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Early Detection and Management of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation

This study is currently recruiting participants.
Verified March 2017 by Jennifer Schneiderman, MD, Ann & Robert H Lurie Children's Hospital of Chicago
Sponsor:
ClinicalTrials.gov Identifier:
NCT03072849
First Posted: March 7, 2017
Last Update Posted: March 7, 2017
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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Jennifer Schneiderman, MD, Ann & Robert H Lurie Children's Hospital of Chicago
  Purpose
This study aims to determine whether or not early spirometric detection and management of obstructive lung disease with combined fluticasone/azithromycin/montelukast therapy (FAM) can attenuate declining lung function, prevent the development of bronchiolitis obliterans, and improve patient outcomes following hematopoietic stem cell transplant.

Condition Intervention
Bronchiolitis Obliterans Syndrome Procedure: Pulmonary function testing Drug: FAM Therapy

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Early Detection and Management of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation

Resource links provided by NLM:


Further study details as provided by Jennifer Schneiderman, MD, Ann & Robert H Lurie Children's Hospital of Chicago:

Primary Outcome Measures:
  • Lung function [ Time Frame: 2 years ]
    Change in lung function at 12 and 24 months post-HSCT

  • Survival [ Time Frame: 2-4 years ]
    Overall survival at 2 years post-HSCT


Secondary Outcome Measures:
  • Risk factor assessment [ Time Frame: 2 years ]
    To identify risk factors for the development of BOS


Estimated Enrollment: 40
Study Start Date: April 2015
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Stem Cell Transplant Recipients
Pediatric patients ages 6-18 years who have received allogenic hematopoietic stem cell transplant for any reason.
Procedure: Pulmonary function testing
Each enrolled patient will receive pulmonary function testing every three months. Pulmonary function testing includes spirometry, plethysmography, and diffusion capacity measurements.
Other Names:
  • PFT
  • Spirometry
  • Plethysmography
  • Diffusion capacity
Drug: FAM Therapy
All patients who have evidence of early airflow obstruction on pulmonary function testing will be started on FAM therapy. Early airflow obstruction is defined by a FEV1 decline of ≥10% predicted in addition to a FVC <0.8.
Other Names:
  • Fluticasone (Inhaled)
  • Azithromycin
  • Montelukast

Detailed Description:

Bronchiolitis obliterans syndrome (BOS) is an inflammatory condition of the lungs that leads to obstructive physiology, irreversible fibrosis of terminal bronchioles, and obliteration of the small airways. In both children and adults, the prevalence of BOS is approximately 6% in those with chronic graft-vs-host disease (cGVHD), although this may be a gross underestimation given current diagnostic guidelines. Once diagnosed, the prognosis is extremely unfavorable. BOS carries a mortality rate of approximately 40-60%, with a five year survival rate of 13%.

Early on, BOS is symptomatically silent. Once symptoms are present, there is a high likelihood of irreversible disease regardless of the combination of immune suppression used. Given these circumstances, early diagnosis is of utmost importance, and can be characterized by an isolated and subclinical decline in lung function. Recent studies have suggested that early decline in lung function on pulmonary function testing (PFT) may be representative of developing BOS.

Due to the lack of consistent screening and diagnostic criteria, many patients with evolving BOS elude a timely diagnosis, thereby jeopardizing their chance of survival. In response, several experts have recommended frequent PFT screening and a modified, less stringent set of diagnostic criteria with the goal of establishing earlier diagnosis and timely intervention.

Traditionally, treatment of BOS has included aggressive immunosuppression, leaving patients at risk for life-threatening invasive infections, multi-system co-morbidities, and the threat of lung transplantation. Recent studies have demonstrated that early management with agents such as inhaled corticosteroids (ICS), macrolides, and leukotriene receptor antagonists (LTRA) can lead to improvements in both lung function and clinical symptoms.

This study aims to evaluate the utility of frequent and routine pulmonary surveillance in pediatric patients who have undergone allogenic HSCT. Our prospective study design provides a novel framework for the implementation of standardized lung function screening every three months in the first two years following HSCT. With this, we hypothesize that standardized PFT screening will improve diagnostic sensitivity and allow for earlier intervention in patients with evolving airway obstruction and BO.

This study also aims to evaluate the efficacy of inhaled fluticasone, azithromycin, and montelukast (FAM therapy) in the management of early airflow obstruction in pediatric patients following allogenic HSCT. Early airflow obstruction is defined by pulmonary function testing (FEV1 decline of ≥10% predicted with a FVC <0.8). With this, we hypothesize that FAM therapy will attenuate the progression of airflow obstruction and improve lung function in those with irreversible airflow obstruction at one and two years when compared to historical controls.

