Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
|First Received Date ICMJE||August 23, 2006|
|Last Updated Date||June 19, 2013|
|Start Date ICMJE||July 2006|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE||Not Provided|
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00368446 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease|
|Official Title ICMJE||Genetic Disorders of Mucociliary Clearance|
Healthy volunteers and patients with diseases that involve problems clearing mucus from the lungs will be examined and tested to better understand the reasons for recurring lung infections in these patients and to try to develop better ways to diagnose and treat them. The study will also try to identify the genes responsible for these diseases.
Healthy volunteers 18 years of age and older and patients 2 years of age or older with suspected primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF) or pseudohypoaldosteronism (PHA) may be eligible for this study. Patients enrolled in the Natural History Study of Nontuberculous Mycobacteria at NIH or other NIH natural history protocols may also be enrolled. Participants undergo the following tests and procedures during a 1-day visit at the NIH Clinical Center, as follows:
All patients and normal volunteers have the following procedures:
All patients have the following additional procedures:
Patients suspected of having a variant of CF or PHA, including nontuberculous mycobacterial lung disease, have the following additional procedures:
Background: Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that have been increasingly associated with human disease, commonly involving the lung. Post menopausal Caucasian women seem particularly predisposed to the development of peripheral nodules and dilated airways (bronchiectasis) associated with these organisms. These women have distinguishing body characteristics of being taller and thinner than age and gender matched controls yet have no identifiable systemic immune defects. There is, however, considerable overlap with genetic disorders of mucociliary clearance such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). The Genetic Diseases of Mucociliary Clearance Consortium (GDMCC) is one of 10 consortia in the Rare Diseases Clinical Research Network formed under the Office of Rare Diseases in collaboration with NCRR, NICHD, NINDS, NIAMS, NIDDK, NHLBI in response to the Rare Diseases Act of 2002. The GDMCC is comprised of 5 geographically-dispersed clinical research sites that are designed to study rare diseases which involve defects in clearance of mucus secretions from the airways (defective "mucociliary clearance"). These sites will collaborate in diagnostic, genetic, and other studies in patients with impairments of mucociliary clearance, including primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). These studies are also applicable to diseases where altered airways clearance may play a primary or contributory role such as nontuberculous mycobacterial lung disease, chronic granulomatous disease, and the hyper-IgE syndromes. Disorders such as PCD, CF, and PHA reflect genetic defects in airway host-defense, and typically result in chronic infection of the airways. Patients with these disorders of the conducting airways and sinuses have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. These patients may also have sub-optimal management of their clinical disease, because the cause of these disorders is not well-defined, and treatment regimens are usually not driven by evidence-based medicine.
Aims: The major aim of this study is to employ a systematic approach to the diagnostic and functional evaluation of these patients with chronic airways disease in individual patients, better define host susceptibility to infections from environmental organisms such as the nontuberculous mycobacteria, and potentially lead to the development of better diagnostic techniques, including genetic testing. In addition, we will compare/contrast clinical features (phenotype) across these disorders. A rigorous cross-sectional comparison of the clinical features will provide better understanding of the clinical disease of these disorders; in turn this will lead not only to a better standard of clinical care, but will also assist in the identification of novel therapeutic approaches.
Methods: This is a cross-sectional diagnostic / mechanistic protocol to investigate airway host-defenses. The patient populations for these studies include individuals with recurring airway infections such as those with nontuberculous mycobacteria lung disease who may have defective airway host defenses as a predisposing factor, individuals carrying a tentative diagnosis of the three known genetic disorders of mucociliary clearance (PCD, variant CF, or PHA), and individuals suspected to have one of these disorders but with inadequate or inconclusive diagnostic tests. Individuals in this latter category must have a preliminary clinical evaluation to evaluate for other more common disorders that may have similar manifestations including classical CF, immunodeficiency, asthma, and severe gastroesophageal reflux. The evaluation will include a detailed assessment of clinical features; specialized laboratory measurements such as nasal potential difference to evaluate the function of chloride and sodium channels associated with CF and PHA, nasal biopsy specimens and nasal nitric oxide measurements to assess cilia structure and function which are abnormal in PCD; and genetic studies to identify disease - causing mutations in genes associated with CF, PCD, and PHA.
|Study Type ICMJE||Observational|
|Study Design ICMJE||Time Perspective: Prospective|
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Not Provided|
|Study Population||Not Provided|
|Intervention ICMJE||Not Provided|
|Study Group/Cohort (s)||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
Overview: Inclusion criteria reflect the two-fold purpose of this protocol. It is primarily intended to evaluate the cohort of patients followed at the NIH Clinical Center under Protocol 01-I-0202, Natural History, Genetics, Phenotype, and Treatment of Mycobacterial Infections, and in this regard, the inclusion criteria mirror those of that protocol. Secondly it is part of the multicenter collaborative protocol as a participating site in the Genetic Disorders of Mucociliary Clearance Consortium, one of the Rare Disease Clinical Consortia sponsored by the Office of Rare Diseases. There is a clear-cut need for geographically dispersed centers to have expertise in the diagnostic evaluation and treatment of patients with rare diseases of the airways, including patients with suspected PCD, non-classical or variant CF, and PHA. The 5 sites will perform rigorous diagnostic evaluations utilizing innovative, but standardized methods (SOPs contained in Manual of Operations). As a participating site in the Consortium, we will cast a broad net to include as many participants as feasible. This will include a multi-center standardized diagnostic evaluation and clinical evaluation, giving us a better chance to define the clinical spectrum of disease.
The criteria for participants to enter this study mandates that each patient either be enrolled in the 01-I-0202, Natural History, Genetics, Phenotype, and Treatment of Mycobacterial Infections or related NIH Natural History Protocol, or if referred as part of the Consortium, have received a standard (current clinical practice) diagnostic evaluation that includes testing for asthma, severe gastroesophageal reflux and/or classic CF, prior to enrolling in the Consortium study. Healthy adult control participants will be enrolled for comparison assessment of noninvasive nasal nitric oxide and nasal potential difference measurements only. The health status of these control participants will be assessed with the standardized clinical history, family history, physical exam including height and weight, vital signs, oximetry, and spirometry measurements.
To enter the study, individuals with a suspected mucociliary clearance defect (n=100) must be age 2 years or older and meet one of the 4 following profiles:
To enter the study as a healthy control (n=25), individuals must be age 18 or older and free of any known disease, chronic medical conditions, family history of cystic fibrosis or primary ciliary dyskinesia, or any cognitive impairment or significant disability that might preclude voluntary consent or the ability to safely comply with the instructions or sit through the testing.
Persons who cannot be evaluated at the Clinical Center or who have severe cognitive impairment or other severe disability that precludes the ability to understand instructions or sit/lie still for the evaluation will be excluded. Certain conditions may preclude specific procedures included in the protocol, but may still allow pertinent parts of this diagnostic evaluation. These conditions/procedures may include: pregnancy/Chest PA/Lat x-ray; allergy to pilocarpine /sweat testing. For reversible conditions such as acute upper airway infection, significant epistaxis within the prior week (not related to #2 below), or lower airway infection with uncontrollable coughing, the participant may need to be rescheduled upon resolution.
For nasal nitric oxide and nasal potential difference measurements or nasal mucosal scrape biopsies:
|Ages||2 Years and older|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00368446|
|Other Study ID Numbers ICMJE||060217, 06-I-0217|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||National Institute of Allergy and Infectious Diseases (NIAID)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||June 2013|
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