Conditions: Bone Marrow Transplant Infection Infection in Marrow Transplant Recipients Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Pneumonia Cancer Acute Leukemia
Keywords: Ribavirin Ribavirin Aerosol Respiratory Syncytial Virus RSV upper respiratory tract infection URI Lower respiratory tract Infection LRI pneumonia aerosolized ribavirin HSCT Hematopoietic stem cell transplantation oral ribavirin therapy
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 48
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if ribavirin can help to control RSV in patients with immune systems that have been weakened by a stem cell transplant. Researchers also want to compare the effectiveness of the drug when it is given by mouth to when it is inhaled. The safety of the drug in both methods of delivery will be studied.

Ribavirin is designed to prevent the RSV virus from making more copies of itself in the body.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study and the study doctor thinks that the disease requires treatment at this time, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. You will have an equal chance of being assigned to either group:

* If you are in Group 1, you will receive the inhaled form of ribavirin. You will inhale ribavirin 3 times a day for 3 hours each time in a tent in a hospital room. You will receive the drug for up to 10 days.
* If you are in Group 2, you will take capsules of ribavirin 3 times a day for up to 10 days.

If the study doctor does not think that the disease requires treatment at this time, you will be assigned to Group 3. If you are in Group 3, you will not receive treatment with ribavirin, but you will have the same tests and procedures at the study visits described below.

Study Visits:

At all study visits, you will be asked about how you are feeling, about any side effects or symptoms you may be having, and about any other drugs you may be taking.

On Day 3 (+/- 1 day):

* You will have a physical exam, including measurement of your vital signs
* Your nasal passages will be checked for RSV.

On Days 7 and 14 (+/- 1 day):

* Blood (about 2 teaspoons) will be drawn for routine tests.
* You will have a physical exam, including measurement of your vital signs
* Your nasal passages will be checked for RSV.

Length of Study:

If you are in Groups 1 or 2, you will receive the study drug for up to 10 days. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. If your doctor thinks you need treatment longer than 10 days, you will receive that as part of your routine care. This may mean changing to receiving the drug in inhaled form if you began the study receiving it by mouth.

All participants will have end-of-study and follow-up visits, as described below.

End-of-Study Visit:

If you are in Groups 1 or 2, the end-of-study visit will be about 14 days after your last dose of the study drug. If you are in Group 3, the end-of-study visit will take place at about Day 21. The following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs.
* Blood (about 4 teaspoons) will be drawn for routine tests and to check for RSV antibodies.
* Your nasal passages will be checked for RSV.
* You will be asked about how you are feeling, about any side effects or symptoms you may be having, and about any drugs you may be taking.

Follow-Up Visit:

About 6 to 10 weeks after your last dose of study drug, you will have a pulmonary function test to check your lung function.

This is an investigational study. Ribavirin is FDA approved and commercially available for the treatment of hepatitis C when given by mouth, and for severe RSV in children when inhaled. Giving the drug to adults with weak immune systems after a stem cell transplant is investigational.

Up to 96 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Group 1: Inhaled form of Ribavirin 60 milligrams/milliliter 3 times/day for 3 hours for up to 10 days. arm 2: Group 2: Ribavirin Capsules 20 mg/kg orally 3 times/day for up to 10 days. arm 3: Group 3: No Ribavirin treatment.

Interventions: intervention 1: Ribavirin intervention 2: Ribavirin
Intervention descriptions: intervention 1: Modified schedule of 60 milligrams/milliliter for 3-hour period 3 times/day for at least 5 days by aerosolization via a SPAG-2 generator via a face mask. intervention 2: One time loading dose of 10 mg/kg oral dose then 20 mg/kg orally (rounded to the nearest 200 mg dose) divided into three doses per day (max 1800 mg/day).

Protocol document:
Prot_SAP_000.pdf: 
 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
 
 
An Open Label Randomized Controlled Trial To Prevent the Progression of 
Respiratory Syncytial Virus Upper Respiratory Tract Infection to Lower 
Respiratory Tract Infection in patients after Hematopoietic Stem Cell Transplant. 
 
