- ICH GCP
- Реестр клинических исследований США
- Клиническое испытание NCT00221845
Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE)
Molecular Mechanisms of Disease Progression and Renoprotective Pharmacotherapy in Children With Chronic Renal Failure
Обзор исследования
Статус
Условия
Подробное описание
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.
Тип исследования
Регистрация (Действительный)
Фаза
- Фаза 3
Контакты и местонахождение
Места учебы
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Budapest, Венгрия, 1083
- Semmelweis University Budapest, 1st Department of Pediatrics
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Berlin, Германия, 13353
- Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology
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Essen, Германия, 45122
- University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit
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Hamburg, Германия, 20246
- University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology
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Hannover, Германия, 30623
- Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology
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Heidelberg, Германия, 69120
- Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg
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Leipzig, Германия, 04129
- Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit
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Mainz, Германия, 55131
- Johannes Gutenberg University Mainz, Department of Pediatrics,
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Marburg, Германия, 35037
- Philipps University Marburg, Dept. of Pediatrics
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Rostock, Германия, 18050
- University Children's Hospital, Dept. of Nephrology
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Genoa, Италия, 16148
- G.Gaslini Institute, Nephrology Unit
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Milano, Италия, 20122
- Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica
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Padova, Италия, 35128
- Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria
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Rome, Италия, 00165
- Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis
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Torino, Италия, 10126
- Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto
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Vilnius, Литва, 2600
- Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit
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Cracow, Польша, 30-663
- Jagellonian University Medical College, Department of Pediatric Nephrology
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Gdansk, Польша, 80-211
- Medical University of Gdansk, Pediatric Nephrology Department
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Szczecin, Польша, 71-344
- Clinic of Pediatrics, Pomeranian Academy of Medicine
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Warsaw, Польша, 04-736
- Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department
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Porto, Португалия, 4202 - 451
- Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics
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Belgrade, Сербия, 11000
- Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit
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Adana, Турция, 01330
- Cukurova University School of Medicine, Dept. of Pediatric Nephrology
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Ankara, Турция, 06100
- Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology
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Istanbul, Турция, 34303
- Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics
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Istanbul, Турция, 34390
- University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics
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Izmir, Турция, 35100
- Ege University Medical Faculty, Dept. of Pediatric Nephrology
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Paris, Франция, 75015
- Hopital Necker, Division of Pediatric Nephrology
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Paris, Франция, 75015
- Inserm U574
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Strasbourg, Франция, 67098
- Hopiteaux Universitaires de Strasbourg
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Prague, Чешская Республика, 150 18
- University Hospital Motol, 1st Department of Pediatrics
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Zürich, Швейцария, 8032
- University Children's Hospital, Nephrology Unit
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Stockholm, Швеция, 14186
- Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics
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Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
Принимает здоровых добровольцев
Полы, имеющие право на обучение
Описание
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
Учебный план
Как устроено исследование?
Детали дизайна
- Основная цель: Уход
- Распределение: Рандомизированный
- Интервенционная модель: Параллельное назначение
- Маскировка: Нет (открытая этикетка)
Оружие и интервенции
Группа участников / Армия |
Вмешательство/лечение |
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Активный компаратор: Conventional BP Control
Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age.
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ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
Другие имена:
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
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.
Другие имена:
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Экспериментальный: Intensified BP Control
Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age.
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ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
Другие имена:
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
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.
Другие имена:
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Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Временное ограничение |
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Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.
Временное ограничение: two-monthly
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two-monthly
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Вторичные показатели результатов
Мера результата |
Временное ограничение |
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Effect of treatment on urinary protein excretion
Временное ограничение: two-monthly
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two-monthly
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Effect of treatment on blood pressure
Временное ограничение: two-monthly
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two-monthly
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Safety of treatment
Временное ограничение: initially weekly, than two-monthly
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initially weekly, than two-monthly
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Соавторы и исследователи
Спонсор
Соавторы
Следователи
- Главный следователь: Franz Schaefer, MD, University of Heidelberg, Children's Hospital
- Главный следователь: Otto Mehls, MD, University of Heidelberg, Children's Hospital
Публикации и полезные ссылки
Общие публикации
- 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.
- 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.
- Gimpel 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.
- Grenda 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.
- 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, 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.
- Schonfelder 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.
- Matteucci 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.
- Wuhl 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.
- Jourdan 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.
- Litwin 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.
- Wuhl 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.
- Hadtstein 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.
- Wuhl 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.
Даты записи исследования
Изучение основных дат
Начало исследования
Первичное завершение (Действительный)
Завершение исследования (Действительный)
Даты регистрации исследования
Первый отправленный
Впервые представлено, что соответствует критериям контроля качества
Первый опубликованный (Оценивать)
Обновления учебных записей
Последнее опубликованное обновление (Оценивать)
Последнее отправленное обновление, отвечающее критериям контроля качества
Последняя проверка
Дополнительная информация
Термины, связанные с этим исследованием
Ключевые слова
Дополнительные соответствующие термины MeSH
- Патологические процессы
- Сердечно-сосудистые заболевания
- Сосудистые заболевания
- Урологические заболевания
- Атрибуты болезни
- Гипертония
- Прогрессирование болезни
- Заболевания почек
- Почечная недостаточность, хроническая
- Почечная недостаточность, хроническая
- Почечная недостаточность
- Молекулярные механизмы фармакологического действия
- Антигипертензивные агенты
- Блокаторы рецепторов ангиотензина II типа 1
- Антагонисты рецепторов ангиотензина
- Телмисартан
Другие идентификационные номера исследования
- QLRT-2001-00908
Эта информация была получена непосредственно с веб-сайта clinicaltrials.gov без каких-либо изменений. Если у вас есть запросы на изменение, удаление или обновление сведений об исследовании, обращайтесь по адресу register@clinicaltrials.gov. Как только изменение будет реализовано на clinicaltrials.gov, оно будет автоматически обновлено и на нашем веб-сайте. .
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