (ICRO)
• Affiliation: Novartis Farmacéutica, S.A.

• Name: Departamento Médico (ICRO)
• Affiliation: Novartis Farmacéutica, S.A.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Written informed consent obtained.

2. Male or female subject > and equal 18 years old

3. Subject randomized within 24 hr of completion of transplant surgery.

4. Recipient of a kidney with a cold ischemia time < 30 hours.

5. Recipient of a primary (or secondary, if first graft is not lost due to immunological reasons) renal transplant from a deceased heart beating, living unrelated, living related non-human leukocyte antigen identical or an expanded criteria donor.
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 2040
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 200

Exclusion criteria:
1. Subject unable to tolerate oral medication at time of randomization.
2. Use of other investigational drugs at the time of enrollment
3. History of hypersensitivity to any of the study drugs or similar chemical classes.
4. multi-organ transplant recipient
5. Recipient of ABO incompatible allograft or complement-dependent lymphocytotoxic (CDC) crossmatch positive transplant
6. high immunological risk by assessment of anti-donor reactivity e.g. high PRA, presence of pre-existing DSA
7. HIV positive
8. HBsAg and/or a HCV positive with evidence of elevated LFTs (ALT/AST levels ? 2.5 times ULN)
9. Recipient of a kidney from a donor who tests positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV)
10. BMI greater than 35
11. severe systemic infections
12. Subject requiring systemic anticoagulation
13. History of malignancy
14. severe restrictive or obstructive pulmonary disorders
15. severe hypercholesterolemia or hypertriglyceridemia
16. white blood cell (WBC) count ? 2,000 /mm3 or with platelet count ? 50,000 /mm3.
17. Pregnant or nursing (lactating) women
18. Women of child-bearing potential


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

Health Condition(s) or Problem(s) studied

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

Adult kidney transplant recipients.
MedDRA version: 16.0 Level: LLT Classification code 10064848 Term: Chronic kidney disease System Organ Class: 100000004857

Intervention(s)

Trade Name: Certican 0,25mg
Product Name: Certican 0.25mg
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 0,5mg
Product Name: Certican 0.5mg
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: 0.50-

Trade Name: Certican 0,75mg
Product Name: Certican 0.75mg
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 1mg
Product Name: Certican 1.0mg
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: 1.00-

Trade Name: PROGRAF 0,5 mg
Product Name: PROGRAF 0,5 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987-11-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: PROGRAF 1MG
Product Name: PROGRAF 1 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987-11-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-

Trade Name: PROGRAF 5MG
Product Name: prograf 5 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987-11-3
Other descriptive name: PROGRAF
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trad

Primary Outcome(s)

Main Objective: Evaluate the effect of everolimus with reduced exposure CNI versus MPA with standard exposure CNI on the binary composite of treated biopsy-proven acute rejection (tBPAR) or eGFR < 50
mL/min/1.73m2 (estimated glomerular filtration rate by MDRD4 formula) at Month 12 post-transplantation.

Secondary Objective: Key secondary objectives:

- To evaluate everolimus with reduced exposure CNI compared to MPA plus standard exposure CNI at 12 months post-transplantation with respect to the composite efficacy failure rate of (treated biopsy proven acute rejection (tBPAR), graft loss or death).
- To evaluate the binary composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2 (MDRD4) Month 12 among compliant subjects.

See protocol section 2.2 for other secondary objectives.

Timepoint(s) of evaluation of this end point: At 12-month after transplantation.

Primary end point(s): The primary analysis will be performed on the Full Analysis Set following the intent-to-treat principle. The primary endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 will be tested at the significance level of 0.05. Event rates will be compared between groups using a 2-stage approach (hierarchical testing strategy). First, noninferiority of EVR plus reduced CNI vs. MPA plus standard CNI will be evaluated using a 10% non-inferiority margin. If this is significant, then superiority will be evaluated. Based on the closed testing principle, no multiplicity adjustment will be made for testing for both non-inferiority and superiority.

Secondary Outcome(s)

Secondary end point(s): With respect to the key secondary endpoint - composite efficacy failure of tBPAR, graft loss or death at Month 12, non-inferiority of EVR plus reduced CNI vs. MPA plus standard CNI will be evaluated at the significance level of 0.05 using a 10% non-inferiority margin based on the Full Analysis Set.
To evaluate the binary composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2 (MDRD4) Month 12 among compliant subjects.

Timepoint(s) of evaluation of this end point: At 12-month after transplantation.

Secondary ID(s)

CRAD001A2433

2013-000322-66-DE

Source(s) of Monetary Support

Novartis Pharma Services AG