Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)

• ClinicalTrials.gov Identifier: NCT01148550
• Recruitment Status: Recruiting
• First Posted: June 22, 2010
• Last Update Posted: April 22, 2021
• Sponsor: Arbor Research Collaborative for Health
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Michigan
• Information provided by (Responsible Party): Arbor Research Collaborative for Health

Study Description

Brief Summary:

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.

Condition or disease
Acute Liver Failure; Mitochondrial Diseases; End Stage Liver Disease; Respiratory Chain Deficiencies, Mitochondrial; Disorder of Fatty Acid Oxidation

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 Design

• Study Type: Observational
• Estimated Enrollment: 67 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Longitudinal Study of Mitochondrial Hepatopathies
• Study Start Date: July 2010
• Estimated Primary Completion Date: May 2024
• Estimated Study Completion Date: May 2024

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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
3. 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
4. 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

Secondary Outcome Measures :

1. 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)
2. 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)
3. 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
4. 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
5. 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

Biospecimen Retention:   Samples With DNA

Blood plasma and serum samples with DNA

Eligibility Criteria

• Ages Eligible for Study: up to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

A total of 67 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 below.

Criteria

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 genders, 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 onocytes), 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 3b. 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.

B. Potential subjects who have already had a liver transplant must 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 genders, 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.

Contacts and Locations

Contacts

Contact: Terese Howell, BS, CCRC; 734-369-9683; terri.howell@arborresearch.org

Contact: Joanne Lord, BA,LPN,CCRC; 734-369-9965; joanne.lord@arborresearch.org

Locations

United States, California

Children's Hospital Los Angeles; Recruiting

Los Angeles, California, United States, 90027

Contact: Catherine Goodhue, CPNP 323-361-4566 cgoodhue@chla.usc.edu

Principal Investigator: Kasper Wang, MD

Sub-Investigator: Danny Thomas, MD

Sub-Investigator: Nisreen Soufi, MD

Sub-Investigator: Sonia Michail, MD

Sub-Investigator: Rohit Kohil, MD

University of California at San Francisco (UCSF); Active, not recruiting

San Francisco, California, United States, 94143

United States, Colorado

Children's Hospital Colorado; Recruiting

Aurora, Colorado, United States, 80045

Contact: Matthew Steinbeiss 720-777-4800 matthew.steinbeiss@childrenscolorado.org

Contact: Mikala Kauma 720-777-1294 mikaela.kauma@childrenscolorado.org

Principal Investigator: Ronald J Sokol, MD

Sub-Investigator: Michael Narkewicz, MD

Sub-Investigator: Cara Mack, MD

Sub-Investigator: Shikha Sundram, MD

Sub-Investigator: Johan Van Hove, MD

Sub-Investigator: Amy Feldman, MD

Sub-Investigator: Dania Brigham, MD

United States, Georgia

Children's Healthcare of Atlanta - Emory University; Recruiting

Atlanta, Georgia, United States, 30322

Contact: Rita Tory 404-785-1467 rita.tory@choa.org

Contact: Jeanette McFall 404-785-0421 jeanette.mcfall@choa.org

Principal Investigator: Saul Karpen, MD, Ph.D

Sub-Investigator: Nitika Gupta, MD

Sub-Investigator: Miriam Vos, MD, MSPH

Sub-Investigator: Rene Romero, MD

United States, Illinois

Ann & Robert H. Lurie Children's Hospital; Recruiting

Chicago, Illinois, United States, 60611

Contact: Susan M. Kelly, RN, BSN 312-227-3523 skelly@luriechildrens.org

Contact: Mary Riordan, CCRP 312-227-4558 mriordan@luriechildrens.org

Principal Investigator: Estella Alonso, MD

Sub-Investigator: Lee Bass, MD

United States, Indiana

Riley Hospital for Children; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Ann Klipsch, RN 317-944-9605 aeye@iu.edu

