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Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis

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. Identifier: NCT01661491
Recruitment Status : Recruiting
First Posted : August 9, 2012
Last Update Posted : July 5, 2019
Information provided by (Responsible Party):
Yale University

Brief Summary:
Cystic Fibrosis (CF) is a fatal, recessive genetic disorder characterized by progressive inflammation and lung damage. It is unclear whether current treatment strategies, which focus on detection and eradication of pathogenic microorganisms in the lung, are the best way to prevent the initiation of early inflammation and lung damage. This study asks how early acquisition of microbial flora occurs in infants with CF and healthy baby controls, and whether this process initiates or influences early inflammation and clinical disease progression in CF.

Condition or disease
Cystic Fibrosis

Detailed Description:

Cystic Fibrosis is the most common lethal genetic disorder in Caucasian populations. Mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) affect its ability to act as a chloride channel. The recent development of a transgenic pig model of CF has demonstrated that newborn CF lungs, free of bacteria and inflammation at birth, become colonized with a mixed microbial flora that likely initiates early inflammatory changes which precede clinically apparent deterioration in lung function.

Because chronic infection and inflammation play central roles in CF disease progression and exacerbations, many clinicians and researchers have focused on identifying pathogens associated with CF infection and inflammation. Recent studies outside the area of CF, however, have clearly demonstrated that "non-pathogens", such as the commensal flora carried by all humans at multiple mucosal sites, engage the host's innate and adaptive immune systems constantly. This interaction between "microbiome" and host genome is responsible for appropriate development and function of protective inflammatory and immune responses.

We hypothesize that acquisition of a commensal flora by newborns with CF may play a critical role in initiating pathogenic inflammatory responses that subsequently lead to lung damage. The acquired commensal flora may initially be identical to that of a non-CF infant, but may be altered by the direct or indirect effects of CFTR mutation on the mucosal environment. Such an altered flora is likely to encode different metabolic and regulatory functions, and may directly influence host inflammatory responses. If so, a novel therapeutic opportunity may exist to modulate this commensal flora, or to manipulate its immunomodulatory functions in a way that interrupts the insidious cycle of inflammation and damage that characterizes CF.

We propose to test our hypothesis in three specific aims: (1) Describe the acquisition and evolution of gut and respiratory tract microbiomes in CF infants and non-CF controls; (2) Determine the relationship between the microbiota and markers of inflammation in these two cohorts; and (3) Determine whether early declines in lung function are associated with inflammatory biomarkers or microbiome composition/function. This study is novel in its focus on a rarely studied population, at a time when interventions might significantly impact progression of this lethal disease and preserve pulmonary function. Its innovation lies in applying state of the art technologies and methods to samples that can be collected simply and non-invasively, thus increasing the likelihood that the findings of this study can be translated into clinical practice.

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Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis
Study Start Date : August 2012
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

Cystic Fibrosis
Infants and toddlers with Cystic Fibrosis
Non-cystic fibrosis controls
Infants and toddlers without Cystic Fibrosis

Primary Outcome Measures :
  1. Change from Baseline in the Average Unifrac Value in Fecal Microbiome & Metagenome Composition at 4 years [ Time Frame: 4 years ]
    High throughput sequencing will be used to identify microbial taxa and microbial genes present in feces, and to determine how these change over a period of 4 years

Secondary Outcome Measures :
  1. Change from Baseline in the Amounts of Calprotectin at 4 years [ Time Frame: 4 years ]
    Fecal calprotectin will be measured by elisa

  2. Change from Baseline in the Amounts of Short Chain Fatty Acids at 4 years [ Time Frame: 4 years ]
    Fecal short chain fatty acids will be measured by gas chromatography

Biospecimen Retention:   Samples Without DNA
Fecal samples

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.

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Ages Eligible for Study:   3 Months to 4 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Infants and children up to the age of 4 with Cystic Fibrosis, and age-matched controls without cystic fibrosis will be eligible for this study. Participants will be recruited from the Cystic Fibrosis clinic and Primary Care Clinic of the Yale New Haven Hospital.

Cystic Fibrosis participants:

Inclusion Criteria:

  • laboratory diagnosis of Cystic Fibrosis

Exclusion Criteria:

  • Major organ system disease other than Cystic Fibrosis
  • History of prematurity

Non Cystic Fibrosis control participants:

Inclusion Criteria:

  • Proof of a negative newborn CF screening test

Exclusion Criteria:

  • Major organ system disease
  • History of prematurity

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 identifier (NCT number): NCT01661491

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Contact: Marie Egan, MD (203) 785-2480
Contact: Barbara Kazmierczak, MD, PhD (203) 785-4140

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United States, Connecticut
Cystic Fibrosis Clinic, Yale New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06520
Contact: Marie Egan, MD    203-785-2480      
Sponsors and Collaborators
Yale University
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Principal Investigator: Barbara I Kazmierczak, MD PhD Yale University
Principal Investigator: Marie Egan, MD Yale University

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Responsible Party: Yale University Identifier: NCT01661491    
Other Study ID Numbers: 1206010476
First Posted: August 9, 2012    Key Record Dates
Last Update Posted: July 5, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Cystic Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases