Steroids, Azithromycin, Montelukast, and Symbicort (SAMS) for Viral Respiratory Tract Infection Post Allotransplant

Does Increasing Immunosuppression Prevent Transplant-associated Lung-disease Triggered by Viral Respiratory Tract Infection Following Allogeneic Stem Cell Transplant? A Pilot Study

For many patients with blood cancers, stem cell transplantation from a family member or from an unrelated donor remains the only potentially curative option. Unfortunately, up to 40% of patients develop chronic lung disease after the transplant, which substantially increases the risk of death in the long-term. Currently, patients with transplant-related lung disease are treated with some combination of steroids and other immunosuppressant drugs, but only about 1 out of 5 improve.

The importance of our study is that the investigators aim to prevent the development of transplant-related chronic lung disease in the first place. Because a strong risk factor for such chronic lung disease is a prior viral respiratory tract infection, the investigators think there is a window of opportunity to intervene. As soon as "cold and flu" symptoms start, the investigators will treat patients with a combination of drugs aimed at eliminating damaging immune responses triggered by the virus. In the absence of such treatment, the investigators believe these lung-damaging immune responses would persist even after the virus disappears. Our hope is that preventive treatment might avoid the development of chronic lung disease, and this would substantially increase long-term survival in our transplant patients.

This is a pilot study. Once feasibility is established, the investigators will seek to expand this study into a definitive clinical trial.

Study Overview

• Status: Terminated
• Conditions: Respiratory Tract Infections; Lung Diseases, Interstitial; Bronchiolitis Obliterans; Cryptogenic Organizing Pneumonia
• Intervention / Treatment: Drug: Prednisone; Drug: Azithromycin; Drug: Montelukast; Drug: Symbicort

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Maisonneuve-Rosemont Hospital (Hôpital Maisonneuve-Rosemont)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Allogeneic transplant within the prior 1 year
• Age greater than or equal to 18 years
• Capable of informed consent
• Neutrophil engraftment has occurred
• This is the first clinically-recognized episode of viral respiratory tract infection after transplant

Exclusion Criteria:

• Proof or high suspicion for bacterial, fungal or any non-viral microorganism causing pneumonia
• CMV, VZV or HSV pneumonia
• Prior diagnosis of a chronic transplant-related non-infectious pulmonary complication (ex: BO, COP)
• Treating physician believes the risk of systemic steroids is too great
• Currently receiving prednisone at or greater than 0.25 mg/kg/day or the equivalent dose of another steroid
• Currently receiving pentostatin
• Mycophenolate initiated de novo or increased within the past 4 weeks
• Use of inhaled corticosteroids within the past 2 weeks for at least 1 week
• Haploidentical or T-cell depleted graft
• Lack of pre-transplant pulmonary function tests
• Evidence of a prior symptomatic viral respiratory tract infection following transplant, whether treated or not
• Allergy or adverse reaction to any of the study drugs
• Relapse or progression of the underlying malignancy
• Palliative care

