Clinical trial NCT00396435: Correction of Anaemia and Progression of Renal Failure on Transplanted Patients
Official title: Multicenter, Prospective, Randomised, Open-label Study, Evaluating the Effect of Two Levels of Haemoglobin on Quality of Life and Speed of Progression of Renal Insufficiency on Renal Transplanted Patients With Chronic Graft Dysfunction (CGD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Anaemia
Renal Transplantation
Kidney Failure
Keywords: anaemia
renal transplantation
kidney failure
Lead sponsor: Centre Hospitalier Universitaire, Amiens
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2006-11-07
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate, on renal transplanted patients with CGD, the effect of two levels of haemoglobin on quality of life at 6 months and the speed of progression of renal function degradation at 24 months.

This study will recruit 140 patients in 21 centers in France.

Detailed description: The number of patients arriving each year at the stage of final renal insufficiency (IRT) and requiring the dialysis of substitution does not cease growing, in parallel with continuous ageing of the population in industrialized countries. The incidence of the IRT is approximately 110 new patients per million inhabitants per year, which represents an annual progression from approximately 4% to 8% according to areas.Approximately 35000 patients are currently treated by dialysis, 90% by hemodialysis and 10% per peritoneal dialysis . The other alternative to the treatment of the IRT is renal transplantation. Approximately 2000 patients are transplanted each year in France, and it is estimated that a minimum of 3000 transplantations should annually be carried out in order to answer at the request of the patients registers on a chronic program of dialysis and in to be transplanted age.

The total number of patients living with a functional graft is approximately 15000.

The IRT is a major problem of public health and its cost is considerable: for less than 50000 patients, this one represents nearly 4% of the annual budget of the social security. To slow down the progression of the IRC represents a major therapeutic challenge, including at the transplanted patients.

The physiopathological mechanisms proposed to explain the harmful role of anaemia in the progression of the renal lesions during the IRC rest on the tissue hypoxia induced by the reduction in haemoglobin. The tissue hypoxia supports the development of the interstitial fibrosis by stimulating the production of type I collagen and some inhibitors of metalloproteases, implied in the extracellular matrix degradation. The hypoxia also stimulates the synthesis of TGF-beta, pro-fibrosing factors implied in the progression of many renal diseases, in particular the nephropathy diabetic. By reducing the hypoxia thanks to the correction of anaemia by the EPO, one can hope to slow down the progression of the interstitial fibrosis, and thus the progression of the renal insufficiency. Lastly, the correction of anaemia reduces resistance to insulin and the secondary hyperinsulinism to uraemia, improves the dyslipidemia and the oxidizing stress, factors also implied in the progression of many nephropathies, diabetic or not.

It appears that anaemia is a factor of risk of progression of the chronic nephropathies. To slow down the progression of the chronic dysfunction of the graft is an important challenge because of shortage of graft and impossibility, in the current state of the French centers of renal transplantation to carry out the number of necessary grafts to provide for the current waiting list. Our hypothesis, if it is checked, should make it possible to very appreciably improve the quality of life of the transplanted patients and to slow down the progression of their IRC, thus delaying the duration before return in dialysis.

Population: Renal patients transplanted since at least 12 months, presenting a CGD defined by 20 ml/mn/1,73 m2 \> Clcr \< 50 ml/mn/1,73 m2 and an anaemia (Hb \< 11,5 g/dl)

The patients answering the criteria of selection will be assigned by randomization with the one of the two following groups:

* Group a: target haemoglobin: 13 to 15 g/dl
* Group b: target haemoglobin: 10,5 to 11,5 g/dl

Criteria of inclusion

* Adults of male or female sex of more than 18 years
* Patients having profited from one 1st or one the 2nd renal Transplantation
* Patients Transplanted since more than 1 year
* Patients having a CGD defined by Clcr \< 50 ml/mn/1,73 m2
* Patients presenting an anaemia: Hb lower than 11,5 g/dl
* Absence of deficiency out of iron
* Patients having given their in writing consent

Study Treatment: Neorecormon® (Epoétine beta) under cutaneous injection

The objective of the study is to show a difference between group A "haemoglobin target: 13 to 15 g/dl" and group it B "haemoglobin target: 10,5 to 11,5 g/dl", with regard to the renal function.

