Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)

Study Description

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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

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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 2019
Estimated Study Completion Date :	May 2019

Groups and Cohorts

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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

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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

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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

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Contacts

Contact: Peg Hill-Callahan, BS, LSW	734-369-9674	peg.hill-callahan@arborresearch.org
Contact: Ellen Lachance, BS	734-369-9963	ellen.lachance@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
Contact: Janelle Gonzalez 323-361-3113 jangonzalez@chla.usc.edu
Principal Investigator: Kasper Wang, MD
Sub-Investigator: Danny Thomas, MD
Sub-Investigator: Nanda Kerker, MD
Sub-Investigator: Sonia Michail, 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: Michelle Hite 720-777-4690 michelle.hite@childrenscolorado.org
Contact: Darci Anderson 720-777-9911 darci.anderson@childrenscolorado.org
Sub-Investigator: Michael Narkewicz, MD
Principal Investigator: Ron Sokol, MD
Sub-Investigator: Cara Mack, MD
Sub-Investigator: Shikha Sundram, MD
Sub-Investigator: Johan Van Hove, MD
United States, Georgia
Children's Healthcare of Atlanta	Recruiting
Atlanta, Georgia, United States, 30322
Contact: Rita Tory 404-785-1467 rita.tory@choa.org
Contact: Ngoc Ly Nguyen 404-727-1463 ngocly.nguyen@choa.org
Sub-Investigator: Rene Romero, MD
Sub-Investigator: Nitika Gupta, MD
Sub-Investigator: Miriam Vos, MD, MSPH
Principal Investigator: Saul Karpen, 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
Sub-Investigator: Lee Bass, MD
Principal Investigator: Estella Alonso, MD
United States, Indiana
Riley Hospital for Children	Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Ann Klipsch, RN 317-944-9605 aeye@iupui.edu
Principal Investigator: Jean Molleston, MD
Sub-Investigator: Molly Bozic
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
Contact: Kelly Gindling, RN, BSN 513-803-7482 kelly.gindling@cchmc.org
Principal Investigator: Jorge Bezerra, MD
Sub-Investigator: Joseph Palermo, MD
Sub-Investigator: James Heubi, MD
Sub-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: Sarah Wong 267-426-8412 skwong@email.chop.edu
Sub-Investigator: David Piccoli, MD
Sub-Investigator: Elizabeth Rand, MD
Principal Investigator: Kathy Loomes, MD
Children's Hospital of Pittsburgh	Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Kathy Bukauskas, RN 412-692-5180 kathryn.bukauskas@chp.edu
Contact: Paula Layton, RN 412-692-5811 paula.layton2@upmc.edu
Principal Investigator: Robert Squires, MD
Sub-Investigator: Douglas Lindblad, MD
Sub-Investigator: George Mazariegos, MD
Sub-Investigator: Jim Squires, MD
Sub-Investigator: Veena Venkat, MD
United States, Texas
Texas Children's Hospital	Recruiting
Houston, Texas, United States, 77030
Contact: Cynthia Tsai 832-822-3634 ct2@bcm.edu
Contact: Laurel Cavallo 832-822-1053 Laurel.Cavallo@bcm.edu
Principal Investigator: Benjamin Shneider, MD
Sub-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: Kyle Berg 801-587-5670 Kyle.berg@hsc.utah.edu
Principal Investigator: Stephen Guthery, MD
Sub-Investigator: Kyle Jensen, MD
United States, Washington
Children's Hospital and Regional Medical Center	Recruiting
Seattle, Washington, United States, 98105
Contact: Karen Murray, MD 206-987-2775 karen.murray@seattlechildrens.org
Contact: Melissa Young (206) 987-1037 melissa.young@seattlechildrens.org
Principal Investigator: Karen Murray, MD
Sub-Investigator: Simon Horslen, MD
Sub-Investigator: Evelyn Shu, MD
Canada, Ontario
Hospital for Sick Children	Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Vanessa Simoes 416-813-7654 ext 201594 vanessa.simoes@sickkids.ca
Contact: Elena Reydman 416-813-7654 ext 201594 elena.reydman@sickkids.ca
Sub-Investigator: Vicky Ng, MD
Sub-Investigator: Maria DeAngelis
Principal Investigator: Binita Kamath, MD
Sub-Investigator: Constance O'Connor

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

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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Childhood Liver Disease Research Network Website 

Responsible Party:	Arbor Research Collaborative for Health
ClinicalTrials.gov Identifier:	NCT01148550 History of Changes
Other Study ID Numbers:	MITOHEP 6003; 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:	February 19, 2018
Last Verified:	February 2018
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; End Stage Liver Disease; Mitochondrial Diseases	Liver Failure, Acute; Digestive System Diseases; Hepatic Insufficiency; Metabolic Diseases