Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)

October 13, 2023 updated by: Arbor Research Collaborative for Health
The specific aims of this study are (1) to determine the clinical phenotypes and natural history of hepatic RC and FAO disorders, (2) to determine the correlation between genotype and phenotype, (3) to determine if circulating biomarkers reflect diagnosis and predict liver disease progression and survival with the native liver, (4) to determine the clinical outcome of these disorders following liver transplantation, and (5) to develop a repository of serum, plasma, urine, tissue and DNA specimens that will be used in ancillary studies. To accomplish these aims, the ChiLDREN investigators at clinical sites (currently 15 sites) will prospectively collect defined data and specimens in a uniform fashion at fixed intervals in a relatively large number of subjects. Clinical information and DNA samples to be collected from subjects and their parents will enhance the potential for meaningful research in these disorders. A biobank of subject specimens and DNA samples will be established for use in ancillary studies to be performed in addition to this study.

Study Overview

Status

Recruiting

Conditions

Detailed Description

This study will be conducted as part of the NIH-supported Childhood Liver Disease Research and Education Network (ChiLDREN). ChiLDREN is investigating rare cholestatic liver diseases of childhood: alpha-1 antitrypsin deficiency (A1AT), Alagille's Syndrome (AGS), progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis defects and mitochondrial hepatopathies (all previously studied by the Cholestatic Liver Disease Consortium [CLiC]); biliary atresia (previously studied by the Biliary Atresia Research Consortium [BARC]); neonatal hepatitis; and cystic fibrosis liver disease, which is studied by a new branch of ChiLDREN known as the Cystic Fibrosis Liver Disease (CFLD) Network.

In this protocol, mitochondrial hepatopathies in children and young adults will be investigated. The focus will be on respiratory chain defects (RC) and defects of fatty acid oxidation (FAO). There is little known about the full spectrum of severity and long-term natural history of mitochondrial hepatopathies. Moreover, these disorders have not been subject to prospective, rigorous clinicopathological scrutiny.

Study Type

Observational

Enrollment (Estimated)

67

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 1X8
        • Recruiting
        • Hospital For Sick Children
        • Contact:
        • Sub-Investigator:
          • Vicky Ng, MD
        • Principal Investigator:
          • Binita Kamath, MD
        • Contact:
  • United States
    • California
      • Los Angeles, California, United States, 90027
        • Recruiting
        • Children's Hospital Los Angeles
        • Contact:
        • Sub-Investigator:
          • Danny Thomas, MD
        • Sub-Investigator:
          • Nisreen Soufi, MD
        • Sub-Investigator:
          • Sonia Michail, MD
        • Principal Investigator:
          • Rohit Kohli, MD
      • San Francisco, California, United States, 94143
        • Active, not recruiting
        • University of California at San Francisco (UCSF)
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • Children's Hospital Colorado
        • Contact:
        • Contact:
        • Principal Investigator:
          • Ronald J Sokol, MD
        • Sub-Investigator:
          • Michael Narkewicz, MD
        • Sub-Investigator:
          • Shikha Sundram, MD
        • Sub-Investigator:
          • Johan Van Hove, MD
        • Sub-Investigator:
          • Amy Feldman, MD
        • Sub-Investigator:
          • Dania Brigham, MD
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Children's Healthcare of Atlanta - Emory University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Saul Karpen, MD, Ph.D
        • Sub-Investigator:
          • Nitika Gupta, MD
        • Sub-Investigator:
          • Miriam Vos, MD, MSPH
        • Sub-Investigator:
          • Rene Romero, MD
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Recruiting
        • Ann & Robert H. Lurie Children's Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Estella Alonso, MD
        • Sub-Investigator:
          • Lee Bass, MD
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Recruiting
        • Riley Hospital for Children
        • Principal Investigator:
          • Jean Molleston, MD
        • Contact:
          • Ann Klipsch, RN
          • Phone Number: 317-944-9605
          • Email: aeye@iu.edu
        • Sub-Investigator:
          • Molly Bozic, MD
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Completed
        • Johns Hopkins School of Medicine
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Completed
        • Washington University School of Medicine
    • New York
      • New York, New York, United States, 10029
        • Completed
        • Mount Sinai Medical Center
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Recruiting
        • Children's Hospital Medical Center
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Joseph Palermo, MD
        • Principal Investigator:
          • Alexander Miethke, MD
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Recruiting
        • The Children's Hospital of Philadelphia
        • Principal Investigator:
          • Kathleen Loomes, MD
        • Sub-Investigator:
          • David Piccoli, MD
        • Sub-Investigator:
          • Elizabeth Rand, MD
        • Contact:
        • Contact:
      • Pittsburgh, Pennsylvania, United States, 15224
        • Recruiting
        • UPMC Children's Hospital of Pittsburgh
        • Sub-Investigator:
          • James Squires, MD
        • Principal Investigator:
          • Simon Horslen, MD
        • Contact:
        • Contact:
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • Texas Children's Hospital (Baylor College of Medicine)
        • Principal Investigator:
          • Paula Hertel, MD
        • Sub-Investigator:
          • Benjamin Shneider, MD
        • Contact:
        • Contact:
    • Utah
      • Salt Lake City, Utah, United States, 84113
        • Recruiting
        • University of Utah
        • Contact:
        • Principal Investigator:
          • Stephen Guthery, MD
        • Sub-Investigator:
          • Kyle Jensen, MD
        • Sub-Investigator:
          • Linda Book, MD
        • Contact:
    • Washington
      • Seattle, Washington, United States, 98105
        • Recruiting
        • Seattle Children's Hospital
        • Principal Investigator:
          • Pamela Valentino, MD
        • Contact:
        • Sub-Investigator:
          • Evelyn Hsu, MD
        • Sub-Investigator:
          • Niviann Blondet, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

