Prospective Analysis of the Treatment of Progressive Familial Intrahepatic Cholestasis (TreatFIC) (TreatFIC)

The project has the following general aims:

1. Natural course and prognosis: To prospectively follow the natural course and prognosis of the different types of PFIC, to broaden the understanding of the different very rare diseases and to allow predictions about the course of disease in different types of PFIC.
2. Efficacy: To define the course of disease in FIC patients and identify associations with different treatments (symptomatic treatments, interruption of the enterohepatic circulation by surgical or medical means and other therapies such as corrector/potentiator or exon skipping therapy. The course of disease will be characterized by biochemical, clinical and surgical parameters, including liver transplantation.
3. Safety: To define the complications associated with the different treatments (symptomatic treatments, interruption of the enterohepatic circulation by surgical or medical means and other therapies such as corrector/potentiator or exon skipping therapy, liver transplantation). Follow up will be as long as possible.
4. (Surrogate) biomarker response: Biochemical parameters will be longitudinally collected and associated with changes in treatments / course of disease.
5. Genotype-phenotype relationships: If patient numbers permit, to establish genotype-phenotype relationships for (non)responsiveness towards different treatments in patients with genetic mutations causing the different forms of FIC disease.

Study Overview

• Status: Recruiting
• Conditions: Progressive Familial Intrahepatic Cholestasis
• Intervention / Treatment: Other: observational study

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Henkjan J Verkade, MD, PhD, Professor; Phone Number: 31-50-3614147; Email: h.j.verkade@umcg.nl; pfic@bkk.umcg.nl
• Study Contact Backup: Name: Willem S Lexmond, MD, PhD; Phone Number: 31-50-3614147; Email: w.s.lexmond@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700 RB
    • Recruiting
    • University Medical Center Groningen
    • Contact: Henkjan J Verkade, MD, PhD, Professor; Phone Number: 31-50-3614147; Email: h.j.verkade@umcg.nl; pfic@bkk.umcg.nl
    • Contact: Willem S Lexmond, MD, PhD; Phone Number: 31-50-3614147; Email: w.s.lexmond@umcg.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The diagnosis of a PFIC type disease needs to be performed according to the international guidelines, based on (episodes with a) low gamma-GT cholestasis and identification of disease-causing mutations in the indicated genes.

Description

Inclusion Criteria:

- Genetically confirmed cases of a PFIC type disease: FIC1 deficiency, BSEP deficiency, MDR3 deficiency, TJP2 deficiency, FXR deficiency, SLC51A deficiency, USP53 deficiency, KIF12 deficiency, ZFYE19 deficiency, MYO5B deficiency, SEMA7A deficiency, VPS33B deficiency, PSKH1 deficiency.

Exclusion Criteria:

- Cases with suspected PFIC type disease, but without genetic testing data available.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
FIC1-deficiency; genetically proven deficiency of FIC1 (FIC1). Disease is also known as PFIC1.	Other: observational study; The interventions are not determined by the study, which is purely observational on "real world data".; Other Names: liver transplantation; natural history; surgical biliary diversion; IBAT-inhibition
MDR3-deficiency; genetically proven deficiency of Multi Drug Resistance protein type 3 (MDR3, ABCB4). Disease is also known as PFIC3.	Other: observational study; The interventions are not determined by the study, which is purely observational on "real world data".; Other Names: liver transplantation; natural history; surgical biliary diversion; IBAT-inhibition
Other genetic subtypes of Familiai Intrahepatic Cholestasis; TJP2 deficiency (TJP2), FXR deficiency (NR1H4), SLC51A deficiency (SLC51A), USP53 deficiency (USP53), KIF12 deficiency (KIF12), ZFYE19 deficiency (ZFYVE19), MYO5B deficiency (MYO5B), SEMA7A deficiency (SEMA7A), VPS33B deficiency, (VPS33B), PSKH1 deficiency (PSKH1)	Other: observational study; The interventions are not determined by the study, which is purely observational on "real world data".; Other Names: liver transplantation; natural history; surgical biliary diversion; IBAT-inhibition
BSEP-deficiency; genetically proven deficiency of Bile Salt Export Pump (BSEP, ABCB11). Disease is also known as PFIC2.	Other: observational study; The interventions are not determined by the study, which is purely observational on "real world data".; Other Names: liver transplantation; natural history; surgical biliary diversion; IBAT-inhibition

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with liver transplantation	The number (percentage) of patients undergoing liver transplantation related to the age of the patient	at 5, 10, 15 and 18 years of age, as well as >18 years of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants that succumbed	Mortality related to age of the patient	at 5, 10, 15 and 18 years of age, as well as >18 years of age

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participant undergoing a surgical biliary diversion	Number of participant undergoing a surgical biliary diversion related to age	at 5, 10, 15 and 18 years of age, as well as >18 years of age

Collaborators and Investigators

• Sponsor: University Medical Center Groningen

Publications and helpful links

General Publications

• 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.
• 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.
• Felzen A, Verkade HJ. The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments. Eur J Med Genet. 2021 Nov;64(11):104317. doi: 10.1016/j.ejmg.2021.104317. Epub 2021 Aug 31.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2023
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): December 1, 2033

Study Registration Dates

• First Submitted: January 10, 2025
• First Submitted That Met QC Criteria: January 10, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 21, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: liver transplantation; ASBT; PFIC; biliary diversion; IBAT
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Liver Diseases; Bile Duct Diseases; Cholestasis; Cholestasis, Intrahepatic
• Other Study ID Numbers: UGroningen - PaNaMaID11162

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Ownership of individal patient data will remain in the hands of the participating centers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No