Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients

Hypertension Clinical Trial

— ESCAPE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00221845
• Other study ID #: QLRT-2001-00908
• Status: Completed
• Phase: Phase 3
• First received: September 15, 2005
• Last updated: January 11, 2010
• Start date: January 1998
• Est. completion date: January 2010

Study information

• Verified date: January 2010
• Source: Heidelberg University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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.

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 5 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 400
• Est. completion date: January 2010
• Est. primary completion date: July 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years to 18 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Kidney Disease
• Children
• Chronic Renal Failure
• Congenital Kidney Disease
• Disease Progression
• Hypertension
• Kidney Diseases
• Kidney Failure, Chronic
• Renal Insufficiency

Intervention

Drug:
• ACE Inhibition
ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
• Intensified Blood Pressure Control
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
• Add-on Angiotensin Receptor Blockade
In patients who show persistent or breakthrough proteinuria at the end of the initial study period, telmisartan (50 mg/m²/day) will be added to the existing medication.

Locations

Country	Name	City	State
Czech Republic	University Hospital Motol, 1st Department of Pediatrics	Prague
France	Hopital Necker, Division of Pediatric Nephrology	Paris
France	Inserm U574	Paris
France	Hopiteaux Universitaires de Strasbourg	Strasbourg
Germany	Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology	Berlin
Germany	University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit	Essen
Germany	University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology	Hamburg
Germany	Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology	Hannover
Germany	Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg	Heidelberg
Germany	Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit	Leipzig
Germany	Johannes Gutenberg University Mainz, Department of Pediatrics,	Mainz
Germany	Philipps University Marburg, Dept. of Pediatrics	Marburg
Germany	University Children's Hospital, Dept. of Nephrology	Rostock
Hungary	Semmelweis University Budapest, 1st Department of Pediatrics	Budapest
Italy	G.Gaslini Institute, Nephrology Unit	Genoa
Italy	Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica	Milano
Italy	Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria	Padova
Italy	Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis	Rome
Italy	Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto	Torino
Lithuania	Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit	Vilnius
Poland	Jagellonian University Medical College, Department of Pediatric Nephrology	Cracow
Poland	Medical University of Gdansk, Pediatric Nephrology Department	Gdansk
Poland	Clinic of Pediatrics, Pomeranian Academy of Medicine	Szczecin
Poland	Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department	Warsaw
Portugal	Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics	Porto
Serbia	Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit	Belgrade
Sweden	Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics	Stockholm
Switzerland	University Children's Hospital, Nephrology Unit	Zürich
Turkey	Cukurova University School of Medicine, Dept. of Pediatric Nephrology	Adana
Turkey	Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology	Ankara
Turkey	Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics	Istanbul
Turkey	University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics	Istanbul
Turkey	Ege University Medical Faculty, Dept. of Pediatric Nephrology	Izmir

Sponsors (5)

Lead Sponsor	Collaborator
Heidelberg University	Aventis Pharmaceuticals, Baxter Healthcare Corporation, Boehringer Ingelheim, European Commission

Countries where clinical trial is conducted

Czech Republic,  France,  Germany,  Hungary,  Italy,  Lithuania,  Poland,  Portugal,  Serbia,  Sweden,  Switzerland,  Turkey, 

References & Publications (13)

Chinali M, de Simone G, Matteucci MC, Picca S, Mastrostefano A, Anarat A, Caliskan S, Jeck N, Neuhaus TJ, Peco-Antic A, Peruzzi L, Testa S, Mehls O, Wühl E, Schaefer F; ESCAPE Trial Group. Reduced systolic myocardial function in children with chronic renal insufficiency. J Am Soc Nephrol. 2007 Feb;18(2):593-8. Epub 2007 Jan 10. — View Citation

ESCAPE Trial Group, Wühl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, Testa S, Jankauskiene A, Emre S, Caldas-Afonso A, Anarat A, Niaudet P, Mir S, Bakkaloglu A, Enke B, Montini G, Wingen AM, Sallay P, Jeck N, Berg U, Caliskan S, Wygoda S, Hohbach-Hohenfellner K, Dusek J, Urasinski T, Arbeiter K, Neuhaus T, Gellermann J, Drozdz D, Fischbach M, Möller K, Wigger M, Peruzzi L, Mehls O, Schaefer F. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009 Oct 22;361(17):1639-50. doi: 10.1056/NEJMoa0902066. — View Citation

