Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials
Trial record 2 of 11 for:    "Hirschsprungs disease"

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Cedars-Sinai Medical Center
Sponsor:
Collaborators:
Karolinska University Hospital and Karolinska Institute
Children's Hospital Los Angeles
Children's Hospital of Oakland
University of Michigan
Information provided by (Responsible Party):
Philip K. Frykman, MD, PhD, MBA, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier:
NCT02193685
First received: July 9, 2014
Last updated: July 17, 2014
Last verified: July 2014
  Purpose

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
Hirschsprung Disease
Hirschsprung Associated Enterocolitis

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Identification of Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease

Resource links provided by NLM:


Further study details as provided by Cedars-Sinai Medical Center:

Primary Outcome Measures:
  • To identify genetic associations in HD patients who display HAEC phenotype [ Time Frame: 7 years ] [ Designated as safety issue: No ]

    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:
  • To identify immunological markers in HD patients who display HAEC phenotype [ Time Frame: 8 years ] [ Designated as safety issue: No ]
    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:
  • To identify microbial markers in HD patients who display HAEC phenotype [ Time Frame: 8-10 years ] [ Designated as safety issue: No ]
    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 will be collected at screening or at 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 known 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. This will not require the collection of an additional blood sample. 3. Collect and store fresh fecal specimens for future evaluation by molecular methodologies to determine relative proportions of enteric microflora.


Estimated Enrollment: 400
Study Start Date: February 2010
Estimated Study Completion Date: December 2025
Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)
Groups/Cohorts
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 17 Years
Genders Eligible for Study:   Both
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
  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: NCT02193685

Contacts
Contact: Philip K Frykman, MD, PhD, MBA 310-423-7779 ext 37779 philip.frykman@cshs.org
Contact: Denice M Dubuclet, DC 310-423-6996 ext 6996 denice.dubuclet@cshs.org

Locations
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    310-423-7779    philip.frykman@cshs.org   
Contact: Denice M Dubuclet, DC    310-423-6996 ext 36996    denice.dubuclet@cshs.org   
Principal Investigator: Philip K Frykman, MD, PhD, MBA         
Sponsors and Collaborators
Cedars-Sinai Medical Center
Karolinska University Hospital and Karolinska Institute
Children's Hospital Los Angeles
Children's Hospital of Oakland
University of Michigan
Investigators
Principal Investigator: Philip K Frykman, MD, PhD, MBA Associate Professor, Surgery and Biomedical Sciences Associate Director, Pediactic Surgery for Cedars-Sinai Medical Center
  More Information

No publications provided

Responsible Party: Philip K. Frykman, MD, PhD, MBA, Associate Director, Pediatric Surgery, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT02193685     History of Changes
Other Study ID Numbers: Biomarkers of HAEC
Study First Received: July 9, 2014
Last Updated: July 17, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Cedars-Sinai Medical Center:
(HAEC) Hirschsprung Associated Entrocolistis
(HD) Hirschsprung Disease
(IBD) Inflammatory Bowel Disease
Children

Additional relevant MeSH terms:
Enterocolitis
Hirschsprung Disease
Colonic Diseases
Congenital Abnormalities
Digestive System Abnormalities
Digestive System Diseases
Gastroenteritis
Gastrointestinal Diseases
Intestinal Diseases
Megacolon

ClinicalTrials.gov processed this record on November 20, 2014