A Study to Compare How the Body Absorbs and Processes Two Different Formulations of the Anti-rejection Medication Tacrolimus (Advagraf® or Prograf®) in Children Receiving an Organ Transplant, and How Safe and Effective They Are Over a Longer Period of Time
- Conditions
- Heart TransplantationKidney TransplantationLiver Transplantation
- Interventions
- Registration Number
- NCT01614665
- Lead Sponsor
- Astellas Pharma Europe Ltd.
- Brief Summary
The purpose of this study is to compare how the body absorbs and processes two different formulations of the anti-rejection medication tacrolimus (Advagraf® or Prograf®) in children receiving an organ transplant, and how safe and effective they are over a longer period of time.
This study is for children less than 16 years old. No minimum age has been set, however, to be included in this study participants must able to swallow the medication capsules intact.
- Detailed Description
Participants undergoing primary heart, kidney or liver transplantation and meeting the Inclusion Criteria and complying with the Exclusion Criteria prior to initiation of tacrolimus therapy will be enrolled.
Participants will be randomized to treatment with either Advagraf® or Prograf®. The randomization will be on a 1:1 basis stratified by organ and centre.
The study is divided in to two parts:
Part A: The initial pharmacokinetic part of the study.
Part B: A long term follow-up of one year. The main objective of Part A of the study is to collect PK data following administration of Advagraf® and Prograf® in de novo pediatric allograft recipients. Part B allows comparison of the safety and efficacy profiles of Advagraf® vs. Prograf® for longer term (52 weeks) post allograft transplantation.
Part C: Continuation of long-term follow-up (from Day 365 onwards). Participants who have completed Part B and to whom continued treatment with Advagraf® is not currently available, will be offered participation in a continuation of long-term follow-up Part C. Part C will continue until Advagraf® becomes available to these participants or these participants' discontinuation, whichever is the earliest.
This applies to participants in the following countries: Czech Republic, Italy, UK and Poland only.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 44
- The subject is aged <16 years of age, undergoing primary liver, kidney or heart allograft transplantation
- The subject must be able to swallow intact Prograf® or Advagraf® capsules
- Subjects, treated since transplantation with Basiliximab or ATG/ Mycophenolate Mofetil (MMF)/steroids, whose gastric motility has resumed and whose renal function is adequate on Day 1 (Heart only)
- Subject is receiving a multi-organ transplant or has previously received an organ transplant (including re-transplantation)
- Subject with pulmonary vascular resistance ≥4 Wood units despite medication
- Subject with significant renal impairment, defined as having serum creatinine ≥230 μmol/l (≥2.6 mg/dl) pre-transplantation. (Not applicable for renal transplanted subjects)
- Subject with significant liver disease, defined as having continuously elevated SGPT/ALT and/or SGOT/AST and/or total bilirubin levels of ≥3 times the upper value of the normal range of the investigational site during the past 28 days. (Not applicable for liver transplanted subjects)
- Subject with malignancies or a history of malignancy within the last 5 years, with the exception of those with basalioma or squamous cell carcinoma of the skin that has been treated successfully. (Not applicable for transplanted subjects with a primary organ diagnosis of cancer)
- Subject requiring systemic immunosuppressive medication for any other indication than transplantation
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Tacrolimus Prolonged Release Tacrolimus prolonged release Participants receive tacrolimus prolonged release once daily starting from day 1 for 4 weeks for in Part A, and continue to receive tacrolimus prolonged release once daily up to end of Part B and of the study. Tacrolimus Tacrolimus Participants receive tacrolimus twice daily starting from day 1 for 4 weeks for in Part A, and continue to receive tacrolimus twice daily up to end of Part B and C of the study.
- Primary Outcome Measures
Name Time Method Area Under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours (AUC0-24h) for Tacrolimus (Part A) Days 1, 7 and 28 at predose, 1, 2, 4, 6, 12, 13, 14, 16, 18 and 24 hours postdose Number of Participants with Adverse Events (Part A + B) From first dose of study drug up to 7 days after last dose of study drug in Part B (up to 53 weeks) Safety is assessed by adverse events (AEs), which includes abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induces clinical signs or symptoms, needs active intervention, interruption or discontinuation of study medication or is clinically significant. A serious AE (SAE) is an event resulting in death, persistent or significant disability/incapacity or congenital anomaly or birth defect, is life-threatening, requires or prolongs hospitalization or is considered medically important.
Number of Participants with Adverse Events (Part C) Up to 9 years Safety is assessed by adverse events (AEs), which includes abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induces clinical signs or symptoms, needs active intervention, interruption or discontinuation of study medication or is clinically significant. A serious AE (SAE) is an event resulting in death, persistent or significant disability/incapacity or congenital anomaly or birth defect, is life-threatening, requires or prolongs hospitalization or is considered medically important.
