Clinical trial NCT00571272: Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC)
Official title: Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC)
Study type: OBSERVATIONAL
Overall status: SUSPENDED
Conditions: Liver Diseases
Alagille Syndrome
Alpha 1-Antitrypsin Deficiency
Keywords: Cholestatic Liver Disease
Cholestasis
Childhood Diseases
Genetic Diseases
Bile Acid Synthesis and Metabolism Defects
Progressive Familial Intrahepatic Cholestasis
Lead sponsor: Arbor Research Collaborative for Health
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2007-12-11
Enrollment: 1675
Sex: ALL
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will consist of 400 participants with Alagille syndrome, 400 with alpha-1 trypsin deficieny (of which up to 25 may be siblings of participants), 300 with PFIC (or BRIC), and 50 with bile acid synthesis defects.

Brief summary: Cholestasis is a condition in which bile is not properly transported from the liver to the small intestine. Cholestasis can be caused by an array of childhood diseases, including the genetic diseases Alagille syndrome (ALGS), alpha-1 antitrypsin (a-1AT) deficiency, bile acid synthesis and metabolism defects, and progressive familial intrahepatic cholestasis (PFIC) or benign recurrent intrahepatic cholestasis(BRIC). This study will investigate the natural history and progression of the four previously mentioned cholestatic liver diseases to provide a better understanding of the causes and effects of the diseases.

Detailed description: Cholestasis is a rare condition that involves a reduction or obstruction of bile flow from the liver to the small intestine. When bile flow is hindered, a waste product pigment called bilirubin can escape into the bloodstream and build up to harmful levels. This may lead to the easily recognizable cholestatic symptoms of jaundice, itching, and impaired growth and eventually to more serious health problems. Four rare genetic liver disorders- ALGS, a-1AT, bile acid synthesis and metabolism defects, and PFIC-account for about 20% to 30% of all infant cases of cholestasis. These four disorders compose a group of related diseases that can cause significant growth problems during childhood, serious liver problems, the need for liver transplantation, and potentially death. More research on these rare liver diseases is necessary to develop a scientific basis for improvement in diagnostic techniques and treatments. Current diagnostic procedures are complex, and the development of simpler diagnostic tests would facilitate early diagnosis and treatment. This study will investigate the natural history and progression of the four previously mentioned cholestatic liver diseases to provide a better understanding of the causes and effects of the diseases.

Participation in this study will last 20 years and will consist of a baseline visit and 20 annual follow-up visits. The study will enroll infants through adults 25 years of age who have, or are suspected of having, one of the four genetic cholestatic liver diseases. Individuals who are siblings of a-A1T participants and have underlying disease with no evidence of liver involvement may also be enrolled. Study visits will involve review of clinical information, family history, and any clinically indicated treatments and their outcomes; a physical exam; laboratory tests; and radiologic and imaging evaluations. In addition to these standard of care evaluations, participants will undergo several special research evaluations, including quality of life questionnaires, neurodevelopmental evaluations, hearing exams, liver histology studies, and collection of serum, plasma, urine, and blood for DNA. Serum, plasma, and blood for DNA will also be collected from both biological parents and from affected siblings of participants with a-A1T or ALGS. Genetic testing will be performed using the collected specimens.

Eligibility criteria: Inclusion Criteria:

1. Children and young adults diagnosed with one of the four cholestatic diseases from birth through 25 years old.
2. Siblings of participants with alpha-1-antitrypsin deficiency, who are affected with alpha-1-antitrypsin deficiency, but have no evidence of liver disease.
3. Both sexes, all races and ethnic groups.
4. Participant meets the enrollment criteria for one of the four cholestatic liver diseases.
5. Patient and/or parent/legal guardian have the ability to provide written informed consent for enrollment.

Exclusion Criteria:

1. Inability to comply with the longitudinal follow-up described in the protocol.

Primary outcomes:
measure: Demonstration of disease progression for each of the four cholestatic liver diseases of the study, including liver transplantation, death, growth failure, worsening liver function, and developmental complications of portal high blood pressure
timeFrame: Measured at baseline and annually through year 10
Secondary outcomes:
measure: Jaundice (total serum bilirubin of greater than 2.0 mg/dl)
timeFrame: Measured at baseline and annually through year 10
measure: Listing for liver transplantation
timeFrame: Measured at baseline and annually through year 10
measure: Calculated Pediatric End-Stage Liver Disease (PELD) score for participants less than 12 years of age or Model for End-Stage Liver Disease (MELD) score for participants 12 years of age or older
timeFrame: Measured at baseline and annually through year 10
measure: Health related quality of life
timeFrame: Measured at baseline and annually through year 10
measure: Growth (length and weight Z-score)
timeFrame: Measured at baseline and annually through year 10
measure: Bone mineral density (lumbar and spine total body)
timeFrame: Measured at baseline in ALGS and PFIC/BRIC subjects
measure: Presence of hearing loss (ALGS and PFIC)
timeFrame: Measured at baseline
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco (UCSF)
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Emory University
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University Hospital
state: Maryland
city: St. Louis
country: United States
facility: St. Louis University - Cardinal Glennon Children's Medical Center
state: Missouri
city: St. Louis
country: United States
facility: Washington University School of Medicine/St. Louis Children's Hospital
state: Missouri
city: New York City
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Cincinnati
country: United States
facility: Cincinnati's Children's Memorial Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Baylor School of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Kathleen Loomes, MD
role: STUDY_CHAIR
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Ed Doo, MD
role: STUDY_DIRECTOR
affiliation: University of Michigan
name: John Magee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Arbor Research Collaborative for Health
name: Lisa Henn, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Averell Sherker, MD
role: STUDY_DIRECTOR
References:
citation: Leung DH, Sorensen LG, Ye W, Hawthorne K, Ng VL, Loomes KM, Fredericks EM, Alonso EM, Heubi JE, Horslen SP, Karpen SJ, Molleston JP, Rosenthal P, Sokol RJ, Squires RH, Wang KS, Kamath BM, Magee JC; Childhood Liver Disease Research Network (ChiLDReN). Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver. J Pediatr Gastroenterol Nutr. 2022 Jan 1;74(1):96-103. doi: 10.1097/MPG.0000000000003337.
citation: Teckman JH, Rosenthal P, Abel R, Bass LM, Michail S, Murray KF, Rudnick DA, Thomas DW, Spino C, Arnon R, Hertel PM, Heubi J, Kamath BM, Karnsakul W, Loomes KM, Magee JC, Molleston JP, Romero R, Shneider BL, Sherker AH, Sokol RJ; Childhood Liver Disease Research Network (ChiLDReN). Baseline Analysis of a Young alpha-1-Antitrypsin Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension. J Pediatr Gastroenterol Nutr. 2015 Jul;61(1):94-101. doi: 10.1097/MPG.0000000000000753.