A total of 150 children and young adults with suspected or documented hepatic RC defect or FAO defect between birth and 18 years old from both genders and all races and ethnic groups that meet inclusion/exclusion criteria as defined above

Description

Subjects in Group 1 (Mitochondrial Hepatopathy group) must meet all of the following inclusion criteria:

  1. Children and young adults with suspected or documented hepatic RC defector FAO defect from birth to 18 years old (through 18 years).
  2. Both sexes, all races and ethnic groups.
  3. Participants must meet one of the following sets of criteria (A or B):

A. Potential subjects presenting with acute or chronic liver disease or acute liver failure but who have not had a liver transplant must meet one of Clinical Criteria 1 and one of Clinical Criteria 2 listed below:

  1. Clinical Criteria 1 (any one of the following)

    • 1.Acute liver failure, defined as severe liver dysfunction and either 1) INR >1.5 or prothrombin time > 15 seconds with encephalopathy or 2) INR > 2.0 or prothrombin time > 20 seconds with or without encephalopathy; occurring within 8 weeks of onset of illness; with no known underlying chronic liver disease, or
    • 2.Acute liver disease defined as elevated AST or ALT >1.25 ULN and CK <1000u/L or conjugated bilirubin >2.0 mg/dl and >20% of total bilirubin, or

    • 3.Chronic liver disease defined as:

      • elevated ALT or AST (>1.25 ULN) for > 6 months, or
      • conjugated hyperbilirubinemia (conjugated [direct] > 2.0 mg/dl and > 20% of total bilirubin) for > 6 months or
      • clinical stigmata of chronic liver disease, including chronic hepatomegaly, clinical findings or complications of cirrhosis or portal hypertension, impaired liver synthetic function, intractable pruritus explainable only by liver disease or end-stage liver disease, or
      • abnormal liver histology including hepatic fibrosis or cirrhosis, microvesicular steatosis, canalicular cholestasis, ballooned granular red hepatocytes (AKA oncocytes), intralobular collapse/regeneration And

  2. Clinical Criteria 2 (any one of the following):

    • 1.Prior history of extra-hepatic organ involvement accompanied by any one or more of the signs and symptoms associated with mitochondrial dysfunction (e.g.

hypotonia, neuro-developmental delay, seizure disorder requiring treatment with valproic acid, nystagmus, cardiomyopathy, renal tubulopathy, bone marrow failure, myopathy, hearing loss), or

  • 2.Lactic acidosis (arterial blood or free-flowing venous blood level >2.5 mmol/L or >22.5 mg/dl at any age and increased lactate:pyruvate ratio [>25.0]) or
  • 3.Hypoglycemia (blood glucose <45 mg/dl on any measurement) and hypoketonuria (<1+ for urine ketones by dipstick on urine specimen obtained within 4 hours after collecting blood with low glucose concentration), or
  • 4.Abnormal acyl carnitine profile, or
  • 5.Documented biochemical (enzymatic) or genetic diagnosis

B. Potential participants who have undergone a liver transplantation because of acute liver failure or end stage liver disease due to suspected or confirmed mitochondrial hepatopathy; the transplantation may have been performed at a non-ChiLDREN medical center or at a ChiLDREN Clinical Site. Participants will meet Criteria 1 and either criteria 2 or criteria 3 below:

  • 1.Previous liver transplantation, AND

  • 2.Suspected mitochondrial liver disease, based upon meeting one or more of the following criteria:

