Ignite Creation Date:
2025-12-25 @ 4:27 AM
Ignite Modification Date:
2026-02-25 @ 4:59 PM
Study NCT ID:
NCT04242420
Status:
UNKNOWN
Last Update Posted:
2021-08-16
First Post:
2019-12-20
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Connexin Genotypes in Cystic Fibrosis
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D003550', 'term': 'Cystic Fibrosis'}, {'id': 'D007249', 'term': 'Inflammation'}, {'id': 'D003966', 'term': 'Camurati-Engelmann Syndrome'}], 'ancestors': [{'id': 'D010182', 'term': 'Pancreatic Diseases'}, {'id': 'D004066', 'term': 'Digestive System Diseases'}, {'id': 'D008171', 'term': 'Lung Diseases'}, {'id': 'D012140', 'term': 'Respiratory Tract Diseases'}, {'id': 'D030342', 'term': 'Genetic Diseases, Inborn'}, {'id': 'D009358', 'term': 'Congenital, Hereditary, and Neonatal Diseases and Abnormalities'}, {'id': 'D007232', 'term': 'Infant, Newborn, Diseases'}, {'id': 'D010335', 'term': 'Pathologic Processes'}, {'id': 'D013568', 'term': 'Pathological Conditions, Signs and Symptoms'}, {'id': 'D010009', 'term': 'Osteochondrodysplasias'}, {'id': 'D001848', 'term': 'Bone Diseases, Developmental'}, {'id': 'D001847', 'term': 'Bone Diseases'}, {'id': 'D009140', 'term': 'Musculoskeletal Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D005838', 'term': 'Genotype'}, {'id': 'D012119', 'term': 'Respiration'}, {'id': 'D001287', 'term': 'Attachment Sites, Microbiological'}, {'id': 'D001800', 'term': 'Blood Specimen Collection'}], 'ancestors': [{'id': 'D055614', 'term': 'Genetic Phenomena'}, {'id': 'D012143', 'term': 'Respiratory Physiological Phenomena'}, {'id': 'D002943', 'term': 'Circulatory and Respiratory Physiological Phenomena'}, {'id': 'D040481', 'term': 'Genome Components'}, {'id': 'D016678', 'term': 'Genome'}, {'id': 'D040342', 'term': 'Genetic Structures'}, {'id': 'D013048', 'term': 'Specimen Handling'}, {'id': 'D019411', 'term': 'Clinical Laboratory Techniques'}, {'id': 'D019937', 'term': 'Diagnostic Techniques and Procedures'}, {'id': 'D003933', 'term': 'Diagnosis'}, {'id': 'D011677', 'term': 'Punctures'}, {'id': 'D013514', 'term': 'Surgical Procedures, Operative'}, {'id': 'D008919', 'term': 'Investigative Techniques'}]}}, 'protocolSection': {'designModule': {'phases': ['NA'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'NA', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'DIAGNOSTIC', 'interventionModel': 'SINGLE_GROUP', 'interventionModelDescription': 'Evaluation of clinical parameters by genotype'}, 'enrollmentInfo': {'type': 'ESTIMATED', 'count': 300}}, 'statusModule': {'overallStatus': 'UNKNOWN', 'lastKnownStatus': 'RECRUITING', 'startDateStruct': {'date': '2002-04', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2021-08', 'completionDateStruct': {'date': '2024-12-31', 'type': 'ESTIMATED'}, 'lastUpdateSubmitDate': '2021-08-08', 'studyFirstSubmitDate': '2019-12-20', 'studyFirstSubmitQcDate': '2020-01-24', 'lastUpdatePostDateStruct': {'date': '2021-08-16', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2020-01-27', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2023-12-31', 'type': 'ESTIMATED'}}, 'outcomesModule': {'otherOutcomes': [{'measure': 'Colonisation with Pseudomonas aeruginosa', 'timeFrame': '3 years', 'description': 'Never, Intermittent or chronic according to Leeds criteria'}, {'measure': 'CF related diabetes mellitus', 'timeFrame': 'through study completion, an average