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Microbiome and Volatile Organic Compounds in Patients With CDH (CDHVOCS)

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. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03787160
Recruitment Status : Active, not recruiting
First Posted : December 25, 2018
Last Update Posted : August 19, 2019
Sponsor:
Collaborator:
University of Rostock
Information provided by (Responsible Party):
Warncke Gert, MD, Medical University of Graz

Brief Summary:

Despite improved prenatal diagnostics and therapeutic possibilities, congenital diaphragmatic hernia (CDH) represents a cross-disciplinary challenge. With an incidence of 1:2000-1:5000, it is a common disease that effects centres of paediatrics and juvenile medicine. The etiology is still unclear. Patients with this diagnosis are usually affected by other comorbities such as failure to thrive, gastroesophageal reflux, funnel chest, etc. Depending on the extent of CDH, a more or less pronounced lung hypoplasia with functional impairment occurs. The health-relevant importance of the human microbiome is increasingly evident. While it was previously particularly associated with the gastrointestinal tract, other systems such as the pulmonary microbiome have become the focus of scientific interest.

Research into changes in the microbiome and volatile organic compounds (VOCs) could provide new insights into the underlying mechanisms and therapeutic measures of this disease.


Condition or disease Intervention/treatment Phase
Congenital Diaphragmatic Hernia Diagnostic Test: initial VOC Diagnostic Test: initial fecal microbiome Diagnostic Test: initial pulmonary microbiome Diagnostic Test: Maximum oxygen uptake Diagnostic Test: Functional residual capacity Dietary Supplement: Probiotic treatment Diagnostic Test: VOC probiotic Diagnostic Test: Fecal microbiome probiotic Diagnostic Test: Pulmonary microbiome probiotic Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Basic Science
Official Title: Determining the Effect of Probiotics on Microbiome and Volatile Organic Compounds in Patients After Surgical Repair of Congenital Diaphragmatic Hernia
Actual Study Start Date : March 22, 2018
Estimated Primary Completion Date : October 1, 2019
Estimated Study Completion Date : October 1, 2019


Arm Intervention/treatment
Active Comparator: CDH Group
10 patients after surgical closure of CDH will undergo VOC profile analysis (2 breath samples) (initial VOC), fecal sampling for 16S rDNA based pyrosequencing (initial fecal microbiome) and deep induced sputum sampling for 16S rDNA pyrosequencing (initial pulmonary microbiome), bicycle spiroergometry to determine the maximum oxygen uptake (maximum oxygen uptake), body plethysmography, spirometry and N2-multiple breath washout testing to determine the functional residual capacity (functional residual capacity). Thereafter patients will receive probiotic treatment with OmniBiotic6 (R) (Allergosan, Graz, Austria) 1 sachet daily for 3 months (probiotic treatment). Three months after discontinuing probiotic treatment VOC testing (VOC probiotics), fecal microbiome sampling (fecal microbiome probiotics) and deep induced sputum testing (pulmonary microbiome probiotics) will be repeated and compared to the results of the initial tests.
Diagnostic Test: initial VOC
Difference in VOC profile between patients with CDH and healthy controls (2 samples per patient will be obtained after obtaining informed consent).

Diagnostic Test: initial fecal microbiome
Difference of alpha and beta diversity and relative fecal bacterial abundance between patients with CDH and healthy controls (1 stool sample will be taken per patient after obtaining informed consent)

Diagnostic Test: initial pulmonary microbiome
Difference of alpha and beta diversity and relative pulmonary bacterial abundance between patients with CDH and healthy controls (1 deep induced sputum sample will be taken per patient after obtaining informed consent)

Diagnostic Test: Maximum oxygen uptake
Comparison of the maximum oxygen uptake (corrected for body weight and gender) as determined by bicycle spiroergometry between patients with CDH and healthy controls

Diagnostic Test: Functional residual capacity
FRC will be determined by spirometry, bodyplethysmography and N2-breath wash out method. FRC will be compared between patients after CDH and healthy controls.

Dietary Supplement: Probiotic treatment
CDH patients will receive OmniBiotic 6(R) (Allergosan, Graz, Austria) probiotic supplementation 1 sachet daily for 3 months.

