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Natural History of Granulomatosis With Polyangiitis: Clinical and Genetic Biomarkers of Airway Disease NoAAC PR-03 Study (NoAAC PR-03)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03182049
Recruitment Status : Withdrawn (Funding was not able to be secured for the study and no participants enrolled.)
First Posted : June 9, 2017
Last Update Posted : April 27, 2020
North American Airway Collaborative (NoAAC)
Vasculitis Patient Powered Research Network (VPPRN)
Vasculitis Clinical Research Consortium (VCRC)
Information provided by (Responsible Party):
Alexander Gelbard, MD, Vanderbilt University Medical Center

Brief Summary:

The ultimate goal of this prospective natural history study is to define the natural history of the obstructive airway manifestations of Granulomatosis with polyangiitis (GPA).

Additionally this proposal seeks to develop biomarkers of disease activity and define their correlation with clinical outcomes in an effort to transform clinical care and shape future drug development for this devastating rare disease.

Condition or disease Intervention/treatment
Granulomatosis With Polyangiitis Procedure: Airway assessment Procedure: Rheumatology assessment

Detailed Description:

Granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) is a rare multisystem necrotizing granulomatous vasculitis of small and medium vessels. Nearly 20% of GPA patients suffer life-threatening obstruction of their airways. Even when survived, airway involvement can render patients in this disease subset unable to communicate, struggling to breath, and dependent on a tracheostomy for survival. Airway disease frequently leads to irreversible physiologic impairment and is highly correlated with reduced quality of life in GPA.

Prior to the 1970s, patients with GPA had a 1-year mortality rate of >80%, primarily due to renal or lung failure. The introduction of combination cyclophosphamide and glucocorticoid treatment 4 decades ago greatly improved patient outcomes, turning this into a more chronic long-term disease. However, while progress has been made in the development of successful treatment regimes for systemic disease, the role of current therapies in ameliorating the airway complications of GPA is unknown. The evolution of GPA into a chronic disease has brought the management of the airway manifestations of GPA to the forefront. The natural history of the airway disease in GPA has never been longitudinally characterized, and there are no reliable biomarkers of clinical outcome.

In GPA the incidence of airway stenosis localized to the anatomic region below the vocal cord (subglottic stenosis) has been estimated to be 16%-50%. It may occur in isolation as the presenting symptom of GPA, or as a late-stage manifestation of disease. Although stenosis is frequently limited to the subglottis, it may extend up to involve to vocal cords, or down to involve the distal trachea and bronchi. Unfortunately, studies have documented a relatively high incidence of multilevel airway involvement (34%) in GPA. In one series of 44 patients, one in five had evidence of laryngeal stenosis. Studies have also found a high incidence of metachronous bronchial disease.

Laryngeal and Bronchial stenosis appear to be progressive and occur after the onset of subglottic stenosis, but the true natural history of airway involvement in GPA is unknown.

GPA is a member of the anti-neutrophil cytoplasmic antibody (ANCA) vasculitides. Given the strong association of GPA with ANCA production, much focus has been placed on understanding the mechanisms of ANCA production and pathogenesis. The factors by which ANCAs are initially generated are poorly understood. The majority of in vitro and animal model research implicating neutrophils and T cells as the principal inflammatory cells in GPA is surprising given the known impressive clinical treatment response to B cell depletion with rituximab. This discordance reinforces that the knowledge gap between pathogenesis and therapy is GPA is wide.

The distinction between focused airway disease and severe systemic disease has important therapeutic implications. The course of airway stenosis in GPA has been found to run independently of the systemic disease course and is often refractory to standard systemic therapy. In one representative case series, subglottic stenosis (SGS) was diagnosed in 49% of patients while they were receiving systemic treatment, and 56% of the patients who required tracheostomies did so despite having been treated for at least 2 months with systemic immunosuppressive agents. Developing novel therapeutics to control airway-focused GPA and prevent the development and/or progression of destructive airway damage is desperately needed.

Because of the small numbers of patients affected, and with clinical experience dispersed among a small number of clinical referral centers, the natural history of rare diseases is often poorly described. When knowledge about disease is insufficient to guide clinical development, well-designed natural history studies are critical to developing and proving the efficacy of novel therapeutics.

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Study Type : Observational
Actual Enrollment : 0 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Natural History of Granulomatosis With Polyangiitis: Clinical and Genetic Biomarkers of Airway Disease: North American Airway Collaborative (NoAAC) PR-03 Study
Estimated Study Start Date : December 2020
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : May 2023

Group/Cohort Intervention/treatment
GPA (Wegener's granulomatosis) patients Procedure: Airway assessment
Airway Specialist (Otolaryngology, Pulmonology, Thoracic Surgery), assess clinical location and degree of airway compromise, glottic mobility, and sinonasal disease.

Procedure: Rheumatology assessment
Clinically assess systemic function (renal/pulmonary ect), biochemical profile (routine labs), neurocognitive function, and completing entry BVAS tool.

Primary Outcome Measures :
  1. Time to recurrent intervention (TTR) [ Time Frame: 5 years ]
    The time between interventions aimed at preserving an open airway.

Secondary Outcome Measures :
  1. Patient Reported Outcome Measures [ Time Frame: 5 years ]
    Patient Quality of Life assessment: Voice (VHI10)

  2. Patient Reported Outcome Measures [ Time Frame: 5 years ]
    Patient Quality of Life assessment: Breathing (Clinical Dyspnea questionnaire or CDQ)

  3. Patient Reported Outcome Measures [ Time Frame: 5 years ]
    Patient Quality of Life assessment: Eating (EAT10)

  4. Patient Reported Outcome Measures [ Time Frame: 5 years ]
    Patient Quality of Life assessment: general quality of life (SF12)

  5. Disease Assessment clinical tool [ Time Frame: 5 years ]
    Birmingham Vasculitis Activity Score (BVAS)

Biospecimen Retention:   Samples With DNA

We plan to obtain a small amount of blood at a time when other medically indicated labs, operative or office-based procedures occur.

Excess tissue obtained at standard of care surgical biopsy will be preserved for molecular study.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Adult Granulomtosis with Polyangiitis Population Affected by Obstructive Airway Disease patients are eligible for enrollment.

Inclusion Criteria:

  • Greater than or equal to 18 years of age.
  • Stenotic Airway Disease (laryngeal, subglottic, distal tracheal or bronchial)

Exclusion Criteria:

  • <18years of age
  • Patients without capacity to consent for themselves
  • History of significant laryngotracheal traumatic injury.
  • Endotracheal intubation 2 years prior to presentation.
  • Major anterior neck surgery.
  • History of neck irradiation.
  • History of caustic or thermal injury to the laryngotracheal complex.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03182049

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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University Medical Center
North American Airway Collaborative (NoAAC)
Vasculitis Patient Powered Research Network (VPPRN)
Vasculitis Clinical Research Consortium (VCRC)
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Principal Investigator: Alexander Gelbard, MD Vanderbilt University Medical Center
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Responsible Party: Alexander Gelbard, MD, Assistant Professor, Department of Otolaryngology, Vanderbilt University Medical Center Identifier: NCT03182049    
Other Study ID Numbers: 161780
First Posted: June 9, 2017    Key Record Dates
Last Update Posted: April 27, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alexander Gelbard, MD, Vanderbilt University Medical Center:
Granulomatosis with polyangiitis
Wegener's granulomatosis
Subglottic Stenosis
Bronchial Stenosis
Additional relevant MeSH terms:
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Granulomatosis with Polyangiitis
Systemic Vasculitis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Autoimmune Diseases
Immune System Diseases