Multicentre, Open Label, Randomized, Two-arm, Parallel-group Study to Assess Efficacy and Safety of ENVARSUS® Compared With Tacrolimus Used as Per Current Clinical Practice in the Initial Maintenance Setting in de Novo Kidney Transplant Patients

Envarsus® is a prolongedrelease formulation of tacrolimus. In Phase III studies
in stable and de novo kidney transplant patients Envarsus® has already proven
to be non inferior compared to twice daily tacrolimus in terms of a composite
end-point of death, graft failure, acute rejection. Moreover Envarsus® is
associated with a more rapid achievement of target trough levels, with more
constant levels and fewer dose adjustments needed over the first year
post-transplantation.

Primary Objective
To compare tacrolimus dosing of the new Envarsus®-based immunosuppressive
regimen with current clinical practice over 6 months following de novo renal
transplantation in a real-life setting in different European Countries.

Secondary Objectives
- To evaluate the efficacy, safety and tolerability of the study treatments in
terms of additional pharmacokinetic parameters and of clinical outcome
measures.

- To describe the current tacrolimus-based immunosuppressive strategies for
renal transplantation as for local clinical practice in different European
Countries.

A Multicentre, Open label, Randomized, Two-arm, parallel-group study of
Envarsus® compared with tacrolimus used as per current clinical practice in the
initial maintenance setting in de novo kidney transplant patients.

Envarsus® (tacrolimus) prolonged-release tablets once daily, orally, provided
in 0.75, 1.0, and 4.0 mg dose strengths.
Envarsus® treatment will commence at the starting dose of 0.17 mg/kg/day within
24 h from renal graft reperfusion following transplantation; the first dose of
Envarsus® cannot be administered before transplantation.
Patients will have their dose adjusted to maintain tacrolimus whole blood
trough levels within the standard reference ranges of 5-15 ng/ml in the first
three months and in the range 5-10 ng/ml afterwards.

The oral formulation of tacrolimus as for the current clinical practice at each
investigational Centre (i.e. Prograf or Advagraf oral formulations)

Side effects, risks and interactions

Very common side effects (may affect more than 1 in 10 people):
- Increased blood sugar, diabetes mellitus, increased potassium in the blood
- Difficulty in sleeping
- Trembling, headache
- Increased blood pressure
- Liver function tests abnormal
- Diarrhoea, nausea
- Kidney problems

Common side effects (may affect up to 1 in 10 people):
- Reduction in blood cell counts (platelets, red or white blood cells),
increase in white blood cell counts, changes in red blood cell counts (seen in
blood tests)
- Reduced magnesium, phosphate, potassium, calcium or sodium in the blood,
fluid overload, increased uric acid or lipids in the blood, decreased appetite,
increased acidity of the blood, other changes in the blood salts (seen in blood
tests)
-Anxiety symptoms, confusion and disorientation, depression, mood changes,
nightmare,
hallucination, mental disorders
- Fits, disturbances in consciousness, tingling and numbness (sometimes
painful) in the hands and feet, dizziness, impaired writing ability, nervous
system disorders. Seizure in case you*ll take Prograf
- Blurred vision, increased sensitivity to light, eye disorders
- Ringing sound in your ears
- Reduced blood flow in the heart vessels, faster heartbeat
- Bleeding, partial or complete blocking of blood vessels, reduced blood
pressure
- Shortness in breath, disorders of the respiratory tissues in the lung,
collection of liquid around the lung, inflammation of the pharynx, cough,
flu-like symptoms
- Stomach problems such as inflammation or ulcer causing abdominal pain or
diarrhoea, bleeding in the stomach, inflammation or ulcer in the mouth,
collection of fluid in the belly, vomiting, abdominal pain, indigestion,
constipation, passing wind, bloating, loose stools
- Bile duct disorders, yellowing of the skin due to liver problems, liver
tissue damage and inflammation of the liver
- Itching, rash, hair loss, acne, increased sweating
- Pain in joints, limbs or back, muscle cramps
- Insufficient function of the kidneys, reduced production of urine, impaired
or painful urination
- General weakness, fever, collection of fluid in your body, pain and
discomfort, increase of the enzyme alkaline phosphatase in your blood, weight
gain, feeling of temperature disturbed
- Insufficient function of your transplanted organ


Uncommon side effects (may affect up to 1 in 100 people):
- Changes in blood clotting, reduction in the number of all types of blood
cells (seen in blood tests)
- Dehydration, inability to urinate
- Abnormal blood test results: reduced protein or sugar, increased phosphate,
increase of the
enzyme lactate dehydrogenase
- Coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and
language abnormalities, memory problems
- Clouding of the eye lens, impaired hearing
- Irregular heartbeat, stop of heartbeat, reduced performance of your heart,
disorder of the heart muscle, enlargement of the heart muscle, stronger
heartbeat, abnormal ECG, heart rate and pulse abnormal
- Blood clot in a vein of a limb, shock
- Difficulties in breathing, respiratory tract disorders, asthma
- Obstruction of the gut, increased blood level of the enzyme amylase, reflux
of stomach content in your throat, delayed emptying of the stomach
- Inflammation of the skin, burning sensation in the sunlight
- Joint disorders
- Painful menstruation and abnormal menstrual bleeding
- Multiple organ failure, flu-like illness, increased sensitivity to heat and
cold, feeling of pressure on your chest, jittery or abnormal feeling, weight
loss