Short Title: Use of oral ribavirin for the treatment of RSV upper respiratory tract infection in 
patients after HSCT 
 
 
 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
Protocol Body 
 
 
 
1.0 
Objectives 
 
Primary Objectives: 
 
1) 
To determine whether oral ribavirin given for therapy of Respiratory Syncytial Virus 
(RSV) upper respiratory tract infection (URI) can prevent its progression to Lower respiratory 
tract Infection (LRI)-pneumonia, when compared to aerosolized ribavirin – modified regimen in 
HSCT recipients at moderate or high risk for progression.  
 
 
Secondary Objectives: 
 
1) 
To determine the safety of oral ribavirin therapy when compared to  aerosolized ribavirin. 
 
2) 
To calculate the cost effectiveness of using oral ribavirin when compared to aerosolized 
ribavirin. 
 
3) 
To compare RSV viral loads in nasal washes and/or other respiratory specimens and RSV 
neutralizing antibodies in serum between patients on both arms of the study and a observational 
arm where low risk patients for progression are not receiving either regimen of ribavirin.  
 
2.0 Background 
 
Over the past 2 decades, it has become apparent that community respiratory viruses (e.g. RSV, 
influenza, parainfluenza, picornavirus) can cause serious infections in patients with cancer, 
particularly in patients with acute leukemia and after hematopoietic stem cell transplantation 
(HSCT) recipients, resulting in substantial morbidity and mortality. They are also associated with 
bacterial or fungal co-infections leading to the development of respiratory super-infections. 
Though studies have shown that many RSV infections may resolve uneventfully without therapy, 
some patients do progress to LRI, increasing the morbidity and the mortality of such patients. In 
fact, a recent study concluded that cancer patients with RSV LRI, and with severe 
immunodeficiency and pre-engraftment are at high risk for RSV-attributed mortality. The use of 
ribavirin based regimens has been shown to halt this progression and reduce the morbidity and 
mortality in mainly case series from single institutions with no data from randomized or 
nonrandomised trials. Furthermore, in a recent systematic review on the use of ribavirin either 
orally, intravenously or in its aerosolized form, we determined that such therapy may halt 
progression of RSV from the upper to the lower respiratory tract with better survival in patients 
after HSCT transplantation (Figure, Shah J and Chemaly RF, Blood, March 2011).  
 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
 
Abbreviations: AR= Aerosolized ribavirin; IR= Intravenous ribavirin; OR= Oral ribavirin 
 
Aerosolized ribavirin is the recommended therapy for RSV LRI and became the standard of care 
in many cancer centers. It has been used for treatment of LRI in leukemic and HSCT patients, 
usually in combination with IVIG. Because of the substantial morbidity and risk of fatality from 
LRI, ribavirin is also given pre-emptively to high-risk cancer patients with RSV URI to prevent 
progression to LRI. Despite its potential benefits, the drug is not routinely recommended due to 
inconvenience of administration, cost, and questionable efficacy because of lack of randomised 
controlled trials. The cost of a 10 day course of aerosolized ribavirin alone could be between 
$50,000 and $80,000, based on estimates from our financial department. While RSV infection 
involving only the URT may resolve uneventfully in some immunosuppressed patients, the 
infection can progress to the LRT with a substantial increase in mortality rate in many other 
patients.  Hence, many of these patients who present with RSV URI are treated with aerosolized 
ribavirin to prevent progression. In the above mentioned systematic review, we concluded that 
“prompt diagnosis of RSV infection should be coupled with an aggressive approach to 
management in HSCT patients who have at least one identifiable risk factor for progression to 
LRI, such as absolute lymphocyte count (ALC) less than 300/μL or GVHD, with early initiation 
of ribavirin therapy in either aerosolized or oral form before development of RSV LRI. The oral 
form of this drug should be explored further, as it is less expensive and probably has fewer and 
milder side effects than the aerosolized formulation”. It is common practice in many institutions 
(in the United States and Europe) to initiate oral ribavirin therapy for RSV infections in HSCT 
recipients instead of the aerosolized form because of all the above mentioned limitations of the 
latter.    
 
