NAtural Course and Prognosis of PFIC and Effect of Biliary Diversion

Официальное название

NAtural Course and Prognosis of PFIC and Effect of Biliary Diversion (NAPPED Study), Meta-analysis of Individual Patient Data of PFIC Before and After Surgery (Bile Diversion or Liver Transplantation)

Обзор

The natural course of PFIC syndromes and the effect of diversion techniques, have so far not been characterized in a rigorous manner within a larger population of patients. In fact, the clinical or biochemical parameters which most directly define and/or predict the success of reduced enterohepatic circulation (either by surgical diversion or medically) are still unclear. The present project aims to: 1. Define the natural course of disease in patients with genetically defined FIC1 deficiency (PFIC1), BSEP deficiency (PFIC2), MDR3 deficiency (PFIC3) and other subtypes of the PFIC disease family (including e.g. Myo5B deficiency, TJP2 deficiency, a.o.), with respect to relevant biochemical and clinical parameters (and if available, histological). Included will be patients homozygous for a known, disease-causing mutation, patients compound homozygous for two disease-causing mutations or heterozygous for one disease-causing mutation in combination with the corresponding clinical phenotype . 2. Define the change in the natural course of disease in response to biliary diversion surgery and or liver transplantation, based on short- and long(er)-term changes in biochemical (if available, histological) and clinical parameters, including outcome measures. Follow up after transplantation will be limited, follow up after surgical biliary diversion will be as long as possible. 3. Assessment of biochemical variables as possible surrogate endpoints for clinical hard endpoints. If possible this allows for identification of low-risk to high-risk patients early during follow-up. 4. If patient numbers permit, to establish genotype-phenotype relationships for the most common genetic mutations causing the indicated diseases. Based on this project it is anticipated that the investigators are able: * to characterize the variation in natural course of disease (whether or not genotype dependent) to allow clinicians to rationally select a target population for assessing the effect of medical intervention, rather than surgical biliary diversion); * to identify and qualify one or more biomarkers that independently predict either improved or poor clinical outcomes of surgical biliary diversion; * to investigate if the identified biomarker(s) can be used as surrogate end point(s) for assessing and predicting outcomes with novel interventional strategies.

Вмешательства

• Процедура Surgical biliary diversion
  Surgical interruption of enterohepatic circulation

Первичные конечные точки

• Number of participants with liver transplantation [Срок оценки: at 18 years of age, as well as >18 years of age (until 65 years of age)]
• Number of participants that succumbed [Срок оценки: at 18 years of age, as well as >18 years of age (until 65 years of age)]

Вторичные конечные точки (1)

• Number of participant undergoing a surgical biliary diversion [Срок оценки: at 5, 10, 15 and 18 years of age, as well as >18 years of age (until 65 years of age)]

Критерии участия

Критерии включения

Clinical suspicion for FIC1-, BSEP- or MDR3-deficiency or of any other subtype of the PFIC family

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Нидерланды · 1 центр

• University Medical Center Groningen — Groningen

Публикации

• van Wessel DBE, Gonzales E, Hansen BE, Verkade HJ. Defining the natural history of rare genetic liver diseases: Lessons learned from the NAPPED initiative. Eur J Med Genet. 2021 Jul;64(7):104245. doi: 10.1016/j.ejmg.2021.104245. Epub 2021 May 13. PMID 33991701
• Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Emerick K, Antoniou A, Wanty C, Fischler B, Jacquemin E, Wali S, Blanchard S, Nielsen IM, Bourke B, McQuaid S, Lacaille F, Byrne JA, van Eerde AM, Kolho KL, Klomp L, Houwen R, Bacchetti P, Lobritto S, Hupertz V, McClean P, Mieli-Vergani G, Shneider B, Nemeth A, Sokal E, Freimer NB, Knisely AS, Rosenthal P, Whitington PF, Pawlowska J, Thompso PMID 20447715
• Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H, Ozcay F, Al-Hussaini HF, Bassas AF, Verkade HJ, Fischler B, Nemeth A, Kotalova R, Shneider BL, Cielecka-Kuszyk J, McClean P, Whitington PF, Sokal E, Jirsa M, Wali SH, Jankowska I, Pawlowska J, Mieli-Vergani G, Knisely AS, Bull LN, Thompson RJ. Severe bile salt export pump deficien PMID 18395098
• Bull LN, van Eijk MJ, Pawlikowska L, DeYoung JA, Juijn JA, Liao M, Klomp LW, Lomri N, Berger R, Scharschmidt BF, Knisely AS, Houwen RH, Freimer NB. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 1998 Mar;18(3):219-24. doi: 10.1038/ng0398-219. PMID 9500542
• Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, Bernard O, Jacquemin E. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010 May;51(5):1645-55. doi: 10.1002/hep.23539. PMID 20232290
• Bull LN, Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Dodge JL, Emerick K, Wanty C, Wali S, Blanchard S, Lacaille F, Byrne JA, van Eerde AM, Kolho KL, Houwen R, Lobritto S, Hupertz V, McClean P, Mieli-Vergani G, Sokal E, Rosenthal P, Whitington PF, Pawlowska J, Thompson RJ. Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. PMID 29761168
• Droge C, Bonus M, Baumann U, Klindt C, Lainka E, Kathemann S, Brinkert F, Grabhorn E, Pfister ED, Wenning D, Fichtner A, Gotthardt DN, Weiss KH, McKiernan P, Puri RD, Verma IC, Kluge S, Gohlke H, Schmitt L, Kubitz R, Haussinger D, Keitel V. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. J Hepatol. 2017 Dec;67(6 PMID 28733223
• Wang KS, Tiao G, Bass LM, Hertel PM, Mogul D, Kerkar N, Clifton M, Azen C, Bull L, Rosenthal P, Stewart D, Superina R, Arnon R, Bozic M, Brandt ML, Dillon PA, Fecteau A, Iyer K, Kamath B, Karpen S, Karrer F, Loomes KM, Mack C, Mattei P, Miethke A, Soltys K, Turmelle YP, West K, Zagory J, Goodhue C, Shneider BL; Childhood Liver Disease Research Network (ChiLDReN). Analysis of surgical interruption PMID 28027587

Идентификаторы

NCT: NCT03930810 · METc2017.106

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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