Gimpel C, Wühl E, Arbeiter K, Drozdz D, Trivelli A, Charbit M, Gellermann J, Dusek J, Jankauskiene A, Emre S, Schaefer F; ESCAPE Trial Group. Superior consistency of ambulatory blood pressure monitoring in children: implications for clinical trials. J Hypertens. 2009 Aug;27(8):1568-74. doi: 10.1097/HJH.0b013e32832cb2a8. — View Citation

Grenda R, Wühl E, Litwin M, Janas R, Sladowska J, Arbeiter K, Berg U, Caldas-Afonso A, Fischbach M, Mehls O, Sallay P, Schaefer F; ESCAPE Trial group. Urinary excretion of endothelin-1 (ET-1), transforming growth factor- beta1 (TGF- beta1) and vascular endothelial growth factor (VEGF165) in paediatric chronic kidney diseases: results of the ESCAPE trial. Nephrol Dial Transplant. 2007 Dec;22(12):3487-94. Epub 2007 Sep 26. — View Citation

Hadtstein C, Wühl E, Soergel M, Witte K, Schaefer F; German Study Group for Pediatric Hypertension. Normative values for circadian and ultradian cardiovascular rhythms in childhood. Hypertension. 2004 Mar;43(3):547-54. Epub 2004 Jan 26. — View Citation

Jourdan C, Wühl E, Litwin M, Fahr K, Trelewicz J, Jobs K, Schenk JP, Grenda R, Mehls O, Tröger J, Schaefer F. Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents. J Hypertens. 2005 Sep;23(9):1707-15. — View Citation

Litwin M, Wühl E, Jourdan C, Trelewicz J, Niemirska A, Fahr K, Jobs K, Grenda R, Wawer ZT, Rajszys P, Tröger J, Mehls O, Schaefer F. Altered morphologic properties of large arteries in children with chronic renal failure and after renal transplantation. J — View Citation

Matteucci MC, Wühl E, Picca S, Mastrostefano A, Rinelli G, Romano C, Rizzoni G, Mehls O, de Simone G, Schaefer F; ESCAPE Trial Group. Left ventricular geometry in children with mild to moderate chronic renal insufficiency. J Am Soc Nephrol. 2006 Jan;17(1):218-26. Epub 2005 Nov 9. — View Citation

Schönfelder EM, Knüppel T, Tasic V, Miljkovic P, Konrad M, Wühl E, Antignac C, Bakkaloglu A, Schaefer F, Weber S; ESCAPE Trial Group. Mutations in Uroplakin IIIA are a rare cause of renal hypodysplasia in humans. Am J Kidney Dis. 2006 Jun;47(6):1004-12. — View Citation

Tabatabaeifar M, Schlingmann KP, Litwin M, Emre S, Bakkaloglu A, Mehls O, Antignac C, Schaefer F, Weber S; ESCAPE Trial Group. Functional analysis of BMP4 mutations identified in pediatric CAKUT patients. Pediatr Nephrol. 2009 Dec;24(12):2361-8. doi: 10.1007/s00467-009-1287-6. Epub 2009 Aug 14. — View Citation

Wühl E, Hadtstein C, Mehls O, Schaefer F; Escape Trial Group. Home, clinic, and ambulatory blood pressure monitoring in children with chronic renal failure. Pediatr Res. 2004 Mar;55(3):492-7. Epub 2003 Nov 19. — View Citation

Wühl E, Hadtstein C, Mehls O, Schaefer F; ESCAPE Trial Group. Ultradian but not circadian blood pressure rhythms correlate with renal dysfunction in children with chronic renal failure. J Am Soc Nephrol. 2005 Mar;16(3):746-54. Epub 2005 Jan 12. — View Citation

Wühl E, Mehls O, Schaefer F; ESCAPE Trial Group. Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure. Kidney Int. 2004 Aug;66(2):768-76. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.		two-monthly	No
Secondary	Effect of treatment on urinary protein excretion		two-monthly	No
Secondary	Effect of treatment on blood pressure		two-monthly	No
Secondary	Safety of treatment		initially weekly, than two-monthly	Yes