We also validated a scoring system on a cohort of 284 allogeneic HSCT recipients and 
determined the risk of progressing to LRI and mortality based on the score assigned. Briefly, a 
weighted index accounting for the number and intensity of immunodeficiency markers was 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
developed and validated in this cohort. Adjusted relative risks calculated from Cox proportional 
hazards regression modeling were assigned as weights to these immunodeficiency markers; 
absolute neutrophil count (ANC), ALC; myeloablative chemotherapy; corticosteroids in past 30 
days; GvHD; HSCT within 30 days or pre-engraftment or both; and age were utilized to generate 
an immunodeficiency score (ISS) (range: 0–12) for each patient. ISS scores were discretized to 
classify patients into low-risk (0-2), moderate-risk (3-6), and high-risk (7-12) groups. Each 
increased level of the ISS was accompanied by stepwise increases in the cumulative morbidity 
(LRI) and mortality attributable to immunodeficiency. There were significant differences in the 
progression to LRI and mortality (p<0.0001) based on the scoring classification groups. RSV-
targeted antiviral therapy given at the URI stage was a significant predictor of LRI and mortality. 
The ISS predicted the risk of these outcomes more proficiently, when the system was stratified 
by treatment (Table).  This new ISS provides an easy, practical, and clinically applicable method 
of predicting the risk of progression to RSV LRI and death in allo-HSCT recipients who have or 
have not received antiviral therapy (Abstract in the Proceedings of the 51th ICAAC meeting in 
Chicago, IL, 9/2011). Based on these results, only patients with ISS of at least 3 (moderate to 
high risk) will be offered therapy for RSV URI.  
 
 
 
 
Therapy at URI 
Stage 
No Therapy at URI 
Stage 
Total 
 
 
 
% 
n 
N 
% 
n 
N 
% 
n 
N 
Progression 
to LRI 
Low  
6 
4 
70 
38 
18 
48 
19 
22 
118 
Moderate  
14 
12 
85 
51 
27 
53 
28 
39 
138 
High  
33 
5 
15 
100 
13 
13 
64 
18 
28 
Total  
12 
21 
170 
51 
58 
114 
28 
79 
284 
 
 
 
 
 
 
 
 
 
 
 
 
Mortality 
Low  
2 
2 
70 
3 
1 
48 
3 
3 
118 
Moderate  
4 
3 
85 
11 
6 
53 
7 
9 
138 
High  
20 
3 
15 
62 
8 
13 
39 
11 
28 
Total  
5 
8 
170 
13 
15 
114 
8 
23 
284 
 
The recommended method for ribavirin administration at our institution is a daily dose of 6g 
delivered at a concentration of 20 milligrams/milliliter for 18 hours daily (standard regimen) 
aerosolization by a small-particle aerosol generator unit (SPAG-2) via a face mask inside a 
scavenging tent for 5 to 10 days. A modified regimen with dose of 60 milligrams/milliliter (or 2 
grams) given over 3 hours period every 8 hours for 5 to 10 days has also been used. A recent 
randomized trial completed at our institution showed that the probability of progression to 
pneumonia while on the modified regimen is less than the rate of pneumonia on the standard 
regimen (probability of 0.889; unpublished data; Oral presentation at the 49th Interscience 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
Conference on Antimicrobial Agents and Chemotherapy, 2009). Although this dosage schedule 
has been used, either one can be inconvenient for patients, and makes routine patient care more 
difficult.  
 
Alternatively, many patients have been treated with oral ribavirin with particularly encouraging 
results (Figure above). This drug has been approved by the Food and Drug Administration 
(FDA) in combination with interferon alfa-2b for the treatment of Hepatitis C and it is 
commercially available in generic form. Although oral ribavirin was adopted as part of the 
armamentarium for therapy of RSV infection in immunocompromised patients in many centers 
in the US and Europe, further trials are necessary to demonstrate its efficacy and safety. A recent 
study done in Basel, Switzerland reported a total of 19 HSCT patients treated with oral ribavirin, 
of these 11 patients had URI, while 8 had LRI. A decrease in RSV viral loads of 2 log10 
copies/mL within 7 days after treatment initiation was seen in 11 patients and none progressed to 
LRI or died. Another 6 patients reported a mean decrease in RSV load of 2 log10 copies/mL 
within 14 days of diagnosis, LRI occurred in 2 patients and 1 died. The authors also found that 
the rate of disease progression and mortality rate to be comparable to studies evaluating 
aerosolized ribavirin (Khanna et al, CID 2008:46 407). They further concluded that prospective, 
multicenter studies are needed to identify effective antiviral treatment for RSV infection among 
immunocompromised patient groups, where systemic ribavirin could be an option.  
 
