TACrolimus in Renal Transplantation: Individualization by Pharmacogenetic
Condition: Kidney Transplantation
Study type: Interventional
Phase: Phase 4

Summary: 
      Renal transplantation is the treatment of choice of the chronic renal insufficiency arrived
      at its final stage. Tacrolimus is an immunosuppressant treatment used for the prevention of
      episodes of acute rejection. Tacrolimus is characterized by a narrow therapeutic index and
      important interindividual variations of its pharmacokinetic characteristics. Proteins CYP3A4
      and CYP3A5 are responsible of intestinal and hepatic metabolism of Tacrolimus. Various
      polymorphisms for CYP3A5 and CYP3A4 were described and several retrospective studies
      suggested an association between a genetic polymorphism of CYP3A5 and the pharmacokinetic
      parameters of Tacrolimus. In particular, we showed that the presence of an allele CYP3A5*1
      was associated to the use of more important amounts of Tacrolimus to obtain the desired blood
      concentrations.

      This study is a national, multicentric, prospective, opened, randomized on two arms of
      treatment. 280 receivers of a renal transplant in 12 centres will be included. The genotyping
      of gene CYP3A5 will be carried out in the 6 days following transplantation. During the first
      week, the patients will be treated by basiliximab, MMF and corticosteroids. They will be
      randomized (central randomization) in D6 to receive either Tacrolimus at 0.2 mg/kg/d, or at a
      dosage adapted to their genotype. After determination of the first residual blood
      concentration of Tacrolimus realized after six oral intakes, the daily amounts of Tacrolimus
      could be modified if necessary to reach the desired blood concentrations. The total duration
      of the study for a patient is 3 months after transplantation.

      The objective of this study is to evaluate the impact of the adaptation, according to the
      genotype of the CYP3A5 of the patient, of the first amount of Tacrolimus on the first
      residual blood concentration of Tacrolimus, keeping in mind the aim of the individualization
      of dosage schedule by pharmacogenetic approach.

      Principal criterion : Comparison, between the two groups, of the percentage of patients for
      whom the first blood concentration of Tacrolimus evaluated 3 days (D10) after the first
      administration of Tacrolimus ranges between 10 and 15 ng/ml.

      Statistics will be carried out in intention to treat. The principal criterion will be
      analyzed by the test of chi-2.
    

Detailed description: 
      Inclusion criteria

        -  Patients, male or female, 18 to 65 years old.

        -  Patients receiving a first or a second isolated renal graft coming from a donor alive or
           deceased,

        -  The patients in age to procreate must have a negative test of pregnancy before being
           included in this study and will have to agree to use effective contraceptive
           measurements throughout the study.

        -  Patients able to include/understand the aims and the risks of the study, having been
           fully informed and having given their writing consent to take part in this study.
           Patients unable to write and/or read but having fully understood the oral information
           given by the investigator and having given their oral consent in the presence of an
           independent witness.

      Non-inclusion criteria

        -  Patients who receive several grafts.

        -  Patients requiring a treatment by azathioprin.

        -  Pregnant woman or nursing mother

        -  Patients receiving an incompatible graft ABO.

        -  Patients receiving or requiring immunosuppressant drugs prohibited by the protocol.

        -  Patients with a peak of historical antibody equal to or greater than 50% of the panel.

        -  Patients suffering from serious gastro-intestinal disorders which interfere with their
           capacity to receive or to absorb an oral form and patients presenting severe diarrhoea.

        -  Patients with symptomatic GI ulcer

        -  HIV or HTLV1 positive patients or their donors

        -  Patients presenting or having presented in the 5 last years one or several malignant
           tumours, except baso or spinocellular cutaneous epithelioma successfully treated.

        -  Patients with systemic infections requiring a treatment at the entry in the study.

        -  Patients having a leukocyte numeration lower than 2,5.109/l or haemoglobin lower than
           5g/dl.

        -  Patients with drug-addiction whatever it is, or psychiatric disorder which, according to
           the point of view of the investigator, could invalidate the communication with
           investigator or interfere with the compliance of the patient.

        -  Patients who take part simultaneously in another therapeutic test or who received a
           study treatment less than 30 days before the entry in this study.

        -  Patients having already been included in this study.

        -  Patients allergic or intolerant with corticoids, macrolides, Tacrolimus, mycophenolate
           mofetil or basiliximab

      The inclusion period is planned for 15 month. The inclusion of the patients will take place
      before transplantation. After transplantation, a centralized genotyping of CYP3A5 will be
      carried out for each patient. A sample of blood will be taken the day of transplantation.

