Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor:
Collaborator:
University of Michigan
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT01148550
First received: June 18, 2010
Last updated: October 17, 2013
Last verified: October 2013
  Purpose

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

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Longitudinal Study of Mitochondrial Hepatopathies

Resource links provided by NLM:


Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • Listing for liver transplant [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Listing for liver transplant

  • Liver transplantation [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Liver transplantation

  • Involvement of other organ systems known to be associated with mitochondrial diseases [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Involvement of other organ systems known to be associated with mitochondrial diseases

  • Death [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Death


Secondary Outcome Measures:
  • Growth failure [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Growth failure (defined as weight or length Z-score for age < -2)

  • Worsening liver function [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Worsening liver function (defined as PELD >10)

  • Complications of portal hypertension [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Complications of portal hypertension

  • Neurodevelopmental outcome [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Neurodevelopmental outcome

  • Health related Quality of Life [ Time Frame: Measured/assessed at baseline, 6 months, Years 1,2,3,4,5, and at time of liver transplant, liver or muscle biopsy or hospitalization for critical illness if applicable ] [ Designated as safety issue: No ]
    Health related Quality of Life


Biospecimen Retention:   Samples With DNA

Blood plasma and serum samples with DNA


Estimated Enrollment: 67
Study Start Date: July 2010
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
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

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.

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01148550

Contacts
Contact: Joan M Hines, MPH 720-777-2598 joan.hines@childrenscolorado.org

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Kasper Wang, MD    323-361-2338    kwang@chla.usc.edu   
Contact: Catherine Goodhue, CPNP    323-361-4566    cgoodhue@chla.usc.edu   
Principal Investigator: Kasper Wang, MD         
Sub-Investigator: Henri Ford, MD         
Sub-Investigator: Sylvie Lebel, MD         
Sub-Investigator: Danny Thomas, MD         
University of California at San Francisco (UCSF) Recruiting
San Francisco, California, United States, 94143
Contact: Philip Rosenthal, MD    415-476-5892    prosenth@peds.ucsf.edu   
Contact: Camille Langlois    415-476-1756    langloisc@peds.ucsf.edu   
Principal Investigator: Phillip Rosenthal, MD         
Sub-Investigator: Melvin Heyman, MD         
Sub-Investigator: John Roberts, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Ron Sokol, MD    720-777-6669    ronald.sokol@childrenscolorado.org   
Contact: Michelle Hite    720-777-4690    michelle.hite@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: Saul Karpen, MD    404-727-1463    skarpen@emory.edu   
Contact: Dana Hankerson    404-785-6027    dana.hankerson-dyson@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: Peter Whitington, MD    312-227-4615    pwhitington@luriechildrens.org   
Contact: Susan M. Kelly, RN, BSN    312-227-3523    skelly@luriechildrens.org   
Principal Investigator: Peter Whitington, MD         
Sub-Investigator: Lee Bass, MD         
Sub-Investigator: Ricardo Superina, MD         
Sub-Investigator: Estella Alonso, MD         
United States, Indiana
Riley Hospital for Children Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Jean Molleston, MD    317-274-3774    jpmolles@iupui.edu   
Contact: Beth Byam    317-274-3774    ebyam@iupui.edu   
Principal Investigator: Jean Molleston, MD         
Sub-Investigator: Molly Bozic         
United States, Maryland
Johns Hopkins School of Medicine Recruiting
Baltimore, Maryland, United States, 21287
Contact: Kathy Schwarz, MD    410-955-8769    kschwarz@jhmi.edu   
Contact: Kim Kafka, RN, BSN    410-614-8583    kfehily2@jhmi.edu   
Sub-Investigator: Wilkrom Karnsakul, MD         
Principal Investigator: Kathy Schwarz, MD         
United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Contact: Yumi Turmelle, MD    314-454-6173    turmelle_y@kids.wustl.edu   
Contact: Kathleen Harris    314-747-5708    harris_k@kids.wustl.edu   
Principal Investigator: Yumi Turmelle, MD         
Sub-Investigator: Robert Heuckeroth, MD         
Sub-Investigator: David Rudnick, MD, PhD         
Sub-Investigator: Alexander Weymann, MD         
United States, New York
Mount Sinai Medical Center Recruiting
New York, New York, United States, 10029
Contact: Ronen Arnon, MD    212-659-8060    ronen.arnon@mountsinai.org   
Contact: Sheetal Ramnath    212-659-8046    sheetal.ramnath@mountsinai.org   
Principal Investigator: Ronen Arnon, MD         
United States, Ohio
Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Jorge Bezerra, MD    513-636-4928    jorge.bezerra@chmcc.org   
Contact: Andrea Ferris    513-803-0675    andrea.ferris@cchmc.org   
Principal Investigator: Jorge Bezerra, MD         
Sub-Investigator: John Bucuvalas, 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: Kathy Loomes, MD    215-426-7223    loomes@email.chop.edu   
Contact: Jessi Erlichman    215-590-2525    erlichman@email.chop.edu   
Sub-Investigator: Josh Friedman         
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: Benjamin Shneider, MD    412-692-5180    benjamin.shneider@chp.edu   
Contact: Kathy Bukauskas, RN    412-692-5811    kathryn.bukauskas@chp.edu   
Principal Investigator: Benjamin Schneider, MD         
Sub-Investigator: Douglas Lindblad, MD         
Sub-Investigator: George Mazariegos, MD         
United States, Washington
Children's Hospital and Regional Medical Center Recruiting
Seattle, Washington, United States, 98105
Contact: Karen Murray, MD    206-987-2587    karen.murray@seattlechildrens.org   
Contact: Melissa Young    (206) 987-1037    melissa.young@seattlechildrens.org   
Principal Investigator: Karen Murray, MD         
Sub-Investigator: Simon Horslen, MD         
Canada, Ontario
Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Vicky Ng, MD    416-813-6555    vicky.ng@sickkids.ca   
Contact: Kelsey Hunt    416-813-7654 ext 813-7654    kelsey.hunt@sickkids.ca   
Principal Investigator: Vicky Ng, MD         
Sub-Investigator: Yaron Avitzur, MD         
Sub-Investigator: Maria DeAngelis         
Sub-Investigator: Peter Durie, MD         
Sub-Investigator: Nicola Jones, MD         
Sub-Investigator: Binita Kamath, MD         
Sub-Investigator: Krista Murch         
Sub-Investigator: Constance O'Connor         
Sponsors and Collaborators
University of Michigan
Investigators
Study Chair: Ronald J Sokol, MD University of Colorado, Denver
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT01148550     History of Changes
Other Study ID Numbers: MITOHEP 6003
Study First Received: June 18, 2010
Last Updated: October 17, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
neonatal acute liver failure
late-onset liver failure
cholestasis,
fatty liver,
liver dysfunction,
cirrhosis

Additional relevant MeSH terms:
Liver Diseases
Liver Failure
Liver Failure, Acute
End Stage Liver Disease
Mitochondrial Diseases
Digestive System Diseases
Hepatic Insufficiency
Metabolic Diseases

ClinicalTrials.gov processed this record on July 22, 2014