A systematic evaluation of oral ribavirin as an alternative therapeutic regimen for RSV infection 
needs to be explored. A double blind randomized comparative trial is not feasible due to the 
relatively small number of HSCT patients with this infection every year on the national level. We 
would like to conduct this phase II randomized trial to evaluate the efficacy and safety of oral 
ribavirin for prevention of RSV LRI when compared to aerosolized regimen ("modified 
regimen"). If oral use of ribavirin is as effective as the aerosolized regimen, this would be 
immensely beneficial to the patients as it would make the administration of ribavirin easier and 
more convenient and may prevent hospitalization in a good proportion of patients with 
tremendous impact on cost savings. Furthermore, it may increase its use and also encourage its 
early use in the therapy of RSV URI, which may have a favorable impact on overall morbidity 
and mortality in our immunocompromised patients. 
 
3.0 Background Drug Information and Dosage 
 
Ribavirin in its oral or aerosolized form is commercially available. Drug information is provided  
in the attached package insert (Appendix D).  
 
Oral ribavirin has been used at varying doses for treatment of RSV based on bioavailability and a 
large volume of distribution.  A loading dose of 10 mg/kg orally has been used as bioavailability 
can range from 30-74% due to first pass metabolism (Khanna N, et al. Clin Infect Dis. 
2008;46(3):402-412). Due to the short duration of therapy, 5 to 10 days, this will help to increase 
ribavirin concentration more quickly. After the loading dose, a total daily dose of 20 mg/kg/day 
divided into three doses given with food (max dose of 1800 mg per day). This dosing strategy 
falls within a previous efficacy and toxicity trial where doses between 15-45 mg/kg/day were 
employed (Chakrabarti S, et al. Bone Marrow Transplant. 2001;28(8):759-763). Efficacy and 
decreased toxicity were found in the lower dose cohorts 15-30 mg/kg/day. 
 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
4.0 Patient Eligibility 
 
Inclusion criteria: 
 
4.1 
HSCT patients with either moderate risk or high risk immunodeficiency based on 
immunodeficiency scoring system would be eligible for entry on study if a nasopharyngeal wash 
or throat swab specimen is positive by rapid RSV antigen testing and/or on culture within 72 
hours (therapeutic arms). (Please see Appendix E for definitions and Immunodeficiency Scoring) 
 
4.2 
HSCT patients with low risk immunodeficiency based on immunodeficiency scoring 
system would be eligible for entry on study if a nasopharyngeal wash or throat swab specimen is 
positive by rapid RSV antigen testing and/or on culture within 72 hours but will not be 
randomized to therapeutic arms and will be followed as per standard of care (observational arm). 
 
4.3  
Patients must be at least 18 years of age and able to swallow pills. 
 
4.4  
Patients with RSV infection limited to the URT as documented by negative Chest 
radiographic findings within the last 48 hours of enrollement and pulse oxygenation of more than 
90 mm of Hg on room air. 
 
4.5  
Women of child bearing potential with a negative urine or blood pregnancy test within a 
month of enrollment (only for patients who are going to be randomised to either therapeutic 
arms). 
 
4.6  
 Patients with Hemoglobin levels more than or equal to 8 g/dl would be eligible for the 
study even if they are currently receiving blood products. 
 
4.7  
Patients may receive up to 2 doses of aerosolized ribavirin on the modified regimen 
before enrollment into the study.  
 
Exclusion criteria: 
 
4.1  
Patients with previous history of hypersensitivity to ribavirin or its components 
 
4.2  
Women who are pregnant or plan a pregnancy within 8 weeks after completion of 
treatment (only for patients who are going to be randomised to either therapeutic arms). 
 
4.3  
Patients with evidence of RSV LRI as documented by a positive rapid RSV antigen 
testing and/or culture on nasal washes AND new or progressive infiltrates on chest radiographic 
studies suggestive of viral etiology and/or pulse oxygen less than 90 mm of Hg on room air. 
 