  Eligibility

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Ages Eligible for Study:   6 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Pediatric patients undergoing allogenic hematopoietic stem cell transplant
Criteria

Inclusion Criteria:

  1. Diagnosis: Patients undergoing myeloablative allogenic hematopoietic stem cell transplant for any indication (both malignant and non-malignant) are eligible.
  2. Graft: Eligible patients will have one or more of the following donor stem cell sources:

    • Bone marrow
    • Placental blood (umbilical cord blood)
    • Cytokine mobilized peripheral blood
  3. Eligible patients will have one of the following sources of donor stem cells:

    • HLA matched family member
    • Partially matched family member (mismatched for a single HLA locus at A, B, C or DR)
    • Fully HLA matched or partially mismatched unrelated marrow or peripheral blood stem cells (per institutional donor selection standards)
    • HLA matched or partially mismatched (at least 4/6 match at A, B, DR) cord blood.
  4. Conditioning Regimen: Patients expecting to receive any type of myeloablative HSCT conditioning regimen are eligible.
  5. Prior therapies: Patients undergoing stem cell transplant of any kind.
  6. Required laboratory parameters: Patients able to adequately perform pulmonary function testing per ATS/ERS guidelines, as determined by the enrolling investigator and trained respiratory therapists.
  7. The patient and/or the patient's legally authorized guardian must acknowledge in writing that consent to become a study subject has been obtained in accordance with the institutional policies approved by the U.S. Department of Health and Human Services. Informed consent must be signed prior to registration on study.

Exclusion Criteria:

  1. Subjects with a previous solid organ transplant.
  2. Recurrent or progressive malignancy requiring anti-cancer therapy.
  3. Subjects with evidence of underlying obstructive pulmonary disease prior to transplant (clinical history of asthma or baseline FEV1 <80% predicted with FEV1/FVC <80%).
  4. Known history of allergy or intolerance to Montelukast, Zafirleukast, Azithromycin, Erythromycin, Clarithromycin, Prednisone, or Sirolimus.
  5. Chronic supplemental oxygen requirement or hypoxemia <92% SpO2.
  6. Clinical asthma (variable and recurrent symptoms of airflow obstruction and airway hyper-responsiveness).
  7. Pregnancy or nursing: All females of childbearing age must have a negative serum or urine pregnancy test <7 days before study drug administration.
  8. Chronic treatment with any inhaled steroid for >1 month in past three months.
  9. Treatment with montelukast or zafirukast for >1 month in past three months.
  10. Treatment with systemic steroids for >1 month in past three months.
  11. Treatment with any FDA non-approved study medication within the past four weeks. Off label treatment with FDA approved medication is allowed.
  12. Evidence of any viral, bacterial, or fungal infection involving the lung and not responding to appropriate treatment.
  13. Inability to perform pulmonary function testing (PFT), as determined by the enrolling investigator or PFT lab.
  14. Any condition that, in the opinion of the enrolling investigator, would interfere with the subject's ability to comply with the study requirements.
  Contacts and Locations
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 ClinicalTrials.gov identifier (NCT number): NCT03072849


Contacts
Contact: Jennifer Schneiderman, MD, MS 312-227-4865 jschneiderman@luriechilderens.org
Contact: Matthew F Abts, MD 312-227-6260 mabts@luriechildrens.org

Locations
United States, Illinois
Ann & Robert H Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Jennifer Schneiderman, MD, MS    312-227-4000    jschneiderman@luriechildrens.org   
Contact: Joseph Laskowski    (312)227-4000    jlaskowski@luriechildrens.org   
Sponsors and Collaborators
Ann & Robert H Lurie Children's Hospital of Chicago
  More Information

Publications:

Responsible Party: Jennifer Schneiderman, MD, MD, MS, Ann & Robert H Lurie Children's Hospital of Chicago
ClinicalTrials.gov Identifier: NCT03072849     History of Changes
Other Study ID Numbers: SCT 1214 BOS
First Submitted: March 2, 2017
First Posted: March 7, 2017
Last Update Posted: March 7, 2017
Last Verified: March 2017

Keywords provided by Jennifer Schneiderman, MD, Ann & Robert H Lurie Children's Hospital of Chicago:
Pediatrics
Airflow obstruction
Chronic graft-vs-host disease
Bronchiolitis obliterans syndrome

Additional relevant MeSH terms:
Syndrome
Bronchiolitis
Bronchiolitis Obliterans
Disease
Pathologic Processes
Bronchitis
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Infections