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Enrolling by invitationNCT03930810NAPPEDUpdated Jan 17, 2025

NAtural Course and Prognosis of PFIC and Effect of Biliary Diversion

An observational study in Progressive Familial Intrahepatic Cholestasis, sponsored by University Medical Center Groningen. Enrolling by invitation at 1 site in Netherlands. Open to participants aged 0 Years to 65 Years. Per ClinicalTrials.gov, last updated 2025-01-17.

Sponsored by University Medical Center Groningen · Observational

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Study type
Observational
Model
Cohort
Time perspective
Retrospective
Enrollment
1,500
Ages
0 Years to 65 Years
Sex
All
01

Study summary

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.
02

Conditions studied

  • Progressive Familial Intrahepatic Cholestasis
03

In context

Cholestasis, progressive familial intrahepatic 1

33 studies on the registry are indexed under Cholestasis, progressive familial intrahepatic 1; 13 are open to participants now.

This study's planned enrollment of 1,500 is above the median of 200 across 17 observational studies indexed under Cholestasis, progressive familial intrahepatic 1.

Browse Cholestasis, progressive familial intrahepatic 1 studies →

Lead sponsor

University Medical Center Groningen is the lead sponsor of 627 studies on the registry; 175 are open to participants now.

Browse University Medical Center Groningen studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
0 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No
Sampling method
Probability sample

Study population

The diagnosis of PFIC needs to be performed according to the international guidelines, based on (episodes with) the clinical symtpoms and identification of disease-causing mutations in the respective genes.

Eligibility criteria

Inclusion Criteria:

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

05

Study design

Observational model
Cohort
Time perspective
Retrospective
Enrollment
1,500 participants (estimated)
Patient registry
No

Groups and cohorts

  • FIC1 deficiency (PFIC1), BSEP deficiency (PFIC2), MDR3 deficiency (PFIC3) and other PFIC subtypes

    Procedure: Surgical biliary diversion

Interventions

  • ProcedureSurgical biliary diversion

    Surgical interruption of enterohepatic circulation

06

What researchers measure

Primary outcomes

  1. Number of participants with liver transplantation

    Underwent liver transplant

    Time frame: at 18 years of age, as well as >18 years of age (until 65 years of age)

  2. Number of participants that succumbed

    Succumbed

    Time frame: at 18 years of age, as well as >18 years of age (until 65 years of age)

Secondary outcomes

  1. Number of participant undergoing a surgical biliary diversion

    Underwent surgical biliary diversion

    Time frame: at 5, 10, 15 and 18 years of age, as well as >18 years of age (until 65 years of age)

