Clinical trial NCT03930810: NAtural Course and Prognosis of PFIC and Effect of Biliary Diversion
Official title: 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)
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Progressive Familial Intrahepatic Cholestasis
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2019-04-29
Enrollment: 1500
Sex: ALL
Minimum age (years): 0
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
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.

Brief 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.


Eligibility criteria: Inclusion Criteria:

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

Primary outcomes:
measure: Number of participants with liver transplantation
timeFrame: at 18 years of age, as well as >18 years of age (until 65 years of age)
measure: Number of participants that succumbed
timeFrame: at 18 years of age, as well as >18 years of age (until 65 years of age)
Secondary outcomes:
measure: Number of participant undergoing a surgical biliary diversion
timeFrame: at 5, 10, 15 and 18 years of age, as well as >18 years of age (until 65 years of age)
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
References:
citation: 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.
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