    • Had a prior history of extra-hepatic organ involvement accompanied by signs and symptoms associated with mitochondrial dysfunction (e.g., hypotonia, neuro-developmental delay, seizure disorder requiring treatment with valproic acid, nystagmus, cardiomyopathy, renal tubulopathy, bone marrow failure, myopathy, hearing loss), OR
    • A prior history of lactic acidosis (arterial blood or free-flowing venous blood level >2.5 mmol/L or >22.5 mg/dl at any age and increased lactate:pyruvate ratio [>25.0]), OR
    • A prior history of hypoglycemia (blood glucose <45 mg/dl on any measurement) and hypoketonuria (≤1+ for urine ketones by dipstick on urine specimen obtained within 4 hours after collecting blood with low glucose concentration), OR
    • A prior history of an abnormal acyl carnitine profile, OR
    • Documented biochemical (enzymatic) or genetic diagnosis of a mitochondrial disorder
  • 3.A documented (confirmed) mitochondrial disorder based upon the confirmation criteria specified in protocol.

Subjects in Group 2 (Suspected Mitochondrial Hepatopathy not meeting Group 1 enrollment criteria) must meet the following inclusion criteria:

  1. Children and young adults with suspected hepatic RC defect or FAO defect between birth through 18 years but who do not meet clinical inclusion criteria listed above for acute or chronic liver disease or acute liver failure.
  2. Both sexes, all races and ethnic groups.

Subjects in either Group 1 or 2 must not have any of the following exclusion criteria:

  1. Inability to comply with the longitudinal follow-up described below.
  2. Failure of a family/patient to sign the informed consent/assent document or the HIPAA authorization form.
  3. Known Medium Chain Acyl CoA Dehydrogenase deficiency (MCAD).
  4. Other known causes of liver disease.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Group 1
Mitochondrial Hepatopathy Disease Group
Group 2
Subjects with Suspected Mitochondrial Hepatopathy who do not meet the enrollment criteria for Group 1 Subjects with Suspected Mitochondrial Hepatopathy who do not meet the enrollment criteria for Group 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Listing for liver transplant
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Listing for liver transplant
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Liver transplantation
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Liver transplantation
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Involvement of other organ systems known to be associated with mitochondrial diseases
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Involvement of other organ systems known to be associated with mitochondrial diseases
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Death
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Death
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Growth failure
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Growth failure (defined as weight or length Z-score for age < -2)
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Worsening liver function
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Worsening liver function (defined as PELD >10)
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Complications of portal hypertension
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Complications of portal hypertension
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Neurodevelopmental outcome
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Neurodevelopmental outcome
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Health related Quality of Life
Time Frame: Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable
Health related Quality of Life
Measured/assessed at baseline, 6 months, Years 1 through 10, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Arbor Research Collaborative for Health

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Michigan

Investigators

  • Study Director: Ed Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Study Director: Averell Sherker, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Study Chair: Ronald J Sokol, MD, University of Colorado, Denver
  • Principal Investigator: John C Magee, MD, University of Michigan
  • Principal Investigator: Lisa Henn, PhD, Arbor Research Collaborative for Health - Data Coordinating Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 18, 2010

Primary Completion (Estimated)

May 1, 2024

Study Completion (Estimated)

May 1, 2024

Study Registration Dates

First Submitted

June 18, 2010

First Submitted That Met QC Criteria

June 18, 2010

First Posted (Estimated)

June 22, 2010

Study Record Updates

Last Update Posted (Actual)

October 16, 2023

Last Update Submitted That Met QC Criteria

October 13, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MITOHEP Study-ChiLDReN Network
  • U01DK062436 (U.S. NIH Grant/Contract)
  • U01DK062456 (U.S. NIH Grant/Contract)
  • U01DK103149 (U.S. NIH Grant/Contract)
  • U01DK103140 (U.S. NIH Grant/Contract)
  • U01DK103135 (U.S. NIH Grant/Contract)
  • U01DK084575 (U.S. NIH Grant/Contract)
  • U01DK084538 (U.S. NIH Grant/Contract)
  • U01DK084536 (U.S. NIH Grant/Contract)
  • U01DK062503 (U.S. NIH Grant/Contract)
  • U01DK062500 (U.S. NIH Grant/Contract)
  • U01DK062497 (U.S. NIH Grant/Contract)
  • U01DK062481 (U.S. NIH Grant/Contract)
  • U01DK062470 (U.S. NIH Grant/Contract)
  • U01DK062466 (U.S. NIH Grant/Contract)
  • U01DK062453 (U.S. NIH Grant/Contract)
  • U01DK062452 (U.S. NIH Grant/Contract)
  • U01DK062445 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The data will be transferred to NIDDK at the end of the study.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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