| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prophylaxis of heart transplant rejection. |
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| E.1.1.1 | Medical condition in easily understood language |
| Prevention of the rejection of a transplanted heart |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 | 10050432 |
| E.1.2 | Term | Prophylaxis against heart 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 |
| The primary objective of the study is to compare renal function between Arm 1 and Arm 2 at the end of the study [52 weeks after conversion from the primary immunosuppressive agent (Prograf® or ciclosporin) to Advagraf®]. Renal function will be primarily assessed by estimated Glomerular Filtration Rate (eGFR) using the Modification Diet in Renal Disease (MDRD4) formula. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To compare the efficacy and safety profiles of Arm 1 versus Arm 2;
• To compare rates of rejection in the two arms of the study
• To compare renal function between study end and Baseline study visit 1, before the start of study drug treatment with Advagraf (study entry / Visit 1)
• To compare renal function between study end and week 12 (visit 4: time of randomization to standard or reduced dose of Advagraf)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years.
2. Received a heart transplant at least 6 months and no longer than 8 years prior to starting study treatment.
3. Subjects who are otherwise stable heart transplant recipients with mild to moderate decline in renal function as evidenced by
• a baseline eGFR 30-60 ml/min estimated using the MDRD4 formula at the time of enrollment prior to starting study treatment t OR
• a baseline eGFR between 60-90 ml/min estimated using the MDRD4 formula prior to starting study treatment with at least a 10% decline in eGFR in the 12 months prior to enrolment.
4. Female and male subjects agree to maintain highly effective birth control during the study and for 90 days after discontinuation of dosing with study drugs. 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 Intrauterine Devises (IUDs), sexual abstinence or vasectomized partner.
5. Capable of understanding the purpose and risks of the study, has been fully informed and has given written informed consent (signed Informed Consent Form (ICF) has been obtained).
6. Subject’s immunosuppressive regimen (combination of medicines i.e. the individual drugs used)* remained unchanged for a minimum of 12 weeks prior to enrollment. *minor changes to doses of individual drugs are acceptable if the Investigator regards the subject and the overall regimen as stable during this period.
7. Receiving a Prograf® or ciclosporin based immunosuppressive regimen.
8. Subject should be able to receive Advagraf, if clinically indicated , after the completion of the study period.
|
|
| E.4 | Principal exclusion criteria |
Subject will be excluded from participating if any of the following apply:
1. Previously received an organ transplant other than a heart.
2. Acute rejection episode within 6 weeks prior to starting study treatment requiring treatment or a steroid resistant acute rejection episode requiring treatment within 12 weeks prior to starting study treatment .
3. Evidence of malignant disease within the last 5 years other than Basal Cell Carcinoma or Squamous Cell Carcinoma of the skin.
4. Pregnant woman or breast-feeding mother.
5. Subject or donor known to be HIV positive.
6. Known allergy or intolerance to tacrolimus, macrolide antibiotics, steroids or to the excipients of the study medication.
7. Any unstable medical condition that could interfere with the study objectives in the opinion of the Investigator.
8. Currently participating in another interventional clinical trial, and/or has taken an investigational drug within 28 days prior to enrollment.
9. Any form of substance abuse, psychiatric disorder or condition which, in the opinion of the Investigator, may complicate communication with the Investigator.
10. Unlikely to comply with the visits scheduled in the protocol.
11. Poor left ventricular function, defined as LVEF ≤ 30%.
12. Proteinuria >1g/24 hours.
13. Elevated SGPT/ALT and/or SGOT/AST and/or total bilirubin levels ≥ 3 times the upper value of the normal range of the investigational site.
14. Subject with a tacrolimus trough level less than 6ng/ml at baseline.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The Primary Variable is renal function assessed by eGFR at 52 weeks (or at final post-randomization assessment if earlier) following conversion to Advagraf® using the MDRD4 formula. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 52 weeks after conversion to Advagraf |
|
| E.5.2 | Secondary end point(s) |
• Change in renal function from baseline (visit 1) to randomization.
• Change of renal function from pre-randomization (Visit 4 / Week 12) to study end (Week 52).
• Time to death
• Time to graft loss
• Time to efficacy failure (efficacy failure is defined as the composite endpoint of biopsy prove acute rejection ≥ grade 2R (in accordance with International Society of Heart and Lung Transplantation (ISHLT) criteria), graft loss, re-transplantation, death or lost to follow up).
Acute rejections
• Number of treated acute rejection episodes (steroid sensitive and resistant)
• Severity of biopsy-proven acute rejection episodes
• Number of biopsy-proven acute rejection episodes
Safety Variables:
• Incidence of AEs
• Incidence of AEs of special interest (diabetes mellitus, hyperlipidemia, hypercholesterolemia, and hypertension)
• Laboratory parameters
• Left ventricular ejection fraction (LVEF)
• Left ventricular end diastolic volume
Renal Function:
• Renal function at 52 weeks following conversion to Advagraf® estimated using a Cystatin C based formula
• Renal function at 52 weeks following conversion to Advagraf® estimated using the Cockcroft and Gault formula
• Renal function at 52 weeks following conversion to Advagraf® estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
Additional Variables:
• EQ-5D Questionnaire
• MMAS Questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study from randomization to 52 weeks after conversion to Advagraf |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Colombia |
| Taiwan |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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