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard of Care; Standard of Care includes fluids, antipyretics, ribavirin for RSV infection, and oseltamivir for influenza infection, and intravenous immune globulin for patients with low IgG levels.
Experimental: SAMS; Subjects randomized to the SAMS arm will receive a four-drug combination (Steroids, Azithromycin, Montelukast, and Symbicort).	Drug: Prednisone; Prednisone 0.75 mg/kg actual body weight/day PO for 7 days followed by a 7 day taper.; Other Names: Deltasone; Steroids; Drug: Azithromycin; Azithromycin 250 mg PO daily for 2 weeks, then 3 times per week until 3 months; Drug: Montelukast; Montelukast 10 mg PO qhs for 3 months; Other Names: Singulair; Drug: Symbicort; Symbicort 200/6 mcg, 2 inhalations every 12 hours for 3 months; Other Names: Budesonide; Formoterol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of new chronic lung disease	The incidence rate of new non-infectious pulmonary complications within the 6 month follow-up period will be calculated. Non-infectious pulmonary complications include new airflow obstruction, new restrictive lung disease, and new mixed obstruction/restriction as measured by spirometry at study enrolment, 2 and 8 weeks following viral infection, and by full pulmonary function tests at 3 and 6 weeks following viral infection.	6 months following diagnosis of the viral respiratory tract infection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of non-infectious pulmonary complications	Non-infectious pulmonary complications (NIPCs) include airflow obstruction, restrictive lung disease, and mixed obstruction/restriction as determined by pulmonary function tests. The prevalence of NIPCs will be determined among subjects surviving to 6 months post viral respiratory tract infection.	6 months following the diagnosis of viral respiratory tract infection
Long-term functional impairment as defined by need for supplemental oxygen	The percentage of subjects needing at least 1 month of supplemental oxygen on most days per week, not counting the period of symptomatic viral respiratory tract infection, will be determined in both arms.	6 months post viral respiratory tract infection
Patient-perceived long-term functional impairment	A FACT-BMT questionnaire will be administered at baseline and again to subjects surviving 6 months post respiratory tract infection to measure patient-perceived functional impairment.	6 months post viral respiratory tract infection
Time to clearance of viral infection	Subjects in whom a respiratory virus is detected will undergo repeat testing every 2 weeks until the virus is no longer detectable. This is an exploratory analysis. The natural history of many of these community-acquired viruses in the transplant population is not known.	Every 2 weeks until virus is no longer detectable
Incidence of progression to respiratory failure	This endpoint includes admission to hospital because of documented desaturation, need for supplemental oxygen, and need for mechanical ventilation.	21 days after enrolment
Incidence of bacterial or fungal superinfection	The incidence of secondary bacterial and fungal pneumonias will be compared in the two arms, to verify that the added immunosuppression does not contribute to further infectious complications.	Within 21 days after enrolment
Incidence of various other infectious complications	The incidence of various other infectious complications, specifically including but not limited to CMV reactivations and CMV disease, zoster, and septicemia will be monitored in both arms.	Within 6 months after enrolment
Overall survival from date of viral respiratory tract infection		3 months post enrolment
Overall survival from date of viral respiratory tract infection		6 months post enrolment
Overall survival from date of transplant to end of study follow-up		6 months post enrolment
Overall survival at 1 year post-transplant	This measure will be applied to the group overall and also analyzed according to subgroups of patients presenting viral respiratory tract infections within 30 days of transplant, 31-100 days of transplant, and 101-365 days of transplant.	1 year post-transplant
Cumulative incidence of death attributable to transplant associated lung disease		6 months post enrolment
Cumulative incidence of death from other causes		6 months post enrolment

Collaborators and Investigators

• Sponsor: Maisonneuve-Rosemont Hospital
• Collaborators: The Canadian Blood and Marrow Transplant Group
• Investigators: Principal Investigator: Elizabeth F Krakow, MD,CM, FRCPC, Maisonneuve-Rosemont Hospital; Principal Investigator: Sandra Cohen, MD, FRCPC, Maisonneuve-Rosemont Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 30, 2013

Study Registration Dates

• First Submitted: September 8, 2011
• First Submitted That Met QC Criteria: September 9, 2011
• First Posted (Estimate): September 12, 2011

Study Record Updates

• Last Update Posted (Actual): October 20, 2021
• Last Update Submitted That Met QC Criteria: October 13, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Pulmonary disease, chronic obstructive; Viral respiratory tract infections; Respiratory syncytial viruses; Influenza virus A; Influenza virus B; Transplantation, Allogeneic
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Idiopathic Pulmonary Fibrosis; Pulmonary Fibrosis; Idiopathic Interstitial Pneumonias; Lung Diseases; Infections; Communicable Diseases; Respiratory Tract Infections; Lung Diseases, Interstitial; Bronchiolitis; Bronchiolitis Obliterans; Cryptogenic Organizing Pneumonia; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Adrenergic Agonists; Anti-Bacterial Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Budesonide; Montelukast; Prednisone; Azithromycin; Formoterol Fumarate; Budesonide, Formoterol Fumarate Drug Combination
• Other Study ID Numbers: HMR1102