The calculation of the number of patients is thus based on a model of covariance analysis in repeated measurements of clearance of creatinin on the whole of the times evaluated between J0 and M24 and on the following hypothesis:

* H0: no effect groups during the two years of follow-up
* H1: Effect groups, evolution different from the values of Clcr during the follow-up

The alfa-risk (probability of rejecting H0 wrongly) was fixed at 5% The beta-risk (probability of keeping H0 wrongly) at 10% The total number of patients to be randomized was estimated at 140 (70 by group) This number of patients will also make it possible to test the scores of quality of life with a power higher than 90%

Eligibility criteria: Inclusion Criteria:

* Adults male or female of 18 years male or female sex to 70 years
* Patients having profited from one 1st or one the 2nd transplantation
* Patients transplanted since more than 1 year and less than 20 years.
* Patients having a CDG defined by a clearance of creatinin, lower than 50 ml/mn/1,73 m2 (according to Gault and Cockcroft) and whose renal function is stable over the last 3 months (variation of Scr of less than 20% over the last 3 months)
* Patients presenting an anaemia: Hb lower than 11.5 g/dl
* No deficiency out of iron: Saturation of the transferrin \> 20% and ironnemia \> 50 mg/l at the time of the screening visit
* Patients having given their written consent

Exclusion Criteria:

* Major forms of drepanocytosis or thalassaemia
* Iron Deficit (CST \< 20% or ferritin \< 50 mg/l)
* Haemolysis (haptoglobin \< 0,30 g/l)
* Severe renal insufficiency: Clcr \< 20 ml/min/1,73 m2
* Severe Hyperparathyroidy (serum PTH \> 800 pg/ml)
* Evolutionary chronic inflammatory Disease (CRP \> 15 mg/l)
* Acute or chronic infectious disease
* Evolutionary neoplasic Disease
* Infection by the HIV and viral cirrhosis
* Recent Antecedents of MI or AIT (\< 3 months)
* Severe Arteritis of the lower limbs (Stage III or IV)
* Acute Rejection requiring a treatment in the 3 previous months
* Blood Transfusion on the last 3 months
* Evolutionary GI Ulcer on the last 3 months
* Severe Arterial HyperTension not controlled by medicamentous treatment (NOT \> 170 mm Hg or PAD \> 100 mm Hg under treatment)
* Epilepsy of recent diagnosis
* Relevant biological value(at screening visit) : - Proteinuria \> 3 g/24h
* Serum Albumin \< 30 g/l
* Platelets \> 600.000/µl
* Programmed heavy surgery
* Pregnancy or breast feeding
* Administration of an experimental drug in the 30 days preceding the screening visit
* Known Over-sensitiveness to Epoetin beta
* Patients under Sirolimus
* Patients under EPO at screening visit

Primary outcomes:
measure: eClcr by Cockcroft formula
timeFrame: 2 years
Secondary outcomes:
measure: Measure CDG by the clearance of Iohexol
timeFrame: 2 years
measure: 1/Scr at J0, 6 months, 12 months, 18 months and 24 months Scr with J0, 6, 12, 18 and 24 months
timeFrame: 2 years
measure: Proteinuria and micro-albuminuria at J0, 12 and 24 months
timeFrame: 2 years
measure: Evaluation of the quality of life in the 2 groups of patients per self-evaluation at J0 and 6 months
timeFrame: 6 months
measure: Adverse events, in particular cardiovascular events: MI, AIT, Arteritis of lower limb, revascularisation,
timeFrame: 2 years
measure: Biological tolerance: Albuminemia, pre-albuminemia, CRP, plasmatic Cholesterol, HDL and LDL
timeFrame: 2 years
measure: Level of blood pressure at the beginning and the end of the study and comparison of the number of antihypertensive drugs received by patients before and after the 24 months of follow-up
timeFrame: 2 years
measure: Number of units of beta-EPO managed in the 2 groups
timeFrame: 2 years
measure: Number of patients receiving blood transfusions
timeFrame: 2 years
Other outcomes:
Locations:
city: Amiens
country: France
facility: Hôpital Sud
city: Bois-Guillaume
country: France
facility: Hôpital de Bois Guillaume
city: Bordeaux
country: France
facility: Hôpital Pellegrin
city: Caen
country: France
facility: Hôpital Clémenceau
city: Clermont Ferrand
country: France
facility: CHU Clermont Ferrand - Hôpital Gabriel Monpied
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Grenoble
country: France
facility: Hôpital de la Tronche
city: Lille
country: France
facility: Hôpital Calmette
city: Limoges
country: France
facility: Hôpital Dupuytren
city: Marseille
country: France
facility: Hôpital de la Conception
city: Nice
country: France
facility: Hôpital Pasteur
city: Paris
country: France
facility: Hôpital Necker - Enfants Malades
city: Poitiers
country: France
facility: Hôpital de la Milétrie
city: Reims
country: France
facility: Hôpital Maison Blanche
city: Rennes
country: France
facility: Hôpital Pontchaillou
city: Strasbourg
country: France
facility: Hôpital Civil
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulouse
country: France
facility: Hôpital Rangueil
city: Tours
country: France
facility: CHU de Tours - Hôpital Bretonneau
city: Vandoeuvre les Nancy
country: France
facility: Hôpital Brabois
Study officials:
affiliation: CHU Amiens
name: Gabriel Choukroun, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Necker- Enfants Malades - PARIS
name: Franck Martinez, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: