Comparison of Immunosuppression Protocols After LTx in Children
Condition: Liver Transplantation
Study type: Interventional
Phase: Phase 4

Summary: 
      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
    

Detailed description: 
      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      gradually (over 1 month) withdrawn from MMF administration 90 days after transplantation if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
    

Intervention name(s): tacrolimus, steroids, mycophenolate mofetil
Intervention type(s): Drug
Intervention MeSH terms: Mycophenolic Acid; Tacrolimus
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: immunosuppression,; steroid avoidance,; liver transplantation,; children