07

Study locations

1 site
08

References and documents

Publications

  • 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. PubMed 33991701 ↗
  • Felzen A, van Wessel DBE, Gonzales E, Thompson RJ, Jankowska I, Shneider BL, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipinski P, Czubkowski P, Rock N, Shagrani M, Broering D, Nicastro E, Kelly D, Nebbia G, Arnell H, Fischler B, Hulscher JBF, Serranti D, Arikan C, Polat E, Debray D, Lacaille F, Goncalves C, Hierro L, Munoz Bartolo G, Mozer-Glassberg Y, Azaz A, Brecelj J, Dezsofi A, Calvo PL, Grabhorn E, Hartleif S, van der Woerd WJ, Kamath BM, Wang JS, Li L, Durmaz O, Kerkar N, Jorgensen MH, Fischer R, Jimenez-Rivera C, Alam S, Cananzi M, Laverdure N, Ferreira CT, Guerrero FO, Wang H, Sency V, Kim KM, Chen HL, de Carvalho E, Fabre A, Bernabeu JQ, Zellos A, Alonso EM, Sokol RJ, Suchy FJ, Loomes KM, McKiernan PJ, Rosenthal P, Turmelle Y, Horslen S, Schwarz K, Bezerra JA, Wang K, Hansen BE, Verkade HJ; NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. JHEP Rep. 2022 Nov 16;5(2):100626. doi: 10.1016/j.jhepr.2022.100626. eCollection 2023 Feb. PubMed 36687469 ↗
  • 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, Thompson RJ, Bull LN. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010 Jul;53(1):170-8. doi: 10.1016/j.jhep.2010.01.034. Epub 2010 Apr 13. PubMed 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 deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008 Apr;134(4):1203-14. doi: 10.1053/j.gastro.2008.01.038. Epub 2008 Jan 18. PubMed 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. PubMed 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. PubMed 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. Hepatol Commun. 2018 Mar 30;2(5):515-528. doi: 10.1002/hep4.1168. eCollection 2018 May. PubMed 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):1253-1264. doi: 10.1016/j.jhep.2017.07.004. Epub 2017 Jul 19. PubMed 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 of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology. 2017 May;65(5):1645-1654. doi: 10.1002/hep.29019. Epub 2017 Mar 22. PubMed 28027587 ↗
  • van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipinski P, Czubkowski P, Rock N, Shagrani M, Broering D, Algoufi T, Mazhar N, Nicastro E, Kelly DA, Nebbia G, Arnell H, Bjorn Fischler, Hulscher JBF, Serranti D, Arikan C, Polat E, Debray D, Lacaille F, Goncalves C, Hierro L, Munoz Bartolo G, Mozer-Glassberg Y, Azaz A, Brecelj J, Dezsofi A, Calvo PL, Grabhorn E, Sturm E, van der Woerd WJ, Kamath BM, Wang JS, Li L, Durmaz O, Onal Z, Bunt TMG, Hansen BE, Verkade HJ; NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) consortium. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020 Jul;73(1):84-93. doi: 10.1016/j.jhep.2020.02.007. Epub 2020 Feb 20. PubMed 32087350 ↗
  • van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Shneider BL, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipinski P, Czubkowski P, Rock N, Shagrani M, Broering D, Algoufi T, Mazhar N, Nicastro E, Kelly D, Nebbia G, Arnell H, Fischler B, Hulscher JBF, Serranti D, Arikan C, Debray D, Lacaille F, Goncalves C, Hierro L, Munoz Bartolo G, Mozer-Glassberg Y, Azaz A, Brecelj J, Dezsofi A, Luigi Calvo P, Krebs-Schmitt D, Hartleif S, van der Woerd WL, Wang JS, Li LT, Durmaz O, Kerkar N, Horby Jorgensen M, Fischer R, Jimenez-Rivera C, Alam S, Cananzi M, Laverdure N, Targa Ferreira C, Ordonez F, Wang H, Sency V, Mo Kim K, Chen HL, Carvalho E, Fabre A, Quintero Bernabeu J, Alonso EM, Sokol RJ, Suchy FJ, Loomes KM, McKiernan PJ, Rosenthal P, Turmelle Y, Rao GS, Horslen S, Kamath BM, Rogalidou M, Karnsakul WW, Hansen B, Verkade HJ; Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium. Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency. Hepatology. 2021 Aug;74(2):892-906. doi: 10.1002/hep.31787. Epub 2021 Jul 13. PubMed 33666275 ↗

Individual participant data

Plan to share: Undecided

09

Timeline

Tracking since Sep 25, 2026
ElapsedEstimatedEstimated, not yet reached

Started Jan 2017 (actual). Primary completion is estimated for Jan 2032, 179 months after the start.

How these figures are worked out, and which studies are left out of them.

Registered
Apr 19, 2019
First posted
Apr 29, 2019
StartActual
Jan 26, 2017
Primary completionEst.
Jan 1, 2032
CompletionEst.
Jan 1, 2032
Last update
Jan 17, 2025
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.
When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on Jan 17, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT03930810
Lead sponsor
University Medical Center Groningen
Responsible party
Prof. Dr. Henkjan J. Verkade (Principal Investigator, Professor of Pediatrics, University Medical Center Groningen) — Principal investigator
First posted
Apr 29, 2019
Start date
Jan 26, 2017
Primary completion
Jan 1, 2032 (estimated)
Completion
Jan 1, 2032 (estimated)
Last update
Jan 17, 2025

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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