4.4  
Patients with positive RSV by rapid antigen testing and/or culture in bronchoalveolar 
lavage regardless of the chest radiographic findings at study entry. 
 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
4.5  
Patients who are considered to be moderately or severely anemic as per the NCI 
classification will not be included in the study, i.e patients with hemoglobin level less than 8 
g/dl.  
 
4.6  
Patients with Total Bilirubin, Aspartate Aminotransferase (AST) and/or Alanine 
Aminotransferase (ALT) three times the upper limit of  normal. 
 
4.7  
Male partners of women who are pregnant (only for patients who are going to be 
randomised to either therapeutic arms). 
 
4.8  
Patients with known history of autoimmune hepatitis, Hepatitic C or those with 
hemoglobinopathies (eg, thalassemia major, sickle cell anemia). 
 
4.9 
Patients with creatinine clearance less than or equal to 50 ml/min. 
 
5.0 
Patients taking didanozine, azthioprine, or nucleoside reverese transciptase inhibitors. 
 
Patients who will be enrolled on the observational arm have to meet inclusion criteria #4.2, 4.3, 
and 4.4 and exclusion criteria #4.3 and 4.4 only as these patients will not receive theray for RSV. 
 
5.0 Treatment Plan 
 
This is an open label randomised trial. All eligible patients will be randomized to receive 
ribavirin therapy either at the modified schedule of 60 mg/ml of the drug for a 3-hour period 3 
times/day for at least 5 days by aerosolization via a SPAG-2 generator via a face mask OR 
patients will receive a one time loading dose of 10 mg/kg oral dose then 20 mg/kg orally 
(rounded to the nearest 200 mg dose) divided into three doses per day at a maximum of total 
dose of 1800 mg/day (therapeutic arms). The duration of either regimen is recommended to be 
up to 10 days but could be extended for more than 10 days at the discretion of the treating 
physician.  
 
In addition, patients will receive inhalational bronchodilator therapy consistent of Xopenex 0.63 
mg HHN every 6-8 hours as needed and as per standard of care. Patients may receive albuterol 
(2.5 mg per 3ml for adults) nebulization, if Xopenex is not tolerated. Patients will not be given 
IVIG or palivizumab for treatment of the RSV URI. Patients who develop evidence of LRI at 
any time will be considered reaching the primary endpoint and will be managed at the discretion 
of the treating physician as per standard of care (for example, patients can be treated by the 
standard or the modified aerosolized regimen with or without IVIG or palivizumab).  
 
Patients with mild immundeficiency who are at low risk (scoring of 0-2 on ISS) for progression 
and when treatment is not indicated for RSV URI as per standard of care (observational arm) will 
be followed prospectively once a week up to 4 weeks from the diagnosis of RSV. 
 
For schedule of events tables see PDOL appendix I. 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
 
6.0 Pretreatment evaluation 
 
6.1 
Patients will be identified based on eligibility criteria. After a patient is identified and 
expresses interest, the study will be explained by the study team and the informed consent form 
will be given to the patient to be signed.  
 
6.2 
All patients should have an initial nasopharyngeal wash positive for RSV by rapid testing 
and/or culture at onset of therapy unless a positive result was obtained from a specimen during 
the preceding 72 hours.  
 
6.3 
Routine blood tests will be obtained as per the standard of care within 48 hours of study 
entry as follows: 
 
 
A.  
Hemoglobin, Hematocrit, WBC with differential if available, platelets count, 
pregnancy test from urine or blood for women of child-bearing potential. 
 
 
B.  
Chemistry profile – BUN, Creatinine, Total bilirubin, Aspartate Aminotransferase 
(AST) and/or Alanine Aminotransferase (ALT), and alkaline phosphatase. 
 
 
C.  
Nasal washes and blood at the time of enrollement will be taken and saved for 
testing for RSV viral loads and titers and  neutralizing antibodies in serum at a later date (see 
section 7.1). 
 
6.4  
An initial history and physical examination. 
 
6.5 
A chest radiographic study (i.e. chest radiographs and/or CT scan of chest) will be 
obtained if not done within preceding 48 hours as per standard of care. 
 
