Comparison of Immunosuppression Protocols After LTx in Children
Comparison of Immunosuppression Protocols After LTx in Children
Open label, randomised, prospective, onecentre Investigator Driven Study:

 Comparison of two protocols of immunosuppression after liver Tx in children:

 A: Study group - FK506-MMF. Immunosupression protocol: Methylprednisolone 10 mg/kg
 intraoperatively i.v. FK506 Day 0 or 1 orally (0,15 mg/kg/D in two doses).MMF max. dosage 30
 mg/kg/D p.o. day 0 through day 90.

 B. Control group - Tacrolimus, steroids. Immunosupression protocol: Methylprednisolone 10
 mg/kg bm intraoperatively Children < 25kg bm: Methylprednisolone taper from 100 mg/D on day 0
 to MP 10 mg on day 7 Children > 25kg bm: Methylprednisolone taper from 200 mg/D on day 0 to
 MP 20 mg on day 7 Week 2-4 Prednisone - 0,5-0,3 mg/kg/D; Week 4-12 Prednisone -0,3-0,2
 mg/kg/D; Month 4-6 Prednisone 0,2 - 0,1 mg/kg/D Month 7 - Steroid withdrawal FK506 Day 0 or 1
 orally (0,15 mg/kg/D in two doses).

 Primary end points:

 Number of rejections, number of steroid-resistant rejections.

 Secondary end points:

 Patients and graft survival Dyslipidemia one year after transplantation Hypertension one year
 after transplantation Hyperglycemia/Diabetes de novo one year after transplantation Renal
 function before Tx and 1 year after Tx
A: Study group

 FK506-MMF.

 Immunosupression protocol:

 Metylprednisolon 10 mg/kg intraoperatively i.v.

 FK506 Day 0 or 1 oraly (0,15 mg/kg/D in two doses).

 MMF max. dosage 30 mg/kg/D p.o. day 0 through day 90 according to patient condition and
 therapeutic MMF blood concentration

 Tailoring:

 Immunosupression protocol will be tailored according to the cause of liver failure: patients
 with autoimmune liver disease (autoimmune hepatitis, PBC, PSC, overlap syndrome etc) would be
 maintained on MMF. All other recipients including cryptogenic liver cirrhosis will be
 gradually (over 1 month) withdrawn from MMF administration 90 days after transplantation if
 there is:

 1. good kidney function (S-creatinin < 150 umol/l) enabling to achieve and maintain
 Tacrolimus trough levels above 6 ng/ml and

 2. if there was no more than one episode of acute rejection of the graft which resolved
 completely.

 Targeted Tacrolimus trough levels:

 Month 1 - 3 through levels 10-15 ng/ml Month 4-6 10-12 ng/ml Month 7-12 10 - 6 ng/ml

 Rejection treatment:

 1. Tacrolimus dose adjustment to upper limit of target level if last Tacrolimus trough
 level is below the intended limit.

 2. Steroid boluses would be administered Metylprednisolon 10 mg/kg daily 3 consecutive
 days. No steroid taper. Control biopsy after normalisation of LFTs.

 3. After two attacks of acute rejection before MMF disontinuation Prednison dose would be
 introduced on at least 0,3 mg/D for 3 months.

 4. After second attack of AR after MMF discontinuation Prednison dose would be introduced
 on at least 0,3 mg/D for 6 months.

 5. Steroid resistant rejection: biopsy proven rejection persisting after three courses of
 steroid pulses. Steroid resistant rejection would be treated according to local praxis.

 Concomitant drugs:

 Antiviral and antibacterial prophylaxis according to current centre praxis. Prophylaxis of
 cholestasis and prophylaxis/treatment of the bone disease where applicable.

 B. Control group

 Tacrolimus, steroids.

 Immunosupression protocol:

 Metylprednisolon 10 mg/kg bm intraoperatively Children < 25kg bm: Metylprednisolon taper from
 100 mg/D on day 0 to MP 10 mg on day 7 Children > 25kg bm: Metylprednisolon taper from 200
 mg/D on day 0 to MP 20 mg on day 7 Week 2-4 Prednison - 0,5-0,3 mg/kg/D Week 4-12 Prednison
 -0,3-0,2 mg/kg/D Month 4-6 Prednison 0,2 - 0,1 mg/kg/D Month 7 - Steroid withdrawal

 FK506 Day 0 or 1 orally (0,15 mg/kg/D in two doses).

