Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease (HAEC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02193685
Recruitment Status : Recruiting
First Posted : July 18, 2014
Last Update Posted : August 12, 2016
Sponsor:
Collaborators:
Karolinska University Hospital
Children's Hospital Los Angeles
UCSF Benioff Children’s Hospital Oakland
University of Michigan
The University of Texas Health Science Center, Houston
Information provided by (Responsible Party):
Philip K. Frykman, MD, PhD, MBA, Cedars-Sinai Medical Center

Brief Summary:

To identify demographic, clinical, genetic, immunologic and/or microbial (i.e., fecal stream characterization) risk factors that influence the likelihood of development of the HAEC phenotype in children who carry the diagnosis of HD. The newly formed HAEC Collaborative Research Group (HCRG) will utilize the 4 participating centers in the current consortia and recruit additional centers to enroll children diagnosed with Hirschsprung disease.

1a: To recruit 200 patients with Hirschsprung disease without HAEC.

1b: To recruit 200 patients with Hirschsprung disease and HAEC using standardized diagnostic criteria by collaborating with participating members of the HAEC Collaborative Research Group[1].

1c: To collect clinical and demographic information from well-characterized HD patients both with and without HAEC.

1d: To collect samples blood for DNA for genome wide association study (GWAS) by high throughput SNP technology and mutational analysis of known HSCR genes.

1e: To collect serum samples at the time of recruitment in a subset cohort (n=50 HD only, n=50 HD + HAEC) for serological immune markers known for inflammatory bowel disease (IBD) including ANCA, ASCA, OMPC, I2, and CBir1 and any newly identified markers.

1f: To collect and store fresh fecal specimens for future evaluation by molecular methodologies to determine relative proportions of enteric microflora in a subset cohort (n=50 HD only, n=50 HD + HAEC) of children (<18 years).

1g: To establish a Centralized Data Coordinating Center for data collection, data quality and detailed data analyses (CSMC) and tissue bank (CSMC) to facilitate specimen analysis for this study.

The HAEC risk factor identification will be completed by multivariate logistic regression analysis. Genetic association will be studied for each SNP in the GWAS together with all other potential risk factors. Further analysis will be carried out to evaluate multiple SNPs/genes simultaneously.


Condition or disease
Hirschsprung Disease Enterocolitis

Show Show detailed description

Layout table for study information
Study Type : Observational
Estimated Enrollment : 400 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Identification of Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
Study Start Date : February 2010
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2025


Group/Cohort
Subjects with HAEC
There is no intervention involvement. The clinical data and biologic specimens collected during the study will serve as an invaluable resource for a wide spectrum of clinical and translational ancillary studies directly related to the aims and goals of the study.
Subjects without HAEC
A subgroup of children who have Hirschsprung Disease may or may not develop enterocolitis; therefore we will be identifying the bio-markers in children with or without associated enterocolitis.



Primary Outcome Measures :
  1. To identify genetic associations in HD patients who display HAEC phenotype [ Time Frame: 7 years ]

    Rationale & hypothesis:

    Currently there is no generally accepted pathogenic hypothesis for Hirschsprung Associated Enterocolitis. A number of hypotheses propose the role of host genetics, host immune responses, and environmental factors such as microbial triggers, including in particular, enteric flora, resulting in disease susceptibility and development. These factors (host immune/inflammatory cells, intestinal epithelia and microbial flora) and their interactions may also be important determinants of disease phenotype and disease progression. Therefore we hypothesize that there are identifiable immunologic, genetic, enteric flora profiles along with clinical risk factors that influence development of HAEC phenotype.



Secondary Outcome Measures :
  1. To identify immunological markers in HD patients who display HAEC phenotype [ Time Frame: 8 years ]
    There is recent evidence that some HD patients who were thought to have refractory HAEC, actually developed IBD. Levin, DN et al. JPGN 2012. This aim is to explore the possibility that there may be similarities between the immune mechanisms involved in HAEC and IBD.


