E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Caucasian paediatric kidney transplant recipients |
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E.1.1.1 | Medical condition in easily understood language |
Caucasian paediatric kidney transplant recipients |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
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 assess, whether the tacrolimus full-area under the curve concentration with blood samples drawn before and 1.5, 2, 4, 6, 8, 12, 13.5, 14, 16, 20, 24 hrs after administration in compliant patients without any protocol deviations is bioequivalent between immediate-release tacrolimus (Prograf®) therapy and Envarsus®-therapy when a dose converting factor of 0.7 is used. |
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E.2.2 | Secondary objectives of the trial |
To assess efficacy in terms of residual expression of NFAT regulated genes (pharmacodynamics), potential influence of pharmacogenetics, trough levels and doses of prolonged-release tacrolimus (Envarsus®), the level of adherence, cumulative dosage and signs of tacrolimus toxicity and adverse events, biopsy proven rejections as well as a decrease in eGFR >10% of baseline and DSAs are determined. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. caucasian paediatric kidney transplant recipients (single-organ recipients) 2. aged ≥ 8 years but ≤ 18 years who are under tacrolimus (Prograf®) therapy and who are able to swallow tablets with a minimum dose of 0.75 mg / day Envarsus® 3. not less than 6 months after transplantation 4. stable kidney function (delta GFR < 10 ml/min/1.73 m2 (CKiD formula)) over the last 3 months 5. • women of childbearing potential - who is practicing true abstinence from sexual intercourse (periodic abstinence and withdrawal are not acceptable) or - who has sexual relationship with female partners only and/or with sterile male partners; or • women of childbearing potential and sexually active with fertile male partner must: - who have a negative pregnancy test during screening and - who agree to use reliable methods of contraception from the time of screening, during the study and for a period of four weeks following the last administration of study medication (for details please refer to chapter 6.2) or: • without childbearing potential defined as follows: -females before menarche or -at least 6 weeks after surgical sterilization bybilateral tubal ligation or bilateral oophorectomy or -hysterectomy or uterine agenesis 6. patient/parents/legal guardian(s) must be capable of understanding purpose and risks of the study 7. signed informed consent obtained by patient and parents/legal guardians |
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E.4 | Principal exclusion criteria |
1. coefficient of variation of tacrolimus trough level > 0.35 over the previous 6 months 2. pregnancy/breast feeding 3. instable kidney function 4. hypersensitivity to any of the components of the medications used. 5. patient is not eligible for any reason according to the investigator’s valuation 6. patient with known positive HIV-1 or HCV test 7. participation in another clinical trial (other investigational drugs or devices at the time of enrolment or within 30 days prior to enrolment)
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome variable / hypothesis: Full tacrolimus AUC over 24 hours under Envarsus® treatment (conversion factor 0.7) is 80-125% of the AUC of immediate-release tacrolimus (Prograf®). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The Primary end point will be evaluated at the end of the trial. |
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E.5.2 | Secondary end point(s) |
Secondary outcome variables for both study phases: pharmacodynamic analysis, pharmacogenetic analysis, conversion factor, tacrolimus trough levels, coefficient of variation of tacrolimus, number of dose adjustments, eGFR comparing the two study phases, cytokine/chemokine pattern (immunomonitoring), adverse events, treatment failure rate (composite endpoint: any patient who experienced death, graft failure, BPAR or lost to follow-up), limited sampling strategy (LSS) driven 24h-AUC estimation, NFAT expression, composition of gut microbial metabolism and its contribution to tacrolimus pharmacokinetics. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary end points will be evaluated at the end of the trial. |
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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 | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.6 | Cross over | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |