Longitudinal Observational Study on the Course of Cystic Fibrosis Lung Disease in Patients Following Newborn Screening (TRACK-CF)

The purpose of this study is to further characterize early CF lung disease in newborns, infants and toddlers with cystic fibrosis (CF).

Study Overview

• Status: Recruiting
• Conditions: Cystic Fibrosis Lung Disease

Detailed Description

Cystic fibrosis (CF) is the most common lethal genetic multisystem disease in Germany. Although life expectancy increased over the last decades, most of the CF patients die in young adulthood due to chronic CF lung disease with respiratory failure. CF lung disease is caused by a disturbed transport of salt and water by airway epithelia and dehydration of airway surfaces as a result of the underlying genetic defect in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gen. Up to now, no causal therapies for the majority of patients with CF are available. Little is known about onset and natural course as well as influencing factors of CF lung disease. Therefore, the first aim of this prospective, multicenter, uncontrolled, non-randomized, explorative longitudinal study is characterization of the onset and early course of CF lung disease. For this reason we will primarily include patients diagnosed by CF newborn screening (CF-NBS) or for any other reason in the first four months of life (early diagnosed, ED). In a second step we will compare data from these patients to those diagnosed clinically later in life (late diagnosed, LD). This will allow us to investigate the effect of early diagnosis and start of therapy. Starting at diagnosis, we will use data from annual routine check-ups (imaging like chest MRI, pulmonary function tests, microbiology from swabs and sputum, laboratory values, anthropometry) as well as data from a facultative, study-related bronchoscopy with lavage (microbiology, inflammation and immunology) for correlation with the course of CF lung disease (generation of hypotheses). Further study-related investigations are monthly telephone interviews on bronchopulmonary symptoms by a study nurse on the basis of a questionnaire and quarterly assessment of health-related quality of life on the basis of a validated questionnaire.

We expect to gain a deeper insight into onset and early course of CF lung disease from the results of this study. So far, there is no trial that investigated the different aspects of CF lung disease (function, morphology, infectiology, inflammation) complementary in a longitudinal setting. We assume that knowledge on the natural history of CF lung disease in the vulnerable phase of early childhood has a great impact on the future development of new therapies (from symptomatic to causal). This shall lead to a further improvement in life expectancy and quality of life of patients with CF.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Mirjam Stahl, MD; Phone Number: +49 6221 56 37049; Email: Mirjam.Stahl@med.uni-heidelberg.de
• Study Contact Backup: Name: Marcus A Mall, MD; Phone Number: +49 6221 56 4502; Email: Marcus.Mall@med.uni-heidelberg.de

Study Locations

• Germany
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Recruiting
      • University Children's Hospital Heidelberg, Cystic Fibrosis Centre
      • Contact: Mirjam Stahl, MD; Phone Number: +49 6221 56 37049; Email: Mirjam.Stahl@med.uni-heidelberg.de
      • Principal Investigator: Olaf Sommerburg, MD
      • Contact: Marcus A Mall, MD; Phone Number: +49 6221 56 4502; Email: Marcus.Mall@med.uni-heidelberg.de
      • Principal Investigator: Marcus A Mall, MD
      • Sub-Investigator: Mirjam Stahl, MD
      • Sub-Investigator: Simon Y Gräber, MD
      • Sub-Investigator: Susanne Hämmerling, MD
  • Hessen
    • Gießen, Hessen, Germany, 35392
      • Recruiting
      • University Hospital Giessen and Marburg GmbH
      • Contact: Lutz Nährlich, MD; Phone Number: +49 (0) 641 985-57621; Email: lutz.naehrlich@paediat.med.uni-giessen.de
      • Principal Investigator: Lutz Nährlich, MD
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Recruiting
      • Medizinische Hochschule Hannover
      • Contact: Christian Dopfer, MD; Phone Number: +49 (0)1761 532 3325; Email: dopfer.christian@mh-hannover.de
      • Principal Investigator: Christian Dopfer, MD
  • Schleswig-Holstein
    • Lübeck, Schleswig-Holstein, Germany, 23538
      • Recruiting
      • University Children's Hospital Schleswig-Holstein
      • Contact: Matthias V Kopp, MD; Phone Number: +49 (0) 451 5002550; Email: matthias.kopp@uksh.de
      • Principal Investigator: Matthias V Kopp, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with CF diagnosed in the first 4 months of life (corrected age of 4 months in preterms) not before January 1st, 2006 build up the early diagnosed (ED) group. Early identification can be achieved by newborn screening, clinical diagnosis (e.g. patients with meconium ileus), due to positive family history or prenatal diagnosis. Patients with CF diagnosed after the first 4 months of life and after January 1st, 2006, are included as a comparison group with clinically diagnosed patients (late diagnosed, LD). Both groups (ED and LD) are investigated after the same investigational plan with all investigations that are part of the annual check-up and additional, study-related monthly telephone interviews on bronchopulmonary symptoms, quarterly assessment of QoL and voluntarily yearly bronchoscopy with broncho-alveolar lavage.

Description

Inclusion Criteria:

1. Newly diagnosed patients with Cystic Fibrosis (CF). Diagnosis of CF: at least one of the following three international accepted criteria is fulfilled: i) sweat chloride ≥ 60mEq/L and/or ii) 2 CF-causing mutations in the CFTR gene and/or iii) changes typical for CF in the transepithelial potential difference in nasal or rectal epithelium.

