| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Renal function in kidney transplant
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| 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 |
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| 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 evaluate whether planned transition between 90 and 150 days post-transplantation to SRL-based therapy from TAC-based therapy is associated with a clinically relevant degree of improvement in renal function (≥ 5.0 mL/min/1.73 m2) compared to continuation of TAC-based therapy.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety of planned transition between 90 and 150 days post-transplantation to SRL-based therapy from TAC-based therapy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Screening:
1. Male or female subjects aged 18 years or older.
2. Recipients who are 14 days prior to transplantation up through 14 days after transplantation.
3. Recipients of a primary, living- or deceased-donor renal allograft.
4. All female and male subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control for the duration of the study and for 3 months after the last dose of test article. A subject is biologically capable of having children even if he or she is using contraceptives or if his or her sexual partner is sterile or using contraceptives.
Inclusion Criteria for Randomization:
1. Ninety (90) to 150 days post-transplantation.
2. Treatment with TAC and an IMPDH inhibitor initiated ≤ 30 days of transplantation and has remained on both for the 30 days prior to randomization.
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| E.4 | Principal exclusion criteria |
Exclusion Criteria for Screening
1. Recipients of multiple organ transplants (i.e., any prior or concurrent transplantation of any organs including prior renal transplant).
2. Recipients of adult or pediatric en bloc kidney transplants.
3. Recipients who required or will require desensitization protocols.
4. Known history of focal segmental glomerulosclerosis (FSGS) or membrano-proliferative glomerulonephritis (MPGN).
5. Evidence of active systemic or localized major infection, as determined by the investigator.
6. Received any investigational drugs or devices ≤ 30 days prior to transplantation.
7. Known or suspected allergy to SRL, TAC, IMPDH inhibitors, macrolide antibiotics, iothalamate, iodine, iodine-containig products, including contrast media, other compounds related to these products/classes of medication or shellfish.
8. History of malignancy ≤ 3 years of screening (except for adequately treated basal cell or squamous cell carcinoma of the skin).
9. Recipients who are known to be human immunodeficiency virus (HIV) positive.
10. Women who are biologically capable of having children with a positive urine or serum pregnancy test at screening.
11. Breastfeeding women.
Exclusion Criteria for Randomization:
1. Any major illness/condition that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in and completion of the study, or could preclude the evaluation of the subject’s response.
2. Planned treatment with immunosuppressive therapies other than those described in the protocol.
3. Subjects who underwent CS withdrawal or avoidance and did not receive antibody induction at the time of transplantation with anti-thymocyte globulin (rabbit) (rATG) (Thymoglobulin®), anti-thymocyte globulin (equine) (Atgam®) or alemtuzumab (Campath®).
4. Subjects who have had CS discontinued ≤ 30 days before randomization.
5. Calculated GFR < 40 mL/min/1.73m2 using the simplified Modification of Diet in Renal Disease (MDRD) formula ≤ 2 weeks prior to randomization.
6. Spot urine protein to creatinine ratio (UPr/Cr ) ≥ 0.5 ≤ 2 weeks prior to randomization.
7. Banff (2007) grade 2 or higher acute T-cell-mediated or any acute antibody-mediated rejection at any time post-transplantation.
8. Any acute rejection (biopsy-confirmed or presumed) ≤ 30 days before randomization.
9. More than 1 episode of acute rejection (biopsy-confirmed or presumed).
10. Known Banff (2007) interstitial fibrosis and tubular atrophy (IF/TA) ≥ grade 2 or recurrent/de novo glomerular disease.
11. Major surgery ≤ 2 weeks prior to randomization.
12. Active post-operative complication, e.g. infection, delayed wound healing.
13. Total white blood cell count < 2,000/mm3 or absolute neutrophil count (ANC)
< 1000, or platelet count < 100,000/mm3 ≤ 2 weeks prior to randomization.
14. Fasting triglycerides > 400 mg/dL (> 4.5 mmol/L) or fasting total cholesterol > 300 mg/dL (> 7.8 mmol/L) ≤ 2 weeks prior to randomization regardless of whether or not on lipid-lowering therapy.
15. Women who are biologically capable of having children with a positive urine or serum pregnancy test at randomization.
16. Breastfeeding women.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent of subjects who demonstrate a ≥ 5 ml/min/1.73m2 improvement in measured GFR from randomization to 24 months post-transplantation by on-therapy analysis. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 months after transplant |
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| E.5.2 | Secondary end point(s) |
1. Percent of subjects who demonstrate a ≥ 5 ml/min/1.73m2 improvement in measured GFR from randomization to 12 months post-transplantation by On-therapy analysis.
2. Percent of subjects who demonstrate a ≥ 5 ml/min/1.73m2 improvement in measured GFR from randomization to 12 and 24 months post-transplantation by ITT analysis.
3. Measured GFR and change from randomization to 12 and 24 months post-transplantation.
4. Slope of measured GFR from randomization to 24 months post-transplantation.
5. Percent of subjects who demonstrate a ≥ 5 ml/min/1.73m2 improvement in calculated GFR from randomization to 12 and 24 months post-transplantation.
6. Calculated GFR and change from randomization to 6, 12, 18, and 24 months post-transplantation.
7. Slope of calculated GFR from randomization to 24 months post-transplantation.
8. Serum creatinine and change from randomization to 12 and 24 months post-transplantation.
9. Serum creatinine at 6, 12, 18, and 24 months post-transplantation. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 6, 12, 18 and 24 months after transplant |
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| 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| China |
| Germany |
| Italy |
| Spain |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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