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

2010年1月11日 更新者：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.

調査の概要

状態

完了

条件

介入・治療

詳細な説明

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.

研究の種類

介入

入学 (実際)

400

段階

  • フェーズ 3

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

  • イタリア
      • Genoa、イタリア、16148
        • G.Gaslini Institute, Nephrology Unit
      • Milano、イタリア、20122
        • Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica
      • Padova、イタリア、35128
        • Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria
      • Rome、イタリア、00165
        • Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis
      • Torino、イタリア、10126
        • Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto
  • スイス
      • Zürich、スイス、8032
        • University Children's Hospital, Nephrology Unit
  • スウェーデン
      • Stockholm、スウェーデン、14186
        • Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics
  • セルビア
      • Belgrade、セルビア、11000
        • Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit
  • チェコ共和国
      • Prague、チェコ共和国、150 18
        • University Hospital Motol, 1st Department of Pediatrics
  • ドイツ
      • Berlin、ドイツ、13353
        • Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology
      • Essen、ドイツ、45122
        • University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit
      • Hamburg、ドイツ、20246
        • University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology
      • Hannover、ドイツ、30623
        • Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology
      • Heidelberg、ドイツ、69120
        • Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg
      • Leipzig、ドイツ、04129
        • Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit
      • Mainz、ドイツ、55131
        • Johannes Gutenberg University Mainz, Department of Pediatrics,
      • Marburg、ドイツ、35037
        • Philipps University Marburg, Dept. of Pediatrics
      • Rostock、ドイツ、18050
        • University Children's Hospital, Dept. of Nephrology
  • ハンガリー
      • Budapest、ハンガリー、1083
        • Semmelweis University Budapest, 1st Department of Pediatrics
  • フランス
      • Paris、フランス、75015
        • Hopital Necker, Division of Pediatric Nephrology
      • Paris、フランス、75015
        • Inserm U574
      • Strasbourg、フランス、67098
        • Hopiteaux Universitaires de Strasbourg
  • ポルトガル
      • Porto、ポルトガル、4202 - 451
        • Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics
  • ポーランド
      • Cracow、ポーランド、30-663
        • Jagellonian University Medical College, Department of Pediatric Nephrology
      • Gdansk、ポーランド、80-211
        • Medical University of Gdansk, Pediatric Nephrology Department
      • Szczecin、ポーランド、71-344
        • Clinic of Pediatrics, Pomeranian Academy of Medicine
      • Warsaw、ポーランド、04-736
        • Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department
  • リトアニア
      • Vilnius、リトアニア、2600
        • Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit
  • 七面鳥
      • Adana、七面鳥、01330
        • Cukurova University School of Medicine, Dept. of Pediatric Nephrology
      • Ankara、七面鳥、06100
        • Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology
      • Istanbul、七面鳥、34303
        • Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics
      • Istanbul、七面鳥、34390
        • University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics
      • Izmir、七面鳥、35100
        • Ege University Medical Faculty, Dept. of Pediatric Nephrology

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

3年～18年 (子、大人)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

全て

説明

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

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：ランダム化
  • 介入モデル：並列代入
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
アクティブコンパレータ：Conventional BP Control
Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age.
薬：ACE Inhibition
ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
他の名前：
  • Delix
薬：Intensified Blood Pressure Control
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
薬：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.
他の名前：
  • ミカルディス
実験的：Intensified BP Control
Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age.
薬：ACE Inhibition
ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
他の名前：
  • Delix
薬：Intensified Blood Pressure Control
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
薬：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.
他の名前：
  • ミカルディス

この研究は何を測定していますか？

主要な結果の測定

結果測定
時間枠
Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.
時間枠：two-monthly
two-monthly

二次結果の測定

結果測定
時間枠
Effect of treatment on urinary protein excretion
時間枠：two-monthly
two-monthly
Effect of treatment on blood pressure
時間枠：two-monthly
two-monthly
Safety of treatment
時間枠：initially weekly, than two-monthly
initially weekly, than two-monthly

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Heidelberg University

協力者

Baxter Healthcare Corporation
Boehringer Ingelheim
Aventis Pharmaceuticals
European Commission

捜査官

  • 主任研究者：Franz Schaefer, MD、University of Heidelberg, Children's Hospital
  • 主任研究者：Otto Mehls, MD、University of Heidelberg, Children's Hospital

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

一般刊行物

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始

1998年1月1日

一次修了 (実際)

2007年7月1日

研究の完了 (実際)

2010年1月1日

試験登録日

最初に提出

2005年9月15日

QC基準を満たした最初の提出物

2005年9月15日

最初の投稿 (見積もり)

2005年9月22日

学習記録の更新

投稿された最後の更新 (見積もり)

2010年1月12日

QC基準を満たした最後の更新が送信されました

2010年1月11日

最終確認日

2010年1月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

  • QLRT-2001-00908

この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。

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