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

11 gennaio 2010 aggiornato da: 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.

Panoramica dello studio

Stato

Completato

Condizioni

Intervento / Trattamento

Descrizione dettagliata

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.

Tipo di studio

Interventistico

Iscrizione (Effettivo)

400

Fase

  • Fase 3

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

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

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

Da 3 anni a 18 anni (Bambino, Adulto)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

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

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Comparatore attivo: Conventional BP Control
Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age.
Droga: ACE Inhibition
ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
Altri nomi:
  • Delix
Droga: Intensified Blood Pressure Control
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
Droga: 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.
Altri nomi:
  • Micardis
Sperimentale: Intensified BP Control
Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age.
Droga: ACE Inhibition
ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
Altri nomi:
  • Delix
Droga: Intensified Blood Pressure Control
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
Droga: 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.
Altri nomi:
  • Micardis

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Lasso di tempo
Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.
Lasso di tempo: two-monthly
two-monthly

Misure di risultato secondarie

Misura del risultato
Lasso di tempo
Effect of treatment on urinary protein excretion
Lasso di tempo: two-monthly
two-monthly
Effect of treatment on blood pressure
Lasso di tempo: two-monthly
two-monthly
Safety of treatment
Lasso di tempo: initially weekly, than two-monthly
initially weekly, than two-monthly

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Heidelberg University

Collaboratori

Baxter Healthcare Corporation
Boehringer Ingelheim
Aventis Pharmaceuticals
European Commission

Investigatori

  • Investigatore principale: Franz Schaefer, MD, University of Heidelberg, Children's Hospital
  • Investigatore principale: Otto Mehls, MD, University of Heidelberg, Children's Hospital

Pubblicazioni e link utili

La persona responsabile dell'inserimento delle informazioni sullo studio fornisce volontariamente queste pubblicazioni. Questi possono riguardare qualsiasi cosa relativa allo studio.

Pubblicazioni generali

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio

1 gennaio 1998

Completamento primario (Effettivo)

1 luglio 2007

Completamento dello studio (Effettivo)

1 gennaio 2010

Date di iscrizione allo studio

Primo inviato

15 settembre 2005

Primo inviato che soddisfa i criteri di controllo qualità

15 settembre 2005

Primo Inserito (Stima)

22 settembre 2005

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Stima)

12 gennaio 2010

Ultimo aggiornamento inviato che soddisfa i criteri QC

11 gennaio 2010

Ultimo verificato

1 gennaio 2010

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • QLRT-2001-00908

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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