Rare side effects (may affect up to 1 in 1,000 people):
- Small bleedings in your skin due to blood clots
- Increased muscle stiffness
- Blindness, deafness
- Collection of fluid around the heart
- Acute breathlessness
- Cyst formation in your pancreas
- Problems with blood flow in the liver
- Serious illness with blistering of skin, mouth, eyes and genitals; increased
hairiness
- Thirst, fall, feeling of tightness in your chest, decreased mobility, ulcer

Very rare side effects (may affect up to 1 in 10,000 people):
- Muscular weakness
- Abnormal heart scan
- Liver failure
- Painful urination with blood in the urine
- Increase of fat tissue
- Alteration of the electrical activity of your heart called "QT prolongation
in case you*ll take Advagraf.

Cases of BK virus associated nephropathy, as well as cases of JC virus
associated progressive multifocal leukoencephalopathy (PML), have been reported
in patients treated with immunosuppressants, including tacrolimus.
Benign as well as malignant neoplasms including EBV-associated
lymphoproliferative disorders and skin malignancies have been reported in
association with tacrolimus treatment.

Cases of pure red cell aplasia (a very severe reduction in red blood cell
counts), agranulocytosis (a severely lowered number of white blood cells) and
haemolytic anaemia (decreased number of red blood cells due to abnormal
breakdown) have been reported.

Effects on ability to drive and use machines
Do not drive or use any tools or machines if you feel dizzy or sleepy, or have
problems seeing clearly after taking study drugs. These effects are more
frequent if you also drink alcohol.

Risks of the Blood Collection
You may have pain, swelling, or bruising around the vein where your blood is
collected. You may feel dizzy or you may faint. You may get an infection at the
site of needle insertion.

Risks of the ECG
Placement of the leads may cause skin irritation, redness, or burning of the
skin at the site where the leads were attached. There may be minor discomfort,
similar to removing a bandage, when the leads placed on your chest are removed
from your skin.

Unknown Risks
The study drugs and procedures in this study may have risks that are not known
at this time.
You will be told in a timely manner of new information that may affect whether
you will want to continue to participate in this study.

Interactions
Well-known interactions between tacrolimus and a number of other drugs and
herbal products exist. Upon such interactions, tacrolimus blood levels can be
affected and result either as low as to be non-protective from immune
rejection, or as high as to be toxic. Known interacting drugs are listed below:
- Antifungal medicines: ketoconazole, fluconazole, itraconazole, voriconazole,
clotrimazole.
- Macrolide antibiotics: erythromycin, clarithromycin, josamycin, and
rifampicin.
- HIV protease inhibitors: ritonavir, nelfinavir, saquinavir
- HCV protease inhibitors: telaprevir, boceprevir.
- Medicines for gastric ulcer and acid reflux (e.g. omeprazole, lansoprazole or
cimetidine)
- Antiemetics used to treat nausea and vomiting (e.g. metoclopramide).
- Cisapride or the antacid magnesium-aluminium-hydroxide, used to treat
heartburn.
- Contraceptive pill or other hormone treatments based on ethinylestradiol, or
danazol
- Calcium channel blockers such as nifedipine, nicardipine, diltiazem and
verapamil, used to treat high blood pressure or cardiac arrythmia.
- Amiodarone, an anti-arrhythmic drug.
- Medicines known as *statins* used to lower lipid, cholesterol and
triglycerides, blood concentrations.
- Phenytoin and phenobarbital, used to treat epilepsy.
- Corticosteroids such as prednisolone and methylprednisolone, used to treat
inflammations or suppress the immune system.
- Nefazodone, used to treat depression.
- Herbal preparations containing St. John*s Wort (Hypericum perforatum).

Avoid grapefruit (also as juice) while on treatment with study drugs, since it
can also affect tacrolimus blood levels.

The following drugs may worsen kidney or nervous system problems when taken
together with tacrolimus:
- anti-inflammatory drugs (NSAIDs, e.g. ibuprofen) used for fever, inflammation
and pain;
- amphotericin B, used to treat fungal infections;
- antivirals (e.g. aciclovir), used to treat viral infections.

Vaccinations
Live vaccines should be avoided.

Pregnancy
For female patients, there may be unknown risks to the foetus (unborn child)
linked to the study drugs, therefore, female patients of childbearing
potential, must not be pregnant. Women of childbearing potential have to use
during their study participation the following reliable methods of
contraception:
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
b. Hormonal contraception (implantable, injectable, patch, oral)
c. Barrier methods of contraception: condom, occlusive cap (diaphragm or
cervical vaults/caps) with spermicidal foam/gel/film/cream/suppository
d. Male sterilization (with the appropriate post-vasectomy documentation of the
absence of sperm in the ejaculate).
True abstinence is acceptable only if reflecting your preferred life style.

At the first visit a pregnancy test is to be carried out if with woman of a
fertile age.

Exposure to sun
Exposure to the sun and UV (ultraviolet) light whilst taking study drugs should
be limited. Appropriate protective clothing should be worn and sunscreen with
the highest sun protection factor should be used.