ChildrenPhase 3ESCAPENCT00221845
Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients
A Phase 3 study testing ACE Inhibition and Add-on Angiotensin Receptor Blockade in people with Children and Chronic Renal Failure, run by Heidelberg University at 33 sites in 12 countries.
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. Read more about this study
- Who is it for?
- Ages 3 to 18 years
- Conditions the study is for
- Children, Chronic Renal Failure, Hypertension
- What is being tested?
- ACE Inhibition and Add-on Angiotensin Receptor Blockade
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 400 participants
- Where
- 33 sitesin 12 countries
- Study dates
- Jan 1998to Jan 2010
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 9Show fewer
- 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
Trial locations and contacts
33 sites in 12 countries.
33 sites in 12 countries
Germany9 sites
Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology
Berlin, 13353
University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit
Essen, 45122
University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology
Hamburg, 20246
Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology
Hanover, 30623
Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg
Heidelberg, 69120
Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit
Leipzig, 04129
Johannes Gutenberg University Mainz, Department of Pediatrics,
Mainz, 55131
Philipps University Marburg, Dept. of Pediatrics
Marburg, 35037
University Children's Hospital, Dept. of Nephrology
Rostock, 18050
Italy5 sites
G.Gaslini Institute, Nephrology Unit
Genoa, 16148
Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica
Milan, 20122
Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria
Padova, 35128
Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis
Rome, 00165
Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto
Torino, 10126
Turkey (Türkiye)5 sites
Cukurova University School of Medicine, Dept. of Pediatric Nephrology
Adana, 01330
Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology
Ankara, 06100
Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics
Istanbul, 34303
University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics
Istanbul, 34390
Ege University Medical Faculty, Dept. of Pediatric Nephrology
Izmir, 35100
Poland4 sites
Jagellonian University Medical College, Department of Pediatric Nephrology
Cracow, 30-663
Medical University of Gdansk, Pediatric Nephrology Department
Gdansk, 80-211
Clinic of Pediatrics, Pomeranian Academy of Medicine
Szczecin, 71-344
Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department
Warsaw, 04-736
France3 sites
Hopital Necker, Division of Pediatric Nephrology
Paris, 75015
Inserm U574
Paris, 75015
Hopiteaux Universitaires de Strasbourg
Strasbourg, 67098
Czechia1 site
University Hospital Motol, 1st Department of Pediatrics
Prague, 150 18
Hungary1 site
Semmelweis University Budapest, 1st Department of Pediatrics
Budapest, 1083
Lithuania1 site
Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit
Vilnius, 2600
Portugal1 site
Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics
Porto, 4202 - 451
Serbia1 site
Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit
Belgrade, 11000
Sweden1 site
Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics
Stockholm, 14186
Switzerland1 site
University Children's Hospital, Nephrology Unit
Zurich, 8032
About this study
Official title: Molecular Mechanisms of Disease Progression and Renoprotective Pharmacotherapy in Children With Chronic Renal Failure
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.
Read the 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 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.
- Conditions
- Children, Chronic Renal Failure, Hypertension, Acquired Kidney Disease, Congenital Kidney Disease
- Being tested
- ACE Inhibition, Intensified Blood Pressure Control, Add-on Angiotensin Receptor Blockade
- Keywords
- Ramipril, Hypertension, Chronic renal failure, Disease progression, Left ventricular hypertrophy, Intima media thickness, Cardiovascular disease, Biomarkers, Gene polymorphisms
- Medical subject headings
- Kidney Failure, Chronic, Hypertension, Disease Progression, Hypertrophy, Left Ventricular, Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ACE InhibitionDrug
Also called Delix
ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
Intensified Blood Pressure ControlDrug
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
Add-on Angiotensin Receptor BlockadeDrug
Also called Micardis
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.
| Study group | Role | What they receive |
|---|---|---|
| Conventional BP Control | Active comparator | Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age. Receives: Drug: ACE Inhibition; Drug: Intensified Blood Pressure Control; Drug: Add-on Angiotensin Receptor Blockade |
| Intensified BP Control | Experimental | Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age. Receives: Drug: ACE Inhibition; Drug: Intensified Blood Pressure Control; Drug: Add-on Angiotensin Receptor Blockade |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.
