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History of Changes for Study: NCT03141814
Asthma Origins and Remission Study
Latest version (submitted July 12, 2017) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 May 3, 2017 None (earliest Version on record)
2 July 12, 2017 Recruitment Status, Eligibility, Study Status, Groups and Interventions, Study Design and Study Identification
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Study NCT03141814
Submitted Date:  May 3, 2017 (v1)

Open or close this module Study Identification
Unique Protocol ID: NL2015001
Brief Title: Asthma Origins and Remission Study
Official Title: A Better Understanding of Molecular Mechanisms Leading to Asthma and Its Remission
Secondary IDs:
Open or close this module Study Status
Record Verification: May 2017
Overall Status: Recruiting
Study Start: October 2015
Primary Completion: October 2018 [Anticipated]
Study Completion: October 2018 [Anticipated]
First Submitted: May 3, 2017
First Submitted that
Met QC Criteria:
May 3, 2017
First Posted: May 5, 2017 [Actual]
Last Update Submitted that
Met QC Criteria:
May 3, 2017
Last Update Posted: May 5, 2017 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: University Medical Center Groningen
Responsible Party: Principal Investigator
Investigator: Maarten van den Berge
Official Title: MD PhD
Affiliation: University Medical Center Groningen
Collaborators: GlaxoSmithKline
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: No
Open or close this module Study Description
Brief Summary:

Asthma is characterized by chronic airway inflammation of the large and small airways. Asthma patients often have episodes with symptoms of dyspnea, wheezing and nocturnal awakening. Currently available inhaled anti-inflammatory treatments reduce the airway inflammation and treatment but do not cure the disease. Therefore asthma patients often need life-long treatment to control their asthma.

In a small subset of patients, their asthma resolves spontaneously. This phenomenon is called asthma remission. Subjects with asthma remission do not experience symptoms or signs of airway inflammation anymore and do not require inhaled treatments. Some subjects with asthma remission also have a completely normal lung function without signs of bronchial hyperresponsivess: they have complete asthma remission. Unfortunately, asthma remission occurs only in a small subset of 15-25% of asthma patients.Objective: to determine the underlying mechanisms and molecular events leading to remission of asthma.

Detailed Description:

Rationale: Asthma inception occurs only in susceptible individuals, and is often triggered by specific environmental factors, such as respiratory viruses and aeroallergens. Although asthma is generally viewed as a chronic persistent disease, remission of asthma is possible in a subset of patients. This is highly relevant, since understanding mechanisms that contribute to asthma inception and remission may teach us how asthma can be stopped and thus may provide novel avenues for the treatment of asthma. In adulthood, average remission rates of asthma are approximate 2% per year 1. We observed that remission in adulthood is more likely with earlier onset of asthma, less airway obstruction, more severe bronchial hyperresponsiveness, and smoking cessation. A proper definition of remission is very important; we therefore introduced the terms 'clinical remission' and 'complete remission' 2. Clinical remission was defined as the absence of asthma symptoms and no use of asthma medication, complete remission as the absence of asthma symptoms, no use of asthma medication, normal lung function and no bronchial hyperresponsiveness. In a longitudinal study of 119 allergic asthmatic children followed-up for 30 years, our group found that clinical remission occurred in 30% and complete remission in 22% of all cases.

Objective: to determine the underlying mechanisms and molecular events involved in the inception and remission of asthma.

Methods: We will include a 40 subjects divided over the following 4 groups: i) clinical asthma remission (10 subjects), ii) complete asthma remission (10 subjects), iii) ongoing asthma (10 patients), iv) non-asthmatic healthy controls (10 subjects) in a cross-sectional study. All subjects will be extensively clinically characterized including respiratory symptoms/questionnaires, in- and expiratory CT-scans, and parameters of large and small airway function and inflammation. In addition, blood and nasal epithelial brushes will be obtained to study the genetic and epigenetic mechanisms of asthma remission. Finally, bronchoscopy with bronchial biopsies and brushes will be performed under conscious sedation. Bronchial biopsies from all four patient groups will be used for index FACS sorting of the three most important cell types orchestrating the asthmatic inflammatory process: i.e. B lymphocytes, CD4+ T cells and CD8+ T cells. We will perform single cell whole-genome transcriptome sequencing on at least 100 cells of each type and the primary outcome of the study is to identify how the transcriptomic profile of bronchial epithelial cells is changed between asthma patients and healthy controls as a consequence of asthma inception and what transcriptomic profile changes occur in CD4+ CD8+ and B lymphocytes in the airways from subjects with asthma remission compared to patients with ongoing asthma and healthy controls.