 Intended Tacrolimus trough levels:

 Month 1 -3 through levels 10-15 ng/ml Month 4-6 10-12 ng/ml Month 7-12 6-10 ng/ml

 Rejection treatment:

 1. Tacrolimus dose adjustment to upper limit of target level if last Tacrolimus trough
 level is below the intended limit.

 2. Steroid boluses would be administered Metylprednisolon 10 mg/kg bm daily 3 consecutive
 days. No steroid taper, return to previous steroid dose. Control biopsy after
 normalisation of LFTs.

 3. After two attacks of acute rejection Prednison dose would be maintained on at least 0,3
 mg/D for 3 months.

 4. Steroid resistant rejection: biopsy proven rejection persisting after three courses of
 steroid pulses. Steroid resistant rejection would be treated according to local praxis.

 Biopsy: Liver biopsy should be taken in any suspicion of graft rejection or disease
 recurrence. Protocol biopsy would be taken according to local practice, liver biopsy in
 one-year after transplantation is mandatory.

 Primary end points:

 Number of rejections, number of steroid-resistant rejections.

 Secondary end points:

 Patients and graft survival Dyslipidemia one year after transplantation Hypertension one year
 after transplantation Hyperglycemia/Diabetes de novo one year after transplantation Renal
 function before Tx and 1 year after Tx

 Inclusion criteria:

 Subjects who meet all of the following criteria are eligible for this study:

 1. Male or female patients, not older than 18 years old.

 2. Primary liver transplantation

 3. Patient is capable of understanding the purpose and risks of the study and has been
 informed both orally and in writing and has given informed consent

 Exclusion criteria:

 Subjects who meet one or more of the following criteria are not eligible for this study:

 1. Female patients who are pregnant or are breast feeding

 2. Patients > 18 years old

 3. Combined liver-kidney transplantation

 4. Recipient of second liver graft

 5. Patients are allergic, hyper-sensitive or intolerant to HCO-60 or structurally related
 compounds, macrolide antibiotics or tacrolimus.

 6. Patients with known HIV-anamnesis

 7. Patient requires ongoing dosing with a systemic immunosuppressive drug at study entry
 for another indication than the prophylaxis of liver graft rejection

 8. Patient has significant, uncontrolled concomitant infections and/or severe diarrhea,
 vomiting, or active peptic ulcer.

 9. Patient is participating or has participated in another clinical study and/or is taking
 or has been taking an investigational drug in the past 28 days.

 10. Other reasons which depend on the assessment of the physician (no MMF will be given to
 patients with severe persistent hypersplenism (WBC < 3.500/ml, platelets < 50.000/ml)

 Informed Consent:

 Patient, who will give written consent for participation in the study and will fulfil all the
 inclusion and exclusion criteria, will be included in the study. After inclusion into the
 study, the patient may withdraw at any time for any reason.

 Follow-up: (time of one patient observation ) -12 months

 Number of centers: 1 Number of patients: 40 Indication: - Primary Liver transplantation
 Duration of study: 36 months Enrollment period: 18 months
Inclusion Criteria:

 -  Subjects who meet all of the following criteria are eligible for this study:

 1. Male or female patients, not older than 18 years old.

 2. Primary liver transplantation

 3. Patient is capable of understanding the purpose and risks of the study and has
 been informed both orally and in writing and has given informed consent

 Exclusion Criteria:

 -  Subjects who meet one or more of the following criteria are not eligible for this
 study:

 1. Female patients who are pregnant or are breast feeding

 2. Patients > 18 years old

 3. Combined liver-kidney transplantation

 4. Recipient of second liver graft

 5. Patients are allergic, hyper-sensitive or intolerant to HCO-60 or structurally
 related compounds, macrolide antibiotics or tacrolimus.

 6. Patients with known HIV-anamnesis

 7. Patient requires ongoing dosing with a systemic immunosuppressive drug at study
 entry for another indication than the prophylaxis of liver graft rejection

 8. Patient has significant, uncontrolled concomitant infections and/or severe
 diarrhoea, vomiting, or active peptic ulcer.

 9. Patient is participating or has participated in another clinical study and/or is
 taking or has been taking an investigational drug in the past 28 days.

 10. Other reasons which depend on the assessment of the physician (no MMF will be
 given to patients with severe persistent hypersplenism (WBC < 3.500/ml, platelets
 < 50.000/ml)