7.0 Evaluation During Study 
 
7.1 
Nasal washes for the therapeutic arm will be repeated on day 3 ±1 day, day 7 (± 1 days), 
day 14 (+ 1 days), and by day 14 + 1 days after end of therapy; and will be stored at 6-8 degrees 
Celsius until it can be taken to Dr. Piedra’s laboratory for analysis. Blood specimens for the 
therapeutic arm will be drawn at enrollment and 14 +/- 1 days after end of therapy.  These 
specimens will be shipped for batch analysis to Dr. Pedro Piedra laboratory at Baylor College of 
Medicine (One Baylor Plaza, Room 248E, Houston, Texas) for viral loads, titers and for 
neutralizing antibodies testing (Please see references 7-9 for methods). For patients on the 
observational arm, nasal washes for RSV viral loads will be done once a week for 4 weeks and 
blood specimens will be taken at enrollment and the 4th week on study for neutralizing 
antibodies testing and for RSV viral load. Leftover of blood and nasal washes will be saved at Dr 
Piedra’s laboratory for future testing. 
 
7.2 
Routine blood tests as in 6.3 will be repeated at least once weekly until study is 
completed as part of the standard of care for patients who are on the therapeutic arms. Patients on 
observational arm will have routine blood tests done at enrollment and the 4th week on study. 
 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
7.3 
Patients will be monitored for signs and symptoms of URI and LRI (Please see Appendix 
G and H for Clinical Assessment Tool). Patients who are hospitalized will be seen 2 times a 
week from the time of enrollment until discontinuation of ribavirin therapy. Patients who are not 
hospitalized will be monitored twice a week until the discontinuation of therapy or once a week 
for 4 weeks for patients on the observational arm. Any possible evidence of pulmonary infection 
should be confirmed by a repeat chest radiographic study and/or oxygen saturation level. All 
patients on the therapeutic arms will have a final visit 14 days + 1 days after end of therapy.  
 
7.4 
Follow-up after end of therapy or discontinuation of therapy: Patients will be seen 14 
days + 1 days after discontinuation of therapy for the final determination of response, unless 
there is progression to pneumonia. In the latter scenario or if study drug is discontinued for 
Serious Adverse Events (SAEs), patients will be followed for up to 14 days from the time of 
occurance of the event or until resolution of the SAE whichever occurs last or up to 30 days from 
the last dose of the study drug.  
 
7.5 
Physical Exams for the therapeutic arm will be done at day 3 ±1 day, day 7 (± 1 days), 
day 14 (+ 1 days), and then 14 days (+ 1 days) after end of therapy. Concomitant medications 
that are used to treat LRI will be recorded day (3 ±1 day), day 7 (± 1 days), and then at 14 days 
(+ 1 days) after end of therapy. Physical exams for observational arm will be done once a week 
for 4 weeks. 
 
7.6 
As standard of care, patients will have pulmonary function tests scheduled bewteen 6-10 
weeks after completing therapy for RSV.   
 
8.0 Criteria for Response 
 
The principal investigator or his delegates will make the initial or preliminary determination of 
response at 14 + 1 days after end of therapy. Patients will be considered as a success if there are 
no signs (clinical and/or radiologic) or symptoms of progression to pneumonia at the end of 
study, that is 14 + 1 days after discontinuation of therapy or at week 4 of follow-up for patients 
on the observational arm. At the end of each winter season and without knowledge of the 
determination of response of the PI or delegates, an independent internal panel (1 expert in 
HSCT and 1 in Infectious Diseases to be determined) will review each case and determine failure 
(pneumonia) or success (no evidence of pneumonia) rate on each arm of the study. The panel 
will have the final determination of response.  
 
9.0 Criteria for Removal from the Study 
 
9.1 
Patients will be considered to have failed therapy if they develop evidence of pulmonary 
infection secondary to RSV (documented by chest radiographic study and/or Oxygen saturation 
level less than 90 mm Hg on room air). Therapy could be stopped or could be changed to either 
the standard or the modified regimen of aerosolized ribavirin if the patient is on the oral schedule 
and changed to the standard or continued on the modified regimen of aerosolized ribavirin if the 
patient is on the aerosolized regimen; all at the discretion of the primary care service. IVIG 
500mg/kg every other day for 4 doses or Synagis (palivizumab) 15mg/kg as a single dose can be 
used in combination with aerosolized ribavirin. 
 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
9.2 
Adverse events to ribavirin requiring discontinuation of therapy are: deterioration of 
respiratory function, abnormal liver function tests (>5 x the upper normal limits), frequent 
bronchospasms not responding to bronchodilators, hypotension and cardiac arrest.  
 
