ESCAPE Trial

Condition(s) targeted: Children; Chronic Renal Failure; Hypertension; Aquired Kidney Disease; Congenital Kidney Disease

Intervention: ramipril (Drug); intensified blood pressure control (Procedure)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: University of Heidelberg

Official(s) and/or principal investigator(s):
Franz Schaefer, MD, Principal Investigator, Affiliation: University of Heidelberg, Children's Hospital
Otto Mehls, MD, Principal Investigator, Affiliation: University of Heidelberg, Children's Hospital

In children with chronic kidney disease, progression to end-stage renal failure is associated with high patient morbidity and poor quality of life. In adults, inhibition of the renin angiotensin system (RAS) slows down the rate of renal failure progression. This concept is as yet unproven in children, in whom chronic renal failure (CRF) is more commonly due to hypo/dysplastic malformations than to acquired glomerulopathies as typical for adult chronic kidney disease. The current project aims at assessing the genetic and molecular mechanisms and cardiovascular consequences of progressive CRF and to develop a strategy of pharmacological renoprotection in children.

Official title: Molecular Mechanisms of Disease Progression and Renoprotective Pharmacotherapy in Children With Chronic Renal Failure

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Primary outcome:

Change in creatinine clearance (regression line slope of an individual’s creatinine clearance)

Time interval to renal ‘loss’ as defined by an absolute decrease in creatinine clearance by 50 %.

Secondary outcome:

Effect of treatment on urinary protein excretion

Effect of treatment on blood pressure

Safety of treatment

Detailed description: Chronic kidney diseases affecting the nephron mass are characterized by a progressive decline of glomerular filtration rate (GFR) occurring irrespectively of the cause of the renal damage once a critical number of nephrons has been lost. Current clinical research efforts focus on preventive strategies to slow down or arrest disease progression. Systemic hypertension and glomerular hyperfiltration with resulting proteinuria and activation of vasoactive, profibrotic and proinflammatory systems have been identified as major causes of further nephron damage. Angiotensin converting enzyme (ACE) inhibitors are not only potent antihypertensive agents but also reduce proteinuria, glomerulosclerosis and tubulointerstitial fibrosis via reduction of the local angiotensin tone in the kidney, and have been demonstrated to slow down renal failure progression in adult patients. Childhood-onset ESRD is a rare but particularly devastating disease with poor life expectancy and quality of life. Chronic renal failure in children is caused by a different spectrum of nephropathies than in adults, with a preponderance of congenital or inherited abnormalities. Since hypertension, proteinuria and tubulointerstitial fibrosis are also common in pediatric chronic renal failure, there is a rationale for pharmacological renoprotection by ACE inhibition in children. The prospective, randomized European clinical trial launched by our consortium will provide the critical mass to assess several aspects of renoprotective therapy in children. Specifically, the trial is designed to address the following scientific objectives:

Objective 1 is to evaluate whether ACE inhibition is equally effective in slowing down the progression rate of chronic renal failure in children with different congenital and acquired renal disorders. 400 pediatric patients will be stratified according to their underlying diseases, and the rate of loss in glomerular filtration rate will be assessed from 6 months before to 3 years after start of treatment with the ACE inhibitor ramipril.

Objective 2 of the trial is to evaluate whether renal failure progression in patients treated with a fixed dose of ramipril can be further slowed down by additional antihypertensive treatment, achieving a blood pressure below the 50th percentile. To this end, patients will be randomized upon initiation of ramipril to either intensified (aiming below 50th percentile of 24-hour mean arterial pressure) or conventional antihypertensive treatment.

Several gene polymorphisms have been described that may affect the rate of renal failure progression and/or the individual susceptibility to ACE inhibition. These polymorphisms include genes encoding for key proteins of the renin-angiotensin system and extracellular matrix turnover. In addition, we will screen for novel polymorphisms in genes determining structural proteins of the glomerular filter, and search for gene mutations causing renal hypo-/dysplasia. Objective 3 is to evaluate whether any of these mutations predict spontaneous disease progression and the therapeutic response to ACE inhibition and intensified blood pressure control.

