Clinical trial NCT04242420: Connexin Genotypes in Cystic Fibrosis
Official title: Impact of Connexin 37, Connexin 43 on Clinical Disease Phenotype in Delta F508 Homozygous Patients With Cystic Fibrosis (CF) (CF-Modifier)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cystic Fibrosis
Inflammation
Keywords: connexin 37+43, MBL, TGF beta
Lung function
Interleukin 8
Lead sponsor: University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn)
Sponsor class: OTHER
Collaborators: name: Goethe University
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
First posted: 2020-01-27
Enrollment: 300
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Evaluation of clinical parameters by genotype
Primary purpose: DIAGNOSTIC

Brief summary: Background: There is wide variety in lung disease phenotype for the delta F508 (homozygous) genotype. A leukocyte driven inflammation is most important for the pathogenesis of pulmonary disease in CF. Blood cytokines correlate negatively with pulmonary function in delta F508 homozygous patients. Gap junction proteins might be of importance for the influx of blood cells into the lung and may influence the course of pulmonary inflammation. A primary analysis (Horn et al. 2020) has shown that GJA4 variants (rs41266431) are linked to more severe disease in CF. This is very similar to variants of MBL.

Aims: To assess the relationship between gap junction proteins alpha 1 (GJA1/Connexin 43) and alpha 4 (GJA4/connexin 37) genotypes and clinical disease phenotype. Moreover are GJA4 variants in terms of clinical phenotype independent of MBL variants.

Methods:Patients homozygous for delta F508 get recruited from the CF centres of Bonn, Frankfurt and Amsterdam. Sequence analysis is performed for connexin 43 and 37 and MBL genotypes. Clinical disease is assessed longitudinally over 3 years by pulmonary function tests (FEV1 (forced expiratory volume in one second), FVC (=(forced vital capacity), FEF75 % (Forced expiratory flow at 75% of the pulmonary volume) pred), BMI (percentiles), P. aeruginosa colonization, diabetes mellitus and survival to end-stage CF lung disease (death or lung transplantation).

Detailed description: Progressive pulmonary destruction is the major cause of morbidity and mortality in human subjects with cystic fibrosis. Many studies could not find an association between delta F 508 and severity of pulmonary disease . The most important factor in CF lung disease is an inflammation driven by leukocytes and cytokines. The investigators have provided evidence in former studies that cytokines (Interleukin-8 (IL-8), tumour necrosis factor (TNF) alpha, Lipopolysaccahride binding protein (LBP), transforming growth factor (TGF) ß)measured in blood correlate negatively with lung function in delta 508 homozygous patients.

The question arises, what other factors influence recruitment of proinflammatory leukocytes from blood capillaries into the lung .

Connexins are a family of transmembrane proteins, which oligomerize into hexameric structures to form a hemichannel (connexon) and ultimately pair with a partner hemichannel in an adjacent cell to form gap junction intercellular communication channels (GJIC) . There is evidence of expression of connexin 37 (=gap junction protein A4 (GJA4)) on macrophages in humans. Moreover there is evidence of expression of connexin 37 on vascular endothelia in humans . Connexin 37 is expressed on human neutrophils . Pulmonary disease in CF is dominated by a leukocyte driven inflammation. GAP junction proteins might be of importance for the influx of blood cells into the lung. In this regard, the hypothesis was that Cx37 or Cx43 genotypes have an impact on clinical disease phenotype in CF patients homozygous for delta F508. The first analysis (Horn et al 2020) has shown a clinical phenotype linked to the GJA4 genotype is very similar to MBL variants. In this regard the question arises whether there is a link between the MBL variant alleles and the GJA4 variants. Moreover some TGFbeta genotypes are linked to certain pulmonary phenotypes. So we are looking for interactions between Cx37 and TGFbeta genotypes and their impact on the clinical phenotype as well.

Eligibility criteria: Inclusion Criteria:

Homozygosity for delta F 508

Exclusion Criteria:

treatment with systemic steroids 14 days preceding this trial, participation in another study within the past 30 days, treatment with Orkambi or status after lung transplantation (for assessment of all parameters except survival).

Primary outcomes:
measure: Survival to end stage lung disease
timeFrame: through study completion, on average 27 years
measure: Lung function parameter: FEV1
timeFrame: 3 years
measure: Lung function parameters: FVC
timeFrame: 3 years
measure: Lung function parameters: FEF75
timeFrame: 3 years
Secondary outcomes:
measure: Interleukin-8 in blood
timeFrame: through study completion, an average of 3 year
measure: Interleukin-8 in sputum
timeFrame: through study completion, an average of 3 year
measure: White blood cell count
timeFrame: through study completion, an average of 3 year
measure: Inflammatory markers in sputum
timeFrame: through study completion, an average of 3 year
Other outcomes:
measure: Colonisation with Pseudomonas aeruginosa
timeFrame: 3 years
measure: CF related diabetes mellitus
timeFrame: through study completion, an average of 3 year
Locations:
city: Frankfurt
country: Germany
facility: University Hospital
state: Hessia
city: Bonn
country: Germany
facility: University Hospital
state: Nordrhine-Westphalia
city: Amsterdam
country: Netherlands
facility: University Hospital
Study officials:
affiliation: University Hospital, Bonn
name: Sabina Schmitt-Grohe, MD
role: PRINCIPAL_INVESTIGATOR
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