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

Study Overview
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Brief Summary
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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.

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

Conditions
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Respiratory Tract Infections, Bronchiolitis Obliterans, Cryptogenic Organizing Pneumonia, Lung Diseases, Interstitial

Intervention / Treatment
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* Drug: Prednisone
* Drug: Azithromycin
* Drug: Montelukast
* Drug: Symbicort


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard of Care<br>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<br>Subjects randomized to the SAMS arm will receive a four-drug combination (Steroids, Azithromycin, Montelukast, and Symbicort). | Drug: Prednisone<br>* Prednisone 0.75 mg/kg actual body weight/day PO for 7 days followed by a 7 day taper.<br>* Other names: Steroids;Drug: Azithromycin<br>* Azithromycin 250 mg PO daily for 2 weeks, then 3 times per week until 3 months<br>Drug: Montelukast<br>* Montelukast 10 mg PO qhs for 3 months<br>* Other names: Singulair;Drug: Symbicort<br>* Symbicort 200/6 mcg, 2 inhalations every 12 hours for 3 months<br>* Other names: Formoterol;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary disease, chronic obstructive, Viral respiratory tract infections, Respiratory syncytial viruses, Influenza virus A, Influenza virus B, Transplantation, Allogeneic