      The randomization will be carried out according to a 1:1 mode, by unequal blocks and
      stratified on the center according to group A (Tacrolimus given at D7,dosage:0,20 mg/kg/d)
      versus group B (managed Tacrolimus given at D7 dosage adapted to genotype CYP3A).

      VISITS

      The participation of the patient in this study will be 3 months. For this period, 7 visits
      are planned. D0 being considered as the day of the closing of the skin.

        -  Before transplantation Visit 1: inclusion visit(in the 4 days before transplantation)
           The day of transplantation a blood taking will be carried out on EDTA tube for CYP 3 A5
           genotyping

        -  After transplantation (D0 = day of closing of the skin)

             -  Visit 2: J6 (randomization)

             -  Visit 3: J10

             -  Visit 4: J14

             -  Visit 5: M1 + - 3 days

             -  Visit 6: M2 + - 3 days

             -  Visit 7: M3 + - 7 days

      TREATMENTS:

      -Tacrolimus In the two arms of treatment Tacrolimus will be given at D7 post transplantation
      according to the group of randomization.

      The first dosage schedule of Tacrolimus will be different according to the group of
      randomization:

        -  Group A: 0,10 mg/kg 2 times per day for all the patients

        -  Group B:

             -  0,125 mg/kg 2 times per day (CYP3A5 *1/*1 or *1/*3)

             -  0,075 mg/kg 2 times per day (CYP3A5*3/*3)

      A first residual blood concentration (C0) of Tacrolimus will be evaluated after 6
      administrations of Prograf®, at D10. The dosage schedule of Tacrolimus will then be adapted
      freely according to the therapeutic pharmacological follow-up of Tacrolimus specified in the
      protocol, that is to say 10 to 15 ng/ml, whatever the group of randomization.

        -  Basiliximab All the patients will receive two injections of basiliximab per intravenous
           way (first injection before transplantation and second injection at D4),20 Mg by intake.

        -  Corticotherapy in decreasing amount as follows:

             -  D0: 500 Mg

             -  D1: 125 Mg

             -  D2 - D15: 20 Mg

             -  D16 - M1: 15 Mg

             -  M1 - M3: 10 Mg

        -  MMF The MMF will be given 3 gr. per day during the first 15 days, then 2 G per day
           adapted according to the clinical and biological tolerance.

      During this study the following treatments will not be authorized :

        -  immunosuppressants other than those proposed; ciclosporin, sirolimus, azathioprine,
           plasmatic exchanges; intravenous immunoglobulins.

        -  Gastric bandages [gastric protections (inhibitors of the H+ pump) are authorized].

        -  Treatments presenting an interaction with P-glycoprotein or cytochromes P450 3A

        -  Any drug not having a marketing authorization. All the concomitant drugs taken by the
           patient during this study must be written in the CRF as all the drugs the patient would
           have taken in the 7 days before transplantation.

      The analysis of this test will be done at the end of the inclusion on all the patients
      according to the principle of Intention To Treat Analysis.

      The patients being able to be excluded from this analysis will be:

        -  patients not having taken no amount of the evaluated drug

        -  patients without data collected after the randomization

      An analysis per-protocol will be carried out. From this analysis could be excluded in an
      additional way to the preceding analysis:

        -  declared patients not compliants

        -  patients who left the study for another reason that the inefficiency of the treatment or
           an undesirable event

        -  patients having taken during the study one or more prohibited treatments which can
           influence the effectiveness.

      STATISTIC

      Calculation of the necessary number of subjects:

      One defines as a success: The event "blood concentration of Tacrolimus is between 10 and 15
      ng/ml after 6 administrations per bone" One defines as a failure: The event "blood
      concentration of Tacrolimus is not between 10 and 15 ng/ml after 6 administrations per bone".

      The awaited percentage of event is 40% in group A (dosage schedule of Tacrolimus according to
      recommendations: 0,20/kg/d).

      It is made the assumption that the adaptation of the dosage schedule of Tacrolimus according
      to genetics will increase the success rate to 60%.

      By setting an alpha risk = 5%, a beta risk = 10%, in bilateral formulation, by balancing the
      randomization (1/1), it are necessary to include 140 subjects by group to show an absolute
      difference of 20% of success between the 2 groups, that is to say 1 year of inclusion and 1
      year and 3 months of study.
    

Intervention name(s): Tacrolimus
Intervention type(s): Drug
Intervention description(s): Administration Twice a day after adjustment to blood level
Intervention MeSH terms: Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: kidney transplantation; Tacrolimus; P450 3A5 cytochrome; genotype