9.3 
Anemia may occur due to ribavirin and therapy would be discontinued if there is 
evidence of severe hemolysis and/or the patient develops severe anemia as per the NCI 
classification i.e. Hemoglobin below 8 g/dl for more than 48 hours and does not respond to blood 
and/or blood products transfusion.  
  
10.0 Cost Analysis 
 
All patients who receive aerosolized ribavirin have to be hospitalized for the entire duration of 
the therapy, or even more depending on the patient condition. Patients who will be treated with 
oral ribavirin may be hospitalized at the discretion of the primary service. An average per day 
cost of keeping patients in hospital for ribavirin administration will be obtained from the 
financial department and institutional records and will be used to calculate the total cost of 
treating patients with ribavirin using the following formula: 
 
Total cost of treating the patients with ribavirin (aerosolized or oral) = cost of keeping the patient 
in-hospital per day for RSV × total number of days the patient is kept in hospital + cost of the 
drug (aerosolized and oral ribavirin) and its administration (for aerosolized ribavirin). 
 
This will be compared to the total cost of administering oral ribavirin on an outpatient basis by 
adding the total cost of the drug and the follow up visits. In either arm of the study, if a patient 
progresses to pneumonia, the total cost of treating the patient with aerosolized ribavirin (if 
applicable) will be calculated using the above formula and added to the total cost.  
 
11.0 Statistical Considerations 
 
This is a randomized phase II non-inferiority screening trial following the principles described 
by Rubinstein et al. (2005). Our primary outcome for this trial is progression to lower respiratory 
tract infection (i.e., pneumonia) by day 14 after the completion of therapy. Patients who are 
found to have pneumonia by day 14 after completion of therapy will be considered treatment 
failures. Patients who have not developed pneumonia by day 14 after completion of therapy will 
be considered treatment successes. 
 
Randomization 
 
Patients will be randomized to either aerosolized ribavirin (standard therapy) or oral ribavirin 
(experimental therapy) using the CORe patient registration system. Block randomization will be 
utilized and stratified by risk of progression (moderate versus high). 
 
Sample Size 
 
We expect that 20% of patients randomized to aerosolized ribavirin will be considered treatment 
failures, and we expect that 15% of patients randomized to oral ribavirin will be considered 
treatment failures. With a non-inferiority margin of 10%, a sample size of 38 patients per 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
treatment arm will yield 80% power to reject the following null hypothesis with a 1-sided 
significance level of 0.20: 
 
H0: πoral - πaerosol > 0.10 
 
H1: πoral - πaerosol < 0.10 
 
where πaerosol is the treatment failure rate for aerosolized ribavirin and πoral is the treatment failure 
rate for oral ribavirin. We expect to enroll these patients over 2 winter seasons. 
 
This sample size calculation includes an interim analysis for futility using the methods of Lan 
and DeMets (1983) with an O’Brien-Fleming (1979) stopping boundary. The futility analysis 
will be conducted once 38 patients have been evaluated for treatment failure. We expect the 
timing of this futility analysis to be after the first winter season of the study. The nominal 
significance level for this futility analysis is 0.6040, and the nominal significance level at the end 
of the study is 0.2116.  
 
This sample size calculation was performed using East 5.2 (Copyright © 2008, Cytel Inc., 
Cambridge, MA). 
 
For the observational arm, up to 20 patients will be enrolled for a total of 96 patients for the 
whole trial.  
 
Analysis 
 
We will use descriptive statistics to summarize the demographic and clinical characteristics of 
patients in each treatment arm and the observational arm. 
 
We will use the Cochran-Mantel-Haenszel test stratified by risk groupto test the null hypothesis 
stated above. We will also estimate the treatment failure rates with exact 95% binomial 
confidence intervals for each treatment arm. 
 
