Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)
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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 |
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Acute Liver Failure, Mitochondrial Liver Disease, End Stage Liver Disease, Hepatic RC Defect, FAO Defect |
Study Type: | Observational |
Study Design: | Observational Model: Cohort Time Perspective: Prospective |
Official Title: | Longitudinal Study of Mitochondrial Hepatopathies |
- 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
- 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 |
Groups/Cohorts |
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Group 1
Mitochondrial Hepatopathy Disease Group
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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.
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Ages Eligible for Study: | up to 18 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Sampling Method: | Non-Probability Sample |
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.
Subjects in Group 1 (Mitochondrial Hepatopathy group) must meet all of the following inclusion criteria:
- Children and young adults with suspected or documented hepatic RC defector FAO defect from birth to 18 years old (through 18 years).
- Both genders, all races and ethnic groups.
- 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:
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
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:
- 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.
- Both genders, all races and ethnic groups.
Subjects in either Group 1 or 2 must not have any of the following exclusion criteria:
- Inability to comply with the longitudinal follow-up described below.
- Failure of a family/patient to sign the informed consent/assent document or the HIPAA authorization form.
- Known Medium Chain Acyl CoA Dehydrogenase deficiency (MCAD).
- Other known causes of liver disease.
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Contact: Joan M Hines, MPH | 720-777-2598 | hines.joan@tchden.org |
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 | |
Sub-Investigator: Larry Wang, MD, PhD | |
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: Danuta Filipowski 415-476-1756 filipowskid@peds.ucsf.edu | |
Principal Investigator: Phillip Rosenthal, MD | |
Sub-Investigator: Melvin Heyman, MD | |
Sub-Investigator: John Roberts, MD | |
United States, Colorado | |
The Children's Hospital | Recruiting |
Denver, Colorado, United States, 80045 | |
Contact: Ron Sokol, MD 720-777-6669 sokol.ron@tchden.org | |
Contact: Michelle Hite 720-777-4690 hite.michelle@tchden.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 | Not yet recruiting |
Atlanta, Georgia, United States, 30322 | |
Contact: Rene Romero, MD 404-785-1832 rene.romero@choa.org | |
Contact: Nicholas Raviele 404-727-3189 nicholas.raviele@emory.edu | |
Principal Investigator: Rene Romero, MD | |
Sub-Investigator: Nitika Gupta, MD | |
Sub-Investigator: Miriam Vos, MD, MSPH | |
United States, Illinois | |
Children's Memorial Hospital | Not yet recruiting |
Chicago, Illinois, United States, 60614 | |
Contact: Peter Whitington, MD 773-975-8816 pwhittington@childrensmemorial.org | |
Contact: Susan M. Kelly, RN, BSN 773-868-8931 skelly@childrensmemorial.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 | |
John Hopkins School of Medicine | Recruiting |
Baltimore, Maryland, United States, 21287 | |
Contact: Kathy Schwarz, MD 410-955-8769 kschwarz@jhmi.edu | |
Contact: Kim Pfeifer, 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 | Not yet 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 | |
Sub-Investigator: Joseph Palermo, MD | |
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: Frederick J Suchy, MD 212-241-6933 frederick.suchy@mssm.edu | |
Contact: Nacole Brown 212-659-8046 nacole.brown@mountsinai.org | |
Principal Investigator: Frederick J Suchy, MD | |
Sub-Investigator: Nanda Kerkar, 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: Jan Dietz 513-636-7266 jan.dietz@cchmc.org | |
Principal Investigator: Jorge Bezerra, MD | |
Sub-Investigator: John Bucuvalas, MD | |
Sub-Investigator: Kevin Bove, 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: Barbara Harber, MD 215-590-2985 haber@email.chop.edu | |
Contact: Jessi Erlichman 215-590-2525 erlichman@email.chop.edu | |
Principal Investigator: Barbara Harber, MD | |
Sub-Investigator: Josh Friedman | |
Sub-Investigator: Kathleen Loomes, MD | |
Sub-Investigator: David Piccoli, MD | |
Sub-Investigator: Elizabeth Rand, MD | |
Sub-Investigator: Pierre Russo, 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: Ronald Jaffe, MD | |
Sub-Investigator: Douglas Lindblad, MD | |
Sub-Investigator: George Mazariegos, MD | |
United States, Texas | |
Texas Children's Hospital/Baylor College of Medicine | Not yet recruiting |
Houston, Texas, United States, 77030 | |
Contact: Saul Karpen, MD, PhD 832-824-3754 skarpen@bcm.tmc.edu | |
Contact: Kim Pieplow 832-824-3756 kkw@bcm.tcm.edu | |
Principal Investigator: Saul Karpen, MD | |
Sub-Investigator: Beth Carter, MD | |
Sub-Investigator: Milton Finegold, MD | |
United States, Washington | |
Children's Hospital and Regional Medical Center | Not yet 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 | Not yet recruiting |
Toronto, Ontario, Canada, M5G 1X8 | |
Contact: Vicky Ng, MD 416-813-6555 vicky.ng@sickkids.ca | |
Contact: Diane Blonski, MSc 416-813-7654 ext 1594 diane.blonski@sickkids.ca | |
Principal Investigator: Vicky Ng, MD | |
Sub-Investigator: Yaron Avitzur, MD | |
Sub-Investigator: Maria DeAngelis | |
Sub-Investigator: Peter Durie, MD | |
Sub-Investigator: Annie Fecteau, MD | |
Sub-Investigator: Nicola Jones, MD | |
Sub-Investigator: Binita Kamath, MD | |
Sub-Investigator: Krista Murch | |
Sub-Investigator: Constance O'Connor |
Study Chair: | Ronald J Sokol, MD | University of Colorado, Denver |
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Additional Information:
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No publications provided
Responsible Party: | Ronald J. Sokol, MD, The Children's Hospital |
ClinicalTrials.gov Identifier: | NCT01148550 History of Changes |
Other Study ID Numbers: | MITOHEP 6003 |
Study First Received: | June 18, 2010 |
Last Updated: | July 10, 2012 |
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 Digestive System Diseases Hepatic Insufficiency |
ClinicalTrials.gov processed this record on October 17, 2012