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Onderzoek naar het voorkˇmen van nierfalen na levertransplantatie door aanpassing van de afweerremmende middelen.


- candidate number8250
- NTR NumberNTR2419
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR22-jul-2010
- Secondary IDs30908 ABR
- Public TitleOnderzoek naar het voorkˇmen van nierfalen na levertransplantatie door aanpassing van de afweerremmende middelen.
- Scientific TitleA 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.
- ACRONYMLOL III
- hypothesisThe 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) studiedLiver transplantation, Efficacy, Safety, Advagraf, Optimizing immunosuppressive therapy
- Inclusion criteria1. 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 criteria1. 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 receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-okt-2010
- planned closingdate1-okt-2016
- Target number of participants196
- InterventionsLow-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 outcomePercentage of patients with cGFR < 60ml/min at 36 months after transplantation.
- Secondary outcome1. 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;
4. Retransplantation;
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.
- TimepointsTimepoint 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 siteN/A
- statusplanned
- CONTACT FOR PUBLIC QUERIESMD. PhD. H.J. Metselaar
- CONTACT for SCIENTIFIC QUERIESMD. PhD. H.J. Metselaar
- Sponsor/Initiator Erasmus Medical Center, Department of Gastroenterology and Hepatology
- Funding
(Source(s) of Monetary or Material Support)
Astellas Pharma B.V
- PublicationsN/A
- Brief summaryA 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)
- RECORD22-jul-2010 - 11-apr-2011


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