INVESTIGATING NEW ONSET DIABETES MELLITUS IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING AN ADVAGRAF-BASED IMMUNOSUPPRESSIVE REGIMEN WITH OR WITHOUT CORTICOSTEROIDS – A MULTICENTER, TWO ARM, RANDOMIZED, OPEN LABEL CLINICAL STUDY - ADVANCE

• Register: EUCTR
• Last refreshed on: 13 May 2013
• Main ID: EUCTR2010-019638-28-FI
• Date of registration: 05/04/2011
• Prospective Registration: Yes
• Primary sponsor: Astellas Pharma Europe Ltd.
• Public title: INVESTIGATING NEW ONSET DIABETES MELLITUS IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING AN ADVAGRAF-BASED IMMUNOSUPPRESSIVE REGIMEN WITH OR WITHOUT CORTICOSTEROIDS – A MULTICENTER, TWO ARM, RANDOMIZED, OPEN LABEL CLINICAL STUDY - ADVANCE
• Scientific title: INVESTIGATING NEW ONSET DIABETES MELLITUS IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING AN ADVAGRAF-BASED IMMUNOSUPPRESSIVE REGIMEN WITH OR WITHOUT CORTICOSTEROIDS – A MULTICENTER, TWO ARM, RANDOMIZED, OPEN LABEL CLINICAL STUDY - ADVANCE
• Date of first enrolment: 05/05/2011
• Target sample size: 1166
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-019638-28
• 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

Belgium, Czech Republic, Estonia, Finland, France, Germany, Hungary, Italy, Latvia, Lithuania, Netherlands, Portugal, Romania, Spain, Sweden

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age = 18 years.
2. End stage kidney disease and a suitable candidate for primary renal transplantation or retransplantation (unless the graft was lost from rejection within 6 months).
3. Receiving a kidney transplant from a deceased or living (non HLA identical) donor with compatible AB0 blood type.
4. Female subjects of childbearing potential must have a negative serum or urine pregnancy test at enrollment and must agree to maintain highly effective birth control during the study.
A highly effective method of birth control is defined as those which result in a low failure rate (CPMP/ICH/286/95 modified) of less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomized partner.
5. Capable of understanding the purpose and risks of the study, fully informed and having given written informed consent (signed Informed Consent has been obtained).
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
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Receiving or having previously received an organ transplant other than a kidney.
2. Cold ischemia time of the donor kidney > 30 hours.
3. Panel Reactive Antibody (PRA) >20%.
4. Previous renal transplant lost within one year for immunological reasons.
5. Receiving a graft from a non-heart-beating donor other than of Maastricht category 3 (withdrawal of support awaiting cardiac arrest).
6. Significant liver disease, defined as having continuously elevated SGPT/ALT and/or
SGOT/AST and/or total bilirubin levels = 2 times the upper value of the normal range of the investigational site or is receiving a graft from a hepatitis C or B positive donor.
7. Diagnosis of Diabetes Mellitus prior to transplantation (treated with prescribed
medications or diet controlled) or where there is evidence of a previous positive OGTT in the patients medical history or previous diagnosis of gestational diabetes or Baseline HbA1C =6.5mmol/L.
8. Requiring initial sequential or parallel therapy with immunosuppressive antibody
preparation(s).
9. Requiring ongoing dosing with a systemic immunosuppressive drug prior to
transplantation (e.g. for Lupus Disease, FSGN etc) other than minimal levels of
immunosuppressant following failure of a previous transplantation without nephrectomy.
10. Where Physician considers long term steroid treatment is necessary for the prevention of recurrent auto immune mediated renal disease or if the subject requires ongoing dosing with corticosteroids during the study for any other condition.
11. Significant, uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or active peptic ulcer.
12. Pregnant woman or breast-feeding mother.
13. Subject or donor known to be HIV positive.
14. Known allergy or intolerance to tacrolimus, macrolide antibiotics, corticosteroids,
Basiliximab, mycophenolate mofetil or any of the product excipients.
15. Evidence of malignant disease within the last 5 years other than Basal Cell Carcinoma or Squamous Cell Carcinoma.
16. Currently participating in another clinical trial and/or has taken an investigational drug within 28 days prior to randomization.
17. Any form of substance abuse, psychiatric disorder or condition which, in the opinion of the investigator, may complicate communication with the investigator.
18. Unlikely to comply with the visits scheduled in the protocol.


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]

Prophylaxis of rejection in kidney allograft recipients (by immunosuppression)
MedDRA version: 13.1 Level: LLT Classification code 10050436 Term: Prophylaxis against renal transplant rejection System Organ Class: 10042613 - Surgical and medical procedures

Intervention(s)

Trade Name: Advagraf
Pharmaceutical Form: Prolonged-release 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: Advagraf
Pharmaceutical Form: Prolonged-release 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: Advagraf
Pharmaceutical Form: Prolonged-release capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987-11-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3-

Trade Name: Advagraf
Pharmaceutical Form: Prolonged-release capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987-11-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Secondary Objective: to compare the safety and efficacy profiles of the two therapy regimens with each other

Main Objective: To compare the two treatment arms with regard to incidence of new onset diabetes Mellitus as per the American Diabetic Association criteria at any point up to 24 weeks after kidney transplantation.
Arm 1: Advagraf + Basiliximab + MMF + Steroids (discontinued at 10 days)
Arm 2: Advagraf + Basiliximab + MMF + Steroids (optional intra-op Bolus only)

Primary end point(s): The primary endpoint of the study is the incidence of New Onset Diabetes Mellitus defined as:
Occurrence of NODAT as per ADA criteria at any point up to 24 weeks after kidney transplantation:

1. HbA1C =6.5% at or after the week 12 visit. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.
OR
2. FPG =126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 hours prior to blood sampling.*
OR
3. 2-h plasma glucose =200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*
OR
4. Symptoms of hyperglycemia and a casual plasma glucose =200 mg/dl (11.1mmol/l). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss.

* In the absence of unequivocal hyperglycemia, criteria 2) & 3) should be confirmed by repeat testing (using the same test) =30 days after the initial positive assessment. A repeat test is not required for 1) and 4). A single HbA1C result of = 6.5% at or after week 12 or unequivocal hyperglycemia (4) is sufficient to confirm diagnosis of NODAT.

For 2) & 3) the diagnosis will be classed as the time of the first test showing above criteria only if confirmed by a second reading using the same test, or if treatment for diabetes has been initiated
As per protocol, HbA1C will be measured at Baseline, Week 12 Week 24. OGTT will be measured at Week 8 and again at Week 24. Glucose will be measured at all study visits. The investigator may perform additional tests using the above methods at their discretion.

Timepoint(s) of evaluation of this end point: As per protocol, HbA1c will be measured at baseline, Week 12, Week 24.

Secondary Outcome(s)

Secondary end point(s): Efficacy failure defined using a composite endpoint consisting of any of the following:
a) graft loss, b) biopsy confirmed acute rejection, c) graft dysfunction.
Postive Oral Glucose Test, Renal function, Acute rejection, Subject and graft survival, Change from baseline in HbA1c levels at week 12 and week 24

Timepoint(s) of evaluation of this end point: Trouhgout the study

Secondary ID(s)

PMR-EC-1211

2010-019638-28-FR

Source(s) of Monetary Support

Astellas Pharma Europe Ltd.