of 3 year', 'description': 'Assessment via patient charts/ registry'}], 'primaryOutcomes': [{'measure': 'Survival to end stage lung disease', 'timeFrame': 'through study completion, on average 27 years', 'description': 'End stage lung disease: Death or lung transplantation'}, {'measure': 'Lung function parameter: FEV1', 'timeFrame': '3 years', 'description': 'Best FEV1 value in % predicted of the year according to German registry according to Global lung initiative (GLI)'}, {'measure': 'Lung function parameters: FVC', 'timeFrame': '3 years', 'description': 'Best FVC value in % predicted of the year according to German registry according to Global lung initiative (GLI)'}, {'measure': 'Lung function parameters: FEF75', 'timeFrame': '3 years', 'description': 'Best FEF75 value in % predicted of the year according to German registry according to Global lung initiative (GLI)'}], 'secondaryOutcomes': [{'measure': 'Interleukin-8 in blood', 'timeFrame': 'through study completion, an average of 3 year', 'description': 'single spot value (cross-sectional)'}, {'measure': 'Interleukin-8 in sputum', 'timeFrame': 'through study completion, an average of 3 year', 'description': 'single spot value (cross-sectional)'}, {'measure': 'White blood cell count', 'timeFrame': 'through study completion, an average of 3 year', 'description': 'Leukocytes (single spot value (cross-sectional))'}, {'measure': 'Inflammatory markers in sputum', 'timeFrame': 'through study completion, an average of 3 year', 'description': 'Leukocyte count in sputum (single spot value (cross-sectional))'}]}, 'oversightModule': {'oversightHasDmc': False, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['connexin 37+43, MBL, TGF beta', 'Lung function', 'Interleukin 8'], 'conditions': ['Cystic Fibrosis', 'Inflammation']}, 'referencesModule': {'references': [{'pmid': '16207846', 'type': 'BACKGROUND', 'citation': 'Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, Zariwala M, Fargo D, Xu A, Dunn JM, Darrah RJ, Dorfman R, Sandford AJ, Corey M, Zielenski J, Durie P, Goddard K, Yankaskas JR, Wright FA, Knowles MR; Gene Modifier Study Group. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med. 2005 Oct 6;353(14):1443-53. doi: 10.1056/NEJMoa051469.'}, {'pmid': '8166795', 'type': 'RESULT', 'citation': 'Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. N Engl J Med. 1993 Oct 28;329(18):1308-13. doi: 10.1056/NEJM199310283291804.'}, {'pmid': '17099022', 'type': 'RESULT', 'citation': 'McKone EF, Goss CH, Aitken ML. CFTR genotype as a predictor of prognosis in cystic fibrosis. Chest. 2006 Nov;130(5):1441-7. doi: 10.1378/chest.130.5.1441.'}, {'pmid': '15579374', 'type': 'RESULT', 'citation': 'Schmitt-Grohe S, Naujoks C, Bargon J, Wagner TO, Schubert R, Hippe V, Zielen S. Interleukin-8 in whole blood and clinical status in cystic fibrosis. Cytokine. 2005 Jan 7;29(1):18-23. doi: 10.1016/j.cyto.2004.09.004.'}, {'pmid': '16183806', 'type': 'RESULT', 'citation': 'Schmitt-Grohe S, Hippe V, Igel M, von Bergmann K, Posselt HG, Krahl A, Smaczny C, Wagner TO, Nikolazik W, Schubert R, Lentze MJ, Zielen S. Lipopolysaccharide binding protein, cytokine production in whole blood, and lipoproteins in cystic fibrosis. Pediatr Res. 2005 Nov;58(5):903-7. doi: 10.1203/01.PDR.0000182598.98167.24. Epub 2005 Sep 23.'