We will tabulate adverse events for each treatment arm by severity and relationship to study 
therapy. 
 
We will use descriptive statistics to summarize the costs associated with each treatment arm. 
Costs for each patient will be calculated as described in section 10.0 above. 
 
We will use descriptive statistics to summarize the RSV viral loads and neutralizing antibodies 
for each treatment arm and the observational arm. 
 
12.0 Reporting Requirements & Drug Accountability 
 
A case report form will be required for each patient entered on study (please see appendix G and 
H).  An interim safety analysis of the data focusing on SAEs will be done after each winter 
season. 


 
 
Protocol # 2011-0813 
 
 
04-07-2014 
 
 
We will maintain the study drug records of aerosolized ribavirin including documentation 
of the amount received and duration as per respiratory therapy protocol. For oral 
ribavirin, subjects should bring their medication bottles back at each visit even if they are 
empty so site personnel can assess study drug compliance.  
 
13.0 References: 
 
1. Shah J, Chemaly RF,. Management of RSV infections in Adult Recipients of 
Hematopoietic Stem Cell Transplant: Review of the Literature. Blood. 2011 Mar 
10;117(10):2755-63. 
 
2. Chemaly, RF, Gosh S, Bodey GP, et al. Respiratory Viral Infections in Adults With 
Hematologic Malignancies and Human Stem Cell Transplantation Recipients: A 
Retrospective Study at a Major Cancer Center. Medicine (Baltimore) 85(5):278-287, 
2006. 
 
3. Khanna N, Widmer AF, Decker M, et al. Respiratory syncytial virus infection in patients 
with hematological diseases: single-center study and review of the literature. Clin Infect 
Dis. 2008 Feb 1;46(3):402-12. 
 
4. Rathod DB, Torres H, Munsell M, Bodey G, Davis M, Saifan C, Raad I, Champlin R, 
Chemaly RF. Continuous Versus Intermittent Dose Schedule of Aerosolized Ribavirin 
for Treatment of RSV Upper Respiratory Tract Infection (URI) in Pts with Hematological 
Malignancies: An Adaptive Randomized Trial. Oral Presentation at 49th Interscience 
Conference on Antimicrobial Agents and Chemotherapy, 2009. 
 
5. Shah DP, Ghantoji SS, Shah JN, El Taoum KK, Hosing C, Rondon G, Popat U, 
Sorrentino M, Champlin R, Chemaly RF. Immunodeficiency Scoring System for 
Predicting RSV-associated Morbidity And Mortality In Allogeneic Hematopoietic Stem-
cell Transplant Recipients. Poster presentation at the 51st ICAAC Conference, Chicago 
IL, 9/2011. 
 
6. Chakrabarti S, Collingham KE, Holder K, et al. Pre-emptive oral ribavirin therapy of 
paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study. 
Bone Marrow Transplant. 2001;28(8):759-763. 
 
7. Laham FR, Trott AA, Bennett BL, Kozinetz CA, Jewell AM, Garofalo RP, Piedra PA. 
LDH concentration in nasal-wash fluid as a biochemical predictor of bronchiolitis 
severity. Pediatrics. 2010 Feb;125(2):e225-33. 
 
8. Bennett BL, Garofalo RP, Cron SG, Hosakote YM, Atmar RL, Macias CG, Piedra PA. 
Immunopathogenesis of respiratory syncytial virus bronchiolitis. J Infect Dis. 2007 May 
15;195(10):1532-40.  
 


 
 
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9. Garcia DF, Hiatt PW, Jewell A, Schoonover SL, Cron SG, Riggs M, Grace S, Oermann 
CM, Piedra PA Human metapneumovirus and respiratory syncytial virus infections in 
older children with cystic fibrosis. Pediatr Pulmonol. 2007 Jan;42(1):66-74. 
 
10. Lan KKG and DeMets DL.  Discrete sequential boundaries for clinical trial.  Biometrika 
1983;70:659-663. 
 
11. O’Brien PC and Fleming TR.  A multiple testing procedure for clinical trials.  Biometrics 
1979;35:549-556. 
 
12. Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized phase II trials 
and a proposal for phase II screening trials. J Clin Oncol 2005; 23:7199-7206.