Nasal Nitric Oxide Across Mutations in Primary Ciliary Dyskinesia

Primary Ciliary Dyskinesia Clinical Trial

— nNO_PCD  

Official title:

High or Low. Nasal Nitric Oxide Across Mutations in Primary Ciliary Dyskinesia. A Genotype/Phenotype Analysis of Nasal NO in Patients With PCD Within the European Reference Network (ERN)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04949308
• Other study ID #: JR_nNO_PCD_09_2020
• Status: Recruiting
• Start date: January 1, 2021
• Est. completion date: December 31, 2022

Study information

• Verified date: June 2021
• Source: University Hospital Muenster
• Contact: Johanna Raidt, MD
• Phone: +49 251 83 40003
• Email: Johanna.Raidt[@]ukmuenster.de
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by dysfunction of motile cilia associated with recurrent infections of the airways, laterality defects (Situs inversus totalis in about 50% of cases) and fertility problems. At present, mutations in > 45 genes associated with PCD and mucociliary clearance disorders have been identified, representing most likely two thirds of all human cases.

The aims of this study are:

1. Correlation between nasal NO levels and distinct PCD genotypes

2. Determination of further parameters potentially associated with nasal NO levels in genotyped PCD individuals

1. course of clinical manifestations (e.g. neonatal distress, infections, bronchiectasis)

2. diagnostic results (HVMA, TEM, IF)

3. lung function outcome (FVC, FEV1)

Description:

Nasal Nitric Oxide (nNO) concentration is usually low or very low in patients with Primary Ciliary Dyskinesia (PCD) for yet unknown reasons (1).

Measured nNO holds a strong ability to separate healthy subjects from patients with PCD in both childhood and adulthood and across several different nNO sampling modalities (2) (3-5) and nNO is widely used as an important supplementary diagnostic test for PCD work up in both Europe (6) and North America (7). Low nNO in PCD was first reported 26 years ago (8). Nasal NO has been associated with host paranasal sinus defense as sufficient nNO production in non-PCD subjects is thought to play a role in maintaining paranasal sinus sterility (9). Furhermore, ciliary beating seems to be upregulated by a NO dependent pathway in bovine airway epithelium (10), influencing mucociliary clearance. However, human in vitro studies of ciliated airway cells in air-liquid-interface (ALI) culture have been ambiguous as to whether the biosynthesis of NO in PCD is impaired (11) (12) or not (13; 14) and the etiology of low nNO in PCD and presumed link to ciliary beating remains unclear. So far, attempts to link PCD phenotype and genotype has indicated that patients with PCD harboring CCDC39 and CCDC40 mutations may have a poorer lung function development (15).

In rare cases of PCD (<5%) (16) nNO concentration is within normal range. More than 14 different PCD-causing genes (e.g RSPH1, GAS8, RPGR, CCNO, CCDC103, CFAP221, DNAH9, FOXJ1, GAS2L2, LRRC56, NEK10, SPEF2, STK36, TTC12) has been associated with nNO values above the agreed cut off for nNO-production rate of 77 nL/min in a few patients with PCD (16). However, individuals with NEK10 or FOXJ1 mutations, for example, display a very severe respiratory phenotype (17), but making a diagnosis is challenging because of normal nNO values as well as apparently normal ciliary beating.

Since nNO also holds potential as an outcome parameter in future clinical trials of PCD, better understanding of nNO in PCD is warranted.

Demand of large number of patients with PCD is crucial, keeping the rareness of nearnormal and normal nNO levels in PCD in mind. Motivated by the analysis of lung function in a large cohort of genotyped PCD-patients, this multicenter Involvement across international PCD centers is an obvious opportunity for gaining such further knowledge with the focus on nasal NO.

The aims of this study are:

1. Correlation between nasal NO levels and distinct PCD genotypes

2. Determination of further parameters potentially associated with nasal NO levels in genotyped PCD individuals

1. course of clinical manifestations (e.g. neonatal distress, infections, bronchiectasis)

2. diagnostic results (HVMA, TEM, IF)

3. lung function outcome (FVC, FEV1)

Inclusion criteria:

1. Patients with a genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD

2. PCD individuals of all age groups with at least one nNO measurement performed according to diagnostic guidelines. Serial nNO measurements should be included if available (e.g. yearly), at least for infants and young children

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2000
• Est. completion date: December 31, 2022
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

1. Patients with a genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD

2. PCD individuals of all age groups with at least one nNO measurement performed according to diagnostic guidelines. Serial nNO measurements should be included if available (e.g. yearly), at least for infants and young children

Exclusion Criteria:

-

Related Conditions & MeSH terms

• Ciliary Motility Disorders
• Dyskinesias
• Primary Ciliary Dyskinesia

Locations

Country	Name	City	State
Germany	University Hospital Münster	Münster	NRW

Sponsors (37)

Lead Sponsor

Collaborator

University Hospital Muenster

Abderrahmane Mami Hospital, Bambino Gesù Hospital and Research Institute, Charite University, Berlin, Germany, Federico II University, Göteborg University, Hacettepe University, Hadassah Medical Organization, Hannover Medical School, Hospital de Niños R. Gutierrez de Buenos Aires, Hospital Vall d'Hebron, KU Leuven, Marmara University, Medical University of Vienna, NOVA Medical School, Oslo University Hospital, Rigshospitalet, Denmark, Royal Brompton & Harefield NHS Foundation Trust, Ruhr University of Bochum, Schneider Children's Medical Center, Israel, The Leeds Teaching Hospitals NHS Trust, University Children's Hospital, Zurich, University College, London, University Hospital of Cologne, University Hospital, Martin, University Hospital, Motol, University of Belgrade, University of Bern, University of Dundee, University of Geneva, Switzerland, University of Leicester, University of Nicosia, University of Pisa, University of Sao Paulo, University of Southampton, University of Valencia, VU University Medical Center

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Genotype-nasal Nitric Oxide Corelation	nNO in correlation to the genetic make-up	up to 20 years retrospective