}, {'pmid': '16622779', 'type': 'RESULT', 'citation': 'Schmitt-Grohe S, Stuber F, Book M, Bargon J, Wagner TO, Naujoks C, Schubert R, Lentze MJ, Zielen S. TNF-alpha promoter polymorphism in relation to TNF-alpha production and clinical status in cystic fibrosis. Lung. 2006 Mar-Apr;184(2):99-104. doi: 10.1007/s00408-005-2568-x.'}, {'pmid': '24062613', 'type': 'RESULT', 'citation': 'Eickmeier O, Boom Lv, Schreiner F, Lentze MJ, NGampolo D, Schubert R, Zielen S, Schmitt-Grohe S. Transforming growth factor beta1 genotypes in relation to TGFbeta1, interleukin-8, and tumor necrosis factor alpha in induced sputum and blood in cystic fibrosis. Mediators Inflamm. 2013;2013:913135. doi: 10.1155/2013/913135. Epub 2013 Aug 26.'}, {'pmid': '26009202', 'type': 'RESULT', 'citation': 'Dempsie Y, Martin P, Upton PD. Connexin-mediated regulation of the pulmonary vasculature. Biochem Soc Trans. 2015 Jun;43(3):524-9. doi: 10.1042/BST20150030.'}, {'pmid': '15955304', 'type': 'RESULT', 'citation': 'Chanson M, Derouette JP, Roth I, Foglia B, Scerri I, Dudez T, Kwak BR. Gap junctional communication in tissue inflammation and repair. Biochim Biophys Acta. 2005 Jun 10;1711(2):197-207. doi: 10.1016/j.bbamem.2004.10.005. Epub 2004 Oct 30.'}, {'pmid': '11834520', 'type': 'RESULT', 'citation': 'Kwak BR, Mulhaupt F, Veillard N, Gros DB, Mach F. Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2002 Feb 1;22(2):225-30. doi: 10.1161/hq0102.104125.'}, {'pmid': '12525569', 'type': 'RESULT', 'citation': 'Zahler S, Hoffmann A, Gloe T, Pohl U. Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration. J Leukoc Biol. 2003 Jan;73(1):118-26. doi: 10.1189/jlb.0402184.'}, {'pmid': '25301274', 'type': 'RESULT', 'citation': 'Saez PJ, Shoji KF, Aguirre A, Saez JC. Regulation of hemichannels and gap junction channels by cytokines in antigen-presenting cells. Mediators Inflamm. 2014;2014:742734. doi: 10.1155/2014/742734. Epub 2014 Sep 9.'}, {'pmid': '33193670', 'type': 'RESULT', 'citation': 'Horn T, Ludwig M, Eickmeier O, Neerinex AH, Maitland-van der Zee AH, Smaczny C, Wagner TOF, Schubert R, Zielen S, Majoor C, Bos LD, Schmitt-Grohe S. Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis. Front Genet. 2020 Oct 28;11:570403. doi: 10.3389/fgene.2020.570403. eCollection 2020.'}, {'pmid': '37525914', 'type': 'DERIVED', 'citation': 'Laubach JP, Ludwig M, Horn T, Eickmeier O, Smaczny C, Schubert R, Zielen S, Majoor C, Aydin M, Schnell A, Schmitt-Grohe S. Transforming Growth Factor ss1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis. Front Biosci (Landmark Ed). 2023 Jul 19;28(7):138. doi: 10.31083/j.fbl2807138.'}]}, 'descriptionModule': {'briefSummary': '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.\n\nAims: 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.\n\nMethods: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).', 'detailedDescription': '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.\n\nThe question arises, what other factors influence recruitment of proinflammatory leukocytes from blood capillaries into the lung .\n\nConnexins 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.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['CHILD', 'ADULT', 'OLDER_ADULT'], 'minimumAge': '6 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\nHomozygosity for delta F 508\n\nExclusion Criteria:\n\ntreatment 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).'