Diagnostic Test: VOC probiotic
Determination of the VOC profile 3 months after discontinuing probiotic treatment. Comparison to the profiles before the treatment.

Diagnostic Test: Fecal microbiome probiotic
Determination of the fecal microbiome from 1 sample per patient (alpha and beta diversity, relative bacterial abundance at the genus level) 3 months after discontinuing probiotic treatment. Comparison to the profiles before the treatment.

Diagnostic Test: Pulmonary microbiome probiotic
Determination of the fecal microbiome from 1 deep induced sputum sample per patient (alpha and beta diversity, relative bacterial abundance at the genus level) 3 months after discontinuing probiotic treatment. Comparison to the profiles before the treatment.

Control Group
10 healthy controls (age and sex matched) will undergo VOC profile analysis (2 breath samples) (initial VOC), fecal sampling for 16S rDNA based pyrosequencing (initial fecal microbiome) and deep induced sputum sampling for 16S rDNA pyrosequencing (initial pulmonary microbiome), bicycle spiroergometry to determine the maximum oxygen uptake (maximum oxygen uptake), body plethysmography, spirometry and N2-multiple breath washout testing to determine the functional residual capacity (functional residual capacity).
Diagnostic Test: initial VOC
Difference in VOC profile between patients with CDH and healthy controls (2 samples per patient will be obtained after obtaining informed consent).

Diagnostic Test: initial fecal microbiome
Difference of alpha and beta diversity and relative fecal bacterial abundance between patients with CDH and healthy controls (1 stool sample will be taken per patient after obtaining informed consent)

Diagnostic Test: initial pulmonary microbiome
Difference of alpha and beta diversity and relative pulmonary bacterial abundance between patients with CDH and healthy controls (1 deep induced sputum sample will be taken per patient after obtaining informed consent)

Diagnostic Test: Maximum oxygen uptake
Comparison of the maximum oxygen uptake (corrected for body weight and gender) as determined by bicycle spiroergometry between patients with CDH and healthy controls

Diagnostic Test: Functional residual capacity
FRC will be determined by spirometry, bodyplethysmography and N2-breath wash out method. FRC will be compared between patients after CDH and healthy controls.




Primary Outcome Measures :
  1. Analysis of the pulmonary microbiome in the sputum of CDH group versus control group. [ Time Frame: 12 months ]
    OTUs (Operational Taxonomic Units) will be visualized as OTU tables, bar charts and PCOA (Principal Coordinates Analysis) plots using the Qiime core microbiome script. For the different groups alpha-diversity (Chao 1 index, Shannon Index etc.) will be compared. Additionally, we will compare beta-diversity by Adonis test. Relative abundances of the bacteria at the different levels (phylum to genus) will be compared between the groups by using Kruskal Wallis Test.

  2. Analysis of VOCs in the respiratory air by needle-trap microextraction (NTME) and stool by solid phase microextraction (SPME) of CDH group versus control group. [ Time Frame: 12 months ]

    From the results of the patient measurements, those substances and substance concentrations are determined which are specific for study group 1 and group 2, i.e. compounds which are not present in the comparison group or only in significantly lower or higher concentrations. The selected volatile markers, as well as any volatile contaminants that may have been detected in the environment, are stored in an analytical reference database and, after elimination of the contamination, bundled into possibly disease-specific marker profiles. The VOCs are recorded and displayed in the following order. The unit in which the VOCs are measured is pars per billion (ppb).

    Class (for example carbons) VOCs (ppb) CDHV1 (congenital diaphragmatic hernia group visit 1) CDHK (congenital diaphragmatic hernia - control group visit 1) CDHV2 (congenital diaphragmatic hernia group visit 2) CDHV3 (congenital diaphragmatic hernia group visit 3) p-value


  3. Analysis of the lung function: Lung clearance index (LCI) is derived from multiple breath washout tests of CDH group versus control group. [ Time Frame: 12 months ]
    The LCI is about 7 (range from 6.45-7.78) for healthy individuals and is a number without a unit.

  4. Analysis of the lung function: Forced expiratory volume in one second (FEV1) measured with spirometry of CDH group versus control group. [ Time Frame: 12 months ]
    The FEV1 is the forced expiratory volume within the first second (liter/second), generated by a maximal voluntary exhalation after maximum inspiration before, usually described as the Tiffeneau-Index in % of FVC (FEV1/FVC).

