|- candidate number||8250|
|- NTR Number||NTR2419|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||22-jul-2010|
|- Secondary IDs||30908 ABR|
|- Public Title||Onderzoek naar het voorkˇmen van nierfalen na levertransplantatie door aanpassing van de afweerremmende middelen.|
|- Scientific Title||A multi-center randomized, open label, controlled study in primary liver transplantation comparing long term renal function in recipients treated with standard dose extended release tacrolimus alone and recipients treated with a combination of low dose extended release tacrolimus and low dose sirolimus.|
|- ACRONYM||LOL III|
|- hypothesis||The long term renal outcome for patients receiving a combination of low dose sirolimus and low dose extended release tacrolimus is estimated to be 15% better than standard dose extended release tacrolimus.|
|- Healt Condition(s) or Problem(s) studied||Liver transplantation, Efficacy, Safety, Advagraf, Optimizing immunosuppressive therapy|
|- Inclusion criteria||1. Primary liver transplantation or retransplantation within 14 days after first transplantation;|
2. Use of Advagraf at least 2 weeks prior to randomization;
3. Patent hepatic artery;
4. Closed abdominal wound;
5. Stable graft function;
6. Positive informed consent at time of randomization;
7. Age 18-70 years.
|- Exclusion criteria||1. Treatment with investigational drugs within 3 months before start of therapy;|
2. Multi organ transplantation;
3. cGFR < 30 ml/min;
4. Proteinuria > 800 mg/24 h;
5. Hyperlipidemia refractory to optimal medical management (Cholesterol > 9 mmol/l and/or triglycerides > 8.5 mmol/l). Patients with controlled hyperlipidemia are acceptable at the time of randomization;
6. Known hypersensitivity to sirolimus or its derivatives;
7. Thrombocytes < 50 x 109 /L;
8. Leukocytes < 2.5 x 109 /L;
9. Haemoglobin < 6 mmol/L;
10. Biopsy proven rejection 2 weeks prior to randomization;
11. HIV positivity;
12. Signs of recurrent or de novo cancer;
13. Patients with non-HCC malignancies within the past 5 years (excluding successfully treated squamous cell carcinoma and basal cell carcinoma of the skin);
14. Evidence of significant local or systemic infection;
15. Pregnancy or breast feeding;
16. Women of child-bearing potential not willing to take oral contraception;
17. Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study.
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-okt-2010|
|- planned closingdate||1-okt-2016|
|- Target number of participants||196|
|- Interventions||Low-dose tacrolimus in combination with low dose sirolimus versus standard dose of tacrolimus.
All participants will receive the same medication at first. Induction with basiliximab and mycophenolate; at day 4 +/- 1 start twice daily tacrolimus (5-10 ng/ml); Between day 14-21 conversion to once daily Advagraf (5-10 ng/ml); MPA stop at day 30; steroids 10 mg daily.
Randomization at 90 days (range 80-100 days ) after LTx.
Arm I: Continue standard dose once daily Advagraf (5- 10 ng/ml); steroids 7.5 mg and lower or discontinue steroids at 180 days after transplantation at discretion of physician.
Arm II: Conversion to once daily 2 mg (low dose) Sirolimus (3-5 ng/ml) and 2 mg (low dose) Advagraf (3-5 ng/ml); 7.5 mg steroids and lower or discontinue steroids at 180 days after transplantation at discretion of physician.
|- Primary outcome||Percentage of patients with cGFR < 60ml/min at 36 months after transplantation.|
|- Secondary outcome||1. Incidence of and time to de novo malignancy at 36 months after transplantation;|
2. Incidence of and time to recurrent malignancy;
3. Biopsy proven rejection;
5. Percentage of patients with cGFR <60ml/min at 12 and 24months after transplantation;
6. cGFR at 12, 24 and 36 months after transplantation;
7. Incidence of De novo diabetes mellitus at 12, 24 and 36 months after transplantation;
8. Quality of life using SF-36 questionnaires at 12, 24 and 36 months after transplantation;
9. Severity of fatigue using FSS at 12, 24 and 36 months after transplantation;
10. Safety (serious adverse events);
11. Tolerability of combination sirolimus and extended release tacrolimus (percentage of patients completing treatment and reasons for dose adjustments);
12. Percentage of patients on combination sirolimus and extended release tacrolimus converted to monotherapy extended release tacrolimus due to lack of tolerability or efficacy of combination sirolimus and extended release tacrolimus.
|- Timepoints||Timepoint primary outcome:|
Percentage of patients with cGFR < 60ml/min at 36 months after transplantation.
Timepoints secondary outcomes:
1. Incidence of and time to recurrent malignancy;
2. Percentage of patients with cGFR <60ml/min at 12 and 24months after transplantation;
3. cGFR at 12, 24 and 36 months after transplantation;
4. Incidence of De novo diabetes mellitus at 12, 24 and 36 months after transplantation;
5. Quality of life using SF-36 questionnaires at 12, 24 and 36 months after transplantation;
6. Severity of fatigue using FSS at 12, 24 and 36 months after transplantation.
|- Trial web site||N/A|
|- CONTACT FOR PUBLIC QUERIES||MD. PhD. H.J. Metselaar|
|- CONTACT for SCIENTIFIC QUERIES||MD. PhD. H.J. Metselaar|
|- Sponsor/Initiator ||Erasmus Medical Center, Department of Gastroenterology and Hepatology|
(Source(s) of Monetary or Material Support)
|Astellas Pharma B.V|
|- Brief summary||A phase III multicenter, randomized, open label study to evaluate the efficacy and safety up to 3 years of a regimen with a combination of low-dose extended-release tacrolimus and sirolimus in comparison with standard-dose extended-release tacrolimus. The patients are randomized between 80 and 100 days after liver transplantation in 2 arms:|
1. Arm 1 will receive once daily combination therapy of normal dosed extended-release tacrolimus and prednisone for 3 months and monotherapy once daily extended-release tacrolimus thereafter up to 3 years after liver transplantation;
2. Arm 2 will receive once daily combination therapy of low doses sirolimus and extended-release tacrolimus and prednisone for 3 months and combination therapy of low dose sirolimus and extended-release tacrolimus thereafter for up to 3 years after liver transplantation.
The aim of the study is to reduce the number of patients with a moderate-severe renal impairment after liver transplantation. The primary endpoint is percentage of patients with cGFR < 60ml/min at 36 months after transplantation.
|- Main changes (audit trail)|
|- RECORD||22-jul-2010 - 11-apr-2011|