| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prophylaxis of rejection in kidney allograft recipients (by immunosuppression) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prevention of kidney transplant rejection |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050436 |
| E.1.2 | Term | Prophylaxis against renal transplant rejection |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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) |
|
| E.2.2 | Secondary objectives of the trial |
| to compare the safety and efficacy profiles of the two therapy regimens with each other |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 one year).
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). |
|
| E.4 | Principal 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%. (Highest level in 6 months prior to transplant.)
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 patient's medical history or previous diagnosis of gestational diabetes or pre-Baseline HbA1C ≥6.5%.
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. |
|
| E.5 End points |
| E.5.1 | 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 1-3 should be confirmed by repeat testing (using the same test) ≥30 days after the initial positive assessment. Unequivocal hyperglycemia is sufficient to confirm diagnosis of NODAT. A repeat test is not required for Criteria 4.For the OGTT, the glucose drink should be druk over the course of 5 minutes. Timing of the test is taken from the beginning of the drink. Blood samples must be collected 2 hours after the test load (ideally within 5 minutes of the 120 minute time).
For criteria 1), 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.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
● Efficacy failure, composite endpoint consisting of any of the following:
a) graft loss
b) biopsy confirmed acute rejection (BCAR);
c) graft dysfunction.
● Positive Oral Glucose Tolerance Test (OGTT) at 8 weeks .
● Repeat OGTT at 24 weeks.
● Assess the role of recipient biomarkers on efficacy rate.
● Renal function.
● Acute rejections by signs and symptoms.
• Biopsy confirmed acute rejections:
● Subject and graft survival.
● Change from baseline in HbA1C levels at week 12 and week 24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Colombia |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Switzerland |
| Turkey |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study is defined as the last subject’s last protocol-defined assessment (performance of End of Study Visit or follow-up visit in the case of a withdrawn subject). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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