2. Age and mode of diagnosis:

   • Early diagnosed (ED): Initial diagnosis following CF-NBS or for other reasons in the first 4 months of life (in preterms corrected age of 4 months) after January 1st, 2006. Other reasons could be prenatal diagnostics, meconium ileus or positive family history.
   • Late diagnosed (LD): Diagnosed after the fourth month of life due to clinical symptoms; initial diagnosis after January 1st, 2006.

Exclusion Criteria:

All patients are excluded who themselves or whose parents do not want to participate or that withdraw from the study; or those in whom the diagnosis of CF is unsure.

Further exclusion criteria are:

1. Preterms <30th week of gestation
2. Longer period of mechanical ventilation in first 3 months of life
3. A significant medical disease or condition other than CF likely to interfere with the child's ability to complete the entire protocol
4. Previous major surgery except for meconium ileus or atresia of the intestine
5. Other major organ dysfunction, excluding pancreatic or hepatic dysfunction or another condition due to CF
6. Physical findings that would compromise the safety of the subject or the quality of the study data as determined by investigator
7. Chronic lung disease other than CF (e.g. bronchopulmonary dysplasia)
8. History of adverse reaction to medication for sedation or known claustrophobia

Criteria, which lead to a displacement of the procedures in sedation until the child has recovered: - Clinically significant upper airway obstruction as determined by investigator (e.g.

severe laryngomalacia, markedly enlarged tonsils, significant snoring, diagnosed obstructive sleep apnoea)

- Severe gastroesophageal reflux, defined as persistent frequent emesis despite anti-reflux therapy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Early diagnosed (ED); Children diagnosed with CF in the first 4 months of life.
Late diagnosed (LD); Children diagnosed with CF after the first 4 months of life.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion with morphological and/or perfusion changes due to CF lung disease after chest MRI score in both groups	At age of 1, 2, 3, ...., 10 years of age
Proportion of patients with impairments in pulmonary function tests (e.g. multiple breath washout (MBW)) in both groups	At age of 1, 2, 3, ...., 10 years of age

Secondary Outcome Measures

Outcome Measure	Time Frame
Rate of protocol-defined pulmonary exacerbations in both groups (ED vs. LD) that are necessitating an antibiotic therapy orally, intravenously or per inhalation	At age of 1, 2, 3, ...., 10 years of age
Spontaneous development of infection or spectrum of pathogens, respectively, in throat and nose swabs as well as other airway secretions from routine diagnostics and if applicable bronchoalveolar lavage fluid (BALF)	At age of 1, 2, 3, ...., 10 years of age
From the patients in whom PsA or other CF pathogens could not be isolated at the beginning of their participation, comparison of the portion of patients with a positive culture during participation in both groups (ED and LD)	At age of 1, 2, 3, ...., 10 years of age
Time to first detection of a CF pathogen in both groups	At age of 1, 2, 3, ...., 10 years of age
Time to first pulmonary exacerbation in both groups	At age of 1, 2, 3, ...., 10 years of age
Portion of patients with increased biochemical inflammatory markers in both groups and magnitude of elevation	At age of 1, 2, 3, ...., 10 years of age
Frequency of symptoms from monthly telephone interviews in both groups	At age of 1, 2, 3, ...., 10 years of age
Health-related quality of life in both groups quarterly via Cystic Fibrosis Questionnaire (CFQ)	At age of 1, 2, 3, ...., 10 years of age
Development of body weight, body height, ideal weight-for-height (IWFH), Body-Mass-Index (BMI), respiratory rate and oxygen saturation at room air in both groups	At age of 1, 2, 3, ...., 10 years of age
Proportion with morphological changes due to CF lung disease after modified Chrispin-Norman Score for assessment of chest X-ray in both groups	At age of 1, 2, 3, ...., 10 years of age
Magnitude and severity of alterations typical for CF by assessment with chest MRI and X-ray score in both groups	At age of 1, 2, 3, ...., 10 years of age
Magnitude of impairment of pulmonary function test in both groups	At age of 1, 2, 3, ...., 10 years of age

Collaborators and Investigators

• Sponsor: Heidelberg University
• Collaborators: German Center for Lung Research
• Investigators: Principal Investigator: Marcus A Mall, MD, University Hospital Heidelberg

Publications and helpful links

General Publications

• Stahl M, Steinke E, Graeber SY, Joachim C, Seitz C, Kauczor HU, Eichinger M, Hammerling S, Sommerburg O, Wielputz MO, Mall MA. Magnetic Resonance Imaging Detects Progression of Lung Disease and Impact of Newborn Screening in Preschool Children with Cystic Fibrosis. Am J Respir Crit Care Med. 2021 Oct 15;204(8):943-953. doi: 10.1164/rccm.202102-0278OC.
• Stahl M, Wielputz MO, Graeber SY, Joachim C, Sommerburg O, Kauczor HU, Puderbach M, Eichinger M, Mall MA. Comparison of Lung Clearance Index and Magnetic Resonance Imaging for Assessment of Lung Disease in Children with Cystic Fibrosis. Am J Respir Crit Care Med. 2017 Feb 1;195(3):349-359. doi: 10.1164/rccm.201604-0893OC.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: October 16, 2014
• First Submitted That Met QC Criteria: October 16, 2014
• First Posted (Estimated): October 21, 2014

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Children; Cystic Fibrosis; Infant; Toddler; Newborn screening
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Lung Diseases, Interstitial; Fibrosis; Lung Diseases; Pulmonary Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: UKH-TRACK-1