Open or close this module Conditions
Conditions: Asthma
Keywords:
Open or close this module Study Design
Study Type: Observational
Observational Study Model: Case-Control
Time Perspective: Prospective
Biospecimen Retention: Samples With DNA
Biospecimen Description: blood sputum bronchial biopsies bronchial brushes nasal brushes particles in exhaled air
Enrollment: 40 [Anticipated]
Number of Groups/Cohorts 4
Open or close this module Groups and Interventions
Groups/Cohorts Interventions
asthma
10 patients with ongoing ashma
complete asthma remission
10 subjects with complete asthma remission
clinical asthma remission
10 subjects with clinical asthma remission
non-asthmatic healthy controls
10 subjects without respiratory symptoms and normal lung function and no bronchial hyperresponsiveness to methacholine and/or AMP
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Single cell sequencing data
[ Time Frame: baseline ]

Single cell mRNA sequencing of lymphocytes in bronchial biopsies and blood eosinophils
Secondary Outcome Measures:
1. Spirometry
[ Time Frame: baseline ]

FEV1, FVC, FEV1/FVC, FEF25-75.
2. body box
[ Time Frame: baseline ]

RV, RV/TLC, FRC, IC, ERV
3. HRCT
[ Time Frame: baseline ]

emphysema and small airways disease
4. Airway inflammation
[ Time Frame: baseline ]

Sputum, blood, biopsy inflammatory cell counts, exhaled nitric oxide, small particles in exhaled breath
5. Small airways disease
[ Time Frame: baseline ]

Multiple breath nitrogen washout: LCI, Sacin, Scond
6. genetic and genome-wide mRNA, non-coding RNA, and DNA methylation
[ Time Frame: baseline ]

assessed in bronchial and nasal epithelial brushes, biopsies and blood
Open or close this module Eligibility
Study Population:
  • 10 patients with a documented history of asthma who have clinical asthma remission.
  • 10 patients with a documented history of asthma who have complete asthma remission.
  • 10 patients with current asthma.
  • 10 healthy subjects.
Sampling Method: Non-Probability Sample
Minimum Age: 18 Years
Maximum Age: 55 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: Yes
Criteria:

Inclusion criteria for all subjects:

  • Age between 18 and 55 years old.
  • Smoking history ≤ 10 packyears.

Specific inclusion criteria for the 4 different groups:

  • Group 1. Subjects with clinical asthma remission:
    • Documented history of asthma diagnosed according to latest GINA guidelines, i.e. respiratory symptoms and either bronchodilator reversibility (improvement in FEV1 of more than 12% of baseline (and at least 200 mL) after inhalation of 800 µg salbutamol.
    • No use of asthma medications such as inhaled or oral corticosteroids, β2-agonists or anticholinergics.
    • No symptoms of wheeze or asthma attacks during the last 3 years.
  • Group 2. Subjects with complete asthma remission
    • Documented history of asthma diagnosed according to latest GINA guidelines, i.e. respiratory symptoms and either bronchodilator reversibility (improvement in FEV1 of more than 12% of baseline (and at least 200 mL) after inhalation of 800 µg salbutamol.
    • No use of asthma medications such as inhaled or oral corticosteroids, β2-agonists or anticholinergics.
    • No symptoms of wheeze or asthma attacks during the last 3 years.
    • FEV1 > 90% predicted.
    • Absence of bronchial hyperresponsiveness, i.e. both PC20 methacholine > 8 mg/ml and PC20 AMP > 320 mg/ml.
  • Group 3. Patients with ongoing asthma
    • Documented history of asthma diagnosed according to latest GINA guidelines, i.e. respiratory symptoms and either bronchodilator reversibility (improvement in FEV1 of more than 12% of baseline (and at least 200 mL) after inhalation of 800 µg salbutamol.
    • Use of inhaled corticosteroids or Either persistent symptoms of wheeze, cough, or dyspnea or regular use of β2 agonists at least once a week during the last 2 months.
    • PC20 methacholine < 8 mg/ml.
  • Group 4. Non-asthmatic controls
    • No history of asthma.
    • No use of inhaled corticosteroids or β2-agonists for a period longer than 1 month.
    • No symptoms of wheeze, nocturnal dyspnea, or bronchial hyperresponsiveness.
    • PC20 methacholine > 8 mg/ml, FEV1/FVC > 70% and FEV1 > 80% predicted.
Open or close this module Contacts/Locations
Central Contact Person: Maarten van den Berge, MD, PhD
Telephone: +31-50-3615260
Email: m.van.den.berge@umcg.nl
Central Contact Backup: Martijn Nawijn, PhD
Telephone: +31-50-3610998
Email: m.nawijn@umcg.nl
Study Officials: Maarten van den Berge, MD PhD
Principal Investigator
University Medical Center Groningen
Locations: Netherlands
UMCG
[Recruiting]
Groningen, Netherlands, 9713
Contact:Contact: Huib AM Kerstjens, prof. dr. +31 50 3610280 h.a.m.kerstjens@umcg.nl
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations:
Links:
Available IPD/Information:

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