}, 'identificationModule': {'nctId': 'NCT04242420', 'briefTitle': 'Connexin Genotypes in Cystic Fibrosis', 'organization': {'class': 'OTHER', 'fullName': "University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn)"}, 'officialTitle': 'Impact of Connexin 37, Connexin 43 on Clinical Disease Phenotype in Delta F508 Homozygous Patients With Cystic Fibrosis (CF) (CF-Modifier)', 'orgStudyIdInfo': {'id': 'BN 178/01'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'OTHER', 'label': 'Connexin genotype', 'description': 'Genotyping', 'interventionNames': ['Diagnostic Test: Genotyping', 'Diagnostic Test: Lung function', 'Diagnostic Test: Microbiology', 'Diagnostic Test: Blood sample', 'Diagnostic Test: Induced Sputum']}], 'interventions': [{'name': 'Genotyping', 'type': 'DIAGNOSTIC_TEST', 'description': 'Genotyping for single nucleotide polymorphisms for Connexin 37\\&43, Mannose binding lectin (MBL) and transforming growth factor beta (TGF beta) genotypes', 'armGroupLabels': ['Connexin genotype']}, {'name': 'Lung function', 'type': 'DIAGNOSTIC_TEST', 'description': 'Spirometry,', 'armGroupLabels': ['Connexin genotype']}, {'name': 'Microbiology', 'type': 'DIAGNOSTIC_TEST', 'description': 'Bacterial culture from Sputum or swab', 'armGroupLabels': ['Connexin genotype']}, {'name': 'Blood sample', 'type': 'DIAGNOSTIC_TEST', 'description': 'Interleukin-8 assay (via chemiluminescence) blood cell count', 'armGroupLabels': ['Connexin genotype']}, {'name': 'Induced Sputum', 'type': 'DIAGNOSTIC_TEST', 'description': 'Interleukin-8 assay (via chemiluminescence) blood cell count', 'armGroupLabels': ['Connexin genotype']}]}, 'contactsLocationsModule': {'locations': [{'zip': '60590', 'city': 'Frankfurt', 'state': 'Hessia', 'status': 'RECRUITING', 'country': 'Germany', 'contacts': [{'name': 'Christina Smaczny, MD', 'role': 'CONTACT', 'email': 'smaczny@em.uni-frankfurt.de', 'phone': '0049-69-6301', 'phoneExt': '4232'}], 'facility': 'University Hospital', 'geoPoint': {'lat': 49.68333, 'lon': 10.53333}}, {'zip': '53113', 'city': 'Bonn', 'state': 'Nordrhine-Westphalia', 'status': 'RECRUITING', 'country': 'Germany', 'contacts': [{'name': 'Sabina Schmitt-Grohe, MD', 'role': 'CONTACT', 'email': 's.schmitt-grohe@ukbonn.de', 'phone': '004915254568942'}], 'facility': 'University Hospital', 'geoPoint': {'lat': 50.73438, 'lon': 7.09549}}, {'city': 'Amsterdam', 'status': 'RECRUITING', 'country': 'Netherlands', 'contacts': [{'name': 'Anne Neerinx-vanStuvyenberg, PhD', 'role': 'CONTACT', 'email': 'a.vanstuyvenbergneerincx@amc.uva.nl'}], 'facility': 'University Hospital', 'geoPoint': {'lat': 52.37403, 'lon': 4.88969}}], 'centralContacts': [{'name': 'Sabina Schmitt-Grohe, MD', 'role': 'CONTACT', 'email': 's.schmitt-grohe@ukbonn.de', 'phone': '004915254568942'}], 'overallOfficials': [{'name': 'Sabina Schmitt-Grohe, MD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'University Hospital, Bonn'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': "University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn)", 'class': 'OTHER'}, 'collaborators': [{'name': 'Goethe University', 'class': 'OTHER'}, {'name': 'Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)', 'class': 'OTHER'}], 'responsibleParty': {'type': 'PRINCIPAL_INVESTIGATOR', 'investigatorTitle': 'Principal investigator', 'investigatorFullName': 'Sabina Schmitt-Grohe', 'investigatorAffiliation': "University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn)"}}}}