Measured: two-monthly
Secondary outcomes (3)
Effect of treatment on urinary protein excretion
Measured: two-monthly
Effect of treatment on blood pressure
Measured: two-monthly
Safety of treatment
Measured: initially weekly, than two-monthly
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Sep 2005 (estimated)
- Study startJan 1998
- Primary completionJul 2007
- Study completionJan 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for ChildrenStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 400 participants (actual)
Sponsor and investigators
- Lead sponsor
- Heidelberg University
- Sponsor type
- University, hospital or other
- Collaborators
- European Commission, Boehringer Ingelheim, Baxter Healthcare Corporation, Aventis Pharmaceuticals
- Investigators
- Franz Schaefer, MD, Principal investigator, University of Heidelberg, Children's HospitalOtto Mehls, MD, Principal investigator, University of Heidelberg, Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00221845
- Sponsor's protocol ID
- QLRT-2001-00908
- Acronym
- ESCAPE
- Status last verified
- Jan 2010
- First submitted
- 15 Sep 2005
- Last updated
- 12 Jan 2010
- Results posted
- No
- Data monitoring committee
- Yes
Publications
ESCAPE Trial Group; Wuhl 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, Moller 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.
PubMed 19846849Tabatabaeifar 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.
PubMed 19685083Gimpel C, Wuhl 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.
PubMed 19550356Grenda R, Wuhl 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. doi: 10.1093/ndt/gfm300. Epub 2007 Sep 26.
PubMed 17901069Chinali 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, Wuhl 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. doi: 10.1681/ASN.2006070691. Epub 2007 Jan 10.
PubMed 17215443Schonfelder EM, Knuppel T, Tasic V, Miljkovic P, Konrad M, Wuhl 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. doi: 10.1053/j.ajkd.2006.02.177.
PubMed 16731295Matteucci MC, Wuhl 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. doi: 10.1681/ASN.2005030276. Epub 2005 Nov 9.
PubMed 16280471Wuhl 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. doi: 10.1111/j.1523-1755.2004.00802.x.
PubMed 15253732Jourdan C, Wuhl E, Litwin M, Fahr K, Trelewicz J, Jobs K, Schenk JP, Grenda R, Mehls O, Troger 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. doi: 10.1097/01.hjh.0000178834.26353.d5.
PubMed 16093916Litwin M, Wuhl E, Jourdan C, Trelewicz J, Niemirska A, Fahr K, Jobs K, Grenda R, Wawer ZT, Rajszys P, Troger J, Mehls O, Schaefer F. Altered morphologic properties of large arteries in children with chronic renal failure and after renal transplantation. J Am Soc Nephrol. 2005 May;16(5):1494-500. doi: 10.1681/ASN.2004110932. Epub 2005 Mar 16.
PubMed 15772249Wuhl 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. doi: 10.1681/ASN.2004070537. Epub 2005 Jan 12.
PubMed 15647341Hadtstein C, Wuhl 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. doi: 10.1161/01.HYP.0000116754.15808.d8. Epub 2004 Jan 26.
PubMed 14744931Wuhl 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. doi: 10.1203/01.PDR.0000106863.90996.76. Epub 2003 Nov 19.
PubMed 14630977Speer T, Schunk SJ, Sarakpi T, Schmit D, Wagner M, Arnold L, Zewinger S, Azukaitis K, Bayazit A, Obrycki L, Kaplan Bulut I, Duzova A, Doyon A, Ranchin B, Caliskan S, Harambat J, Yilmaz A, Alpay H, Lugani F, Balat A, Arbeiter K, Longo G, Melk A, Querfeld U, Wuhl E, Mehls O, Fliser D, Schaefer F; 4C Study Investigators, ESCAPE Trial Investigators. Urinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort study. Lancet Child Adolesc Health. 2023 Jun;7(6):405-414. doi: 10.1016/S2352-4642(23)00049-4. Epub 2023 Apr 26.