Glomerular endothelin (ET1) synthesis is upregulated in chronic renal failure, and urinary ET1 excretion is correlated with disease progression. ET1 antagonists partially preserve renal function and decrease proteinuria independent of the angiotensin tone. Objective 4 of the trial is to assess ET1 turnover before and after start of ACE inhibition, and to evaluate a possible predictive role of ET1 and/or ET1 degrading peptidase excretion for the persistence of proteinuria and disease progression during ACE inhibition and intensified antihypertensive therapy.

Long-term survival of children with chronic renal failure is compromised by precocious atherosclerosis and excessive cardiovascular morbidity. Objective 5 is to assess and correlate prospectively the metabolic causes and morphological consequences of uremic cardiovascular disease in children, and to define their relationship with disease progression during ACE inhibition and intensified blood pressure control. Homocysteine metabolism, apolipoprotein variability, gene polymorphisms putatively involved in atherosclerosis, inflammation states, myocardial function and carotid intima-media thickness will be assessed and compared to a reference group of age-matched healthy children.

Minimum age: 3 Years. Maximum age: 18 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age 3-18 years

- Moderate state of renal failure (creatinine clearance 15 - 75 ml / min / 1. 73 m²)

- Mean arterial blood pressure (ABPM) > 50. percentile and/or antihypertensive treatment

- Written informed consent

Exclusion Criteria:

- Age <3 years or >18 years at start of study

- Unstable clinical condition (vomiting, anorexia, etc) or superimposed important

disease

- Unilateral or bilateral renal artery stenosis

- Urological surgery possibly affecting renal function expected during study period

- Insufficient compliance with prescribed antihypertensive medication during the run-in

period

- Secondary renal diseases such as lupus, amyloidosis and primary hyperoxaluria, and

patients treated with immunosuppressive agents (including corticosteroids)

- Severe primary cardiac disease, hepatic insufficiency and malabsorption syndrome

- Erythropoietin or growth hormone therapy with a duration of less than 3 months prior

to run-in period

- Pregnancy

University Hospital Motol, 1st Department of Pediatrics, Prague 150 18, Czech Republic

INSERM U574, Paris 75015, France

Hopital Necker, Division of Pediatric Nephrology, Paris 75015, France

Hopiteaux Universitaires de Strasbourg, Strasbourg 67098, France

Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg, Heidelberg 69120, Germany

Johannes Gutenberg University Mainz, Department of Pediatrics,, Mainz 55131, Germany

Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology, Berlin 13353, Germany

Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology, Hannover 30623, Germany

Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit, Leipzig 04129, Germany

Philipps University Marburg, Dept. of Pediatrics, Marburg 35037, Germany

University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit, Essen 45122, Germany

University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology, Hamburg 20246, Germany

University Children's Hospital, Dept. of Nephrology, Rostock 18050, Germany

Semmelweis University Budapest, 1st Department of Pediatrics, Budapest 1083, Hungary

G.Gaslini Institute, Nephrology Unit, Genoa 16148, Italy

Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis, Rome 00165, Italy

Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica, Milano 20122, Italy

Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria, Padova 35128, Italy

Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto, Torino 10126, Italy

Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit, Vilnius 2600, Lithuania

Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department, Warsaw 04-736, Poland

Medical University of Gdansk, Pediatric Nephrology Department, Gdansk 80-211, Poland

Clinic of Pediatrics, Pomeranian Academy of Medicine, Szczecin 71-344, Poland

Jagellonian University Medical College, Department of Pediatric Nephrology, Cracow 30-663, Poland

Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics, Porto 4202 - 451, Portugal

Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit, Belgrade 11000, Serbia and Montenegro

Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics, Stockholm 14186, Sweden

University Children's Hospital, Nephrology Unit, ZÜRICH 8032, Switzerland

Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics, Istanbul 34303, Turkey

University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics, Istanbul 34390, Turkey

Ege University Medical Faculty, Dept. of Pediatric Nephrology, Izmir 35100, Turkey

Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology, Ankara 06100, Turkey

Cukurova University School of Medicine, Dept. of Pediatric Nephrology, Adana 01330, Turkey

Starting date: January 1998
Ending date: September 2005
Last updated: September 15, 2005