Contact: Cindy Sawyers, BSRT 317-278-1421 clsawyer@iu.edu

Principal Investigator: Jean Molleston, MD

Sub-Investigator: Molly Bozic, MD

Sub-Investigator: Girish Rao, MD

United States, Maryland

Johns Hopkins School of Medicine; Completed

Baltimore, Maryland, United States, 21287

United States, Missouri

Washington University School of Medicine; Completed

Saint Louis, Missouri, United States, 63110

United States, New York

Mount Sinai Medical Center; Completed

New York, New York, United States, 10029

United States, Ohio

Children's Hospital Medical Center; Recruiting

Cincinnati, Ohio, United States, 45229

Contact: Julie Denlinger, RN, BSN 513-636-7818 julie.denlinger@cchmc.org

Sub-Investigator: Jorge Bezerra, MD

Sub-Investigator: Joseph Palermo, MD

Sub-Investigator: James Heubi, MD

Principal Investigator: Alexander Miethke, MD

United States, Pennsylvania

The Children's Hospital of Philadelphia; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Jessi Erlichman, MPH 215-590-2525 erlichman@email.chop.edu

Contact: Iraklis Petrof 267-426-8613 petrofi@email.chop.edu

Sub-Investigator: David Piccoli, MD

Sub-Investigator: Elizabeth Rand, MD

Principal Investigator: Kathleen Loomes, MD

UPMC Children's Hospital of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Contact: Kathryn Bukauskas, RN, CCRC 412-692-7703 kathryn.bukauskas@chp.edu

Contact: Adam Kufen, RN, CCRC 412-692-6558 adam.kufen@chp.edu

Principal Investigator: Robert Squires, MD

Sub-Investigator: James Squires, MD

Sub-Investigator: Patrick Mckiernan, MD

United States, Texas

Texas Children's Hospital (Baylor College of Medicine); Recruiting

Houston, Texas, United States, 77030

Contact: Laurell Cavallo 832-822-1053 Laurel.cavallo@bcm.edu

Contact: Cynthia Tsai, MPH 832-822-3634 ct2@bcm.edu

Sub-Investigator: Benjamin Shneider, MD

Principal Investigator: Paula Hertel, MD

United States, Utah

University of Utah; Recruiting

Salt Lake City, Utah, United States, 84113

Contact: Ann Rutherford 801-585-9495 ann.rutherford@hsc.utah.edu

Contact: Tyler Hall 801-587-5670 tyler.hall@hsc.utah.edu

Principal Investigator: Stephen Guthery, MD

Sub-Investigator: Kyle Jensen, MD

Sub-Investigator: Linda Book, MD

United States, Washington

Seattle Children's Hospital; Recruiting

Seattle, Washington, United States, 98105

Contact: Melissa Young 206-987-1037 melissa.young@seattlechildrens.org

Contact: Kara Cooper 206-987-4636 kara.cooper@seattlechildrens.org

Principal Investigator: Simon Horslen, MD

Sub-Investigator: Evelyn Hsu, MD

Sub-Investigator: Niviann Blondet, MD

Canada, Ontario

Hospital for Sick Children; Recruiting

Toronto, Ontario, Canada, M5G 1X8

Contact: Deepika Sharma 416-813-7654 ext 201594 deepika.sharma@sickkids.ca

Contact: Claudia Quammie 416-813-7654 ext 201594 claudia.quammie@sickkids.ca

Sub-Investigator: Vicky Ng, MD

Principal Investigator: Binita Kamath, MD

Sponsors and Collaborators

Arbor Research Collaborative for Health

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

University of Michigan

Investigators

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

More Information

Additional Information:

Childhood Liver Disease Research Network (ChiLDReN) website 

• Responsible Party: Arbor Research Collaborative for Health
• ClinicalTrials.gov Identifier: NCT01148550
• Other Study ID Numbers: MITOHEP Study-ChiLDReN Network; 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 ); U01DK062456 ( U.S. NIH Grant/Contract ); U01DK062453 ( U.S. NIH Grant/Contract ); U01DK062452 ( U.S. NIH Grant/Contract ); U01DK062445 ( U.S. NIH Grant/Contract ); U01DK062436 ( U.S. NIH Grant/Contract )
• First Posted: June 22, 2010
• Last Update Posted: April 22, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The data will be transferred to NIDDK at the end of the study.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Arbor Research Collaborative for Health:

neonatal acute liver failure; late-onset liver failure; cholestasis,; fatty liver,; liver dysfunction,; cirrhosis

Additional relevant MeSH terms:

Liver Diseases; Liver Failure; Hepatic Insufficiency; End Stage Liver Disease; Liver Failure, Acute; Mitochondrial Diseases; Digestive System Diseases; Metabolic Diseases