PubMed 37119829
Study at a glance
From the registry record, last updated by the sponsor on 12 Jan 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Molecular Mechanisms of Disease Progression and Renoprotective Pharmacotherapy in Children With Chronic Renal Failure
- ClinicalTrials.gov ID
- NCT00221845
- Acronym / sponsor ID
- ESCAPE / QLRT-2001-00908
- Conditions
- Children, Chronic Renal Failure, Hypertension, Acquired Kidney Disease, Congenital Kidney Disease
- Keywords
- Ramipril, Hypertension, Chronic renal failure, Disease progression, Left ventricular hypertrophy, Intima media thickness, Cardiovascular disease, Biomarkers
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 400 participants (actual)
- Lead sponsor
- Heidelberg UniversityUniversity, hospital or other
- Collaborators
- European Commission, Boehringer Ingelheim, Baxter Healthcare Corporation, Aventis Pharmaceuticals
- Study start
- Jan 1998
- Primary completion
- Jul 2007 (actual)
- Study completion
- Jan 2010 (actual)
- First posted
- 22 Sep 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Conventional BP Control | Active comparator | Drug: ACE Inhibition, Drug: Intensified Blood Pressure Control, Drug: Add-on Angiotensin Receptor BlockadeTargeted 24-hour mean arterial pressure will be the 50th-95th percentile for age. |
| Intensified BP Control | Experimental | Drug: ACE Inhibition, Drug: Intensified Blood Pressure Control, Drug: Add-on Angiotensin Receptor BlockadeTargeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age. |
Who may qualify
- Ages
- 3 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ACE InhibitionAlso: DelixACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects. | Drug | Conventional BP Control, Intensified BP Control |
| Intensified Blood Pressure ControlAny antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed. | Drug | Conventional BP Control, Intensified BP Control |
| Add-on Angiotensin Receptor BlockadeAlso: MicardisIn 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. | Drug | Conventional BP Control, Intensified BP Control |
Primary outcome
Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.
Time frame: two-monthly
3 secondary outcomes
Effect of treatment on urinary protein excretion
Time frame: two-monthly
Effect of treatment on blood pressure
Time frame: two-monthly
Safety of treatment
Time frame: initially weekly, than two-monthly
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jan 2010.
- Background: PubMed 19846849ESCAPE Trial Group; Wuhl 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, Moller 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.
- Background: PubMed 19685083Tabatabaeifar 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.
- Background: PubMed 19550356Gimpel C, Wuhl 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.
- Background: PubMed 17901069Grenda R, Wuhl 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. doi: 10.1093/ndt/gfm300. Epub 2007 Sep 26.
- Background: PubMed 17215443Chinali 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, Wuhl 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. doi: 10.1681/ASN.2006070691. Epub 2007 Jan 10.
- Background: PubMed 16731295Schonfelder EM, Knuppel T, Tasic V, Miljkovic P, Konrad M, Wuhl 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. doi: 10.1053/j.ajkd.2006.02.177.
- Background: PubMed 16280471Matteucci MC, Wuhl 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. doi: 10.1681/ASN.2005030276. Epub 2005 Nov 9.
- Results publication: PubMed 15253732Wuhl 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. doi: 10.1111/j.1523-1755.2004.00802.x.
- Results publication: PubMed 16093916Jourdan C, Wuhl E, Litwin M, Fahr K, Trelewicz J, Jobs K, Schenk JP, Grenda R, Mehls O, Troger 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. doi: 10.1097/01.hjh.0000178834.26353.d5.
- Results publication: PubMed 15772249Litwin M, Wuhl E, Jourdan C, Trelewicz J, Niemirska A, Fahr K, Jobs K, Grenda R, Wawer ZT, Rajszys P, Troger J, Mehls O, Schaefer F. Altered morphologic properties of large arteries in children with chronic renal failure and after renal transplantation. J Am Soc Nephrol. 2005 May;16(5):1494-500. doi: 10.1681/ASN.2004110932. Epub 2005 Mar 16.
- Results publication: PubMed 15647341Wuhl 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. doi: 10.1681/ASN.2004070537. Epub 2005 Jan 12.
- Results publication: PubMed 14744931Hadtstein C, Wuhl 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. doi: 10.1161/01.HYP.0000116754.15808.d8. Epub 2004 Jan 26.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Franz Schaefer, MD principal investigator
University of Heidelberg, Children's Hospital
Otto Mehls, MD principal investigator
University of Heidelberg, Children's Hospital
33 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing ACE Inhibition and Add-on Angiotensin Receptor Blockade in people with Children and Chronic Renal Failure, run by Heidelberg University at 33 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Jan 2010. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 33 sites in Germany, Italy, Turkey (Türkiye), Poland, France and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy. (time frame: two-monthly). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00221845, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jan 2010.