- Secondary Outcome Measures
Name Time Method Maximum Concentration (Cmax) of Tacrolimus (Part A) Days 1, 7 and 28 at predose, 1, 2, 4, 6, 12, 13, 14, 16, 18 and 24 hours postdose Time to Attain Maximum Concentration (tmax) of Tacrolimus (Part A) Days 1, 7 and 28 at predose, 1, 2, 4, 6, 12, 13, 14, 16, 18 and 24 hours postdose Trough Concentration (C12) for Tacrolimus (Part A) Days 1, 7 and 28, 12 hours after dosing Trough Concentration (C24) for Tacrolimus (Part A) Days 1, 7 and 28, 24 hours after dosing Correlation between AUC24 & C24 (Part A) Days 1, 7 and 28 at predose, 1, 2, 4, 6, 12, 13, 14, 16, 18 and 24 hours postdose Number of Participants with Acute Rejections (Part A + B) Up to Week 52 Rejection episodes/acute rejections are indicated by clinical and/or laboratory signs, and are classified according to their rejection specific treatment: •Spontaneously Resolving Acute Rejection: not treated with new or increased corticosteroid medication, antibodies or any other medication and resolved, irrespective of any tacrolimus dose changes; •Corticosteroid Sensitive Acute Rejection: treated with new or increased corticosteroid medication only and which has resolved, irrespective of any tacrolimus dose changes; •Corticosteroid Resistant Acute Rejection: did not resolve following treatment with corticosteroids; - Resolved with further treatment: any acute rejection with an end date AND a treatment other than corticosteroid used; - Unresolved with further treatment: any acute rejection with no end date AND a treatment other than corticosteroid used; - Unresolved with no further treatment: any acute rejection with no end date AND ONLY corticosteroid treatment was used.
Number of Participants with Biopsy-proven Acute Rejection Episodes (BPARs) (Part A + B) Up to Week 52 BPAR episodes are defined as acute rejection episodes confirmed by biopsy, and are classified according to their rejection specific treatment: •Spontaneously Resolving Acute Rejection: not treated with new or increased corticosteroid medication, antibodies or any other medication and resolved, irrespective of any tacrolimus dose changes; •Corticosteroid Sensitive Acute Rejection: treated with new or increased corticosteroid medication only and which has resolved, irrespective of any tacrolimus dose changes; •Corticosteroid Resistant Acute Rejection: did not resolve following treatment with corticosteroids; - Resolved with further treatment: any acute rejection with an end date AND a treatment other than corticosteroid used; - Unresolved with further treatment: any acute rejection with no end date AND a treatment other than corticosteroid used; - Unresolved with no further treatment: any acute rejection with no end date AND ONLY corticosteroid treatment used.
Severity of Biopsy Proven Acute Rejection Episodes (Part A + B) Up to Week 52 The severity of BPARs is categorized with specific criteria by organ: For kidney transplant participants, according to Banff '97 Diagnostic categories for renal allograft biopsies - Banff '07 update (C4d deposition, Acute antibody-mediated rejection I, II, and III, Acute T cell mediated rejection IA, IB, IIA, IIB and III); for liver transplant participants, according to 1997 Banff Schema for Grading of Liver Allograft Rejection - Rejection Activity Index (mild, moderate, severe or indeterminate/borderline); for heart, according to Standardized Nomenclature of the International Society of Heart and Lung Transplantation - Standardised Cardiac Biopsy Grading: Acute Cellular Rejection 2004 (mild, moderate, severe).
Patient Survival (Part A + B) Up to Week 52 Patient survival is defined as the time from first dose of study drug to the date of death from any cause.
Graft Survival (Part A + B) Up to Week 52 Graft survival is defined as the time from the first dose of study drug to graft loss. Graft loss is defined as retransplantation, nephrectomy (in case of kidney transplantation), death or dialysis (in case of kidney transplantation) ongoing at end of study or at discontinuation, unless superseded by follow-up information.
Efficacy Failure (Part A + B) Up to Week 52 Efficacy failure is defined as the composite of the following: death, graft loss, BPAR and unknown outcome. A participant is considered to have an unknown outcome if he/she does not have the event of interest (death, graft loss, BPAR) or does not have a study assessment prior to day 335.
Trial Locations
- Locations (10)
Site FR32
🇫🇷Paris Cedex 15, France
Site CZ61
🇨🇿Prague 5, Czechia
Site FR33
🇫🇷Bron Cedex, France
Site PL71
🇵🇱Warsaw, Poland
Site IT52
🇮🇹Rome, Italy
Site GB43
🇬🇧Birmingham, United Kingdom
Site GB46
🇬🇧Liverpool, United Kingdom
Site GB44
🇬🇧London, United Kingdom
Site GB42
🇬🇧Manchester, United Kingdom
Site GB45
🇬🇧London, United Kingdom