  5. Analysis of the cardiopulmonary capacity: Resting ECG of CDH group versus control group. [ Time Frame: 12 months ]
    A Resting ECG recording the resting heart rate, the rhythm, the PQ duration, the width and height of the QRS complex, the QT duration, and the ST segment is recorded.

  6. Analysis of the cardiopulmonary capacity: Systolic and diastolic blood pressures of CDH group versus control group. [ Time Frame: 12 months ]
    Noninvasiv systolic and diastolic blood pressures are assessed (Unit: mmHg).

  7. Analysis of the cardiopulmonary capacity: Body height of CDH group versus control group. [ Time Frame: 12 months ]
    Body height is measured in cm.

  8. Analysis of the cardiopulmonary capacity: Body weight of CDH group versus control group. [ Time Frame: 12 months ]
    Body weight is measured in kg.

  9. Analysis of the cardiopulmonary capacity: Body mass index (BMI) of CDH group versus control group. [ Time Frame: 12 months ]
    Body mass index is calculated in kg body weight/body height².

  10. Analysis of the cardiopulmonary capacity: Muscle mass of CDH group versus control group. [ Time Frame: 12 months ]
    Muscle mass is specified in kg/body height².

  11. Analysis of the cardiopulmonary capacity: Body fat of CDH group versus control group. [ Time Frame: 12 months ]
    Body fat is specified in percent of body weight.

  12. Analysis of the cardiopulmonary capacity: Aerobic performance of CDH group versus control group. [ Time Frame: 12 months ]
    Aerobic performance is specified in percent of normal values of the Austrian cardiological society.

  13. Analysis of the cardiopulmonary capacity: Maximal oxygen uptake of CDH group versus control group. [ Time Frame: 12 months ]
    Measurements by spiroergometry: Maximal oxygen uptake in ml/kg/min.

  14. Analysis of the cardiopulmonary capacity: Ventilation of CDH group versus control group. [ Time Frame: 12 months ]
    Measurements by spiroergometry: Ventilation in liter/min.

  15. Analysis of the cardiopulmonary capacity: Oxygen pulse of CDH group versus control group. [ Time Frame: 12 months ]
    Measurements by spiroergometry: Oxygen pulse in ml/beats per minute.

  16. Analysis of the cardiopulmonary capacity: Oxygen uptake of CDH group versus control group. [ Time Frame: 12 months ]
    Respiratory exchange ratio = oxygen uptake in ml/carbon dioxide release in ml.

  17. Analysis of the cardiopulmonary capacity: Breathing reserve of CDH group versus control group. [ Time Frame: 12 months ]
    Unit: Percent of FEV1 x 35.


Secondary Outcome Measures :
  1. Alterations of pulmonary microbiome after probiotic treatment for a period of 3 months in patients with CDH. [ Time Frame: 12 months ]
    After sampling for microbiome and VOC analysis and carrying out lung function measurements and sports medical examination, the participants in the study group will take a probiotic (Omnibiotic 6, purchased from the Allergosan Institute, dietary supplement) for a period of 3 months. Immediately afterwards and another month later, measurements of the pulmonary microbiome are taken.

  2. Alterations of VOCs in the respiratory air after probiotic treatment for a period of 3 months in patients with CDH. [ Time Frame: 12 months ]
    After sampling for microbiome and VOC analysis and carrying out lung function measurements and sports medical examination, the participants in the study group will take a probiotic (Omnibiotic 6, purchased from the Allergosan Institute, dietary supplement) for a period of 3 months. Immediately afterwards and another month later, measurements of the VOCs in the breath are taken.

  3. Analysis of the lung function: Forced expiratory flow (FEF25-75). [ Time Frame: 12 months ]
    Measured by body plethysmography and spirometry: FEF25-75 = Forced expiratory flow 25-75% vital capacity (= MMEF), Unit: l/s.

  4. Analysis of the lung function: Forced expiratory flow (FEF25). [ Time Frame: 12 months ]
    Measured by body plethysmography and spirometry: FEF25 = Forced expiratory flow at the time, when 75% of the vital capacity is exhaled (MEF25), Unit: l/s.

