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

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Brief Title

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

Official Title

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

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.

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

      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

      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

      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.

Study Type


Primary Outcome

Time to recurrent intervention (TTR)

Secondary Outcome

 Patient Reported Outcome Measures


Granulomatosis With Polyangiitis


Airway assessment

Study Arms / Comparison Groups

 GPA (Wegener's granulomatosis) patients


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

December 2020

Completion Date

May 2023

Primary Completion Date

May 2022

Eligibility Criteria

        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.




18 Years - N/A

Accepts Healthy Volunteers



Alexander Gelbard, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

Vanderbilt University Medical Center


 North American Airway Collaborative (NoAAC)

Study Sponsor

Alexander Gelbard, MD, Principal Investigator, Vanderbilt University Medical Center

Verification Date

August 2020