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

11. ledna 2010 aktualizováno: Heidelberg University

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.

Přehled studie

Postavení

Dokončeno

Podmínky

Intervence / Léčba

Detailní popis

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.

Typ studie

Intervenční

Zápis (Aktuální)

400

Fáze

  • Fáze 3

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní místa

  • Francie
      • Paris, Francie, 75015
        • Hopital Necker, Division of Pediatric Nephrology
      • Paris, Francie, 75015
        • Inserm U574
      • Strasbourg, Francie, 67098
        • Hopiteaux Universitaires de Strasbourg
  • Itálie
      • Genoa, Itálie, 16148
        • G.Gaslini Institute, Nephrology Unit
      • Milano, Itálie, 20122
        • Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica
      • Padova, Itálie, 35128
        • Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria
      • Rome, Itálie, 00165
        • Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis
      • Torino, Itálie, 10126
        • Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto
  • Krocan
      • Adana, Krocan, 01330
        • Cukurova University School of Medicine, Dept. of Pediatric Nephrology
      • Ankara, Krocan, 06100
        • Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology
      • Istanbul, Krocan, 34303
        • Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics
      • Istanbul, Krocan, 34390
        • University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics
      • Izmir, Krocan, 35100
        • Ege University Medical Faculty, Dept. of Pediatric Nephrology
  • Litva
      • Vilnius, Litva, 2600
        • Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit
  • Maďarsko
      • Budapest, Maďarsko, 1083
        • Semmelweis University Budapest, 1st Department of Pediatrics
  • Německo
      • Berlin, Německo, 13353
        • Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology
      • Essen, Německo, 45122
        • University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit
      • Hamburg, Německo, 20246
        • University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology
      • Hannover, Německo, 30623
        • Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology
      • Heidelberg, Německo, 69120
        • Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg
      • Leipzig, Německo, 04129
        • Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit
      • Mainz, Německo, 55131
        • Johannes Gutenberg University Mainz, Department of Pediatrics,
      • Marburg, Německo, 35037
        • Philipps University Marburg, Dept. of Pediatrics
      • Rostock, Německo, 18050
        • University Children's Hospital, Dept. of Nephrology
  • Polsko
      • Cracow, Polsko, 30-663
        • Jagellonian University Medical College, Department of Pediatric Nephrology
      • Gdansk, Polsko, 80-211
        • Medical University of Gdansk, Pediatric Nephrology Department
      • Szczecin, Polsko, 71-344
        • Clinic of Pediatrics, Pomeranian Academy of Medicine
      • Warsaw, Polsko, 04-736
        • Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department
  • Portugalsko
      • Porto, Portugalsko, 4202 - 451
        • Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics
  • Srbsko
      • Belgrade, Srbsko, 11000
        • Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit
  • Česká republika
      • Prague, Česká republika, 150 18
        • University Hospital Motol, 1st Department of Pediatrics
  • Švédsko
      • Stockholm, Švédsko, 14186
        • Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics
  • Švýcarsko
      • Zürich, Švýcarsko, 8032
        • University Children's Hospital, Nephrology Unit

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

3 roky až 18 let (Dítě, Dospělý)

Přijímá zdravé dobrovolníky

Ne

Pohlaví způsobilá ke studiu

Všechno

Popis

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

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: Randomizované
  • Intervenční model: Paralelní přiřazení
  • Maskování: Žádné (otevřený štítek)

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Aktivní komparátor: Conventional BP Control
Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age.
Lék: ACE Inhibition
ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
Ostatní jména:
  • Delix
Lék: Intensified Blood Pressure Control
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
Lék: 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.
Ostatní jména:
  • Micardis
Experimentální: Intensified BP Control
Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age.
Lék: ACE Inhibition
ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
Ostatní jména:
  • Delix
Lék: Intensified Blood Pressure Control
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
Lék: 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.
Ostatní jména:
  • Micardis

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Časové okno
Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.
Časové okno: two-monthly
two-monthly

Sekundární výstupní opatření

Měření výsledku
Časové okno
Effect of treatment on urinary protein excretion
Časové okno: two-monthly
two-monthly
Effect of treatment on blood pressure
Časové okno: two-monthly
two-monthly
Safety of treatment
Časové okno: initially weekly, than two-monthly
initially weekly, than two-monthly

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

Heidelberg University

Spolupracovníci

Baxter Healthcare Corporation
Boehringer Ingelheim
Aventis Pharmaceuticals
European Commission

Vyšetřovatelé

  • Vrchní vyšetřovatel: Franz Schaefer, MD, University of Heidelberg, Children's Hospital
  • Vrchní vyšetřovatel: Otto Mehls, MD, University of Heidelberg, Children's Hospital

Publikace a užitečné odkazy

Osoba odpovědná za zadávání informací o studiu tyto publikace poskytuje dobrovolně. Mohou se týkat čehokoli, co souvisí se studiem.

Obecné publikace

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia

1. ledna 1998

Primární dokončení (Aktuální)

1. července 2007

Dokončení studie (Aktuální)

1. ledna 2010

Termíny zápisu do studia

První předloženo

15. září 2005

První předloženo, které splnilo kritéria kontroly kvality

15. září 2005

První zveřejněno (Odhad)

22. září 2005

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Odhad)

12. ledna 2010

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

11. ledna 2010

Naposledy ověřeno

1. ledna 2010

Více informací

Termíny související s touto studií

Klíčová slova

Další relevantní podmínky MeSH

Další identifikační čísla studie

  • QLRT-2001-00908

Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .

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