  5. Analysis of the lung function: Forced expiratory flow (FEF50). [ Time Frame: 12 months ]
    Measured by body plethysmography and spirometry: FEF50 = Forced expiratory flow at 50% of the exhaled vital capacity (= MEF50), Unit: l/s.

  6. Analysis of the lung function: Forced expiratory volume (FEV1). [ Time Frame: 12 months ]
    Measured by body plethysmography and spirometry: FEV1 = Forced expiratory volume in 1 s, Unit: l.

  7. Analysis of the lung function: Tiffeneau-Index (FEV1%FVC). [ Time Frame: 12 months ]
    Measured by body plethysmography and spirometry: FEV1%FVC = Tiffeneau-Index, described in % of the forced vital capacity, Unit: %.

  8. Analysis of the lung function: Functional residual capacity (FRC). [ Time Frame: 12 months ]
    Measured by body plethysmography and spirometry: FRC = Functional residual capacity, Unit: l.

  9. Analysis of the lung function: Through "multiple breath washout" acquired FRC (RC(MBW)). [ Time Frame: 12 months ]
    RC(MBW): Through "multiple breath washout" acquired FRC, Unit: l.

  10. Analysis of the lung function: Through body plethysmography acquired FRC (RC(pleth)). [ Time Frame: 12 months ]
    Measured by body plethysmography: RC(pleth): Through body plethysmography acquired FRC (= ITGV, intra thoracic gas volume), Unit: l.

  11. Analysis of the lung function: Forced vital capacity (FVC). [ Time Frame: 12 months ]
    Measured by spirometry: FVC = Forced vital capacity, Vital capacity acquired through a forced exhaled manoeuvre, Unit: l.

  12. Analysis of the lung function: Intrathoracic gasvolume (ITGV). [ Time Frame: 12 months ]
    Measured by body plethysmography: ITGV = Intrathoracic gasvolume (= FRC(pleth)), Unit: l.

  13. Analysis of the lung function: Max. expiratory flow (MEF25). [ Time Frame: 12 months ]
    Measured by spirometry: MEF25 = Max. expiratory flow when 75% of the vital capacity is exhaled (= FEF25), Unit: l/s.

  14. Analysis of the lung function: Max. expiratory flow (MEF50). [ Time Frame: 12 months ]
    Measured by spirometry: MEF50 = Max. expiratory flow when 50% of the vital capacity is exhaled (= FEF50), Unit: l/s.

  15. Analysis of the lung function: Max. expiratory flow (MMEF). [ Time Frame: 12 months ]
    Measured by spirometry: MMEF = Max. expiratory flow (= FEF25-75), Unit: l/s.



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age from 6-16 years
  • Age 0-6 months at time of CDH-OP (except control group)
  • reliable diagnosis of congenital diaphragmatic hernia (except control group)
  • surgical occlusion with patch (except control group)
  • surgical occlusion without patch (except control group)
  • given approval

Exclusion Criteria:

  • chronic pulmonary diseases
  • Infection within 4 weeks before the test date
  • unaccepted consent

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): NCT03787160


Locations
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Austria
Department of Department of Pediatric and Adolescent Surgery, Medical University of Graz
Graz, Steiermark, Austria, 8036
Sponsors and Collaborators
Medical University of Graz
University of Rostock
Investigators
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Study Director: Till Holger, MD Department of Pediatric and Adolescent Surgery, Medical University of Graz
Principal Investigator: Ernst Eber, MD Department of Pediatric and Adolescent Medicine, Medical University of Graz
Principal Investigator: Gert Warncke, MD Department of Pediatric and Adolescent Surgery, Medical University of Graz

Publications:

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Responsible Party: Warncke Gert, MD, Principal Investigator, Medical University of Graz
ClinicalTrials.gov Identifier: NCT03787160     History of Changes
Other Study ID Numbers: 28-528 ex 15/16
First Posted: December 25, 2018    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Warncke Gert, MD, Medical University of Graz:
congenital diaphragmatic hernia
volatile organic compounds
microbiome
pulmonary function
multiple breath washout

Additional relevant MeSH terms:
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Hernias, Diaphragmatic, Congenital
Hernia
Hernia, Diaphragmatic
Pathological Conditions, Anatomical
Congenital Abnormalities