Other Outcome Measures:
  1. To identify microbial markers in HD patients who display HAEC phenotype [ Time Frame: 8-10 years ]
    Data suggest that altered gut microbial populations may be partially responsible for the development of HAEC in susceptible HD patients. Most studies have focused on Clostridium difficile, because two groups reported increased frequency of C. diff. toxin positive stools in HD patients with HAEC compared with those without HAEC .[10, 11] Other groups subsequently reported very low frequencies of C. diff. toxin positivity in their patients with HAEC, thereby calling into question the role C. diff. plays in the pathogenesis of HAEC.[12] Other investigators have found E. coli, C. diff. and Cryptosporidium adherent to enterocytes on histological examinations of colon biopsies of patients with HAEC.[5] These findings indicate a breech in the protective mucus gel layer covering the luminal surface of the colon, leading to invasion of the epithelial barrier. Taken together, these studies suggest that the intestine-microbial interaction may be important in the pathogenesis of HAEC.


Biospecimen Retention:   Samples With DNA

Procedures include prospective data collection from medical records venipuncture and stool collection. 4 cc of blood will be drawn at the screening visit for genetic and immune testing. Additional 8.5 cc of blood will be drawn for CSMC patients for establishment of cell lines.

1. Stool sample collected at screening or follow-up if patient unable to provide at screening.

DNA will be prepared from blood for Genome Wide Association Study and mutational analysis 2. Serological immune markers for inflammatory bowel disease (IBD) including ANCA, ASCA, OMPC, I2, and CBir1 and any newly identified markers. These tests will only be performed on patients who consent to the immune response sub-study. No additional blood sample required. 3. Collect and store fresh fecal specimens for future evaluation by molecular methodologies to determine relative proportions of enteric microflora.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Children with Hirschsprung disease under the age of 17 years.
Criteria

Inclusion Criteria:

  • 1. Males and females of all ages with a confirmed diagnosis of HD based on standardized histological criteria. Only Males and females ages 0 to 17 with a confirmed diagnosis of HD based on standardized histological criteria will be enrolled at CSMC.
  • 2. Able to provide written informed assent if between the ages of 7 and 17. If age 6 and under, able to participate with parental permission.
  • 3. Have consented to have specimens tested for genetics, immune responses, stool microflora.

Case Ascertainment:

All patients with a confirmed diagnosis of HD are eligible for enrollment. A diagnosis of HD for this study will require:

  • 1)Documented histopathology showing absence of ganglion cells and is consistent with the diagnosis of HD.

Exclusion Criteria:

  • 1. Intestinal neuronal dysplasia
  • 2. Pseudo-obstruction

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02193685


Contacts
Layout table for location contacts
Contact: Philip K Frykman, MD, PhD, MBA 310-423-6235 philip.frykman@cshs.org
Contact: Denice M Dubuclet, DC 310-423-6996 denice.dubuclet@cshs.org

Locations
Layout table for location information
United States, California
Cedars-Sinai Medical Center 8723 Alden Drive, Suite 240 Recruiting
Los Angeles, California, United States, 90048
Contact: Philip K Frykman, MD, PhD, MBA    310-423-6235    philip.frykman@cshs.org   
Contact: Denice M Dubuclet, DC    310-423-6996    denice.dubuclet@cshs.org   
Principal Investigator: Philip K Frykman, MD, PhD, MBA         
Sponsors and Collaborators
Cedars-Sinai Medical Center
Karolinska University Hospital
Children's Hospital Los Angeles
UCSF Benioff Children’s Hospital Oakland
University of Michigan
The University of Texas Health Science Center, Houston
Investigators
Layout table for investigator information
Principal Investigator: Philip K Frykman, MD, PhD, MBA Associate Professor, Surgery and Biomedical Sciences Associate Director, Pediactic Surgery for Cedars-Sinai Medical Center

Publications of Results:
Other Publications:
Layout table for additonal information
Responsible Party: Philip K. Frykman, MD, PhD, MBA, Associate Director, Pediatric Surgery, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT02193685    
Other Study ID Numbers: Biomarkers of HAEC
First Posted: July 18, 2014    Key Record Dates
Last Update Posted: August 12, 2016
Last Verified: August 2016
Keywords provided by Philip K. Frykman, MD, PhD, MBA, Cedars-Sinai Medical Center:
(HAEC) Hirschsprung Associated Entrocolistis
(HD) Hirschsprung Disease
(IBD) Inflammatory Bowel Disease
Children
Additional relevant MeSH terms:
Layout table for MeSH terms
Enterocolitis
Hirschsprung Disease
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Digestive System Abnormalities
Megacolon
Colonic Diseases
Congenital Abnormalities